The presence of postmenopausal bleeding as prognostic parameter in patients with endometrial cancer: a retrospective multi-center study

Abstract Background To date, there is no consensus on the utility of screening procedures for the early detection of endometrial cancer. The value of transvaginal ultrasound for screening of asymptomatic endometrial cancer has been discussed controversially. This study was conducted to evaluate whether asymptomatic patients with endometrial cancer have a better prognosis than symptomatic patients with endometrial cancer diagnosed after postmenopausal bleeding. Methods In the present multi-center study, the effect of the presence of postmenopausal bleeding on prognosis was evaluated retrospectively in 605 patients with endometrial cancer using patients' files. 543 patients (133 patients were asymptomatic, 410 patients were symptomatic) with endometrioid endometrial cancer were enrolled in all further analysis. Student's t-test, Cox regression analysis and Kaplan-Meier analysis were used were appropriate. Results Presence/absence of a postmenopausal bleeding was not associated with tumor stage (p = 0.2) and age at diagnosis (p = 0.5). Asymptomatic patients with endometrial cancer had a significantly higher rate of well and moderate-differentiated tumors compared to symptomatic patients (p = 0.008). In univariable and multivariable survival analysis, tumor stage, tumor grade, and patients' age at diagnosis, but not presence/absence of a postmenopausal bleeding, were associated with disease free and overall survival. Conclusion Asymptomatic patients with endometrial cancer have a higher rate of well differentiated tumors compared to patients with a postmenopausal bleeding prior to diagnosis. The prognosis of both groups of patients was similar.</p

Surveillance for endometrial cancer with transvaginal ultrasonography of breast cancer patients under tamoxifen treatment

The association of endometrial thickness with the risk of developing endometrial cancer (EC) within 2 years was investigated in a consecutive cohort of 1205 breast cancer patients under tamoxifen treatment, undergoing transvaginal ultrasonography (TVUS) for follow-up purpose (asymptomatic, 1068) or for abnormal uterine bleeding (AUB, 137). Linkage with tumour registry allowed for the follow-up of 3184.3 person-years. According to underlying incidence, 1.85 EC cases were expected in the study cohort while 12 were observed (observed/expected ratio=6.49, 95% CI 3.35–11.33; asymptomatic=4.09, 95% CI 1.65–8.43, symptomatic=35.71, 95% CI 11.59–83.34). No EC was observed with thickness (half layer) <3 mm. Raising this threshold increased specificity with a substantial loss of sensitivity (⩾3, ⩾4, ⩾6, ⩾9 mm; spec.=25.8, 44.5, 76.1, 91.5%, sens.=100, 91.6, 75.0, 66.6%). The presence of AUB was rather specific (88.94%) but poorly sensitive (41.67%). A combination of AUB presence/absence and thickness allowed the best accuracy (AUB + thickness ⩾3, ⩾4 or ⩾5; sens.=100, 81.6 or 91.6%; spec.=22.8, 40.4, or 56.7%). Breast cancer patients under tamoxifen might be selected for further invasive assessment on the basis of AUB and endometrial thickness assessed at TVUS

Survival of endometrial cancer patients in Germany in the early 21st century: a period analysis by age, histology, and stage

<p>Abstract</p> <p>Background</p> <p>Population-based studies on endometrial cancer providing survival estimates by age, histology, and stage have been sparse. We aimed to derive most up-to-date and detailed survival estimates for endometrial cancer patients in Germany.</p> <p>Methods</p> <p>We used a pooled German national dataset including data from 11 cancer registries covering a population of 33 million people. 30,906 patients diagnosed with endometrial cancer in 1997-2006 were included. Period analysis was performed to calculate 5-year relative survival (RS) in 2002-2006. Trends in survival between 2002 and 2006 were examined using model-based period analysis. Age-adjustment was performed using five age groups (15-44, 45-54, 55-64, 65-74, and 75+ years).</p> <p>Results</p> <p>Overall, age-adjusted 5-year relative survival in 2002-2006 was 81%. A moderate age gradient was observed, with 5-year RS decreasing from 90% in the age group 15-49 years to 75% in the age group 70+ years. Furthermore prognosis varied strongly by histologic subtypes and stage, with age-adjusted 5-year RS ranging from 43% (for sarcoma) to 94% (for squamous metaplasia), and reaching 91% for localized, 51% for regional, and 20% for distant stage. Except for age group 65-74 years, no significant improvement in survival was seen during the recent 5-year period under investigation.</p> <p>Conclusion</p> <p>In this comprehensive population-based survival analysis of patients with endometrial cancer from Germany, prognosis of endometrial cancer moderately varied by age, and strongly varied by histology and stage. While prognosis is rather good overall, further improvement in 5-year relative survival of endometrial cancer patients has been stagnating in the early 21^stcentury.</p

