The role of E-Cadherin expression in primary site of breast cancer.

PURPOSE: The tumour's ability to metastasize is the major cause for fatal outcomes in cancer diseases. In breast cancer, aberrant E-Cadherin expression has been linked to invasiveness and poor prognosis. METHOD: We assessed expression of E-Cadherin by immunohistochemistry in primary tumour tissue from 125 female breast cancer patients. Staining intensities were analysed using the immunoreactive score (IRS). We investigated E-Cadherin expression and its associations with clinicopathological parameters (age, tumour size, lymph node status, grade, hormone receptors, Her2 Status) as well as with recurrence and survival. RESULTS: Increased, rather than aberrant E-Cadherin expression was found and was associated with poor outcome (p = 0.046). Our data show an association between elevated E-Cadherin in primary tumour tissue and an unfavourable negative prognosis in patients. CONCLUSION: This association was somehow unexpected as loss of E-Cadherin has long been regarded as a prerequisite for development of invasiveness and metastases. Our findings support the notion that E-Cadherin promotes, rather than suppresses, development of metastasis and invasiveness.

Prevention of Cervical Cancer: Guideline of the DGGG and the DKG (S3 Level, AWMF Register Number 015/027OL, December 2017) - Part 1 with Introduction, Screening and the Pathology of Cervical Dysplasia.

Aims Annual opportunistic screening for cervical carcinoma has been carried out in Germany since 1971. The creation of this S3 guideline meets an important need, outlined in the National Cancer Plan, with regard to screening for cervical cancer, as the guideline aims to provide important information and support for planned organized screening for cervical cancer in Germany. Methods With the financial support of German Cancer Aid, 21 professional societies developed evidence-based statements and recommendations (classified using the GRADE system) for the screening, management and treatment of precancerous conditions of the cervix. Two independent scientific institutes compiled systematic reviews for this guideline. Recommendations The first part of this short summary presents the pathological basis and considers various questions related to screening for cervical cancer. As also reported in earlier reviews, the meta-analysis by Kleijnen Systematic Reviews showed that HPV-based screening offers better protection against invasive cervical cancer compared to cytology-based screening. The authors of this guideline therefore recommend - in accordance with the guideline of the Joint National Committee of Germany (Gemeinsamer Bundesauschuss, G-BA) - that women aged 35 and above should be examined at regular intervals (at least every 3 years) and undergo HPV-based screening. Co-testing can also be carried out. Women between the ages of 20 and 35 should have cytological screening every 2 years.

Prevention of Cervical Cancer: Guideline of the DGGG and the DKG (S3 Level, AWMF Register Number 015/027OL, December 2017) - Part 2 on Triage, Treatment and Follow-up.

Aims Annual opportunistic screening for cervical carcinoma has been done in Germany since 1971. The creation of this S3 guideline meets an important need, outlined in the National Cancer Plan, with regard to screening for cervical cancer, as this guideline aims to provide important information and support for planned organized screening for cervical cancer in Germany. Methods With the financial support of German Cancer Aid, 21 professional societies developed evidence-based statements and recommendations (classified using the GRADE system) for the screening, management and treatment of precancerous conditions of the cervix. Two independent scientific institutes compiled systematic reviews for this guideline. Recommendations The second part of this short summary deals with the triage, treatment and follow-up care of cervical dysplasia. With regard to those women who do not participate in screening, the guideline authors recommend sending out repeat invitation letters or an HPV self-collection kit. Colposcopy should be carried out for further investigation if cytology findings are Pap II-p and HPV test results are positive or if the results of an HPV 16 or HPV 18 screening test are positive. A single abnormal Pap smear should be triaged and investigated using HPV testing or p16/Ki67 dual staining.

TA-MUC1 as detected by the fully humanized, therapeutic antibody Gatipotzumab predicts poor prognosis in cervical cancer.

