Prognostic value of HPV-mRNA in sentinel lymph nodes of cervical cancer patients with pN0-status.

Up to 15% of patients with cervical cancer and pN0-status develop recurrent-disease. This may be due to occult metastatic spread of tumor cells. We evaluated the use of human-papillomavirus-(HPV)-mRNA as a molecular marker for disseminated tumor cells to predict the risk of recurrence. For this prospective, multi-center prognostic study, 189 patients free of lymphnode metastases by conventional histopathology could be analyzed. All patients underwent complete lymphadenectomy. Of each sentinel node (SLN) a biopsy was taken for the detection of HPV-E6-E7-mRNA. Median follow-up time after surgery was 8.1 years. HPV-mRNA could be detected in SLN of 52 patients (27.5%). Recurrence was observed in 22 patients. Recurrence-free-survival was significantly longer for patients with HPV-negative SLN (log rank p = 0.002). By Cox regression analysis the hazard ratio (95%CI) for disease-recurrence was 3.8 (1.5 - 9.3, p = 0.004) for HPV-mRNA-positive compared to HPV-mRNA-negative patients. After adjustment for tumor size as the most influential covariate the HR was still 2.8 (1.1 - 7.0, p = 0.030). In patients with cervical cancer and tumor-free lymph nodes by conventional histopathology HPV-mRNA-positive SLN were of prognostic value independent of tumor size. Particularly, patients with tumors larger than 20mm diameter could possibly benefit from further risk stratification using HPV-mRNA as a molecular marker.

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.

Malnutrition and clinical outcome in gynecologic patients.

OBJECTIVES: An association between malnutrition and poor patient outcome has been established in various medical fields, but there is a general lack of data on the prevalence of malnutrition among gynecologic patients. Therefore an assessment of malnutrition is needed to detect malnourished patients in gynecology and initiate nutritional therapy if needed. STUDY DESIGN: Between 2011 and 2012 at our Gynecologic Department of a German University Hospital, 397 patients were evaluated regarding the risk of malnutrition and occurrence of complications during the time of hospitalization. The Nutritional Risk Screening (NRS) 2002 system was used to estimate the risk level for malnutrition. Of the 397 patients, 336 received surgery and 61 were treated conservatively. Patients were included independently of surgical intervention or age. The parameters for the clinical outcome were complications and time of hospitalization. RESULTS: A severe risk of malnutrition was diagnosed in 142 patients (35.8%) according to an NRS score of ≥3. Furthermore, a significantly higher complication rate among those patients who were at risk for malnutrition (NRS 1-2) (7.8%) or who were malnourished (NRS ≥3) (22.8%) was found (p<0.001 χ(2)). Regarding the length of stay (LOS) in hospital, the medial hospitalization time increased from 7 to 10 days when patients were malnourished (NRS score ≥3) (p<0.001). CONCLUSIONS: Malnutrition occurs frequently among gynecologic patients. Adequate perioperative nutritional supportive therapy should be considered in malnourished patients to improve their clinical outcome.

KRAS, BRAF genotyping reveals genetic heterogeneity of ovarian borderline tumors and associated implants.

BACKGROUND: Patients diagnosed for a serous ovarian borderline tumor (s-BOT) typically present with an excellent clinical outcome. However there have been controversies concerning the prognostic impact of so-called implants, an extra ovarian spread occurring alongside the s-BOT in certain cases. It remains obscure whether these implants actually resemble metastasis owning the same genetic pattern as the ovarian primary or whether they develop independently. METHODS: The current study, in the aim of further clarifying the genetic origin of implants, assessed BRAF/KRAS hot spot mutations and the p53/p16INK4a immunophenotype of s-BOTs and corresponding implants (n=49) of 15 patients by pyro-sequencing and immunostaining, respectively. RESULTS: A significant proportion of both s-BOTs and implants showed KRAS or BRAF mutation and though p16INK4a was found to be abundantly expressed, p53 immunoreactivity was rather low. When genotypes of BRAF/KRAS mutated s-BOTs and corresponding implants were compared no patient presented with a fully matching mutation profile of s-BOTs and all corresponding implants. CONCLUSIONS: The current study reveals genetic heterogeneity of s-BOTs and implants, as none of the markers examined showed constant reciprocity. Hence, our findings may assist to explain the different clinical presentation of s-BOTs and implants and might encourage to applying more individualized follow up protocols.

