Prenatal Congenital Heart Disease and Placental Phenotypes: Preserved Neonatal Weight Despite Small Placentas.

Background: Congenital heart disease (CHD) affects 8 in 1,000 live births with significant postnatal implications including growth failure, neurodevelopmental delay, and mortality. The placenta develops concomitantly with the fetal heart. High rates of placental pathology and discordant growth in pregnancies affected by CHD highlight the significance of the fetal-placental-cardiac axis. Objectives: This study aimed to characterize the relationship between neonatal birthweight (BW), head circumference, placental weight (PW), and placental pathology in pregnancies affected by CHD. PW:BW provides a surrogate to assess placental efficiency, or nutrient exchange and delivery by the placenta, across CHD phenotypes. Methods: Retrospective cohort of 139 live-born singletons with postnatally confirmed CHD with placental pathology. Placental examination, infant BW, head circumference, and CHD categories (septal defects, right-sided defects, left-sided defects, conotruncal anomalies, and others) were included. Chi-square, Fisher's exact, or Kruskall-Wallis tests and multinomial logistic regressions, as appropriate. Results: Median birthweight and head circumference percentile was 33 and 35, respectively. Placental pathology was documented in 37% of cases. PW to BW ratios were <10th percentile for 78% and <3rd percentile for 54% of the cohort, with no difference between CHD categories (P = 0.39 and P = 0.56, respectively). Conclusions: Infants with CHD have preserved BW and head circumferences in the setting of small placentas and increased prevalence of placental pathology, suggesting placental efficiency. Detection of abnormal placental growth could add prenatal diagnostic value. Placental and neonatal discordant growth may allude to a vascular anomaly predisposing fetuses to developing CHD. Further studies are needed to explore fetal nutrient delivery and utilization efficiency.

Increased Urinary Cadmium Levels in Foreign-Born Asian Women-An NHANES Study of 9639 U.S. Participants.

The purpose of this study was to determine the disparities and trends in demographics, social behaviors, and occupations for cadmium exposure in the U.S. Data were obtained from the NHANES database from 2007 to 2016. Analysis of variance tests were used to compare the association of the geometric mean values of urinary cadmium levels and various demographic and behavioral characteristics. We also conducted multivariable logistic regression while adjusting for these factors to determine the risk of toxic urinary cadmium levels (≥2 µg/g) across various patient characteristics. Of the 9639 participants, 52.8% were ≥45 years old, 51.7% female, and 48.3% male. White, Black, Mexican American, other Hispanic, and Asian comprised 66.4%, 11.5%, 8.7%, 5.8%, and 5.5%, respectively. Over 82% of participants were U.S. born. A total of 19.6% were current smokers. On multivariate analysis, older age (OR: 8.87), current smoking (OR = 5.74), Asian race (OR = 4.52), female sex (OR = 4.32), and foreign nativity (OR = 1.83) were significantly associated with higher cadmium levels. Older, Asian, foreign-born females showed a measurement of 0.69 µg/g, a value more than three-fold the sample population's mean of 0.20 µg/g. A trend analysis demonstrated a cadmium level decrease over time (OR = 0.47). Asians had the highest urinary cadmium levels, especially older, foreign-born females. Smoking and poverty were also associated with significant elevations in cadmium levels.

The impact of state legalization on rates of marijuana use in pregnancy in a universal drug screening population.

OBJECTIVE: To evaluate the effect of state legalization of rate on marijuana use in pregnancy in a population with universal drug screening. METHODS: This is a retrospective cohort study from July 2016 to December 2018 of pregnant women who had universal drug screening of marijuana use before and after legalization of recreational marijuana in California on 1 January 2018. Maternal medical conditions and neonatal outcomes associated with usage were also evaluated. Student's t-test, Wilcoxon rank-sum test, and multiple linear regression were used for statistical analyses. RESULTS: Of 466 women, initial marijuana usage in pregnancy confirmed by urine drug test increased after legalization from 6 to 11% (p = .05). Factors associated with marijuana usage included younger age, white or black race, single marital status, psychiatric disorders, intimate partner violence and concomitant tobacco and alcohol use. 73% of users in this study had cessation of marijuana use with subsequent negative UDT. There was no statistical difference in rates of preterm birth, small for gestational age, NICU admission, or Apgar scores, when adjusted for other risk factors. CONCLUSION: Rates of marijuana usage in pregnant women who underwent universal drug screening increased after legalization. There were no differences in neonatal outcomes between users and non-users.

Trends in extent of surgical cytoreduction for patients with ovarian cancer.