BACKGROUND: Gatipotuzumab is a fully humanized antibody which was designed to detect a cancer-specific glyco-modification of MUC1 (termed 'TA-MUC1') and which was optimized to effectively trigger antibody-dependent-cell-mediated cytotoxicity (ADCC) in cancer cells. Clinical trials investigating therapeutic efficacy of this antibody have been published recently. The current analysis aimed to determine whether TA-MUC1-as detected by Gatipotuzumab-is expressed in cervical cancer tissue and whether binding of Gatipotuzumab is associated with clinico-pathological variables including recurrence free (RFS) and overall survival (OS). METHODS: Cervical cancer tissue (n = 250) was stained for TA-MUC1 using Gatipotuzumab employing a standardized immunohistochemistry protocol. Staining was scored by applying the IR-score. Results were binarized and tested for association to clinico-pathological parameters. RESULTS: TA-MUC1 as stained by Gatipotuzumab was detected in 188 (75.2%) out of the 250 cervical cancer cases investigated. Expression of TA-MUC1 was restricted to cancer cells and was positively correlated with viral oncoprotein E6. Membrane staining of TA-MUC1 predicted significantly reduced RFS and OS. Importantly, expression of TA-MUC1 at the cell surface identified a group of early stage cervical cancer patients with exceptional short RFS and OS. CONCLUSIONS: We report TA-MUC1-the antigen detected by Gatipotzumab-to be widely expressed in cervical cancer tissue and to localize to the cell membrane. The latter is seen as a pre-requisite to target this epitope by antibody-drug conjugates or antibodies eliciting ADCC. Since especially, membrane localization of TA-MUC1 predicted poor prognosis, evaluating Gatipotuzumab for its therapeutic efficacy in cervical cancer may turn attractive.

The G protein-coupled estrogen receptor (GPER/GPR30) may serve as a prognostic marker in early-stage cervical cancer.

BACKGROUND: Estrogen signalling is transmitted via various receptors and multiple intracellular signalling pathways. Estrogen receptor alpha (ERα)-mediated transcription of target genes has been demonstrated to be closely linked to human papilloma virus (HPV)-induced carcinogenesis in case of cervical cancer. So far, the role of non-genomic estrogen signals in cervical cancer, e.g. transmitted by the G protein-coupled estrogen receptor (GPER) remains to be rather elusive. Today's knowledge on the role of GPER in cervical cancer is sparse and-to the best of our knowledge-GPER has not been investigated in context with clinicopathological parameters or prognosis of cervical cancer. Therefore, the current study investigated whether GPER is expressed in cervical cancer tissue. Further, GPER was correlated to clinicopathological parameters, tissue markers of cervical carcinogenesis and to patient overall and recurrence-free survival. MATERIALS AND METHODS: Cervical cancer tissue was collected from 156 patients during surgery between 1993 and 2002. GPER immunostaining was performed on all the cases and correlated to clinicopathological data. More than half of all patients were diagnosed at advanced stage (FIGO II-IV 93/156; 59.6%) of disease. The large majority of patients presented with tumours of intermediate or high grade (G2-3 140/152, 92.1%). 22 cervical cancer-related deaths (22/156, 14.1%) were documented during the follow-up period. RESULTS: GPER was detected in various subcellular staining patterns. In 129/156 (82.7%) cases GPER was expressed in the tumour cell cytoplasm (GPERcyt). GPER immunopositivity at the cell membrane (GPERmem) was found in 114/156 (73.1%) cases. While co-occurrence of both membrane and cytoplasmic staining (GPERcyt + GPERmem) was detected in the majority of tissue samples (101/156; 64.7%), only few cases (14/156, 9.0%) were classified as not expressing GPER at all. GPERcyt was positively correlated with tumour grade. Statistical associations of GPER and both p16 and p53 were detected. Finally, immunopositivity of GPERcyt was predictive for favourable overall as well as recurrence-free survival in cervical cancer of early stage (FIGO I). CONCLUSION: This retrospective study reports GPERcyt to be associated with improved overall and recurrence-free survival in early-stage cervical cancer. Further investigations are needed thus to determine whether this observation may be of clinical impact. Interestingly, Raloxifene-a GPER-activating selective estrogen receptor modulator-has recently been demonstrated to be preventive for cervical cancer relapse in mice. Whether this effect is only reliant on raloxifene blocking ERα or may also be related to activation of GPER remains to be determined.

Influence of Circulating Tumour Cells on Production of IL-1α, IL-1ß and IL-12 in Sera of Patients with Primary Diagnosis of Breast Cancer Before Treatment.

