PurposeThe phase I study characterized the safety, pharmacokinetics, anti-tumor activity, and recommended phase II dose/schedule of LY3164530 in patients with advanced or metastatic cancer.MethodsPatients received LY3164530 on days 1 and 15 (Schedule 1: 300, 600, 1000, and 1250 mg) or Days 1, 8, 15, and 22 (Schedule 2: 500 and 600 mg) of each 28 days cycle. Dose escalation used a modified toxicity probability interval model.ResultsDose escalation defined a maximum tolerated dose (MTD) of 1000 mg on Schedule 1 and 500 mg on Schedule 2. Treatment-emergent adverse events related to study treatment were consistent with epidermal growth factor receptor (EGFR) inhibition and included maculopapular rash/dermatitis acneiform (83%, Grade 3/4 17%), hypomagnesemia (55%, Grade 3/4 7%), paronychia (35%), fatigue (28%, Grade 3/4 3%), skin fissures (24%), and hypokalemia (21%, Grade 3/4 7%). Partial response was achieved in three patients on Schedule 2 with colorectal cancer (n = 2) or squamous cell cancer. Overall response rate (ORR) was 10.3%, disease control rate (ORR + stable disease [SD]) was 51.7 and 17.2% of patients had SD ≥ 4 months. The in vivo stability of the bispecific antibody was confirmed. Schedule 2 provided greater and more consistent inhibition of mesenchymal-epithelial transition (MET)/EGFR throughout the dosing interval than Schedule 1.ConclusionsAlthough this study defined the LY3164530 MTD and pharmacokinetics on both schedules, significant toxicities associated with EGFR inhibition and lack of a potential predictive biomarker limit future development. Nonetheless, the results provide insight into the development of bispecific antibody therapy.Electronic supplementary materialThe online version of this article (10.1007/s00280-018-3623-7) contains supplementary material, which is available to authorized users.

Objective To compare the efficacy and safety of recombinant anti-D (R-anti-D) with conventional polyclonal anti-D (Poly anti-D) in preventing maternal-fetal rhesus D (RhD) alloimmunization and to investigate the immunogenicity of R-anti-D. Methods This was a randomized, open-label, multi-center clinical trial conducted in RhD-negative pregnant women who did not receive antenatal anti-D who delivered RhD-positive babies and showed negative indirect Coombs tests (ICTs) at baseline. The women were randomized in a 2:1 ratio to R-anti-D or Poly anti-D groups and were administered 300 mcg (IM) of the corresponding drug within 72 hours of delivery. ICT was performed 72 hours, 90 days, and 180 days after anti-D injection. Serum samples were collected to check for the development of antibodies against R-anti-D at days 90 and 180, using bridging enzyme-linked immunosorbent assay. The proportion of subjects who had positive ICT results at days 90 and 180 were compared between the groups using Fisher's exact test. Results A total of 144 women were randomized to the R-anti-D group and 71 to the Poly anti-D group. Three women in the R-anti-D and none in the Poly anti-D group had a positive ICT result at day 90. No woman in either group had positive ICT result at day 180. Both drugs were well tolerated with only 4 reports of adverse events in each group-all were mild, non-serious, and resolved without sequelae. No subject developed antibodies against R-anti-D. Conclusion The studied R-anti-D is comparable in efficacy to conventional Poly anti-D and is safe and non-immunogenic.

Background Pregnancy is a physiologic condition which is unique in that it alters the physiology of each organ in the body. Cardiovascular changes during pregnancy are significant and start at 6 to 8 weeks of gestation. Physiologic cardiovascular changes during pregnancy suggest the chance of altered electrocardiographic (ECG) parameters during pregnancy. Study of variations in ECG in normal pregnant women serves as a basis to detect pathologic changes in pregnant women. Material and Methods This is a cross-sectional data of case series of pregnant women across all stages of gestation who attended antenatal clinic of our teaching hospital, on Women's Day (March 8, 2017). A 12-lead ECG was recorded in all the participants in supine position. The parameters noted from the ECG include heart rate, PR interval, QRS duration, QRS axis, corrected QT (QTc) interval, and ST-T changes. Results Total 151 pregnant women were studied. The average age was 23.38 ± 3.49 years. With respect to gestational age, 12 (7.94%), 48 (31.78%), and 91 (60.26%) women were in the first, second, and third trimesters of pregnancy, respectively. With respect to parity, 60 (39.7%) were primigravidae and 91 (60.26%) were multigravidae. The mean ECG heart rate was increased (100.15 ± 12.48 beats/min). The mean systolic blood pressure (109.67 ± 9.34 mm Hg) and the mean diastolic blood pressure (71.32 ± 6.89 mm Hg) were decreased. The mean of ECG intervals and durations (PR, QRS, QTc) were in normal range (0.14 ± 0.01, 0.08 ± 0.008, and 407.83 ± 11.98, respectively). There was no abnormal P-wave dispersion. Even though the QTc was in normal range in 63.56% of pregnant women, this parameter was in upper quadrant of the normal range. General linear regression demonstrated that systolic blood pressure and palpitations were the only variables to independently predict QTc in upper quadrant of normal range (p = 0.05, 0.03, respectively). Conclusion The cardiovascular hemodynamic adaptation to pregnancy is a well-established fact that is also seen in our study. There is shortening of PR interval and QRS duration. Even though QTc is with in normal range, in more than half (63.56%) of pregnant women, it is in the upper quadrant of the normal range.

