Douglas J. Creedon

Cancer and Pregnancy: Parallels in Growth, Invasion, and Immune Modulation and Implications for Cancer Therapeutic Agents

Many proliferative, invasive, and immune tolerance mechanisms that support normal human pregnancy are also exploited by malignancies to establish a nutrient supply and evade or edit the host immune response. In addition to the shared capacity for invading through normal tissues, both cancer cells and cells of the developing placenta create a microenvironment supportive of both immunologic privilege and angiogenesis. Systemic alterations in immunity are also detectable, particularly with respect to a helper T cell type 2 polarization evident in advanced cancers and midtrimester pregnancy. This review summarizes the similarities between growth and immune privilege in cancer and pregnancy and identifies areas for further investigation. Our PubMed search strategy included combinations of terms such as immune tolerance, pregnancy, cancer, cytokines, angiogenesis, and invasion. We did not place any restrictions on publication dates. The knowledge gained from analyzing similarities and differences between the physiologic state of pregnancy and the pathologic state of cancer could lead to identification of new potential targets for cancer therapeutic agents.

Prediction of Treatment Outcomes After Global Endometrial Ablation

OBJECTIVE: To report rates of amenorrhea and treatment failure after global endometrial ablation and to estimate the association between patient factors and these outcomes by developing and validating prediction models. METHODS: From January 1998 through December 2005, 816 women underwent global endometrial ablation with either a thermal balloon ablation or radio frequency ablation device; 455 were included in a population-derived cohort (for model development), and 361 were included in a referral-derived cohort (for model validation). Amenorrhea was defined as cessation of bleeding from immediately after ablation through at least 12 months after the procedure. Treatment failure was defined as hysterectomy or reablation for patients with bleeding or pain. Logistic and Cox proportional hazard regression models were used in model development and validation of potential predictors of outcomes. RESULTS: The amenorrhea rate was 23% (95% confidence interval [CI] 19–28%) and the 5-year cumulative failure rate was 16% (95% CI 10–20%). Predictors of amenorrhea were age 45 years or older (adjusted odds ratio [aOR] 2.6, 95% CI 1.6–4.3); uterine length less than 9 cm (aOR 1.8, 95% CI 1.1–3.1); endometrial thickness less than 4 mm (aOR 2.7, 95% CI 1.2–6.3); and use of radio-frequency ablation instead of thermal balloon ablation (aOR 2.8, 95% CI 1.7–4.9). Predictors of treatment failure included age younger than 45 years (adjusted hazard ratio [aHR] 2.6, 95% CI 1.3–5.1); parity of 5 or greater (aHR 6.0, 95% CI 2.5–14.8); prior tubal ligation (aHR 2.2, 95% CI 1.2–4.0); and history of dysmenorrhea (aHR 3.7, 95% CI 1.6–8.5). After global endometrial ablation, 23 women (5.1%, 95% CI 3.2–7.5%) had pelvic pain, three (0.7%, 95% CI 0.1–1.9%) were pregnant, and none (95% CI 0–0.8%) had endometrial cancer. CONCLUSION: Population-derived rates and predictors of treatment outcomes after global endometrial ablation may help physicians offer optimal preprocedural patient counseling. LEVEL OF EVIDENCE: II