BACKGROUND: Circulating tumour cells (CTCs) have been found to be a prognostic marker for reduced disease-free survival (DFS), distant DFS, breast cancer-specific survival, and overall survival (OS) before the start of systemic treatment. Determination of CTCs with the CellSearch System (Veridex, Raritan, NJ, USA) is a valuable but time-consuming and costly method. Therefore, the aim of this study was to evaluate cytokine profiles as a marker for CTC involvement. PATIENTS AND METHODS: Patients chosen for this study were defined as women with breast cancer who agreed to participate in the phase I SUCCESS study. CTC analysis, the blood sampling time points, and the methodology were prospectively designed, and the prognostic value of the CTCs was defined as a scientific objective of the study protocol. A total of 100 patients positive for CTCs and an additional 100 patients negative for CTCs were matched into pairs. Matching criteria were histopathological grading, lymph node status, hormone receptor type, TNM classification and survival vs. tumour associated death. Commercial enzyme-linked immunosorbent assay (ELISA) was used to screen the blood serum samples for the Th1 cytokines: interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12), IL-1α, IL-1ß, IL-2 and IL-18. The correlation of cytokine levels to the matching criteria listed above were analyzed with the Spearman correlation coefficient and the Mann-Whitney-U rank-sum test. RESULTS: The IL-1α level was significantly lower in the CTC-positive patient group (p=0.043) but significantly higher in the CTC-negative progesterone receptor-positive collective (p=0.029). Furthermore, in patients who survived, significantly higher IL-12p40 levels were found in those with lymph node involvement (p=0.041) and those with triple-negative breast cancer (p=0.043). Of patients who died, those with oestrogen receptor-negative disease had higher IL-1α (p=0.050) and higher IL-1ß (p=0.034) levels. Moreover, of those who died, those with triple-negative breast cancer had significantly higher IL-1α levels (p=0.033). In patients with grade 2 tumour, patients with HER2/neu expression had significantly higher IFN-γ levels (p=0.031) and those with no lymph node involvement had significantly higher IL-1α levels (p=0.014). In the collective with grade 3 tumour, patients with progesterone receptor-negative disease had significantly higher IL12p70 concentrations (p=0.048), while those with triple-negative breast cancer had lower IL12p40 levels (p=0.033). CONCLUSION: Regarding CTC involvement, we speculate that IL-1α might be a marker for the release of tumour cells into the circulation and not into the lymphatic system. In addition, IL-1α like IL-1ß appears to be related to CTC release in patients with breast cancer.

Real-Time qPCR-Based Detection of Circulating Tumor Cells from Blood Samples of Adjuvant Breast Cancer Patients: A Preliminary Study.

BACKGROUND: Circulating tumor cells (CTCs) are cells that detach from a primary tumor, circulate through the blood stream and lymphatic vessels, and are considered to be the main reason for remote metastasis. Due to their origin, tumor cells have different gene expression levels than the surrounding blood cells. Therefore, they might be detectable in blood samples from breast cancer patients by real-time quantitative polymerase chain reaction (RT-qPCR). MATERIALS AND METHODS: Blood samples of healthy donors and adjuvant breast cancer patients were withdrawn and the cell fraction containing white blood cells and tumor cells was enriched by density gradient centrifugation. RNA was isolated and reverse transcribed to cDNA, which was then used in TaqMan real-time PCR against cytokeratin (CK)8, CK18 and CK19. 18S and GAPDH were used as controls. RESULTS: All 3 CKs were, on average, found to be significantly higher expressed in adjuvant breast cancer samples compared to negative controls, probably due to the presence of CTCs. Unfortunately, gene expression levels could not be correlated to tumor characteristics. CONCLUSIONS: RT-qPCR could make up a new approach for the detection of CTCs from blood samples of breast cancer patients, but a correlation of the PCR data to gold standard methods in CTC detection would help to further improve the informative value of the qPCR results.

Determination of Interleukin-4, -5, -6, -8 and -13 in Serum of Patients with Breast Cancer Before Treatment and its Correlation to Circulating Tumor Cells.

