Objective Bacteria have been identified in different regions of the placenta. Here, we tested the hypothesis that the maternal basal plate of the placenta harbors microbes which may be associated with adverse pregnancy outcomes. Study Design We performed a cross-sectional study of pregnancies from a single tertiary care hospital. Maternal medical and obstetric characteristics were obtained and pregnancies followed prospectively for outcomes and placental collection. After delivery, systematic random sampling of the placental basal plate was performed. Paraffin sections of basal plates were stained with four histological stains and scored for morphological evidence of bacteria. Results Of 195 total patients in the study, Gram positive and negative intracellular bacteria of diverse morphologies were documented in the basal plates of 27% of all placentas. 35% of the patients delivered preterm. No difference was noted between placental basal plates from preterm or term gestations. Intracellular bacteria were found in the placental basal plates of 54% spontaneous preterm deliveries before 28 weeks, and in 26% of term spontaneous deliveries (p=0.02). Intracellular bacteria were also documented in placentas without clinical or pathologic chorioamnionitis. Conclusions 27% of placentas demonstrated intracellular bacteria in the placental basal plate using morphological techniques. Thus, the maternal basal plate is a possible source of intrauterine colonization and placental pathological examination could include examination for bacteria in this important maternal fetal interface.

Background The leading cause of mortality for patients with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the development of malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma. In the setting of NF1, this cancer type frequently arises from within its common and benign precursor, plexiform neurofibroma (PN). Transformation from PN to MPNST is challenging to diagnose due to difficulties in distinguishing cross-sectional imaging results and intralesional heterogeneity resulting in biopsy sampling errors. Methods and findings This multi-institutional study from the National Cancer Institute and Washington University in St. Louis used fragment size analysis and ultra-low-pass whole genome sequencing (ULP-WGS) of plasma cell-free DNA (cfDNA) to distinguish between MPNST and PN in patients with NF1. Following in silico enrichment for short cfDNA fragments and copy number analysis to estimate the fraction of plasma cfDNA originating from tumor (tumor fraction), we developed a noninvasive classifier that differentiates MPNST from PN with 86% pretreatment accuracy (91% specificity, 75% sensitivity) and 89% accuracy on serial analysis (91% specificity, 83% sensitivity). Healthy controls without NF1 (participants = 16, plasma samples = 16), PN (participants = 23, plasma samples = 23), and MPNST (participants = 14, plasma samples = 46) cohorts showed significant differences in tumor fraction in plasma (P = 0.001) as well as cfDNA fragment length (P < 0.001) with MPNST samples harboring shorter fragments and being enriched for tumor-derived cfDNA relative to PN and healthy controls. No other covariates were significant on multivariate logistic regression. Mutational analysis demonstrated focal NF1 copy number loss in PN and MPNST patient plasma but not in healthy controls. Greater genomic instability including alterations associated with malignant transformation (focal copy number gains in chromosome arms 1q, 7p, 8q, 9q, and 17q; focal copy number losses in SUZ12, SMARCA2, CDKN2A/B, and chromosome arms 6p and 9p) was more prominently observed in MPNST plasma. Furthermore, the sum of longest tumor diameters (SLD) visualized by cross-sectional imaging correlated significantly with paired tumor fractions in plasma from MPNST patients (r = 0.39, P = 0.024). On serial analysis, tumor fraction levels in plasma dynamically correlated with treatment response to therapy and minimal residual disease (MRD) detection before relapse. Study limitations include a modest MPNST sample size despite accrual from 2 major referral centers for this rare malignancy, and lack of uniform treatment and imaging protocols representing a real-world cohort. Conclusions Tumor fraction levels derived from cfDNA fragment size and copy number alteration analysis of plasma cfDNA using ULP-WGS significantly correlated with MPNST tumor burden, accurately distinguished MPNST from its benign PN precursor, and dynamically correlated with treatment response. In the future, our findings could form the basis for improved early cancer detection and monitoring in high-risk cancer-predisposed populations.

