Immune checkpoint molecules soluble program death ligand 1 and galectin-9 are increased in pregnancy.

PROBLEM: Pregnancy requires balance between tolerance to the haploidentical fetus and the mother's ability to mount immune responses. There are parallels to this phenomenon that occur in metastatic cancer. We assessed soluble program death ligand-1 soluble PD-L1 (sPD-L1) and galectin-9 in the blood of pregnant women during gestation as these molecules are highly involved in immune suppression during cancer. METHOD OF STUDY: Maternal blood was collected from 30 primigravida women at monthly intervals during pregnancy, delivery and 6-week post-partum. Blood was analyzed for sPD-L1 and galectin-9 concentrations by ELISA. Term placentas were collected in formalin and IHC was completed for PD-L1 and galectin-9 expression. RESULTS: Maternal blood levels of sPD-L1 (0.438 ng/mL) and galectin-9 (1976 pg/mL) were elevated early in normal pregnancies compared to non-pregnant controls (0.242 ng/mL and 773 pg/mL, respectively). sPD-L1 increased throughout gestation, whereas galectin-9 remained elevated until parturition; both proteins returned to control levels post-partum. Women carrying male fetuses had significantly higher galectin-9 levels, but not sPD-L1, than those carrying females (2263 pg/mL vs 1874 pg/mL; P = .0005). Trophoblast cells of the term placenta coexpress galectin-9 and PD-L1. CONCLUSION: Immune-regulatory molecules galectin-9 and sPD-L1 increased during pregnancy and may play a role in immune tolerance that is critical for the fetus.

Potential contribution of the uterine microbiome in the development of endometrial cancer.

BACKGROUND: Endometrial cancer studies have led to a number of well-defined but mechanistically unconnected genetic and environmental risk factors. One of the emerging modulators between environmental triggers and genetic expression is the microbiome. We set out to inquire about the composition of the uterine microbiome and its putative role in endometrial cancer. METHODS: We undertook a study of the microbiome in samples taken from different locations along the female reproductive tract in patients with endometrial cancer (n = 17), patients with endometrial hyperplasia (endometrial cancer precursor, n = 4), and patients afflicted with benign uterine conditions (n = 10). Vaginal, cervical, Fallopian, ovarian, peritoneal, and urine samples were collected aseptically both in the operating room and the pathology laboratory. DNA extraction was followed by amplification and high-throughput next generation sequencing (MiSeq) of the 16S rDNA V3-V5 region to identify the microbiota present. Microbiota data were summarized using both α-diversity to reflect species richness and evenness within bacterial populations and ß-diversity to reflect the shared diversity between bacterial populations. Statistical significance was determined through the use of multiple testing, including the generalized mixed-effects model. RESULTS: The microbiome sequencing (16S rDNA V3-V5 region) revealed that the microbiomes of all organs (vagina, cervix, Fallopian tubes, and ovaries) are significantly correlated (p < 0.001) and that there is a structural microbiome shift in the cancer and hyperplasia cases, distinguishable from the benign cases (p = 0.01). Several taxa were found to be significantly enriched in samples belonging to the endometrial cancer cohort: Firmicutes (Anaerostipes, ph2, Dialister, Peptoniphilus, 1-68, Ruminococcus, and Anaerotruncus), Spirochaetes (Treponema), Actinobacteria (Atopobium), Bacteroidetes (Bacteroides and Porphyromonas), and Proteobacteria (Arthrospira). Of particular relevance, the simultaneous presence of Atopobium vaginae and an uncultured representative of the Porphyromonas sp. (99 % match to P. somerae) were found to be associated with disease status, especially if combined with a high vaginal pH (>4.5). CONCLUSIONS: Our results suggest that the detection of A. vaginae and the identified Porphyromonas sp. in the gynecologic tract combined with a high vaginal pH is statistically associated with the presence of endometrial cancer. Given the documented association of the identified microorganisms with other pathologies, these findings raise the possibility of a microbiome role in the manifestation, etiology, or progression of endometrial cancer that should be further investigated.

Persistent microbial dysbiosis in preterm premature rupture of membranes from onset until delivery.