The G-protein coupled estrogen receptor (GPER/GPR30) is a gonadotropin receptor dependent positive prognosticator in ovarian carcinoma patients.

Follicle stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHCGR) were demonstrated to impact upon survival of patients suffering from epithelial ovarian cancer (EOC). Though structure wise the G-protein coupled estrogen receptor (GPER/GPR30) is related to FSHR/LHCGR, its prognostic impact in EOC remains controversial. We recently found that FSHR negative patients represent a specific EOC subgroup that may behave differently in respect to both treatment response and prognosis. Hence, the current study aimed to analyze how GPER may interact with the FSHR/LHCGR system in EOC and whether the prognostic significance of GPER in EOC cases (n=151) may be dependent on the FSHR/LHCGR immunophenotype of the tumor. Ovarian cancer cell lines were used to study how FSH and LH regulate GPER and whether GPER activation differentially affects in vitro cell proliferation in presence/absence of activated FSHR/LHCGR. In EOC tissue, GPER correlated with FSHR/LHCGR and was related to prolonged overall survival only in FSHR/LHCGR negative patients. Although GPER was found to be specifically induced by LH/FSH, GPER agonists (4-Hydroxy-Tamoxifen, G1) reduced EOC cell proliferation only in case of LH/FSH unstimulated pathways. To the same direction, only patients characterized as LHCGR/FSHR negative seem to gain from GPER in terms of survival. Our combined tissue and in vitro results support thus the hypothesis that GPER activation could be of therapeutic benefit in LHCGR/FSHR negative EOC patients. Further studies are needed to evaluate the impact of GPER activation on a clinical scheme.

Inducers of G-protein coupled estrogen receptor (GPER) in endometriosis: potential implications for macrophages and follicle maturation.

Endometriosis is an estrogen dependent chronic inflammation and thus a condition of stress. Though the G-protein coupled estrogen receptor (GPER) has been shown to be up-regulated in ovarian endometriosis, insights involved in inducing this receptor expression are largely elusive. Therefore, this study investigated whether stress-related factors (ACTH, prednisolone) or inflammatory factors (IL-1ß, TNFα, and PGE(2)) factors may affect GPER. To further link GPER to endometriosis pathophysiology it was tracked in macrophages and follicles of endometriotic ovaries. This study found GPER expression to be modulated by stress-related hormones as well as inflammation and to be up-regulated in endometriosis-associated macrophages. At the same time, follicles of ovaries affected by endometriosis presented significantly reduced GPER positivity when compared to controls, suggesting a possible way by which endometriosis may affect folliculogenesis. The multiple roles of GPER as presented herein make it a promising future candidate for targeted molecular endometriosis treatment.

Her-2/neu expression is a negative prognosticator in ovarian cancer cases that do not express the follicle stimulating hormone receptor (FSHR).

BACKGROUND: Anti-Her-2 treatment is successfully administered to Her-2 overexpressing breast cancer patients and significantly implicates upon their survival. Building on these promising results, anti-Her-2 treatment protocols were tested as an option for epithelial ovarian cancer (EOC) as well. However Her-2 signalling is known to be modulated by G-protein coupled receptors (GPCR). Since a common GPCR in ovarian cancer is the FSH receptor (FSHR), we investigated the prognostic significance of Her-2 in patients that had been stratified according to their FSHR status. FINDINGS: A total number of 153 EOC patients were included in this study. Her-2 positivity was assessed using a standard protocol. Intriguingly Her-2 turned out to be an independent prognostic marker for poor overall survival only in those patients that did not express FSHR. This did neither apply for the whole panel nor in case of FSHR co-expression. CONCLUSIONS: We thus conclude that Her-2 can be a negative prognosticator only in FSHR negative EOC cases. Hence by stratifying EOC patients according to their FSHR expression status, we introduce a diagnostic protocol to effectively select EOC patients that would most probably respond to anti-Her-2 treatment. This observation could be of clinical importance in terms of selecting the patient that would most likely benefit from anti-Her-2 treatment.

