Cancer screening with multicancer detection tests: A translational science review.

Multicancer detection (MCD) tests use a single, easily obtainable biospecimen, such as blood, to screen for more than one cancer concurrently. MCD tests can potentially be used to improve early cancer detection, including cancers that currently lack effective screening methods. However, these tests have unknown and unquantified benefits and harms. MCD tests differ from conventional cancer screening tests in that the organ responsible for a positive test is unknown, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Among two prospective studies involving greater than 16,000 individuals, MCD tests identified those who had some cancers without currently recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported MCD test sensitivities range from 27% to 95% but differ by organ and are lower for early stage cancers, for which treatment toxicity would be lowest and the potential for cure might be highest. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy to detect different cancers in asymptomatic individuals, whether these tests can detect cancer sufficiently early for effective treatment and mortality reduction, the degree to which these tests may contribute to cancer overdiagnosis and overtreatment, whether MCD tests work equally well across all populations, and the appropriate diagnostic evaluation and follow-up for patients with a positive test.

Centring the health of women across the HIV research continuum.

Despite tremendous advances in HIV research, women and gender diverse people-particularly women from racial and ethnic groups under-represented in research, transgender women, and young women-remain disproportionately affected by HIV. Women and gender diverse people face unique challenges and have been under-represented in HIV research. The National Institutes of Health (NIH) is tasked to apply fundamental knowledge about the nature and behaviour of living systems to enhance health, lengthen life, and reduce disability. Rigorous exploration of-and interventions for-the individual, social, biological, structural, and environmental factors that influence HIV prevention, transmission, treatment, and cure is crucial to advance research for women, girls, and gender diverse people across the lifespan. In this Position Paper, we introduce a framework for an intersectional, equity-informed, data-driven approach to research on HIV and women and highlight selected issues for women and gender diverse people, including HIV prevention, HIV cure, ageing with HIV, substance use and misuse, violence, pregnancy, and breastfeeding or chestfeeding. This framework underlines a new HIV and Women Signature Programme from the NIH Office of AIDS Research and Office of Research on Women's Health that advances the NIH vision for women's health, in which all women receive evidence-based HIV prevention, treatment, and care across their lifespan tailored to their unique needs, circumstances, and goals. The time is now to centre the health of women, girls, and gender diverse people across the HIV research continuum.

Gender as a social and structural variable: research perspectives from the National Institutes of Health (NIH).

Gender is a social and structural variable that encompasses multiple domains, each of which influences health: gender identity and expression, gender roles and norms, gendered power relations, and gender equality and equity. As such, gender has far-reaching impacts on health. Additional research is needed to continue delineating and untangling the effects of gender from the effects of sex and other biological variables. The National Institutes of Health (NIH) vision for women's health is a world in which the influence of sex and/or gender are integrated into the health research enterprise. However, much of the NIH-supported research on gender and health has, to date, been limited to a small number of conditions (e.g., HIV, mental health, pregnancy) and locations (e.g., sub-Saharan Africa; India). Opportunities exist to support transdisciplinary knowledge transfer and interdisciplinary knowledge building by advancing health-related social science research that incorporates best practices from disciplines that have well-established methods, theories, and frameworks for examining the health impacts of gender and other social, cultural, and structural variables.

Gender encompasses multiple domains, each of which influences health: identity and expression; roles and norms; relations; and power. This commentary focuses on gender-related research at the National Institutes of Health (NIH); identifies areas of opportunity for future health research efforts on gender; and articulates a vision for the robust, transdisciplinary incorporation of gender as a social, cultural, and structural variable into the NIH research agenda. The NIH vision for women's health is a world in which the influence of sex and/or gender are integrated into the health research enterprise. However, much of the NIH-supported research on gender and health has, to date, been limited to a small number of conditions (e.g., HIV, mental health, pregnancy) and locations (e.g., sub-Saharan Africa; India). Approaching the influences of gender on health with scientific rigor is critical to advancing health research that promotes health equity.

Reflecting on Progress in and Establishing Benchmarks for Sex and Gender Health Education.

