Adjuvant vaginal cuff brachytherapy for high-risk, early stage endometrial cancer.

PURPOSE: To report outcomes following adjuvant high-dose-rate vaginal brachytherapy (VBT) with or without chemotherapy for high-intermediate risk (HIR) and high-risk, early stage endometrial cancer as defined in Gynecologic Oncology Group trial 0249. MATERIAL AND METHODS: From May 2000 to January 2014, 68 women with HIR and high-risk endometrial cancer underwent surgical staging followed by VBT. Median VBT dose was 21 Gy delivered in three fractions prescribed to 0.5 cm depth. Paclitaxel 175 mg/m(2) and carboplatin area under the curve 6 was administered every 21 days in sequence with VBT. Actuarial survival estimates were calculated using the Kaplan-Meier method. RESULTS: Patient demographics included a median age of 66 years (range: 36-91) and stages IA (49%), IB (38%), and II (13%), respectively. Thirty-one (46%) patients had HIR disease with endometrioid histology, and 33 (48%) patients had serous or clear cell histology. Thirty-seven (54%) patients received a median 3 cycles (range: 3-6) of chemotherapy in addition to VBT, and 65 patients (96%) completed all prescribed therapy. During a median follow up of 33.1 months (range: 4.0-161.7), four patients have recurred, including one vaginal recurrence. The 3-year estimates of vaginal, pelvic, and distant recurrences were 1.9%, 2.4%, and 9.1%, respectively. The 3-year rates of disease-free and overall survival were 87.7% and 93.9%, respectively. CONCLUSIONS: Early outcomes with adjuvant VBT with or without chemotherapy demonstrate high rates of vaginal and pelvic control for women with HIR disease. Early vaginal and pelvic relapses in high-risk patients suggest that pelvic external beam radiotherapy is warranted in this subgroup, but additional data from large phase III trials is warranted.

Inter- and intra-individual variation in allele-specific DNA methylation and gene expression in children conceived using assisted reproductive technology.

Epidemiological studies have reported a higher incidence of rare disorders involving imprinted genes among children conceived using assisted reproductive technology (ART), suggesting that ART procedures may be disruptive to imprinted gene methylation patterns. We examined intra- and inter-individual variation in DNA methylation at the differentially methylated regions (DMRs) of the IGF2/H19 and IGF2R loci in a population of children conceived in vitro or in vivo. We found substantial variation in allele-specific methylation at both loci in both groups. Aberrant methylation of the maternal IGF2/H19 DMR was more common in the in vitro group, and the overall variance was also significantly greater in the in vitro group. We estimated the number of trophoblast stem cells in each group based on approximation of the variance of the binomial distribution of IGF2/H19 methylation ratios, as well as the distribution of X chromosome inactivation scores in placenta. Both of these independent measures indicated that placentas of the in vitro group were derived from fewer stem cells than the in vivo conceived group. Both IGF2 and H19 mRNAs were significantly lower in placenta from the in vitro group. Although average birth weight was lower in the in vitro group, we found no correlation between birth weight and IGF2 or IGF2R transcript levels or the ratio of IGF2/IGF2R transcript levels. Our results show that in vitro conception is associated with aberrant methylation patterns at the IGF2/H19 locus. However, very little of the inter- or intra-individual variation in H19 or IGF2 mRNA levels can be explained by differences in maternal DMR DNA methylation, in contrast to the expectations of current transcriptional imprinting models. Extraembryonic tissues of embryos cultured in vitro appear to be derived from fewer trophoblast stem cells. It is possible that this developmental difference has an effect on placental and fetal growth.

DNA methylation and gene expression differences in children conceived in vitro or in vivo.

Epidemiological data indicate that children conceived in vitro have a greater relative risk of low birth-weight, major and minor birth defects, and rare disorders involving imprinted genes, suggesting that epigenetic changes may be associated with assisted reproduction. We examined DNA methylation at more than 700 genes (1536 CpG sites) in placenta and cord blood and measured gene expression levels of a subset of genes that differed in methylation levels between children conceived in vitro versus in vivo. Our results suggest that in vitro conception is associated with lower mean methylation at CpG sites in placenta and higher mean methylation at CpG sites in cord blood. We also find that in vitro conception-associated DNA methylation differences are associated with gene expression differences at both imprinted and non-imprinted genes. The range of inter-individual variation in gene expression of the in vitro and in vivo groups overlaps substantially but some individuals from the in vitro group differ from the in vivo group mean by more than two standard deviations. Several of the genes whose expression differs between the two groups have been implicated in chronic metabolic disorders, such as obesity and type II diabetes. These findings suggest that there may be epigenetic differences in the gametes or early embryos derived from couples undergoing treatment for infertility. Alternatively, assisted reproduction technology may have an effect on global patterns of DNA methylation and gene expression. In either case, these differences or changes may affect long-term patterns of gene expression.

