Predictors of Decreased Quality of Life in Breast Cancer Survivors Five Years After Diagnosis.

PURPOSE: Due to improved therapy, early diagnosis, and growing incidence rates, the number of long-term breast cancer survivors is increasing. Survivors can still be affected by aftercare, resulting in reduced quality of life (QoL). Thus, in this study, we investigated possible predictors of decreased physical and social functioning in breast cancer survivors. METHODS: In a German multicenter prospective study, we enrolled 759 female patients with breast cancer before surgery (t1), and contacted them again 5 years after surgery (t4). Data on QoL were assessed at t4 using the European Organization for Research and Treatment of Cancer QoL Core Questionnaire (EORTC QLQ-C30) and its breast cancer module EORTC QLQ-BR23. Predictors of decreased physical and social functioning were analyzed using logistic regression with odds ratios as effect estimates and 95% confidence intervals. Thresholds for the clinical importance of detrimental effects on QoL were defined according to Giesinger. RESULTS: Questionnaires from 759 patients were retrieved at t1. Of these, 456 participated in the study at t4. Poor QoL 5 years after diagnosis was reported by 20%-50% of the participants. Age, mastectomy, chemotherapy, education, employment, cohabitation, psychiatric comorbidities at t1, anxiety, depression, and intensity of physical activity emerged as predictors of decreased physical and social functioning 5 years after diagnosis. CONCLUSION: Relief of symptoms and improvement in the QoL should be priorities in aftercare. Detecting patients with a decreased QoL is a rising challenge. Healthcare providers should take special care of patients aged 50-59 years, patients with psychiatric comorbidities and depression, and patients who have undergone mastectomy.

Morphokinetic analysis of early human embryonic development and its relationship to endometriosis resection: a retrospective time-lapse study using the KIDScore™ D3 and D5 implantation data algorithm.

RESEARCH QUESTION: Does complete resection of endometriosis improve embryo quality as assessed by morphokinetic parameters using time-lapse microscopy? DESIGN: For this retrospective study we analysed 237 fertilised, cultured and transferred embryos from 128 fresh IVF and/ or ICSI transfer cycles. Endometriosis was confirmed or excluded by laparoscopy. Patients were stimulated with recombinant FSH using GnRH agonist and antagonist protocols. After fertilisation, a time-lapse incubation system was used for observation. Embryo quality was assessed using the KIDScore™ D3 and D5 implantation data algorithm. RESULTS: The analysis showed a median KIDScore™ D5 of 2.6 (on a scale of 1 to 9.9) for embryos from patients with endometriosis without complete resection. The control group without endometriosis achieved a score of 6.8 (p = 0.003). The median score for embryos from endometriosis patients with complete resection was 7.2, which was a significant increase compared to embryos from patients without complete resection (p = 0.002). We observed an effect size of r = 0.4 for complete resection versus no resection of endometriosis using the KIDScore™ D5. There were no differences in KIDScore™ D3 between the three patient groups. Pregnancy and miscarriage rates showed the same clinical trends. In three of our four case series of patients who underwent IVF/ ICSI cycles before and after complete resection, we found a marked improvement in embryo quality after complete resection. CONCLUSIONS: Complete resection of endometriosis could significantly improve the otherwise poor embryo quality of patients undergoing IVF-procedures. The data, therefore, strongly support recommending surgery to patients with endometriosis prior to assisted reproduction.

The programmed cell death protein 1 (PD1) and the programmed cell death ligand 1 (PD-L1) are significantly downregulated on macrophages and Hofbauer cells in the placenta of preeclampsia patients.