ABSTRACT: Sex and gender influence every aspect of human health; thus, sex- and gender-related topics should be incorporated in all aspects of health education curricula. Sex and gender health education (SGHE) is the rigorous, intersectional, data-driven integration of sex and gender into all elements of health education. A multisectoral group of thought leaders has collaborated to advance SGHE since 2012. This cross-sector collaboration to advance SGHE has been successful on several fronts, primarily developing robust interprofessional SGHE programs, hosting a series of international SGHE summits, developing sex- and gender-specific resources, and broadening the collaboration beyond medical education. However, other deeply entrenched challenges have proven more difficult to address, including accurate and consistent sex and gender reporting in research publications, broadening institutional support for SGHE, and the development and implementation of evaluation plans for assessing learner outcomes and the downstream effects of SGHE on patient care. This commentary reflects on progress made in SGHE over the first decade of the current collaboration (2012-2022), articulates a vision for next steps to advance SGHE, and proposes 4 benchmarks to guide the next decade of SGHE: (1) integrate sex, gender, and intersectionality across health curricula; (2) develop sex- and gender-specific resources for health professionals; (3) improve sex and gender reporting in research publications; and (4) develop evaluation plans to assess learner and patient outcomes.

Structural Sexism and Cancer Care: The Effects on the Patient and Oncologist.

Despite progress toward equity within our broad social context, the domains of gender as a social, cultural, and structural variable continue to exert influence on the delivery of oncology care. Although there have been vast advances in our understanding of the biological underpinnings of cancer and significant improvements in clinical care, disparities in cancer care for all women-including cisgender, transgender, and gender diverse women-persist. Similarly, despite inclusion within the oncology physician workforce, women and gender minorities, particularly those with additional identities under-represented in medicine, still face structural barriers to clinical and academic productivity and career success. In this article, we define and discuss how structural sexism influences both the equitable care of patients with cancer and the oncology workforce and explore the overlapping challenges in both realms. Solutions toward creating environments where patients with cancer of any gender receive optimal care and all physicians can thrive are put forward.

Public Priorities in Women's Health: Analysis of Request for Information Published to Inform "Advancing NIH Research on the Health of Women: A 2021 Conference".

Objectives: To assist with planning a congressionally requested conference on women's health research, the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) invited comments to characterize public concerns related to any or all of the specified public health issues: maternal morbidity and mortality (MMM); stagnant rates of cervical cancer survival; and the growing incidence of chronic debilitating conditions in women (CDCW). This analysis summarizes public priorities in women's health research. Materials and Methods: All comments received in response to a request for information were open coded and a master list of keywords was created, and comments were categorized. Comments addressing CDCW were categorized using a conceptual framework developed by the NIH. Results: Two hundred forty-seven comments were coded and analyzed. One hundred four comments (42%) addressed MMM; 182 comments (73%) discussed CDCW; and 27 comments (10%) addressed cervical cancer. Comments focused on CDCW most frequently addressed female-specific conditions (83%). The 10 most frequently identified keywords in order of frequency from the manual coding were as follows: (1) MMM, (2) racial disparities, (3) access to care, (4) provider training, (5) mental health, (6) Black or African American women, (7) screening, (8) quality of care, (9) time to diagnosis, and (10) social determinants of health. Conclusions: Comments demonstrate a broad range of concerns related to the health of women, including MMM, CDCW, and cervical cancer. A wide array of commenters included patients, advocacy groups, and academic and professional organizations originating from geographically diverse locations. These comments reflect a strong desire from the public to prioritize research on the health of women.

Chronic conditions in women: the development of a National Institutes of health framework.

Rising rates of chronic conditions were cited as one of the key public health concerns in the Fiscal Year (FY) 2021 U.S. Senate and House of Representatives appropriations bills, where a review of current National Institutes of Health (NIH) portfolios relevant to research on women's health was requested. Chronic conditions were last defined by the US Department of Health and Human Services (HHS) in 2010. However, existing definitions of chronic conditions do not incorporate sex or gender considerations. Sex and gender influence health, yet significant knowledge gaps exist in the evidence-base for prevention, diagnosis, and treatment of chronic diseases amongst women. The presentation, prevalence, and long-term effects of chronic conditions and multimorbidity differs in women from men. A clinical framework was developed to adequately assess the NIH investment in research related to chronic conditions in women. The public health needs and NIH investment related to conditions included in the framework were measured. By available measures, research within the NIH has not mapped to the burden of chronic conditions among women. Clinical research questions and endpoints centered around women can be developed and implemented; clinical trials networks with expanded or extended eligibility criteria can be created; and data science could be used to extrapolate the effects of overlapping or multiple morbidities on the health of women. Aligning NIH research priorities to address the specific needs of women with chronic diseases is critical to addressing women's health needs from a life course perspective.

PARP inhibitors in the treatment of ARID1A mutant ovarian clear cell cancer: PI3K/Akt1-dependent mechanism of synthetic lethality.

