A Novel System for Precise Grading of Glioma.

Gliomas are the most common type of primary brain tumors and one of the highest causes of mortality worldwide. Accurate grading of gliomas is of immense importance to administer proper treatment plans. In this paper, we develop a comprehensive non-invasive multimodal magnetic resonance (MR)-based computer-aided diagnostic (CAD) system to precisely differentiate between different grades of gliomas (Grades: I, II, III, and IV). A total of 99 patients with gliomas (M = 49, F = 50, age range = 1-79 years) were included after providing their informed consent to participate in this study. The proposed imaging-based glioma grading (GG-CAD) system utilizes three different MR imaging modalities, namely; contrast-enhanced T1-MR, T2-MR known as fluid-attenuated inversion-recovery (FLAIR), and diffusion-weighted (DW-MR) to extract the following imaging features: (i) morphological features based on constructing the histogram of oriented gradients (HOG) and estimating the glioma volume, (ii) first and second orders textural features by constructing histogram, gray-level run length matrix (GLRLM), and gray-level co-occurrence matrix (GLCM), (iii) functional features by estimating voxel-wise apparent diffusion coefficients (ADC) and contrast-enhancement slope. These features are then integrated together and processed using a Gini impurity-based selection approach to find the optimal set of significant features. The reduced significant features are then fed to a multi-layer perceptron artificial neural networks (MLP-ANN) classification model to obtain the final diagnosis of a glioma tumor as Grade I, II, III, or IV. The GG-CAD system was evaluated on the enrolled 99 gliomas (Grade I = 13, Grade II = 22, Grade III = 22, and Grade IV = 42) using a leave-one-subject-out (LOSO) and k-fold stratified (with k = 5 and 10) cross-validation approach. The GG-CAD achieved 0.96 ± 0.02 quadratic-weighted Cohen's kappa and 95.8% ± 1.9% overall diagnostic accuracy at LOSO and an outstanding diagnostic performance at k = 10 and 5. Alternative classifiers, including RFs and SVMlin produced inferior results compared to the proposed MLP-ANN GG-CAD system. These findings demonstrate the feasibility of the proposed CAD system as a novel tool to objectively characterize gliomas using the comprehensive extracted and selected imaging features. The developed GG-CAD system holds promise to be used as a non-invasive diagnostic tool for Precise Grading of Glioma.

Non invasive prenatal testing (NIPT) for common aneuploidies and beyond.

Non invasive prenatal Testing (NIPT) is changing the practice of prenatal diagnosis worldwide. It provides high sensitivity and specificity in screening for common aneuploidies. As a result, it has reduced the number of invasive procedures, thereby reducing their associated risk of pregnancy miscarriage. NIPT is based on the detection and analysis of cell free fetal DNA (cffDNA) that is obtained from a maternal peripheral blood sample. Advanced laboratory detection and purification technology has improved the performance of NIPT and allowed the introduction of new applications in recent years. The introduction of Next Generation Sequencing (NGS) into clinical practice has rendered NIPT to have high sensitivity in the screening of aneuploidy. It has also allowed detecting and investigating the fetal genome from maternal plasma. Fetal Whole Exome Sequencing (WES) provides non invasive prenatal diagnosis of inherited monogenic disorders and can also offer a diagnosis of an underlying cause of fetal anomalies that have a normal karyotype. The following will review the current and potential future applications of NIPT and discuss the advantages and disadvantages of the various NIPT techniques. The role of public healthcare system plays in the provision of the test, and the psychological impact of NIPT on the end-users will also be highlighted.

Implications of non-invasive prenatal testing for identifying and managing high-risk pregnancies.

Non-invasive prenatal testing is regularly used to screen for aneuploidies and Rhesus status of a fetus. Since 1997 when free fetal DNA (ffDNA) in the maternal circulation was first identified, it has been hypothesized that it may be possible to use non-invasive prenatal testing (NIPT) to identify high-risk pregnancies including pre-eclampsia, growth restriction and preterm birth. Since then there has been much interest in this area as a way to identify and understand disease processes. This review presents the current evidence for this approach. For pre-eclampsia the hypothesis is that ffDNA would increase but the evidence for this is heterogenous across studies and trimesters. There is however increasing agreement between studies that by the third trimester ffDNA is more likely to be raised in pre-eclamptic patients than controls. For preterm birth, again, the main hypothesis is that ffDNA should increase. The results are also heterogenous, with some studies finding increased ffDNA prior to preterm birth, and others finding no change. For fetal growth restriction, there are competing theories for reduced and increased ffDNA and some studies suggest that levels are raised and some reduced. There are complexities in interpreting all of this evidence as the studies' designs, patient populations, and especially in the context of growth restriction, the definitions are not clear. Furthermore, authors use different biochemical tests and different units to describe their results, making meta-analysis difficult. All of these issues and conflicting findings lead us to the conclusion that currently there is yet no definitive place in clinical practice for NIPT to support the diagnosis and management of high-risk pregnancies. However, it is vital that this research continues as it could open the door to better understanding of the disease process and novel approaches to management.