PURPOSE: To identify patient and hospital characteristics associated with extended surgical cytoreduction in the treatment of ovarian cancer. METHODS: A retrospective analysis using the National Inpatient Sample (NIS) database identified women hospitalized for surgery to remove an ovarian malignancy between 2013 and 2017. Extended cytoreduction (ECR) was defined as surgery involving the bowel, liver, diaphragm, bladder, stomach, or spleen. Chi-square and logistic regression were used to analyze patient and hospital demographics related to ECR, and trends were assessed using the Cochran-Armitage test. RESULTS: Of the estimated 79,400 patients undergoing ovarian cancer surgery, 22% received ECR. Decreased adjusted odds of ECR were found in patients with lower Elixhauser Comorbidity Index (ECI) scores (OR 0.61, p<0.001 for ECI 2, versus ECI≥3) or residence outside the top income quartile (OR 0.71, p<0.001 for Q1, versus Q4), and increased odds were seen at hospitals with high ovarian cancer surgical volume (OR 1.25, p<0.001, versus low volume). From 2013 to 2017, there was a decrease in the proportion of cases with extended procedures (19% to 15%, p<0.001). There were significant decreases in the proportion of cases with small bowel, colon, and rectosigmoid resections (p<0.001). Patients who underwent ECR were more likely treated at a high surgical volume hospital (37% vs 31%, p<0.001) over the study period. For their hospital admission, patients who underwent ECR had increased mortality (1.6% vs. 0.5%, p<0.001), length of stay (9.6 days vs. 5.2 days, p<0.001), and mean cost ($32,132 vs. $17,363, p<0.001). CONCLUSIONS: Likelihood of ECR was associated with increased medical comorbidity complexity, higher income, and undergoing the procedure at high surgical volume hospitals. The proportion of ovarian cancer cases with ECR has decreased from 2013-17, with more cases performed at high surgical volume hospitals.

Uterine clear cell carcinoma risk in White versus non-White US subpopulations: does race matter?

OBJECTIVE: To determine incidence rates of uterine clear cell carcinoma among non-White US subpopulations. METHODS: Data from the United States Cancer Statistics and National Cancer Database from 2004 to 2016 were analyzed using descriptive statistics. RESULTS: A total of 488,811 women were diagnosed with uterine cancer from 2004-2016. Of these, 73.3% were endometrioid, 6.6% were serous, 5.3% were carcinosarcoma, 1.4% were clear cell, and 13.4% were other. Blacks had the highest incidence rate of uterine clear cell compared with Whites, Asian/Pacific Islanders, and American Indian/Alaska Natives (0.59 vs. 0.31, 0.29, and 0.24, respectively). Overall mean age at diagnosis was 68.6 years, with the youngest age in Asian/Pacific Islanders compared to Whites, Blacks, and American Indian/Alaska Natives (65.9 vs. 68.7, 68.6, and 66.3 years, respectively). Analysis of the Asian subpopulation revealed significantly younger age at diagnosis in Vietnamese women (55.8 years) compared with 72.4 years in Japanese, 68.6 years in Pacific Islander, 66.6 years in Indian/Pakistani, 65.9 years in Filipino, 65.8 years in Chinese, 65.2 years in Korean, and 63.7 years in other Asians. CONCLUSIONS: Black women are two times more likely to be diagnosed with uterine clear cell carcinoma compared with other races. Asians present at younger ages, with Vietnamese women most likely to be diagnosed at the youngest age.

Readmissions after ovarian cancer cytoreduction surgery: The first 30 days and beyond.

BACKGROUND AND OBJECTIVES: Postoperative readmissions are often used to assess quality of surgical care. This study compared 30-day vs 31- to 90-day readmission following surgery for ovarian, fallopian tube, or primary peritoneal cancer. METHODS: This retrospective study of the 2010-2015 Nationwide Readmissions Database characterized 90-day readmissions following cytoreductive surgery for these cancers. Each patient's first postoperative hospitalization was included. Univariate analysis compared patient demographics and reasons for readmission. Multivariable regression identified independent predictors of readmission. RESULTS: Of an estimated 76 652 patients, 10 264 (13.4%) were readmitted within 30 days, and 6942 (9.1%) between 31 and 90 days. The 30-day readmissions were more frequently associated with postoperative infection, while 31- to 90-day readmissions were more frequently associated with renal or hematologic diagnoses. Predictors of any 90-day readmission included index hospitalization longer than 7 days (adjusted odds ratio (AOR) 1.61 [1.48-1.75], P < .001), extended surgical procedure (AOR 1.41 [1.30-1.53], P < .001), pulmonary circulation disorder (AOR = 1.34 [1.13-1.60], P = .001), and diabetes mellitus (AOR = 1.12 [1.02-1.24], P = .020). CONCLUSIONS: Readmission rates remain high during the 31- to 90-day postoperative period in ovarian cancer patients, although these readmissions are less frequently related to postoperative complications. Prospective study is merited to optimize surveillance beyond the initial 30 days after ovarian cancer surgery.

