Clinical implementation of the sFlt-1/PlGF ratio to identify preeclampsia and fetal growth restriction: A prospective cohort study.

OBJECTIVE: To analyze the usefulness of a clinical protocol for early detection of preeclampsia and/or fetal growth restriction (PE/FGR) using, in previously selected pregnancies, the measurement of the sFlt-1/PlGF ratio at 24-28 weeks of gestation. STUDY DESIGN: Prospective observational cohort study carried out in a single tertiary hospital in Spain. 5601 consecutive singleton pregnancies with complete follow-up were included. High-risk women for PE/FGR were selected by combining data from maternal history and second trimester uterine artery Doppler. Subsequently these patients underwent intensive monitoring, including the measurement of the sFlt-1/PlGF ratio at 24-28 weeks to predict PE/FGR. MAIN OUTCOME MEASURES: Early, intermediate and late PE/FGR (delivery <32 + 0, 32 + 0 - <36 + 0 and ≥36 + 0 weeks, respectively). RESULTS: Overall incidence of early, intermediate and late PE/FGR was 0.3%, 0.7% and 3.2%, respectively, being higher in the 4.3% of women selected for intensive monitoring: 5.8%, 8.7% and 15.4%, respectively (all p < 0.001). The area under the curve (AUC) with 95%CI of the sFlt-1/PlGF ratio for detecting early PE/FGR was 0.98 (0.97-1.00), and the sFlt-1/PlGF ratio >95th centile showed a sensitivity (%) of 100 (95%CI, 78.5-100) and specificity (%) of 80.6 (95%CI, 75.0-85.2). The AUC of the sFlt-1/PlGF ratio for detecting intermediate and late PE/FGR was of 0.87 (95%CI, 0.77-0.97) and 0.68 (95%CI, 0.58-0.79), respectively. CONCLUSION: A contingent strategy of measuring the sFlt-1/PlGF ratio at 24-28 weeks in women previously selected by clinical factors and uterine artery Doppler enables an accurate prediction of PE/FGR. This performance is optimal to predict PE/FGR requiring delivery before 32 weeks.

The role of angiogenic biomarkers and uterine artery Doppler in pregnant women with systemic lupus erythematosus or antiphospholipid syndrome.

OBJECTIVE: To evaluate the usefulness of the uterine artery mean pulsatility index (mPI-UtA) and the sFlt-1/PlGF ratio in women with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS) for the prediction of placental dysfunction-related adverse outcomes (AO), namely pre-eclampsia (PE) and intrauterine growth restriction (IUGR), and for differential diagnosis between PE and SLE flares. STUDY DESIGN: Observational prospective cohort study of 57 pregnant women with SLE or APS. MAIN OUTCOME MEASURES: mPI-UtA and sFlt-1/PlGF ratio in maternal serum were obtained at four gestational age periods (11-14, 19-22, 24-29 and 32-34 weeks). Comparisons among pregnancies with normal outcome, SLE flare and AO were performed. RESULTS: Overall, we had 44 ongoing pregnancies (36 with SLE and 8 with APS) of which most (n = 35, 80%) were uncomplicated. The overall rate of AO was 9% (n = 4), that was diagnosed at a mean (SD) gestational age of 34.1 (7.5) weeks. Five SLE patients (14%) suffered a SLE flare. No differences for these markers were found between normal pregnancies and those affected by SLE flare. mUtA-PI values were significantly higher in the AO group when compared with normal and SLE flare groups, at 19-22 weeks (1.52, 0.95 and 0.76) and 32-34 weeks (1.13, 0.68 and 0.65), respectively. The sFlt-1/PlGF ratio was significantly higher in the AO group at 24-29 weeks (191.1, 3.1 and 9.2), respectively. CONCLUSION: Our preliminary results indicate that mPI-UtA and sFlt1/PlGF ratio may be useful to predict AO in women with SLE, and to make the differential diagnosis with a lupus flare.

