Peripheral Blood Classical Monocytes and Plasma Interleukin 10 Are Associated to Neoadjuvant Chemotherapy Response in Breast Cancer Patients.

Worldwide, breast cancer (BC) is the leading cause of cancer death among women. For many patients the most effective treatment is a resection surgery that removes the tumor. Within this subset, patients sometimes receive chemotherapy treatment (CT) prior to surgery aiming to reduce tumor size in order to preserve healthy breast tissue. This strategy is commonly called neoadjuvant chemotherapy (NAC). This approach also offers an opportunity to determine treatment sensitivity, especially in aggressive tumors. Post NAC absence of residual disease is associated to long term survival in BC patients and is used to define the need of adjuvant therapy options. Studies suggest that NAC allows the recognition of tumor antigens by immune cells potentiating the eradication of the tumor. However, the dynamic changes in patients' immune cells under NAC remain unclear. Here, we assessed changes in leucocyte and cytokine profiles in order to determine its association to NAC response in BC patients. Peripheral blood patient samples were taken prior to each NAC cycle to assess the abundance of leukocyte subsets and serum cytokines in 20 patients. These immunological features were associated with clinical outcomes including pathological response. We found a positive correlation between plasma Interleukin 10 (IL-10) and classical monocytes in HER2+ BC patients under NAC. We also observed a trend between increased IL-10 and classical monocytes levels and lower rates of pathologic complete response at the end of NAC. These data support the notion that monocyte subsets and IL-10 could be applied as a novel indicator of NAC efficacy in HER2+ BC patients. Finally, we confirm a key role of the immune system in cancer progression and CT response.

The Neutrophil to Lymphocyte Ratio Predicts the Response to Neoadjuvant Chemotherapy in Luminal B Breast Cancer.

Objective: Tumor response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients is a predictor for overall survival. The aim of our study was to determine a relationship between the neutrophil to lymphocyte ratio (NLR) prior to NAC, BC subtypes and the probability of a pathologic complete response (pCR). Materials and Methods: Medical records were collected retrospectively from Centro de Cancer at Red Salud UC-Christus. Clinical data collected included peripheral blood cell counts, BC subtype at diagnosis and the pathology report of surgery after chemotherapy. Results: A total of 88 patients were analyzed. Approximately, a 25% had a pCR, and displayed a significant correlation between BC subtype and pCR (p= 0.0138 Chi2); this was more frequent in epidermal growth factor receptor type 2 (HER2) enriched subtype patients (54%). Luminal B BC patients with a pCR had significantly lower NLR levels (t test, p= 0.0181). Conclusions: HER2-enriched tumors had a higher probability of pCR. In Luminal B tumors, NLR had a statistically significant relationship with the probability of pCR. In this subtype, NLR could be a useful biomarker to predict tumor response to NAC. Further studies including other clinical parameters for systemic inflammation such as platelet counts, intratumoral NLR or body mass index could help identify patients that would get the most benefit from NAC.

Características clínicas y pronóstico de pacientes con cáncer de mama HER2 positivo avanzado, en la era antes y después de terapias anti-HER2 / Survival of patients with advanced HER2+ breast cancer. Analysis of a cancer center database

Background: HER2+ breast cancer (BC) subtype overexpresses the Human Epidermal growth factor Receptor type-2 (HER2) and is characterized by its aggressiveness and its high sensitivity to monoclonal antibody-based HER2-targeted therapies. Aim: To assess the prognosis and evaluate the impact of novel anti-HER2 therapies on advanced HER2+ BC patients treated at our institution over the last decades. Material and Methods: Analysis of the patient database at a cancer center of a university hospital. Information about the subtype of cancer was obtained in 2,149 of 2,724 patients in the database. Eighteen percent of the latter were HER2+. We analyzed data of 83 of these patients with advanced disease. Results: Median overall survival (OS) was 24 months. For patients treated between 1997-2006 median OS was 17 months and for those treated in the period 2007-2017 median OS was 32 months (p = 0.09). Conclusions: A non-significant trend towards better survival in the last decade was observed. HER2+ BC overall survival has improved in our center. This can be probably attributed to the use of novel more effective anti-HER2 therapies.

