International Society of Paediatric Oncology (SIOP) Global Mapping Programme: Latin American Society of Pediatric Oncology (SLAOP) country-level report.

BACKGROUND: Latin American countries are improving childhood cancer care, showing strong commitment to implement the Global Initiative for Childhood Cancer, but there are scant publications of the situation at a continental level. METHODS: As part of the International Society of Paediatric Oncology Global Mapping project, delegates of each country participating in the Latin American Society of Pediatric Oncology (SLAOP) and chairs of national pediatric oncology societies and cooperative groups were invited to provide information regarding availability of national pediatric cancer control programs (NPCCP), pediatric oncology laws, pediatric oncology tumor registries, and training programs and support to diagnosis and treatment. RESULTS: Nineteen of the 20 countries participating in SLAOP responded. National delegates reported nine countries with NPCCP and four of them were launched in the past 5 years. National pediatric tumor registries are available in eight countries, and three provided published survival results. Fellowship programs for training pediatric oncologists are available in 12 countries. National delegates reported that eight countries provide support to most essential diagnosis and treatments and 11 provide partial or minimal support that is supplemented by civil society organizations. Seven countries have a pediatric oncology law. There are three international cooperative groups and four national societies for pediatric oncology. CONCLUSION: Despite many challenges, there were dramatic advances in survivorship, access to treatment, and availability of NPCCP in Latin America. Countries with highest social development scores in general provide more complete support and are more likely to have NPCCP, training programs, and reported survival results.

Sandwich-Type Electrochemical Paper-Based Immunosensor for Claudin 7 and CD81 Dual Determination on Extracellular Vesicles from Breast Cancer Patients.

This study is focused on identifying novel epithelial markers in circulating extracellular vesicles (EVs) through the development of a dual sandwich-type electrochemical paper-based immunosensor for Claudin 7 and CD81 determination, as well as its validation in breast cancer (BC) patients. This immunosensor allows for rapid, sensitive, and label-free detection of these two relevant BC biomarkers. Under optimum conditions, the limit of detection for Claudin 7 was 0.4 pg mL-1, with a wide linear range of 2 to 1000 pg mL-1, while for CD81, the limit of detection was 3 pg mL-1, with a wide linear range of 0.01 to 10 ng mL-1. Finally, we validated Claudin 7 and CD81 determination in EVs from 60 BC patients and 20 healthy volunteers, reporting higher diagnostic accuracy than the one observed with classical diagnostic markers. This analysis provides a low-cost, specific, versatile, and user-friendly strategy as a robust and reliable tool for early BC diagnosis.

Prognostic factors in patients with vulvar cancer: the VULCAN study.

OBJECTIVE: This study aimed to analyze the prognostic factors for overall and progression-free survival in patients with vulvar cancer. METHODS: This international, multicenter, retrospective study included 2453 patients diagnosed with vulvar cancer at 100 different institutions. Inclusion criteria were institutional review board approval from each collaborating center, pathologic diagnosis of invasive carcinoma of the vulva, and primary treatment performed at the participating center. Patients with intraepithelial neoplasia or primary treatment at non-participating centers were excluded. Global survival analysis and squamous cell histology subanalysis was performed. RESULTS: After excluding patients due to incomplete data entry, 1727 patients treated for vulvar cancer between January 2001 and December 2005 were registered for analysis (1535 squamous, 42 melanomas, 38 Paget's disease and 112 other histologic types). Melanomas had the worse prognosis (p=0.02). In squamous vulvar tumors, independent factors for increase in local recurrence of vulvar cancer were: no prior radiotherapy (p<0.001) or chemotherapy (p=0.006), and for distant recurrence were the number of positive inguinal nodes (p=0.025), and not having undergone lymphadenectomy (p=0.03) or radiotherapy (p<0.001), with a HR of 1.1 (95% CI 1.2 to 1.21), 2.9 (95% CI 1.4 to 6.1), and 3.1 (95% CI 1.7 to 5.7), respectively. Number of positive nodes (p=0.008), FIGO stage (p<0.001), adjuvant chemotherapy (p=0.001), tumor resection margins (p=0.045), and stromal invasion >5 mm (p=0.001) were correlated with poor overall survival, and large case volume (≥9 vs <9 cases per year) correlated with more favorable overall survival (p=0.05). CONCLUSIONS: Advanced patient age, number of positive inguinal lymph nodes, and lack of adjuvant treatment are significantly associated with a higher risk of relapse in patients with squamous cell vulvar cancer. Case volume per treating institution, FIGO stage, and stromal invasion appear to impact overall survival significantly. Future prospective trials are warranted to establish these prognostic factors for vulvar cancer.

