Jason Franasiak

Metformin is associated with improved survival in endometrial cancer.

OBJECTIVE Preclinical evidence suggests that metformin exhibits anti-tumorigenic effects in endometrial cancer. We sought to investigate the association of metformin on endometrial cancer outcomes. METHODS A multi-institutional IRB-approved retrospective cohort analysis was conducted comparing endometrial cancer patients with diabetes mellitus who used metformin (based on medication review at the time of diagnosis) to those who did not use metformin from 2005 to 2010. Metformin use on treatment related outcomes (TTR: time to recurrence; RFS: recurrence free survival; OS: overall survival) were evaluated using univariate and multivariate modeling. RESULTS 24% (363/1495) endometrial cancer patients were diabetic, of whom 54% used metformin. Metformin users were younger and heavier than non-users, though nearly all were postmenopausal and obese. 75% of both groups had endometrioid histology. Stage, grade, and adjuvant therapy distributions were similar. Metformin users had improved RFS and OS. Non-metformin users had 1.8 times worse RFS (95% CI: 1.1-2.9, p = 0.02) and 2.3 times worse OS (95% CI: 1.3-4.2, p = 0.005) after adjusting for age, stage, grade, histology and adjuvant treatment. Metformin use was not associated with TTR. CONCLUSION Metformin use was associated with improved RFS and OS but not TTR, most likely due to improving all-cause mortality. Its role in modifying cancer recurrence remains unclear. Prospective studies that capture metformin exposure prior to, during and post endometrial cancer treatment may help define the role of metformin upon cancer specific and overall health outcomes.

Obstetrical and neonatal outcomes from the BEST Trial: single embryo transfer with aneuploidy screening improves outcomes after in vitro fertilization without compromising delivery rates

OBJECTIVE We sought to determine whether performing elective single embryo transfer (eSET) after trophectoderm biopsy and rapid aneuploidy screening results in improved obstetrical and neonatal outcomes compared with transferring 2 untested embryos. STUDY DESIGN The Blastocyst Euploid Selective Transfer (BEST) Trial enrolled infertile couples with a female partner up to age 42 years who were undergoing in vitro fertilization. They were randomized to receive transfer of a single euploid embryo (eSET) or to the standard of care with transfer of 2 embryos that were not biopsied for aneuploidy screening (untested 2-embryo transfer). Gestational age at delivery, birthweight, and neonatal intensive care unit (NICU) lengths of stay were compared with Mann-Whitney U. The risk of preterm delivery, low birthweight, and NICU admission were compared with χ(2). RESULTS Among the 175 randomized patients, the delivery rates were similar (69% after euploid eSET vs 72% after untested 2-embryo transfer; P = .6) through the fresh cycle and up to 1 frozen transfer, with a dramatic difference in multiple births (1.6% vs 47%; P < .0001). The risk of preterm delivery (P = .03), low birthweight (P = .002), and NICU admission (P = .04) were significantly higher after untested 2-embryo transfer. Babies born after untested 2-embryo transfer spent >5 times as many days in the NICU (479 vs 93 days; P = .03). CONCLUSION By enhancing embryo selection with a validated method of aneuploidy screening, a single euploid embryo with high reproductive potential can be selected for transfer. Using this approach, eSET can be performed without compromising delivery rates and improving the chance of having a healthy, term singleton delivery after in vitro fertilization.

Physical strain and urgent need for ergonomic training among gynecologic oncologists who perform minimally invasive surgery