Can Histological Grade and Mitotic Index Replace Ki67 to Determine Luminal Breast Cancer Subtypes?

Introduction: Breast cancer can be classified into subtypes based on immunohistochemical markers, with Ki67 expression levels being used to divide luminal BC tumors in luminal A and B subtypes; however, Ki67 is not routinely determined due to a lack of standardization. Objective: To evaluate histological grade and Eliminate: the mitotic index to determine if they can be used as an alternative method to Ki67 staining for luminal subtype definition. Methods: We evaluated estrogen receptor positive breast cancer tissue samples. Pathological analysis included determination of Ki67. A low level of Ki67 was defined as <14% positive cells. Results: We evaluated 151 breast cancer samples; 24 (15,9%) were classified as I; 74 as HG II (49%), and 53 (35,1%) as HG III. The median value for Ki67 was 13% (range: <1% - 82%) and for MI was 2 (0-12). Histological grade I tumors exhibited Ki67 values significantly lower than HG II and III tumors (Anova, Tamhane test p=0,001). A higher Ki67 value was related to a higher MI (Rho Sperman p=0,336; R2= 0,0273). ROC curve analysis determined that a MI ≥ 3 had a sensibility of 61.9% and specificity of 66.7% in predicting a high Ki67 value (≥14%) (area under the curve: 0,691; p =0,0001). A HG I tumor or HG II-III with MI ≤2, had a high probability of corresponding to a LA tumor (76,3%), as defined using Ki67 expression, while the probability of a LB subtype was higher with HG II-III and a MI ≥3 (57.4%). Global discrimination was 68.1%. Conclusions: For the LA subtype, our predictive model showed a good correlation of HG and MI with the classification based on Ki67<14%. In the LB subtype, the model showed a weak correlation; therefore Ki67 determination seems to be needed for this group of patients.

[Survival of patients with advanced HER2+ breast cancer. Analysis of a cancer center database]. / Características clínicas y pronóstico de pacientes con cáncer de mama HER2 positivo avanzado, en la era antes y después de terapias anti-HER2.

BACKGROUND: HER2+ breast cancer (BC) subtype overexpresses the Human Epidermal growth factor Receptor type-2 (HER2) and is characterized by its aggressiveness and its high sensitivity to monoclonal antibody-based HER2-targeted therapies. AIM: To assess the prognosis and evaluate the impact of novel anti-HER2 therapies on advanced HER2+ BC patients treated at our institution over the last decades. MATERIAL AND METHODS: Analysis of the patient database at a cancer center of a university hospital. Information about the subtype of cancer was obtained in 2,149 of 2,724 patients in the database. Eighteen percent of the latter were HER2+. We analyzed data of 83 of these patients with advanced disease. RESULTS: Median overall survival (OS) was 24 months. For patients treated between 1997-2006 median OS was 17 months and for those treated in the period 2007-2017 median OS was 32 months (p = 0.09). CONCLUSIONS: A non-significant trend towards better survival in the last decade was observed. HER2+ BC overall survival has improved in our center. This can be probably attributed to the use of novel more effective anti-HER2 therapies.