Negative Social Evaluation Impairs Executive Functions in Adolescents With Excess Weight: Associations With Autonomic Responses.

BACKGROUND: Adolescents with excess weight suffer social stress more frequently than their peers with normal weight. PURPOSE: To examine the impact of social stress, specifically negative social evaluation, on executive functions in adolescents with excess weight. We also examined associations between subjective stress, autonomic reactivity, and executive functioning. METHODS: Sixty adolescents (aged 13-18 years) classified into excess weight or normal weight groups participated. We assessed executive functioning (working memory, inhibition, and shifting) and subjective stress levels before and after the Trier Social Stress Task (TSST). The TSST was divided into two phases according to the feedback of the audience: positive and negative social evaluation. Heart rate and skin conductance were recorded. RESULTS: Adolescents with excess weight showed poorer executive functioning after exposure to TSST compared with adolescents with normal weight. Subjective stress and autonomic reactivity were also greater in adolescents with excess weight than adolescents with normal weight. Negative social evaluation was associated with worse executive functioning and increased autonomic reactivity in adolescents with excess weight. CONCLUSIONS: The findings suggest that adolescents with excess weight are more sensitive to social stress triggered by negative evaluations. Social stress elicited deterioration of executive functioning in adolescents with excess weight. Evoked increases in subjective stress and autonomic responses predicted decreased executive function. Deficits in executive skills could reduce cognitive control abilities and lead to overeating in adolescents with excess weight. Strategies to cope with social stress to prevent executive deficits could be useful to prevent future obesity in this population.

Increased food choice-evoked brain activation in adolescents with excess weight: Relationship with subjective craving and behavior.

OBJECTIVE: We used functional magnetic resonance imaging (fMRI) to assess brain regions associated with food choices between appetizing (i.e., high sugar, high fat) and plain food in adolescents with excess weight and those with normal weight. The associations between choice-evoked brain activation and subjective food craving and behavioral food choices were also evaluated. METHODS: Seventy-three adolescents (aged 14-19 years), classified into excess weight (n = 38) or normal weight (n = 39) groups, participated in the study. We used a food-choice fMRI task, between appetizing and plain food, to analyse brain activation differences between groups. Afterwards, participants assessed their "craving" for each food presented in the scanner. RESULTS: Adolescents with excess weight showed higher brain activation in frontal, striatal, insular and mid-temporal regions during choices between appetizing and standard food cues. This pattern of activations correlated with behavioral food choices and subjective measures of craving. CONCLUSIONS: Our findings suggest that adolescents with excess weight have greater food choice-related brain reactivity in reward-related regions involved in motivational and emotional responses to food. Increased activation in these regions is generally associated with craving, and increased dorsolateral prefrontal cortex is specifically associated with appetizing food choices among adolescents with excess weight, which may suggest greater conflict in these decisions. These overweight- and craving-associated patterns of brain activation may be relevant to decision-making about food consumption.

Increased corticolimbic connectivity in cocaine dependence versus pathological gambling is associated with drug severity and emotion-related impulsivity.

Neural biomarkers for the active detrimental effects of cocaine dependence (CD) are lacking. Direct comparisons of brain connectivity in cocaine-targeted networks between CD and behavioural addictions (i.e. pathological gambling, PG) may be informative. This study therefore contrasted the resting-state functional connectivity networks of 20 individuals with CD, 19 individuals with PG and 21 healthy individuals (controls). Study groups were assessed to rule out psychiatric co-morbidities (except alcohol abuse and nicotine dependence) and current substance use or gambling (except PG). We first examined global connectivity differences in the corticolimbic reward network and then utilized seed-based analyses to characterize the connectivity of regions displaying between-group differences. We examined the relationships between seed-based connectivity and trait impulsivity and cocaine severity. CD compared with PG displayed increased global functional connectivity in a large-scale ventral corticostriatal network involving the orbitofrontal cortex, caudate, thalamus and amygdala. Seed-based analyses showed that CD compared with PG exhibited enhanced connectivity between the orbitofrontal and subgenual cingulate cortices and between caudate and lateral prefrontal cortex, which are involved in representing the value of decision-making feedback. CD and PG compared with controls showed overlapping connectivity changes between the orbitofrontal and dorsomedial prefrontal cortices and between amygdala and insula, which are involved in stimulus-outcome learning. Orbitofrontal-subgenual cingulate cortical connectivity correlated with impulsivity and caudate/amygdala connectivity correlated with cocaine severity. We conclude that CD is linked to enhanced connectivity in a large-scale ventral corticostriatal-amygdala network that is relevant to decision making and likely to reflect an active cocaine detrimental effect.

