Efficacy and Safety of Single Oral Dosing of Secnidazole for Trichomoniasis in Women: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Delayed-Treatment Study.

BACKGROUND: Trichomonas vaginalis is the most prevalent nonviral sexually transmitted infection. We evaluated the efficacy and safety of secnidazole vs placebo in women with trichomoniasis. METHODS: Women with trichomoniasis, confirmed by a positive T. vaginalis culture, were randomized to single-dose oral secnidazole 2 g or placebo. The primary endpoint was microbiological test of cure (TOC) by culture 6-12 days after dosing. At the TOC visit, participants were given the opposite treatment. They were followed for resolution of infection afterward and offered treatment at subsequent visits, if needed. Fifty patients per group (N = 100) provided approximately 95% power to detect a statistically significant difference between treatment groups. RESULTS: Between April 2019 and March 2020, 147 women enrolled at 10 sites in the United States. The modified intention-to-treat (mITT) population included 131 randomized patients (secnidazole, n = 64; placebo, n = 67). Cure rates were significantly higher in the secnidazole vs placebo group for the mITT population (92.2% [95% confidence interval {CI}: 82.7%-97.4%] vs 1.5% [95% CI: .0%-8.0%]) and for the per-protocol population (94.9% [95% CI: 85.9%-98.9%] vs 1.7% [95% CI: .0%-8.9%]). Cure rates were 100% (4/4) in women with human immunodeficiency virus (HIV) and 95.2% (20/21) in women with bacterial vaginosis (BV). Secnidazole was generally well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were vulvovaginal candidiasis and nausea (each 2.7%). No serious TEAEs were observed. CONCLUSIONS: A single oral 2 g dose of secnidazole was associated with significantly higher microbiological cure rates vs placebo, supporting a role for secnidazole in treating women with trichomoniasis, including those with HIV and/or BV. CLINICAL TRIALS REGISTRATION: NCT03935217.

Advanced Imaging for the Diagnosis and Treatment of Coexistent Renal and Müllerian Abnormalities.

PURPOSE OF REVIEW: Abnormal development of the uterus, cervix, and proximal 2/3 of the vagina results in Müllerian duct anomalies. Because of the close embryologic relationship between the developing female genital and urinary tracts, abnormalities of the urinary tract often accompany Müllerian duct anomalies. Magnetic resonance imaging (MRI) is the current gold standard-imaging modality in the evaluation of the anomalies of the female reproductive tract. This article discusses the imaging evaluation of Müllerian duct and accompanying urinary tract anomalies with a particular focus on the MRI findings. RECENT FINDINGS: Several studies have shown high concordance between MRI and three-dimensional ultrasound (3D US) in the evaluation of Müllerian duct abnormalities. 3D US is more cost effective than MRI but has not yet been fully substantiated as a comparable modality to MRI. Additionally, 3D US does not help elucidate concomitant anomalies of the urologic system. Müllerian duct anomalies are often associated with abnormalities of the urinary tract. Evaluation with MRI is important for the diagnosis of Müllerian duct anomalies and also helps with potential surgical planning.

How Accurate Is Oncologist Knowledge of Fertility Preservation Options, Cost, and Time in Female Adolescents and Young Adults?

Purpose: Often cited barriers to fertility preservation (FP) among female adolescent and young adult (AYA) cancer patients include cost and time. We hypothesized that oncologists overestimate the time and costs required for female FP. Methods: We distributed an electronic survey to physicians in oncology-related departments. The survey assessed the knowledge and utilization of gonadotoxic therapies, FP options and requirements, and FP referral patterns. Student's t, Fisher's exact, ANOVA, and Wilcoxon signed-rank tests were used for continuous variables as appropriate; the chi-squared test was used for categorical variables. Results: Among respondents who reported prescribing gonadotoxic agents to AYAs (n = 38), 79% reported often/always discussing FP options, while only half referred to a reproductive specialist often/always. A smaller proportion of pediatric oncologists discussed FP often/always (p = 0.04) and most referred <25% of patients to a reproductive specialist; however, the majority of other specialists referred ≥75% of patients to a reproductive specialist (p = 0.001). While most respondents accurately estimated the time required to complete FP, the majority overestimated the cost of an FP procedure. Knowledge of FP options was inconsistent, with 63.2% reporting that suppression of the hypothalamic-pituitary-ovarian-axis is an option for FP, with 82.6% of these classifying it as standard of care. Conclusions: With variation across specialties, most oncology specialists prescribing gonadotoxic therapies for AYA females discuss FP, while a smaller proportion refer patients for FP. Despite relative accuracy in estimating the time required for FP, they overestimate costs of FP. Educational curricula related to FP are necessary across oncology specialties, especially pediatric oncology.

