Sentinel Lymph Node Mapping in Presumed Low- and Intermediate-Risk Endometrial Cancer Management (SLIM): A Multicenter, Prospective Cohort Study in The Netherlands.

The aim was to investigate the incidence of sentinel lymph node (SLN) metastases and the contribution of SLN mapping in presumed low- and intermediate-risk endometrial cancer (EC). A multicenter, prospective cohort study in presumed low- and intermediate-risk EC patients was performed. Patients underwent SLN mapping using cervical injections of indocyanine green and a minimally invasive hysterectomy with bilateral salpingo-oophorectomy. The primary outcome was the incidence of SLN metastases, leading to adjusted adjuvant treatment. Secondary outcomes were the SLN detection rate and the occurrence of complications. Descriptive statistics and univariate general linear model analyses were used. A total of 152 patients were enrolled, with overall and bilateral SLN detection rates of 91% and 61%, respectively. At final histology, 78.9% of patients (n = 120) had truly low- and intermediate-risk EC. Macro- and micro-metastases were present in 11.2% (n = 17/152), and three patients had isolated tumor cells (2.0%). Nine patients (5.9%) had addition of adjuvant radiotherapy based on SLN metastases only. In 2.0% of patients with high-risk disease, adjuvant therapy was more limited due to negative SLNs. This study emphasizes the importance of SLN mapping in presumed early-stage, grade 1 and 2 EC, leading to individualized adjuvant management, resulting in less undertreatment and overtreatment.

Species differences in the effect of pregnancy on lymphocyte cytokine production between human and rat.

In the present study, we evaluated whether lymphocyte cytokine production during human and rat pregnancy shifts toward T helper cell type 2 (Th2) cytokine production. Therefore, blood samples were taken during the follicular and luteal phase and during pregnancy in rats and humans. Whole blood was ex vivo-stimulated with phorbol 12-myristate 13-acetate and calcium ionophore and intracellular interferon-gamma (IFN-gamma) and interleukin (IL)-4 production, and the percentage of cells in the various lymphocyte populations was measured using flow cytometry. Rats and humans adapted their immune responses to pregnancy but have different strategies: During human pregnancy, the percentage of lymphocytes producing IFN-gamma was decreased, and the percentage IL-4-producing lymphocytes was not affected. The rat adapts its immune response to pregnancy by decreasing the total number of the various lymphocyte populations, and the percentage of IFN-gamma- or IL-4-producing lymphocytes was not affected or increased (% IFN-gamma-producing cytotoxic lymphocytes). It is speculated that during rat pregnancy, there is no need to decrease the number of IFN-gamma-producing lymphocytes, as in nonpregnant rats, the total number of IFN-gamma-producing lymphocytes after stimulation is relatively low, and there is no necessity for a further decrease. In nonpregnant humans, the percentage IFN-gamma-producing lymphocytes is much higher and probably dangerous for pregnancy, and therefore, this percentage needs to decrease during pregnancy. In conclusion, although the data from humans concur with the Th1/Th2 paradigm, the data from rats do not concur with this paradigm. The present studies therefore challenge the classical Th1/Th2 paradigm during pregnancy.

Sex hormones and the immune response in humans.

In addition to their effects on sexual differentiation and reproduction, sex hormones appear to influence the immune system. This results in a sexual dimorphism in the immune response in humans: for instance, females produce more vigorous cellular and more vigorous humoral immune reactions, are more resistant to certain infections, and suffer a higher incidence of autoimmune diseases. Disease expression is also affected by the reproductive status of the female. As sex steroids--estrogens, progesterone and testosterone--differ between gender and within different reproductive stages, a lot of research has focussed on the effects of sex hormones on immune responses. Although there is also a vast literature on the effects of sex hormones on immune responses in animals, in this review we will focus on the most intriguing effects and mechanisms by which sex hormones affect different components of the immune system in humans.

17beta-estradiol and progesterone do not influence the production of cytokines from lipopolysaccharide-stimulated monocytes in humans.

OBJECTIVE: To test whether 17beta-estradiol or progesterone influence the cytokine productive capacity of lipopolysaccharide (LPS)-stimulated monocytes in humans. DESIGN: Prospective study. SETTING: Academic research institution. PATIENT(S): Seven women in the luteal phase of a normal ovarian cycle, 13 oral contraceptive users, 10 men, and 10 postmenopausal women. INTERVENTION(S): Blood samples collected from women in the luteal phase and from oral contraceptive users were used to study the in vivo effect of 17beta-estradiol and progesterone on monocyte cytokine production. Blood samples collected from men and postmenopausal women were used for in vitro incubation with 17beta-estradiol and progesterone. MAIN OUTCOME MEASURE(S): The percentage of monocytes producing tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) after in vitro LPS-stimulation was determined. RESULT(S): No in vivo relation in the productive capacities of LPS-stimulated monocytes in the luteal phase of the ovarian cycle was found between progesterone and TNF-alpha or IL-1beta; or between 17beta-estradiol and TNF-alpha or IL-1beta. Moreover, the production of TNF-alpha and IL-1beta by LPS-stimulated monocytes did not vary between periods of oral contraceptive use and nonuse. The production of TNF-alpha and IL-1beta by LPS-stimulated monocytes in the blood of men and postmenopausal women in vitro was not influenced by incubation with different concentrations of 17beta-estradiol or progesterone. CONCLUSION(S): We could not find evidence for a causal relationship between 17beta-estradiol or progesterone and TNF-alpha- or IL-1beta-production. We conclude that 17beta-estradiol and progesterone do not influence the cytokine-production capacity of LPS-stimulated monocytes in humans.