Ephrin reverse signaling mediates palatal fusion and epithelial-to-mesenchymal transition independently of Tgfß3.

The mammalian secondary palate forms from shelves of epithelia-covered mesenchyme that meet at midline and fuse. The midline epithelial seam (MES) is thought to degrade by apoptosis, epithelial-to-mesenchymal transition (EMT), or both. Failure to degrade the MES blocks fusion and causes cleft palate. It was previously thought that transforming growth factor ß3 (Tgfß3) is required to initiate fusion. Members of the Eph tyrosine kinase receptor family and their membrane-bound ephrin ligands are expressed on the MES. We demonstrated that treatment of mouse palates with recombinant EphB2/Fc to activate ephrin reverse signaling (where the ephrin acts as a receptor and transduces signals from its cytodomain) was sufficient to cause mouse palatal fusion when Tgfß3 signaling was blocked by an antibody against Tgfß3 or by an inhibitor of the TgfßrI serine/threonine receptor kinase. Cultured palatal epithelial cells traded their expression of epithelial cell markers for that of mesenchymal cells and became motile after treatment with EphB2/Fc. They concurrently increased their expression of the EMT-associated transcription factors Snail, Sip1, and Twist1. EphB2/Fc did not cause apoptosis in these cells. These data reveal that ephrin reverse signaling directs palatal fusion in mammals through a mechanism that involves EMT but not apoptosis and activates a gene expression program not previously associated with ephrin reverse signaling.

Therapeutic adherence in primary care depressed patients: a longitudinal study.

INTRODUCTION: Lack of adherence has been associated to lower efficacy of anti-depressant treatment, increasing the risk of recurrence and persistence of clinical symptoms. Patients with poor medication adherence have more concomitant medical illnesses and somatic symptoms. Furthermore, this increases use of healthcare services. METHOD: Longitudinal and observational study on therapeutic adherence level in depressive outpatients treated in 3 Primary Care (PC) centers. Eight evaluations during 6 months were carried out in 29 patients over 18, with DSM-IV-TR major depression diagnosis. The purpose of the present study was to determine adherence level, to analyze socio-demographic factors and clinical profiles involved in adherence, and to observe the evolution of depressive symptoms. RESULTS: Good therapeutic adherence was observed in 72.4% of patients. Significant differences in the Drug Attitude Inventory (U=107.5; p=0.036) were found. This tool evaluates the perceived effect of the medication, with a better perception observed in adherent patients. In those patients a progressive reduction on the Hamilton Depression Scale was found over the course of six monthly follow-up visits, with clinical remission observed in month 4. The analysis of survival rate did not reveal any significant difference between the two groups [Log Rank (χ2=1.610, p=0.205)]. CONCLUSIONS: The therapeutic adherence observed in this longitudinal PC study is high, and it is associated with an improvement in the illness. A better perceived effect of the treatment showed a significant connection to an improvement in symptoms of depression.

Ephrin reverse signaling controls palate fusion via a PI3 kinase-dependent mechanism.

Secondary palate fusion requires adhesion and epithelial-to-mesenchymal transition (EMT) of the epithelial layers on opposing palatal shelves. This EMT requires transforming growth factor ß3 (TGFß3), and its failure results in cleft palate. Ephrins, and their receptors, the Ephs, are responsible for migration, adhesion, and midline closure events throughout development. Ephrins can also act as signal-transducing receptors in these processes, with the Ephs serving as ligands (termed "reverse" signaling). We found that activation of ephrin reverse signaling in chicken palates induced fusion in the absence of TGFß3, and that PI3K inhibition abrogated this effect. Further, blockage of reverse signaling inhibited TGFß3-induced fusion in the chicken and natural fusion in the mouse. Thus, ephrin reverse signaling is necessary and sufficient to induce palate fusion independent of TGFß3. These data describe both a novel role for ephrins in palate morphogenesis, and a previously unknown mechanism of ephrin signaling.

