Pharmacokinetic and safety study of subcutaneously administered weekly ING-1, a human engineere monoclonal antibody targeting human EpCAM, in patients with advanced solid tumors.

BACKGROUND: ING-1 is a high-affinity, human engineeredtrade mark monoclonal antibody that recognizes a 40 kilodalton epithelial cell adhesion molecule (EpCAM) glycoprotein that is expressed in high levels on most adenocarcinomas and is an attractive target for immunotherapy. METHODS: ING-1 was administered subcutaneously weekly at doses between 0.1 and 2 mg/kg/week. Pharmacokinetic samples were drawn during weeks 1 and 6. RESULTS: Fourteen patients with advanced refractory cancer received a median of 6 (range 1-9) doses of ING-1. At 1 mg/kg, a 62-year-old man with colon cancer developed reversible grade 3 pancreatitis after the third dose. His plasma ING-1 levels were similar to the other two patients dosed at 1 mg/kg. Two patients dosed at 0.6 mg/kg experienced stable disease at 6 weeks. Peak drug levels increased with dose and time, suggesting drug accumulation with repeated dosing. Low human anti-human antibody response was noted in three of the 13 patients assessed and was directed towards the variable region of ING-1. CONCLUSIONS: Weekly ING-1 administered subcutaneously was well tolerated at 0.6 mg/kg/week and further experience at this dose is warranted to demonstrate safety. The risk of pancreatitis and the marginal anti-tumor effect may preclude further monotherapy studies; however, combination studies with chemotherapy are warranted.

Vascular endothelial growth factor but not placental growth factor promotes trophoblast syncytialization in vitro.

OBJECTIVE: The object of this study was to determine the effect of epithelial growth factor (EGF), vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) on the differentiation of first-trimester and term cytotrophoblasts. METHODS: The first-trimester trophoblasts were isolated from villous tissue obtained at suction termination (n = 5), and the term trophoblasts were isolated from placentas (n = 6) at elective cesarean. Cultured cells were stimulated with EGF, VEGF, or PlGF at 0.5, 5, and 50 ng/mL, in the presence or absence of N(G)-nitro-L-arginine methyl ester hydrochloride (10(-4) M). Syncytialized trophoblasts were identified by immunostaining with antidesmosomal protein and anti-cytokeratin-7, whereas nuclei were counted in each syncytia using hematoxylin. RESULTS: Without treatment, background levels of syncytialization were significantly higher in term preparations than first-trimester cells. With VEGF and EGF, the number and size of syncytia increased significantly for the first-trimester cytotrophoblasts (P <.05). Neither VEGF nor EGF had any effect on the syncytialization of cultured cells at term. Nitric oxide showed no involvement in syncytial induction, and PlGF had no effect on syncytialization of cytotrophoblasts, from either the first or third trimester. CONCLUSION: Both EGF and VEGF appeared to enhance the in vitro syncytialization of first trimester cytotrophoblasts.

Computerised analysis of the fetal heart rate and relation to acidaemia at delivery.

OBJECTIVE: To identify the individual features of the computerised analysis of the cardiotocograph that relate to arterial pH and base deficit at delivery. DESIGN: Retrospective observational study. SETTING: Teaching hospital labour wards. PARTICIPANTS: 679 women requiring continuous intrapartum fetal monitoring. METHODS: Fetal heart and uterine contraction data were obtained using the Nottingham Fetal ECG monitor. Fetal heart rate patterns for the last half-hour preceding delivery were analysed using a computer algorithm developed for intrapartum application. The significance of the areas under receiver operator characteristic curves were calculated. MAIN OUTCOME MEASURES: Umbilical arterial pH and base deficit at delivery. RESULTS: Three parameters, fetal bradycardia, total deceleration area and the deceleration area after a contraction had receiver operator characteristic curves that significantly predict a low umbilical arterial pH and base deficit at delivery (areas under receiver-operator characteristic curves = 0.53, SD 0.01 P = 0.03; 0.60, SD 0.03 P = 0.002; 0.62 SD 0.04 P < 0.001, respectively). Tachycardia, accelerations and variability did not. CONCLUSIONS: The individual components of the computerised analysis of the fetal heart rate that predict acidaemia at delivery are identified.

In utero perfusing fraction maps in normal and growth restricted pregnancy measured using IVIM echo-planar MRI.

The aim of this study was to measure and portray blood movement in the placenta in vivo in normal and growth restricted pregnancies, using Intra Voxel Incoherent Motion (IVIM) magnetic resonance imaging. Thirteen patients with apparently normal healthy pregnancies were scanned at 31+/-7 (mean+/-s.d.) weeks gestation and seven patients with intrauterine growth restriction (IUGR) were scanned at 31+/-4 weeks. A region of interest (ROI) was defined encompassing the placenta between the decidual and chorionic plates. The volume of moving blood within each imaging voxel of the ROI was then calculated as a percentage of the total voxel volume (f per cent). This information was colour coded to produce maps of moving blood volume. The placenta was segmented length ways into two zones of approximately equal area, termed inner and outer, the latter being adjacent to the uterine wall. f was fitted for the average in the outer zone (f(out)) and inner zone (f(in)). The parameter (f(out)-f(in)) was then calculated for each subject. This was positive in 12/13 of the normal cases and zero for one case (+10 per cent+10, mean+/-s.d.). For pregnancy affected by IUGR this value was negative in all cases (-4 per cent+/-3). Perfusion fraction mapping identified differences in function within the normal placenta in vivo, and between the placentae of normal and IUGR pregnancies. The technique has potential applications in managing, and investigating the aetiology of, pregnancy compromise.

