Peripherally-driven myeloid NFkB and IFN/ISG responses predict malignancy risk, survival, and immunotherapy regime in ovarian cancer

BackgroundTumors can influence peripheral immune macroenvironment, thereby creating opportunities for non-invasive serum/plasma immunobiomarkers for immunostratification and immunotherapy designing. However, current approaches for immunobiomarkers’ detection are largely quantitative, which is unreliable for assessing functional peripheral immunodynamics of patients with cancer. Hence, we aimed to design a functional biomarker modality for capturing peripheral immune signaling in patients with cancer for reliable immunostratification.MethodsWe used a data-driven in silico framework, integrating existing tumor/blood bulk-RNAseq or single-cell (sc)RNAseq datasets of patients with cancer, to inform the design of an innovative serum-screening modality, that is, serum-functional immunodynamic status (sFIS) assay. Next, we pursued proof-of-concept analyses via multiparametric serum profiling of patients with ovarian cancer (OV) with sFIS assay combined with Luminex (cytokines/soluble immune checkpoints), CA125-antigen detection, and whole-blood immune cell counts. Here, sFIS assay’s ability to determine survival benefit or malignancy risk was validated in a discovery (n=32) and/or validation (n=699) patient cohorts. Lastly, we used an orthotopic murine metastatic OV model, with anti-OV therapy selection via in silico drug–target screening and murine serum screening via sFIS assay, to assess suitable in vivo immunotherapy options.ResultsIn silico data-driven framework predicted that peripheral immunodynamics of patients with cancer might be best captured via analyzing myeloid nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) signaling and interferon-stimulated genes' (ISG) responses. This helped in conceptualization of an ‘in sitro’ (in vitro+in situ) sFIS assay, where human myeloid cells were exposed to patients’ serum in vitro, to assess serum-induced (si)-NFκB or interferon (IFN)/ISG responses (as active signaling reporter activity) within them, thereby ‘mimicking’ patients’ in situ immunodynamic status. Multiparametric serum profiling of patients with OV established that sFIS assay can: decode peripheral immunology (by indicating higher enrichment of si-NFκB over si-IFN/ISG responses), estimate survival trends (si-NFκB or si-IFN/ISG responses associating with negative or positive prognosis, respectively), and coestimate malignancy risk (relative to benign/borderline ovarian lesions). Biologically, we documented dominance of pro-tumorigenic, myeloid si-NFκB responseHIGHsi-IFN/ISG responseLOW inflammation in periphery of patients with OV. Finally, in an orthotopic murine metastatic OV model, sFIS assay predicted the higher capacity of chemo-immunotherapy (paclitaxel–carboplatin plus anti-TNF antibody combination) in achieving a pro-immunogenic peripheral milieu (si-IFN/ISG responseHIGHsi-NFκB responseLOW), which aligned with high antitumor efficacy.ConclusionsWe established sFIS assay as a novel biomarker resource for serum screening in patients with OV to evaluate peripheral immunodynamics, patient survival trends and malignancy risk, and to design preclinical chemo-immunotherapy strategies.

Prenatal serum screening for Down syndrome and neural tube defects in the United States: Changes in utilization patterns from 2012 to 2020

Objective To compile current usage of serum-based prenatal screening for Down syndrome in the United States and compare it with results from a similar 2011/2012 survey. Setting The College of American Pathologists maternal screening proficiency testing survey includes a supplemental question on the first of three yearly distributions. Methods Information regarding tests offered and the monthly number of pregnancies tested for US-based laboratories were reviewed. Results were stratified by size of laboratory, tests offered, and pregnancies tested. Findings were compared to an earlier survey. Results Fifty-six laboratories reported they will have screened 1,131,336 pregnancies in 2020. Of these, 36% are screened by stand-alone first trimester testing, 48% by stand-alone second trimester testing, and 16% using tests that integrate results from both trimesters. Eighty percent of all serum screens were provided by the five laboratories that performed the most screens (at least 50,000). These five performed similar proportions of first or second trimester screens (42.2% and 41.8%, respectively). Compared to eight years earlier, there are now 54% fewer laboratories. Pregnancies screened using the first trimester, second trimester, and integrated protocols were lower by 27%, 69%, and 72%, respectively. The serum screening activity in the US showed a 62% decrease from 2012 levels. During 2012–2020, the number of cell-free DNA tests increased from negligible to 1,492,332. Conclusions Maternal serum screening for common aneuploidies has changed significantly in eight years with fewer laboratories, a shift toward larger laboratories and a 2.5-fold reduction in pregnancies tested, likely due to the introduction of cell-free DNA screening.

Clinical experience of Umbilical Cord cysts from a Chinese single centre

BackgroundThe aim of this series was to guide the prenatal management of umbilical cord cysts by summarizing their clinical datas.MethodsA retrospected study from Jan 2012 to May 2019 was conducted in our centre from Women’s Hospital, School of Medicine, Zhejiang University. Clinical datas and pregnancy outcomes of women with umbilical cord cysts were reviewed from the hospital’s electronic record and descriptive information about the umbilical cord cysts were depicted from both the sonograms and macrography.ResultsTwenty-eight women were diagnosed with umbilical cord cysts during the last six years,of whom only three had therapeutic abortion for fetal malformations and twenty-three were diagnosed between 12 + and 38 + gestational week(GW). Eight had only maternal serum screening, six had non-invasive prenatal testing (NIPT) directly and six had both tests. Three had karyotype analysis while five cases had no record.With maternal serum screening,one had high risk and the other one had middle risk and they both further had NIPT low risk.Still another one had a HCG multiple of median (MoM) up to 2.9 whose fetal had left kidney cyst.Except umbilical cord cysts, six fetus had other sructural defects including multiple malformation,single umbilical artery,acromphalus and kidney absence or cyst.There were still two cases had fetal arrhythmia and atrial premature beats.The mean delivery week was 39 + GW, six women had successful vaginal delivery and the remaing had cesarean section. The mean birth weight was 3120 g and the majority had a good pregnancy outcome.ConclusionsUmbilical cord cysts were rare but might warn fetal structural defects or chromosomal abnormality. Systematic ultrasound assessment and karyotype analysis or NIPT at least should be suggested in their prenatal counseling. More attention should be paid to fetal distress during pregnancy and vaginal delivery could be a choose unless they had other contraindication.