Exchange of cellular components between platelets and tumor cells: impact on tumor cells behavior.

Background: Platelets are active players in tumorigenesis, although the exact interactive mechanisms and their direct impact on tumor cells remain largely unknown. Methods: Bidirectional transference of lipids, proteins and RNA between platelets and tumor cells and its impact on tumor cell behavior and tumor process are analyzed in this work. Phenotypic, genetic and functional modifications induced by platelets were analyzed both in tumor cell lines and in circulating tumor cells (CTCs). Results: Data from these assays showed that platelets transferred structural components to tumor cells with higher efficiency than tumor cells to platelets (p = 0.001). This biological interplay occurred by direct contact, internalization or via extracellular vesicles. As a result, tumor cells acquired platelet markers (CD61 and CD42), showed decreased EpCAM, expressed epithelial-to-mesenchymal transition markers, and increased proliferation rates. Moreover, we were able to detect CD61 in CTCs from early and advanced prostate cancer. Conclusions: Our results demonstrated, for the first time, that platelets educate tumor cells by highly efficient transference of lipids, proteins and RNA through different mechanisms. These results suggest that tumor cells and CTCs might acquire highly dynamic and aggressive phenotypes due to platelets interaction including EMT, stem-like phenotype and high proliferative rates.

Psychometric properties of the IDS-SR30 for the assessment of depressive symptoms in Spanish population.

BACKGROUND: Due to the high prevalence of depression, it is clinically relevant to improve the early identification and assessment of depressive episodes. The main objective of the present study was to examine the psychometric properties of the IDS-SR30 (Self-rated Inventory of Depressive Symptomatology) in a large Spanish sample of depressive patients. METHODS: This prospective, naturalistic, multicenter, nationwide epidemiological study conducted in Spain included 1595 adult patients (65.3% females) with a DSM-IV Major Depressive Disorder (MDD. IDS-SR30 and the Hamilton Depression Rating Scale (HDRS, 21 items)were administered to the sample. Data was collected during 2 routine visits. The second assessment was carried out after 10 ± 2 weeks after first assessment. RESULTS: The IDS-SR30 showed good internal consistency (α = 0.94) and high item total correlations (≥ 0.50) were found in 70% of the items. The convergent validity was 0.85. Results of the principal component analysis (PCA) and confirmatory factor analyses (CFA) showed that a three factor model (labelled mood/cognition, anxiety/somatic and sleep) is adequate for the current sample. CONCLUSIONS: The Spanish version of the IDS-SR30 seems a reliable, valid and useful tool for measuring depression symptomatology in Spanish population.

Clinical differences between first and recurrent episodes in depressive patients.

BACKGROUND: Depressive disorder is one of the most common mental disorders in primary care. Depression is often a chronic disorder with recurrent episodes. Little is known about the differences in clinical profile between first and recurrent episodes. The aim of the study is to analyze the differences between clinical presentation of first and subsequent episodes of depressive disorders in primary care patients. METHOD: A cross-sectional epidemiologic study in primary care centers in Spain was designed. A total of 10,257 primary care patients having a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition major depressive episode were analyzed. Clinical symptoms were measured using the Montgomery Asberg Depression Scale. Patient Health Questionnaire was used to assess somatic symptoms. RESULTS: There were 40.6% of patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for recurrent depression. Compared with those diagnosed of their first major depressive disorder, recurrent patients had greater rates and severity of depressive (t = -7.85, P < .001) and somatic symptoms (t = 5.64, P < .001). The severity of symptoms also increases with number of episodes (F = 40.2, P < .001, for depressive symptoms; F = 27.8, P < .001, for somatic symptoms). First-episode patients were more likely to experience reduced appetite (adjusted odds ratio, 1.2) and suicidal thoughts (adjusted odds ratio, 1.2). CONCLUSION: There are differences in the clinical profile of initial and recurrent episodes in primary care depressive patients. Each recurrent depressive episode seems to have a greater impact on symptoms and well-being. The identification of a specific depression symptom profile in first or recurrent episodes is needed to improve the long-term management of major depressive episode patients in primary care settings.

Mental disorders among frequent attenders in primary care: a comparison with routine attenders.