Cardiotocography only versus cardiotocography plus PR-interval analysis in intrapartum surveillance: a randomised, multicentre trial. FECG Study Group.

BACKGROUND: There is a need to improve the sensitivity and specificity of fetal monitoring during labour. We compared the gold standard, cardiotocography, with cardiotocography plus time-interval analysis of the fetal electrocardiogram in fetal surveillance. The aim was to find out whether time-interval analysis decreased the need for operative intervention due to fetal distress. METHODS: We did a randomised, prospective trial in five hospitals in the UK, Hong Kong, the Netherlands, and Singapore. 1038 women undergoing high-risk labours were randomly assigned fetal monitoring by cardiotocography alone, or cardiotocography plus fetal electrocardiography (ECG). Outcomes measured were rates of operative intervention, and neonatal outcome. Analysis was by intention to treat. FINDINGS: 515 women were assigned management by cardiotocography, and 523 cardiotocography plus fetal ECG. There was a trend towards fewer operative interventions for presumed fetal distress in the time-interval analysis plus cardiotocography group (63 [13%] vs 78 [16%]), but this was not significant (relative risk 0.80 [95% CI 0.59-1.08], p=0.17). There was no significant difference between groups in the proportion of babies who had an umbilical arterial pH of 7.15 or less (51 [11%] vs 49 [11%]; 1.01 [0.7-1.47]), or in the frequency of unsuspected acidaemia (42 [9%] vs 35 [8%]; 1.17 [0.76-1.79]). INTERPRETATION: The addition of time-interval analysis of the fetal electrocardiogram during labour did not show a significant benefit in decreasing operative intervention. There was no significant difference in neonatal outcome.

Effect of fetal magnetic resonance imaging on fetal heart rate patterns.

OBJECTIVE: Our aim was to record the fetal heart rate before and during magnetic resonance imaging to observe the effects of the magnetic resonance imaging process on fetal heart rate parameters during imaging. STUDY DESIGN: Fetal heart rate recordings were obtained in 10 pregnant volunteers at the time of magnetic resonance imaging. All the pregnant women were at term (37-41 weeks) with singleton fetuses in the cephalic presentation. The scanning was performed on a 0.5-T purpose-built superconductive magnet by use of echo-planar imaging. The fetal heart recordings were obtained with a modified Sonicaid Meridian 800 (Oxford) Doppler ultrasound monitor. Recordings of the fetal heart were made for a period of at least 15 minutes outside the magnet and then for at least 15 minutes inside the magnet. RESULTS: There were no significant changes in any fetal heart rate parameters before and during the magnetic resonance imaging, as determined by the Wilcoxon matched-pairs signed-ranks test (P >.3). CONCLUSION: This is the first report of fetal heart rate recording during magnetic resonance imaging of the fetus. Magnetic resonance imaging does not produce demonstrable effects on fetal heart rate patterns.

Improving intrapartum surveillance: an individualised T/QRS ratio?

OBJECTIVES: To test the T/QRS ratio of the fetal electrocardiogram for normal distribution and assess the potential value of an individualised T/QRS ratio threshold to depict abnormality in the detection of fetal compromise during labour. STUDY DESIGN: A retrospective analysis of twenty intrapartum fetal electrocardiogram recordings obtained on the labour ward of the Queen's Medical Centre, Nottingham. RESULTS: In two of the twenty cases the T/QRS ratio was normally distributed. An increase in the T/QRS ratio over the 97.5th and 99.5th centile for 2 consecutive minutes, calculated on an individual basis, would appear to discriminate best between biochemically compromised and non-compromised fetuses. In no case was the T/QRS ratio seen to exceed 0.25 for periods previously described to be related to poor outcome. CONCLUSION: T/QRS ratio changes with individually calculated criteria for abnormality may be of benefit in the detection of fetal compromise but the effect on the intervention rate remains to be established. The use of an absolute threshold for T/QRS ratio abnormality which is based on the assumption of a normal distribution needs to be viewed with caution.

Long-term implications of caesarean section.

Previous reports have linked caesarean section with subsequent reduced fertility, increased rates of miscarriage/ectopic, time delay to next baby and lower fetal weight. However, most reports studied women delivering before 1980. The aim of this study was to assess whether these findings still apply. Five hundred and seventy-six primiparous women delivered by caesarean section during 1992-93 and 576 controls were identified and followed for five years. No difference was observed for the time (months) to next pregnancy/delivery, proportion suffering miscarriage or ectopic or the number of subsequent children (P > 0.05, Mann-Whitney U/chi-squared). Subgroup analysis by indication for caesarean section yielded similar results. Subsequent babies in the caesarean section group were statistically smaller and delivered earlier (median 3.4 kg/39 weeks, P <0.01, Mann-Whitney U) compared with the control group (median 3.5 kg/40 weeks). These differences are probably due to an increased rate of elective caesarean section in the caesarean section group. This study has largely refuted the findings of previous publications. Women delivered by caesarean section in the 1990s can be reassured that future fertility and miscarriage/ectopic risk will not be affected.

Trans-tracheal ventilation complicated by bilateral pneumothoraces and pneumoperitoneum.

Following induction of general anaesthesia for emergency caesarean section the trachea could not be intubated, and ventilation was established only following two cricothyroidotomies. The baby was delivered unimpaired, and tracheostomy subsequently performed. On the intensive care unit, maternal cardiorespiratory variables were satisfactory, although surgical emphysema of the face and neck became apparent. Increasing abdominal distension was relieved by suction to a pelvic drain. Radiographs revealed bilateral pneumothoraces, pneumomediastinum and pneumoperitoneum, which were resolved by intrapleural drainage.