Transcriptome-based network analysis reveals a spectrum model of human macrophage activation.

Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.

Placental Invasion into the Small Bowel Intestine Through a Myomectomy Scar: A Case Report With Literature Review.

Although extremely rare, uterine damage after hysteroscopic myomectomy sets the precondition for various life-threatening placental attachment disorders like placenta percreta (PP) or scar pregnancy. Due to vast clinical similarities, these terms are often used interchangeably. We report a case of a 47-yr-old patient at 27 wk + 4 d of gestation who presented with rectal bleeding. Clinical history revealed a previous uterine posterior wall myomectomy. The patient received intensive diagnostic work-up including sonography and magnetic resonance imaging. Under the suspicion of a bleeding Meckel diverticulum, an emergency laparotomy was performed. Intraoperatively it was observed that the placental tissue infiltrated the small bowel intestine at the location of the previous myomectomy. The adjacent intestine and the infiltrating placenta were surgically removed. The placenta could be easily detached from the uterus, which is why no hysterectomy was performed. Retrospectively, no radiologic or clinical hints of PP or scar pregnancy were evident before the surgery. Moreover, the pathologic work-up carried out afterwards proved no histopathologic evidence for PP. Our case underlines several clinical and pathologic difficulties. First, invasive placenta disorders including infiltration of intestinal organs have to be considered even after minor surgical interventions such as myomectomy. Second, clinical presentation is extremely variable and sometimes misleading, depending on the localization and the type of invasion. Our case underlines the importance of histopathologic work-up for distinguishing between various placenta attachment disorders such as PP and scar pregnancy. Given the large overlap in clinical presentation, pathophysiology and definition, we propose that the current definitions for PP and scar pregnancy have to be carefully reevaluated and broadened.

Clinical spectrum of female genital malformations in prenatal diagnosis.

INTRODUCTION: Fetal genital malformations represent a rare and heterogeneous group of congenital malformations of the disorders of sexual development (DSD) spectrum. METHODS: A thorough literature review on the main topics in the prenatal approach towards DSD was conducted. RESULTS: First, a thorough overview on prenatal characteristics of the most common fetal genital malformations of ovaries, uterus and external genitalia, and second, a standardized approach for differential diagnosis in the presence of direct and indirect prenatal signs of DSDs. CONCLUSIONS: This review is mainly directed towards the aspects of female genital malformations with  aspects of male DSD explained as well to aid in the prenatal differential diagnosis.

Fetal Cardiac Intervention in Critical Aortic Stenosis with Severe Mitral Regurgitation, Severe Left Atrial Enlargement, and Restrictive Foramen Ovale.

OBJECTIVE: To assess the intrauterine course and outcome of fetal cardiac intervention (FCI) in fetuses with critical aortic stenosis (CAS), severe mitral regurgitation (MR), severe left atrial dilatation (LAD), and restrictive foramen ovale (RFO) or intact atrial septum. METHODS: All fetuses with a prenatal diagnosis of CAS, severe MR, severe LAD, and RFO were retrospectively collected in one tertiary center for fetal medicine over a period of 10 years. Video recordings, pre- and postnatal charts were reviewed for cardiac and extracardiac anomalies, intrauterine course, and postnatal outcome. RESULTS: Nineteen fetuses with CAS, severe MR, severe LAD, and RFO were diagnosed in the study period. In 5 cases, FCI was not considered as the parents either opted for expectative management or for termination. In the remaining 14 fetuses, 21 FCI were performed: 14 balloon valvuloplasties, 2 atrioseptostomies, and 5 fetal atrial stent insertions. Seven of 14 fetuses (50%) had fetal hydrops, 5 of 14 fetuses (36%) presented with intact atrial septum. Procedure-related death occurred in 5 fetuses after aortic valvuloplasty or concomitant atrioseptostomy but in none after fetal atrial stenting. Due to progressive hydrops, two terminations of pregnancy were performed. Among the 7 live births, 3 died in the neonatal period. The remaining 4 received single ventricle palliation, 2 following fetal aortic valvuloplasty and 2 after fetal atrial stent insertion. CONCLUSIONS: CAS with severe MR, severe LAD, and RFO has a high overall mortality even in cases undergoing intrauterine intervention. Parameters that accurately predict the intrauterine and postnatal outcome have yet to be defined.