Preeclampsia is a pregnancy-specific disease which is characterized by abnormal placentation, endothelial dysfunction, systemic inflammation and disruption of the immune system. The goal of this study was to characterize the PD-1/PD-L1 system, an important immune checkpoint system, on macrophages and Hofbauer cells (HBC) in the placenta of preeclamptic patients. The expression of the macrophage markers CD68 and CD163 as well as the proteins PD1 and PD-L1 in the placenta of preeclamptic patients was examined by immunohistochemistry and immunofluorescence in comparison to the placenta of healthy pregnancies. The numbers of CD68-positive and CD163-positive macrophages were significantly downregulated in the decidua (p = 0.021 and p = 0.043) and in the chorionic villi (p < 0.001 and p < 0.001) of preeclamptic patients. The majority of macrophages in the decidua and the chorionic villi were identified to be CD163-positive, indicating a predominantly M2-polarisation. The expression of PD1 on maternal macrophages of the decidua (p < 0.001) and on Hofbauer cells (p < 0.001) was shown to be significantly lower in preeclampsia. Looking at the protein PD-L1 the expression was proven to be downregulated on maternal macrophages in the decidua of preeclamptic patients (p = 0.043). This difference was only caused by a downregulation of PD-L1 expression in male offspring (p = 0.004) while there was no difference in female offspring (p = 0.841). The variation of the immune checkpoint molecules PD1 and PD-L1 in preeclampsia might play an important role in the development of inflammation seen in preeclamptic patients. It might thereby be an important target in the therapy of preeclampsia.

Obesity in pregnancy is associated with macrophage influx and an upregulated GRO-alpha and IL-6 expression in the decidua.

About one third of all reproductive-aged women are affected by obesity. Maternal obesity is linked to an adverse outcome for both mother and child. The expression of the pro-inflammatory IL-6 and GRO-alpha as well as the infiltration of macrophages in the placenta of obese, non-diabetic pregnancies was examined by immunohistochemistry in comparison to the placenta of normal weight women. In obese pregnancies the influx of macrophages was significantly increased (p = 0.012). The protein expression of IL-6 and GRO-alpha was significantly elevated (p = 0.036 and p < 0.001, respectively) in the decidua of adipose females.

Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases.

PURPOSE: Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody-drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. METHODS: This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. RESULTS: In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. CONCLUSION: HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important.

Optimized process quality in certified breast centers through adherence to stringent diagnostic and therapeutic algorithms effects of structural as well as socio-demographic factors on start of therapy.

PURPOSE: An increasing incidence of breast cancer can be observed worldwide. Since a delay of therapy can have a negative impact on prognosis, timely cancer care is an important quality indicator. By receiving treatment at a certified breast cancer center, the patient has the best chance of treatment in accordance with guidelines and the best prognosis. The identification of risk factors for a delay of therapy is of central importance and should be the basis for a continuous optimization of treatment at breast cancer centers. METHODS: This retrospective study included women with breast cancer (primary diagnosis, relapse, or secondary malignancy) at the University Hospital Würzburg in 2019 and 2020. Data were retrieved from patients' records. Correlations and regression analyses were performed to detect potential risk factors for treatment delay. RESULTS: Patients who received the histological confirmation of breast cancer at an external institution experienced a later therapy start than those patients who received the histological confirmation at the University Hospital Würzburg itself. (35.7 vs. 32.2 days). The interval between histological confirmation and the first consultation at the University Hospital Würzburg correlated statistically significant with age, distress and distance to the hospital. CONCLUSION: Patients with an in-house diagnosis of breast cancer are treated more quickly than those whose diagnosis was confirmed in an external institution. We identified factors such as increased age, greater distance to the hospital as well as increased distress to prolong the time until start of oncological treatment. Intensified patient care should be offered to these subgroups.

High RIG-I and EFTUD2 expression predicts poor survival in endometrial cancer.

PURPOSE: Endometrial cancer is the most common gynecological malignancy. The helicase RIG-I, a part of the innate immune system, and EFTUD2, a splicing factor which can upregulate RIG-I expression, are shown to influence tumor growth and disease progression in several malignancies. For endometrial cancer, an immunogenic cancer, data about RIG-I and EFTUD2 are still missing. The aim of this study was to examine the expression of RIG-I and EFTUD2 in endometrial cancer. METHODS: 225 specimen of endometrial cancer were immunohistochemically stained for RIG-I and EFTUD2. The results were correlated to clinicopathological data, overall survival (OS) and progression-free survival (PFS). RESULTS: High RIG-I expression correlated with advanced tumor stages (FIGO: p = 0.027; pT: p = 0.010) and worse survival rates (OS: p = 0.009; PFS: p = 0.022). High EFTUD2 expression correlated to worse survival rates (OS: p = 0.026; PFS: p < 0.001) and was determined to be an independent marker for progression-free survival. CONCLUSION: Our data suggest that the expression of RIG-I and EFTUD2 correlates with survival data, which makes both a possible therapeutic target in the future.

