Potential angiogenic biomarkers in hereditary hemorrhagic telangiectasia and other vascular diseases.

Biomarkers are new tools framed in precision and personalized medicine. Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic vascular disease with disturbances in the angiogenic pathways. Descriptive evidence supports that some angiogenesis-related molecules are differently detected in HHT patients compared to healthy subjects. These molecules are also related to diagnosis, prognosis, complications and therapy monitoring in other common vascular diseases. Despite the need for improving knowledge before applying them in daily clinical practice, there are good candidates to be considered as potential biomarkers in HHT and other vascular diseases. In the present review, the authors aim to summarize and discuss current evidence regarding the main putative angiogenic biomarkers by describing the biological role of each biomarker, the evidence related to HHT and their potential use in this and other common vascular diseases from a clinical point-of-view.

Translational medicine in hereditary hemorrhagic telangiectasia.

Scientific community have gained lots of new insights in the genetic and biochemical background of different conditions, rare diseases included, settling the basis for preclinical models that are helping to identify new biomarkers and therapeutic targets. Translational Medicine (TM) is an interdisciplinary area of biomedicine with an essential role in bench-to-bedside transition enhancement, generating a circular flow of knowledge transference between research environment and clinical setting, always centered in patient needs. Here, we present different tools used in TM and an overview of what is being done related to hereditary hemorrhagic telangiectasia (HHT), as a disease's model. This work is focused on how this combination of basic and clinical research impacts in HHT patient's daily clinical management and also looking into the future. Further randomized clinical trials with HHT patients should assess the findings of this bench-to-bedside transition. The benefits of this basic and clinical research combination, may not only be important for HHT patients but for patients with other vascular diseases sharing angiogenic disturbances.

Adrenomedullin as a potential biomarker involved in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Adrenomedullin (AM) is a vasoactive peptide mostly secreted by endothelial cells with an important role in preserving endothelial integrity.  The relationship between AM and hereditary hemorrhagic telangiectasia (HHT) is unknown. We aimed to compare the serum levels and tissue expression of AM between HHT patients and controls. METHODS: Serum AM levels were measured by radioimmunoassay and compared between control and HHT groups. AM levels were also compared among HHT subgroups according to clinical characteristics. The single nucleotide polymorphism (SNP) rs4910118 was assessed by restriction analysis and sequencing. AM immunohistochemistry was performed on biopsies of cutaneous telangiectasia from eight HHT patients and on the healthy skin from five patients in the control group. RESULTS: Forty-five HHT patients and 50 healthy controls were included, mean age (SD) was 50.7 (14.9) years and 46.4 (9.9) years (p = 0.102), respectively. HHT patients were mostly female (60% vs 38%, p = 0.032). Median [Q1-Q3] serum AM levels were 68.3 [58.1-80.6] pg/mL in the HHT group and 47.7 [43.2-53.8] pg/mL in controls (p<0.001), with an optimal AM cut-off according to Youden's J statistic of 55.32 pg/mL (J:0.729). Serum AM levels were similar in the HHT subgroups. No patient with HHT had the SNP rs4910118. AM immunoreactivity was found with high intensity in the abnormal blood vessels of HHT biopsies. CONCLUSIONS: We detected higher AM serum levels and tissue expression in patients with HHT than in healthy controls. The role of AM in HHT, and whether AM may constitute a novel biomarker and therapeutic target, needs further investigation.

Two-dimensional visualization and measurement of the fetal optic chiasm: improving counseling for antenatal diagnosis of agenesis of the septum pellucidum.