Isolated bladder exstrophy in prenatal diagnosis.

PURPOSE: Isolated classic bladder exstrophy (CBE) is the most common variant of the bladder-exstrophy-epispadias complex (BEEC). The BEEC represents a spectrum ranging from isolated epispadias over CBE to the most severe form, cloacal exstrophy. We report on a series of 12 cases with CBE diagnosed prenatally and illustrate the spectrum of prenatal ultrasound findings with comparison to prior published reports on this entity. METHODS: This was a retrospective study involving 12 fetuses with CBE at two large tertiary referral centers in Germany over a 14-year period (2004-2018). RESULTS: Median diagnosis was made with ultrasound in 24 + 5 (IQR25,75: 21 + 2, 29 + 0) weeks of gestation. All fetuses presented with the pathognomonic findings non-visualization of the fetal bladder and protruding abdominal mass below the umbilical cord insertion. All fetuses showed normal kidney anatomy and normal amniotic fluid throughout pregnancy. Epispadia was visible prenatally on ultrasound in 6/8 male fetuses. 1/12 Parents opted for termination of pregnancy, 11/12 fetuses were live born and received reconstructive surgery. CONCLUSIONS: Isolated CBE is an extremely rare prenatal sonographic finding. Prenatal diagnostics should exclude additional malformations within the spectrum of cloacal malformations.

Prenatal Diagnosis of Enterolithiasis in 20 Cases.

BACKGROUND: Enterolithiasis is a sonographic sign defined by hyperechogenic foci within the - often distended - fetal bowel. OBJECTIVES: We report on a series of 20 cases with enterolithiasis diagnosed prenatally and illustrate the spectrum of associated malformations. METHOD: This was a retrospective study involving 20 fetuses with enterolithiasis at two large tertiary referral centers in Germany over a 17-year period (2000-2017). RESULTS: Median diagnosis was made with ultrasound at 18+2 weeks of gestation (IQR25,75: 14+5, 26+5). Additional malformations included urogenital malformations (cloacal malformation in 7/20 fetuses [35%] and kidney defects in 7/20 fetuses [35%]), cardiac malformations (3/20 fetuses [15%]), and vertebral malformations (5/20 fetuses [25%]). Of 20 fetuses, 14 could be attributed to the anorectal malformation spectrum, 3/20 fetuses presented with caudal regression syndrome, and 1 fetus with bilateral kidney agenesis, congenital diaphragmatic aplasia, and enterovesical fistula, respectively. CONCLUSION: Enterolithiasis is a rare prenatal sonographic feature. Because of the frequent occurrence of uro-recto-genital malformations, thorough prenatal counseling should be performed.

Prenatal Diagnosis of Hydro(metro)colpos: A Series of 20 Cases.