The Pregnancy Zone Protein (PZP) is significantly downregulated in the placenta of preeclampsia and HELLP syndrome patients.

Preeclampsia is characterized by maternal hypertension and multi-organ injury. Elongation factor Tu GTP binding domain containing 2 (EFTUD 2) and the Pregnancy Zone Protein (PZP) seem to be important immunomodulatory factors in early gestation. Little is known about the role of EFTUD2 and PZP in disorders of late pregnancy like preeclampsia, HELLP syndrome and intrauterine growth restriction (IUGR). PZP, EFTUD2 and hCG expression was investigated by immunohistochemistry in the placenta of healthy pregnancies (n = 13), preeclampsia (n = 11), HELLP syndrome (n = 12) and IUGR (n = 8). Correlation analysis of protein expression was performed via Spearman correlation coefficient. The characterization of EFTUD2 and PZP expressing cells was evaluated by double-immunofluorescence. After cultivation of the chorion carcinoma cell line BeWo with hCG the expression of PZP and EFTUD2 was investigated by immunocytochemistry. PZP expression was significantly downregulated in the syncytiotrophoblast (ST) and extravillous trophoblast (EVT) of preeclampsia (ST: p 0.001, EVT:p = 0.019) and HELLP syndrome (ST: p = 0.004, EVT: p = 0.035). The expression of EFTUD2 was significantly lower in preeclampsia (ST: p = 0.003, EVT: p 0.001), HELLP syndrome (ST: p = 0.021, EVT: = 0.001, EVT: p = 0.001). EVTs were identified as EFTUD2 and PZP expressing cells by double-immunofluorescence. Stimulation of BeWo chorion carcinoma cells with hCG 1000 IU/mL for 48 h resulted in a significant upregulation of PZP expression (p = 0.027). Our results indicate that PZP and EFTUD2 might be involved in the development of placental dysfunction in preeclampsia and HELLP syndrome.

Evaluating a novel 3D printed model for simulating Large Loop Excision of the Transformation Zone (LLETZ).

BACKGROUND: Electrosurgical excisions are common procedures for treating cervical dysplasia and are often seen as minor surgeries. Yet, thorough training of this intervention is required, as there are considerable consequences of inadequate resections, e.g. preterm birth, the risk of recurrence, injuries and many more. Unfortunately, there is a lack of sufficiently validated possibilities of simulating electrosurgeries, which focus on high fidelity and patient safety. METHODS: A novel 3D printed simulator for examination and electrosurgical treatment of dysplastic areas of the cervix was compared with a conventional simulator. Sixty medical students experienced a seminar about cervical dysplasia. Group A underwent the seminar with the conventional and Group B with the novel simulator. After a theoretical introduction, the students were randomly assigned by picking a ticket from a box and went on to perform the hands-on training with their respective simulator. Each student first obtained colposcopic examination training. Then he or she performed five electrosurgical excisions (each). This was assessed with a validated score, to visualize their learning curve. Furthermore, adequate and inadequate resections and contacts between electrosurgical loop and vagina or speculum were counted. Both groups also assessed the seminar and their simulator with 18 questions (Likert-scales, 1-10, 1 = strongly agree / very good, 10 = strongly disagree / very bad). Group B additionally assessed the novel simulator with four questions (similar Likert-scales, 1-10). RESULTS: Nine of 18 questions showed statistically significant differences favoring Group B (p < 0.05). Group B also achieved more adequate R0-resections and less contacts between electrosurgical loop and vagina or speculum. The learning curves of the performed resections favored the novel simulator of Group B without statistically significant differences. The four questions focusing on certain aspects of the novel simulator indicate high appreciation of the students with a mean score of 1.6 points. CONCLUSION: The presented novel simulator shows several advantages compared to the existing model. Thus, novice gynecologists can be supported with a higher quality of simulation to improve their training and thereby patient safety.