Frequent attenders account for a large proportion of primary care (PC) contacts, referrals, and prescriptions. Psychosocial and emotional distress is related to the high use of health services. Few studies have focused on the association between mental disorders assessed using structured interviews and frequent use of PC services.The aim of this study was to determine the factors associated with frequent attendance at primary healthcare units, focusing specifically on mental disorders. A two-phase screening epidemiological study comparing frequent attenders and routine attenders in five primary health care units was designed. Three hundred eighteen frequent attenders and 203 patients who attended the same units on a routine basis were compared. Sociodemographic and clinical data were obtained from statistical records and medical charts. Patients with a total score equal or higher than 7 points on the General Health Questionnaire-28 (GHQ-28) were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry. All the scores obtained on the GHQ were statistically different in the two populations. Frequency of mental disorders also differed significantly between both groups, with somatoform and affective disorders being the most prevalent ICD-10 categories among frequent attenders. The presence of depressive disorders and somatoform disorders is the most powerful predictive factor for frequent attendance. High comorbidity was found among frequent attenders with somatoform disorder. Frequent attendance at primary healthcare units is associated with depressive and somatoform disorders. Psychiatric comorbidity could be a confounder, particularly because affective and somatoform disorders often overlap in PC patients.

Mental disorders, chronic conditions and psychological factors: a path analysis model for healthcare consumption in general practice.

To explore potential individual determinants of healthcare utilization in primary care (PC) using a structural equation modelling approach. Atotal of 638 patients from five PC units were randomly selected. Mental disorders, psychological distress and other psychological factors were assessed with the 28-item General Health Questionnaire (GHQ-28) and the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). Medical records and ICD-10 diagnosis were used to measure somatic morbidity. There is a negative relationship between the presence of mental disorders and psychological well-being (-0.74), and a negative relationship with use of health services (-0.25). Age has a positive and significant relationship with the presence of chronic diseases (0.49), which has a positive and significant relationship with limitation of daily activities (0.18). This limitation has a positive relationship with poor perception of health (0.57) and with psychological well-being (0.03). Findings confirm the existence of specific pathways in PC health use. Health service use depends on the patient's psychological well-being and on the presence of chronic medical conditions. Healthcare professionals need to pay attention to the comorbidity of mental disorders and chronic medical conditions in order to identify frequent attenders and to decrease the inappropriate use of healthcare services.

Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation.

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment.

Effectiveness of hygienic-dietary recommendations as enhancers of antidepressant treatment in patients with depression: study protocol of a randomized controlled trial.

BACKGROUND: In recent years some studies have been published supporting the efficacy of light exposure, physical activity, sleep control and a Mediterranean diet pattern on the improvement or prevention of depression. However, to our knowledge, there have been no studies using all these measures together as an adjuvant antidepressant strategy. METHODS: Multicenter, randomized, controlled, two arm-parallel, clinical trial. Eighty depressed patients undergoing standard antidepressant treatment will be advised to follow four additional hygienic-dietary recommendations about exercise, diet, sunlight exposure and sleep. Outcome measures will be assessed before and after the 6 month intervention period. DISCUSSION: We expect the patients in the active recommendations group to experience a greater improvement in their depressive symptoms. If so, this would be a great support for doctors who might systematically recommend these simple and costless measures, especially in primary care. TRIAL REGISTRATION: ISRCTN59506583.

EGFR detection in extracellular vesicles of breast cancer patients through immunosensor based on silica-chitosan nanoplatform.

In the present work, we designed a microfluidic electrochemical immunosensor with enough sensibility and precision to quantify epithermal growth factor receptor (EGFR) in plasma extracellular vesicles (EVs) of plasma from breast cancer patients. The sensor employs SiNPs coated with chitosan (SiNPs-CH) as reaction's platform, based on the covalently immobilization of monoclonal anti-EGFR on SiNPs-CH retained in the central channel (CC) of the microfluidic device. The synthetized SiNPs-CH were characterized by UV-visible spectroscopy (UV-visible), energy dispersive spectrometry (EDS), Nanoparticle Tracking Analysis (NTA) and transmission electron microscopy (TEM). EGFR was quantified by a direct sandwich immunoassay measuring through a horseradish peroxidase (HRP)-conjugated anti-EGFR. The enzymatic product (benzoquinone) was detected by reduction at - 100 mV on a sputtering gold electrode. The measured current was directly proportional to the level of EGFR in human serum samples. The linear range was from 0 ng mL-1 to 50 ng mL-1. The detection limit was 1.37 pg mL-1, and the within- and between-assay coefficients of variation were below 6.25%. Finally, plasma samples from 30 early breast cancer patients and 20 healthy donor were analyzed by the novel method. EGFR levels in EVs (EVs-EGFR) were significantly higher than in the healthy control group (p = 0.002) and also, more sensitivity and specificity than normal serum markers like CEA and CA15.3 has been observed. EVs-EGFR concentration correlates with EGFR tumor status (p = 0.0003) as well as it correlate with the tumor size and pathological grade. To conclude, plasma EVs are suitable for proteomic characterization of cancer disease, as long as the employed method has sufficient sensitivity, like the case of immune-electrochemical nanosensors with incremented reaction surface.