Técnicas de aspirado endotraqueal en neonatos: una revisión de la literatura / Endotracheal aspiration techniques in neonates: a literature review / Técnicas de aspirado endotraqueal em neonatos: uma revisão da literatura

Introducción: Para el neonato con ventilación mecánica asistida la técnica de aspiración a través del tubo endotraqueal se hace indispensable para conservarlo libre de secreciones, de esta forma, se mantiene la vía aérea permeable. En el área hospitalaria, la práctica para realizar este procedimiento contempla una técnica cerrada y otra abierta. Ambas son indispensables en el manejo correcto del paciente, cuando se usan adecuadamente. Objetivo: Analizar a través de la evidencia científica disponible, las ventajas y/o desventajas de las técnicas cerrada y abierta en el paciente neonato intubado. Metodología: Se llevó a cabo una revisión bibliográfica en las bases de datos de Pubmed, CUIDEN, Cochrane y LILACS. Además, se examinaron las listas de referencias de los artículos seleccionados. Desarrollo: Tras la revisión de los resultados y la aplicación de los criterios de inclusión fueron seleccionados seis artículos para el análisis en profundidad de los mismos. Resultados y conclusiones: En el recién nacido que está intubado, la literatura establece que la técnica cerrada ofrece mayores ventajas a los neonatos. Los autores concluyen esto, debido a que la técnica cerrada mantiene el volumen pulmonar y la presión intracraneana en parámetros estables, asimismo, mediante esta técnica se previene la hipoxia e hipoxemia por lo cual se conserva adecuadamente la saturación de oxígeno, el llenado capilar y la frecuencia cardiaca durante el procedimiento.

Introduction: In neonates under assisted ventilation, the endotracheal aspiration techniques become necessary in order to maintain the baby's airway free of secretions. Within the hospital area, the practice of these procedures includes a closed and an open technique. Both are crucial for the correct management of these patients and should always be properly performed. Objective: To analyze, through available scientific evidence, the advantages and disadvantages of the open and closed endotracheal aspiration techniques in the neonatal patient under assisted ventilation. Methodology: A bibliographical review was conducted on the PubMed, CUIDEN, Cochrane, and LILACS databases. In addition, the reference lists of the selected articles were also examined. Development: After the review and application of the inclusion criteria, a total of six articles were selected for in-depth analysis. Results and conclusions: The literature on the neonate under assisted ventilation suggests that the closed endotracheal aspiration technique offers more advantages because it maintains the pulmonary volume and the intracranial pressure within stable ranges, and also, it prevents hypoxia and hypoxemia, adequately maintaining the oxygen saturation, the capillary refill, and the cardiac frequency during the procedure.

Introdução: Para o neonato com ventilação mecânica assistida a técnica de aspiração através do tubo endotraqueal se faz indispensável para conservá-lo livre de secreções, mantendo assim, a via aérea permeável. Na área hospitalar, a prática para realizar este procedimento contempla uma técnica fechada e outra aberta. Ambas são indispensáveis no funcionamento correto do paciente, quando se usam adequadamente. Objetivo: Analisar através da evidencia científica disponível, as vantagens e/ou desvantagens das técnicas técnica fechada e aberta no paciente neonato intubado. Metodologia: Levou-se a cabo uma revisão bibliográfica nas bases de dados de Pubmed, CUIDEN, Cochrane e LILACS. Além disso, examinaram-se nas listas de referências dos artigos selecionados. Desenvolvimento: Após da revisão dos resultados e da aplicação dos critérios de inclusão, foram selecionados seis artigos para a análise exaustiva dos mesmos. Resultados e conclusões: No recém-nascido que está intubado, a literatura estabelece que a técnica fechada oferece maiores vantagens nos neonatos. Os autores concluem isto, devido a que a técnica fechada mantem o volume pulmonar e a pressão ointracraneana em parâmetros estáveis, assim mesmo, mediante esta técnica previne-se a hipóxia e hipoxemia, conservando adequadamente a saturação do oxigênio, o enchimento capilar e a frequência cardíaca durante o procedimento.

Uterine artery Doppler and sFlt-1/PlGF ratio: prognostic value in early-onset pre-eclampsia.