BACKGROUND: Hydrocolpos and hydrometrocolpos are rare malformations caused by accumulation of secretion due to congenital obstruction of the vagina. Hydro(metro)colpos may be isolated or can be combined with other malformations as part of a syndromic disorder. We report on a series of 20 cases with hydro(metro)colpos diagnosed prenatally, delineate the differential diagnoses, and illustrate the spectrum of associated malformations. SUBJECTS AND METHODS: This was a retrospective study involving 20 fetuses with hydro(metro)colpos at two large tertiary referral centers in Germany over an 18-year period (2000-2017). RESULTS: The median diagnosis was made at 30+4 weeks of gestation, the earliest at 20+6 weeks, the latest at 37+2 weeks. All 20 fetuses presented with the typical cystic structure behind the fetal bladder. Additional malformations included urogenital malformations, hexadactyly, and heart defects. Postnatal follow-up revealed that hydro(metro)colpos was associated with anorectal malformation in 11/20 fetuses, McKusick-Kaufman syndrome or Bardet-Biedl syndrome in 4/20 fe tuses, Mayer-Rokitansky-Küster-Hauser syndrome in 3/20 fetuses, and Herlyn-Werner-Wunderlich syndrome in 1/20. In 1 fetus pressure from an intraabdominal teratoma resulted in prenatal hydro(metro)colpos. CONCLUSION: Hydro(me tro)colpos is a rare prenatal sonographic feature. Multidisciplinary prenatal counseling should include all potential syndromes that can present with hydro(metro)colpos in the prenatal setting.

Outcome of Bronchopulmonary Sequestration with Massive Pleural Effusion after Intrafetal Vascular Laser Ablation.

OBJECTIVE: To assess the outcome of 12 fetuses with bronchopulmonary sequestration (BPS) and massive pleural effusion after intrafetal vascular laser ablation (VLA). METHODS: All fetuses with BPS and massive pleural effusion that were treated with intrafetal VLA during a 5-year period (2012-2016) were reviewed for safety, intrauterine course, and postnatal outcome. RESULTS: In the study period, 12 fetuses with BPS were treated with VLA. In 7 (58.3%) fetuses, complete cessation of blood flow was achieved after the first VLA, while in 5 (41.7%) fetuses, residual perfusion of the feeding vessel was demonstrated at follow-up. A second intervention was successful in 4 of 5 (80%) fetuses. Overall, in 11 of 12 (91.7%) fetuses, complete coagulation of the feeding vessel could be achieved, followed by a reduction in size or complete resolution of the BPS. All 11 fetuses with successful prenatal intervention were live-born at a median gestational age of 39+1 (range, 37+5-41+2) weeks. Postnatally, 2 (18.2%) of the 11 newborns underwent sequestrectomy, as well as the preterm newborn on which a second fetal intervention was not feasible. CONCLUSION: VLA is an effective and safe treatment of BPS that appears to be of benefit in improving prognosis and decreasing the need for postnatal sequestrectomy.

Thoracoamniotic Shunting for Fetal Hydrothorax: Predictors of Intrauterine Course and Postnatal Outcome.

OBJECTIVE: To assess predictors for survival and complications among a relatively large cohort of fetuses with hydrothorax treated by thoracoamniotic shunting. METHODS: All cases with hydrothorax treated by thoracoamniotic shunting in a 10-year period (2002-2011) in two centers were retrospectively reviewed. RESULTS: A total of 78 fetuses with hydrothorax treated with thoracoamniotic shunting were included in the study. Mean gestational age at diagnosis was 25.6 weeks (12-34 weeks). Initial thoracoamniotic shunting was performed at a mean gestational age of 26.5 weeks (16-33 weeks). A mean of 2.53 shunts (1-7) were inserted per fetus. Of the 78 fetuses, 9 (11.5%) died in utero, 69 (88.5%) were born alive and 46 (59%) survived. Prognostic markers significantly associated with nonsurvival were polyhydramnios, hydrops placentae and mediastinal shift at initial scan, onset of hydrops after first shunt placement, rupture of membranes, a shunt-birth interval <4 weeks and low gestational age at birth. In our cohort, fetuses with trisomy 21 had a significantly better survival than euploid fetuses. CONCLUSIONS: Although associated with a significant rate of repeated interventions, thoracoamniotic shunting in fetuses with severe hydrothorax results in an overall survival rate of 59%. Fetuses with hydrothorax and trisomy 21 have a better survival when compared to euploid fetuses.

Impact of Extended Primary Surgery on Suboptimally Operable Patients With Advanced Ovarian Cancer.