The role of Interleukin-18 in recurrent early pregnancy loss.

BACKGROUND: A successful pregnancy is a unique and complex immunological state. Cytokines seem to be crucial for the implementation of a tolerogenic environment at the feto-maternal interphase towards the semi-allogenic fetus. Importantly, the switch from a Th1- to a Th2 cytokine profile might play a key role. Interestingly, Interleukin-18 (IL-18) can induce either Th1 or Th2 immune response depending on the local cytokine environment. Therefore, this study investigates the expression of IL-18 in early pregnancy loss. PATIENTS AND METHODS: The TaqMan® Human Cytokine Network Array was carried out with placental tissue of patients with healthy pregnancies (n = 15) and recurrent miscarriage (n = 15) in order to investigate differences in IL-18 mRNA expression. Immunohistochemical staining was applied to examine the IL-18 protein expression in the syncytiotrophoblast and decidua of healthy pregnancies (n = 15), spontaneous (n = 12) and recurrent miscarriage (n = 9). The characterization of IL-18 expressing cells in the decidua was evaluated by double-immunofluorescence. Correlation analysis between IL-18 protein expression and clinical data of the study population was performed via spearman correlation coefficient. RESULTS: Gene expression analysis revealed a 4,9-times higher expression of IL-18 in recurrent miscarriage patients. IL-18 protein expression was significantly upregulated only in the decidua in the recurrent miscarriage group (p = 0.031). We did not observe significant changes of IL-18 protein expression in spontaneous miscarriage specimens when compared to healthy controls (p = 0.172). Double-immunofluorescence identified decidual stroma cells as IL-18 expressing cells. Correlation analysis showed a significant negative correlation of IL-18 protein expression and gestational age in healthy controls (r = -,745, p = 0.034). Also, a positive correlation of IL-18 and maternal age was observed in patients suffering from recurrent pregnancy loss (r =, 894, p = 0.041). CONCLUSION: Our results indicate that IL-18 expression might be necessary in early gestation but requires a tight regulation for a successful ongoing pregnancy. In the present study we observed that a significant upregulation of IL-18 in the decidua was restricted to patients with recurrent miscarriage and therefore might be interesting as a diagnostic marker. Further studies need to evaluate the exact pathophysiological mechanisms.

Total Mesometrial Resection With (Neo)Adjuvant Chemotherapy in Locally Advanced Cervical Cancer: A Tumor Response Score.

BACKGROUND/AIM: There is a lack of data concerning the surgical treatment of locally advanced squamous cell carcinoma of the uterine cervix (LACC) with neoadjuvant and adjuvant chemotherapy (NACT, ACT) as well as total mesometrial resection (TMMR). The aim of the study was to present a novel approach for treating LACC using a tumor response score for NACT. PATIENTS AND METHODS: A total of 12 patients with LACC were treated with NACT [cisplatin, ifosfamide, paclitaxel (TIP)], TMMR and ACT containing TIP. To measure the response during NACT, we scored i) the maximum tumor diameter (maxTD) in gynecological examination, ii) the MRI for radiologic maxTD, iii) the tumor volume and iv) the squamous cell carcinoma antigen before and after two applications of TIP. RESULTS: TIP reduced all score-parameters in 10 of 12 patients (p<0.005). We found a possible reduction of lymph node metastasis in 72.7%. The proposed score detected sufficient and insufficient tumor response. CONCLUSION: TIP followed by TMMR with ACT could be a possibility for patients denying radiochemotherapy. The tumor response score can detect patients with inadequate benefit from NACT.

The decidual expression of Interleukin-7 is upregulated in early pregnancy loss.

