Antineoplastic Drug Synergy of Artesunate with Navitoclax in Models of High-Grade Serous Ovarian Cancer.

Artesunate belongs to a class of medications derived from the sweet wormwood plant (Artemisia annua) known as artemisinins. Artesunate has traditionally been used as a frontline treatment for severe malaria but has also demonstrated antineoplastic activity against various malignancies, including ovarian cancer. Data suggest that artesunate exacerbates cellular oxidative stress, triggering apoptosis. In the current study, we investigated the ability of navitoclax, an inhibitor of the antiapoptotic Bcl-2 protein family, to enhance artesunate efficacy in ovarian cancer cells. Artesunate and navitoclax both demonstrated antiproliferative effects on 2D and 3D ovarian cancer cell models as single agents. Upon combination of navitoclax with artesunate, antineoplastic drug synergy was also observed in each of the 2D cell lines and ovarian tumor organoid models tested. Further investigation of this drug combination using intraperitoneal CAOV3 xenograft models in BALB/scid mice showed that the artesunate/navitoclax doublet was superior to single-agent artesunate and vehicle control treatment. However, it did not outperform single-agent navitoclax. With optimization, this drug combination could provide a new therapeutic option for ovarian cancer and warrants further preclinical investigation.

Variables Associated With Resolution and Persistence of Ovarian Cysts.

OBJECTIVE: To estimate surveillance intervals of incident ovarian cysts, and describe variables associated with cyst resolution times. METHODS: The UK-OCST (University of Kentucky Ovarian Cancer Screening Trial) was a prospective cohort that enrolled 47,762 individuals over 30 years, including 2,638 individuals with incident cysts. Cyst diameter and structure and patient age, body mass index, use of hormone therapy (HT), family history of ovarian cancer, and menopausal status were examined as variables associated with cyst resolution using t tests, χ 2 test, Kaplan Meier, and Cox multiple regression. RESULTS: Of 2,638 individuals with incident cysts, 1,667 experienced resolution (63.2%) within 1.2 years, and 971 experienced persistence (36.8%). Within 1 year, unilocular and septated cysts had similar resolution rates (35.4% and 36.7%, respectively, P >.05), but time to resolution was shorter for unilocular cysts compared with septated cysts (mean 1.89 years vs 2.58 years, respectively, P <.001). Both unilocular and septated cysts smaller than 3 cm resolved faster than cysts larger than 6 cm ( P <.001). Variables associated with percent resolution included being of younger age, premenopausal status (but not for synchronous bilateral cysts), and those reporting a family history of ovarian cancer ( P <.05). Variables associated with a faster cyst resolution rate included being older than age 70 years and not using hormone therapy. Body mass index and family history were not associated with cyst resolution time. CONCLUSION: Different surveillance times may be appropriate depending on cyst structure and size and patient age and HT use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04473833.

Hemoglobin level associates with survival in women from Appalachian Kentucky with uterine cervix cancer.

Introduction: The purpose of this retrospective study was to determine the relationship between pretherapy hemoglobin levels and progression-free survival among women with uterine cervix cancer undergoing concurrent weekly cisplatin and radiotherapy followed by brachytherapy. Methods: Patients with advanced-stage II-IVA uterine cervix cancer were grouped by hemoglobin level (Hgb ≥ 12.0, 11.9-10.0, or < 10.0 g/dL). Endpoints were progression-free survival, overall survival, and local control. Results: Between 01/2001 and 07/2022, 168 patients contributed demographic, tumor, pretherapy hemoglobin, and outcome data with a median follow-up of 31 months. Progression-free survival at three years was 73% (95% confidence interval: 58%-84%), 71% (95% confidence interval: 56%-82%), and 62% (95% confidence interval: 44%-75%) for the Hgb ≥ 12.0, 11.9-10.0, or < 10.0 g/dL groups, respectfully (P < 0.001). In addition, pretherapy hemoglobin levels were significant with treatment outcome when included in a multivariate analysis of prognostic variables. Discussion: In conclusion, the difference in pretherapy hemoglobin level was prognostic of progression-free survival.

Implementation of Nurse Navigation Improves Rate of Molecular Tumor Testing for Ovarian Cancer in a Gynecologic Oncology Practice.