BACKGROUND/AIM: Circulating tumor cells (CTCs) in women with breast cancer are an indication of prognosis before starting systemic treatment. The aim of this study was the evaluation of cytokine profiles as marker for CTC involvement. MATERIALS AND METHODS: The analysis of CTCs, the time of blood sampling and the methodology were prospectively designed. There were two groups of patients: 100 women with a positive result for presence of CTCs and 100 women negative for CTCs. These groups were matched into pairs by tumor factors and survival/death. A multi-array ELISA was used to screen T-helper cell (Th) 2 cytokines. The results were analyzed by Spearman correlation coefficient and Mann-Whitney U-test. RESULTS: In patients who were CTC-negative, expression of interleukin-8 (IL-8) and IL-13 was increased (p=0.017 and p=0.045, respectively) if they were negative for progesterone receptor. In patients who died from their tumor, correlation between hormone receptor negativity and an increase in IL-4 was found. IL-5 was increased in patients with lymph node-positive and human epidermal growth factor receptor 2 (HER2)-positive disease (p=0.042). Moreover IL-4 was increased in patients with progesterone receptor-positive and estrogen receptor-negative status (p=0.024). Furthermore, the level of IL-6 was increased in patients with tumor grade G3 without progesterone receptor expression. CONCLUSION: Th2 cytokines are significantly modified in patients who are CTC-negative and progesterone receptor-positive. We suppose that an increase of IL-4 depends on hormone receptor status. In literature, a correlation between IL-4 and resistance to apoptosis is described. We suspect that IL-4 is responsible for the poor outcome of these cases.

FOXP3+ Cells Recruited by CCL22 into Breast Cancer Correlates with Less Tumor Nodal Infiltration.

BACKGROUND: Regulatory T-cells (Tregs) are a T-cell subpopulation with suppressive capacities, which are specifically attracted by C-C motif chemokine 22 (CCL22). Treg infiltration of tumors is associated with a poor prognosis in many patients. We aimed to investigate whether CCL22 is expressed in human breast cancer and whether its presence is associated with Treg infiltration. MATERIALS AND METHODS: Eighty paraffin-embedded human breast cancer samples were stained for CCL22 and for the Treg-specific transcription factor forkhead box P3 (FOXP3). Expression was evaluated in a semi-quantitative manner. RESULTS: FOXP3(+) cells infiltrated 50% of the breast tumors. Moreover, Treg infiltrated 93% of the tertiary lymphoid structures. CCL22 expression positively correlated with FOXP3(+) cell infiltration into the tertiary lymphoid structures. CONCLUSION: Our results demonstrate that CCL22 expression correlates with infiltration by FOXP3(+) cells. Interestingly, Treg presence negatively correlated with positive nodal status. In addition to their unfavorable role as mediators of evasion from antitumor immune response, Tregs might also have a beneficial role by reducing inflammation thereby limiting early tumor growth and spreading.

Expression of the Tumor-associated Mucin 1 Epitope Analyzed with the Humanized PankoMab-GEX™ Antibody in Malignant and Normal Tissues of the Head and Neck.

BACKGROUND: During neoplasia, glycosylation changes. In this setting, mucins, especially mucin 1 (MUC1), become carriers for oncofetal carbohydrates and relieve invasive growth. The recently described tumor-associated MUC1 epitope TA-MUC1 is primarily restricted to malignancies and is overexpressed in these tissues. The humanized monoclonal antibody PankoMab-GEX specifically recognizes TA-MUC1. MATERIALS AND METHODS: Laryngeal cancer specimens (n=125) and normal tissue of head and neck (n=7) were used in this study. Paraffin-embedded sections were incubated with PankoMab-GEX. Staining reaction was carried out using peroxidase (POD) labeling and diaminobenzidine (DAB). Breast cancer tissue was used as positive control and negative control used non-specific mouse IgM. Semi-quantitative evaluation by two independent double-blinded investigators, including a pathologist, used the immunoreactive score (IRS) of Remmele and Stegner. RESULTS: A total of 31 out of 125 laryngeal cancer specimens were classified as G1. Of these, 22 (71%) were completely negative for TA-MUC1, the remaining 9 showed very weak staining, with an IRS of 2. A total of 94 cases of cancer specimens were classified as G2 and G3; 34 of them were also negative, but 60 had an IRS of up to 9. All investigated normal tissue of the upper aerodigestive tract was completely negative for TA-MUC1. CONCLUSION: G1 tumors are completely negative or do not reach an IRS relevant range. The finding that G1 tumors are completely negative for TA-MUC1 or have IRS≤2 can be helpful for histopathological examination, especially concerning tumor grading. Therefore, this antibody holds great potential for use as a therapeutic antibody in laryngeal cancer.