OBJECTIVE: To develop an objective method for visualizing and measuring the fetal optic chiasm (OC) using transvaginal two-dimensional (2D) ultrasound in the coronal plane and to report measurements in fetuses with agenesis of the septum pellucidum (SP). METHODS: This was a prospective cross-sectional study of 115 morphologically normal fetuses in low-risk pregnancies, between 21 and 30 weeks' gestation. The OC was measured in a coronal plane at the level of the third ventricle and was seen as a horizontally aligned dumbbell-shaped structure of moderate echogenicity. In addition, OC measurements from eight fetuses with agenesis of the SP and complete follow-up were compared with the reference range. RESULTS: OC measurements were obtained in 110/115 normal fetuses and showed that OC increases linearly with gestational age. Our method of measurement demonstrated good intraobserver repeatability and excellent interobserver reproducibility. Among the eight fetuses with agenesis of the SP, five had normal OC measurements and five had normal vision postnatally. Pregnancy continued to term in all cases and the follow-up period varied from 6 months to 7 years. CONCLUSION: Our study demonstrates that it is possible to visualize and measure the OC directly on a 2D ultrasound coronal plane. In fetuses with agenesis of the SP, the morphology and width of the OC visual pathway could prove a relevant tool for assessing its development. It would also help in the difficult task of providing antenatal counseling when faced with the diagnosis of agenesis of the SP. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Anterior and posterior complexes: a step towards improving neurosonographic screening of midline and cortical anomalies.

OBJECTIVE: To describe the anatomical structures that form the anterior (AC) and posterior (PC) complexes of the fetal brain and to categorize their anomalies in fetuses with cerebral abnormalities. METHODS: We analyzed retrospectively volume datasets from 100 normal fetuses between 20 and 30 weeks' gestation. On the axial transventricular plane, our analysis of the AC included the interhemispheric fissure (IHF), the callosal sulcus (CS), the genu of the corpus callosum (CC), the cavum septi pellucidi (CSP) and the anterior horns (AH) of the lateral ventricles. The PC included the splenium of the CC, the medial wall of the lateral ventricles, the CS and the parieto-occipital fissure (POF). We then categorized AC/PC findings in 32 fetuses with agenesis of the septi pellucidi, schizencephaly, callosal dysgenesis, cortical malformation and hypoxic-ischemic brain injury. RESULTS: The structures forming the AC and PC were visible in 100% and 92%, respectively, of normal cases. In the AC, the CSP was square-shaped in 73% of cases and it was triangular in 27%; the AH was comma-shaped in 92% of cases and triangular in the remainder. In the PC, the splenium of the CC interrupted and bridged the midline and was delimited posteriorly by the CS and the IHF. The POF was visible posteriorly. We categorized AC and PC abnormalities according to the main deviation from normality in their anatomical structures. The AC was abnormal in 30/32 cases and the PC was abnormal in 16/32 cases. In the two cases with normal AC, the PC was abnormal. CONCLUSION: Normal appearance of AC and PC seems to be a strong indicator of fetal central nervous system normality. Morphological abnormalities in both complexes are robust markers of midline defects, but not exclusively so. The majority of fetuses with cortical malformations showed a defect in the AC.

The PDGFRß-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors.

PURPOSE: We examined whether PI3K-AKT or extracellular signal-regulated kinase (ERK) signaling pathways could play a role in the development of cisplatin (CDDP) resistance in testicular germ cell tumor (TGT) cells. EXPERIMENTAL DESIGN: We compared AKT and ERK activation levels in CDDP-sensitive testicular tumor cells and in their corresponding CDDP-resistant-derived cells. We also analyzed these pathways in orthotopic testicular tumors and human patient samples. RESULTS: Our results indicated that there was overactivation of AKT in CDDP-resistant cells compared with sensitive cells, but no effect on activated ERK levels. We observed an increase in mRNA and protein levels for platelet-derived growth factor (PDGF) receptor ß and PDGF-B ligand. These were responsible for AKT overactivation in CDDP-resistant cells. When PDGFRß levels were decreased by short hairpin RNA (shRNA) treatment or its activation was blocked by pazopanib, CDDP-resistant cells behaved like sensitive cells. Moreover, CDDP-resistant cells were more sensitive to incubation with PDGFRß inhibitors such as pazopanib or sunitinib than sensitive cells, a finding consistent with these cells being dependent on this signaling pathway. We also found overexpression of PDGFRß and pAKT in CDDP-resistant choriocarcinoma orthotopic tumor versus their CDDP-sensitive counterparts. Finally, we found high PDGFRß levels in human testicular tumors, and overexpression in CDDP-resistant testicular choriocarcinomas compared with the CDDP-sensitive and nontreated tumors. CONCLUSIONS: The PDGFRß-AKT pathway plays a critical role in the development of CDDP resistance in testicular tumoral cells.

ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor.

In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.

Progeny of Lgr5-expressing hair follicle stem cell contributes to papillomavirus-induced tumor development in epidermis.

Epidermal keratinocytes and hair follicle (HF) stem cells (SCs) expressing oncogenes are competent at developing squamous cell carcinomas (SCCs) in epidermis and HFs, respectively. To determine whether bulge and hair germ (HG) SCs from HF contribute to SCC generation at distant epidermis, the most frequent epidermal region where these lesions arise in human skin, we used a skin cancer mouse model expressing E6 and E7 oncoproteins from Human papillomavirus (HPV) 16 in SCs and basal keratinocytes. This previously described mouse model recapitulates the human skin papillomavirus-induced SCC pathology. We show that E6 and E7 expression promote the expansion of keratin 15 (K15)-expressing cells. These K15(+) aberrant cells exhibit some HGSC markers and diminished expression of Tcf3 and Sox9 hair SC specification genes, which are accumulated in HFs and mislocalized to interfollicular epidermis. Leucine-rich G-protein-coupled receptor 5 (Lgr5)-expressing SCs, localized in the bulge and HG, are the origin of the expanded K15(+) cell population. A large subset of the Lgr5(+) SC progeny, expressing K15 and P-cadherin, is aberrantly mobilized to the upper region of HFs and the epidermis, and accumulates at E6/E7-induced pre-neoplastic lesions and epidermal tumors. These findings indicate that aberrant accumulation of altered SCs in HFs and their subsequent migration to the epidermis contribute to HPV-induced tumor development.

Absent mandibular gap in the retronasal triangle view: a clue to the diagnosis of micrognathia in the first trimester.

OBJECTIVE: To describe a new ultrasound technique that may be useful for the diagnosis of micrognathia in the first trimester of pregnancy. METHODS: The retronasal triangle (RNT) view is a technique that captures the coronal plane of the face in which the primary palate and the frontal processes of the maxilla are visualized simultaneously. Normal first-trimester fetuses display a characteristic gap between the right and left body of the mandible in this view (the 'mandibular gap'). The presence or absence of this gap was evaluated and measured prospectively during real-time scanning (n = 154) and retrospectively by analyzing three-dimensional (3D) datasets (n = 50) in normal first-trimester fetuses undergoing screening for aneuploidy at 11-13 weeks' gestation. 3D datasets from 12 fetuses with suspected micrognathia were also collected and examined retrospectively for the same features. RESULTS: The mandibular gap was identified in all 204 normal fetuses and increased linearly with increasing crown-rump length (y = 0.033x + 0.435; R(2) = 0.316), with no statistically significant differences between measurements obtained by two-dimensional ultrasound and 3D offline analysis. Among fetuses with suspected micrognathia, three 3D datasets were excluded from analysis because of poor image quality in one and the diagnosis of a normal chin in two. In the remaining nine fetuses, the mandibular gap was absent and was replaced by a bony structure representing the receding chin in seven (77.8%) cases and was not visualized due to severe retrognathia in the remaining two (22.2%) cases. All fetuses with micrognathia had associated anomalies, including seven with aneuploidy and two with skeletal dysplasia. CONCLUSIONS: The RNT view may be a helpful technique for detecting micrognathia in the first trimester. The absence of the mandibular gap or failure to identify the mandible in this view is highly suggestive of micrognathia and should prompt a targeted ultrasound scan to assess for other anomalies. Further research is needed to determine the false-positive and false-negative rates of this technique.

Fetal optic nerve sheath measurement as a non-invasive tool for assessment of increased intracranial pressure.