OBJECTIVES: Extensive surgical efforts to achieve an optimal debulking (no residual tumor) in primary surgery of ovarian cancer are today's criterion standard in gyneco-oncologic surgery. However, it is controversial whether extensive surgery, including resections of metastases in the upper abdomen and bowel resections, is justifiable in patients with not completely operable lesions. METHODS: All patients who had undergone surgery for ovarian cancer in the years 2002 to 2013 at our institution were viewed (n = 472). We retrospectively identified 278 operations for primary ovarian cancer. Ninety-six (35%) of the 278 patients showed postoperative tumor residuals and were included in this study. RESULTS: Fifty-five (57%) of 96 patients underwent bowel resection, showing significantly higher complication rates (64% vs 39% minor complications, P = 0.017; 31% vs 9.8% severe complications, P = 0.013) compared with patients without bowel resections as well as no improvement in progression-free or overall survival (median overall survival, 19.5 vs 32.9; P = 0.382). Multiple anastomoses (≥2) were associated with higher rates for anastomotic leakage (16.7% vs 2.6%, P = 0.02) and a higher mortality (16.7% vs 0%, P = 0.04) compared with patients with only 1 anastomosis. Extensive surgery of the upper abdomen was not associated with a significant increase in complication rates. CONCLUSIONS: Because of the increased morbidity of bowel resections without any evidence for improvement of survival, we suggest to restrain from further resection of intestines if an optimal debulking seems not feasible after removal of the major tumor bulk.

Development of obstetrical and gynecological journals, 2007 to 2013: a trend analysis.

PURPOSE: To analyze the trends and developments among journals in the specialty of obstetrics and gynecology. METHODS: Using the Journal Citation Reports from 2007 to 2013, we analyzed the impact factor (IF), Eigenfactor® Score (ES), and Article Influence® Score (AIS) of 43 journals in the field of obstetrics and gynecology published in this time period. RESULTS: From 78 journals of the Journal Citation Report 2013, 43 were selected for this study. The mean IF grew from 1.68 ± 0.97 in 2007 to 2.12 ± 1.05 in 2013, the ES from 0.0113 ± 0.0169 to 0.0114 ± 0.0140, and the AIS from 0.513 ± 0.302 to 0.663 ± 0.359. Differences in the IF, ES, and AIS between journals from the United States versus Europe could be observed. In most cases, the IF, ES, and AIS increased between 2007 and 2013. Strong correlations could be found between IF, AIS, and ES. CONCLUSIONS: The overall mean IF for obstetrical and gynecological journals increased over the analyzed time period. The IF remains the standard measure to compare scientific journals. It correlates well with two major alternative measures of scientific impact, the ES and especially the AIS. Other measures are evolving and might show superior usage in the future.

Prognostic significance of tumor-associated macrophages in endometrial adenocarcinoma.

OBJECTIVE: Endometrial adenocarcinoma is one of the most common gynecologic malignancies worldwide and in stages confined to the uterus considered to have an excellent prognosis. However, in advanced or recurrent cases when surgery fails to achieve disease control other treatment options are less effective. Thus, new therapeutic avenues are needed. METHODS: To provide the rationale for the use of novel agents that target immune checkpoints 163 type I endometrial cancer samples were immunohistochemically screened for the presence of CD163(+) tumor-associated macrophages and Foxp3(+) regulatory T cells. Further, a D2-40-based evaluation of lymph vessel density and lymphovascular space invasion was carried out. Correlation analysis with clinicopathological parameters was performed; Kaplan-Meier curves were generated; multivariate analysis was undertaken as appropriate. RESULTS: A substantial amount of tumor-associated macrophages and regulatory T cells was detected in all specimens characterizing endometrial cancer as an immunogenic tumor. However, only the increased infiltration of tumor-associated macrophages was proportionally associated with advanced FIGO stages, high tumor grade, increased lymph vessel density, lymphovascular space invasion and lymph node metastasis. Thus, the presence of tumor-associated macrophages indicates aggressive tumor behavior and appeared to be an independent prognostic factor for recurrence-free survival. CONCLUSIONS: Our results make future therapeutic approaches that target tumor-associated macrophages reasonable to improve the outcome of women with advanced or recurrent endometrial adenocarcinoma.