Pregnancy's Stronghold on the Vaginal Microbiome

Objective To assess the vaginal microbiome throughout full-term uncomplicated pregnancy. Methods Vaginal swabs were obtained from twelve pregnant women at 8-week intervals throughout their uncomplicated pregnancies. Patients with symptoms of vaginal infection or with recent antibiotic use were excluded. Swabs were obtained from the posterior fornix and cervix at 8–12, 17–21, 27–31, and 36–38 weeks of gestation. The microbial community was profiled using hypervariable tag sequencing of the V3–V5 region of the 16S rRNA gene, producing approximately 8 million reads on the Illumina MiSeq. Results Samples were dominated by a single genus, Lactobacillus, and exhibited low species diversity. For a majority of the patients (n = 8), the vaginal microbiome was dominated by Lactobacillus crispatus throughout pregnancy. Two patients showed Lactobacillus iners dominance during the course of pregnancy, and two showed a shift between the first and second trimester from L. crispatus to L. iners dominance. In all of the samples only these two species were identified, and were found at an abundance of higher than 1% in this study. Comparative analyses also showed that the vaginal microbiome during pregnancy is characterized by a marked dominance of Lactobacillus species in both Caucasian and African-American subjects. In addition, our Caucasian subject population clustered by trimester and progressed towards a common attractor while African-American women clustered by subject instead and did not progress towards a common attractor. Conclusion Our analyses indicate normal pregnancy is characterized by a microbiome that has low diversity and high stability. While Lactobacillus species strongly dominate the vaginal environment during pregnancy across the two studied ethnicities, observed differences between the longitudinal dynamics of the analyzed populations may contribute to divergent risk for pregnancy complications. This helps establish a baseline for investigating the role of the microbiome in complications of pregnancy such as preterm labor and preterm delivery.

A multi-omic systems-based approach reveals metabolic markers of bacterial vaginosis and insight into the disease.

Background Bacterial vaginosis (BV) is the most common vaginal disorder of reproductive-age women. Yet the cause of BV has not been established. To uncover key determinants of BV, we employed a multi-omic, systems-biology approach, including both deep 16S rRNA gene-based sequencing and metabolomics of lavage samples from 36 women. These women varied demographically, behaviorally, and in terms of health status and symptoms. Principal Findings 16S rRNA gene-based community composition profiles reflected Nugent scores, but not Amsel criteria. In contrast, metabolomic profiles were markedly more concordant with Amsel criteria. Metabolomic profiles revealed two distinct symptomatic BV types (SBVI and SBVII) with similar characteristics that indicated disruption of epithelial integrity, but each type was correlated to the presence of different microbial taxa and metabolites, as well as to different host behaviors. The characteristic odor associated with BV was linked to increases in putrescine and cadaverine, which were both linked to Dialister spp. Additional correlations were seen with the presence of discharge, 2-methyl-2-hydroxybutanoic acid, and Mobiluncus spp., and with pain, diethylene glycol and Gardnerella spp. Conclusions The results not only provide useful diagnostic biomarkers, but also may ultimately provide much needed insight into the determinants of BV.

The vaginal microbiome in health and disease

Infections of the vaginal tract result from perturbations in the complex interactions between the microbiome and the host vaginal ecosystem. Recent data have linked specific vaginal microbes and urogenital infection with preterm birth. Here we discuss how next-generation sequencing-based approaches to study the vaginal microbiome will be important for defining what constitutes an imbalance of the microbiome and the associated host conditions that lead to subsequent infection and disease states. These studies will provide clinicians with reliable diagnostic tools and treatments for women who are at increased risk for vaginal infections, preterm birth, HIV and other sexually acquired diseases, and will provide opportunities for intervention.

Hysterosalpingography for Assessing Efficacy of Essure Microinsert Permanent Birth Control Device

OBJECTIVE The Essure microinsert is a new U.S. Food and Drug Administration-approved method of birth control. The objective of this study is to report our initial experience using hysterosalpingography (HSG) to assess its efficacy for permanent tubal occlusion. CONCLUSION The Essure microinsert produced tubal blockage in all patients. As this device may become more widely used, radiologists should be aware of the devices appearance and be able to assess device position and presence of tubal occlusion on HSG.

Pathologic Characteristics of Hysterectomy Specimens in Women Undergoing Hysterectomy after Global Endometrial Ablation

STUDY OBJECTIVE To describe uterine pathologic features in women who underwent hysterectomy because of failed global endometrial ablation (GEA). DESIGN Retrospective cohort study from 1998 through 2005 (Canadian Task Force classification III). SETTING Tertiary referral center. PATIENTS Sixty-nine women who underwent hysterectomy because of GEA failure. INTERVENTIONS Pathology reports were available for 67 patients. Descriptions of hysterectomy specimens after GEA were reviewed. MEASUREMENTS AND MAIN RESULTS Rates of pathologic findings in hysterectomy specimens after failed GEA were determined. Reasons for hysterectomy in the 67 patients with available pathology reports were bleeding in 34 (51%), pain in 19 (28%), and bleeding and pain in 14 (21%). The pathology reports of these specimens showed leiomyomas in 33 specimens (49%); intramural myomas were present in 15 women (44%) who underwent hysterectomy because of bleeding and 8 women (42%) who underwent hysterectomy because of pain. Hematometra was identified in 7 pathologic specimens (10%). Specifically, hematometra was identified in specimens from 5 of 19 women who underwent hysterectomy because of pain (26%). CONCLUSION Hematometra was a significant finding in women who underwent hysterectomy because of persistent pain after GEA. A possible pathologic predictor of GEA failure may be intramural leiomyomas.