PURPOSE: The purpose of this study was to assess the impact of implementing a Nurse Navigator (NN) to improve the rate and timeliness of molecular tumor testing. METHODS: This is an evaluation of the impact of education sessions, consensus building, and NN implementation for molecular tumor testing in patients with epithelial ovarian cancer. The NNs' responsibilities included attending tumor boards and ensuring Next Generation Sequencing (NGS) is ordered, reviewed, and coordinated for appropriate patients. RESULTS: NNs significantly improved NGS testing rates from 35.29% to 77.27%, p = 0.002. Ordering a targeted panel test (TPT) was the most common reason for not ordering NGS in the pre-NN cohort (13/22, 59%). The total turnaround time for testing was reduced after the introduction of NNs from 145.2 days to 42.8 days, p < 0.0001. The post-NN group had a significantly higher rate of actionable mutations identified for the recurrent setting [67.6% versus 20.8% (p = 0.0005)] and a trend towards a higher rate of actionable mutations identified in the frontline setting [41.2% versus 33.3% (p = 0.41)]. CONCLUSION: NNs significantly improved somatic tumor testing rates and timeliness for patients with ovarian cancer. Discontinuing TPT in favor of NGS revealed a higher rate of actionable tumor mutations that would have been missed with TPT alone.

Robot-assisted laparoscopic removal of an extraperitoneal pelvic solitary fibrous tumor.

•Pelvic SFTs are rare, typically benign soft tissue neoplasms that pose a diagnostic challenge for gynecologists.•Retroperitoneal pelvic SFTs can mimic gynecologic malignancies and should be considered in diagnosis of a solitary pelvic mass.•Pathologic diagnosis is typically confirmed by immunohistochemistry staining positively for CD34 and STAT6.•Complete surgical excision is recommended for these tumors and can be completed with a minimally invasive approach.•Close long-term follow-up is necessary due to possible recurrence or metastasis, especially for high-risk pathologic features.

Subsequent Ultrasonographic Non-Visualization of the Ovaries Is Hastened in Women with Only One Ovary Visualized Initially.

Because the effects of age, menopausal status, weight and body mass index (BMI) on ovarian detectability by transvaginal ultrasound (TVS) have not been established, we determined their contributions to TVS visualization of the ovaries when one or both ovaries are visualized on the first ultrasound exam. A total of 29,877 women that had both ovaries visualized on their first exam were followed over 202,639 prospective TVS exams and 9703 women that had only one ovary visualized on their first exam were followed over 63,702 ultrasonography exams. All images were reviewed by a physician. While non-visualization of both ovaries increased with age in women selected on the basis of the visualization of only one ovary on their first ultrasound exam, one or both ovaries could be visualized in two out of every three women at 80 years of age and more than 50% of women over 80 years of age. At each age, more non-visualizations were associated with women that had only one ovary visualized on their first visit. Having only one ovary visualized on the first exam advanced non-visualizations by an average of ~10 years across all ages and by >20 years in women under 40 years of age. Conclusions: Having only one ovary visualized on an initial ultrasound exam considerably hastens complete non-visualization for this population; however, in these women, ovaries can still be visualized well past menopause, and body habitus is not limiting to TVS ovarian imaging, thus TVS should be considered capable of capturing an ovarian image in two out of every three women at 80 years of age.

Targeted suppression of gibberellin biosynthetic genes ZmGA20ox3 and ZmGA20ox5 produces a short stature maize ideotype.

Maize is one of the world's most widely cultivated crops. As future demands for maize will continue to rise, fields will face ever more frequent and extreme weather patterns that directly affect crop productivity. Development of environmentally resilient crops with improved standability in the field, like wheat and rice, was enabled by shifting the architecture of plants to a short stature ideotype. However, such architectural change has not been implemented in maize due to the unique interactions between gibberellin (GA) and floral morphology which limited the use of the same type of mutations as in rice and wheat. Here, we report the development of a short stature maize ideotype in commercial hybrid germplasm, which was generated by targeted suppression of the biosynthetic pathway for GA. To accomplish this, we utilized a dominant, miRNA-based construct expressed in a hemizygous state to selectively reduce expression of the ZmGA20ox3 and ZmGA20ox5 genes that control GA biosynthesis primarily in vegetative tissues. Suppression of both genes resulted in the reduction of GA levels leading to inhibition of cell elongation in internodal tissues, which reduced plant height. Expression of the miRNA did not alter GA levels in reproductive tissues, and thus, the reproductive potential of the plants remained unchanged. As a result, we developed a dominant, short-stature maize ideotype that is conducive for the commercial production of hybrid maize. We expect that the new maize ideotype would enable more efficient and more sustainable maize farming for a growing world population.