Thyroid hormone receptor (TR)alpha and TRbeta expression in breast cancer.

UNLABELLED: There is evidence that breast cancer patients suffer from thyroid disorders. However, the relation between thyroid receptor (TR) expression and breast cancer remains unknown so far. Therefore, the aim of this study was an immunohistochemical analysis of TR expression in breast cancer patients. MATERIALS AND METHODS: The expression of the combined antibody TRalpha1 and 2 and TRalpha1 or 2 alone as well as the expression of combined TRbeta1 and 2 and TRbeta1 or 2 alone was investigated with specific monoclonal or polyclonal antibodies in 82 patients. All patients presented with a first diagnosis of sporadic breast cancer. The ABC method was used for staining and staining intensities were analyzed using the IRS score. RESULTS: Both TRalpha and TRbeta were expressed in the nuclei of breast cancer cells. In 24% (28/78) of the slides TRalpha1 and 2 IRS was positive. Immunopositivity for TRalpha1 was found in 55/78 slides, for TRalpha 2 in 54/79 slides (71 and 68%, respectively). The expression of TRbeta1 and 2 showed a positive detection in 33/77 (43%) of the slides, for TRbeta1 it was 43/79 (54%), for TRbeta2 60/76 (79%). Significant correlations of the expression of TRs - especially TRalpha2 - were found with further prognostic histopathological parameters such as tumor size, axillary lymph node involvement, grading and hormone receptor status. Multivariate analysis showed a trend for TRalpha2 as an independent predictor of disease-free and overall survival. DISCUSSION: Our results revealed specific alterations in the expression of TRs - especially of TRalpha2 - in breast cancer patients, suggesting it as a marker with possible prognostic validity.

Staining of MUC1 in ovarian cancer tissues with PankoMab-GEX detecting the tumour-associated epitope, TA-MUC1, as compared to antibodies HMFG-1 and 115D8.

PankoMab-GEX is a novel humanized and glycooptimized antibody, which recognizes a novel specific tumour epitope of MUC1 (TA-MUC1). The aim of this study was to evaluate PankoMab-GEX binding to a variety of ovarian cancer specimens (n=156) and to normal ovarian tissue. In addition, PankoMab-GEX staining was compared to that of the well-known anti-MUC1 antibodies HMFG-1 and 115D8. PankoMab-GEX showed positive reactivity in serous (100% of cases, mean IRS 8.23), endometrioid (95% of cases, mean IRS 6.40), mucinous (58% of cases, mean IRS 4.17), and clear cell (92% of cases, mean IRS 7.58) carcinomas. In contrast to HMFG-1, healthy ovarian tissue was not recognized by PankoMab-GEX. Staining with antibody 115D8 was increased with staging. Cytoplasmic PankoMab-GEX staining increased with tumour grade, but no correlation was found with staging. Univariate Kaplan-Meier analysis revealed a tendency of reduced survival of patients with high expression of TA-MUC1. The findings are encouraging with respect to a potential use of PankoMab-GEX as a new therapeutic antibody for the treatment of ovarian cancer patients.

Dual-energy CT for the evaluation of silicone breast implants.