OBJECTIVES There is limited data regarding physical strain and minimally invasive gynecologic surgery (MIS). We sought to evaluate ergonomic strain among gynecologic oncologists. METHODS An online survey was sent to all physician members of the Society of Gynecologic Oncology in North America in 2010. The survey contained 42 questions and data was analyzed using univariate and bivariate analyses with summary statistics, t-tests, and chi-squared test. RESULTS There were 260 respondents (31.2%) to the survey. Case mix was 26% benign and 64% oncologic surgery. Over 52% of respondents had been in practice for greater than 11 years and 52% practice in an academic setting. Physical discomfort related to MIS was reported in 88% (216/244) of surgeons with 52% reporting persistent pain. Increased pain symptoms were associated with surgeons height, glove size, age and female gender. Patient body mass index (BMI) was associated with pain symptoms in surgeons performing conventional laparoscopic surgery, but not robotic surgery. To decrease pain, surgeons changed positions (78%), limited the number of cases per day (14%), spread cases throughout the week (6%), or limited the total number of cases (3%). Only 29% had received treatment at any time for pain symptoms. Treatment included physical therapy (59%), medical management (28%), surgery (13%), and time off (1%). Only 16% of those with pain symptoms had received formal ergonomic training. CONCLUSION Physical strain rates of 88% are far greater than previously reported. Such prevalent occupational strain presents a growing problem in the face of increasing demand for MIS.

The complex triad of obesity, diabetes and race in Type I and II endometrial cancers: Prevalence and prognostic significance

BACKGROUND We examined the distribution of obesity, diabetes, and race in Type I and Type II endometrial cancers (EC) and their associations with clinical outcomes. METHODS A multi-institutional retrospective analysis of Type I and II EC cases from January 2005 to December 2010 was conducted. Type I (endometrioid), Type II (serous and clear cell), low grade (LG) (grade 1 and 2 endometrioid), and high grade (HG) (grade 3 endometrioid, serous, clear cell) cohorts were compared. Univariate and multivariate analyses were used to determine time-to-recurrence (TTR), recurrence-free survival (RFS), and overall survival (OS). RESULTS Type I EC patients were more frequently obese than Type II (66% versus 51%, p<0.0001) and had similar rates of diabetes (25% versus 23%, p=0.69). African-Americans (AA) had higher median BMI than Caucasians in both Type I (p<0.001) and II (p<0.001) ECs, and were twice as likely to have diabetes (p<0.001). In Type I EC, DM was associated with worse RFS and OS in unadjusted and adjusted models (RFS HR 1.38, 95%CI 1.01-1.89; OS HR 1.86, 95%CI 1.30-2.67), but not with TTR. BMI was associated with improved TTR in the adjusted analysis for Type I EC (HR 0.98, 95%CI 0.95-1.0), but not with RFS or OS. There was no association between DM or BMI and outcomes in Type II or HG EC. AA race was not associated with RFS or OS on adjusted analyses in any group. CONCLUSIONS Obesity and diabetes are highly prevalent in Type I and II ECs, especially in AA. DM was associated with worse RFS and OS in Type I EC. Neither DM nor BMI was associated with outcomes in Type II or HG EC.

Expanded carrier screening in an infertile population: how often is clinical decision making affected?

Purpose:Options for preconception genetic screening have grown dramatically. Expanded carrier screening (ECS) now allows for determining carrier status for hundreds of genetic mutations by using a single sample, and some recommend ECS prior to in vitro fertilization. This study seeks to evaluate how often ECS alters clinical management when patients present for infertility care.Methods:All patients tested with ECS at a single infertility care center from 2011 to 2014 were evaluated. The overall rate of positive ECS results and the number of couples who were carriers of the same genetic disorder were evaluated.Results:A total of 6,643 individuals were tested, representing 3,738 couples; 1,666 (25.1%) of the individuals had a positive test result for at least one disorder. In 8 of the 3,738 couples, both members of the couple were positive for the same genetic disorder or had a test result that placed them at risk of having an affected child. Three of eight cases were cystic fibrosis. In this cohort, ECS affected clinical care eight times after 6,643 tests (0.12%, confidence interval: 0.05–0.24%) in 3,738 couples (0.21%, confidence interval: 0.09–0.42%).Conclusions:ECS is becoming more widespread. In a large case series, ECS affected clinical decision making for patients presenting for infertility care in 0.21% of cases. This information must be weighed when utilizing these tests and may be a helpful part of patient counseling.Genet Med 18 11, 1097–1101.