OBJECTIVES: To describe the sonographic technique for assessment of the fetal optic nerve sheath and to report on three fetuses with intracranial lesions and enlarged optic nerve sheath diameter (ONSD) compared with normal controls matched for gestational age (GA). METHODS: In this cross-sectional study ONSD was measured sonographically in three fetuses (aged 23, 24 and 35 gestational weeks) with intracranial findings associated with increased intracranial pressure (ICP; dural thrombosis and intracranial tumors) as well as 42 healthy controls matched for GA ± 1 week (aged 22-25 and 34-36 weeks). For fetal eye assessment, transabdominal and transvaginal routes and high-resolution transducers were used for optimal visualization depending on fetal position. Measurements were made using an axial view at the level of the orbits, with the fetal face positioned towards the transducer. The ONSD was measured 1.5 or 2 mm behind the papilla (depending on GA) in all fetuses. Mean ± 2 SD ONSD of controls were calculated for each GA and compared with data from the three fetuses with intracranial pathology. RESULTS: In the 42 normal fetuses, ONSD increased from 1.2 mm at 23 weeks to 2.6 mm at 36 weeks. The measurements at 36 weeks correlated well with those observed in newborns. ONSD measurements of the three cases were above mean + 2 SD of values obtained from healthy controls at the same GA and also exceeded values of fetuses that were 1 week older. CONCLUSIONS: Fetal ONSD measurement is feasible using a technique similar to that used in adults and children. ONSD enlargement was observed in all three fetuses with intracranial lesions and may be an early tool with which to diagnose increased ICP.

Can syndromic macrocephaly be diagnosed in utero?

OBJECTIVES: To compare the outcomes of fetuses with apparently isolated macrocephaly and those with associated findings, and to compare prenatal findings with postnatal diagnoses in children with syndromic macrocephaly. METHODS: We reviewed the files of all patients referred for suspected fetal macrocephaly, during a 10-year period from 2000, to a large prenatal diagnosis unit with expertise in fetal neurology counseling. Macrocephaly was defined as head circumference (HC) > 2 SDs of the norm. Patients with confirmed HC > 2 SD were identified and contacted, and their development was evaluated. RESULTS: Adequate data for analysis were available for 98 patients, in 82 of whom the fetal macrocephaly was considered isolated (Group A), and in 16 of whom associated fetal anomalies were identified (Group B). Macrocephaly was diagnosed earlier in Group B patients (28.4 vs. 32.3 weeks, P = 0.069), and the HC in Group B patients was larger (Z-score 2.95 vs. 2.3, P < 0.001). From Group A there were 81 liveborn; one of whom was diagnosed as having infantile autism. From Group B, there were nine liveborn. The associated central nervous system findings, as demonstrated by ultrasound and magnetic resonance imaging, included mild ventriculomegaly, malformations of cortical development, callosal abnormalities, overdeveloped sulcation, large cavum septi pellucidi, large subarachnoid spaces, mega cisterna magna, periventricular pseudocyst, open operculum and vermian dysgenesis. Syndromic diagnosis was made in utero in five fetuses and after birth in three. In eight patients, associated malformations were confirmed after birth but a specific diagnosis was not reached. CONCLUSIONS: When fetal macrocephaly is associated with other brain or systemic anomalies, syndromic macrocephaly can be diagnosed in utero. Fetuses with syndromic macrocephaly have a significantly larger HC, usually > 2.5 SD above the mean. Isolated macrocephaly, particularly when the HC is < 2.5 SD above the norm, may be clinically benign.

Recent advances in cancer therapy: an overview.

The landscape of cancer treatment has dramatically changed over the last four decades. The age when surgery and radiotherapy were the only effective way to fight tumour growth has ended. A complex scenario where the molecular features of tumours seem to be the cornerstone of any therapy is now emerging. Here we provide an overview on the different approaches to cancer treatment. This review will help the reader to acknowledge the pivotal role of some classic cancer therapies, including surgery, radiation, chemotherapy and endocrine therapy, now better understood in the mechanims underpinning their efficacy. Following, we focus on the understanding of the value of systemic treatment and on an up-date on the novel, up-coming therapies of the current targeted therapy age, including new antibodies, small molecules, antiangiogenics and viral therapy. We briefly elaborate, finally, on new biomarkers development and how it should rule and determine the future of therapeutic research in cancer.

Fetal echocardiography at 11 + 0 to 13 + 6 weeks using four-dimensional spatiotemporal image correlation telemedicine via an Internet link: a pilot study.