OBJECTIVE: The evaluation of breast implants for rupture is currently the domain of ultrasound and MRI, while mammography is of very limited diagnostic value. Recently, specific visualisation of silicone has become feasible using dual-energy CT. Our objective was to evaluate whether it is feasible to identify silicone in breast implants by dual-energy CT and to reliably diagnose or rule out ruptures. METHODS: Seven silicone breast implant specimens were examined on dual-source CT at 100- and 140-kV tube potential with a 0.8-mm tin filter (collimation 128 × 0.6 mm, current-time products 165 and 140 mAsref with modulation, rotation time 0.28 s, pitch 0.55). Two patients scheduled for implant removal or replacement were examined with identical parameters. RESULTS: The silicone of the implant specimens showed a strong dual-energy signal. In one patient, both implants were intact, while a rupture was identified in the other patient. Ultrasound, MRI, surgical findings and histology confirmed the dual-energy CT diagnosis. CONCLUSION: Dual-energy CT may serve as an alternative technique for speedy evaluation of silicone breast implants. Specific clinical studies are required to determine the diagnostic accuracy and define indications for this technique.

A retrospective investigation of women's experience with breast reconstruction after mastectomy.

PURPOSE: A diagnosis of breast cancer is often accompanied by the fear of loss of previous body image and attractiveness. Hence, many patients opt for reconstructive surgery. This study evaluated the effects of different types of reconstructive surgery after mastectomy on the functional and psychological adjustment of patients. METHODS: In a cohort study, patients, who had breast reconstruction after mastectomy by means of four different allogenic or autologues techniques between 1999-2006 were retrospectively interviewed in person or by telephone. The questions addressed complication rates, physical complaints, functional impairments, body image outcomes, sexuality and patient satisfaction. RESULTS: Of 139 patients, 89 (64.7 %) completed the survey. 32 (35.9 %) patients experienced one or more postoperative complications like seroma, hematoma, infections or necrosis. 16 (20 %) and 13 (16 %) patients reported strong and moderate adverse effects on sexuality, respectively. 62 (70 %) patients indicated that they were actively included in the decision making process. Patient ratings of good or bad medical advice were associated with complication rates (p = 0.008). Patients, who evaluated their first preoperative counseling positively, reported higher consent rates when a re-reconstruction became necessary (p ≤ 0.001). Satisfaction with the functional outcome after reconstruction and satisfaction with the cosmetic result was highly correlated (p < 0.001). CONCLUSIONS: A significant association of patient satisfaction with postoperative complications and the decision for a re-reconstruction was demonstrated. Furthermore, our results emphasize the importance of detailed preoperative counseling for women's adjustment to reconstructive surgery.

Immunosuppressive Glycodelin A is an independent marker for poor prognosis in endometrial cancer.

BACKGROUND: Knowledge on immunosuppressive factors in the pathogenesis of endometrial cancer is scarce. The aim of this study was to assess Glycodelin (Gd) and its immunosuppressive isoform Glycodelin A (GdA) in endometrial cancer tissue and to analyze its impact on clinical and pathological features and patient outcome. METHODS: 292 patients diagnosed and treated for endometrial cancer were included. Patient characteristics, histology and follow-up data were available. Gd and GdA was determined by immunohistochemistry and in situ hybridization was performed for Gd mRNA. RESULTS: Endometrial cancer shows intermediate (52.2%) or high (20.6%) expression for Gd in 72.8%, and GdA in 71.6% (intermediate 62.6%, high 9.0%) of all cases. The glycosylation dependent staining of GdA is tumour specific and correlates with the peptide-specific Gd staining though neither of the two is associated with estrogen receptor, progesterone receptor or clinic-pathological features. Also Gd protein positively correlates with Gd mRNA as quantified by in situ hybridization. Gd positive cases have a favourable prognosis (p = 0.039), while GdA positive patients have a poor outcome (p = 0.003). Cox-regression analysis proofed GdA to be an independent prognostic marker for patient survival (p = 0.002), besides tumour stage, grade and the concomitant diagnosis of hypertension. CONCLUSION: Gd and GdA are commonly expressed in endometrial cancer tissue and seem to be of relevance in tumourigenesis. They differ not only in glycosylation but also in their biological activity, since only GdA holds prognostic significance for a poor overall survival in endometrial cancer patients. This finding might be explained by GdAs immunosuppressive capacity.