Background. Preterm Premature Rupture of Membranes (PPROM) is a major leading cause of preterm births. While the cause for PPROM remains unidentified, it is anticipated to be due to subclinical infection, since a large proportion of PPROM patients display signs of chorioamnionitis. Since subclinical infections can be facilitated by dysbiosis, our goal was to characterize the vaginal microbiome and amniotic fluid discharge upon PPROM, through latency antibiotic treatment, and until delivery, to detect the presence of pathogens, microbiota alteration, and microbial response to treatment. Methods. Enrolled subjects (15) underwent routine institutional antenatal care for PPROM, including the administration of latency antibiotics. Serial vaginal swabs were obtained from diagnosis of PPROM through delivery and the sequencing of the V3-V5 region of the 16S rRNA gene was performed for all collected samples. Results. The results show that Lactobacilli species were markedly decreased when compared to vaginal swabs collected from uncomplicated pregnancy subjects with a matched gestational time. Prevotella and Peptoniphilus were the most prevalent taxa in PPROM subjects at presentation. The vaginal microbiome of the PPROM subjects varied substantially intra- and inter-subjects. Several taxa were found to be significantly reduced during and after the antibiotic treatment: Weeksella, Lachnospira, Achromobacter, and Pediococcus. In contrast, Peptostreptococcus and Tissierellaceae ph2 displayed a significant increase after the antibiotic treatment. However, the relative abundance of Lactobacillus, Prevotella, and Peptoniphilus was not substantially impacted during the hospitalization of the PPROM subjects. The deficiency of Lactobacillus, and constancy of known pathogenic species, such as Prevotella and Peptoniphilus during and after antibiotics, highlights the persistent dysbiosis and warrants further investigation into mitigating approaches. Discussion. PPROM is responsible for one third of all preterm births. It is thought that subclinical infection is a crucial factor in the pathophysiology of PPROM because 25-40% of patients present signs of chorioamnionitis on amniocentesis. Here we sought to directly assess the bacterial content of the vagina and leaking amniotic fluid of subjects at presentation, throughout treatment and up until delivery, in order to search for common pathogens, microbiota changes, and microbial response to latency antibiotic treatment. We have found that the vaginal microbiome of PPROM subjects is highly variable and displays significant changes to treatment. However, the unchanging deficiency of Lactobacillus, and persistence of known pathogenic species, such as Prevotella and Peptoniphilus from presentation, through antibiotic treatment and up until delivery, highlights the persistent dysbiosis and warrants further investigation into mitigating approaches.

Hysterosalpingography After Radiofrequency Endometrial Ablation and Hysteroscopic Sterilization as a Concomitant Procedure.

OBJECTIVE: To evaluate the accuracy of hysterosalpingography (HSG) in patients who underwent concomitant radiofrequency endometrial ablation and hysteroscopic sterilization. METHODS: This historical cohort study was conducted at a midwestern academic medical center. A total of 186 women (94 with combined procedure and 92 with sterilization alone) were identified as having undergone intervention between January 1, 2003, and June 30, 2011. Two reviewers blinded to the surgical procedure interpreted the standard clinically indicated HSGs in each group. RESULTS: The primary outcome assessed was the inability to rely on the microinserts for contraception based on HSG interpretation using manufacturers' guidelines (unsatisfactory HSG). Position of the devices and occlusion of tubes were assessed on all 3-month and, when available, all 6-month repeat HSGs. At the 3-month HSG, 5 of 76 (6.6%, 95% confidence interval [CI] 2.2-14.7%) in the sterilization-only group had unsatisfactory HSG compared with 13 of 71 (18.3%, 95% CI 10.1-29.3%) in the combined group (P=.03). After accounting for the seven patients who underwent repeat HSG at 6 months, 3 of 76 (3.95%, 95% CI 0.8-11.1%) in the sterilization-only group had unsatisfactory HSG compared with 13 of 71 (18.31%, 95% CI 10.1-29.3%) in the combined group (P=.005). CONCLUSION: After completing all clinically indicated HSGs, patients who undergo concomitant radiofrequency endometrial ablation and hysteroscopic sterilization have an approximate fivefold increase (odds ratio 5.45, 95% CI 1.48-20.0) in the rate of unsatisfactory HSG for purposes of documenting tubal occlusion. LEVEL OF EVIDENCE: II.

Individualized medicine and the microbiome in reproductive tract.