Combination of uterine natural killer cell immunoglobulin receptor haplotype and trophoblastic HLA-C ligand influences the risk of pregnancy loss: a retrospective cohort analysis of direct embryo genotyping data from euploid transfers

OBJECTIVE To compare maternal uterine natural killer cell immunoglobulin receptor (KIR) genotype and haplotype frequencies between patients whose euploid single-embryo transfer resulted in pregnancy loss and those that resulted in delivery and to determine if the risk of pregnancy loss was affected by the HLA-C genotype content in the embryo. DESIGN Retrospective cohort. SETTING Academic research center. PATIENT(S) Autologous fresh IVF cycles resulting in positive serum β-hCG during 2009-2014. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) 1) Relative risk of pregnancy loss according to maternal KIR genotypes and haplotypes. 2) Comparison of pregnancy loss rates within each KIR haplotype according to HLA-C ligand present in trophectoderm biopsy samples. RESULT(S) A total of 668 euploid single-embryo transfers with stored maternal DNA and available preamplification DNA from prior trophectoderm biopsy samples were studied. KIR2DS1, KIR3DS1, and KIR2DS5 were more common in patients who experienced pregnancy loss. Carriers of KIR A haplotype exhibited a decreased risk of pregnancy loss compared with KIR B haplotype carriers. However, among KIR A haplotype carriers, the risk of loss was significantly influenced by whether the transferred embryo carried a C1 allele versus no C1 alleles. CONCLUSION(S) KIR A haplotype carriers experienced fewer pregnancy losses than KIR B haplotype carriers after euploid single-embryo transfer. However, this risk was modified by HLA-C alleles present in the embryo. High-risk combinations (KIR A/homozygous C2 and KIR B/homozygous C1) resulted in a 51% increased risk of loss over all other combinations.

Longitudinal anti-mullerian hormone in women with polycystic ovary syndrome: an acupuncture randomized clinical trial.

Others have studied acupuncture treatment for polycystic ovary syndrome (PCOS). Anti-müllerian hormone (AMH) is positively correlated with the ovarian follicle pool, thus making it a useful ovarian reserve measure. AMH is elevated in women with PCOS and has been suggested as a diagnostic tool. This study examined the impact of electroacupuncture on AMH concentration in women with PCOS. Seventy-one women with PCOS participated in a randomized, double-blind, sham-controlled clinical trial of acupuncture. Three longitudinal AMH samples over the 5-month protocol were compared with objective ovulation parameters primarily using nonparametric statistics. Results indicated that AMH levels in PCOS were higher than published norms in women without PCOS. There was no difference between the true and sham acupuncture arms in the change in AMH longitudinally. Baseline AMH, but not the change in AMH over time, was inversely correlated with ovulation and menstrual cycle frequencies in both arms combined (P < 0.001). In conclusion, AMH correlated with an increased likelihood of monthly ovulation, as expected from the literature on women without PCOS. The lack of difference by intervention in AMH was consistent with the underlying clinical trial. AMH may be clinically useful to predict which PCOS women are more likely to respond to an intervention.

Challenges facing contemporary preimplantation genetic screening.

Purpose of review Aneuploidy is a leading cause of pregnancy failure. Although initial attempts to perform preimplantation genetic screening did not improve outcomes, validated techniques were developed to safely and effectively increase pregnancy rates. Still, many embryos designated as euploid do not implant. Current approaches are being refined to provide additional biologic insight into why this is the case. At present, the diagnosis and clinical relevance of segmental aneuploidy and mosaicism are amongst the more heavily investigated. Recent findings Class I data have proven the safety of trophectoderm biopsy and validation studies have shown single nucleotide polymorphism array and quantitative PCR can accurately detect whole chromosome aneuploidy. Similar studies to validate next generation sequencing are underway. Although randomized control trials have demonstrated the clinical utility of preimplantation genetic screening, recent data on the impact of mosaicism and segmental aneuploidy require clarification. Summary Several well powered randomized control trials have shown preimplantation genetic screening improves implantation rate. Plausible explanations for euploid failures include undetected mosaicism and segmental aneuploidy. However, the true incidence and dispersion of mosaicism within the embryo is unknown. Likewise, the resolution of detection and clinical significance of segmental aneuploidy is unclear. Further research to validate proposed detection algorithms and class I data to determine if detection impacts outcomes is needed.

