CAR-T Cell Therapy in Ovarian Cancer: Where Are We Now?

The success of chimeric antigen receptor T-cell (CAR-T) therapies in the treatment of hematologic malignancies has led to the investigation of their potential in the treatment of solid tumors, including ovarian cancer. While the immunosuppressive microenvironment of ovarian cancer has been a barrier in their implementation, several early phase clinical trials are currently evaluating CAR-T cell therapies targeting mesothelin, folate receptor a, HER2, MUC16, and B7H3. Ongoing challenges include cytokine-associated and "on-target, off-tumor" toxicities, while most common adverse events include cytokine release syndrome, hemophagocytic lymphohistiocytosis/macrophage activation-like syndrome (HLH/MAS), and neurotoxicity. In the present review, we summarize the current status of CAR-T therapy in ovarian cancer and discuss future directions.

Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR.

Ovarian cancers (OVCAs) and endometrial cancers (EMCAs) with CCNE1-amplification are often resistant to standard of care treatment and represent an unmet clinical need. Previously, synthetic-lethal screening identified loss of the CDK1 regulator, PKMYT1, as synthetically lethal with CCNE1-amplification. We hypothesized that CCNE1-amplification associated replication stress will be more effectively targeted by combining the PKMYT1 inhibitor, lunresertib (RP-6306), with the ATR inhibitor, camonsertib (RP-3500/RG6526). Low dose combination RP-6306 with RP-3500 synergistically increased cytotoxicity more in CCNE1 amplified compared to non-amplified cells. Combination treatment produced durable antitumor activity and increased survival in CCNE1 amplified patient-derived and cell line-derived xenografts. Mechanistically, low doses of RP-6306 with RP-3500 increase CDK1 activation more so than monotherapy, triggering rapid and robust induction of premature mitosis, DNA damage and apoptosis in a CCNE1-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is a novel therapeutic approach to treat CCNE1-amplifed OVCAs and EMCAs.

Experiences of Midwives Attending Home Births in Massachusetts During the COVID-19 Pandemic.

INTRODUCTION: Public interest in home birth in the United States increased during the COVID-19 pandemic. Midwives attend the vast majority of home births and are experts in providing home birth care. However, limited data are available about the experiences of midwives attending home births during the pandemic in the United States. METHODS: We developed a cross-sectional survey comprising 34 questions, which included 5 open-ended questions. The survey was distributed online in June 2021 to midwives attending home birth in Massachusetts. We calculated descriptive statistics for the quantitative survey responses and identified qualitative free-text responses illustrating the results. RESULTS: Eighteen midwives and 2 midwife apprentices responded to the survey, approximately 50% of Massachusetts' total number of midwives known to attend homebirths. The majority of the 20 respondents reported an increase in public interest in home birth (n = 17) and higher caseloads (n = 14) since the start of the pandemic. Respondents reported an increase in the number of clients transferring to their practices at a later gestational age (n = 13) and who identified as people of color (n = 8). They described both better and worse transfer of care to hospital experiences. Work-life balance and unpredictable income were the top 2 reported obstacles to home birth practice. DISCUSSION: The results of our study indicate that midwives providing home birth care in Massachusetts witnessed a surge in demand for their services during the pandemic. Implementing policies and practices that provide support for certified professional midwives could strengthen the home birth workforce, enhance access to home birth options, and optimize transfers to hospital settings when necessary.

Combination DNA Damage Response (DDR) Inhibitors to Overcome Drug Resistance in Ovarian Cancer.

The DNA damage response (DDR) results in activation of a series of key target kinases that respond to different DNA damage insults. DDR inhibitors such as PARP inhibitors lead to the accumulation of DNA damage in tumor cells and ultimately apoptosis. However, responses to DDRi monotherapy in the clinic are not durable and resistance ultimately develops. DDRi-DDRi combinations such as PARPi-ATRi, PAPRi-WEE1i and PARPi-AsiDNA can overcome multiple resistance mechanisms to PARP inhibition. In addition, DDRi-DDRi combinations can provide viable treatment options for patients with platinum-resistant disease. In the present chapter we discuss rationale of DDRi-DDRi strategies that capitalize on genomic alterations found in ovarian cancer and other solid tumors and may provide in the near future new treatment options for these patients.