OBJECTIVE: To evaluate the performance of the mean uterine artery pulsatility index (UtA-PI) and the automated measurement of the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio for the prognostic assessment of both maternal and perinatal outcomes, and the time-to-delivery interval in early-onset (≤ 34 + 0 weeks) pre-eclampsia (PE) cases with attempted expectant management. METHODS: Fifty-one singleton pregnancies with early-onset PE were enrolled in the study. Mean UtA-PI and sFlt/PlGF ratio were measured at diagnosis. The association of each marker and their combinations with adverse maternal and perinatal outcomes was assessed by univariable comparisons and multivariable logistic regression analysis and time-to-delivery interval by survival analysis. RESULTS: Twenty-six (51%) had adverse maternal outcome and 14 (27%) had adverse perinatal outcome. At the time of onset of PE, only gestational age was significantly related to maternal complications. Gestational age at onset, mean UtA-PI and sFlt-1/PlGF ratio were significantly associated with perinatal complications, their combination reaching a sensitivity of 64% with 95% specificity, and an area under the receiver-operating characteristics curve of 0.89 (95% CI, 0.79-0.99). Regarding the time until delivery, 92% (12/13) of cases with sFlt-1/PlGF ratio > 655 and 39% (15/38) of cases with a ratio ≤ 655 delivered within the first 48 h, 8% (1/13) and 19% (7/38), respectively, delivered between 48 h and 7 days and 0% (0/13) and 42% (16/38), respectively, delivered after 7 days. CONCLUSION: Mean UtA-PI and sFlt-1/PlGF ratio in combination with gestational age are useful for the prognostic assessment of perinatal complications at the time of diagnosis of early-onset PE, but this combination has limited value for the prediction of maternal complications. Moreover, sFlt-1/PlGF ratio > 655 is closely related to the need to deliver within 48 h. [[ArtCopyrightmsg]].

Uterine artery Doppler and sFlt-1/PlGF ratio: usefulness in diagnosis of pre-eclampsia.

OBJECTIVE: To evaluate the usefulness of the mean pulsatility index of the uterine arteries (mPI-UtA) and automated measurement of the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio on suspicion or at diagnosis of pre-eclampsia (PE). METHODS: Patients with singleton pregnancies with PE (n = 60) diagnosed according to current recommendations, or with suspected PE (n = 32) defined by (1) blood pressure (BP) ≥ 160/100 mmHg, (2) BP ≥ 140/90 mmHg or proteinuria, together with suggestive clinical symptoms or (3) intrauterine growth restriction (IUGR) at < 34 + 0 weeks, were enrolled and mPI-UtA and the sFlt-1/PlGF ratio were measured. Values > 95(th) centile were considered abnormal. All cases were classified according to occurrence of PE and/or IUGR and subclassified, depending on gestational age at delivery, as early (< 34 + 0 weeks) or late (≥ 34 + 0 weeks). RESULTS: PE was confirmed in 72 cases, in which 32 early deliveries occurred. Isolated IUGR was diagnosed in nine early cases and one late case, while the remaining 10 cases were late deliveries without PE or IUGR. In pregnancies in which PE and IUGR were excluded, mPI-UtA was abnormal in 40% but the sFlt-1/PlGF ratio was normal in 100%. In early PE, mPI-UtA at diagnosis was abnormal in 100% of cases with IUGR and in 91% without IUGR, while sFlt-1/PlGF was abnormal in 100% and 96%, respectively. In late PE, mPI-UtA was abnormal in 50% and 37% of cases with and without IUGR while the sFlt-1/PlGF ratio was abnormal in 50% and 26%, respectively. CONCLUSION: Abnormal mPI-UtA and sFlt-1/PlGF ratio are common in early PE. In late PE, mPI-UtA is normal in most cases and thus not diagnostically useful. The sFlt-1/PlGF ratio shows high specificity but low sensitivity to confirm PE when suspected.

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity.

Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele)=0.55; 95% confidence interval (CI)=0.34-0.89; P=0.014 and HR (per allele)=0.51; 95%CI=0.30-0.86; and P=0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele)=1.72; 95%CI=1.05-2.82; and P=0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR=1.64 (95% CI=1.26-2.14; P=0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series.

Rationalization of genetic testing in patients with apparently sporadic pheochromocytoma/paraganglioma.

Hereditary susceptibility to pheochromocytoma (PCC) and paraganglioma (PGL) represents a very complex genetic scenario. It has been reported that the absence of familial antecedents of the disease does not preclude the existence of a mutation affecting any of the five major susceptibility genes. In fact, 11-24% of apparently sporadic cases (without familial or syndromic antecedents) harbor an unexpected germline mutation, but we do not know what is happening in "truly apparently" sporadic patients (i.e., apparently sporadic cases diagnosed with only one tumor). In the present study, we have analyzed 135 apparently sporadic patients developing a single tumor for the five major susceptibility genes: VHL, RET, SDHB, SDHC, and SDHD. Fourteen percent of cases were found to harbor a germline mutation, and only 2.2% of patients were older than 45 years at onset. By taking into account the tumor location and a threshold age at onset of 45 years, we propose a rational scheme for genetic testing. Analyzing VHL and RET genes would be recommended only in young patients developing a single PCC. On the other hand, genetic testing of SDHD should be done in all patients developing an extra-adrenal tumor before the age of 45, and SDHC could be the responsible gene in cases developing a single head and neck tumor, independently of age. Finally, the analysis of SDHB should always be performed because of its association to malignancy and the low penetrance of mutations affecting this gene.