OBJECTIVES: To assess whether spatiotemporal image correlation (STIC) volumes from fetuses at 11 + 0 to 13 + 6 weeks' gestation can be obtained by a non-expert and whether fetal echocardiography can be performed via a telemedicine link, providing a remote and reproducible diagnosis of the fetal heart condition. METHODS: STIC volume datasets from 35 fetuses at 11 + 0 to 13 + 6 weeks were obtained prospectively by a general obstetrician, transmitted via the Internet and subsequently analyzed systematically by two different reviewers. Forty-nine pregnancies were initially enrolled into the study, but adequate volumes were not obtained for 14. Thirty-four datasets were obtained on transabdominal and one on transvaginal ultrasound examination. A checklist was used that included 18 structures and views relating to the fetal heart evaluation, and each reviewer assigned the variables as normal, abnormal or unsure. Cohen's kappa analysis was used to evaluate the agreement between reviewers and the reported findings were compared with the outcome where available. RESULTS: The mean gestational age was 12 + 3 weeks and the mean (range) crown-rump length was 68 (47-84) mm. The mean maternal age was 33 (range, 26-41) years; 12/35 (34%) were older than 35 years. The four-chamber view obtained was apical in 22/35 (63%) cases and lateral in 13 (37%). Volume datasets were obtained after 12 weeks' gestation in 30/35 fetuses. Three cases had nuchal translucency thickness above the 99(th) percentile, and two of these had an abnormal heart. Five cases had abnormal outcomes. A mean of 3 (range, 1-6) STIC datasets per patient were acquired. The kappa index obtained confirmed interobserver reliability, with good or very good concordance (kappa > 0.6) in 14/18 structures and views related to the heart. CONCLUSIONS: STIC volumes acquired between 11 + 0 and 13 + 6 weeks' gestation could be sent over the Internet and their analysis enabled recognition of most of the structures and views necessary to assess the small fetal cardiac anatomy, with a high degree of interobserver concordance.

Transfrontal three-dimensional visualization of midline cerebral structures.

OBJECTIVE: To compare sonographic visualization of midline cerebral structures obtained by two-dimensional (2D) imaging and three-dimensional (3D) multiplanar and volume contrast imaging in the coronal plane (VCI-C), with transfrontal 3D acquisition. METHODS: Sixty consecutive healthy fetuses in vertex presentation at a mean gestational age of 24 (range, 20-33) weeks underwent 2D and 3D ultrasound examination. Sagittal cerebral planes were reconstructed using 3D acquisition from axial planes by multiplanar analysis and by VCI-C. The reconstructed midline images of both these techniques were compared with the midline structures visualized directly in the A-plane by transfrontal 3D acquisition using a sweep angle of 30 degrees . Measurement of the corpus callosum and cerebellar vermis and visualization of the fourth ventricle and the main vermian fissures were compared. The sharpness of the images was also assessed qualitatively. Mid-sagittal tomographic ultrasound imaging (TUI) was also performed. 3D planes were compared with 2D transfontanelle median planes obtained by transabdominal or, when required, transvaginal sonography. RESULTS: The midline plane could be obtained in 88% of multiplanar, 82% of VCI-C and 87% of transfrontal analyses. Measurements of the corpus callosum and cerebellar vermis obtained by 3D median planes were highly correlated. The clearest and sharpest definition of midline structures was obtained with transfrontal acquisition. Primary and secondary fissures of the cerebellar vermis could be detected in 13-26% of multiplanar, 18-35% of VCI-C and 52-79% of transfrontal analyses. 2D visualization was superior or equal to the 3D transfrontal approach in all the parameters compared. CONCLUSION: 3D planes obtained from axial acquisitions are simpler and easier to display than are transfrontal ones. However, artifacts and acoustic shadowing are frequent in 3D axial acquisition and spatial resolution is better in the direct visualization transfrontal technique. If the standard examination includes a view of the fetal facial profile, a quick 3D acquisition through the frontal sutures provides direct visualization for assessment of the midline structures. We believe that this volumetric methodology could represent a step towards incorporating a comprehensive fetal neuroscan into routine targeted organ evaluation.