Prenatal diagnosis of covered cloacal exstrophy.

The authors present the case of a prenatally diagnosed covered cloacal exstrophy in a female fetus and potential differential diagnoses within the exstrophy-epispadias complex. While on prenatal ultrasound, low-set umbilicus, omphalocele, diastasis of the pubic rami, split vulva and left-sided renal agenesis were suggestive of classic cloacal exstrophy, the presence of bladder filling and the missing characteristic elephant trunk appearance of the usually prolapsing terminal ileum suggested the diagnosis of covered cloacal exstrophy. Besides urogenital anomalies, the fetus presented with an additional small muscular ventricular septal defect. Postnatal presentation showed an omphalocele with a low-set umbilicus and a directly inferior positioned large everted (exstrophic) bladder plate with low positioned ureteric orifices. The external genitalia impressed with rudimentary vulvae and hemiclitorises. An imperforate anus was present, yet bowel movements were passed shortly after birth through a small vesicointestinal fistula positioned at the lower vesical trigone. We conclude that prenatal diagnosis of covered cloacal exstrophy can be made if bladder filling is present during prenatal ultrasound, although the bladder might become exstrophic during later gestation.

Internet Access and Use by Patients with Gynecologic Malignancies: A Cross-Sectional Study.

The influence of digitalization on information-seeking, decision-making properties of patients, therapy monitoring, and patient-physician interactions has and will change the global health sector tremendously. With this study, we add knowledge on the degree of digitalization, digital device availability, the use and availability of home and mobile internet access, and the willingness to use novel forms of patient-physician interactions in a group of gynecologic cancer patients. From July 2017 to March 2022, 150 women with a diagnosis of gynecologic malignancy at the University Hospital of Cologne participated in this questionnaire-based cohort study. Any one of three potential internet access devices (stationary computer, smartphone, or tablet) is owned by 94% of patients and the only patient intrinsic factor that is significantly associated with the property of any one of these internet access devices is age. The Internet is used daily or several times per week to assess information on their disease by 92.8%, 90.1% use the Internet for communicational purposes and 71.9% and 93.6% are willing to communicate with their treating physicians via E-Mail or even novel forms of communication, respectively. In conclusion, the predominant majority of gynecologic cancer patients can be reached by modern internet-based E-Health technologies.

Expression of Potential Antibody-Drug Conjugate Targets in Cervical Cancer.

(1) Background: There is a huge unmet clinical need for novel treatment strategies in advanced and recurrent cervical cancer. Several cell membrane-bound molecules are up-regulated in cancer cells as compared to normal tissue and have revived interest with the introduction of antibody-drug conjugates (ADCs). (2) Methods: In this study, we characterize the expression of 10 potential ADC targets, TROP2, mesotheline, CEACAM5, DLL3, folate receptor alpha, guanylatcyclase, glycoprotein NMB, CD56, CD70 and CD138, on the gene expression level. Of these, the three ADC targets TROP2, CEACAM5 and CD138 were further analyzed on the protein level. (3) Results: TROP2 shows expression in 98.5% (66/67) of cervical cancer samples. CEACAM5 shows a stable gene expression profile and overall, 68.7% (46/67) of cervical cancer samples are CEACAM-positive with 34.3% (23/67) of cervical cancer samples showing at least moderate or high expression. Overall, 73.1% (49/67) of cervical cancer samples are CD138-positive with 38.8% (26/67) of cervical cancer samples showing at least moderate or high expression. (4) Conclusions: TROP2, CEACAM5 or CD138 do seem suitable for further clinical research and the data presented here might be used to guide further clinical trials with ADCs in advanced and recurrent cervical cancer patients.