Cáncer de mama avanzado receptor de estrógeno positivo: manejo sistémico actual / Systemic therapy for estrogen receptor positive advanced breast cancer

El cáncer de mama es la primera causa de muerte por cáncer en mujeres chilenas. Mientras la mayoría de las personas logra curarse de esta enfermedad, un 5% de los casos se presenta inicialmente con enfermedad avanzada y hasta un 20-30% de pacientes con enfermedad localizada pueden sufrir recurrencias sistémicas. La mayoría de las neoplasias mamarias son dependientes del estímulo estrogénico, de allí que la deprivación de estrógenos es la principal estrategia terapéutica. Recientemente, el uso de terapias molecularmente dirigidas en combinación con la terapia endocrina ha logrado mejorar los resultados de sobrevida del cáncer de mama avanzado, con menos efectos colaterales que aquellos producidos por la quimioterapia convencional. El conocimiento de los mecanismos de acción de estas nuevas terapias, sus toxicidades, vías de resistencia y selección de pacientes para lograr los mejores beneficios terapéuticos son aspectos relevantes en el manejo de la enfermedad. Presentamos una revisión del estado actual del manejo del cáncer de mama metastásico hormonodependiente con enfásis en el uso de terapias endocrinas combinadas con terapias moleculares.

Breast cancer is the leading cause of cancer death in Chilean women. While most patientes are cured, five percent of cases present with advanced disease initially and up to 20-30% of patients with localized disease may suffer systemic recurrences. The majority of breast neoplasms are dependent on the estrogenic stimulus, hence the deprivation of estrogen is the main therapeutic strategy. Recently, the use of molecular targeted therapies in combination with endocrine therapy has been successful in improving the survival outcomes of advanced breast cancer, with fewer side effects than those produced by conventional chemotherapy. Knowledge of the mechanisms of action of these new therapies, their toxicities, resistance pathways and patient selection to achieve the best therapeutic benefits are relevant aspects in the management of the disease. We present a review of the current state of management of hormone-dependent metastatic breast cancer with emphasis on the use of endocrine therapies combined with molecular therapies.

High prevalence of vitamin D deficiency in women with breast cancer: The first Chilean study.

BACKGROUND: Breast cancer (BC) is the leading cause of female death from malignancy worldwide. One factor that has been associated to a higher incidence and poor prognosis is a Vitamin D deficiency (measured as 25-Hydroxi-Vitamin D (25OHD)). Our aim was to determine 25OHD levels in serum samples of Chilean BC patients before endocrine therapy and its association to clinical parameters at the time of diagnosis. METHODS: We analyzed clinical records of 105 women, evaluated at the Cancer Center of the Pontificia Universidad Católica de Chile. Serum levels of 25OHD were determined using a chemiluminescent microparticle immunoassay. RESULTS: The prevalence of vitamin D deficiency before endocrine therapy was of 70.5%. Only 7% of our patients showed sufficient vitamin D levels at the beginning of the endocrine treatment. There was a significant correlation found between age and 25OHD levels, and also between body fat percentage and 25OHD levels (r(2) = 0.04; p = 0.021; r(2) = 0.028; p = 0.0432, respectively). Summer 25OHD levels were significantly higher than winter levels (p = 0.0322). CONCLUSION: Vitamin D deficiency is highly prevalent in Chilean BC women before endocrine therapy and 25OHD levels are inversely correlated to the age and body fat percentage of patients. Further studies are needed to determine causal relationship between vitamin D levels and BC development and outcome.

Clinico-Pathologic Subtypes of Breast Cancer Primary Tumors Are Related to Prognosis after Recurrence

Background: Pathological factors, based mainly on immunohistochemistry (IHC) and histological differentiation, are mostly used to differentiate breast cancer (BC) subtypes. Our present aim was to describe the characteristics and survival of a relapsing BC patient cohort based on clinico-pathologic subtypes determined for the primary tumors. Methods: We used a clinico- pathological definition of BC subtypes based on histological grade (HG), estrogen receptor (ER), progesterone receptor (PgR),and epidermal growth factor receptor type 2 (HER2) expression assessed by IHC. We determined variables associated with loco-regional recurrence (LRR), second primaries (SP), systemic recurrence (SR) and post-recurrence survival (PRS). Results: Out of 1,702 patients, 240 (14%) had an event defined as recurrence. Those with recurrent disease were significantly younger than those without,and were initially diagnosed at more advanced stages, with larger tumors, greater lymph nodal involvement and higher HG. With a median follow up of 61 months (1-250), 4.6% of patients without recurrence and 56.6% of patients with an event defined as recurrence had died. The median PRS for the LRR group was 77 months; 75 months for those who developed a SP and 22 months for patients with an SR (p <0.0001). In SR cases, the median PRS was shorter for ER- tumors than for ER+ tumors (15 vs. 26 months, respectively; p = 0.0019, HR 0.44; CI: 0.25-0.44). Conclusions: Subtype, defined through classic histopathologic parameters determined for primary tumors, was found to eb related to type of recurrence and also to prognosis after relapse.