Humans have evolved along with the millions of microorganisms that populate their bodies. These microbes (10(14)) outnumber human cells by 10 to 1 and account for 3 × 10(6) genes, more than ten times the 25,000 human genes. This microbial metagenome acts as our "other genome" and like our own genes, is unique to the individual. Recent international efforts such as the Human Microbiome Project (HMP) and the MetaHIT Project have helped catalog these microbial genomes using culture-independent, high-throughput, next-generation sequencing. This manuscript will describe recent efforts to define microbial diversity in the female reproductive tract because of the impact that microbial function has on reproductive efficiency. In this review, we will discuss current evidence that microbial communities are critical for maintaining reproductive health and how perturbations of microbial community structures can impact reproductive health from the aspect of infection, reproductive cyclicity, pregnancy, and disease states. Investigations of the human microbiome are propelling interventional strategies from treating medical populations to treating individual patients. In particular, we highlight how understanding and defining microbial community structures in different disease and physiological states have lead to the discovery of biomarkers and, more importantly, the development and implementation of microbial intervention strategies (probiotics) into modern day medicine. Finally this review will conclude with a literature summary of the effectiveness of microbial intervention strategies that have been implemented in animal and human models of disease and the potential for integrating these microbial intervention strategies into standard clinical practice.

Growth modeling of the maternal cytokine milieu throughout normal pregnancy: macrophage-derived chemokine decreases as inflammation/counterregulation increases.

Several recent studies have shown differences in the maternal immune milieu at different phases of pregnancy, but most studies have been cross-sectional or of relatively few time points. Levels of 42 cytokines were determined using a multiplex bead-based assay on archived serum from a cohort of pregnant women (N = 16) at median of 18 time points tested, from the first trimester through to parturition, per woman. Unconditional growth modeling was then used to determine time-dependent changes in levels of these cytokines. Macrophage-derived chemokine (MDC, aka CCL22) decreases as pregnancy progresses. IL-1ß, IL-6, IL-8, IL-12p70, IL-13, IL-15, IP-10, and FLT3-ligand increase as a function of gestational weeks, and IFNα2, IL-1ra, IL-3, IL-9, IL-12p40, and soluble CD40 ligand increase as a function of trimester. As pregnancy normally progresses, a maternal shift away from a type 2-biased immune response and toward an inflammatory/counterregulatory response is observed.

Fetal sex-based differences in maternal hormones, angiogenic factors, and immune mediators during pregnancy and the postpartum period.

PROBLEM: 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. METHOD OF STUDY: Using maternal plasma collected during 38 uncomplicated pregnancies (19 males, 19 females), we compared levels of cytokines, sex hormones, and angiogenic factors throughout gestation and postpartum. RESULTS: Male fetal sex was associated with higher levels of proinflammatory cytokines (G-CSF, IL-12p70, IL-21, and IL-33) and angiogenic factors (PlGF and VEGF-A) compared with female fetal sex at multiple timepoints. Female fetal sex was associated with higher levels of regulatory cytokines (IL-5, IL-9, IL-17, and IL-25). IL-27 increased throughout pregnancy regardless of fetal sex. There was no fetal sex-based difference in analyte concentrations at the postpartum measurement. CONCLUSION: Women carrying a male fetus exhibit a more proinflammatory/proangiogenic immune milieu than women carrying a female fetus.

Comparison of medical service use and human papillomavirus vaccination rates among Somali and white/non-Hispanic girls.

OBJECTIVE: This study aimed to determine if there is a relationship between medical use patterns and human papillomavirus (HPV) vaccination rates among a previously studied population of Somali and white/non-Hispanic girls in Rochester, MN. MATERIALS AND METHODS: With the use of a previously identified group of Somali and white/non-Hispanic girls with known HPV vaccination status, the number, type, and age at provider visits were abstracted. Abstraction was blinded to vaccination status and ethnic designation. χ and Student t tests were performed for descriptive analysis of parametric data. For nonparametric data, Wilcoxon rank sum test was performed. RESULTS: Somali girls had fewer provider visits (median = 7, interquartile range [IQR] = 3-12.25) compared with white/non-Hispanic girls (median = 12, IQR = 6-18) (p < .001). Among those who completed the HPV vaccine series, Somali girls had more well-child visits (median = 2, IQR = 1-2) compared with the white/non-Hispanic group (median = 1, IQR = 1-2) (p = .028). There was no difference in the number of emergency department visits or inpatient hospitalization between groups. CONCLUSIONS: White/non-Hispanic girls had higher HPV vaccine completion rates and more provider visits. However, this increase in number of encounters is due to an increase in specialty visits. This is unlikely to account for the increase in HPV vaccination completion rates. Community-based research will likely provide greater insight into the cause(s) of reduced vaccine rates among Somali adolescent girls.

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.

Immunomodulatory effects of sex hormones: requirements for pregnancy and relevance in melanoma.