Metronomic chemotherapy: an antiangiogenic scheduling.

Conventional cytotoxic anticancer chemotherapeutic drugs were developed with the intent of treating cancer by direct killing or inhibition of growth of cycling tumour cells. Recently, however, there has been considerable interest in the notion of exploiting such drugs as angiogenesis inhibitors. The rationale is based on the fact that virtually all classes of cancer chemotherapeutic drugs are designed to damage DNA or disrupt microtubules of dividing cells, and endothelial cell division takes place during new blood vessel formation, including tumour angiogenesis. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses, known as "metronomic chemotherapy", increases the putative antiangiogenic activity of certain drugs. Metronomic chemotherapy refers to the chronic administration of comparatively low doses of cytotoxic drugs at close, regular intervals, with no prolonged drug-free interruptions. The advantage of this strategy is lower toxicity and risk of emergence of drug-resistant tumour cells than conventional administration. This review describes the possible antiangiogenesis basis of this therapeutic strategy, the experimental studies published and the recent clinical studies that explore this less toxic schedule.

Simple approach to prenatal diagnosis of transposition of the great arteries.

OBJECTIVE: To analyze the most relevant anomalies, seen in a sequential segmental transverse views approach to imaging the fetal heart, that provide clues to the diagnosis of complete transposition of the great arteries (TGA). METHODS: We reviewed retrospectively all the cases of isolated TGA diagnosed in our center or submitted for a second opinion through the spatio-temporal image correlation (STIC) telemedicine (TELE-STIC) program. Only transverse cardiac sweeps were obtained. Digital video clips and STIC volumes were reviewed. The abnormal features on four-chamber, five-chamber, three-vessel (3V) and three vessels and trachea (3VT) views were analyzed. RESULTS: The study population consisted of eight fetuses with TGA with normal extracardiac anatomy. The gestational age ranged from 13 to 32 (mean, 23) weeks. The maternal age ranged from 25 to 42 (mean, 32) years. A normal four-chamber view was seen in seven cases. Only one case demonstrated a significant ventricular septal defect. At the level of the five-chamber view a straight course arterial vessel arose from the left ventricle with lateral branches in all fetuses. In the 3V view, the ascending aorta was seen reaching more anteriorly than was the pulmonary artery in six cases. At the level of the 3VT view, two vessels (transverse aortic arch and superior vena cava) rather than three were seen in all cases. CONCLUSION: Our proposed sequential segmental approach to imaging the fetal heart apparently allows, in five-chamber and 3VT views, clear and confident signs to be detected that aid diagnosis of TGA.

Fetal atrioventricular valve junction in normal fetuses and in fetuses with complete atrioventricular septal defect assessed by 4D volume rendering.

OBJECTIVES: To assess the feasibility and clinical potential of 4D volume rendering of the atrioventricular (AV) valve junction, to standardize the acquisition method, and to display the AV valve junction morphology in normal fetuses and in those with a complete atrioventricular septal defect (AVSD). METHODS: We performed sonography in 40 normal fetuses and 10 fetuses with complete AVSD, and volume datasets were acquired from apical and lateral four-chamber views. The render box was placed systematically. First, it included the AV valves, with the reference dot at the level of the crux of the heart. Then, it included the papillary muscles, with the reference dot in the interventricular septum at the level of the distal opening of the tricuspid valve leaflet. RESULTS: Volume acquisition and rendering were technically possible in all cases. Volume rendering of the left ventricle showed the position of the anterolateral and posteromedial papillary muscles in 36/40 normal fetuses (90%). At the level of the right ventricle, the septal, anterior and posterior papillary muscles were visualized in 33/40 normal fetuses (82%). In cases of complete AVSD, the AV valve has five leaflets, with anterosuperior and posteroinferior bridging leaflets straddling the septa. The morphology of the anterosuperior bridging leaflets and the abnormal position of the papillary muscles could be displayed in all cases. CONCLUSIONS: Our study suggests that some of the components of the AV junction can be reconstructed easily from sonographic volumes acquired from an apical or lateral four-chamber view. This new technique may have a role in obtaining views that are not easily accessible by standard sonography, enabling a rapid complementary assessment of normal and abnormal intracardiac anatomy.