Objective The maternal-fetal interface must modulate immune function to allow tolerance of fetal cells while still reacting to pathogens to suppress infection. Human leukocyte antigen-G (HLA-G) is a class Ib major histocompatibility complex protein involved in maternal-fetal tolerance. We posited that alterations in placental HLA-G expression predispose women to preterm birth. The aim of this study was to compare HLA-G expression in the maternal-fetal interface of term versus preterm human placentas. Methods We performed a cross-sectional study of specimens from the basal plate of the human placenta from women enrolled in a tissue specimen and clinical data consortium. Immunohistochemistry with digital microscopic analysis was used to quantify HLA-G protein expression in the basal plate from preterm and term placentas. Results Preterm birth <37 weeks occurred in 29.5% of 149 singleton pregnancies. HLA-G-positive cells occupied one-third of the basal plates, and the HLA-G-positive area was increased by 14% in placentas from preterm births than in those from term births (32.1% in term placentas versus 36.6% in preterm placentas). Conclusion Although HLA-G is required for maternal tolerance of the semi-allogeneic fetus, higher levels of HLA-G expression at the maternal fetal interface is associated with preterm birth.

To report the interim analysis of the phase II single arm noninferiority trial testing the upfront use of dexrazoxane with doxorubicin on progression free survival (PFS) and cardiac function in soft tissue sarcoma (STS). Patients and MethodsPatients with metastatic or unresectable STS who were candidates for first line treatment with doxorubicin were deemed eligible. An interim analysis was initiated after 33/65 patients were enrolled. Using the historical control of 4.6 months progression free survival (PFS) for doxorubicin in the front-line setting, we tested if the addition of dexrazoxane affected the efficacy of doxorubicin in STS. The study was powered so that a decrease of PFS to 3.7 months would be considered non-inferior. Secondary aims included cardiac related mortality, incidence of heart failure/cardiomyopathy, and expansion of cardiac monitoring parameters including 3D echocardiography. Patients were allowed to continue on doxorubicin beyond 600 mg/m 2 if they were deriving benefit and were not demonstrating evidence of symptomatic cardiac dysfunction. ResultsAt interim analysis, upfront use of dexrazoxane with doxorubicin demonstrated a PFS of 8.4 months (95% confidence interval: 5.1 -11.2 months). Only 3 patients were removed from study for cardiotoxicity, all on > 600 mg/m 2 doxorubicin. No patients required cardiac hospitalization or had new, persistent cardiac dysfunction with left ventricular ejection fraction remaining below 50%. The median administered doxorubicin dose was 450 mg/m 2 (interquartile range 300-750 mg/m 2 ). April 4, 2021. Conclusions on

BackgroundThe leading cause of mortality for patients with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome is development of Malignant Peripheral Nerve Sheath Tumor (MPNST), an aggressive soft tissue sarcoma. In the setting of NF1, this cancer type frequently arises from within its common and benign precursor, plexiform neurofibroma (PN). Transformation from the benign PN to MPNST is challenging to diagnose due to difficulties in distinguishing cross-sectional imaging results and intralesional heterogeneity resulting in biopsy sampling errors.Methods and FindingsThis multi-institutional study used ultra-low-pass whole genome sequencing (ULP-WGS) of plasma cell-free DNA (cfDNA) to distinguish between MPNST and PN in patients with NF1. Using copy number to estimate the fraction of plasma cfDNA originating from tumor (tumor fraction), we developed a noninvasive classifier which differentiates MPNST from PN with 91% specificity. Healthy controls without NF1 (subjects = 14, plasma samples= 14), PN (subjects = 45, plasma samples = 45), and MPNST (subjects = 14, plasma samples = 48) cohorts showed significant differences in tumor fraction in plasma (P = 0.006) as well as cfDNA fragment length (P < 0.001) with MPNST samples harboring shorter fragments and being enriched for tumor-derived cfDNA relative to PN and healthy controls. Mutational analysis demonstrated focal NF1 copy number loss in PN and MPNST patient plasma but not in healthy controls. Genomic alterations associated with malignant transformation (focal copy number gains in chromosome 8 and copy number losses in SUZ12, SMARCA2, CDKN2A/B, and chromosome arm 9p) were more prominently observed in MPNST plasma. Furthermore, the sum of longest tumor diameters (SLD) visualized by cross-sectional imaging correlated significantly with paired tumor fractions in plasma from MPNST patients (ρ = 0.50, P = 0.0007). On case series analysis, tumor fraction levels in plasma correlated with treatment response to therapy and minimal residual disease (MRD) detection before relapse.ConclusionsTumor fraction levels derived from copy number alteration analysis of plasma cfDNA using ULP-WGS significantly correlated with MPNST tumor burden, distinguished MPNST from its benign PN precursor, and correlated with treatment response. In the future, our findings could form the basis for improved early cancer detection and monitoring in high-risk cancer-predisposed populations.