Placental Aromatase Is Deficient in Placental Ischemia and Preeclampsia.

INTRODUCTION: Preeclampsia is a maternal hypertensive disorder with uncertain etiology and a leading cause of maternal and fetal mortality worldwide, causing nearly 40% of premature births delivered before 35 weeks of gestation. The first stage of preeclampsia is characterized by reduction of utero-placental blood flow which is reflected in high blood pressure and proteinuria during the second half of pregnancy. In human placenta androgens derived from the maternal and fetal adrenal glands are converted into estrogens by the enzymatic action of placental aromatase. This implies that alterations in placental steroidogenesis and, subsequently, in the functionality or bioavailability of placental aromatase may be mechanistically involved in the pathophysiology of PE. METHODS: Serum samples were collected at 32-36 weeks of gestation and placenta biopsies were collected at time of delivery from PE patients (n = 16) and pregnant controls (n = 32). The effect of oxygen tension on placental cells was assessed by incubation JEG-3 cells under 1% and 8% O2 for different time periods, Timed-mated, pregnant New Zealand white rabbits (n = 6) were used to establish an in vivo model of placental ischemia (achieved by ligature of uteroplacental vessels). Aromatase content and estrogens and androgens concentrations were measured. RESULTS: The protein and mRNA content of placental aromatase significantly diminished in placentae obtained from preeclamptic patients compared to controls. Similarly, the circulating concentrations of 17-ß-estradiol/testosterone and estrone/androstenedione were reduced in preeclamptic patients vs. controls. These data are consistent with a concomitant decrease in aromatase activity. Aromatase content was reduced in response to low oxygen tension in the choriocarcinoma JEG-3 cell line and in rabbit placentae in response to partial ligation of uterine spiral arteries, suggesting that reduced placental aromatase activity in preeclamptic patients may be associated with chronic placental ischemia and hypoxia later in gestation. CONCLUSIONS: Placental aromatase expression and functionality are diminished in pregnancies complicated by preeclampsia in comparison with healthy pregnant controls.

Applying SWATH Mass Spectrometry to Investigate Human Cervicovaginal Fluid During the Menstrual Cycle.

Inherent interindividual and intraindividual variation in the length of the menstrual cycle limits the accuracy of predicting days of peak fertility. To improve detection of days of peak fertility, a more detailed understanding of longitudinal changes in cervicovaginal fluid (CVF) biomarkers during the normal menstrual cycle is needed. The aim of this study, therefore, was to characterize longitudinal changes in CVF proteins during the menstrual cycle using a quantitative, data-independent acquisition mass spectrometry approach. Six serial samples were collected from women (n = 10) during the menstrual cycle. Samples were obtained at two time points for each phase of the cycle: early and late preovulatory, ovulatory, and postovulatory. Information-dependent acquisition (IDA) of mass spectra from all individual CVF samples was initially performed and identified 278 total proteins. Samples were then pooled by time of collection (n = 6 pools) and analyzed using IDA and information-independent acquisition (Sequential Windowed Acquisition of All Theoretical Mass Spectra [SWATH]). The IDA library generated contained 176 statistically significant protein identifications (P < 0.000158). The variation in the relative abundance of CVF proteins across the menstrual cycle was established by comparison with the SWATH profile against the IDA library. Using time-series, pooled samples obtained from 10 women, quantitative data were obtained by SWATH analysis for 43 CVF proteins. Of these proteins, 28 displayed significant variation in relative abundance during the menstrual cycle (assessed by ANOVA). Statistical significant changes in the relative expression of CVF proteins during preovulatory, ovulatory, and postovulatory phases of menstrual cycle were identified. The data obtained may be of utility not only in elucidating underlying physiological mechanisms but also as clinically useful biomarkers of fertility status.

NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction.

During gestation, low oxygen environment is a major determinant of early placentation process, while persistent placental hypoxia leads to pregnancy-related complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR). PE affects 5%-8% of all pregnancies worldwide and is a cause of maternal and fetal morbidity and mortality. During placental development, persistent hypoxia due to poor trophoblast invasion and reduced uteroplacental perfusion leads to maternal endothelial dysfunction and clinical manifestation of PE. Here we hypothesized that nuclear factor of activated T cells-5 (NFAT5), a well-known osmosensitive renal factor and recently characterized hypoxia-inducible protein, is also activated in vivo in placentas of PE and IUGR complications as well as in the in vitro model of trophoblast hypoxia. In JAR cells, low oxygen tension (1% O2) induced NFAT5 mRNA and increased its nuclear abundance, peaking at 16 h. This increase did not occur in parallel with the earlier HIF1A induction. Real-time PCR and Western blot analysis confirmed up-regulation of NFAT5 mRNA and NFAT5 nuclear content in human preeclamptic placentas and in rabbit placentas of an experimentally induced IUGR model, as compared with the control groups. In vitro lambda protein phosphatase (lambda PPase) treatment revealed that increased abundance of NFAT5 protein in nuclei of either JAR cells (16 h of hypoxia) or PE and IUGR placentas is at least partially due to NFAT5 phosphorylation. NFAT5 downstream targets aldose reductase (AR) and sodium-myo-inositol cotransporter (SMIT; official symbol SLC5A3) were not significantly up-regulated either in JAR cells exposed to hypoxia or in placentas of PE- and IUGR-complicated pregnancies, suggesting that hypoxia-dependent activation of NFAT5 serves as a separate function to its tonicity-dependent stimulation. In conclusion, we propose that NFAT5 may serve as a novel marker of placental hypoxia and ischemia independently of HIF1A.

Innate immune system and preeclampsia.

Normal pregnancy is considered as a Th2 type immunological state that favors an immune-tolerance environment in order to prevent fetal rejection. Preeclampsia (PE) has been classically described as a Th1/Th2 imbalance; however, the Th1/Th2 paradigm has proven insufficient to fully explain the functional and molecular changes observed during normal/pathological pregnancies. Recent studies have expanded the Th1/Th2 into a Th1/Th2/Th17 and regulatory T-cells paradigm and where dendritic cells could have a crucial role. Recently, some evidence has emerged supporting the idea that mesenchymal stem cells might be part of the feto-maternal tolerance environment. This review will discuss the involvement of the innate immune system in the establishment of a physiological environment that favors pregnancy and possible alterations related to the development of PE.

Preterm labour: association between labour physiology, tocolysis and prevention.

INTRODUCTION: In developed countries, preterm birth is the major cause of perinatal morbidity, mortality and the most important public health problem in the obstetric field. In the past decades, an increasing trend has been observed regardless of the great efforts focussed on the improvement of our understanding of the physiopathological mechanisms behind preterm labour (PTL) and the improvement in the use of tocolytic drugs. AREAS COVERED: In this review, the authors focus on some points of the physiopathology of labour in order to understand the rationality behind the different management approaches developed for the PTL syndrome. EXPERT OPINION: There is a need to develop new tools for the treatment of patients with PTL. Research focussed on improving tocolysis, the physiology of labour and pathological processes involved in PTL would afford new approaches for the treatment of PTL, allowing clinicians to provide integrative solutions for this multifactorial disease. Recently, the prophylactic use of progesterone pessary and cerclage in women with high risk of premature labour has been reported to reduce the incidence of premature births and improve neonatal outcomes. These results highlight the importance of prediction models in order to establish preventative strategies early in pregnancy.