Neonatal outcomes of pregnancies affected by haemolytic disease of the foetus and newborn and managed with intrauterine transfusion: a service evaluation.

BACKGROUND: This study, conducted in the tertiary Foetal Medicine Unit at St Michael's Hospital, Bristol, was designed to obtain information regarding neonatal outcomes of pregnancies affected by haemolytic disease of the foetus and newborn and managed by intrauterine transfusion, and to determine whether a change in intrauterine transfusion protocol in 2004 had improved safety. The new protocol included attendance of two Foetal Medicine Unit consultants, foetal sedation and use of the intrahepatic vein as an alternative route to placental cord insertion if deemed safer. MATERIALS AND METHODS: Data for pregnancies affected by haemolytic disease of the foetus and newborn as a result of haemolytic red cell alloimmunisation and managed with intrauterine transfusion at St Michael's Hospital between 1999 and 2009 were retrospectively collected using local databases, and medical note review. RESULTS: Overall, 256 relevant intrauterine transfusions were performed. The median number of intrauterine transfusions per pregnancy was two. Ninety-three per cent of the live deliveries had 5-minute APGAR scores ≥9 and 98% were admitted to a Neonatal Intensive Care Unit/Special Care Baby Unit, requiring phototherapy (96%), top-up transfusions (44%: 23.2% immediate, 13.4% late, 7.3% both), and exchange transfusion (37%). An association was found between increased intrauterine transfusion number and reduced phototherapy duration and hospital admission: each additional intrauterine transfusion reduced the duration of phototherapy by 16% (95% CI: 0.72-0.98), and Neonatal Intensive Care Unit/Special Care Baby Unit admission by 44% (95% CI: 0.48-0.66). Following the change in intrauterine transfusion protocol, there was a significant reduction in the number of emergency Caesarean sections occurring directly after an intrauterine transfusion (n =5 vs 0; P =0.02). The foetal loss rate within 48 hours of an intrauterine transfusion was 1.9% per pregnancy, or 0.8% per intrauterine transfusion: no losses occurred under the new protocol (n =3 vs 0; P = NS). DISCUSSION: Although the majority of neonates required admission to a Neonatal Intensive Care Unit/Special Care Baby Unit and phototherapy, the medium-term outcomes were positive. Importantly, the safety of the intrauterine transfusion procedure has improved significantly since the change in protocol.

Quantification of cell free fetal DNA in maternal plasma in normal pregnancies and in pregnancies with placental dysfunction.

OBJECTIVE: To assess the normal levels of free fetal DNA in maternal plasma through pregnancy compared with those in pregnancies complicated with placental dysfunction manifested by preeclampsia and/or fetal growth restriction. STUDY DESIGN: Maternal blood samples from 138 singleton male pregnancies were divided into 3 groups; normal pregnancies (77), preeclampsia (49), and fetal growth restriction (12). Royston and Wright's methods were used to calculate gestational age-related reference limits of free fetal DNA in the 3 groups. The DYS14 gene of the Y chromosome was quantified and compared in maternal plasma by using real-time quantitative polymerase chain reaction. RESULTS: Free fetal DNA in normal pregnancies increased with gestational age. Results were significantly higher in preeclampsia and fetal growth restriction groups than in normal pregnancy and were higher in severe preeclampsia than in milder disease. CONCLUSION: Free fetal DNA is a potential marker for placental dysfunction in pregnancy. Large prospective studies are now needed to investigate its role in the prediction of pregnancy complications and severity and or timing of delivery.

Maternal serum transformed alpha-fetoprotein levels in women with intrauterine growth retardation.

