Circulating tumor DNA monitoring for early recurrence detection in epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. We examined the utility of circulating tumor DNA (ctDNA) as a prognostic biomarker for EOC by assessing its relationship with patient outcome and CA-125, pre-surgically and during post-treatment surveillance. METHODS: Plasma samples were collected from patients with stage I-IV EOC. Cohort A included patients with pre-surgical samples (N = 44, median follow-up: 2.7 years), cohort B and C included: patients with serially collected post-surgically (N = 12) and, during surveillance (N = 13), respectively (median follow-up: 2 years). Plasma samples were analyzed using a tumor-informed, personalized multiplex-PCR NGS assay; ctDNA status and CA-125 levels were correlated with clinical features and outcomes. RESULTS: Genomic profiling was performed on the entire cohort and was consistent with that seen in TCGA. In cohort A, ctDNA-positivity was observed in 73% (32/44) of presurgical samples and was higher in high nuclear grade disease. In cohort B and C, ctDNA was only detected in patients who relapsed (100% sensitivity and specificity) and preceded radiological findings by an average of 10 months. The presence of ctDNA at a single timepoint after completion of surgery +/- adjuvant chemotherapy and serially during surveillance was a strong predictor of relapse (HR:17.6, p = 0.001 and p < 0.0001, respectively), while CA-125 positivity was not (p = 0.113 and p = 0.056). CONCLUSIONS: The presence of ctDNA post-surgically is highly prognostic of reduced recurrence-free survival. CtDNA outperformed CA-125 in identifying patients at highest risk of recurrence. These results suggest that monitoring ctDNA could be beneficial in clinical decision-making for EOC patients.

An integrated molecular profile of endometrioid ovarian cancer.

OBJECTIVE: Endometrioid ovarian carcinoma (EOVC) is an uncommon subtype of epithelial ovarian carcinoma and its molecular characteristics have been incompletely described. Prior sequencing investigations have been limited to targeted gene panels. We performed whole-exome sequencing to build an unbiased genetic profile of molecular alterations in endometrioid ovarian tumors with a goal to better understand this disease in the context of epithelial ovarian cancer and endometrioid uterine cancers. METHODS: Whole-exome sequencing was performed on EOVC samples (n = 26) and matched normals (n = 15). Gene mutations, mutational signatures and copy number variations (CNVs) informed a multi-dimensional regression classifier allowing for comparison to endometrial carcinoma (UCEC) and high grade serous ovarian carcinoma (HGSC). RESULTS: EOVC has a distinct and heterogeneous genomic profile. Identified significantly mutated genes in EOVC (PTEN, CTNNB1, PIK3CA, KMT2D, KMT2B, PIK3R1, ARID1A and TP53) occurred at similar frequencies in UCEC. Hypermutation, resulting from both mismatch repair deficiency (MMRd) and POLE mutation, was observed in EOVC at a frequency similar to UCEC. Like UCEC, a subset of EOVC cases closely resembled HGSC, harboring TP53 mutations, homologous recombination deficiency (HRd) mutation signatures and widespread CNVs. A machine-learning classifier confirmed the heterogeneous composition of EOVC. Potential therapeutic targets were identified in 62% of EOVC cases. We validated our findings in an orthogonal clinical sequencing registry of EOVC cases. CONCLUSIONS: We identified that EOVC are a molecularly heterogeneous group of epithelial ovarian cancers with distinct mutational signatures. In an age of precision oncology, there is a pressing need to understand the unique molecular drivers in uncommon histologic subtypes to facilitate genomically driven oncologic treatments.

Racial and Ethnic Differences in Patient-Reported Acceptability of Adverse Childhood Experience (ACE) Screening in Adult Primary Care.

