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Pembrolizumab is a potent immune-modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE-001, -002, and -006 studies. Longitudinal tumor size modeling was pursued to quantify exposure-response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE-001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy. This revised model structure provided a framework to efficiently evaluate the impact of covariates and pembrolizumab exposure. Both models indicated that exposure to the drug was not a significant predictor of tumor size response, demonstrating that the dose range evaluated (2 and 10 mg/kg every 3 weeks) is likely near or at the plateau of maximal response.

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BACKGROUND: In resting platelets, endothelial cell specific adhesion molecule (ESAM) is located in alpha granules, increasing its cell surface expression following platelet activation. However, the function of ESAM on platelets is unknown. OBJECTIVE: To determine whether ESAM has a role in thrombus formation. METHODS AND RESULTS: We found that following platelet activation ESAM localizes to the junctions between adjacent platelets, suggesting a role for this protein in contact-dependent events that regulate thrombus formation. To test this hypothesis we examined the effect of ESAM deletion on platelet function. In vivo, ESAM(-/-) mice achieved more stable hemostasis than wild-type mice following tail transection, and developed larger thrombi following laser injury of cremaster muscle arterioles. In vitro, ESAM(-/-) platelets aggregated at lower concentrations of G protein-dependent agonists than wild-type platelets, and were more resistant to disaggregation. In contrast, agonist-induced calcium mobilization, alpha(IIb)beta(3) activation, alpha-granule secretion and platelet spreading, were normal in ESAM-deficient platelets. To understand the molecular mechanism by which ESAM regulates platelet activity, we utilized a PDZ domain array to identify the scaffold protein NHERF-1 as an ESAM binding protein, and further demonstrated that it associates with ESAM in both resting and activated platelets. CONCLUSIONS: These findings support a model in which ESAM localizes to platelet contacts following platelet activation in order to limit thrombus growth and stability so that the optimal hemostatic response occurs following vascular injury.

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OBJECTIVE: The purpose of this report is to bring to the attention of obstetric care providers the occurrence in pregnancy of a threatening pulmonary syndrome caused by hantavirus infection. STUDY DESIGN: Two recent cases of hantavirus pneumonitis in pregnancy, one complicated by adult respiratory distress syndrome, are presented. The clinical characteristics and epidemiology of the illness, which has now been reported in 12 western states, are detailed. RESULTS: Hantavirus pulmonary syndrome is characterized by pneumonitis, often progressing to adult respiratory distress syndrome, which is accompanied by thrombocytopenia, lactacidemia, and leukocytosis with a marked left shift. Severe hypoxemia and lactacidemia were associated with a poor perinatal outcome. CONCLUSION: The hantavirus pulmonary syndrome occurring during pregnancy may be life-threatening and may result in fetal hypoxemic damage.

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We investigated the effect of preinduction cervical ripening with the intracervical instillation of dinoprostone (prostaglandin E2 gel, 0.5 mg) on the results of labor induced with intravenous oxytocin. We randomly allocated 79 pregnant women to receive either the intracervial application of dinoprostone gel or placebo gel. Compared with control subjects, the group who received dinoprostone had no difference in induction-to-delivery interval or in cesarean section rate. The dinoprostone group had fewer failed inductions, but there was no difference between the two groups in the number who delivered spontaneously within 24 hours. From review of the literature and a meta-analysis, it was likewise revealed that dinoprostone did not favorably affect the cesarean section rate. Contrary to current opinion, intracervical dinoprostone gel does not appreciably lower the cesarean section rate when used at this dose and route before labor is induced.

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Fetal triploidy can be suspected but not diagnosed based on ultrasonographic findings. A patient was diagnosed with fetal triploidy in the second trimester.

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There are no absolute objective diagnostic criteria for cervical incompetence. Abdominal and endovaginal ultrasonographic assessment of endocervical length, both of which have been associated with technical problems, have been used to establish the diagnosis. Cervical cerclage may be useful in preventing silent cervical dilatation; however, no prospective trials with and without cerclage have been performed when endocervical shortening has been demonstrated by ultrasonography.

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An infant was born to a woman who received intravenous esmolol for intrapartum supraventricular tachyarrhythmia. Despite the very short acting and cardio-selective beta-1 adrenergic blockade induced by that agent, neonatal effects can occur up to 48 hours after delivery.

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Fetal trauma resulting in acute anemia after maternal blunt abdominal trauma is a rare but potentially lethal condition. We recently managed such a case with the use of fetal intravascular transfusion.

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In general the perinatal outcome of oligohydramnios is poor. The diverse etiology of the entity is difficult to pinpoint. Multiple antepartum amnioinfusions can be beneficial in selected cases not associated with malformations, abnormal karyotypes or premature rupture of the membranes. We treated 38 patients with 105 such instillations.