Dual blockade of BRD4 and ATR/WEE1 pathways exploits ARID1A loss in clear cell ovarian cancer.

ARID1A, an epigenetic tumor suppressor, is the most common gene mutation in clear-cell ovarian cancers (CCOCs). CCOCs are often resistant to standard chemotherapy and lack effective therapies. We hypothesized that ARID1A loss would increase CCOC cell dependency on chromatin remodeling and DNA repair pathways for survival. We demonstrate that combining BRD4 inhibitor (BRD4i) with DNA damage response inhibitors (ATR or WEE1 inhibitors; e.g. BRD4i-ATRi) was synergistic at low doses leading to decreased survival, and colony formation in CCOC in an ARID1A dependent manner. BRD4i-ATRi caused significant tumor regression and increased overall survival in ARID1AMUT but not ARID1AWT patient-derived xenografts. Combination BRD4i-ATRi significantly increased γH2AX, and decreased RAD51 foci and BRCA1 expression, suggesting decreased ability to repair DNA double-strand-breaks (DSBs) by homologous-recombination in ARID1AMUT cells, and these effects were greater than monotherapies. These studies demonstrate BRD4i-ATRi is an effective treatment strategy that capitalizes on synthetic lethality with ARID1A loss in CCOC.

Controversies in the Staging of Patients with Locally Advanced Cervical Cancer.

Approximately 10-25% of patients with locally advanced cervical cancer harbor metastases to the para-aortic lymph nodes. Staging of patients with locally advanced cervical cancer can be performed with imaging techniques, such as PET-CT; however, false negative rates can be as high as 20%, especially for patients with pelvic lymph node metastases. Surgical staging can identify patients with microscopic lymph nodes metastases and aid in accurate treatment planning with the administration of extended-field radiation therapy. Data from retrospective studies investigating the impact of para-aortic lymphadenectomy on the oncological outcomes of patients with locally advanced cervical cancer are mixed, while data from randomized controlled trials do not demonstrate a progression-free survival benefit. In the present review, we explore controversies in the staging of patients with locally advanced cervical cancer and summarize the available literature.

Three Missed Critical Nursing Care Processes on Labor and Delivery Units During the COVID-19 Pandemic.

OBJECTIVE: To examine the relationships of three missed critical nursing care processes on labor and delivery units with reduced nursing time at the bedside and adequacy of unit staffing during the COVID-19 pandemic in the United States. DESIGN: A cross-sectional survey. SETTING: Online distribution from January 14 to February 26, 2021. PARTICIPANTS: A national convenience sample (N = 836) of registered nurses employed on labor and delivery units. METHODS: We conducted descriptive analyses on respondent characteristics and critical missed care items adapted from the Perinatal Missed Care Survey. We conducted robust logistic regression analyses to assess the relationships of three missed critical nursing care processes (surveillance of fetal well-being, excessive uterine activity, and development of new maternal complications) with reduced nursing time at the bedside and adequacy of unit staffing during the COVID-19 pandemic. RESULTS: Less nursing time at the bedside was associated with greater odds of missing any of the critical aspects of care, adjusted odds ratio = 1.77, 95% confidence interval [1.12, 2.80]. Adequate staffing greater than or equal to 75% of the time was associated with lower odds of missing any of the critical aspects of care compared to adequate staffing less than or equal to 50% of the time, adjusted odds ratio = 0.54, 95% confidence interval [0.36, 0.79]. CONCLUSION: Perinatal outcomes are dependent on the timely recognition of and response to abnormal maternal and fetal conditions during childbirth. In times of unexpected complexity in care and resource constraints, a focus on three critical aspects of perinatal nursing care is needed to maintain patient safety. Strategies that enable bedside presence of nurses, including maintaining adequate unit staffing, may help to mitigate missed care.

Breastfeeding Awakening.

A nurse-midwife who experienced her own difficulties with breastfeeding writes that there should be fewer obstacles and more systematic support for lactating individuals.

Birth Center Breastfeeding Rates: A Literature Review.