Endometrial Adenocarcinoma: Analysis of Circulating Tumour Cells by RT-qPCR.

BACKGROUND: Endometrial adenocarcinoma is a frequently occurring cancer in women, accounting for 42,000 deaths every year. Despite treatment with standard therapy, occurrence of remote metastases and local recurrences is high. Through help of RT-qPCR minimal residual disease could be detected and characterized, facilitating therapeutic decision making. MATERIALS AND METHODS: A number of marker genes were first tested in model systems and genes that performed best, were consequently used for the examination of 13 blood samples from endometrial carcinoma patients. RESULTS: Cytokeratin 19 and MIG7 were chosen for the analysis in patient samples. Both genes were found up-regulated in small tumours and in one large tumour, but no statistical correlations could be revealed between expression levels of these two genes and tumour characteristics. CONCLUSION: There seems to be a coherence between gene expression and the stage of tumorigenesis, but the number of samples is still too small, to be able to obtain statistical significant differences.

New Marker Genes for Real-Time PCR-based Detection of Circulating Tumour Cells from Blood of Breast Cancer Patients.

BACKGROUND: The detection of circulating tumour cells (CTCs) from peripheral blood of cancer patients can be carried out by real-time PCR approaches using different gene expression levels of tumour cells and surrounding blood cells. MATERIALS AND METHODS: Potential marker genes were first analyzed in a model system and then applied to 20 blood samples of adjuvant breast cancer patients and gene expression levels were correlated to tumour characteristics. RESULTS: The mean of gene expression levels was found elevated for the four genes analyzed in the adjuvant breast cancer patient group in comparison to the samples of the group of healthy donors, but no correlation between gene expression and tumour characteristics could be detected as being statistically significant. CONCLUSION: The results demonstrated, that the employed methodology is functional, but has to be refined by certain approaches like simultaneously running a state-of-the-art system of CTC-detection comparing the results, and by an enlargement of patient collective and number of marker genes.

Immunocytochemical Characterization of Disseminated Tumour Cells from Bone Marrow of Breast Cancer Patients.

BACKGROUND: The occurrence of disseminated tumour cells in bone marrow of patients with breast cancer is linked to a worse prognosis. We present a method for DTC detection from bone marrow samples based on immunocytochemistry, using breast cancer-associated glycosylation molecules as markers for detection and characterization. MATERIALS AND METHODS: A double immunofluorescence staining of a pan-cytokeratin (CK) marker and either Tn or O-Acetyl-GD3 was carried out in artificial and patient bone marrow samples. RESULTS: The sample in which most cells stained positive for CK/Tn and CK/O-AC-GD3, was obtained from a patient who certainly had remote metastases. All other bone marrow samples showed heterogenous staining, so no correlation to tumour characteristics could be revealed. CONCLUSION: A certain characterization of tumour cells can be achieved by a double staining of bone marrow samples with CK and a glycosylation marker. For future studies, analysis should be extended to a larger patient collective and further examination of more glycosylation markers should be carried out.

The role of TF- and Tn-antigens in breast cancer metastasis.

Almost 40 years ago, researchers found out that the Thomsen-Friedenreich (TF) and the Thomsen nouvelle (Tn) antigens could be detected in carcinoma, but not in healthy tissue. A short time after that it became clear that TF and Tn are precursor molecules of the MN-blood group antigens. In normal tissue TF and Tn are coated by glycosyl structures, thereby forming the glycoproteins which are known to account for the MN-blood group, but in malignant tissue these molecules are uncovered.TF, which has an additional Galectin-residue compared to Tn, is correlated with a more favourable prognosis for patients. On the contrary, patients with Tn-bearing tissues have a worse prognosis for overall and progression-free survival. It is known that TF and Tn are involved in the adhesion of tumour cells to the endothelium via a mechanism recruiting Galectin-3 and MUC-1, which is the first step in metastasis formation. Furthermore, it became clear that this pathway can be blocked by a growing number of molecules, thereby creating ways of therapeutical intervention.