BACKGROUND: Given the dose-response relationship between adverse childhood experiences (ACEs) and worse health outcomes, there has been a growing push for routine ACE screening in healthcare settings. OBJECTIVE: This study explored differences in patient-reported acceptability of ACE screening among adult primary care patients. PARTICIPANTS AND SETTING: Participants were adult primary care patients at an academic safety-net internal medicine clinic. Of the 136 patients who elected to participate in this study, 131 (96%) submitted completed surveys. METHODS: Adult primary care patients at an academic safety-net internal medicine clinic completed an ACE screener and follow-up survey assessing their reported acceptability of ACE screening. Patients were also asked to specify their race, ethnicity, gender, and age. Chi-square analysis and Fisher's exact tests were used to examine associations between variables. RESULTS: Among 131 patients, 37% reported 4 or more ACEs. Black/African American patients and Hispanic/Latinx patients were overrepresented in the high ACE score (4 +) group (p < 0.05). Over one in three of all patients did not find ACE screening to be an acceptable part of their primary care. After a Bonferroni adjustment, patient-reported acceptability was not statistically associated with patients' ACE score or patients' race, ethnicity, gender, or age. Notably, however, in our small sample of Native American and Hispanic/Latino patients, over half did not find ACE screening to be acceptable. CONCLUSIONS: There is insufficient evidence to conclude that patients find ACE screening to be an acceptable part of their primary care. Our study is the first to explore how patient-reported acceptability may vary with patient demographics. While our findings revealed no significant associations between patient demographics and acceptability, trends observed within our study suggest that future studies with larger and more representative samples are needed. We consider routine ACE screening to be unsubstantiated and premature, and instead encourage the development of comprehensive trauma-informed practices for which a disclosure of childhood adversity is not necessary.

PET-detected asymptomatic recurrence is associated with improved survival in recurrent cervical cancer.

PURPOSE: We aimed to examine utilization patterns of positron emission tomography scans (PET or PET/CT) beyond 6 months after cervical cancer treatment. We investigated survival outcomes of asymptomatic patients with PET-detected recurrence. METHODS: We performed a retrospective review of 283 patients with stage IA-IVA cervical cancer treated with primary chemoradiation. The 107 patients (37.8%) with recurrence were categorized as "asymptomatic PET-detected recurrence" (n = 23) or "standard detection" (n = 84) and we compared clinical characteristics and outcomes using multivariate logistic regression analysis. RESULTS: Late post-treatment PET (≥ 6 months after treatment) was performed in 35.3% (n = 100). Indications for late post-treatment PET included restaging in setting of known recurrence (23.6%), follow up of prior ambiguous imaging findings (9.7%), and new symptoms or exam findings (6.7%). However, late post-treatment PET was most commonly performed outside of current imaging guidelines, in asymptomatic patients without suspicion for recurrence (60.0%), presumably for surveillance. The median time to recurrence was 12.1 months (IQR 7.3-26.6). 23 patients (21.5%) had recurrence detected late post-treatment PET while asymptomatic (n = 23/107). Patients with asymptomatic PET-detected recurrence had improved survival by 26.3 months compared to the standard detection cohort (50.3 vs 24.0 months, p = 0.0015). On multivariate analysis, predictors of survival after recurrence were presence of distant metastases at diagnosis (p = 0.010) and asymptomatic PET-detected recurrence (p = 0.039). CONCLUSIONS: PET imaging in asymptomatic patients beyond 6 months after treatment may have clinical benefit and warrants further study. Detection of recurrence by PET in asymptomatic patients ≥ 6 months after chemoradiation was associated with prolonged survival by more than   2 years.

Uniformity of Peptide Release Is Maintained by Methylation of Release Factors.