Menstrual Suppression in the Myelosuppressed: A Retrospective Cohort Study.

PURPOSE: Adolescent and young adult female patients receiving myelosuppressive cancer treatments are at risk of abnormal uterine bleeding (AUB). The frequency with which patients with cancer receive menstrual suppression and the agents used have not previously been well-characterized. We studied the rate of menstrual suppression, the effect of suppression on bleeding and blood product utilization, and if there were practice pattern differences between adult and pediatric oncologists. METHODS: We established a retrospective cohort of 90 females with a diagnosis of Hodgkin or non-Hodgkin lymphoma (n = 25), AML (n = 46), or sarcoma (n = 19) and treated with chemotherapy between 2008 and 2019 at our institutions (University of Alabama at Birmingham [UAB] adult oncology: UAB hospital; UAB pediatric oncology: Children's of Alabama). Data were abstracted from the medical record including sociodemographics, primary oncologist specialty (pediatric v adult), cancer details (diagnosis and treatment) and gynecologic course (documented gynecologic history, menstrual suppression agents used, reported AUB outcomes, and treatments). RESULTS: The majority of patients (77.8%) received menstrual suppression. Compared with nonsuppressed patients, suppressed patients had similar rates of packed red blood cell transfusions but higher number of platelet transfusions. Adult oncologists were more likely to document a gynecologic history, consult gynecology, and list AUB as a problem. Among suppressed patients, there was heterogeneity in the agents used for menstrual suppression, with a predilection toward progesterone-only agents; a low rate of thrombotic events was observed. CONCLUSION: Menstrual suppression was common in our cohort with variability in agents used. Pediatric and adult oncologists demonstrated different practice patterns.

Treatment of chemotherapy-induced anemia in ovarian cancer patients: does the use of erythropoiesis-stimulating agents worsen survival?

OBJECTIVE: Considering the paucity of data relating erythropoiesis-stimulating agent (ESA) use to ovarian cancer survival, our objective was to evaluate the effect of ESA as used for the treatment of chemotherapy-induced anemia (CIA) on survival in ovarian cancer patients. MATERIALS AND METHODS: A multi-institution retrospective chart review was performed on ovarian cancer patients. Data collection included patient demographic, surgicopathologic, chemotherapy, ESA, and survival data. Patients were stratified by ever-use of ESA and were compared using appropriate statistical methods. RESULTS: A total of 581 patients were eligible for analysis with 39% (n = 229) patients with ever-use of ESA (ESA-YES) and 61% (n = 352) never-use ESA (ESA-NO). Mean age was 60.4 years with most patients having stage IIIC (60%) of papillary serous histological diagnosis (64%) with an optimal cytoreduction (67%). Median follow-up for the cohort was 27 months. Both ESA-YES and ESA-NO groups were similar regarding age, body mass index, race, stage, histological diagnosis, and debulking status. Compared with the ESA-NO group, ESA-YES patients were significantly more likely to experience recurrence (56% vs 80%, P < 0.001) and death (46% vs 59%, P = 0.002). Kaplan-Meier curves demonstrated a significant reduction in progression-free survival for ESA-YES patients (16 vs 24 months, P < 0.001); however, overall survival was statistically similar between the 2 groups (38 vs 46 months, P = 0.10). When stratifying by ever experiencing a CIA, ESA-YES patients demonstrated a significantly worse progression-free survival (17 vs 24 months, P = 0.02) and overall survival (37 vs 146 months, P < 0.001). CONCLUSIONS: Our data evaluating the use of ESA as a treatment of CIA in ovarian cancer patients are similar to reports in other tumor sites. Considering that patients who used ESA were more likely to experience recurrence and death and to have decreased survival, the use of ESA in ovarian cancer patients should be limited.

Elucidating the domain architecture and functions of non-core RAG1: the capacity of a non-core zinc-binding domain to function in nuclear import and nucleic acid binding.