Gender difference in the non-specific and specific immune response in humans.

PROBLEM: The purpose of this present ex vivo study is to get insight in the sex differences of the basic non-specific and specific immune response. METHOD OF STUDY: Intracellular types 1 and 2 cytokine production by stimulated male and female lymphocytes and monocytes in a whole blood preparation was measured by flow cytometry. RESULTS: Increased percentage interleukin (IL)-12, IL-1 beta and tumor necrosis factor (TNF)-alpha producing monocytes and decreased percentage IL-2 producing lymphocytes, i.e. type 1 cytokine, were found in men as compared with women. CONCLUSION: These results suggest a gender difference in the balance between the specific and non-specific immune response, i.e. a more profound and higher state of excitation of the non-specific immune response and relative suppression of the cellular immune response of the specific immune system in men as compared with women.

Endotoxin-induced cytokine production of monocytes of third-trimester pregnant women compared with women in the follicular phase of the menstrual cycle.

OBJECTIVE: Little is known about the function of the innate immune response during pregnancy. We therefore investigated monocyte cytokine production, as a measure of monocyte function, in pregnant women compared with nonpregnant women. STUDY DESIGN: Whole blood of women in the follicular phase (day 5-6) and of healthy pregnant women (30 weeks) was collected and stimulated with endotoxin (2 microg/mL). After incubation for 4 hours (37 degrees C, 5% carbon dioxide), red blood cells were lysed and white blood cells were permeabilized, followed by staining with anti-CD14 (fluorescein isothiocyanate labeled) and with phycoerythrin-labeled tumor necrosis factor-alpha, interleukin-1beta, or interleukin-12. The cells were analyzed by flow cytometry after fixation. Results are expressed as a percentage cytokine producing cells after endotoxin stimulation. Statistical analysis was performed with the Mann-Whitney U test (P <.05). RESULTS: Compared with the percentage endotoxin-induced cytokine producing peripheral monocytes in women in the follicular phase, this percentage in pregnancy was decreased for interleukin-12 (mean 6.63 +/- 1.34 vs 3.34 +/- 0.87, P <.05) and tumor necrosis factor-alpha (mean 50.20 +/- 5.80 vs 31.29 +/- 5.57, P >.05). No significant difference was seen in the production of interleukin-1beta (mean 58.22 +/- 11.09 vs 47.18 +/- 7.88, P >.05). CONCLUSION: The percentage of interleukin-12 and tumor necrosis factor-alpha producing monocytes is decreased in pregnant women compared with nonpregnant women, suggesting that pregnancy is a proinflammatory state.

Cytokine production in natural killer cells and lymphocytes in pregnant women compared with women in the follicular phase of the ovarian cycle.

OBJECTIVE: To test whether peripheral natural killer (NK) cells, helper T cells, and cytotoxic lymphocytes of pregnant women shift from a type 1 cytokine production toward a type 2 cytokine production as compared with these cells in women in the follicular phase. DESIGN: Prospective study. SETTING: Outpatient clinic. PATIENT(S): Healthy nullipara at 30 weeks' amenorrhea and healthy nonpregnant women in their follicular phase. INTERVENTION(S): Samples of whole blood were stimulated with phorbol myristate acetate (PMA; Sigma Chemical Co., St. Louis, MO) and Ca-ionophore in the presence of monensin (Sigma). Lymphocytes were stained with alpha-CD3, alpha-CD8, and alpha-interferon gamma (IFN-gamma) alpha-interleukin 2 (IL-2), IL-4, or IL-10. Analysis was performed by flow cytometry. Statistical evaluation was done with the Mann-Whitney U test. MAIN OUTCOME MEASURE(S): Percentage NK cells, helper lymphocytes, and cytotoxic lymphocytes that were producing IFN-gamma, IL-2, IL-4, or IL-10. RESULT(S): There is a statistically significant decrease in the percentage of NK cells, and helper and cytotoxic lymphocytes that produced IFN-gamma in pregnant women when compared with women in the follicular phase. There is also a statistically significant decrease in the percentage of helper lymphocytes producing IL-2 in pregnant women compared with nonpregnant women. CONCLUSION(S): We found a decrease in type 1 cytokine production with no change in type 2 cytokine production after in vitro stimulation of "pregnant" NK cells and lymphocytes as compared with "nonpregnant" NK cells and lymphocytes. We suggest that NK cell and lymphocyte response are shifted away from a type 1 immune response during pregnancy.