Ultrasonographic Visualization of the Ovaries to Detect Ovarian Cancer According to Age, Menopausal Status and Body Type.

Because the effects of age, menopausal status, weight and body mass index (BMI) on ovarian detectability by transvaginal ultrasound (TVS) have not been established, we determined their contributions to TVS visualization of the ovaries. A total of 29,877 women that had both ovaries visualized on their first exam were followed over 202,639 prospective TVS exams. All images were reviewed by a physician. While visualization of both ovaries decreased with age, one or both ovaries could be visualized in two of every three women over 80 years of age. Around 93% of pre-menopausal women and ~69% of post-menopausal women had both ovaries visualized. Both ovaries were visualized in ~72% of women weighing over 300 lbs. and in ~70% of women with a BMI over 40. Conclusions: Age had the greatest influence on the visualization of the ovaries. The ovaries can be visualized well past the menopause. Body habitus was not limiting to TVS ovarian imaging, and TVS should be considered capable of imaging one or both ovaries in two of every three women over 80 years of age. Thus, older and obese patients remain good candidates for TVS exams.

Significance of Pelvic Fluid Observed during Ovarian Cancer Screening with Transvaginal Sonogram.

The primary objective was to examine the role of pelvic fluid observed during transvaginal ultrasonography (TVS) in identifying ovarian malignancy. A single-institution, observational study was conducted within the University of Kentucky Ovarian Cancer Screening trial from January 1987 to September 2019. We analyzed true-positive (TP), false-positive (FP), true-negative (TN), and false-negative (FN) groups for the presence of pelvic fluid during screening encounters. Measured outcomes were the presence and duration of fluid over successive screening encounters. Of the 48,925 women surveyed, 2001 (4.1%) had pelvic fluid present during a TVS exam. The odds ratio (OR) of detecting fluid in the comparison group (TN screen; OR = 1) significantly differed from that of the FP cases (benign pathology; OR: 13.4; 95% confidence interval (CI): 9.1-19.8), the TP cases with a low malignant potential (LMP; OR: 28; 95% CI: 26.5-29.5), TP ovarian cancer cases (OR: 50.4; 95% CI: 27.2-93.2), and FN ovarian cancer cases (OR: 59.3; 95% CI: 19.7-178.1). The mean duration that pelvic fluid was present for women with TN screens was 2.2 ± 0.05 encounters, lasting 38.7 ± 1.3 months. In an asymptomatic screening population, free fluid identified in TVS exams was more associated with ovarian malignancy than in the control group or benign ovarian tumors. While pelvic free fluid may not solely discriminate malignancy from non-malignancy, it appears to be clinically relevant and warrants thoughtful consideration.

Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance.

The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC50 value (50.2 µM) being above clinically achievable Cmax. UK1254 had a significantly shorter PFS than the rest of the subjects (p = 0.0253) and was treated as a platinum-resistant recurrence. Subsequent gene expression analysis revealed extensively interconnected, differentially expressed pathways related to NF-kB, cellular differentiation (PRDM6 activation), and the linkage of B-cell receptor signaling to the PI3K-Akt signaling pathway (PI3KAP1 activation). This study demonstrates that patient-derived tumor organoids can be developed from patients at the time of primary or interval debulking surgery and may be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance.

Concurrent hysterectomy and bilateral salpingo-oophorectomy during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for non-gynecologic cancers.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a key component of treatment in non-gynecologic peritoneal surface malignancies. As many as 10-15% of patients with a gastrointestinal primary malignancy will present with carcinomatosis. Maximal cytoreductive surgery directly affects the prognosis of patients. The routine inclusion of hysterectomy with bilateral salpingo-oophorectomy during these procedures optimizes cytoreduction despite negative pre-operative imaging and findings at the time of surgery. In this case series, we review twenty non-gynecologic cancer patients who underwent cytoreductive surgery with concurrent hysterectomy and bilateral salpingo-oophorectomy and HIPEC at our institution.

Disease-Specific Survival of Type I and Type II Epithelial Ovarian Cancers-Stage Challenges Categorical Assignments of Indolence & Aggressiveness.