Introduction: Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme involved in the repair of DNA single-strand breaks (SSB). The recent development of poly(ADP-ribose) polymerase inhibitors (PARPi) results from over 45 years of studies. When the activity of PARP1 or PARP2 is compromised, DNA SSB lesions are unresolved and can be converted to DNA double-strand breaks (DSBs) by the cellular transcription mechanisms. ARID1A (also called BAF250a) is an important component of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex. ARID1A gene demonstrates >50% of mutation rate in ovarian clear-cell carcinomas (OCCC). Mutated or downregulated ARID1A significantly compromises the Homologous Recombination Repair (HRR) of DNA DSB. Results: The present study demonstrated that downregulated or mutated ARID1A attenuates DNA HRR through stimulation of the PI3K/Akt1 pathway and makes tumor cells highly sensitive to PARPi and PARPi/ionizing radiation (IR) combination. We showed that PI3K/Akt1 pathway plays an important role in the sensitization of cancer cell lines with compromised function of ARID1A to PARPi treatment. Discussion: We believe that using of PARPi monotherapy or in combination with radiation therapy is an appealing strategy for treating ARID1A-mutated cancers, as well as many other types of PI3K/Akt1-driven cancers.

What's in it for me?: A value assessment of gynecologic cancer clinical trials for Black women.

OBJECTIVE: Underrepresented groups may be dissuaded from clinical trial participation without perceived value. We therefore comprehensively assessed gynecologic cancer clinical trial protocols for the inclusion of items of value most important to Black individuals. METHODS: ClinicalTrials.gov was queried for NCI-sponsored gynecologic cancer clinical trials in the US between Jan.1994 and Nov.2021. Pre-specified return of value (ROV) items were abstracted from each protocol. Inclusion proportions were calculated for each ROV item and temporal changes assessed with chi-square tests. Temporality of proportional trends was further assessed by slope and departure from linearity calculations. RESULTS: 279 gynecologic cancer clinical trials were included. Most commonly trials had first accrual in 2001-2007 (37%) and involved ovarian cancer (48%), phase II studies (53%), and chemotherapy (60%) or targeted therapy (34%). Trials often included ROV items in basic information (99%), medical record information (99%), and imaging (82%). 41% of trials included ROV items in biomarker testing, 20% genetic testing, and 20% in patient-reported outcome questionnaires. Over time, there were significant increases in the proportion of trials that included genetic (3% to 51%; p < 0.001) and biomarker testing (14 to 78%, p < 0.001). Information on lifestyle risk factors was rare (1%). No trials included ROV items in ancestry, how to connect with other participants, or remuneration. CONCLUSIONS: Gynecologic cancer clinical trials include few design elements that provide high value to Black individuals like lifestyle risk factors, ancestry, and remuneration. In any multi-pronged effort to improve diversity in clinical trial enrollment, inclusion of items valued by Black individuals should be considered.

Current gaps and opportunities in screening, prevention, and treatment of cervical cancer.

In their fiscal year 2021 reports, the US House and Senate Appropriations Committees requested that the National Institutes of Health (NIH) evaluate current research related to women's health and topics that include stagnant cervical cancer survival. In response, the NIH Office of Research on Women's Health, with input from women's health experts; members of the public; representatives from NIH institutes, centers, and offices; and members of the NIH Advisory Committee on Research on Women's Health, reviewed the public health needs and current NIH activities on cervical cancer. The Advancing NIH Research on the Health of Women: A 2021 Conference held in October 2021 reviewed these findings and allowed the identification of opportunities to strengthen research. In this review, the authors summarize public health needs related to cervical cancer and NIH activities in this realm. Cervical cancer has become a rare disease in the United States, yet significant portions of the US population remain under screened or unscreened for cervical cancer, human papillomavirus vaccination rates remain low, access to high-quality treatment remains a challenge for many, and large inequities by race and ethnicity persist. Novel, inclusive, and intentional research is needed to produce improvements in cervical cancer survival within the United States.

Clinical trials and pregnancy.

Traditionally, there has been a reluctance to involve pregnant people in clinical trials due to complex ethical issues surrounding the risk to unborn babies. However it is crucial that new interventions are safe and effective for all patients and ensuring this can be difficult to achieve in the absence of clinical trials.

Perspectives From Advancing National Institutes of Health Research to Inform and Improve the Health of Women: A Conference Summary.