Diagnostic Interview for Genetic Studies (DIGS): inter-rater and test-retest reliability and validity in a Spanish population.

OBJECTIVE: To test the reliability and validity of the DIGS in Spanish population. METHODS: Inter-rater and test-retest reliability of the Spanish version of DIGS was tested in 95 inpatients and outpatients. The resultant diagnoses were compared with diagnoses obtained by the LEAD (Longitudinal Expert All Data) procedure as "gold standard". The kappa statistic was used to measure concordance between blind inter-raters and between the diagnoses obtained by LEAD procedure and through the DIGS. RESULTS: Overall kappa coefficient for inter-rater reliability was 0.956. The kappa value for individual diagnosis varied from major depression=0.877 to schizophrenia=1. Test-retest reliability was 0.926. Kappa for all individual target diagnoses ranged from 0.776 (major depression) to 1. Kappa between LEAD procedure and DIGS ranged from 0.704 (major depression) to 0.825 (bipolar I disorder). CONCLUSION: Most of the DSM-IV major psychiatric disorders can be assessed with acceptable to excellent reliability with the Spanish version of the DIGS interview. The Spanish version of DIGS showed an acceptable to excellent concurrent validity. Giving the good reliability and validity of Spanish version of DIGS it should be considered to identify psychiatric phenotypes for genetics studies.

A comprehensive study of circulating tumour cells at the moment of prostate cancer diagnosis: biological and clinical implications of EGFR, AR and SNPs.

Circulating tumor cells (CTCs) have been recently accepted as prognostic markers in metastatic prostate cancer (PCa). However, very few studies have analyzed their role in early-stage PCa. The aim of this research is to study the value of CTCs at the moment of PCa diagnosis and to identify different subpopulations of CTCs. Patients with PSA value > 4 ng/ml and clinical suspicion of PCa were included. Samples were collected immediately before prostatic biopsy. CTCs were isolated by immunomagnetic technique using a multi-CK specific antibody. Molecular expression of EGFR and AR in the tissue was analysed by real-time PCR. Up to eight different SNPs in patients' blood DNA were studied. In a total of 86 patients, the CTC detection rate was 18.6%. The sensitivity, specificity, positive and negative predictive values of CTCs to detect PCa was 14.2%, 78.4%, 31.2% and 57.4%, respectively. Up to 75% of CTC-positive patients were AR-negative. A direct association was found between the expression of AR in the prostatic tissue and the presence of CTCs in blood (p<0.05). We observed an inverse relation between the expression of EGFR in the tissue and the expression of AR in the CTCs. No significant association between SNPs and CTCs was found. The low detection rate of CTCs in early-stage PCa limits their role as a diagnostic marker. Nevertheless, we show that they may hide important prognostic information. Overexpression of AR in the prostate may facilitate cell dissemination.

Dormant Circulating Tumor Cells in Prostate Cancer: Therapeutic, Clinical and Biological Implications.

Circulating Tumor Cells (CTCs) are a valuable prognostic factor in several solid tumors. By understanding the biological characteristics of CTCs we could better understand the biology of metastasis. CTCs usually adopt a dormant state that is believed to be a strategy to survive in extreme conditions. To enter a dormant state, CTCs undergo numerous phenotypic, genetic and functional mutations that significantly affect the efficacy of the therapies used to kill dormant CTCs. Hence, understanding the biological events involved in the dormancy process of CTCs would allow the identification of new therapeutic targets. Some experimental studies or preclinical models have explored these biological events, as well as the molecular factors that contribute to the maintenance of and release from dormancy. However, few studies have assessed the effects of anticancer therapies on dormant cells. This study reviews current the data currently available on cell dormancy mechanisms in prostate cancer, with a special focus on the functional, genetic and phenotypic plasticity of CTCs and their potential implications in the clinical and therapeutic management of prostate cancer.