The fetal cerebellar vermis: anatomy and biometric assessment using volume contrast imaging in the C-plane (VCI-C).

OBJECTIVES: To describe the normal appearance and study the biometry of the fetal cerebellar vermis by three-dimensional (3D) volume contrast imaging in the coronal (C-) plane (VCI-C). METHODS: A total of 203 normally developed fetuses were examined prospectively at 18-33 weeks' gestation. At the level of the view used to measure the transverse cerebellar diameter (TCD), a VCI-C plane was displayed to examine, using a transabdominal probe, the fetal mid-saggital vermis. The volumes acquired were stored for later review and measurement of the anteroposterior (AP) diameter, craniocaudal (CC) diameter and surface area of the cerebellar vermis. Each dataset was evaluated by two independent observers. Measurements as a function of gestational age (GA), biparietal diameter (BPD), head circumference (HC) and TCD were expressed by regression equations. Interobserver variability was evaluated. Nomograms were produced. In order to validate the use of VCI in fetal biometry, datasets from 57 patients were selected arbitrarily for comparison of their VCI-C measurements with those from mid-sagittal sections of a stored 3D multiplanar examination. Intraclass correlation was used to evaluate the agreement between these measurements. RESULTS: The mean maternal age was 32 years. We were able to measure mid-sagittal CC diameter, mid-sagittal AP diameter and cerebellar vermis surface area in all fetuses. Interobserver variability analysis showed no significant differences between the two observers (P > 0.05). Measurements of the cerebellar vermis (AP diameter, CC diameter and surface area) correlated linearly with GA, BPD, HC and TCD (r > or = 0.82, P < 0.0001). CC and AP diameters estimated from the mid-sagittal section of the multiplanar measurements were significantly correlated with VCI-C measurements (r = 0.96, P < 0.00001 and r = 0.95, P < 0.00001, respectively). CONCLUSIONS: VCI-C is a valuable tool, allowing intrauterine assessment of the normal appearance of the fetal cerebellar vermis. The nomograms developed in this study should enable accurate evaluation of the cerebellar vermis.

Prenatal diagnosis of congenital heart disease using four-dimensional spatio-temporal image correlation (STIC) telemedicine via an Internet link: a pilot study.

OBJECTIVE: To assess whether the spatio-temporal image correlation (STIC) acquisition technique can be taught to a general obstetrician by e-mail; whether STIC volume datasets can be transmitted over the Internet; and whether STIC volume datasets analyzed offline at a remote setting can be used to confirm or exclude major cardiac defects (TELE-STIC). METHODS: This was a prospective study involving 50 pregnant women with gestational ages ranging between 20 and 36 weeks. These patients were selected by two general obstetricians (operators) working in geographically remote areas of Chile. Although both obstetricians were users of equipment capable of four-dimensional (4D) ultrasound with STIC, they lacked skill in the performance of fetal cardiac examination. A dedicated web disk was created to upload the acquired volume datasets using an Internet broadband connection. Offline analysis was performed by a single investigator experienced in fetal echocardiography (the administrator). RESULTS: A telemedicine link via the Internet was possible in all cases. Seventy-seven volume datasets were sent to the web server. A complete cardiac examination according to set criteria was achieved by the administrator in 86% of the cases scanned by one operator and 95% of the cases scanned by the other operator. Three patients had cardiac defects confirmed postnatally, two fetuses had extracardiac anomalies and one fetus had a suspected cardiac defect unconfirmed by second-opinion TELE-STIC. There were two isolated major congenital heart defects. Both patients were given advice by e-mail and teleconference using a web camera about the likely outcome and benefits of scheduling in utero transport to a tertiary care center. CONCLUSIONS: STIC volumes can be obtained by operators inexperienced in fetal echocardiography, transmitted via the Internet, and their analysis enables recognition of most of the structures and views necessary to assess fetal cardiac anatomy. The preliminary use of TELE-STIC allowed us to demonstrate that some intracardiac anomalies can be ruled out and others confirmed, allowing perinatal management to be tailored accordingly.