The health of women remains understudied. In response to a request from Congress, the Office of Research on Women's Health of the National Institutes of Health (NIH) evaluated research on the health of women currently underway related to 1) rising rates of maternal morbidity and mortality, 2) rising rates of chronic debilitating conditions in women, and 3) stagnant cervical cancer survival rates. Input on the three priority areas was obtained from experts in women's health, members of the public, and federal stakeholders. The NIH research portfolios on these three topics were reviewed. On October 20, 2021, a conference on advancing NIH research on women's health was held to present, discuss, and delineate gaps and opportunities in the current portfolio. Across the life course, significant gaps in evidence regarding conditions, disorders, and diseases that occur in women were illustrated. Fundamental basic and translational knowledge gaps in many female-specific conditions and diseases with sex-specific presentations, symptoms, or responses to treatments have hampered the generation of robust scientific data needed to provide high-quality, evidence-based care to women. Key opportunities identified to improve the health of women include enhanced implementation of existing best practices and interventions to reduce disparities. Undertaking intentional clinical research on the health of women will produce significant returns on investment and has the potential to greatly improve human health.

Gynecologic Oncology and Inclusion of Women Into the Surgical Workforce: The Canary in This Coal Mine.

Objective: Women make up a majority of the gynecologic oncology workforce. Increasing the numbers of women in leadership has been proposed as a path towards professional gender equity. This study examined whether leadership gender and departmental infrastructure impact the work environment for women gynecologic oncologists. Methods: Members of a 472-member private Facebook group "Women of Gynecologic Oncology" (WGO) who self-identified as women gynecologic oncologists provided demographics, practice infrastructure, personal experience with workplace bullying, gender discrimination, microaggressions using a REDcap survey platform. Results: Of 250 (53%) respondents to this survey, most were younger than age 50 years (93.6%); White (82.2%) and non-Hispanic (94.3%); married (84.7%); and parenting (75.2%). Practice environments included academic (n=152, 61.0%), hospital employed (n=57, 22.9%), and private practice (n=31, 12.4%), and 89.9% supervised trainees. A significant percent of respondents had experienced bullying (52.8%), gender discrimination (57%) and microaggressions (83%). Age, race, ethnicity, practice setting, or mentorship were not statistically significantly associated with these experiences. Reported perpetrators were varied and included colleagues (84%), patients (44%), staff (41%), administrators (18%), and trainees (16%). Prevalence of bullying (55.0 vs 47.7%, p=0.33), gender discrimination (59.1 vs 52.3%, p=0.33) and microaggressions (83.3 vs 83.0%, p=1.00) were similar irrespective of departmental leadership gender. Conclusions: Women gynecologic oncologists report a high prevalence of workplace bullying, gender discrimination and microaggressions regardless of the gender of their immediate leadership. Proactive and deliberate structural interventions to improve the work environment for surgeons who are women are urgently needed.

Improving the quality of care for patients with advanced epithelial ovarian cancer: Program components, implementation barriers, and recommendations.

The high lethality of ovarian cancer in the United States and associated complexities of the patient journey across the cancer care continuum warrant an assessment of current practices and barriers to quality care in the United States. The objectives of this study were to identify and assess key components in the provision of high-quality care delivery for patients with ovarian cancer, identify challenges in the implementation of best practices, and develop corresponding quality-related recommendations to guide multidisciplinary ovarian cancer programs and practices. This multiphase ovarian cancer quality-care initiative was guided by a multidisciplinary expert steering committee, including gynecologic oncologists, pathologists, a genetic counselor, a nurse navigator, social workers, and cancer center administrators. Key partnerships were also established. A collaborative approach was adopted to develop comprehensive recommendations by identifying ideal quality-of-care program components in advanced epithelial ovarian cancer management. The core program components included: care coordination and patient education, prevention and screening, diagnosis and initial management, treatment planning, disease surveillance, equity in care, and quality of life. Quality-directed recommendations were developed across 7 core program components, with a focus on ensuring high-quality ovarian cancer care delivery for patients through improved patient education and engagement by addressing unmet medical and supportive care needs. Implementation challenges were described, and key recommendations to overcome barriers were provided. The recommendations emerging from this initiative can serve as a comprehensive resource guide for multidisciplinary cancer practices, providers, and other stakeholders working to provide quality-directed cancer care for patients diagnosed with ovarian cancer and their families.

Professional Address during Obstetrics and Gynecology Grand Rounds Introductions: Setting the Stage, Setting the Standard.