BACKGROUND: Maternal immunological rejection of the semi-allogenic fetus is discussed as one of the significant factors involved in early pregnancy loss. An array of cytokines secreted by both maternal and fetal cells is involved in generating a delicate maternal immune tolerance. Interleukin-7 (IL-7) is discussed to play a key role in pro-inflammatory processes, but there is still limited insight into the pathophysiological input on placentation and embryonic development in early pregnancy loss. PATIENTS AND METHODS: Cytokine level differences were identified with quantitative real-time PCR in placental tissue from spontaneous abortions (SA) (n = 18), recurrent spontaneous abortions (RSA) (n = 15), and healthy pregnancies (n = 15) at gestational weeks 7 to 14. Protein expression of IL-7 in the decidua was investigated by immunohistochemistry. IL-7-expressing cells were identified with double-immunofluorescence. RESULTS: Decidua of women with RSA expressed almost 51-times higher values of IL-7 in gene expression analysis. Immunohistochemistry identified a significant upregulation of IL-7 in the decidua of RSA specimens (p = .013) and in the decidua of women with SA (p = .004). Double-immunofluorescence confirmed decidual stroma cells as IL-7-expressing cells. CONCLUSION: Significantly elevated IL-7 values in the decidua of spontaneous and recurrent miscarriages imply a crucial role of the cytokine in the signaling at the feto-maternal interface of the placenta. An overexpression of IL-7 could result in early pregnancy loss by inducing a pro-inflammatory environment. Proven to be valuable in other autoimmune diseases, targeting IL-7 signaling therapeutically may prove to be a very beneficial treatment option for RSA patients.

Interleukin-1 beta is significantly upregulated in the decidua of spontaneous and recurrent miscarriage placentas.

BACKGROUND: Pregnancy is an extraordinarily complex immunological process. For successful pregnancy maintenance the maternal immune system must adapt to and tolerate the semi-allogenic fetus at the fetomaternal interface of the placenta. This balance is regulated by cytokines with a predominant T helper 2 (Th-2) system and a suppressed inflammatory T helper 1 (Th-1) response. This study investigates the role of the Th-1 pro-inflammatory cytokine Interleukin-1 beta (IL-1ß) and its role in early pregnancy loss. PATIENTS AND METHODS: In order to identify differences in IL- ß levels a TaqMan® Human Cytokine Network Array, with placental tissue obtained from patients with healthy pregnancies (n = 15) and recurrent miscarriage (n = 15), was carried out. Protein expression of IL-1ß in the decidua of healthy pregnancies (n = 15), spontaneous (n = 18) and recurrent miscarriages (n = 15), was investigated by immunohistochemistry. The identification of IL-1ß expressing cells in the decidua was done with double-immunofluorescence. RESULTS: Gene expression analysis identified a nearly 54-times higher expression of IL-1ß in placental tissue of patients suffering from recurrent abortion. Immunohistochemistry confirmed a significant upregulation of IL-1ß in the decidua of recurrent miscarriage specimens (p = 0.01) as well as in the decidua of women with spontaneous abortion (p = 0.001). Double-immunofluorescence identified decidual stoma cells as IL-1ß expressing cells. CONCLUSION: Significant upregulation of IL-1ß may be associated with an imbalanced immune system and a procoagulant state that could be responsible for early pregnancy loss. These results provide new evidence of the complex interplay of IL-1ß at the fetomaternal interface and its crucial role in miscarriage processes.

Pregnancy Zone Protein (PZP) is significantly upregulated in the decidua of recurrent and spontaneous miscarriage and negatively correlated to Glycodelin A (GdA).

BACKGROUND: Pregnancy Zone Protein (PZP) is an immunosuppressive protein that is expressed by the placenta and has also been identified in immune cells. When PZP and Glycodelin A (GdA) are combined, they act synergistically to inhibit Th-1 immune response. Little is known about its combined expression and role in normal and disturbed first trimester pregnancy. PATIENTS AND METHODS: We investigated the expression of PZP and GdA in placental tissue obtained from spontaneous miscarriage (SM) (n = 19) and recurrent miscarriage (RM) (n = 17) at gestational weeks 6-13 by immunohistochemistry and on mRNA-level by either TaqMan PCR or in situ hybridization. Placental tissue from legal terminations of healthy pregnancies (n = 15) served as control group. Immunofluorescence double staining was used to analyse the combined expression of PZP and GdA in decidual tissue. RESULTS: The protein level of PZP was significantly increased in decidual stroma of SM samples compared to the decidua of control specimens and also significantly upregulated in the decidual stroma cells in the RM group. Concerning GdA, the decidual stroma revealed a significantly decreased protein level in the group with spontaneous abortions than in the group with healthy pregnancies. There was also a significant downregulation of GdA in the decidual stroma of RM samples compared to the control group. We observed a significant negative correlation of PZP and GdA in decidual stromal tissue of recurrent abortion. We could confirm the staining results for PZP as well as for GdA on mRNA level. Both proteins are co-localized in decidual stroma as analysed by immunofluorescence double staining. CONCLUSION: A balanced expression of GdA and its carrier protein PZP in the decidua seems crucial for a successful ongoing pregnancy. According to our data, these immunosuppressive proteins are co-localized in the decidual tissue and show a negative correlation only in patients suffering from recurrent abortion.