OBJECTIVE: To evaluate maternal serum transformed alpha-fetoprotein (t-AFP) levels in women with intrauterine growth retardation (IUGR). METHODS: 60 pregnant women in two groups were studied: 30 with IUGR and 30 healthy pregnant women as a control group. t-AFP concentrations were determined by ELISA assay. RESULTS: Maternal serum t-AFP levels were higher in women with IUGR than in the control group: 15.39 (10.81-24.01) ng/ml vs. 8.66 (6.22-13.45) ng/ml (p = 0.003). t-AFP levels were even higher in those with fetal hemodynamic redistribution 21.08 (16.02-40.85) ng/ml than in those without 12.15 (10.48-17.45) ng/ml (p = 0.03). CONCLUSIONS: Maternal serum t-AFP is increased in women with IUGR and this elevation is marked in those with fetal hemodynamic redistribution.

Maternal serum alpha-fetoprotein, fetal middle cerebral artery blood flow velocity and fetal haemoglobin in pregnancies at risk of fetal anaemia.

OBJECTIVES: To evaluate the relationships between maternal serum alpha-fetoprotein (MSAFP) levels and both middle cerebral artery (MCA) peak systolic velocity and fetal haemoglobin in women at risk of fetal anaemia. METHODS: Forty-one measurements of MSAFP were carried out in 22 women at risk of fetal anaemia (16 alloimmunised patients and 6 cases of parvovirus infection) who were monitored by using MCA Doppler measurements. The relationships between MSAFP (MoM) and both MCA peak systolic velocity (z-scores) and fetal haemoglobin (MoM) were studied. RESULTS: There were significant correlations between MSAFP and both MCA Doppler measurements (r = 0.56, p = 0.00017) and fetal haemoglobin (n = 13, r = -0.71, p = 0.006). MSAFP was higher in cases with fetal anaemia (n = 10) than in those with normal haemoglobin levels (n = 3) (1.7 +/- 0.4 vs 0.8 +/- 0.1 MoM; p = 0.006). In cases of alloimmunised pregnancies with fetal anaemia, MSAFP elevations preceded the presence of increased MCA Doppler velocity by 2.7 weeks (range 0-9 weeks). CONCLUSION: MSAFP is significantly correlated with both MCA Doppler measurements and fetal haemoglobin. Elevations of MSAFP may appear earlier than MCA Doppler abnormalities in cases of fetal anaemia associated with red blood cell alloimmunisation.

Optimal interval between middle cerebral artery velocity measurements when monitoring pregnancies complicated by red cell alloimmunization.

OBJECTIVE: To evaluate the optimal interval between middle cerebral artery (MCA) Doppler measurements when monitoring pregnancies complicated by red cell alloimmunization. METHODS: Thirty-nine fetal blood samplings (FBS) performed on 24 pregnant women with red blood cell alloimmunization followed up using both MCA peak systolic velocity and time-averaged mean velocity measurements on weekly basis. RESULTS: In total, 65.5 and 37.5% of women with moderate or severe fetal anemia had abnormal MCA Doppler values 1 and 2 weeks, respectively, before FBS was performed. CONCLUSIONS: A weekly assessment of women at risk for fetal anemia is optimal in most of the cases even though 35.5% of cases of moderate or severe fetal anemia are expected to have normal Doppler measurements the week before the decision of doing an FBS is made.

TORCH test for fetal medicine indications: only CMV is necessary in the United Kingdom.

OBJECTIVES: To review the indications and value of TORCH testing (toxoplasma, rubella, cytomegalovirus, herpes) for fetal medicine reasons. METHODS: Analysis of all maternal and fetal TORCH tests requested from a busy Fetal Medicine Unit during nearly a 10-year period. The main ultrasound findings considered as possibly caused by congenital fetal infections were analysed. Pregnancy outcomes for cases with confirmed maternal or fetal infections were studied. RESULTS: Four hundred and sixty-two maternal TORCH tests were performed. Of those, TORCH tests were also performed on fetal samples (amniotic fluid or fetal blood) in 67 cases. Fourteen fetal tests without maternal testing were identified, making the total number of patients tested 476. There were 11 cases of maternal CMV infection (2.3%), 10 cases of fetal CMV infection, and none of the other viruses. Indications for testing included fetal hyperechogenic bowel, hydrops, cerebral ventriculomegaly, echogenic foci, oligohydramnios, polyhydramnios, and IUGR. The most common findings to be actually associated with fetal infections were hyperechogenic bowel, ascites, cardiomegaly, and oligohydramnios. No cases were associated with polyhydramnious, while both IUGR and ventriculomegaly were always associated with other more relevant features. CONCLUSION: In the United Kingdom, complete maternal TORCH testing because of fetal findings on detailed scans is often not necessary. Testing can be limited only to CMV, particularly since other infectious agents, including toxoplasmosis, are uncommon in the United Kingdom. More understanding of the relevance of the different ultrasound features to congenital infections is also important.

