Citations

ObjectivesThis study investigated the reproducibility of standardization of lung‐to‐head ratio measurements in congenital diaphragmatic hernia (CDH) at our center among sonographers after we standardized the method.MethodsWe reviewed ultrasound images of 12 fetuses with CDH at Mayo Clinic from 2010 to 2016. Nine operators (1 maternal‐fetal medicine specialist with experience in measuring the lung‐to‐head ratio and 8 sonographers), who were blinded to previous findings, reviewed 33 selected images from 12 fetuses with left CDH. The method for lung‐to‐head ratio measurement was standardized before starting the measurements. The lung‐to‐head ratio was assessed by different methods to obtain the lung areas: anteroposterior, longest, and area tracing. We evaluated the correlation between operators using the intraclass correlation coefficient (ICC). We also compared agreement between the sonographers and a physician with experience in measuring the lung‐to‐head ratio using a Bland‐Altman analysis.ResultsThe methods with the best interoperator reproducibility were the standardized anteroposterior lung‐to‐head ratio (ICC, 0.69) and the standardized lung‐to‐head ratio tracing (ICC, 0.65) compared to the longest lung‐to‐head ratio (ICC, 0.56). The standardized lung‐to‐head ratio tracing had the best agreement among sonographers and the physician (bias, 0.11; limits of agreement, −0.27 to +0.49) than the anteroposterior lung‐to‐head ratio (bias, 0.35; limits of agreement, −0.13 to + 0.83) and the longest lung‐to‐head ratio (bias, 0.27; limits of agreement, −0.35 to +0.89).ConclusionsWe demonstrated that the lung‐to‐head ratio tracing method has high interoperator reproducibility and the best agreement among the operators at our center. Further multicenter studies are necessary to confirm our results.

What's already known about this topic? LUTO is a rare but life‐threatening condition affecting the fetus and child in which prenatal therapy is currently being offered but remains controversial. A recent RCT comparing this treatment to post‐natal treatment in selected cases failed to come to robust conclusions due to under‐recruitment. So, the controversy persists. What does this study add? In this debate, 2 renown experts in the field develop their arguments pro and against shunting for all LUTO cases based on the current literature and a long‐standing clinical experience in the field of fetal therapy.

ProblemPregnancy requires balance between tolerance to the haploidentical fetus and the mother's ability to mount immune responses. There are parallels to this phenomenon that occur in metastatic cancer. We assessed soluble program death ligand‐1 soluble PD‐L1 (sPD‐L1) and galectin‐9 in the blood of pregnant women during gestation as these molecules are highly involved in immune suppression during cancer.Method of studyMaternal blood was collected from 30 primigravida women at monthly intervals during pregnancy, delivery and 6‐week post‐partum. Blood was analyzed for sPD‐L1 and galectin‐9 concentrations by ELISA. Term placentas were collected in formalin and IHC was completed for PD‐L1 and galectin‐9 expression.ResultsMaternal blood levels of sPD‐L1 (0.438 ng/mL) and galectin‐9 (1976 pg/mL) were elevated early in normal pregnancies compared to non‐pregnant controls (0.242 ng/mL and 773 pg/mL, respectively). sPD‐L1 increased throughout gestation, whereas galectin‐9 remained elevated until parturition; both proteins returned to control levels post‐partum. Women carrying male fetuses had significantly higher galectin‐9 levels, but not sPD‐L1, than those carrying females (2263 pg/mL vs 1874 pg/mL; P = .0005). Trophoblast cells of the term placenta coexpress galectin‐9 and PD‐L1.ConclusionImmune‐regulatory molecules galectin‐9 and sPD‐L1 increased during pregnancy and may play a role in immune tolerance that is critical for the fetus.

What is already known about this topic? Lower urinary tract obstruction is associated with high morbidity and mortality. Fetal cystoscopy may allow the correct identification of the etiology of the obstruction and may provide the adequate treatment. What does this study add? Three‐dimensional virtual navigation is a noninvasive approach that provides an immersive virtual reality in the assessment of fetal structures. Three‐dimensional virtual cystoscopy provides a noninvasive evaluation of fetal lower urinary tract obstruction that in the future may help in the selection of candidates for fetal cystoscopy.

Objective: The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients. Study Selection: Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included. Data Sources: Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies. Data Extraction: Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality. Data Synthesis: Use of aspirin was associated with a 7% (95% CI, 2–12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I 2 = 61.6%). Conclusions: These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis.

Abstract Dysregulation of estrogen receptor gene (ESR1) is an established mechanism of inducing endocrine therapy resistance. We previously discovered a chromosomal translocation event generating an estrogen receptor gene fused in-frame to C-terminal sequences of YAP1 (ESR1-YAP1) that contributed to endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer models. This current study compares functional and pharmacological properties of additional ESR1 gene fusion events of both early stage (ESR1-NOP2) and advanced endocrine therapy resistant (ESR1-YAP1 and ESR1-PCDH11x) breast cancers. The YAP1 and PCDH11x fusions conferred estrogen-independent and fulvestrant-resistant growth in T47D, an ER+ breast cancer cell line in vitro and in vivo, in contrast to the NOP2 fusion which was sensitive to hormone deprivation. Immunohistochemical (IHC) staining of mouse lungs revealed significantly higher numbers of micrometastatic ER+ cells from the T47D tumors expressing the YAP1 and PCDH11x fusions than YFP control and NOP2 fusion. Estrogen response element (ERE) reporter and pull down assays revealed that although all ESR1 fusions studied bound EREs, only the YAP1 and PCDH11x caused ERE activation. Cell lines containing these “canonical” ESR1 fusions upregulated expression of ER responsive genes such as TFF1 and GREB1 in hormone deprived conditions. In contrast, the NOP2 fusion neither induced ERE activity nor upregulated TFF1 and GREB1 gene expression. The proliferative ability of canonical fusion-containing T47D cells was inhibited by palbociclib, a CDK4/6 inhibitor, in a dose-dependent manner. In vivo growth of patient-derived xenograft tumors naturally harboring the ESR1-YAP1 fusion (WHIM18) was significantly reduced in mice fed palbociclib-containing chow. Mice transplanted with WHIM18 also formed lung micrometastases, with an ER IHC staining pattern similar to lungs from YAP1 and PCDH11x fusion expressing T47D xenografts. In conclusion, in-frame ERE activating canonical fusions occur in end-stage, drug resistant, advanced breast cancer and can be added to ESR1 point mutations as a class of somatic mutation that may cause acquired resistance. Endocrine therapy resistant growth induced by these fusions can be treated with CDK4/6 inhibition, using an FDA approved drug, palbociclib, which could potentially improve outcomes in patients with ESR1 translocated tumors. Citation Format: Jonathan T. Lei, Jieya Shao, Jin Zhang, Michael Iglesia, Doug W. Chan, Ryoichi Matsunuma, Xiaping He, Purba Singh, Yoshimasa Kosaka, Robert Crowder, Svasti Haricharan, Shyam Kavuri, Jeremy Hoog, Chanpheng Phommaly, Rodrigo Goncalves, Susana Romalho, Wei-Chu Lai, Oliver Hampton, Anna Rogers, Ethan Tobias, Poojan Parikh, Sherri Davies, Cynthia Ma, Vera Suman, Kelly Hunt, Mark Watson, Katherine A. Hoadley, Aubrey Thompson, Charles Perou, Chad J. Creighton, Chris Maher, Matthew J. Ellis. Estrogen receptor gene fusions drive endocrine therapy resistance in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1033. doi:10.1158/1538-7445.AM2017-1033