Mucin-1 and its relation to grade, stage and survival in ovarian carcinoma patients.

BACKGROUND: Mucin-1 is known to be over-expressed by various human carcinomas and is shed into the circulation where it can be detected in patient's serum by specific anti-Mucin-1 antibodies, such as the tumour marker assays CA 15-3 and CA 27.29. The prognostic value of Mucin-1 expression in ovarian carcinoma remains uncertain. One aim of this study was to compare the concentrations of Mucin-1 in a cohort of patients with either benign or malignant ovarian tumours detected by CA 15-3 and CA 27.29. Another aim of this study was to evaluate Mucin-1 expression by immunohistochemistry in a different cohort of ovarian carcinoma patients with respect to grade, stage and survival. METHODS: Patients diagnosed with and treated for ovarian tumours were included in the study. Patient characteristics, histology including histological subtype, tumour stage, grading and follow-up data were available from patient records. Serum Mucin-1 concentrations were measured with ELISA technology detecting CA 15-3 and CA 27.29, Mucin-1 tissue expression was determined by immunohistochemistry using the VU4H5 and VU3C6 anti-Mucin-1 antibodies. Statistical analysis was performed by using SPSS 18.0. RESULTS: Serum samples of 118 patients with ovarian tumours were obtained to determine levels of Mucin-1. Median CA 15-3 and CA 27.29 concentrations were significantly higher in patients with malignant disease (p< 0.001) than in patients with benign disease.Paraffin-embedded tissue of 154 patients with ovarian carcinoma was available to determine Mucin-1 expression. The majority of patients presented with advanced stage disease at primary diagnosis. Median follow-up time was 11.39 years. Immunohistochemistry results for VU4H5 showed significant differences with respect to tumour grade, FIGO stage and overall survival. Patients with negative expression had a mean overall survival of 9.33 years compared to 6.27 years for patients with positive Mucin-1 expression. CONCLUSIONS: This study found significantly elevated Mucin-1 serum concentrations in ovarian carcinoma patients as compared to those women suffering from benign ovarian diseases. However, it needs to be noted that Mucin-1 concentrations in carcinoma patients showed a rather high variability. Results from immunohistochemistry indicate that Mucin-1 has a prognostic relevance in ovarian carcinomas when evaluating the expression by VU4H5 antibody.

Correlation of thyroid hormone, retinoid X, peroxisome proliferator-activated, vitamin D and oestrogen/progesterone receptors in breast carcinoma.

Non-steroidal nuclear receptors play a major role in breast cancer development. A correlation among, and possible prognostic function of, the members of the nuclear receptor superfamily has been discussed controversially over the years. Hence, we conducted a quantification of the different expression levels of the thyroid receptor (TR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor (PPAR) and vitamin D receptor (VDR) in malignant breast tumour tissue samples. Patients diagnosed and treated for breast cancer between 1990 and 2000 were included. Receptor expression was detected by immunohistochemical staining. Correlation analyses for the expression of the receptors were performed for the clinical and histopathological data. The paraffin-embedded tissue from 82 breast cancer patients was available. The different steroid receptors showed varying results when correlated with known histopathological markers. TRα2 demonstrated the most significant correlations with steroid hormone receptors. Significant correlations between the major isoforms of TR, and between RXR, PPAR and VDR, were demonstrated in the patient sample. The immunohistochemical association of these receptors may provide the first proof of an interaction on the molecular level. This assumption awaits confirmation in studies with larger cohorts.

Steroid hormone receptor expression in ovarian cancer: progesterone receptor B as prognostic marker for patient survival.