Reassuring fetal middle cerebral artery doppler velocimetry in alloimmunised pregnancies: neonatal outcomes without invasive procedures.

OBJECTIVE: To assess the neonatal outcome in red blood cell alloimmunised pregnancies at increased risk of fetal anaemia where invasive testing was avoided based on reassuring middle cerebral artery (MCA) Doppler velocity results. METHODS: We included 28 alloimmunised pregnant women at significant risk of fetal or neonatal anaemia who did not have invasive testing because of reassuring MCA Doppler velocimetry. Women requiring invasive testing or intrauterine transfusion were excluded. Outcome measures were admission to neonatal intensive care unit, cord haemoglobin and bilirubin levels and neonatal therapy. RESULTS: Ten neonates (36%) were anaemic at birth while 18 (64%) had normal haemoglobin. Seven neonates (25%) did not require any form of neonatal therapy, 10 (36%) had phototherapy only, 7 (25%) required exchange transfusions and 4 (14%) top-up transfusions. There were no treatment-related complications. Mean cord haemoglobin was 13.9 g/dl (range 7-18.9) and mean bilirubin was 84.1 micromol/l (range 29-192). CONCLUSION: Avoiding invasive procedures in pregnancies at risk of fetal anaemia by relying on reassuring MCA Doppler velocimetry did not result in life-threatening fetal or neonatal morbidities. The extent of neonatal therapy was acceptable. The routine use of this test can lead to less unnecessary invasive procedures in at-risk fetuses.

Safety of fetal blood sampling by cordocentesis in fetuses with single umbilical arteries.

OBJECTIVES: To examine the safety of cordocentesis in fetuses with single umbilical arteries. METHODS: Retrospective analysis of all cases of cordocenteses in fetuses with single umbilical arteries over a five-year period at one centre. We analysed the records for pregnancy details, outcomes, and procedure-related complications, and compared these to similar data for cordocenteses procedures performed, during the same period, for similar indications in fetuses with three-vessel cords. RESULTS: Twenty-nine eligible cases were identified. All procedures were performed for the indication of fetal structural abnormalities, and seven fetuses (24%) had abnormal karyotypes. The median gestational age at the time of the procedure was 21 weeks (range 19-34 weeks). There were no procedure-related fetal losses but the umbilical artery was inadvertently punctured in one case, resulting in prolonged bradycardia with spontaneous recovery. These outcomes compare favourably to those of a total of 134 cordocenteses procedures in fetuses with three-vessel cords. CONCLUSION: Cordocentesis in cases with single umbilical arteries does not appear to carry more risk than in cases with three-vessel cord, and should continue to be performed by adequately trained specialists when indicated. Extra care should be undertaken to avoid puncturing the umbilical artery.

Prediction of chorionicity in twin pregnancies at 10-14 weeks of gestation.

OBJECTIVE: To examine the accuracy of sonographic determination of chorionicity in twin pregnancies at 10-14 weeks of gestation. DESIGN: Prospective study on the sonographic prediction of chorionicity at 10-14 weeks of gestation. PARTICIPANTS: During a 30 month period, from October 1997 to May 2000, 165 women attending the departments of fetal medicine or ultrasound. METHODS: Sonographic criteria used in the diagnosis of chorionicity were the number of placental sites, the lambda (lambda) and T signs and the thickness of the inter-twin membrane. The diagnosis of chorionicity was made at the time of the ultrasound examination using all these features and subsequently compared with the postnatal diagnosis, confirmed either by placental histology or discordancy in infant sex. RESULTS: In 150 cases with confirmation of chorionicity following delivery, 116 were postnatally classified as dichorionic and 34 monochorionic. Prenatal ultrasound examination correctly identified chorionicity in 149 (99.3%) cases. The most reliable indicator for dichorionicity was a combination using the lambda sign or two separate placentae with a sensitivity and specificity of 97.4% and 100%, respectively. The most useful test in predicting monochorionicity was the T sign with a sensitivity of 100% and specificity of 98.2%. Measurement of the inter-twin membrane thickness was a less reliable indicator where the sensitivity for dichorionicity and specificity for monochorionicity was only 92.6%. CONCLUSIONS: Ultrasound examination of twin pregnancies at 10-14 weeks of gestation predicts chorionicity with a high degree of accuracy using a combination of the number of placentae, lambda and T signs and inter-twin membrane thickness. All hospitals should encourage departments providing ultrasound services to undertake chorionicity determination when examining women with twin pregnancies at this gestation.