Immunotherapy encompasses a wide range of therapies to engage the immune system to target malignancies. In recent years, immunotherapy has made a major impact on treatment of metastatic cancer and ...has altered standard of care for many tumor types. However, predicting and understanding responses across tumor types has been challenging. While some metastatic cancers have shown dramatic responses to immunotherapy, such as melanoma, lung cancer, and renal cell carcinoma, prostate cancer has generally failed to show a significant response. However, small series of prostate cancer patients have shown impressive responses to cellular and immunotherapy. This review summarizes the current data for immunotherapy’s use in prostate cancer, as well as how currently available data might help predict patient responses to immunotherapy. Specifically, we will review vaccine-based therapies, immune checkpoint inhibitors, and future directions that are actively being explored.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
IMPORTANCE: Metabolic changes after maternal bariatric surgery may affect subsequent fetal development. Many relevant perinatal outcomes have not been studied in this postoperative population, and ...the risks associated with short operation-to-birth (OTB) intervals have not been well examined. OBJECTIVE: To examine the risk for perinatal complications in women with a history of bariatric surgery (postoperative mothers POMs) by comparing them with mothers without operations (nonoperative mothers NOMs) and examining the association of the OTB interval with perinatal outcomes. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a population-based retrospective cohort study (January 1, 1980, to May 30, 2013) at hospitals in Washington State. Data were collected from birth certificates and maternally linked hospital discharge data. Participants were all POMs and their infants (n = 1859) and a population-based random sample of NOMs and their infants frequency matched by delivery year (n = 8437). EXPOSURES: Bariatric operation before birth or categories of OTB intervals. MAIN OUTCOMES AND MEASURES: The primary outcomes were prematurity, neonatal intensive care unit (NICU) admission, congenital malformation, small for gestational age (SGA), birth injury, low Apgar score (≤8), and neonatal mortality. Poisson regression was used to compute relative risks (RRs) and 95% CIs, with adjustments for maternal body mass index, delivery year, socioeconomic status, age, parity, and comorbid conditions. RESULTS: A total of 10 296 individuals were included in the analyses for this study. In the overall cohort, the median age was 29 years (interquartile range, 24-33 years). Compared with infants from NOMS, infants from POMs had a higher risk for prematurity (14.0% vs 8.6%; RR, 1.57; 95% CI, 1.33-1.85), NICU admission (15.2% vs 11.3%; RR, 1.25; 95% CI, 1.08-1.44), SGA status (13.0% vs 8.9%; RR, 1.93; 95% CI, 1.65-2.26), and low Apgar score (17.5% vs 14.8%; RR, 1.21; 95% CI, 1.06-1.37). Compared with infants from mothers with greater than a 4-year OTB interval, infants from mothers with less than a 2-year interval had higher risks for prematurity (11.8% vs 17.2%; RR, 1.48; 95% CI, 1.00-2.19), NICU admission (12.1% vs 17.7%; RR, 1.54; 95% CI, 1.05-2.25), and SGA status (9.2% vs 12.7%; RR, 1.51; 95% CI, 0.94-2.42). CONCLUSIONS AND RELEVANCE: Infants of mothers with a previous bariatric operation had a greater likelihood of perinatal complications compared with infants of NOMs. Operation-to-birth intervals of less than 2 years were associated with higher risks for prematurity, NICU admission, and SGA status compared with longer intervals. These findings are relevant to women with a history of bariatric surgery and could inform decisions regarding the optimal timing between an operation and conception.