INTRODUCTION: Breastfeeding rates in the United States fall short of national targets and are marked by racial and ethnic disparities. Birth centers are associated with high rates of breastfeeding initiation and duration, yet no systematic review has compiled reported birth center breastfeeding data. METHODS: A PRISMA-guided literature review was conducted in CINAHL, PubMed, and Web of Science to retrieve quantitative studies that reported breastfeeding data in birth centers. Inclusion criteria focused on English language studies published since 2011 with breastfeeding outcomes from birth centers in the United States. RESULTS: Ten studies were included for analysis. Breastfeeding rates that exceeded actual and target national breastfeeding rates were reported among all 10 studies. Characteristics about breastfeeding outcomes were reported heterogeneously across the studies, which included a range of breastfeeding timepoints (immediately postpartum up to 6 weeks postpartum) and definitions of breastfeeding. DISCUSSION: Although breastfeeding rates reported in birth centers are higher than national breastfeeding rates and targets, authors of the included studies did not explore or analyze these rates in-depth. Developing standard definitions and data collection may enhance research about breastfeeding outcomes in birth centers. CLINICAL IMPLICATIONS: Giving birth in a birth center is associated with higher than national breastfeeding rates.

Choosing a Birth Setting: A Shared Decision-Making Approach.

Perinatal outcomes vary widely depending on individual birth settings (birth center, home, and hospital). The purpose of this case study is to explore a patient-centered, shared decision-making approach to achieve an informed, values-based choice about birth settings. Engaging in a shared decision-making approach regarding birth setting options would support people to have the information and ability to judge for themselves how benefits and risks across birth center, home, and hospital settings would best fit with their values and personal health. A patient decision aid about birth setting options could facilitate increased equity regarding access to birth settings that offer improved perinatal health outcomes, helping to reduce perinatal health disparities in the United States.

Factors influencing birth setting decision making in the United States: An integrative review.

BACKGROUND: The United States has the highest perinatal morbidity and mortality (M&M) rates among all high-resource countries in the world. Birth settings (birth center, home, or hospital) influence clinical outcomes, experience of care, and health care costs. Increasing use of low-intervention birth settings can reduce perinatal M&M. This integrative review evaluated factors influencing birth setting decision making among women and birthing people in the United States. METHODS: A search strategy was implemented within the CINAHL, PubMed, PsycInfo, and Web of Science databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guided the review, and the Johns Hopkins Nursing Evidence-Based Practice model was used to evaluate methodological quality and appraisal of the evidence. The Whittemore and Knafl integrative review framework informed the extraction and analysis of the data and generation of findings. RESULTS: We identified 23 articles that met inclusion criteria. Four analytical themes were generated that described factors that influence birth setting decision making in the United States: "Birth Setting Safety vs. Risk," "Influence of Media, Family, and Friends on Birth Setting Awareness," "Presence or Absence of Choice and Control," and "Access to Options." DISCUSSION: Supporting women and birthing people to make informed decisions by providing information about birth setting options and variations in models of care by birth setting is a critical patient-centered strategy to ensure equitable access to low-intervention birth settings. Policies that expand affordable health insurance to cover midwifery care in all birth settings are needed to enable people to make informed choices about birth location that align with their values, individual pregnancy characteristics, and preferences.

Place of Birth Preferences and Relationship to Maternal and Newborn Outcomes Within the American Association of Birth Centers Perinatal Data Registry, 2007-2020.

PURPOSE: The purpose of this study was to describe sociodemographic variations in client preference for birthplace and relationships to perinatal health outcomes. METHODS: Descriptive data analysis (raw number, percentages, and means) showed that preference for birthplace varied across racial and ethnic categories as well as sociodemographic categories including educational status, body mass index, payer status, marital status, and gravidity. A subsample of medically low-risk childbearing people, qualified for birth center admission in labor, was analyzed to assess variations in maternal and newborn outcomes by site of first admission in labor. RESULTS: While overall clinical outcomes exceeded national benchmarks across all places of admission in the sample, disparities were noted including higher cesarean birth rates among Black and Hispanic people. This variation was larger within the population of people who preferred to be admitted to the hospital in labor in the absence of medical indication. CONCLUSION: This study supports that the birth center model provides safe delivery care across the intersections of US sociodemographics. Findings from this study highlight the importance of increased access and choice in place of birth for improving health equity, including decreasing cesarean birth and increasing breastfeeding initiation.

Humanized Patient-Derived Xenograft Models of Ovarian Cancer.