Similarities between the pathologic progression of cancer and the physiologic process of placentation (eg, proliferation, invasion, and local/systemic tolerance) have been recognized for many years. Sex hormones such as human chorionic gonadotropin, estrogens, progesterone, and others contribute to induction of immunologic tolerance at the beginning of gestation. Sex hormones have been shown to play contributory roles in the growth of cancers such as breast cancer, prostrate cancer, endometrial cancer, and ovarian cancer, but their involvement as putative mediators of the immunologic escape of cancer is still being elucidated. Herein, we compare the emerging mechanism by which sex hormones modulate systemic immunity in pregnancy and their potentially similar role in cancer. To do this, we conducted a PubMed search using combinations of the following keywords: "immune regulation," "sex hormones," "pregnancy," "melanoma," and "cancer." We did not limit our search to specific publication dates. Mimicking the maternal immune response to pregnancy, especially in late gestation, might aid in design of better therapies to reconstitute endogenous antitumor immunity and improve survival.

Nonresectoscopic endometrial ablation in high-risk surgical patients: a cohort study.

STUDY OBJECTIVE: To evaluate the use of nonresectoscopic endometrial ablation in women with high anesthetic and surgical risk compared with low-risk women based on the American Society of Anesthesia (ASA) physical status stratification. DESIGN: This is a cohort study of women who were classified as high-risk (HR) or low-risk (LR) cohorts based on ASA physical status stratification. The ASA classification includes 6 grades: ASAP1, a normal healthy person; ASAP2, mild systemic disease; ASAP3, severe systemic disease; ASAP4, severe systemic disease that is a constant threat to life; ASAP5, a critically ill patient who is not expected to survive without the operation; and ASAP6, declared brain-dead patient whose organs are being removed for donor purposes. Baseline characteristics including comorbidities were obtained. Outcome measures included amenorrhea, treatment failure, and operative complications. The time to treatment failure was compared using Kaplan-Meier analysis. Risk adjustments were performed using regression models. SETTING: Academic medical center in the Upper Midwest. PATIENTS: Seven-hundred eleven women underwent nonresectoscopic endometrial ablation at our institution between January 1998 and December 2005. INTERVENTIONS: Bipolar radiofrequency was used in 448 women and thermal balloon ablation in 263 women. MEASUREMENTS AND MAIN RESULTS: The HR cohort had a higher proportion of women with cardiac disease (27.1% vs. 6.7%, p < .001) and more women with nongynecologic cancer (12.3% vs. 2.9%, Fisher exact test, p < .001). Nonetheless, endometrial ablation had comparable efficacy in both the HR and LR cohorts with 5-year failure rates of 11.7% and 14.8% (p = .659), respectively. Amenorrhea rates were also similar in both cohorts (29.7% vs. 27.2%, p = .645). After adjusting for known confounders including age, parity, dysmenorrhea, previous tubal ligation, uterine length, and the type of the procedure, the calculated hazard ratio for failure in the HR cohort was 0.80 (95% confidence interval; 0.31-1.74, p = .607), and the adjusted odds ratio for amenorrhea was 1.27 (95% confidence interval, 0.71-2.20; p = .411). Complications were rare in both groups. The mortality rate in the HR cohort was significantly higher compared with the LR cohort (7.9% vs. <1%, p < .001), but this was not related to the ablation procedures. CONCLUSION: For women who are high anesthetic and surgical risks because of serious underlying comorbidities, nonresectoscopic endometrial ablation can provide minimally invasive, safe, and effective therapy for menorrhagia.

Completion of the human papillomavirus vaccination series lags in Somali adolescents.

OBJECTIVE: It is unknown whether the Somali population in the United States is likely to participate in human papillomavirus (HPV) vaccination. We aimed to determine whether Somali girls living in a US community are following the recommendations for HPV vaccination. MATERIALS AND METHODS: We conducted a study of HPV vaccination among Somali girls seen at Mayo Clinic, Rochester, MN. Each Somali subject was matched by year of birth to white/non-Hispanic subjects in a 1:3 ratio. We abstracted information between August 1, 2006, and December 31, 2009, related to HPV vaccine series initiation and completion. Initiation and completion frequencies were compared between study groups using the χ(2) test. RESULTS: A total of 251 Somali and 727 white/non-Hispanic girls were identified, using the Rochester Epidemiology Project, who met all inclusion criteria for final analysis. A total of 114 Somali girls (45%) and 334 white/non-Hispanic girls (46%) initiated the series (odds ratio = 0.98; 95% confidence interval = 0.73-1.31), but only 59 Somali girls (52%) completed the vaccination series, compared with 240 (72%) of the white/non-Hispanic girls (odds ratio = 0.42; 95% confidence interval = 0.27-0.65). CONCLUSIONS: We found Somali girls to be generally accepting of initiating the HPV vaccine series but less likely to complete the series as compared with white non-Hispanic girls of the same age.