As part of World Health Organization (WHO) 2016 updated antenatal care (ANC) guidelines routine ultrasonography is recommended, including to detect congenital anomalies. The Ghana Health Service ...(GHS) developed an in-service midwifery ultrasound training course in 2017, which includes fetal anomaly detection. Training rollout has been very limited. We sought to determine proportions of anomalies among neonates presenting to Tamale Teaching Hospital (TTH) that should be prenatally detectable by course-trained midwives in order to determine training program potential utility. We analyzed data from a registry of neonates admitted to TTH with congenital anomaly diagnoses in 2016. We classified ultrasonographic detectability of anomalies at less than or equal to13 and 14-23 weeks gestation, based on GHS course content and literature review. Secondary analysis included 2011-2015 retrospective chart review data. Eighty-five neonates with congenital anomalies were admitted to TTH in 2016. Seventy-three (86%) mothers received greater than or equal to1 ANC visit; 47 (55%) had at least one prenatal ultrasound, but only three (6%) were interpreted as abnormal. Sixteen (19%) and 26 (31%) of the anomalies should be readily detectable by course-trained midwives at less than or equal to13 and 14-23 weeks gestation, respectively. When the 161 anomalies from 2011-2015 were also analyzed, 52 (21%) and 105 (43%) should be readily detectable at less than or equal to13 and 14-23 weeks gestation, respectively. "Optimal conditions" (state-of-the-art equipment by ultrasonography-trained physicians) should readily identify 53 (22%) and 115 (47%) of the anomalies at less than or equal to13 and 14-23 weeks gestation, respectively. Training Ghanaian midwives could substantially increase second trimester anomaly detection, potentially at proportions nearing highly resourced settings. Our data also highlight the need for refinement of the WHO antenatal ultrasonography recommendation for a scan before 24 weeks gestation for multiple purposes. Gestational dating accuracy requires first trimester scanning while fetal anomaly detection is more accurate during second trimester. Further specification will enhance guideline utility.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Enhanced recovery after surgery pathways provide a multidisciplinary, evidence-based approach to the care of surgical patients. They have been shown to decrease postoperative length of stay and cost ...in several surgical subspecialties, including gynecology, but have not been well-studied in obstetric patients who undergo cesarean delivery.
We sought to determine whether the implementation of an enhanced recovery after surgery pathway for cesarean delivery would decrease postoperative length of stay and postoperative direct cost compared with historic controls.
We conducted a retrospective cohort study that compared postoperative length of stay and postoperative direct cost among women on the enhanced recovery after surgery cesarean delivery pathway in the first year of implementation (April 1, 2017, to March 31, 2018; n=531) compared with historic controls (March 1, 2016, to February 28, 2017; n=661). Literature review informed the development of a prototype enhanced recovery after surgery pathway for cesarean delivery based on best practices from previous enhanced recovery after surgery experience in obstetrics (if available) or from other surgical disciplines if there were no available data for obstetrics. When there was not relevant published evidence from obstetrics, the taskforce used clinical experience and expert opinion to develop the pathway. The enhanced recovery after surgery cesarean delivery pathway included preadmission patient education and preoperative, intrapartum, and postoperative elements. Some components reflected standard obstetric care, and others were specific to the enhanced recovery after surgery pathway. Women with pregestational diabetes mellitus who were receiving insulin therapy before pregnancy, women with preeclampsia with severe features, women with complex pain needs, and women with surgical complications were excluded from baseline and implementation groups. Enhanced recovery after surgery cesarean delivery pathway participation was determined by order set usage. Analysis was stratified for women who underwent planned (no labor; n=530) and unplanned (labor; n=662) cesarean delivery. Demographic and clinical characteristics, postoperative length of stay, postoperative direct cost, and readmission rates for the baseline and implementation groups were compared with the use of chi-square and t-tests.
During the first year of implementation, 531 of 640 eligible women (83%) were included in the enhanced recovery after surgery cesarean delivery pathway. Body mass index was marginally higher in the baseline group for unplanned cesarean delivery (32.5±7.1 vs 31.4±6.7 kg/m2; P=.04). Otherwise there were no significant differences in demographic or maternal clinical characteristics between baseline or implementation groups overall or for planned or unplanned cesarean delivery. Compared with baseline, implementation of the enhanced recovery after surgery cesarean delivery pathway resulted in a significant decrease in postoperative length of stay by 7.8% or 4.86 hours overall (P<.001) and for both planned (P=.001) and unplanned (P=.002) cesarean delivery. Total postoperative direct costs decreased by 8.4% or $642.85 per patient overall (P<.001) and for both planned (P<.001) and unplanned (P<.001) cesarean delivery. There were no significant differences in readmission rates.
Implementation of an enhanced recovery after surgery pathway for women who had planned or unplanned cesarean delivery was associated with significantly decreased postoperative length of stay and significant direct cost-savings per patient, without an increase in hospital readmissions. Given that cesarean delivery is 1 of the most common surgical procedures performed in the United States, positively impacting postoperative length of stay and direct cost for women who undergo cesarean delivery could have significant healthcare cost-savings.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pregnancy alters multiple physiological processes including angiogenesis, vasodilation, inflammation, and cellular redox, which are partially modulated by the gasotransmitters hydrogen sulfide (H2S) ...and nitric oxide (NO). In this study, we sought to determine how plasma levels of H2S, NO, and the H2S-related metabolites thiocyanate (SCN−), and methanethiol (CH3SH) change during pregnancy progression.