In vivo modeling of cancer is a critical step in testing novel therapeutic strategies to advance patient care. Here we describe how to develop a humanized patient-derived xenograft (PDX) model of ovarian cancer that uses orthotopically transplanted patient ovarian tumors with autologous transfer of expanded tumor infiltrating T cells (TILs) as a model that can be utilized to test immunomodulating therapeutics in vivo.

CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models.

CCNE1-amplified ovarian cancers (OVCAs) and endometrial cancers (EMCAs) are associated with platinum resistance and poor survival, representing a clinically unmet need. We hypothesized that dysregulated cell-cycle progression promoted by CCNE1 overexpression would lead to increased sensitivity to low-dose WEE1 inhibition and ataxia telangiectasia and Rad3-related (ATR) inhibition (WEE1i-ATRi), thereby optimizing efficacy and tolerability. The addition of ATRi to WEE1i is required to block feedback activation of ATR signaling mediated by WEE1i. Low-dose WEE1i-ATRi synergistically decreases viability and colony formation and increases replication fork collapse and double-strand breaks (DSBs) in a CCNE1 copy number (CN)-dependent manner. Only upon CCNE1 induction does WEE1i perturb DNA synthesis at S-phase entry, and addition of ATRi increases DSBs during DNA synthesis. Inherent resistance to WEE1i is overcome with WEE1i-ATRi, with notable durable tumor regressions and improved survival in patient-derived xenograft (PDX) models in a CCNE1-level-dependent manner. These studies demonstrate that CCNE1 CN is a clinically tractable biomarker predicting responsiveness to low-dose WEE1i-ATRi for aggressive subsets of OVCAs/EMCAs.

Roles and Experiences of Registered Nurses on Labor and Delivery Units in the United States During the COVID-19 Pandemic.

OBJECTIVE: To examine the roles and experiences of labor and delivery (LD) nurses during the COVID-19 pandemic. DESIGN: Cross-sectional survey. SETTING: Online distribution between the beginning of July and end of August 2020. PARTICIPANTS: LD nurses (N = 757) responded to an open-ended question about changes to their roles during the COVID-19 pandemic as part of a larger national survey. METHODS: We calculated descriptive statistics on respondents' characteristics and their hospitals' characteristics. We applied conventional content analysis to free-text comments. RESULTS: We derived four major categories from the responses: Changes in Roles and Responsibilities, Adaptations to Changes, Psychological Changes, and Perceived Effects on LaborSupport. Nearly half (n = 328) of respondents reported changes in their roles and responsibilities during the COVID-19 pandemic. They described adaptations and responses to these changes and perceived effects on patient care. Infection control policies and practices as well as the stress of a rapidly changing work environment affected the provision of labor support and personal well-being. CONCLUSION: The experiences described by respondents conveyed considerable changes in their roles and subsequent direct and indirect effects on quality of patient care and personal well-being. Policies and practices that can facilitate the ability of LD nurses to safely and securely remain at the bedside and provide high-touch, hands-on labor support are needed. The findings of our study can help facilitate the provision of labor support during times of disruption and foster the resiliency of the nursing workforce.

Ovarian granulosa cell tumor characterization identifies FOXL2 as an immunotherapeutic target.

Granulosa cell tumors (GCT) are rare ovarian malignancies. Due to the lack of effective treatment in late relapse, there is a clear unmet need for novel therapies. Forkhead Box L2 (FOXL2) is a protein mainly expressed in granulosa cells (GC) and therefore is a rational therapeutic target. Since we identified tumor infiltrating lymphocytes (TILs) as the main immune population within GCT, TILs from 11 GCT patients were expanded, and their phenotypes were interrogated to determine that T cells acquired late antigen-experienced phenotypes and lower levels of PD1 expression. Importantly, TILs maintained their functionality after ex vivo expansion as they vigorously reacted against autologous tumors (100% of patients) and against FOXL2 peptides (57.1% of patients). To validate the relevance of FOXL2 as a target for immune therapy, we developed a plasmid DNA vaccine (FoxL2-tetanus toxin; FoxL2-TT) by fusing Foxl2 cDNA with the immune-enhancing domain of TT. Mice immunization with FoxL2-TT controlled growth of FOXL2-expressing ovarian (BR5) and breast (4T1) cancers in a T cell-mediated manner. Combination of anti-PD-L1 with FoxL2-TT vaccination further reduced tumor progression and improved mouse survival without affecting the female reproductive system and pregnancy. Together, our results suggest that FOXL2 immune targeting can produce substantial long-term clinical benefits. Our study can serve as a foundation for trials testing immunotherapeutic approaches in patients with ovarian GCT.

Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models.

Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity and sensitivity to ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive to ATRi when combined with PARPi (PARPi-ATRi). Sensitivity to PARPi-ATRi in diverse PARPi and platinum-resistant models, including BRCA1/2 reversion and CCNE1-amplified models, correlate with synergistic increases in replication fork stalling, double-strand breaks, and apoptosis. Surprisingly, BRCA reversion mutations and an ability to form RAD51 foci are frequently not observed in models of acquired PARPi-resistance, suggesting the existence of alternative resistance mechanisms. However, regardless of the mechanisms of resistance, complete and durable therapeutic responses to PARPi-ATRi that significantly increase survival are observed in clinically relevant platinum and acquired PARPi-resistant patient-derived xenografts (PDXs) models. These findings indicate that PARPi-ATRi is a highly promising strategy for OVCAs that acquire resistance to PARPi and platinum.

Correction: Identification of Novel Pathogenic Sequence Variants of the Mismatch Repair Genes During Screening for Lynch Syndrome in a Single Centre of Eastern Hungary.

The original version of this article unfortunately contained a mistake. The variants listed in Table 3 of the original version of this article are not in line with the latest HGVS (Human Genome Variation Society) nomenclature (version 19.01).

Identification of Novel Pathogenic Sequence Variants of the Mismatch Repair Genes During Screening for Lynch Syndrome in a Single Centre of Eastern Hungary.

INTRODUCTION: Lynch syndrome is an autosomal dominant disorder, most frequent leading to colon cancer. Identification of patients with Lynch syndrome and screening of their family members are available prevention approach that can significantly decrease mortality. Unfortunately, routine screening still does not belong to standard of care in Hungary. In this study, we performed a comprehensive screening in order to identify patients with mismatch repair (MMR) mutation between the years of 2011 and 2014. Identified mutations were compared with those already published in the international databases. PATIENTS AND METHODS: Patients who underwent treatment for colorectal cancer at the Surgical Institute of the University of Debrecen were screened using the modified Amsterdam and Bethesda Criteria. Immunohistochemistry and microsatellite analyses were performed in order to identify possible mutation carrier cases. Suspicious cases underwent DNA sequencing to detect mutations in the mismatch repair genes (hMLH1, hMSH2). RESULTS: All together 760 colorectal cancer patients were screened. A total of 28 patients were identified as possible MMR mutation carrier and underwent further genetic evaluation. Pathogenic sequence variants of the MMR gene were found in 5 patients. Hypermethylation of the promoter region of the hMLH1 gene was identified in 2 patients. Two out of the 5 pathogenic sequence variants of the MMR gene were first identified by our group while other 2 mutations were previously published as possible founder mutations. CONCLUSION: Identification of families with Lynch syndrome, while challenging because of variable phenotypes at diagnosis, is feasible with available molecular biological technologies and crucial to reduce mortality caused by this syndrome.

A 100-kiloparsec wind feeding the circumgalactic medium of a massive compact galaxy.

Ninety per cent of baryons are located outside galaxies, either in the circumgalactic or intergalactic medium1,2. Theory points to galactic winds as the primary source of the enriched and massive circumgalactic medium3-6. Winds from compact starbursts have been observed to flow to distances somewhat greater than ten kiloparsecs7-10, but the circumgalactic medium typically extends beyond a hundred kiloparsecs3,4. Here we report optical integral field observations of the massive but compact galaxy SDSS J211824.06+001729.4. The oxygen [O II] lines at wavelengths of 3726 and 3729 angstroms reveal an ionized outflow spanning 80 by 100 square kiloparsecs, depositing metal-enriched gas at 10,000 kelvin through an hourglass-shaped nebula that resembles an evacuated and limb-brightened bipolar bubble. We also observe neutral gas phases at temperatures of less than 10,000 kelvin reaching distances of 20 kiloparsecs and velocities of around 1,500 kilometres per second. This multi-phase outflow is probably driven by bursts of star formation, consistent with theory11,12.