Vitamin D in human reproduction—an evolving landscape

There is a vitamin D deficiency epidemic in the United States that has prompted exploration into many areas of human health and disease. Studies have subsequently linked vitamin D deficiency and insufficiency to many chronic diseases of the cardiovascular and metabolic systems. Given that this steroid hormone has receptors throughout the body including the ovary—in particular the granulosa cells—as well as in the endometrium and placenta, it stands to reason that vitamin D could be impactful on human reproductive success and even obstetrical outcomes. The data that exist to date on reproductive outcomes are variable. Ozkan et al. evaluated follicular fluid in a prospective manner and correlated vitamin D levels to pregnancy outcomes (1). However, they found a lack of correlation between vitamin D concentration and ovarian response parameters, which suggested that perhaps the endometrium and endometrial receptivity may be the key regulators when it comes to vitamin D and reproductive success. This concept of an endometrial receptivity effect was supported by work from Rudick et al. in an oocyte donation model study (2). This theory, however, stands in contrast to other studies that have shown that vitamin D status is not impactful on outcomes when a euploid, synchronous ET is performed (3). It is possible that when embryo competence and quality are controlled to the exent possible by achieving an expanded euploid blastocyt for ET, and endometrial synchrony is accounted for, that the impact of vitamin D may not be seen. If these factors are able to be externally controlled, perhaps vitamin D impacts processes involved before the formation of a euploid embryo and may not be limited simply to ovarian response parameters. Indeed, the story may be more complex and may need to take into account dose of bioactive hormone at the receptor site as well as take a closer look at follicular and oocyte paramters—it may be that the follicular maturation process is impacted. This relationship is quite likely to be influenced by the bioavailability of vitamin D at the target sites. Vitamin D binding protein (VDBP), in the nuclear hormone receptor superfamily, and albumin bind over 99% of the available active hormone, and thus its activity at the receptor is highly dependent upon VDBP concentrations and its polymorphisms, which can vary among ethnicities. When analyzing the direct treatment of granulosa cells by active 1,25-dihydroxyvitamin D3 metabolite, which circumvents and overpowers the VDBP issues, there were changes noted in antim€ ullerian hormone (AMH) receptor gene expression as well as downstream AMH signaling (4). These data begin to shed light on what has been to date a somewhat limited investigation into the direct effect of vitamin D sufficiency or insufficiencys potential mechanism of action as they pertain to reproductive success. Thus, the data from Xu et al. are of great interest (5). Through a primate model that has the ability to study follic-

Discordant Embryonic Aneuploidy Testing and Prenatal Ultrasonography Prompting Androgen Insensitivity Syndrome Diagnosis

BACKGROUND: Multimodal prenatal screening for developmental pathology is increasingly common. In this case, definitive prenatal diagnosis of androgen insensitivity syndrome was diagnosed after discordant results from karyotypes determined by embryonic preimplantation genetic screening and antenatal ultrasound results. CASE: A 38-year-old woman, gravida 2 para 0010, undergoing in vitro fertilization with preimplantation genetic screening transferred one male and one female embryo. An anatomic ultrasonogram revealed two fetuses with female genitalia. Cell-free fetal DNA analyzed using noninvasive prenatal screening demonstrated Y chromosome material, and amniocentesis confirmed one 46,XX and one 46,XY fetus. Sequencing of the androgen receptor for the 46,XY fetus identified a mutation. CONCLUSION: With increased use, discordance among prenatal testing modalities such as preimplantation genetic screening, noninvasive prenatal screening, and ultrasonography will become more common requiring expert navigation to identify true pathology.