Plasma was collected from 45 women at three points: 25–28 weeks gestation, 28–32 week gestation, and at ≥3 months postpartum. Plasma levels of H2S, SCN−, and CH3SH were measured following derivatization using monobromobimane followed by LC-MS/MS. Plasma NO was measured indirectly using the Griess reagent.
NO and SCN− were significantly lower in women at 25–28 weeks gestation and 28–32 weeks gestation than postpartum while plasma H2S levels were significantly lower at 28–32 weeks gestation than postpartum. No significant differences were observed in CH3SH.
Previous reports demonstrated that the production of H2S and NO are stimulated during pregnancy, but we observed lower levels during pregnancy compared to postpartum. Previous reports on NO have been mixed, but given the related effects of H2S and NO, it is expected that their levels would be higher during pregnancy vs. postpartum. Future studies determining the mechanism for decreased H2S and NO during pregnancy will elucidate the role of these gasotransmitters during normal and pathological progression of pregnancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Vitamin A is vital to maternal-fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and concentrations of circulating ...retinol metabolites. The goal of this study was to characterize retinoid concentrations in healthy women (
= 23) during two stages of pregnancy (25-28 weeks gestation and 28-32 weeks gestation) as compared to ≥3 months postpartum. It was hypothesized that plasma retinol, retinol binding protein 4 (RBP4), transthyretin and albumin concentrations would decline during pregnancy and return to baseline by 3 months postpartum. At 25-28 weeks gestation, plasma retinol (-27%), 4-oxo-13-
-retinoic acid (-34%), and albumin (-22%) concentrations were significantly lower, and
-retinoic acid (+48%) concentrations were significantly higher compared to ≥3 months postpartum in healthy women. In addition, at 28-32 weeks gestation, plasma retinol (-41%), retinol binding protein 4 (RBP4; -17%), transthyretin (TTR; -21%), albumin (-26%), 13-
-retinoic acid (-23%) and 4-oxo-13-
-retinoic acid (-48%) concentrations were significantly lower, whereas plasma
-retinoic acid concentrations (+30%) were significantly higher than ≥3 months postpartum. Collectively, the data demonstrates that in healthy pregnancies, retinol plasma concentrations are lower, but
-retinoic acid concentrations are higher than postpartum.
Limited data are available on the effects of pregnancy on the maternal metabolome. Therefore, the objective of this study was to use metabolomics analysis to determine pathways impacted by pregnancy ...followed by targeted confirmatory analysis to provide more powerful conclusions about metabolic alterations during pregnancy. Forty-seven pregnant women, 18-50 years of age were included in this study, with each subject serving as their own control. Plasma samples were collected between 25 and 28 weeks gestation and again ≥3 months postpartum for metabolomics analysis utilizing an HILIC/UHPLC/MS/MS assay with confirmatory targeted specific concentration analysis for 10 of the significantly altered amino acids utilizing an LC/MS assay. Principle component analysis (PCA) on metabolomics data clearly separated pregnant and postpartum groups and identified outliers in a preliminary assessment. Of the 980 metabolites recorded, 706 were determined to be significantly different between pregnancy and postpartum. Pathway analysis revealed three significantly impacted pathways, arginine biosynthesis (
= 2 × 10
and FDR = 1 × 10
), valine, leucine, and isoleucine metabolism (
= 2 × 10
and FDR = 2 × 10
), and xanthine metabolism (
= 4 × 10
and FDR = 4 × 10
). Of these we focused analysis on arginine biosynthesis and branched-chain amino acid (BCAA) metabolism due to their clinical importance and interconnected roles in amino acid metabolism. In the confirmational analysis, 7 of 10 metabolites were confirmed as significant and all 10 confirmed the direction of change of concentrations observed in the metabolomics analysis. The data support an alteration in urea nitrogen disposition and amino acid metabolism during pregnancy. These changes could also impact endogenous nitric oxide production and contribute to diseases of pregnancy. This study provides evidence for changes in both the ammonia-urea nitrogen and the BCAA metabolism taking place during pregnancy.
INTRODUCTION:Women ≥40 years old at delivery are increasing and older women are at higher risk for adverse pregnancy outcomes. We sought to evaluate delivery outcomes in these women.
METHODS:We ...conducted an IRB exempt, retrospective cohort study using data from a multi-center quality initiative. Nulliparous singleton births between 1/2012-12/2017 at participating hospitals were included. Patients with intrapartum transfers, missing birth data, or missing/implausible data for maternal age were excluded. Age was stratified into 4 groups12-19 years, 20-29 years, 30-39 years, and 40-55 years. Rates of delivery outcomes were compared between women aged 20-29 years and 40-55 years using a χ2 test. Adjusted relative risks were calculated after controlling for obesity (body mass index ≥30), race-ethnicity, and chronic hypertension.