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.

An organ system based approach to prognosis in advanced melanoma.

Previous models to study the biology of melanoma have focused on individual factors, such as proliferative and invasive capacity, the microenvironment, angiogenesis, or systemic immune dysfunction. However, all of these factors contribute to melanoma progression in concert. One physiologic phenomenon that typifies the coordination of these processes is placental development, characterized by trophoblast proliferation, invasion into decidual tissues, angiogenesis, and transient organ system-based immune evasion. Herein, we explore expression of 34 proteins involved in placentation and determine their association with an established prognostic factor, tumor infiltrating lymphocytes (TILs), in a 118-patient tumor microarray (TMA). Melanoma expression of CD58 and galectin-9 independently predicted for a favorable prognosis. Patients could be categorized into three clusters based upon patterns of protein expression and TILs. Patients in Cluster 2 demonstrated frequent TILs and superior overall survival. Pathway enrichment using MetaCore (trademark) from GeneGo, a Thompson Reuters company, showed that TIMP2 and CD44 were expressed more frequently within Cluster 2 patients, suggesting a potential association with TILs. A subset of melanoma patients appear to lack an organized immune response to the tumor, which portends a poor prognosis.

Direct aspiration endometrial biopsy via flexible hysteroscopy.

STUDY OBJECTIVE: To determine feasibility and efficacy of direct aspiration endometrial biopsy via the fluid channel of a flexible diagnostic hysteroscope. DESIGN: Retrospective review (Canadian Task Force classification II-3). SETTING: Abnormal uterine bleeding clinic in a tertiary care center. PATIENTS: All women who underwent direct aspiration endometrial biopsy from January 2007 through August 2011 via a flexible diagnostic hysteroscope because traditional office-based endometrial biopsy using a suction piston device was not technically possible. INTERVENTIONS: Diagnostic hysteroscopy followed by direct aspiration endometrial biopsy, accomplished by applying suction to the fluid channel of a 3.1-mm flexible diagnostic hysteroscope via a 10-mL syringe. The hysteroscope tip was agitated within the uterine cavity to obtain a tissue sample. MEASUREMENTS AND MAIN RESULTS: The median age of the 32 identified patients was 50 years; 18 women (56%) were nulliparous, and 10 (31%) were postmenopausal. Thirty-one patients underwent hysteroscopy/direct aspiration biopsy because of abnormal uterine bleeding or postmenopausal bleeding. The vaginoscopic approach was used in 19 patients (59%). Indications for direct aspiration endometrial biopsy included cervical stenosis, inability to pass the endometrial biopsy instrument into the uterine cavity, and patient intolerance of endometrial biopsy. Adequate endometrial samples were obtained in 28 patients (87.5%). In 3 of 4 patients in whom direct aspiration endometrial biopsy did not provide sufficient tissue, hysteroscopy revealed an atrophic-appearing endometrium. The direct aspiration endometrial biopsy diagnosis was confirmed in 5 of 7 patients who subsequently underwent dilation and curettage or hysterectomy. CONCLUSION: Direct aspiration endometrial biopsy is a simple and effective endometrial sampling method when traditional office-based endometrial biopsy is not feasible. Further prospective studies including larger populations are needed to confirm these results.

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.

Mother knows best: lessons from fetomaternal tolerance applied to cancer immunity.

Failure of the immune system to recognize and eradicate tumor cells has deadly consequences. It is possible that the normal host response to the inflammatory environment created by many cancers - the body's natural attempt at wound repair and restoration of tissue integrity - is one of counter-regulation that paradoxically favors tumor growth. A physiologic condition where this situation is favorable (and even required) is that of normal pregnancy, where blastocyst implantation creates endometrial inflammation, and the maternal response in turn supports angiogenesis and tolerance required for placentation. Lack of such inflammation and resultant maternal immunologic engagement can lead to serious pregnancy complications including fetal loss, highlighting how important the fetomaternal immunologic dialogue is for survival. Here, we describe how the dynamics of fetomaternal tolerance can help disentangle complex cancer/host immunologic interactions and provide new avenues for immunologic reconstitution in patients with cancer.

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-ß levels (median 20 ng/ml, Spearman's ρ = 0.81, P = .015)). These findings suggest the possibility of exploring anti-TGF-ß therapy to restore NK function in melanoma.

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.

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.