Factors influencing adverse perinatal outcomes in pregnancies achieved through use of in vitro fertilization.

OBJECTIVE: To determine the associations of specific components of IVF treatment with abnormal perinatal outcomes. DESIGN: Case-control study. SETTING: University-based and community-based infertility centers. PATIENT(S): All viable pregnancies achieved through IVF procedures performed between January 1999 and March 2004. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Infertility etiology, gonadotropin exposure, embryo manipulation, and quality. RESULT(S): Of 455 viable pregnancies identified during the study period, 435 met inclusion criteria. While adjusting for maternal age, race, parity, body mass index, infertility center, and year of IVF procedure, multiple gestations were associated with a 12-fold increased risk of poor perinatal outcome compared to singletons. Ovarian hyperstimulation syndrome significantly increased the risk more than 3-fold (odds ratio = 3.14; 95% confidence interval, 1.08-9.14), while endometrial thickness was found to have a significant protective effect (odds ratio = 0.89; 95% confidence interval, 0.80-0.99). We found no effect of etiology of infertility, dose or type of medication used for stimulation, use of embryo-manipulation techniques, or quality on perinatal outcome. CONCLUSION(S): These data confirm and quantify the risk of perinatal morbidity associated with multiple births. After adjusting for multiple births, ovarian hyperstimulation syndrome and suboptimal endometrial development are associated with adverse outcomes in pregnancies achieved through IVF. Our findings suggest that it may be the endometrium rather than the embryo that influences fetal growth and perinatal outcomes after IVF.

Defining the rise of serum HCG in viable pregnancies achieved through use of IVF.

BACKGROUND: We aimed to characterize the rate of HCG rise associated with viable IVF pregnancies, and to evaluate the association between HCG rise and potentially influential factors. METHODS: We performed a retrospective cohort analysis of all viable pregnancies achieved through IVF at two centres between January 1999 and March 2004. RESULTS: Of the 455 pregnancies resulting in live births, 391 met inclusion criteria and contributed a total of 1052 HCG values. Using random effects models, the best pattern to describe the rise of log HCG was quadratic with the rate of increase slowing at 24 days post-oocyte retrieval. Limiting the analysis to measurements below the discriminatory zone, the linear model adequately characterized the profile. The average slope was 0.403, yielding a predicted increase of 1.50 (50% increase) in 1 day and 2.24 (124%) in 2 days. In the final model, absolute HCG values, but not rate of rise, were significantly higher for twins and triplets and significantly lower for patients with BMI>30 kg/m2. CONCLUSIONS: The HCG profile of viable pregnancies conceived with IVF is quadratic with an earlier plateau than has been reported for non-IVF pregnancies. The average rate of rise is comparable to previous estimates in symptomatic spontaneous conceptions.

Successful infertility treatment in a cancer patient with a significant personal and family history of cancer.

BACKGROUND: Infertility can be a devastating problem for a couple desperate to conceive. Unfortunately, these same women with infertility also bear the burden of an increased risk of ovarian and breast cancer. We present a case of a woman with infertility who persevered despite a personal and family history of cancer to achieve her goal of having a family. CASE: The patient's father had died of breast cancer at an early age. The patient had been unsuccessfully treated for infertility elsewhere before transferring to our institution. A diagnostic laparoscopy revealed an early ovarian cancer treated by oophorectomy only. RESULTS: After a period of observation, infertility treatment was resumed, leading to the successful cesarean delivery of triplets. Although recurrent ovarian cancer was diagnosed at delivery, the patient remains disease free, with three healthy children, 4 years after optimal tumor reductive surgery for stage IC low malignant potential ovarian cancer. CONCLUSIONS: Infertility patients with significant cancer issues may achieve a term delivery and remain disease free for a meaningful length of time with the assistance of their physicians.