Unique transcriptome signature of mouse microglia.

Microglial cells can be derived directly from the dissociated brain tissue by sorting procedures, from postnatal glial cultures by mechanic isolation or from pluripotent stem cells by differentiation. The detailed molecular phenotype of microglia from different sources is still unclear. Here, we performed a whole transcriptome analysis of flow cytometry-sorted microglia, primary postnatal cultured microglia, embryonic stem cell derived microglia (ESdM), and other cell types. Microglia and ESdM, both cultured in serum-free medium, were closely related to sorted microglia and showed a unique transcriptome profile, clearly distinct to other myeloid cell types, T cells, astrocytes, and neurons. ESdM and primary cultured microglia showed strong overlap in their transcriptome. Only 143 genes were differentially expressed between both cell types, mainly derived from immune-related genes with a higher activation status of proinflammatory and immune defense genes in primary microglia compared to ESdM. Flow cytometry analysis of cell surface markers CD54, CD74, and CD274 selected from the microarray confirmed the close phenotypic relation between ESdM and primary cultured microglia. Thus, assessment of genome-wide transcriptional regulation demonstrates that microglial cells are unique and clearly distinct from other macrophage cell types.

Interval debulking surgery in patients with Federation of Gynecology and Obstetrics (FIGO) stage IIIC and IV ovarian cancer.

BACKGROUND: The feasibility of neoadjuvant chemotherapy (NAC) and the outcome in patients with Federation of Gynecology and Obstetrics (FIGO) IIIC and IV ovarian cancer were assessed. PATIENTS AND METHODS: 67 patients undergoing interval debulking surgery (IDS) and ≥ 4 courses of platinum-based NAC were analyzed for survival, perioperative morbidity and mortality. RESULTS: The median follow-up was 30 months. The median progression-free survival (PFS) was 17 months, the overall survival (OS) 34 months. The PFS of patients without residual disease (n = 23; 34.3%) was 31 months (p = 0.003), the OS 65 months (p = 0.001). PFS and OS were significantly longer in patients with no residual disease than in patients with 1-10 mm (n = 34; 47.9%) (p = 0.005 and p = 0.0001, respectively) residual disease. No survival benefit was seen for patients with 1-10 mm compared to > 1 cm (n = 12; 16.9%) residual disease (PFS p = 0.518; OS p = 0.077). 1 patient (1.4%) died; 12 patients needed interventional treatment or operation (16.9%) within the first 30 days postoperatively. Out of these, 5 patients (7.0%) had residual or lasting disability. CONCLUSIONS: NAC and IDS are safe and feasible in this series of patients with unfavorable prognosis. IDS does not change the goal of complete cytoreduction and therefore does not compensate for a less radical surgical approach.

Clinical Applicability of Tissue Polypeptide Antigen and CA-125 in Gynecological Malignancies.

BACKGROUND: Nowadays there still is no sufficient screening tool for ovarian and uterine cancer. OBJECTIVE: The current study aimed to investigate whether cancer antigen 125 (CA-125), tissue polypeptide antigen (TPA) or the combination of both markers are able to act as screening tools for ovarian or uterine cancer. METHODS: A total of 275 blood samples from different cohorts (ovarian cancer, uterine cancer, benign control group) were prospectively drawn and analyzed. RESULTS: Established biomarkers TPA and CA-125 showed elevated serum concentrations in patients with malignant tumors as compared to healthy women and women with benign diseases. In ROC curve analyses, both biomarkers were well able to discriminate between malignant and healthy, benign or overall non-malignant cases in the whole sample, with AUCs of 0.842 and above. While TPA was the best diagnostic marker in patients with uterine cancer, CA 125 was the best in patients with ovarian cancer. CONCLUSIONS: TPA and CA-125 both showed promising results for the detection of gynecologic malignancies. The combination of CA-125 and TPA did not improve sensitivity in comparison to single markers.