Expansion of CD16-Negative Natural Killer Cells in the Peripheral Blood of Patients with Metastatic Melanoma

Altered natural killer (NK) cell function is a component of the global immune dysregulation that occurs in advanced malignancies. Another condition associated with altered NK homeostasis is normal pregnancy, where robust infiltration with CD16− CD9+ NK cells can be identified in decidual tissues, along with a concomitant expansion of CD16− NK cells in the maternal peripheral blood. In metastatic melanoma, we identified a similar expansion of peripheral blood CD16− NK cells (median 7.4% in 41 patients with melanoma compared with 3.0% in 29 controls, P < .001). A subset of NK cells in melanoma patients also expresses CD9, which is characteristically expressed only on NK cells within the female reproductive tract. Expansion of CD16− NK cells was associated with elevated plasma transforming growth factor-beta (TGF-β levels (median 20 ng/ml, Spearmans ρ = 0.81, P = .015)). These findings suggest the possibility of exploring anti-TGF-β therapy to restore NK function in melanoma.

Efficacy of bipolar radiofrequency endometrial ablation vs thermal balloon ablation for management of menorrhagia: A population-based cohort.

STUDY OBJECTIVE To compare the efficacy of bipolar radiofrequency ablation (RFA) and thermal balloon ablation (TBA) using treatment failure and postprocedure amenorrhea as outcome measures. DESIGN Population-based cohort study (Canadian Task Force classification II-2). SETTING Two medical centers in the upper Midwest. PATIENTS Using the medical records linkage system of the Rochester Epidemiology Project, we identified 455 residents of Olmsted County, Minnesota, who underwent global endometrial ablation because of menorrhagia from January 1, 1998, through December 31, 2005. Amenorrhea was defined as complete cessation of menstruation that started immediately after ablation and lasted at least 12 months. Treatment failure was defined as necessity of repeat ablation or hysterectomy because of persistent bleeding or pain. Time to treatment failure for each procedure was compared using Kaplan-Meier plots. Relevant clinical data and complications were abstracted from medical records. Risk adjustments were performed using Cox and logistic regression models. INTERVENTIONS Radiofrequency ablation (n=255) and thermal balloon ablation (n=200). MEASUREMENTS AND MAIN RESULTS Mean (SD) patient age was 43.3 (5.5) years, and median follow-up was 2.2 years. The 3-year cumulative failure rate was 9% (95% confidence interval [CI], 5%-16%) for RFA and 12% (95% CI, 7%-16%) for TBA (p=.26). The difference remained nonsignificant after adjusting for known predictors of treatment failure such as age, parity, pretreatment dysmenorrhea, and tubal ligation (adjusted HR, 0.7; 95% CI, 0.4-1.4; p=.31). However, women had significantly higher rates of amenorrhea after RFA compared with TBA (32% vs 14%; p <.001). This difference remained significant after adjusting for known predictors of amenorrhea such as age, uterine length, and endometrial thickness (adjusted odds ratio, 2.9; 95% CI, 1.7-4.8; p <.001). Complications were infrequent and similar in the 2 groups. CONCLUSION Both RFA and TBA were equally effective treatments for menorrhagia in a population-based cohort. However, women who underwent RFA were 3 times more likely to have postprocedure amenorrhea.

Fetal Sex-Based Differences in Maternal Hormones, Angiogenic Factors, and Immune Mediators During Pregnancy and the Postpartum Period

Several pregnancy complications have disparities based on the sex of the fetus. It is unknown whether the sex of the fetus differentially alters the maternal immune milieu, potentially contributing to the observed differences.