RESULTS:There were 48,093 nulliparous singleton births at 20+0 to 42+6 weeksʼ gestation. After exclusions (n=1891) were removed, the cohort included 46,202 births36,146 (78.2%) in 20-29 years and 1155 (2.5%) in 40-55 years groups. Only 33% of older women achieved a spontaneous vaginal birth, compared to 62% of women age 20-29 (p<0.001). This difference is primarily due to high cesarean delivery (CD) rate (57.7%) in older women, with 25.8% of older women never attempting vaginal birth. Older women are at significantly higher risk of having a CD for all major indications with only a minority (2.8%) of older women having a non-medically indicated CD.
CONCLUSION:Older women have an over 50% risk of CD with lower rate of attempting and achieving vaginal birth. This can be useful in counseling about delivery expectations.
INTRODUCTION:One in 300 opioid-naïve women develop opioid addiction following cesarean delivery (CD). Enhanced recovery after surgery (ERAS) pathways provide a multidisciplinary, evidence-based ...approach to postoperative care and have been shown to decrease postoperative opioid consumption. We implemented an ERAS CD pathway and evaluated the impact on postoperative opioid use and pain scores.
METHODS:We conducted an IRB approved, retrospective cohort study comparing postoperative opioid use and pain scores among women on the ERAS CD pathway in the first year of implementation (4/2017-3/2018, n=531) compared to historical controls (3/2016-2/2017, n=661). Women with pregestational diabetes on insulin preconception, preeclampsia with severe features, and/or complex pain needs were excluded. Analysis was stratified for women undergoing planned (no labor, n=530) and unplanned (labor, n=662) CD. Postoperative opioid use and pain scores were compared using chi-squared and t-tests.
RESULTS:During implementation, 531 (83%) of 640 eligible women were included in the ERAS CD pathway. Compared to baseline, the ERAS CD pathway resulted in an overall decrease of 13.7% (p=0.001) in postoperative opioid use with a 23.2% reduction in patients with unplanned CD (p<0.001). There was no difference in postoperative opioid use in patients with planned CD (p=0.456). ERAS patients with planned CD had a 9.5% reduction in pain scores on postoperative day 0 (p<0.05). There were no other significant differences in pain scores.
CONCLUSION:The ERAS CD pathway was associated with decreased postoperative opioid use overall. Interestingly, the decrease in opioid use was driven by the unplanned CD subset. Further research should explore these differences.
Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of >20% of marketed drugs. CYP2D6 expression and activity exhibit high interindividual variability and is induced during pregnancy. The ...farnesoid X receptor (FXR) is a transcriptional regulator of CYP2D6 that is activated by bile acids. In pregnancy, elevated plasma bile acid concentrations are associated with maternal and fetal risks. However, modest changes in bile acid concentrations may occur during healthy pregnancy, thereby altering FXR signaling. A previous study demonstrated that hepatic tissue concentrations of bile acids positively correlated with the hepatic mRNA expression of CYP2D6. This study sought to characterize the plasma bile acid metabolome in healthy women (
= 47) during midpregnancy (25-28 weeks gestation) and ≥3 months postpartum and to determine if plasma bile acids correlate with CYP2D6 activity. It is hypothesized that during pregnancy, plasma bile acids would favor less hydrophobic bile acids (cholic acid vs. chenodeoxycholic acid) and that plasma concentrations of cholic acid and its conjugates would positively correlate with the urinary ratio of dextrorphan/dextromethorphan. At 25-28 weeks gestation, taurine-conjugated bile acids comprised 23% of the quantified serum bile acids compared with 7% ≥3 months postpartum. Taurocholic acid positively associated with the urinary ratio of dextrorphan/dextromethorphan, a biomarker of CYP2D6 activity. Collectively, these results confirm that the bile acid plasma metabolome differs between pregnancy and postpartum and provide evidence that taurocholic acid may impact CYP2D6 activity during pregnancy. SIGNIFICANCE STATEMENT: Bile acid homeostasis is altered in pregnancy, and plasma concentrations of taurocholic acid positively correlate with CYP2D6 activity. Differences between plasma and/or tissue concentrations of farnesoid X receptor ligands such as bile acids may contribute to the high interindividual variability in CYP2D6 expression and activity.
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