Levels of key enzymes of methionine-homocysteine metabolism in preeclampsia.

OBJECTIVE: To evaluate the role of key enzymes in the methionine-homocysteine metabolism (MHM) in the physiopathology of preeclampsia (PE). METHODS: Plasma and placenta from pregnant women (32 controls and 16 PE patients) were analyzed after informed consent. Protein was quantified by western blot. RNA was obtained with RNA purification kit and was quantified by reverse transcritase followed by real-time PCR (RT-qPCR). Identification of the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and A2756G methionine synthase (MTR) SNP was performed using PCR followed by a high-resolution melting (HRM) analysis. S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH) were measured in plasma using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). The SNP association analysis was carried out using Fisher's exact test. Statistical analysis was performed using a Mann-Whitney test. RESULTS: RNA expression of MTHFR and MTR was significantly higher in patients with PE as compared with controls. Protein, SAM, and SAH levels showed no significant difference between preeclamptic patients and controls. No statistical differences between controls and PE patients were observed with the different SNPs studied. CONCLUSION: The RNA expression of MTHFR and MTR is elevated in placentas of PE patients, highlighting a potential compensation mechanism of the methionine-homocysteine metabolism in the physiopathology of this disease.

Fas ligand(+) fallopian tube epithelium induces apoptosis in both Fas receptor(+) T lymphocytes and endometrial cells.

OBJECTIVE: To establish whether human fallopian tube (FT) epithelium can induce apoptosis in T lymphocytes and endometrial cells. DESIGN: Laboratory-based study. SETTING: Hospital. PATIENT(S): Women undergoing abdominal hysterectomy for FT samples, and women volunteers with and without endometriosis for endometrial biopsies. INTERVENTION(S): FT samples obtained at time of surgery performed in reproductive-aged women with normal menstrual cycles. MAIN OUTCOME MEASURE(S): T lymphocytes or endometrial cells coincubated with FT epithelial cells and assayed for apoptosis by DNA nick-end labeling and caspase-3 activity, with the presence of Fas ligand (FasL) and Fas receptor (FasR) assessed by indirect immunostaining. RESULT(S): The epithelium of the FT-induced apoptosis in T cells as well as in human endometrial cells. The mechanism probably involves the FasL/FasR system; accordingly, we observed FasL at the apical surface of the epithelium and in the stroma of the FT at all phases of the menstrual cycle except during the early proliferative phase. The endometrial samples from patients with endometriosis did not express FasR and were resistant to apoptosis. CONCLUSION(S): In both FasR(+) T lymphocytes and endometrial cells, FasL(+) FT cells induce apoptosis. Data suggest that the FT epithelium acts as a barrier to limit the influx of lymphocytes as well as endometrial cells ascending the tube. Failure of these regulatory mechanisms may be related to the development of endometriosis.

First trimester prediction of early onset preeclampsia using demographic, clinical, and sonographic data: a cohort study.

OBJECTIVE: The aim of this research was to evaluate the performance of a predictive model for early onset preeclampsia (PE) during early gestation. METHOD: Prospective multicenter cohort study was performed in women attending 11-14 weeks ultrasound. Medical history and biometrical variables were recorded and uterine artery Doppler was performed. All patients were followed until postpartum period. Constructed predictive models were compared using the area under the associated receiver operating characteristic curve. Sensitivity, specificity, and likelihood ratios were estimated for each outcome. RESULTS: A total of 627 patients were enrolled. Sixty-five (10.4%) developed gestational hypertension, of which 29 developed PE (4.6% of the total sample) and nine occurred before 34 weeks (1.5% of total sample). Prediction model generated for early onset PE (ePE) with 5% false positive achieve sensitivity of 62.5% and specificity of 95.5%. The positive and negative likelihood ratios for ePE were 13.9 and 0.39, respectively. Development of ePE was significantly associated with history of preterm labor (p = 0.002) and diabetes mellitus (p = 0.02). CONCLUSIONS: This study confirms the advantage of combining multiple variables for prediction of ePE.