Glycosyltransferases as Markers for Early Tumorigenesis.

BACKGROUND: Glycosylation is the most frequent posttranslational modification of proteins and lipids influencing inter- and intracellular communication and cell adhesion. Altered glycosylation patterns are characteristically observed in tumour cells. Normal and altered carbohydrate chains are transferred to their acceptor structures via glycosyltransferases. Here, we present the correlation between the presence of three different glycosyltransferases and tumour characteristics. METHODS: 235 breast cancer tissue samples were stained immunohistochemically for the glycosyltransferases N-acetylgalactosaminyltransferase 6 (GALNT6), ß-1,6-N-acetylglucosaminyltransferase 2 (GCNT2), and ST6 (α-N-acetyl-neuraminyl-2,3-ß-galactosyl-1,3)-N-acetylgalactosamine α-2,6-sialyltransferase 1 (ST6GALNac1). Staining was evaluated by light microscopy and was correlated to different tumour characteristics by statistical analysis. RESULTS: We found a statistically significant correlation for the presence of glycosyltransferases and tumour size and grading. Specifically smaller tumours with low grading revealed the highest incidences of glycosyltransferases. Additionally, Her4-expression but not pHer4-expression is correlated with the presence of glycosyltransferases. All other investigated parameters could not uncover any statistically significant reciprocity. CONCLUSION: Here we show, that glycosyltransferases can identify small tumours with well-differentiated cells; hence, glycosylation patterns could be used as a marker for early tumourigenesis. This assumption is supported by the fact that Her4 is also correlated to glycosylation, whereas the activated form of Her4 does not show such a connection with glycosylation.

Glycosyltransferases as marker genes for the quantitative polymerase chain reaction-based detection of circulating tumour cells from blood samples of patients with breast cancer undergoing adjuvant therapy.

Altered glycosylation is a predominant feature of tumour cells; it serves for cell adhesion and detachment, respectively, and facilitates the immune escape of these cells. Therefore changes in the expression of glycosyltransferase genes could help to identify circulating tumour cells (CTCs) in the blood samples of cancer patients using a quantitative polymerase chain reaction (PCR) approach. Blood samples of healthy donors were inoculated with certain numbers of established breast cancer cell line cells, thus creating a model system. These samples were analysed by quantitative PCR for the expression of six different glycosyltransferase genes. The three genes with the best results in the model system were consecutively applied to samples from adjuvant breast cancer patients and of healthy donors. FUT3 and GALNT6 showed the highest increase in relative expression, while GALNT6 and ST3GAL3 were the first to reach statistically significant different ∆CT-values comparing the sample with and without addition of tumour cells. These three genes were applied to patient samples, but did not show any significant results that may suggest the presence of CTCs in the blood. Although the relative expression of some of the glycosyltransferase genes exhibited reasonable results in the model system, their application to breast cancer patient samples will have to be further improved, e.g. by co-analysis of patient blood samples by gold-standard methods.

Human placental growth hormone: a potential new biomarker in gestational trophoblastic disease.

OBJECTIVES: Gestational trophoblastic disease (GTD) involves a spectrum of abnormal proliferations arising from the placental villous trophoblast. Although the incidence is low, a biomarker with short serum half-life would be a major clinical advance to monitor surgical and medical treatment reducing the socioeconomic burden of multiple control visits as well as patient's anxiety. Placental growth hormone (hGH-V) plays an important role in the regulation of normal placental growth and has shown angiogenic effects. We aimed to determine by immunohistochemistry (IHC) whether hGH-V is expressed in GTD and whether it can be detected in the patient's blood for potential monitoring of surgical or medical treatment procedures. METHODS: Tissue and sera were collected from women undergoing treatment for GTD in a tertiary care university hospital. We evaluated partial and complete hydatidiform moles, invasive moles and choriocarcinoma, n=16. Trophoblast specimens were examined by a newly developed IHC set-up for hGH-V in addition to gross morphologic and histopathological examination. Serum samples were analyzed by a highly sensitive hGH-V specific immunoassay. RESULTS: hGH-V was localized in all entities of GTD to the syncytiotrophoblast by immunohistochemistry. Serum hGH-V was detected for the first time in GTD and was present in a high percentage of all analyzed entities. CONCLUSIONS: hGH-V can be detected in all entities of GTD by IHC as well as by serum analysis and may therefore serve as a novel biomarker for the disease. Its clinical utility in diagnosis of GTD and monitoring surgical or medical treatment needs to be determined in further studies.