BACKGROUND: The repertoire of the antigen-binding receptors originates from the rearrangement of immunoglobulin and T-cell receptor genetic loci in a process known as V(D)J recombination. The initial site-specific DNA cleavage steps of this process are catalyzed by the lymphoid specific proteins RAG1 and RAG2. The majority of studies on RAG1 and RAG2 have focused on the minimal, core regions required for catalytic activity. Though not absolutely required, non-core regions of RAG1 and RAG2 have been shown to influence the efficiency and fidelity of the recombination reaction. RESULTS: Using a partial proteolysis approach in combination with bioinformatics analyses, we identified the domain boundaries of a structural domain that is present in the 380-residue N-terminal non-core region of RAG1. We term this domain the Central Non-core Domain (CND; residues 87-217). CONCLUSIONS: We show how the CND alone, and in combination with other regions of non-core RAG1, functions in nuclear localization, zinc coordination, and interactions with nucleic acid. Together, these results demonstrate the multiple roles that the non-core region can play in the function of the full length protein.

Adolescent emergency contraception usage, knowledge, and perception.

OBJECTIVE: We sought to describe the current usage patterns, knowledge regarding, and perception of emergency contraception in adolescent patients. STUDY DESIGN: We surveyed female patients ages 14 to 21 seen at the Pediatric and Gynecology Clinic regarding emergency contraception. We posed questions to understand adolescent awareness, personal usage, and means of obtaining emergency contraception. We also explored respondent knowledge of emergency contraception and potential barriers to access. RESULTS: Of 261 patients approached, 253 completed the survey with a mean age of 16.7 ± 1.7 years. The majority of respondents (80.2%) had heard of oral emergency contraceptive pills. Among sexually active adolescents, 25.6 % reported personal use. Older adolescents (≥18 years) were more likely to have heard of emergency contraceptive pills, to know someone who used them, and to have used it themselves compared to younger adolescents (all p < 0.05). A minority of respondents knew that emergency contraception could be bought over the counter regardless of age or gender (44.3%) and that parental consent is not required (27.7%). Having ever been sexually active was associated with an increased odds of being correct with regards to the availability and timing of LNG EC. A history of LNG EC use was associated with an increased likelihood of understanding the mechanism of action and side effects of LNG EC. CONCLUSIONS: Though adolescents in our population were aware of emergency contraception, only a small portion had used it themselves. Misunderstandings regarding the availability and safety of emergency contraception were common in our population. IMPLICATIONS: Educating adolescents on the availability, safety, and mechanism of action of LNG EC may improve utilization of LNG EC in this population.

Prevalence and Awareness of Pelvic Floor Disorders in Female Adolescents Seeking Gynecologic Care.

STUDY OBJECTIVE: To determine the prevalence and awareness of pelvic floor disorder symptoms among female adolescents. DESIGN: Cross-sectional study via a written, anonymous survey of adolescents. The survey was composed of validated measures for determination of symptom prevalence. SETTING: Pediatric and adolescent gynecology clinic in the southeast United States. PARTICIPANTS: Female adolescents ages 14-21 years. INTERVENTIONS: None. MAIN OUTCOME MEASURES: We used χ2 analyses for categorical variables and t test for continuous variables. RESULTS: Two hundred sixteen questionnaires were completed. The mean age of respondents was 17.1 (±2.1) years and most respondents had at least heard about urinary (UI) and fecal incontinence (FI; 62.9%). The prevalence of any UI was 31.5%. Urgency UI (UUI) was reported by 15.7% and stress UI was reported by 6.9% of adolescents; 8.8% of participants experienced UUI and stress UI symptoms. FI and pelvic organ prolapse symptoms were reported by 0.9%. There were no differences in reported prevalence rates of UI (31.7% vs 27.9%), FI (1.4% vs 0%), or pelvic organ prolapse (1.4% vs 0%) between younger (14-17 years) and older (18-21 years) adolescent participants, respectively (all P > .05). Although UI was fairly prevalent among respondents, most stated that it had a minimal effect on daily living. CONCLUSION: UI symptoms were common among female adolescents, with UUI being the most reported. Early education regarding pelvic floor disorder symptoms might lead to prevention or empowerment to seek treatment as adolescents age.