BACKGROUND: There is partially conflicting evidence on the influence of the steroid hormones estrogen (E) and progesterone (P) on the development of ovarian cancer (OC). The aim of this study was to assess the expression of the receptor isoforms ER-α/-ß and PR-A/-B in OC tissue and to analyze its impact on clinical and pathological features and patient outcome. METHODS: 155 OC patients were included who had been diagnosed and treated between 1990 and 2002. Patient characteristics, histology and follow-up data were available. ER-α/-ß and PR-A/-B expression were determined by immunohistochemistry. RESULTS: OC tissue was positive for ER-α/-ß in 31.4% and 60.1% and PR-A/-B in 36.2% and 33.8%, respectively. We identified significant differences in ER-ß expression related to the histological subtype (p=0.041), stage (p=0.002) and grade (p=0.011) as well as PR-A and tumor stage (p=0.03). Interestingly, median receptor expression for ER-α and PR-A/-B was significantly higher in G1 vs. G2 OC. Kaplan Meier analysis revealed a good prognosis for ER-α positive (p=0.039) and PR-B positive (p<0.001) OC. In contrast, ER-ß negative OC had a favorable outcome (p=0.049). Besides tumor grade and stage, Cox-regression analysis showed PR-B to be an independent prognostic marker for patient survival (p=0.009, 95% CI 0.251-0.823, HR 0.455). CONCLUSION: ER-α/-ß and PR-A/-B are frequently expressed in OC with a certain variability relating to histological subtype, grade and stage. Univariate analysis indicated a favorable outcome for ER-α positive and PR-B positive OC, while multivariate analysis showed PR-B to be the only independent prognostic marker for patient survival. In conclusion, ER and PR receptors may be useful targets for a more individualized OC therapy.

Human epididymis protein 4 (HE4) in benign and malignant diseases.

BACKGROUND: Human epididymis protein 4 (HE4) is described as a useful new biomarker in ovarian cancer. As HE4 is neither tumor nor organ specific, we intensively investigated the occurrence of this protein in female and male patients with various benign and malignant diseases in order to avoid misinterpretation and to identify potential additional clinical relevance. METHODS: We retrospectively investigated HE4(ARCHITECT R , Abbott Diagnostics, US) in the sera of 205 healthy individuals, 654 patients with benign disorders and 720 patients with cancer before initial treatment. RESULTS: The lowest concentrations of HE4 were observed in healthy men (median 26.2 pmol/L) followed by healthy women (median 40.4 pmol/L). In benign diseases, highest HE4 concentrations were seen in both women and men with renal failure (women, median 1041 pmol/L; men, median 1368pmol/L). In women, the highest HE4 levels in malignant diseases were observed in ovarian cancer (median 242 pmol/l),whereas the highest HE4 concentrations in men occurred in lung cancer (median 89.2 pmol/L). The area under the curve(AUC) of HE4 in women was highest in ovarian cancer and borderline tumors as compared to benign gynecological disorders(88.9 % ), with a sensitivity of 67.4 % at 95 % specificity.Also, significantly elevated concentrations of HE4 with reference to the respective group of benign diseases were observed in uterus corpus and breast cancer as well as in lung cancer for men and women. CONCLUSIONS: HE4 has the highest relevance in ovarian cancer but can be elevated in a variety of benign and malignant diseases.

Glycodelin A is a prognostic marker to predict poor outcome in advanced stage ovarian cancer patients.