Cervical conisation and the risk of preterm delivery: a retrospective matched pair analysis of a German cohort.

PURPOSE: Since the routine screening program for cervical dysplasia by Pap smear was established in the early 1970s, the rate of cervical cancer has continually dropped. Even if a high percentage of cervical dysplasia shows spontaneous restitution, the only effective therapy for persisting cervical dysplasia is local ablation or excision which might be associated with an increased risk of preterm delivery in subsequent pregnancies. However, data from German patients are missing, so the aim of this study was to evaluate the risk of preterm delivery and associated risks in a cohort of patients who had undergone cervical conisation previous to their pregnancies. METHODS: A total of 144 patients with conisation and subsequent pregnancy were identified. They were compared regarding week of delivery and preterm birth, fetal birth weight, fetal outcome and birth procedure (spontaneous delivery, vacuum extraction, primary and secondary cesarean section) with their matched partners. RESULTS: 135 patients with singleton pregnancies and their matched partners were evaluated in the final analysis. The mean age was 33.5 years. Comparing the case and control group we reached significant different results for week of delivery, but not preterm birth defined as birth prior to 37 weeks of gestation. CONCLUSIONS: Within this German cohort cervical conisation did not increase the risk for preterm birth, cesarean section or poor fetal outcome. We therefore conclude that cervical conisation is an appropriate method to treat women with cervical dysplasia also at childbearing age when prevention of cervical cancer is needed.

Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies.

The progesterone receptor (PR) has been increasingly well described as an important mediator of the pathogenesis and progression of breast cancer. The aim of this study was to assess the role of PR status as a prognostic factor in addition to other well-established prognostic factors. Data from five independent German breast cancer centers were pooled. A total of 7,965 breast cancer patients were included for whom information about their PR status was known, as well as other patient and tumor characteristics commonly used as prognostic factors. Cox proportional hazards models were built to compare the predictive value of PR status in addition to age at diagnosis, tumor size, nodal status, grading, and estrogen receptor (ER) status. PR status significantly increased the accuracy of prognostic predictions with regard to overall survival, distant disease-free survival, and local recurrence-free survival. There were differences with regard to its prognostic value relative to subgroups such as nodal status, ER status, and grading. The prognostic value of PR status was greatest in patients with a positive nodal status, negative ER status, and low grading. The PR-status adds prognostic value in addition to ER status and should not be omitted from clinical routine testing. The significantly greater prognostic value in node-positive and high-grade tumors suggests a greater role in the progression of advanced and aggressive tumors.

The G-protein-coupled estrogen receptor (GPER/GPR30) in ovarian granulosa cell tumors.

Ovarian granulosa cell tumors (GCTs) are thought to arise from cells of the ovarian follicle and comprise a rare entity of ovarian masses. We recently identified the G-protein-coupled estrogen receptor (GPER/GPR30) to be present in granulosa cells, to be regulated by gonadotropins in epithelial ovarian cancer and to be differentially expressed throughout folliculogenesis. Thus, supposing a possible role of GPER in GCTs, this study aimed to analyze GPER in GCTs. GPER immunoreactivity in GCTs (n = 26; n (primary diagnosis) = 15, n (recurrence) = 11) was studied and correlated with the main clinicopathological variables. Positive GPER staining was identified in 53.8% (14/26) of GCTs and there was no significant relation of GPER with tumor size or lymph node status. Those cases presenting with strong GPER intensity at primary diagnosis showed a significant reduced overall survival (p = 0.002). Due to the fact that GPER is regulated by estrogens, as well as gonadotropins, GPER may also be affected by endocrine therapies applied to GCT patients. Moreover, with our data supposing GPER to be associated with GCT prognosis, GPER might be considered as a possible confounder when assessing the efficacy of hormone-based therapeutic approaches in GCTs.