Extramedullary Relapse of Acute Lymphoblastic Leukemia Presenting as Abnormal Uterine Bleeding: A Case Report.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Relapse of ALL occurs in 15%-20% of patients, with 2%-6% occurring exclusively in extramedullary sites. Relapse of ALL in gynecologic organs is extremely rare. CASE: We present a case of a 12-year-old girl with a history of ALL who was referred to the pediatric gynecology clinic with abnormal uterine bleeding. She was determined to have an extramedullary uterine relapse of her ALL. SUMMARY AND CONCLUSION: Abnormal uterine bleeding in the setting of childhood malignancy is a frequent reason for consultation to pediatric and adolescent gynecology services. This bleeding is commonly attributed to thrombocytopenia due to bone marrow suppressive chemotherapeutic agents. However, as shown in this report, abnormal uterine bleeding might be a manifestation of an extramedullary relapse.

Self-association and conformational properties of RAG1: implications for formation of the V(D)J recombinase.

RAG1 and RAG2 catalyze the initial DNA cleavage steps in V(D)J recombination. Fundamental properties of these proteins remain largely unknown. Here, self-association and conformational properties of murine core RAG1 (residues 384-1008) were examined. As determined by multi-angle laser light scattering measurements, the molecular masses of two predominant core RAG1 species corresponded to dimeric and tetrameric states. Similar results were obtained using a RAG1 fragment containing residues 265-1008, indicating that a non-core portion of RAG1 does not alter the oligomerization states observed for the core region. The fraction of core RAG1 in the tetrameric state increased significantly at lower ionic strengths (0.2 versus 0.5 M NaCl), indicating that this oligomeric form may factor into the physiological function of RAG1. In addition, the secondary structural content of core RAG1, obtained by circular dichroism spectroscopy, demonstrated a significant dependence on ionic strength with a 26% increase in alpha-helical content from 0.2 to 1.0 M NaCl. Together, these results indicate that structural and oligomerization properties of core RAG1 are strongly dependent on electrostatic interactions. Furthermore, the secondary structure of core RAG1 changes upon binding to DNA, with larger increases in alpha-helical content upon binding to the recombination signal sequence (RSS) as compared with non-sequence-specific DNA. As shown by electrophoretic mobility shift assays, higher order oligomeric forms of core RAG1 bound to the canonical RSS. Furthermore, core RAG2 (residues 1-387) formed complexes with multimeric RAG1 species bound to a single RSS, providing additional support for the physiological relevance of higher order oligomeric states of RAG1.

Anovulatory bleeding in a 12-year-old as presenting sign for rare undifferentiated sarcoma.

BACKGROUND: Abnormal uterine bleeding is a common phenomenon in perimenarchal females. Though most cases of abnormal bleeding are due to anovulatory bleeding or bleeding disorders, rare cases are attributable to underlying malignancy. CASE: Here we report a 12-year-old female patient who presented with abnormal uterine bleeding three months after menarche. She was ultimately diagnosed with a pelvic sarcoma of unknown primary origin. She was subsequently treated with chemotherapy, whole pelvic radiation, and hysterectomy with bilateral salpingo-oophorectomy. SUMMARY: Abnormal uterine bleeding unresponsive to conventional temporizing measures should be thoroughly evaluated. Management of pelvic malignancies in the pediatric population requires cooperation amongst specialists from an array of disciplines.

The central domain of core RAG1 preferentially recognizes single-stranded recombination signal sequence heptamer.

RAG1 and RAG2 initiate V(D)J recombination by introducing DNA double strand breaks between each selected gene segment and its bordering recombination signal sequence (RSS) in a two-step mechanism in which the DNA is first nicked, followed by hairpin formation. The RSS consists of a conserved nonamer and heptamer sequence, in which the latter borders the site of DNA cleavage. A region within RAG1, referred to as the central domain (residues 528-760 of 1040 in the full-length protein), has been shown previously to bind specifically to the double-stranded (ds) RSS heptamer, but with both weak specificity and affinity. However, additional investigations into the RAG1-RSS heptamer interaction are required because the DNA substrate forms intermediate conformations during the V(D)J recombination reaction. These include the nicked and hairpin products, as well as likely base unpairing to produce single-stranded (ss) DNA near the cleavage site. Here, it was determined that although the central domain showed substantially higher binding affinity for ss and nicked versus ds substrate, the interaction with ss RSS was particularly robust. In addition, the central domain bound with greater sequence specificity to the ss RSS heptamer than to the ds form. This study provides important insight into the V(D)J recombination reaction, specifically that significant interaction of the RSS heptamer with RAG1 occurs only after the induction of conformational changes at the RSS heptamer.