Aims To correlate the relationship between the ambulatory blood pressure parameters and the occurrence of the antenatal and postnatal adverse maternofetal events in pregnancy. Methods Observational study designed for 50 pregnant patients who had an appointment to the obstetrics with abnormal blood pressure (BP) measurements and for whom ambulatory blood pressure monitoring (ABPM) was studied between January 2019 and June 2019. Data about age, personal history, obstetrics, family, body mass index (BMI), weight gain in pregnancy, values of blood pressure in the appointment, values recorded in ABPM, delivery and newborn, pregnancy and postpartum events, and follow-up of woman and child. Data were analyzed using descriptive and inferential statistics with Minitab 17.0 for Windows. Results Patients demographic data, clinical history, and laboratory results, including the ABPM parameters, were compiled. Antenatal complications occurred in 22 patients (44%), and postpartum complications were found in 41 patients (82%) whose ABPM values were deranged. Antenatal complications were studied using the binary logistic regression analysis for calculating the role each factor played in the development of hypertension. In the sample studied, mean age was 24.980 with a standard deviation of 4.876 (p = 0.003; minimum age of 19 years and maximum age of 38 years), mean weight of patient was 63.71 with a standard deviation of 63.71 (p = 0.001), mean gravida was 1.780 with a standard deviation of 0.910 (p = 0.034), mean gestation weeks at presentation was 33.000 weeks with a standard deviation of 4.086 (p = 0.041), mean birth weight was 2.226 with a standard deviation of 0.797 (p = 0.000), mean maximum diastole was 109.22 with a standard deviation of 16.53 (p = 0.002), mean day maximum systole was 187.2 with a standard deviation of 203.5 (p = 0.009), mean day minimum diastole was 63.50 with a standard deviation of 12.99 (p = 0.013), all of which had statistical significance. It is found that the nighttime diastolic blood pressure (DBP) and daytime maximum systolic blood pressure (SBP) were the best predictors of adverse events. Among antenatal complications (ANC), the most common complication is intrauterine growth restriction (IUGR), noted in (n = 19, 86.36%) preterm delivery (n = 17, 77.27%) among the 17 babies who were delivered preterm; 12 (70.5%) needed neonatal intensive care unit (NICU) care of which 4 (25%) babies died because of prematurity; intrauterine death (IUD) was noted in 7 (31.81%) patients and eclampsia was seen in 5 (22.72%). Nondippers proðle had a worse survival rate at follow-up until delivery compared with those with a dipper proðle. Postnatal complications were seen in 41 patients; among them, 13 patients (31.7%) had abnormal fundus examination, 15 patients (36.58%) required usage of antihypertensive beyond first postpartum, 9 patients (21.95%) required blood transfusion for severe bleeding in the form of postpartum hemorrhage. Binary logistic regression for systolic dippers versus nondippers shows statistical significance in age (p = 0.023), weight (p = 0.038), and para (p = 0.045) (Table 3). Binary logistic regression for diastolic dippers versus nondippers shows statistical significance in age (p = 0.039), weight (p = 0.020), birth weight (p = 0.010), maximum heart rate (p = 0.043), and ANC (p = 0.007) Adverse events occurred most commonly in nondippers. Systole nondippers is noted in (n = 41, 82%). Dippers is noted in (n = 9, 18%), Diastole nondippers is noted in (n = 39, 78%) Dippers is noted in (n = 11, 22%). Conclusion ABPM recorded blood pressure is very precise. ABPM is the advised method for both diagnostic and therapeutic monitoring of hypertensive pregnancy diseases, mainly in situations like whitecoat hypertension, masked hypertension, nocturnal hypertension, and nondipping profile. In patients with high-risk pregnancy, elderly primigravida, and precious pregnancy, who have a high-risk of developing pregnancy-induced hypertension (PIH) and related complications, early use of ABPM predicts adverse maternofetal events, which when intervened at an earlier date can prevent antenatal and postnatal complications.

Background Pregnancy is associated with profound physiologic alterations in the maternal cardiovascular system. This study aimed to investigate maternal cardiac performance during normal pregnancy by two-dimensional echocardiography parameters and various functional and structural alterations. Methods This was a cross-sectional study of 100 normal pregnant women who attended the antenatal clinic, and all participants had clinical history, physical examination, and 12-lead electrocardiogram. Two-dimensional, M-mode, and Doppler echocardiography was done. Echocardiographic parameters were compared with normal age-matched controls from previously published studies. Results The mean age of the study group was 23.35 ± 3.05 years, mean systolic blood pressure was 110.5 ± 8.69 mm Hg, and mean diastolic blood pressure was 71.6 ± 6.77 mm Hg. There was an increase in left atrial (LA) diameter, left ventricular end diastolic diameter, and interventricular septum (IVS) thickness as gestational age advanced. There was a gradual decrease in E-wave velocity, and E/A ratio increased during the second trimester and decreased during the third trimester. The E-wave deceleration time increased with gestational age There was no statistically significant difference between IVS thickness and E/A ratio (p = 1.000). Conclusion Cardiac chamber dimensions, LV wall thickness, and LA size, most indices of systolic function although within normal range, were significantly higher in pregnant Asian Indian women than in the controls. This study shows that the subtle reduction in myocardial compliance appears as an adaptive response to changes of preload, afterload, and LV geometry.