Mutation prevalence tables for hereditary cancer derived from multigene panel testing.

Multigene panel testing for cancer predisposition mutations is becoming routine in clinical care. However, the gene content of panels offered by testing laboratories vary significantly, and data on mutation detection rates by gene and by the panel is limited, causing confusion among clinicians on which test to order. Using results from 147,994 multigene panel tests conducted at Ambry Genetics, we built an interactive prevalence tool to explore how differences in ethnicity, age of onset, and personal and family history of different cancers affect the prevalence of pathogenic mutations in 31 cancer predisposition genes, across various clinically available hereditary cancer gene panels. Over 13,000 mutation carriers were identified in this high-risk population. Most were non-Hispanic white (74%, n = 109,537), but also Black (n = 10,875), Ashkenazi Jewish (n = 10,464), Hispanic (n = 10,028), and Asian (n = 7,090). The most prevalent cancer types were breast (50%), ovarian (6.6%), and colorectal (4.7%), which is expected based on genetic testing guidelines and clinician referral for testing. The Hereditary Cancer Multi-Gene Panel Prevalence Tool presented here can be used to provide insight into the prevalence of mutations on a per-gene and per-multigene panel basis, while conditioning on multiple custom phenotypic variables to include race and cancer type.

What is the Role of the Oncology Nurse in Fertility Preservation Counseling and Education for Young Patients?

Oncology nurses are uniquely positioned to offer fertility preservation counseling and education for cancer patients of reproductive age, yet there is a dearth of research that focuses on current practice and perceptions of nursing role. In 2013, the American Society of Clinical Oncology extended the duties of fertility preservation counseling among patients of reproductive age undergoing cancer treatment to include registered nurses and other allied health professionals as active partners in the counseling and education process. This study used a cross-sectional descriptive survey to assess current practices, role perceptions, and barriers to fertility preservation counseling among registered nurses working in an academic care setting with outpatient and inpatient services. There were significant gaps in current practices and perceptions of roles regarding fertility preservation counseling. Many nurses expressed the perception that fertility preservation counseling was important, but it was outside the scope of their practice to perform this education. This preliminary work defined need for an interdisciplinary fertility preservation team, communication surrounding educational practice norms, and designated oncofertility navigator.

Oral medroxyprogesterone acetate for the use of ovulation suppression in in vitro fertilization: a cohort trial.

OBJECTIVE: To broadly assess the efficacy of medroxyprogesterone acetate (MPA) for ovulatory suppression during in vitro stimulation compared with gonadotropin-releasing hormone (GnRH) antagonist cycles. DESIGN: Cohort trial. SETTING: A single academic-affiliated private fertility practice. PATIENTS: Patients of all diagnoses aged 18-44 years undergoing autologous in vitro fertilization (IVF) for fertility treatment between 2020 and 2023. INTERVENTIONS: Comparison of MPA vs. antagonist IVF stimulation cycles. MAIN OUTCOME MEASURES: Rates of premature ovulation, oocyte and embryo yield, embryo quality, pregnancy rates, and logistical benefits. RESULTS: Prospective data was collected on 418 patients who underwent MPA protocol ovarian stimulation (MPA group), which was compared with 419 historical control gonadotropin hormone-releasing hormone antagonist cycles (control group). Age was similar between groups (35.6 ± 4.6 vs. 35.7 ± 4.8 years; P = .75). There were no cases of premature ovulation in the MPA group compared with a total of five cases in the control group (0% vs. 1.2%; risk ratio [RR] = 0.09; 95% confidence interval [CI], 0.01, 1.66). No differences were seen between number of oocytes retrieved (14.3 ± 10.2 vs. 14.3 ± 9.7; P = .83), blastocysts (4.9 ± 4.6 vs. 5.0 ± 4.6; P = .89), or euploid blastocysts (2.4 ± 2.6 vs. 2.2 ± 2.4; P = .18) in the MPA vs. control group respectively. Clinical pregnancy rate was similar between groups (70.4% vs. 64.2%; RR = 0.92; 95% CI, 0.72, 1.18). There was no difference in length of IVF stimulation or dose of stimulation medications. Patients in the MPA group saved an average of $491 ± $119 on medications, had an average of one less monitoring visit (4.4 ± 0.9 vs. 5.6 ± 1.1; P<.01), and 5.0 ± 1.2 less injections per cycle. When adjusting for age and ovarian reserve, protocol group (MPA vs. control) did not influence having an embryo available for transfer (76.6% vs. 73.4%; adjusted RR = 1.05; 95% CI, 0.94, 1.14). CONCLUSION: For ovulatory suppression during IVF cycles, MPA was effective at preventing ovulation while demonstrating similar cycle and reproductive outcomes, with the additional benefits of patient cost savings, increased convenience with decreased number of visits, and fewer injections.

Risk of ectopic pregnancy following day-5 embryo transfer compared with day-3 transfer.