Metabolic pathways involved in 2-methoxyestradiol synthesis and their role in preeclampsia.

Preeclampsia (PE) remains a major cause of maternal/fetal morbidity-mortality worldwide. The first stage of PE is characterized by placental hypoxia due to a relative reduction in uteroplacental blood flow, resulting from restricted trophoblast invasion. However, hypoxia is also an essential element for the success of invasion. Under hypoxic conditions, 2-methoxyestradiol (2-ME) could induce the differentiation of cytotrophoblast cells into an invasive phenotype in culture. 2-Methoxyestradiol is generated by catechol-O-methyltransferase, an enzyme involved in the metabolic pathway of estrogens. During pregnancy, circulating 2-ME levels increase significantly when compared to the menstrual cycle. Interestingly, plasma levels of 2-ME are lower in women with PE than in controls, and these differences are apparent weeks or even months before the clinical manifestations of the disease. This article reviews the metabolic pathways involved in 2-ME synthesis and discusses the roles of these pathways in normal and abnormal pregnancies, with particular emphasis on PE.

Low 2-methoxyestradiol levels at the first trimester of pregnancy are associated with the development of pre-eclampsia.

OBJECTIVE: To determine whether maternal plasma levels of 2-methoxyestradiol (2-ME) are decreased early in pregnancies that subsequently develop pre-eclampsia (PE) and whether this difference could be attributed to the presence of Val158Met catechol-O-methyltransferase (COMT) polymorphism in the placenta. METHODS: Clinical characteristics and plasma samples were collected at 11 to 14 weeks prospectively in a cohort of patients. From them, 13 PE and 72 control pregnant women were chosen. Plasma soluble fms-like tyrosine kinase1 and placental growth factor levels were measured by electrochemiluminescence and 2-ME was measured by high-performance liquid chromatography with mass spectrometry/mass spectrometry detection. At delivery, placental tissue was collected and the Val158Met COMT polymorphism was determined by restriction fragment length polymorphism-PCR. RESULTS: At 11 to 14 weeks, patients who would develop PE have significantly lower plasma levels of 2-ME than controls [1.9 ± 2 standard error of the mean (SEM) vs 61.7 ± 27 pg/mL, P < 0.05]. The Val158Met polymorphism was more frequent in controls than in PE patients and the placental presence of COMT polymorphism was associated with a decreased risk of developing PE [PE: 23.1% vs control: 66.6%; χ(2) = 10.9, p = 0.0041]. CONCLUSIONS: Lower plasma concentrations of 2-ME during early pregnancy in patients who subsequently develop PE were found. Presence of placental Val158Met COMT polymorphism is associated with a decreased risk to develop PE, suggesting a protective role against PE.

Pathogenesis of preeclampsia: the genetic component.

Preeclampsia (PE) is one of the main causes of maternal and fetal morbidity and mortality in the world, causing nearly 40% of births delivered before 35 weeks of gestation. PE begins with inadequate trophoblast invasion early in pregnancy, which produces an increase in oxidative stress contributing to the development of systemic endothelial dysfunction in the later phases of the disease, leading to the characteristic clinical manifestation of PE. Numerous methods have been used to predict the onset of PE with different degrees of efficiency. These methods have used fetal/placental and maternal markers in different stages of pregnancy. From an epidemiological point of view, many studies have shown that PE is a disease with a strong familiar predisposition, which also varies according to geographical, socioeconomic, and racial features, and this information can be used in the prediction process. Large amounts of research have shown a genetic association with a multifactorial polygenic inheritance in the development of this disease. Many biological candidate genes and polymorphisms have been examined in their relation with PE. We will discuss the most important of them, grouped by the different pathogenic mechanisms involved in PE.