Termination of protein synthesis on the ribosome is catalyzed by release factors (RFs), which share a conserved glycine-glycine-glutamine (GGQ) motif. The glutamine residue is methylated in vivo, but a mechanistic understanding of its contribution to hydrolysis is lacking. Here, we show that the modification, apart from increasing the overall rate of termination on all dipeptides, substantially increases the rate of peptide release on a subset of amino acids. In the presence of unmethylated RFs, we measure rates of hydrolysis that are exceptionally slow on proline and glycine residues and approximately two orders of magnitude faster in the presence of the methylated factors. Structures of 70S ribosomes bound to methylated RF1 and RF2 reveal that the glutamine side-chain methylation packs against 23S rRNA nucleotide 2451, stabilizing the GGQ motif and placing the side-chain amide of the glutamine toward tRNA. These data provide a framework for understanding how release factor modifications impact termination.

Real-world particulate matter and gaseous emissions from motor vehicles in a highway tunnel.

Recent studies have linked atmospheric particulate matter with human health problems. In many urban areas, mobile sources are a major source of particulate matter (PM) and the dominant source of fine particles or PM2.5 (PM smaller than 2.5 pm in aerodynamic diameter). Dynamometer studies have implicated diesel engines as being a significant source of ultrafine particles (< 0.1 microm), which may also exhibit deleterious health impacts. In addition to direct tailpipe emissions, mobile sources contribute to ambient particulate levels by brake and tire wear and by resuspension of particles from pavement. Information about particle emission rates, size distributions, and chemical composition from in-use light-duty (LD) and heavy-duty (HD) vehicles is scarce, especially under real-world operating conditions. To characterize particulate emissions from a limited set of in-use vehicles, we studied on-road emissions from vehicles operating under hot-stabilized conditions, at relatively constant speed, in the Tuscarora Mountain Tunnel along the Pennsylvania Turnpike from May 18 through 23, 1999. There were five specific aims of the study. (1) obtain chemically speciated diesel profiles for the source apportionment of diesel versus other ambient constituents in the air and to determine the chemical species present in real-world diesel emissions; (2) measure particle number and size distribution of chemically speciated particles in the atmosphere; (3) identify, by reference to data in years past, how much change has occurred in diesel exhaust particulate mass; (4) measure particulate emissions from LD gasoline vehicles to determine their contribution to the observed particle levels compared to diesels; and (5) determine changes over time in gas phase emissions by comparing our results with those of previous studies. Comparing the results of this study with our 1992 results, we found that emissions of C8 to C20 hydrocarbons, carbon monoxide (CO), and carbon dioxide (CO2) from HD diesel emissions substantially decreased over the seven-year period. Particulate mass emissions showed a similar trend. Considering a 25-year period, we observed a continued downward trend in HD particulate emissions from approximately 1,100 mg/km in 1974 to 132 mg/km (reported as PM2.5) in this study. The LD particle emission factor was considerably less than the HD value, but given the large fraction of LD vehicles, emissions from this source cannot be ignored. Results of the current study also indicate that both HD and LD vehicles emit ultrafine particles and that these particles are preserved under real-world dilution conditions. Particle number distributions were dominated by ultrafine particles with count mean diameters of 17 to 13 nm depending on fleet composition. These particles appear to be primarily composed of sulfur, indicative of sulfuric acid emission and nucleation. Comparing the 1992 and 1999 HD emission rates, we observed a 48% increase in the NOx/CO2 emissions ratio. This finding supports the assumption that many new-technology diesel engines conserve fuel but increase NOx emissions.

Assessment of Nontailpipe Hydrocarbon Emissions from Motor Vehicles.

This report evaluates tailpipe and nontailpipe hydrocarbon (HC) emissions from light-duty spark-ignition (SI) vehicles. The sources of information were unpublished data sets, generated mainly from 1990 through 1994, on emissions from volunteer fleets of in-use vehicles in chassis dynamometer and sealed housing for evaporative determination tests, and published chemical mass balance (CMB) source apportionments of HC in roadway tunnels and in urban air. The nontailpipe emissions evaluated comprise running-loss, hot soak, diurnal emissions, and resting-loss emissions. Relations between pressure and purge test failures and actual nontailpipe emissions were also examined.