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Cordocentesis under ultrasound guidance, or percutaneous umbilical blood sampling, was first reported in 1983 by Daffos et al. Since then the method has gained importance in prenatal diagnosis. In 1,011 cases at a women's clinic in Bonn, Federal Republic of Germany, 35% of the cordocentesis cases were done for blood group incompatibilities plus intravascular transfusion in most of the cases. In the remaining 65% the indications for cordocentesis were a rapid karyotype analysis, diagnosis of fetal infections and determination of fetal acid-base status in severe intrauterine growth retardation. Chorionic villus sampling (CVS) and amniocentesis were also performed to detect karyotype anomalies. Amniocentesis constituted 78.8% of the procedures and detected 50% of the karyotype abnormalities. Cordocentesis and CVS constituted 17.3% and 3.9%, respectively, of all the procedures and diagnosed 39% and 11%, respectively, of the abnormalities. Different forms of trisomy were the most common karyotype anomaly. Translocation was noted in 22 cases. Turner's, Klinefelter and triple X syndromes and triploidy were the next major forms.

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Cervical ripening prior to oxytocin stimulation is highly desirable to ensure a successful induction. Prostaglandin E2 has been administered by intracervical, intravaginal and extra-amniotic routes with successful ripening of the cervix. The dose of PGE2 administered is under investigation. Use of 3 or 4 mg of PGE2, although effective, has been reported to be accompanied by uterine hypertonus or fetal heart changes. Lower dose of PGE2 at 0.2 mg and 0.4 mg do not have the above-mentioned side effects but necessitate multiple applications. This randomized double-blinded study incorporated the use of 2 mg of PGE2 administered by intravaginal route in a hydroxyethyl cellulose gel medium. A significant increase in Bishop score (40% higher) was achieved in patients receiving PGE2 as compared to placebo patients. There were no adverse side effects, indicating application of 2 mg of PGE2 as a safe method of cervical ripening prior to induction of labor.

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To assess the reliability of early biometric measurements in pregnancy, transvaginal sonography was performed in 92 pregnancies in the first trimester in a cross-sectional fashion. Measurements included crown-to-rump length (CRL), biparietal diameter (BPD), head and abdominal circumference (HC and AC), and femur length (FL). Stepwise regression analysis of the gestational age was performed. CRL maintained the highest correlation with gestational age (r = 0.99, p less than 0.001). BPD, HC, AC also correlated well. FL showed a less strong correlation with gestational age (r = 0.76, p less than 0.001). CRL remains the standard for early sonography measurements.

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Color Doppler flow mapping of fetal heart was performed in 582 fetuses between 16 and 38 weeks of gestation. Congenital heart diseases were excluded in 522 fetuses correctly. In 59 fetuses structural and/or functional cardiac abnormalities were diagnosed. In one fetus small multiple ventricular septal defects were missed. The most important additional information obtained by color Doppler flow mapping was: (1) Diagnosis of insufficiencies of atrioventricular valves; (2) Demonstration of turbulent high velocity jet in stenosis of semilunar valve; (3) Reverse flow in ascending aorta in atresia of aortic valves and on ductus arteriosus and main pulmonary artery in atresia of pulmonary valves; (4) Reverse perfusion of ductus arteriosus and main pulmonary artery as well as an antegrade turbulent high velocity jet in severe pulmonary stenosis as part of tetralogy of Fallot; (5) Bidirectional interventricular shunting of blood in ventricular septal defect. Color Doppler flow mapping allows rapid screening for flow abnormalities of the fetal heart. Exact localisation of sample volume by pulsed wave Doppler in area of abnormal flow pattern is possible, thus significantly reducing the Doppler examination time. The accuracy of prenatal diagnosis of congenital heart diseases is improved by application of color Doppler flow mapping, in particular in presence of complex cardiac defects.

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Using a fiberoptic probe with a dye indicator, pH was studied in a group of 124 fetuses. Acidotic tissue pH was found to be a far more powerful indicator of fetal, neonatal and maternal problems than acidotic capillary blood pH. The tissue pH related more consistently to obstetric problems throughout labor. A comparison was made of the reliability of fetal acidotic tissue pH and acidotic capillary blood pH data in the identification and prediction of obstetric problems.

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Continuous wave Doppler umbilical artery blood flow velocity wave form is presented in 14 drug addicted mothers between 22-40 weeks of gestational age from New York City. The mean S/D ratio ranged from 2.36 to 4.30. Doppler study of the fetal umbilical artery could be a valuable addition for assessment of fetal well being in drug addicted mothers.

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About 30% of U.S. women of reproductive age smoke cigarettes. The adverse effects of smoking on the adult population have prompted insertion of the surgeon general's warning on cigarette packages. The effects of smoking on pregnancy and the fetus have been well documented, but the causative agent in "smoke" that produces those adverse effects has not been identified. Cadmium, one of the more toxic materials in cigarette smoke, has been studied in the placenta and maternal blood. To further assess the pharmacodynamics of this agent, we conducted studies to investigate the effect of smoking on the thiocyanate and cadmium concentrations in maternal blood, cord blood and amniotic fluid. Our results showed significantly increased cadmium concentrations in maternal blood and cord blood in pregnant women who smoked (P less than .05) and significantly increased amniotic fluid cadmium concentrations in women who smoked heavily during pregnancy. Maternal and cord blood cadmium concentrations correlated strongly with amniotic fluid thiocyanate concentrations.

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Two cases of occipital encephalocele diagnosed late in pregnancy are presented. Early diagnosis of this problem is possible. Parents might elect to terminate pregnancy as the outcome is invariably dismal.

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