The incidence of ectopic pregnancy after IVF is increased approximately 2.5-5-fold compared with natural conceptions; however, the aetiology for this increased risk remains unclear. One proposed practice change to decrease the incidence of ectopic pregnancy is blastocyst embryo transfer on day 5 rather than cleavage-stage embryo transfer on day 3. A retrospective cohort study was conducted to compare the risk of ectopic pregnancy following fresh day-5 embryo transfer with day-3 embryo transfer among women who underwent IVF and achieved pregnancy from 1998 to 2011. There were 13,654 eligible pregnancies; 277 were ectopic. The incidence of ectopic pregnancy was 2.1% among day-3 pregnancies and 1.6% among day-5 pregnancies. The adjusted risk ratio for ectopic pregnancy from day-5 compared with day-3 transfer was 0.71 (95% confidence interval 0.46-1.10). Although this analysis included 13,654 cycles, with a two-sided significance level of 0.05, it had only 21.9% power to detect a difference between the low incidence of ectopic pregnancy among both day-3 and day-5 transfers. In conclusion, this study was not able to demonstrate a difference in the risk of ectopic pregnancy among day-3 compared with day-5 transfers.

Regulation of glutamate release by α7 nicotinic receptors: differential role in methamphetamine-induced damage to dopaminergic and serotonergic terminals.

Regulation of glutamate release is an important underlying mechanism in mediating excitotoxic events such as damage to dopamine (DA) and serotonin (5-HT) neurons observed after exposure to methamphetamine (Meth). One way to regulate glutamate release may be through the modulation of α7 nicotinic acetylcholine (nACh) receptors. Meth administration is known to increase acetylcholine release; however, it is unknown whether Meth increases glutamate release and causes long-term damage to both DA and 5-HT terminals through the activation of α7 nACh receptors. To test this hypothesis, the α7 nACh receptor antagonist, methyllycaconitine (MLA), was administered before the administration of repeated doses of Meth while simultaneously monitoring extracellular striatal glutamate with in vivo microdialysis. In addition, the subsequent long-term decreases in markers of dopaminergic and serotonergic terminals, including DA reuptake transporter (DAT), serotonin reuptake transporter (SERT), vesicular monoamine transporter-2, vesicular DA, and vesicular 5-HT content in the rat striatum, were measured. The results show that MLA pretreatment prevented Meth-induced increases in striatal glutamate and protected against the subsequent long-term decreases in striatal DAT and vesicular DA content without affecting the hyperthermia produced by Meth. In contrast, the Meth-induced decreases in striatal SERT immunoreactivity and vesicular 5-HT content were not affected by MLA. This suggests that the α7 nACh receptor differentially mediates glutamate-dependent damage to DA but not 5-HT terminals in a manner that is independent of hyperthermia. Furthermore, antagonism of α7 nACh receptors may be a possible therapeutic strategy for decreasing extracellular glutamate and preventing the excitotoxic damage observed in other DA-related neurodegenerative disorders.

IVF and embryo development subsequent to ovarian torsion occurring during the resumption of meiosis.

This report describes an unusual case of ovarian torsion during an IVF cycle prior to vaginal oocyte retrieval and the subsequent embryo development. A 27-year-old, whose husband carries a balanced translocation, presented on stimulation day 11 (day after human chorionic gonadotrophin administration) with signs of right ovarian torsion. Transvaginal ultrasound identified decreased right ovarian venous flow but preservation of right ovarian arterial flow. She underwent emergency laparoscopic right ovarian detorsion followed by vaginal oocyte retrieval on postoperative day 1. Ten oocytes were retrieved from the right detorted ovary, 4/10 (40%) were fertilized and 3/4 (75%) became blastocysts. Fifteen oocytes were retrieved from the left ovary, 14/15 (93%) were fertilized and 9/14 (64%) became blastocysts. All 18 embryos biopsied for preimplantation genetic diagnosis carried unbalanced translocations and none were transferred. The markedly reduced fertilization rate of the oocytes from the previously torted ovary is similar to the rate described in a prior report and likely related to decreased but maintained ovarian arterial flow. This report is unique because not only was the patient's ovarian torsion surgically corrected prior to oocyte retrieval but also the embryos originating from the previously torted ovary had excellent development with 75% progressing to the blastocyst stage.

Polyhydramnios, fetal overgrowth, and macrocephaly: prenatal ultrasound findings of Costello syndrome.

Costello syndrome is a multiple congenital anomaly syndrome consisting of dysmorphic facies, cutis laxa, short stature, developmental delay, and mental retardation. Complications include failure to thrive, hypertrophic cardiomyopathy with arrhythmias, and benign and malignant tumors. This report describes a new case of Costello syndrome in a preterm infant born at 27 weeks gestation and diagnosed with Costello syndrome at 7 weeks of life who died at 6 months of age due to cardiac and pulmonary complications. In addition, data were compiled from parent surveys including growth parameters on 16 infants who were subsequently diagnosed with Costello syndrome and had mutation confirmation. The most common prenatal findings in the literature and in this cohort were polyhydramnios and fetal overgrowth with relative macrocephaly. Based on this study, ultrasound identification of polyhydramnios in the context of prenatal overgrowth, especially with relative macrocephaly, needs to raise the possibility of a diagnosis of Costello syndrome in the fetus because of the life-threatening cardiac complications that may occur early in the newborn period.