Balance between matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in the cervical mucus plug estimated by determination of free non-complexed TIMP

<p>Abstract</p> <p>Background</p> <p>The cervical mucus plug (CMP) is a semi-solid structure with antibacterial properties positioned in the cervical canal during pregnancy. The CMP contains high concentrations of matrix metalloproteinase 8 and 9 (MMP-8, MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). This indicates a potential to degrade extracellular matrix components depending on the balance between free non-complexed inhibitors and active enzymes.</p> <p>Methods</p> <p>Thirty-two CMPs collected during active labor at term were analyzed. Twelve CMPs were separated into a cellular and an extracellular/fluid phase and analyzed by gelatin and reverse zymography to reveal MMP and TIMP location. Twenty samples were homogenized, extracted and studied by the TIMP activity assay based on gelatin zymography. Enzyme-linked immunosorbent assay (ELISA) was used to determine TIMP-1, MMP-8 and MMP-9 protein concentrations, and gelatin and reverse zymography used to identify gelatinases and TIMPs, respectively. The Western blotting technique was applied for semi-quantification of alpha2-macroglobulin. An ELISA activity assay was used to detect MMP-8 and MMP-9 activity.</p> <p>Results</p> <p>ProMMP-2, proMMP-9, TIMP-1 and TIMP-2 were almost exclusively located in the fluid phase compared to the cellular phase of the CMP. All the extracted samples contained MMP-8, MMP-9, TIMP-1, TIMP-2 and alpha2-macroglobulin. Free non-complexed TIMP was detected in all the samples analyzed by the TIMP activity assay and was associated with TIMP-1 protein (R = 0.71, p < 0.001) and with the TIMP/MMP molar ratio (1.7 (1.1–2.5) (mean (95% confidence interval)) (R = 0.65, p = 0.002). The ELISA activity assay showed no activity from MMP-8 or MMP-9.</p> <p>Conclusion</p> <p>Due to their extracellular location, potential proteolytic activity from neutrophil-derived MMPs in the CMP could exert a biological impact on cervical dilatation and fetal membrane rupture at term. The functional TIMP activity assay, revealing excess non-complexed TIMP, and a molar inhibitor/enzyme ratio above unity, indicate that refined MMP control prevents CMP-originated proteolytic activity in the surrounding tissue.</p

Nuclear Factor Kappa B Activation Occurs in the Amnion Prior to Labour Onset and Modulates the Expression of Numerous Labour Associated Genes

Background: Prior to the onset of human labour there is an increase in the synthesis of prostaglandins, cytokines and chemokines in the fetal membranes, particular the amnion. This is associated with activation of the transcription factor nuclear factor kappa B (NFkB). In this study we characterised the level of NFkB activity in amnion epithelial cells as a measure of amnion activation in samples collected from women undergoing caesarean section at 39 weeks gestation prior to the onset of labour. Methodology/Principal Findings: We found that a proportion of women exhibit low or moderate NFkB activity while other women exhibit high levels of NFkB activity (n = 12). This activation process does not appear to involve classical pathways of NFkB activation but rather is correlated with an increase in nuclear p65-Rel-B dimers. To identify the full range of genes upregulated in association with amnion activation, microarray analysis was performed on carefully characterised nonactivated amnion (n = 3) samples and compared to activated samples (n = 3). A total of 919 genes were upregulated in response to amnion activation including numerous inflammatory genes such cyclooxygenase-2 (COX-2, 44-fold), interleukin 8 (IL-8, 6-fold), IL-1 receptor accessory protein (IL-1RAP, 4.5-fold), thrombospondin 1 (TSP-1, 3-fold) and, unexpectedly, oxytocin receptor (OTR, 24-fold). Ingenuity Pathway Analysis of the microarray data reveal the two main gene networks activated concurrently with amnion activation are i) cell death, cancer and morphology and ii) cell cycle, embryoni

Impaired leukocyte influx in cervix of postterm women not responding to prostaglandin priming