Cancer Genetic Counseling and Testing: Perspectives of Epithelial Ovarian Cancer Patients and Gynecologic Oncology Healthcare Providers.

Multi-gene panel testing has expanded the genetic information available to cancer patients. The objective was to assess provider behaviors and attitudes and patient knowledge and attitudes towards genetic counseling and testing. An online survey was distributed to Society of Gynecologic Oncology members and a written questionnaire was administered to patients diagnosed with epithelial ovarian cancer at a tertiary care referral center. Most of the 233 (18% response rate) provider respondents were gynecologic oncologists. Access to a genetic counselor was reported by 87% of providers and 55% deferred all testing to genetic counselors. Of 53 ovarian cancer patient respondents, two-thirds had previously seen a genetic counselor or undergone testing. Patients' attitudes about genetic counseling and/or testing were favorable with respect to themselves (70-81%) and their family members (94%). Less than 25% of patients indicated worrying about health care discrimination, lack of privacy, or high cost. Seventy-seven percent of patients demonstrated a desire to obtain genetic information even if the results were not currently actionable, and 20% of providers stated they test for only those genes with guideline-supported actionable results. Provider practice differences were identified in screening and prevention strategies for patients with deleterious non-BRCA mutations and variants of uncertain significance. The variation in clinical interpretation of results associated with poorly defined cancer risks signals a need for more comprehensive training and guidelines to ensure access to evidence-based care.

MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia.

The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. Cancer Res; 77(24); 7038-48. ©2017 AACR.

Disruption of in vivo Chronic Lymphocytic Leukemia Tumor-Microenvironment Interactions by Ibrutinib--Findings from an Investigator-Initiated Phase II Study.

PURPOSE: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B-cell receptor (BCR) signaling. Ibrutinib, a Bruton tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. Although the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment. EXPERIMENTAL DESIGN: Patients received single-agent ibrutinib on an investigator-initiated phase II trial. Serial blood and tissue samples were collected pretreatment and during treatment. Changes in cytokine levels, cellular subsets, and microenvironmental interactions were assessed. RESULTS: Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Furthermore, ibrutinib treatment decreased circulating tumor cells and overall T-cell numbers. Most notably, a reduced frequency of the Th17 subset of CD4(+)T cells was observed concurrent with reduced expression of activation markers and PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4(+)T cells in vitro Finally, in the bone marrow microenvironment, we found that ibrutinib disaggregated the interactions of macrophages and CLL cells, inhibited secretion of CXCL13, and decreased the chemoattraction of CLL cells. CONCLUSIONS: In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the antitumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL. See related commentary by Bachireddy and Wu, p. 1547.

Treatment with Ibrutinib Inhibits BTK- and VLA-4-Dependent Adhesion of Chronic Lymphocytic Leukemia Cells In Vivo.

PURPOSE: Ibrutinib leads to a transient lymphocytosis in patients with chronic lymphocytic leukemia (CLL) that develops within hours of starting drug and is due to the efflux of cells from lymphoid tissues into the blood. We therefore sought to investigate the in vivo effect of ibrutinib on migration and adhesion of CLL cells. EXPERIMENTAL DESIGN: Patients received single-agent ibrutinib (420 mg daily) on an investigator-initiated phase II trial. Serial blood samples were collected pretreatment and during treatment for ex vivo functional assays. RESULTS: Adhesion of CLL cells to fibronectin was rapidly (within hours) and almost completely inhibited (median reduction 98% on day 28, P < 0.001), while the effect on migration to chemokines was more moderate (median reduction 64%, P = 0.008) and less uniform. Although cell surface expression of key adhesion molecules such as CD49d, CD29, and CD44 were modestly reduced, this was only apparent after weeks of treatment. Stimulation of CLL cells from patients on ibrutinib with PMA, which activates PKC independent of BTK, restored the ability of the cells to adhere to fibronectin in a VLA-4-dependent manner. Finally, the addition of ibrutinib to CLL cells adhered to fibronectin in vitro caused the detachment of 17% of the cells, on average; consisten t with in vivo observations of an increasing lymphocytosis within 4 hours of starting ibrutinib. CONCLUSIONS: Inhibition of BTK and VLA-4-dependent adhesion of CLL cells to stroma and stromal components provides a mechanistic explanation for the treatment-induced lymphocytosis and may reduce CD49d-dependent prosurvival signals in the tissue microenvironment.