Avoiding transmitting identified mutations to offspring using preimplantation genetic diagnosis.

BACKGROUND: Preimplantation genetic diagnosis has been used to decrease or avoid the risk of transmitting identified mutations to offspring. CASE: A 29-year-old woman with spondyloepiphyseal dysplasia congenita and her 30-year-old husband with Marfan syndrome underwent in vitro fertilization with preimplantation genetic diagnosis. Two mutation-negative embryos were transferred into a gestational carrier, who became pregnant with twins and delivered two clinically normal neonates. CONCLUSION: Statistically, this couple would be predicted to have a 75% chance of producing an affected embryo. Using preimplantation genetic diagnosis, two dually unaffected embryos were selected and transferred. This experience expands the use of preimplantation genetic diagnosis to cases with multiple autosomal dominant single-gene disorders.

Patients with severe ovarian hyperstimulation syndrome can be managed safely with aggressive outpatient transvaginal paracentesis.

OBJECTIVE: To describe our experience with aggressive outpatient transvaginal paracentesis to manage ovarian hyperstimulation syndrome (OHSS). DESIGN: Retrospective case series. SETTING: Private, academically affiliated IVF center. PATIENT(S): Women undergoing assisted reproductive technologies (ART) and having a diagnosis of OHSS. INTERVENTION(S): Management of OHSS with hospitalization or outpatient transvaginal paracentesis between 1999 and 2007. MAIN OUTCOME MEASURE(S): Grade and stage of OHSS, need for hospitalization, and adverse events. RESULT(S): From 1999 to 2007, we identified 183 patients with OHSS. We began performing outpatient transvaginal paracentesis to treat OHSS in 2002. We have performed 146 outpatient transvaginal paracenteses in 96 patients with no procedure-related complications. With the implementation of early, aggressive, outpatient paracentesis, the number of patients requiring hospitalization for OHSS decreased. From 2006 to 2007, 29 patients were diagnosed with severe OHSS and 25 (86%) were managed as outpatients with transvaginal paracentesis with no complications. CONCLUSION(S): This report represents one of the largest series of patients with OHSS managed with outpatient transvaginal paracentesis. Although there continues to be a small percentage of patients with OHSS who require hospitalization, the vast majority of patients with severe OHSS at our center in the past 2 years had their condition successfully managed as outpatients with use of aggressive transvaginal paracentesis.

Ovarian hyperstimulation syndrome: current views on pathophysiology, risk factors, prevention, and management.

OBJECTIVE: To summarize current views on the pathophysiology, risk factors, prevention, clinical features, and management of Ovarian Hyperstimulation Syndrome (OHSS). DESIGN: Literature review RESULTS: OHSS is a condition characterized by increased capillary permeability, and experimental evidence has identified a provocative link to pathologic vasoactive cytokine actions. Although the ultimate physiologic mechanism of OHSS is not yet known, there are well-known risk factors that must be considered during the administration of medications to treat infertility. Clinical features are consequences of third-spaced intravascular fluid, and OHSS may become life-threatening secondary to thromboembolism or compromised pulmonary or cardiovascular function. Cornerstones of prevention have historically included cycle cancellation, coasting, decreased dosing of human chorionic gonadotropin (hCG) trigger, use of an agonist trigger, and cryopreservation of all embryos. Newer methods of prevention include the administration of a dopamine agonist medication. Management options for OHSS include outpatient transvaginal paracentesis, outpatient transabdominal paracentesis, and inpatient hospitalization with or without paracentesis. CONCLUSIONS: OHSS continues to be a serious complication of assisted reproductive therapy (ART), with no universally agreed upon best method of prevention. Coasting and cryopreservation of all embryos are the most commonly used approaches in the literature, but cycle cancellation is the only method that can completely prevent the development of OHSS. Dopamine agonists are currently being investigated to both prevent and improve the clinical course in OHSS. Recent publications suggest that outpatient paracentesis both prevents the need for inpatient hospitalization and is a cost-effective strategy.

The bile acid synthesis pathway is present and functional in the human ovary.

BACKGROUND: Bile acids, end products of the pathway for cholesterol elimination, are required for dietary lipid and fat-soluble vitamin absorption and maintain the balance between cholesterol synthesis in the liver and cholesterol excretion. They are composed of a steroid structure and are primarily made in the liver by the oxidation of cholesterol. Cholesterol is also highly abundant in the human ovarian follicle, where it is used in the formation of the sex steroids. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe for the first time evidence that all aspects of the bile acid synthesis pathway are present in the human ovarian follicle, including the enzymes in both the classical and alternative pathways, the nuclear receptors known to regulate the pathway, and the end product bile acids. Furthermore, we provide functional evidence that bile acids are produced by the human follicular granulosa cells in response to cholesterol presence in the culture media. CONCLUSIONS/SIGNIFICANCE: These findings establish a novel pathway present in the human ovarian follicle that has the capacity to compete directly with sex steroid synthesis.