Epithelial ovarian cancers (EOC) consist of several sub-types based on histology, clinical, molecular and epidemiological features that are termed "histo-types", which can be categorized into less aggressive Type I and more aggressive Type II malignancies. This investigation evaluated the disease-specific survival (DSS) of women with Type I and II EOC using histo-type, grade, and stage. A total of 200,658 EOC cases were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data. Kaplan-Meier survival analyses, one-factor ANOVA and Chi-square analyses were performed on 10-year DSS survivals. DSS strongly supported a 2-tiered classification (grade 1 vs. grade 2 & 3) for serous EOC. DSS of early stage serous EOC for grade 2 was significantly different from grade 3 indicating that a 2-tier classification for serous EOC applied only to late stage. DSS of Type I EOC was much better than Type II. However, DSS was 46-58% lower with late stage Type I than with early stage Type I indicating that Type I ovarian cancers should not be considered indolent. Early stage Type II EOC had much better DSS than late stage Type II stressing that stage has a large role in survival of both Type I and II EOC.

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.

Hyperthermic intraperitoneal chemotherapy (HIPEC) in conjunction with cytoreductive surgery (CRS) holds promise as an adjunctive treatment strategy in malignancies affecting the peritoneal surface, effectively targeting remaining microscopic residual tumor. HIPEC increases concentrations of chemotherapy directly within the peritoneal cavity compared with the intravenous route and reduces the systemic side effects associated with prolonged adjuvant intraperitoneal exposure. Furthermore, hyperthermia increases tissue penetration and is synergistic with the therapeutic chemotherapy agents used. In ovarian cancer, evidence is building for its use in both primary and recurrent scenarios. In this review, we examine the history of HIPEC, the techniques used, and the available data guiding its use in primary and recurrent ovarian cancer.

Bangladesh Fistula Mission Partnership: Leveraging Assets from the United States Agency for International Development and the Department of Defense to Address a Health Care Crisis in a Developing Nation.

INTRODUCTION: Obstetric fistulae are a leading scourge for women in developing countries resulting, in severe individual suffering and devastating socio-economic repercussions for her family and community. The underlying causes of obstetric fistula stem from multiple factors to include poor nutrition, early marriage, insufficient education and inferior social status of women as well as substandard medical care. The US Agency for International Development (USAID) has invested more than $100 million globally since 2004 to address these factors as well as support women suffering with fistulae. The ultimate goal is to eradicate obstetric fistula in Bangladesh in the next 20 years. Despite these efforts, nearly 20,000 women in Bangladesh, still suffer with this malady. METHODS: To close this gap, USAID and the Department of Defense (DOD) developed a novel Interagency Agreement (IAA) leveraging the surgical skills of military health professionals to scale-up the ongoing fistula care program. The agreement outlined three lines of effort: (1) treat existing fistulae by bolstering surgical capacity of the existing USAID fistula care program; (2) promote fistula mitigation with lectures and hands-on teaching of obstetric care as well as safe gynecologic surgery; and (3) assist with advocacy at higher levels of the Bangladesh government. A Bangladesh Fistula Mission Partnership working group was formed to design and implement this IAA. Critical partners from the US Embassy in Dhaka included USAID (Health, Legal, Contracting), the DOD (Office of Defense Cooperation), and Department of State (Regional Security Officer). Partners from the US Army included United States Army-Pacific Command (Surgeon, Legal, Finance, Security Cooperation, Contracting), Regional Health Command-Pacific (Operations, Legal, Public Affairs), and Tripler Army Medical Center (Department of OBGYN, Operations, Public Affairs). Institutional Review Board approval was not required as the treatments offered were standard of care. RESULTS: The Tripler Army Medical Center (TAMC) health professionals executed the IAA with one pre-deployment site survey and two surgical missions in 2016-2017. The military team supported the surgical repair of 40 pelvic fistulae and perineal tears and provided operative management for an additional 25 patients with pelvic organ prolapse. Furthermore, the team conducted 19 professional lectures and multiple educational forums at hospitals in Kumudini, Khulna and the premier medical university in Dhaka for over 800 attendees including physicians, nurses and students to help prevent obstetric and surgical fistulae. Importantly, the team assisted USAID as subject matter experts in its advocacy to the Bangladesh Ministry of Health for improved maternity care and regulatory oversight. During the missions, the team enhanced their readiness by exercising individual and collective tasks while exposing personnel to the cultural context of the region. CONCLUSION: This IAA was the first USAID funded and DoD-executed health mission in the US Indo-Pacific Command Area of Responsibility. Direct participation in the IAA enabled TAMC to support the US Indo-Pacific Command Theater Campaign Plan, the Department of Defense Instruction 2000.30 on Global Health Engagements, the USAID Country Development Cooperation Strategy, and the US Ambassadors Integrated Country Strategy Objectives in Bangladesh. This effort can serve as a model for future cooperation between USAID and the DoD.