Spliceosome protein EFTUD2 is upregulated in the trophoblast of spontaneous miscarriage and hydatidiform mole.

BACKGROUND: Elongation factor Tu GTP binding domain containing 2 (EFTUD2) is an alternative splicing factor that modulates cell differentiation and activation processes. EFTUD2 is known to modulate immune responses and mutation of the EFTUD2-gene lead to fetal malformation. Little is known about its expression and role in normal and disturbed first trimester pregnancy. PATIENTS AND METHODS: We investigated the expression of EFTUD2 in placental tissue obtained from patients with normal (n = 14), spontaneous miscarriage (n = 15) and molar (n = 14) pregnancy by immunohistochemistry. The expression of EFTUD2 was correlated on the protein level with known immune modulatory proteins like pregnancy zone protein (PZP) and in addition with human chorionic gonadotropin (hCG). Furthermore, we analysed the EFTUD2 and PZP expression in vitro after stimulation of the chorioncarcinoma cell line JEG-3 with hCG. RESULTS: EFTUD2 is significantly upregulated in the syncytiotrophoblast of spontaneous miscarriage (p = 0.003) and molar pregnancy (p = 0.003) compared to week of gestation-adjusted normal first trimester placentas. PZP is negatively correlated (p = 0.021) to EFTUD2 in the syncytiotrophoblast and is therefore significantly downregulated in miscarriage (p = 0.028) and mole pregnancy (p = 0.006). In addition, hCG is positively correlated to EFTUD2 in mole pregnancy. The addition of hCG to chorioncarcinoma cell lines JEG-3 in vitro stimulated EFTUD2 expression in these cells (p = 0.027). CONCLUSION: Regulation of alternative splicing seems crucial for a successful ongoing pregnancy. The up-regulated elongation factor EFTUD2 may have a critical role in miscarriage.

Nectin-2 in ovarian cancer: How is it expressed and what might be its functional role?

Nectin-2 is an adhesion molecule that has been reported to play a role in tumor growth, metastasis and tumor angiogenesis. Herein, we investigated Nectin-2 in ovarian cancer patients and in cell culture. Tumor as well as peritoneal biopsies of 60 ovarian cancer patients and 22 controls were dual stained for Nectin-2 and CD31 using immunohistochemistry. Gene expression of Nectin-2 was quantified by real-time PCR and differences analyzed in relation to various tumor characteristics. In the serum of patients, vascular endothelial growth factor (VEGF) was quantified by ELISA. Effect of VEGF on Nectin-2 expression as well as permeability was investigated in HUVEC. In tumor biopsies, Nectin-2 protein was mainly localized in tumor cells, whereas in peritoneal biopsies, clear colocalization was found in the vasculature. T3 patients had a significantly higher percentage of positive lymph nodes and this correlated with survival. Nectin-2 was significantly upregulated in tumor biopsies in patients with lymph node metastasis and with residual tumor >1 cm after surgery. Nectin-2 expression was significantly suppressed in the peritoneal endothelium of patients associated with significantly increased VEGF serum levels. In cell culture, VEGF stimulation led to a significant downregulation of Nectin-2 which was reversed by VEGF-inhibition. In addition, Nectin-2 knockdown in endothelial cells was associated with significantly increased endothelial permeability. Nectin-2 expression in ovarian cancer may support tumor cell adhesion, leading to growth and lymph node metastasis. In addition, VEGF-induced Nectin-2 suppression in peritoneal endothelium may support an increase in vascular permeability leading to ascites production.