<p>Abstract</p> <p>Background</p> <p>Prolonged pregnancies are associated with increased rate of maternal and fetal complications. Post term women could be divided into at least two subgroups, one where parturition is possible to induce by prostaglandins and one where it is not. Our aim was to study parameters in cervical biopsies in women with spontaneous delivery at term (controls) and compare to those that are successfully induced post term (responders), and those that are not induced (non-responders), by local prostaglandin treatment.</p> <p>Methods</p> <p>Stromal parameters examined in this study were the accumulation of leukocytes (CD45, CD68), mRNAs and/or proteins for the extracellular matrix degrading enzymes (matrix metalloproteinase (MMP)-2, MMP-8 and MMP-9), their inhibitors (tissue inhibitor of MMP (TIMP)-1 and TIMP-2), interleukin-8 (IL-8), the platelet activating factor-receptor (PAF-R), syndecan-1 and estrogen binding receptors (estrogen receptor (ER)α, ERβ and G-coupled protein receptor (GPR) 30) as well as the proliferation marker Ki-67.</p> <p>Results</p> <p>The influx of leukocytes as assessed by CD45 was strongest in the responders, thereafter in the controls and significantly lower in the non-responders. IL-8, PAF-R and MMP-9, all predominantly expressed in leukocytes, showed significantly reduced immunostaining in the group of non-responders, while ERα and GPR30 were more abundant in the non-responders, as compared to the controls.</p> <p>Conclusion</p> <p>The impaired leukocyte influx, as reflected by the reduced number of CD45 positive cells as well as decreased immunostaining of IL-8, PAF-R and MMP-9 in the non-responders, could be one explanation of the failed ripening of the cervix in post term women. If the decreased leukocyte influx is a primary explanation to absent ripening or secondary, as a result of other factors, is yet to be established.</p

Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle

Neuronal activity within the central nervous system (CNS) strictly depends on homeostasis and therefore does not tolerate uncontrolled entry of blood components. It has been generally believed that under normal conditions, the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB) prevent immune cell entry into the CNS. This view has recently changed when it was realized that activated T cells are able to breach the BBB and the BCSFB to perform immune surveillance of the CNS. Here we propose that the immune privilege of the CNS is established by the specific morphological architecture of its borders resembling that of a medieval castle. The BBB and the BCSFB serve as the outer walls of the castle, which can be breached by activated immune cells serving as messengers for outside dangers. Having crossed the BBB or the BCSFB they reach the castle moat, namely the cerebrospinal fluid (CSF)-drained leptomeningeal and perivascular spaces of the CNS. Next to the CNS parenchyma, the castle moat is bordered by a second wall, the glia limitans, composed of astrocytic foot processes and a parenchymal basement membrane. Inside the castle, that is the CNS parenchyma proper, the royal family of sensitive neurons resides with their servants, the glial cells. Within the CSF-drained castle moat, macrophages serve as guards collecting all the information from within the castle, which they can present to the immune-surveying T cells. If in their communication with the castle moat macrophages, T cells recognize their specific antigen and see that the royal family is in danger, they will become activated and by opening doors in the outer wall of the castle allow the entry of additional immune cells into the castle moat. From there, immune cells may breach the inner castle wall with the aim to defend the castle inhabitants by eliminating the invading enemy. If the immune response by unknown mechanisms turns against self, that is the castle inhabitants, this may allow for continuous entry of immune cells into the castle and lead to the death of the castle inhabitants, and finally members of the royal family, the neurons. This review will summarize the molecular traffic signals known to allow immune cells to breach the outer and inner walls of the CNS castle moat and will highlight the importance of the CSF-drained castle moat in maintaining immune surveillance and in mounting immune responses in the CNS

Integrated genomic surveillance enables tracing of person-to-person SARS-CoV-2 transmission chains during community transmission and reveals extensive onward transmission of travel-imported infections, Germany, June to July 2021

BackgroundTracking person-to-person SARS-CoV-2 transmission in the population is important to understand the epidemiology of community transmission and may contribute to the containment of SARS-CoV-2. Neither contact tracing nor genomic surveillance alone, however, are typically sufficient to achieve this objective.AimWe demonstrate the successful application of the integrated genomic surveillance (IGS) system of the German city of Düsseldorf for tracing SARS-CoV-2 transmission chains in the population as well as detecting and investigating travel-associated SARS-CoV-2 infection clusters.MethodsGenomic surveillance, phylogenetic analysis, and structured case interviews were integrated to elucidate two genetically defined clusters of SARS-CoV-2 isolates detected by IGS in Düsseldorf in July 2021.ResultsCluster 1 (n = 67 Düsseldorf cases) and Cluster 2 (n = 36) were detected in a surveillance dataset of 518 high-quality SARS-CoV-2 genomes from Düsseldorf (53% of total cases, sampled mid-June to July 2021). Cluster 1 could be traced back to a complex pattern of transmission in nightlife venues following a putative importation by a SARS-CoV-2-infected return traveller (IP) in late June; 28 SARS-CoV-2 cases could be epidemiologically directly linked to IP. Supported by viral genome data from Spain, Cluster 2 was shown to represent multiple independent introduction events of a viral strain circulating in Catalonia and other European countries, followed by diffuse community transmission in Düsseldorf.ConclusionIGS enabled high-resolution tracing of SARS-CoV-2 transmission in an internationally connected city during community transmission and provided infection chain-level evidence of the downstream propagation of travel-imported SARS-CoV-2 cases