Role of uterine artery Doppler in interpreting low PAPP-A values in first-trimester screening for Down syndrome in pregnancies at high risk of impaired placentation.

OBJECTIVES: Low maternal serum levels of pregnancy-associated plasma protein-A (PAPP-A) are associated with both increased risk of aneuploidies and impaired trophoblastic invasion, while high uterine artery (UtA) resistance is associated with impaired trophoblastic invasion but not with an increased risk of aneuploidies. The aim of this study was to determine whether high UtA resistance plays a role in explaining low PAPP-A levels in the absence of aneuploidies. METHODS: This was a prospective study of 116 singleton pregnancies at high risk for impaired placentation (having at least one major risk factor: prior history of pre-eclampsia, pregestational diabetes mellitus, chronic hypertension, chronic kidney disease, body mass index >30, autoimmune disorder, thrombophilia or recurrent pregnancy loss), booked for routine assessment of risk for aneuploidies by means of the first-trimester combined screening test (nuchal translucency thickness (NT) + PAPP-A + beta-human chorionic gonadotropin (beta-hCG)). Measurement of NT and the mean UtA pulsatility index (PI) were carried out at the 11 to 13 + 6-week scan. All values were calculated in multiples of the median (MoM) adjusted for gestational age. A cut-off risk of 1/270 at time of sampling was adopted to differentiate high- from low-risk groups for trisomy 21. RESULTS: There were 108 patients deemed to be at low risk for trisomy 21 and eight at high risk. None had chromosomal defects, giving a false-positive rate for trisomy 21 of 6.9%. The greatest differences between patients at low risk and those at high risk for trisomy 21 were found in their PAPP-A (0.98 vs. 0.38 MoM, P < 0.01) and beta-hCG (1.09 vs. 1.77 MoM, P = 0.04) values. Greater NT thickness (1.02 vs. 0.90 MoM) and higher mean UtA-PI (1.05 vs. 0.96 MoM) were recorded in the high-risk group, although the differences did not reach statistical significance (P = 0.19 and 0.40, respectively). After log-transformation there were no significant correlations between mean UtA-PI and NT and between mean UtA-PI and beta-hCG. There was a significant negative linear correlation between mean UtA-PI and PAPP-A (r = -0.331; P < 0.01). After adjusting the PAPP-A values by UtA-PI, the false-positive rate for trisomy 21 decreased to 2.6%. CONCLUSION: Mean UtA-PI at the 11 to 13 + 6-week scan may be an effect-modifier variable for PAPP-A that should be taken into account in the first-trimester combined screening for aneuploidies, at least in pregnancies at high risk for impaired placentation.

Molecular characterisation of a common SDHB deletion in paraganglioma patients.

BACKGROUND: Hereditary susceptibility to familial paraganglioma syndromes is mainly due to mutations in one of six genes, including three of the four genes encoding the subunits of the mitochondrial succinate dehydrogenase complex II. Although prevalence, penetrance and clinical characteristics of patients carrying point mutations affecting the genes encoding succinate dehydrogenase have been well studied, little is known regarding these clinical features in patients with gross deletions. Recently, we found two unrelated Spanish families carrying the previously reported SDHB exon 1 deletion, and suggested that this chromosomal region could be a hotspot deletion area. METHODS: We present the molecular characterisation of this apparently prevalent mutation in three new families, and discuss whether this recurrent mutation is due either to the presence of a founder effect or to a hotspot. RESULTS: The breakpoint analysis showed that all Iberian Peninsular families described harbour the same exon 1 deletion, and that a different breakpoint junction segregates in an affected French pedigree. CONCLUSIONS: After haplotyping the SDHB region, we concluded that the deletion detected in Iberian Peninsular people is probably due to a founder effect. Regarding the clinical characteristics of patients with this alteration, it seems that the presence of gross deletions rather than point mutations is more likely related to abdominal presentations and younger age at onset. Moreover, we found for the first time a patient with neuroblastoma and a germline SDHB deletion, but it seems that this paediatric neoplasia in a pheochromocytoma family is not a key component of this disease.