BACKGROUND: Glycodelin is a cell surface glycoprotein offering a unique gender specific carbohydrate configuration. Sialylated carbohydrate structures, which are unusual for mammals, characterize Glycodelin isolated from amniotic fluid (Glycodelin A, GdA). Glycodelin in general exerts multiple, partly opposing functions ranging from immunosuppression to cell differentiation. As these markedly influence tumorigenesis, this study aimed to clarify whether expression of different Glycodelin isoforms is related to clinicopathological characteristics and prognosis of ovarian cancer patients. Further the use of Glycodelin as a serum marker in benign and malignant ovarian diseases was evaluated. METHODS: Ovarian cancer specimens (n = 152) were stained for Glycodelin with carbohydrate and peptide specific antibodies. Associations between Glycodelin expression and histological grading, FIGO stage as well as patient's prognosis were examined. Glycodelin was correlated to expression of gonadotropin receptors and mucin-1, which are discussed as ovarian cancer tissue markers. In addition, Glycodelin serum concentrations were analyzed in patients suffering from benign (n = 73) or malignant (n = 38) ovarian neoplasias. RESULTS: Glycodelin A was found to be an independent prognostic marker for poor prognosis in advanced ovarian cancer patients. GdA staining correlated with gonadotropin receptor (FSHR and LHCGR) and with hCG expression. Gd expression showed a positive correlation with a tumour-associated epitope of mucin 1 (TA-MUC1). Further, compared to ovarian cancer, serum Gd was increased in patients with benign ovarian tumors. CONCLUSION: Glycodelin A might be related to tumor aggressiveness and poor clinical outcome in advanced epithelial ovarian cancer. Glycodelin serum levels found in patients suffering from benign ovarian tumors, might contribute to a more global attenuation during progression of these precursor lesions.

Treatment of breast cancer during pregnancy: an observational study.

BACKGROUND: Little is known about the treatment of breast cancer during pregnancy. We aimed to determine whether treatment for breast cancer during pregnancy is safe for both mother and child. METHODS: We recruited patients from seven European countries with a primary diagnosis of breast cancer during pregnancy; data were collected retrospectively if the patient was diagnosed before April, 2003 (when the registry began), or prospectively thereafter, irrespective of the outcome of pregnancy and the type and timing of treatment. The primary endpoint was fetal health for up to 4 weeks after delivery. The registry is ongoing. The study is registered with ClinicalTrials.gov, number NCT00196833. FINDINGS: From April, 2003, to December, 2011, 447 patients were registered, 413 of whom had early breast cancer. Median age was 33 years (range 22-51). At the time of diagnosis, median gestational age was 24 weeks (range 5-40). 197 (48%) of 413 women received chemotherapy during pregnancy with a median of four cycles (range one to eight). 178 received an anthracycline, 15 received cyclophosphamide, methotrexate, and fluorouracil, and 14 received a taxane. Birthweight was affected by chemotherapy exposure after adjustment for gestational age (p=0·018), but not by number of chemotherapy cycles (p=0·71). No statistical difference between the two groups was observed for premature deliveries before the 37th week of gestation. 40 (10%) of 386 infants had side-effects, malformations, or new-born complications; these events were more common in infants born before the 37th week of gestation than they were in infants born in the 37th week or later (31 [16%] of 191 infants vs nine [5%] of 195 infants; p=0·0002). In infants for whom maternal treatment was known, adverse events were more common in those who received chemotherapy in utero compared with those who were not exposed (31 [15%] of 203 vs seven [4%] of 170 infants; p=0·00045). Two infants died; both were exposed to chemotherapy and delivered prematurely, but both deaths were thought not to be related to treatment. Median disease-free survival for women with early breast cancer was 70·6 months (95% CI 62·1-105·5) in women starting chemotherapy during pregnancy and 94·4 months (lower 95% CI 64·4; upper 95% CI not yet reached) in women starting chemotherapy after delivery (unadjusted hazard ratio 1·13 [95% CI 0·76-1·69]; p=0·539). INTERPRETATION: Although our data show that infants exposed to chemotherapy in utero had a lower birthweight at gestational age than did those who were unexposed, and had more complications, these differences were not clinically significant and, since none of the infants was exposed to chemotherapy in the first trimester, were most likely related to premature delivery. Delay of cancer treatment did not significantly affect disease-free survival for mothers with early breast cancer. Because preterm birth was strongly associated with adverse events, a full-term delivery seems to be of paramount importance. FUNDING: BANSS Foundation, Biedenkopf, Germany and the Belgian Cancer Plan, Ministry of Health, Belgium.