Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers.

Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA1/2 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target of PARP1. We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARPi as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi. SIGNIFICANCE: Currently, there are no reliable biomarkers for response to PARPi outside of homologous recombination deficiency. Herein we present a unique potential biomarker, with clear functional understanding of the molecular mechanism by which DDX21 nucleolar localization can predict response to PARPi.

The Cesarean Scar of Pregnancy: Ultrasound Findings and Expectant Management Outcomes.

OBJECTIVE: The nomenclature has evolved from low implantation to cesarean scar pregnancy (CSP) and criteria are recommended for identification and management. Management guidelines include pregnancy termination due to life-threatening complications. This article applies ultrasound (US) parameters recommended by the Society for Maternal Fetal Medicine (SMFM) in women who were expectantly managed. STUDY DESIGN: Pregnancies were identified between March 1, 2013 and December 31, 2020. Inclusion criteria were women with CSP or low implantation identified on US. Studies were reviewed for niche, smallest myometrial thickness (SMT), and location of basalis blinded to clinical data. Clinical outcomes, pregnancy outcome, need for intervention, hysterectomy, transfusion, pathologic findings, and morbidities were obtained by chart review. RESULTS: Of 101 pregnancies with low implantation, 43 met the SMFM criteria at < 10 weeks and 28 at 10 to 14 weeks. At < 10 weeks, SMFM criteria identified 45out of 76 women; of these 13 required hysterectomy; there were 6 who required hysterectomy but did not meet the SMFM criteria. At 10 to < 14 weeks, SMFM criteria identified 28 out of 42 women; of these 15 required hysterectomy. US parameters yielded significant differences in women requiring hysterectomy, at < 10 weeks and 10 to < 14 weeks' gestational age epochs, but the sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of these US parameters have limitations in identifying invasion to determine management. Of the 101 pregnancies, 46 (46%) failed < 20 weeks, 16 (35%) required medical/surgical management including 6 hysterectomies, and 30 (65%) required no intervention. There were 55 pregnancies (55%) that progressed beyond 20 weeks. Of these, 16 required hysterectomy (29%) while 39 (71%) did not. In the overall cohort of 101, 22 (21.8%) required hysterectomy and an additional16 (15.8%) required some type of intervention, while 66.7% required no intervention. CONCLUSION: SMFM US criteria for CSP have limitations for discerning clinical management due to lack of discriminatory threshold. KEY POINTS: · The SMFM US criteria for CSP at <10 or <14 weeks have limitations for clinical management.. · The sensitivity and specificity of the ultrasound findings limit the utility for management. · The SMT of <1 mm is more discriminating than <3 mm for hysterectomy..

Improving access to perinatal mental health services: the value of on-site resources.

BACKGROUND: Perinatal mood disorders have both short- and long-term negative consequences for mothers and their babies. National organizations recommend universal screening for postpartum depression. Little is known, however, about screening and referral among women living in underserved areas with limited access to care. OBJECTIVE: The objective of this report was to evaluate the utilization of mental health services in an urban, inner-city hospital following the implementation of colocated counseling services across 10 county-sponsored clinics that serve a medically underserved population. We further explored antecedents of a positive postpartum depression screen, factors associated with successful referral, and the rate of perinatal mood disorder diagnoses following universal screening. We hypothesized that integrated mental health services would improve referral rates following positive postpartum depression screening compared with historically separated services. STUDY DESIGN: This was a retrospective cohort study of women undergoing universal postpartum depression screening with deliveries from January 2017 to December 2019 who were compared with a historic cohort from the same population from June 2008 to March 2010. The Edinburgh Postnatal Depression Scale was used to evaluate women at their postpartum visit, and a mental health service referral was offered to women with a score of ≥13. The primary outcome was a comparison of completed referrals between cohorts with and without colocated mental health services following a positive postpartum depression screen. Statistical analysis included chi-square tests with a P value of <.05 being considered significant and adjusted multivariate analyses for perinatal outcomes associated with a positive postpartum screen. RESULTS: Between January 2017 to December 2019, 25,425 women completed a postpartum depression screen with 978 (4%) of those recording a positive screen. After implementation of colocated mental health counselors, completed perinatal mental health referrals significantly increased when compared with the historic cohort without colocated services (57%; 560 of 978 vs 22%; 238 of 1106; P<.001). Adverse neonatal outcomes, such as stillbirth (adjusted risk ratio, 9.5; 95% confidence interval, 6.35-14.26) and neonatal demise (adjusted risk ratio, 14.3; 95% confidence interval, 6.67-30.46), were most strongly associated with a positive depression screen. There were 122 (21%) women with a positive screen who were diagnosed with a depressive disorder in the peripartum period. There were no specific features associated with those who did or did not complete referral. One-fifth of women were referred for psychiatric evaluation following an initial evaluation, and the referral rate was associated with higher scores on the depression screen (P<.001). CONCLUSION: Utilization of mental health services following a positive depression screen more than doubled following the implementation of colocated services.

Managed care, networks and trends in hospital care for mental health and substance abuse treatment in Massachusetts: 1994-1999.

BACKGROUND: Rates of inpatient care for mental health and substance abuse treatment have been reported to fall after the introduction of managed care, but the actual decline may be overstated. Almost all managed care impact studies are based on pre-post comparisons, which have two drawbacks: secular downward trends may be attributed to a managed care effect and self-selection may exaggerate the impact of managed care. Therefore it is useful to examine long-term population-based trends in use associated with the growth of managed care. AIMS OF STUDY: This paper examines trends in inpatient care for mental health and substance abuse treatment in Massachusetts between 1994 and 1999 by service provider and payer. We analyze how managed care impacts the trends in mental health and substance abuse care. METHODS: We provide an overview of the health market in Massachusetts and compare trends in mental health and substance abuse services with all inpatient services. To analyze the impact of managed care, we compare the per discharge cost of managed care and fee for service plans in Medicare and Medicaid. Finally, we examine the role played by hospital networks in managed care. RESULTS: The reduction in service costs for mental health and substance abuse, about 25% in six years, is mostly due to the decline in the average cost per inpatient episode. This is only slightly greater than the decline in costs for all inpatient care. Managed care has reduced both the quantity (average length of stay) and intensity of health care (expenditure per day). Simulations suggest that the creation of hospital networks by managed care accounts for around 50% of the differential between the average costs of the HMO and FFS sectors. DISCUSSION: We find that the cost reductions in mental health and substance abuse services are larger than for physical health, but not by much. The average length of stay and average day cost is lower for managed care plans than for FFS plans, and much of this difference is attributable to the hospitals managed care plans select to participate in their networks. The data are limited to inpatient discharges from Massachusetts and therefore our conclusions may not be readily extended to other places. Furthermore, our analysis is based on the estimated cost rather than the actual payments to hospitals. IMPLICATION FOR HEALTH CARE PROVISION AND USE: The analysis highlights the importance of hospital selection and networks in affecting the cost of care. IMPLICATIONS FOR HEALTH POLICIES: Contrary to popular belief, the analysis shows that the experience of mental health and substance abuse and non-mental health and substance abuse services is similar. Creation of networks is an important strategy in managed care. IMPLICATIONS FOR FURTHER RESEARCH: This paper provides the groundwork for extending the analysis to areas with market characteristics different to those of Massachusetts. Further research should focus on the long-term trends in health outcomes between managed care and fee for service patients.