OBJECTIVE: This study aimed to assess gender dynamics during Obstetrics and Gynecology (Ob/Gyn) Grand Rounds. DESIGN: This was an observational cohort study of Ob/Gyn Grand Rounds introductions at a large academic center. Ob/Gyn Grand Rounds introductions from December 2016 to February 2020 were included. Audio and video components of introductions for those with doctorate degrees were reviewed. Each named reference to the presenter and use of descriptors were collected. Statistical analyses included Fisher's exact test for categorical variables and Student's t-test for continuous variables. SETTING: This study was completed at the University of Wisconsin in the Department of Ob/Gyn PARTICIPANTS: Ob/Gyn Grand Rounds introducers who had complete audio and video components of introductions for those with doctorate degrees. RESULTS: Sixty-four Grand Rounds introductions were reviewed; 57 met inclusion criteria. The majority of introducers and presenters were women. Consistent use of "doctor" was similar by men and women introducers (50% vs. 29%, p = 0.427). Assistant professors were more likely to maintain professional address during introductions, compared to associate or full professors (86% vs. 0% vs. 10%, p < 0.001). Trainees were less likely than faculty to be addressed professionally at any time during introductions (42% vs. 81%, p = 0.017). Descriptors were used for men and women presenters, though men received more female-gendered descriptors than women (5 vs. 1, p = 0.011). Women introducers used productivity descriptors less often than men introducers (8 [15.1%] vs. 5 [55.6%] (p = 0.015)). CONCLUSIONS: Use of professional address was associated with academic rank, but not gender. Men endorsed and received more descriptors emphasizing accomplishments, highlighting qualifications as an expert. Given the professional environment, all Grand Rounds presenters should be introduced using professional titles.

Concordance and discordance between maternal and newborn drug test results.

BACKGROUND: Screening for substance use is recommended during pregnancy, and many clinicians rely on urine drug screening to identify newborns at potential risk for withdrawal. OBJECTIVE: This study aimed to determine the concordance and discordance rates between maternal and neonatal drug testing at or near the time of delivery. STUDY DESIGN: This retrospective chart review was performed at a single institution that employs universal testing for those who consent. Results of maternal and neonatal urine drug testing via immunoassay at delivery were compared. RESULTS: Of 1573 singleton pregnancies, 233 mothers (14.8%) had a positive test result for any substance and 102 of their newborns (43.8%) had concordant positive test results. Of the 285 positive maternal test results for individual substances, 133 (46.7%) were concordant with newborn test results. After removing iatrogenic positives, there were 84 truly discordant pairs representing 5.9% of the total cohort of test pairs, but 29.5% of the pairs with maternal positive test results. When considering the outcome of a newborn positive test result, the overall sensitivity and specificity for the maternal test were 21.1% and 85.8%, respectively. The positive and negative predictive values were 46.7% and 96.4%, respectively. After excluding iatrogenic positive test results, the sensitivity and specificity for maternal testing were 97.8% and 99.4%, respectively, and the negative predictive value of maternal testing for all substances approached 100%. A total of 11 pairs of twins had at least 1 twin with a positive drug test result, and of these, 6 twin pairs (54.5%) had drug test results that were discordant from each other. CONCLUSION: There is a high rate of iatrogenic discrepancy in maternal and neonatal drug testing. After adjusting for iatrogenic positive test results, the negative predictive value of maternal testing is high. Many discrepancies, such as those in twins, remained unexplained by medication administration, and potential reasons for these discrepancies warrant further investigation.

Oncogenic B-Myb Is Associated With Deregulation of the DREAM-Mediated Cell Cycle Gene Expression Program in High Grade Serous Ovarian Carcinoma Clinical Tumor Samples.

Cell cycle control drives cancer progression and treatment response in high grade serous ovarian carcinoma (HGSOC). MYBL2 (encoding B-Myb), an oncogene with prognostic significance in several cancers, is highly expressed in most HGSOC cases; however, the clinical significance of B-Myb in this disease has not been well-characterized. B-Myb is associated with cell proliferation through formation of the MMB (Myb and MuvB core) protein complex required for transcription of mitotic genes. High B-Myb expression disrupts the formation of another transcriptional cell cycle regulatory complex involving the MuvB core, DREAM (DP, RB-like, E2F, and MuvB), in human cell lines. DREAM coordinates cell cycle dependent gene expression by repressing over 800 cell cycle genes in G0/G1. Here, we take a bioinformatics approach to further evaluate the effect of B-Myb expression on DREAM target genes in HGSOC and validate our cellular model with clinical specimens. We show that MYBL2 is highly expressed in HGSOC and correlates with expression of DREAM and MMB target genes in both The Cancer Genome Atlas (TCGA) as well as independent analyses of HGSOC primary tumors (N = 52). High B-Myb expression was also associated with poor overall survival in the TCGA cohort and analysis by a DREAM target gene expression signature yielded a negative impact on survival. Together, our data support the conclusion that high expression of MYBL2 is associated with deregulation of DREAM/MMB-mediated cell cycle gene expression programs in HGSOC and may serve as a prognostic factor independent of its cell cycle role. This provides rationale for further, larger scale studies aimed to determine the clinical predictive value of the B-Myb gene expression signature for treatment response as well as patient outcomes.