Method Comparison and Clinical Performance of Breast Cancer Tumor Markers on Novel Multiplex Immunoassay and Automatized LOCI Technology Platforms.

Tumor marker determinations are valuable tools for the guidance of breast cancer patients during the course of disease. They are assessed on diverse analytical platforms that may be associated with differences according to the methods applied and the clinical performance. To investigate the method dependency and clinical significance of breast cancer protein tumor markers, CEA, CA 15-3, CA 125, CA 19-9 and AFP were measured in a total of 154 biobanked samples from 77 patients with breast cancer, 10 with DCIS, 31 with benign breast diseases and 36 healthy controls using a Millipore multiplex biomarker panel (MP) and an automized version of the routinely used Vista LOCI technology. The markers were compared between methods and investigated for diagnostic performance. CEA, CA 15-3 and AFP showed good correlations between both platforms with correlation coefficients of R = 0.85, 0.85 and 0.92, respectively, in all samples, but similarly also in the various subgroups. CA 125 and CA 19-9 showed only moderate correlations (R = 0.71 and 0.56, respectively). Absolute values were significantly higher for CEA, CA 15-3, CA 125 and AFP in the Vista LOCI as compared with the MP method and vice versa for CA 19-9. The diagnostic performance for discrimination of breast cancer from healthy controls was similar for both methods with AUCs in ROC curves for CEA (MP 0.81, 95% CI 0.72-0.91; LOCI 0.81; 95% CI 0.72-0.91) and CA-15-3 (MP 0.75, 95% CI 0.65-0.86; LOCI 0.67, 95% CI 0.54-0.79). Similar results were obtained for the comparison of breast cancer with benign breast diseases regarding CEA (AUC MP 0.62, 95% CI 0.51-0.73; LOCI 0.64, 95% CI 0.53-0.74) and CA-15-3 (MP 0.70, 95% CI 0.6-0.81; LOCI 0.66, 95% CI 0.54-0.77). Both platforms show moderate to good method comparability for tumor markers with similar clinical performance. However, absolute levels in individual patients should be interpreted with care.

Immunogenic Biomarkers HMGB1 and sRAGE Are Potential Diagnostic Tools for Ovarian Malignancies.

BACKGROUND: High mobility group box 1 (HMGB1), soluble receptor of advanced glycation end products (sRAGE) and programmed cell death markers PD-1 and PD-L1 are immunogenic serum biomarkers that may serve as novel diagnostic tools for cancer diagnosis. METHODS: We investigated the four markers in sera of 231 women, among them 76 with ovarian cancer, 87 with benign diseases and 68 healthy controls, using enzyme immunoassays. Discrimination between groups was calculated using receiver operating characteristic (ROC) curves and sensitivities at fixed 90% and 95% specificities. RESULTS: HMGB1 levels were significantly elevated and sRAGE levels were decreased in cancer patients as compared to benign and healthy controls. In consequence, the ratio of HMGB1 and sRAGE discriminated best between diagnostic groups. The areas under the curve (AUCs) of the ROC curves for differentiation of cancer vs. healthy were 0.77 for HMGB1, 0.65 for sRAGE and 0.78 for the HMGB1/sRAGE ratio, and slightly lower for the differentiation of cancer vs. benigns with 0.72 for HMGB1, 0.61 for sRAGE and 0.74 for the ratio of both. The highest sensitivities for cancer detection at 90% specificity versus benign diseases were achieved using HMGB1 with 41.3% and the HMGB1/sRAGE ratio with 39.2%, followed by sRAGE with 18.9%. PD-1 showed only minor and PD-L1 no power for discrimination between ovarian cancer and benign diseases. CONCLUSION: HMGB1 and sRAGE have differential diagnostic potential for ovarian cancer detection and warrant inclusion in further validation studies.