Nomogram for 30-day morbidity after primary cytoreductive surgery for advanced stage ovarian cancer.

PURPOSE OF INVESTIGATION: Extensive surgical procedures to achieve maximal cytoreduction in patients with advanced stage epithelial ovarian cancer (EOC) are inevitably associated with postoperative morbidity and mortality. This study aimed to identify preoperative predictors of 30-day morbidity after primary cytoreductive surgery for advanced stage EOC and to develop a nomogram for individual risk assessment. MATERIALS AND METHODS: Patients in The Netherlands who underwent primary cytoreductive surgery for advanced stage EOC between January 2004 and December 2007. All peri- and postoperative complications within 30 days after surgery were registered and classified. To investigate predictors of 30-day morbidity, a Cox proportional hazard model with backward stepwise elimination was utilized. The identified predictors were entered into a nomogram. The main outcome was to identify parameters that predict operative risk. RESULTS: 293 patients entered the study protocol. Optimal cytoreduction was achieved in 136 (46%) patients. Thirty-day morbidity was seen in 99 (34%) patients. Morbidity could be predicted by age (p = 0.033; OR 1.024), preoperative hemoglobin (p = 0.194; OR 0.843), and WHO performance status (p = 0.015; OR 1.821) with a optimism-corrected c-statistic of 0.62. Determinants co-morbidity status, serum CA125 level, platelet count, and presence of ascites were comparable in both groups. CONCLUSIONS: Thirty-day morbidity after primary cytoreductive surgery for advanced stage EOC could be predicted by age, hemoglobin, and WHO performance status. The generated nomogram could be valuable for predicting operative risk in the individual patient.

Melanoma risk after ovarian stimulation for in vitro fertilization.

STUDY QUESTION: Do women treated with ovarian stimulation for IVF have an increased risk of melanoma? SUMMARY ANSWER: Ovarian stimulation for IVF does not increase risk of melanoma, even after a prolonged follow-up. WHAT IS KNOWN ALREADY: Although exposure to ultraviolet radiation is the major risk factor for melanoma, associations between female sex steroids and melanoma risk have also been suggested. The results of available studies on fertility drugs and melanoma risk are inconclusive since most studies had several methodological limitations such as short follow-up, a small number of cases and no subfertile comparison group. STUDY DESIGN, SIZE, DURATION: In 1996, a nationwide historic cohort study (the OMEGA-cohort) was established to examine the risk of cancer after ovarian stimulation for IVF. After a median follow-up of 17 years, cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Melanoma risk in the cohort was compared with that in the general population and between the IVF group and non-IVF group using multivariable Cox regression analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The cohort comprises 19 158 women who received IVF between 1983 and 1995 and a comparison group of 5950 women who underwent subfertility treatments other than IVF. Detailed IVF-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Dutch Municipal Personal Records Database. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles was associated with apparent but statistically non-significant risk increases (5-6 cycles HR = 1.92; ≥7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07-10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21). LIMITATIONS, REASONS FOR CAUTION: Despite our large cohort, the number of melanoma cases was rather small, especially in our comparison group, which hampered subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our results are reassuring for women who underwent IVF or are contemplating to start IVF. Since our cohort study is one of the largest published so far, with long-term follow-up, a subfertile comparison group, and detailed IVF-treatment data, our results add important information to the available evidence. STUDY FUNDING/COMPETING INTEREST: This study was supported by grants from the Dutch Cancer Society (NKI 2006-3631), the Health Research and Development Counsel (28-2540) and the Dutch Ministry of Health.

Progesterone-induced cyclin G1 inhibits the proliferation of endometrial epithelial cell and its possible molecular mechanism.

Under normal conditions, progesterone inhi-bits the estrogen-induced proliferation of endometrial epithelium. Our previous studies have shown that cyclin G1 was progesterone-dependent in mouse endometrial epithelium at peri-implantation, and exogenous cyclin G1 suppressed the proliferation of endometrial cancer cells. The objectives of this study are to determine whether cyclin G1, as a negative regulator of the cell cycle, is involved in the antiproliferative action of progesterone on endometrial epithelial cells, and to explore the possible molecular mechanism of cyclin G1 inhibition. The siRNA-mediated elimination of cyclin G1 attenuated the antiproliferative action of progesterone on endometrial epithelial cells. Immunoprecipitation showed that progesterone-induced cyclin G1 could interact with PP2A to mediate its phosphatase activity. The block of PP2A activity also attenuated the antiproliferative action of progesterone on endometrial epithelial cells and increased the phosphorylated Rb. In conclusion, progesterone-induced cyclin G1 mediates the inhibitory effect of progesterone on endometrial epithelial cell proliferation possibly through the recruitment of PP2A to dephosphorylate Rb.

Outcome of BRCA1- compared with BRCA2-associated ovarian cancer: a nationwide study in the Netherlands.

BACKGROUND: Recent studies suggested an improved overall survival (OS) for BRCA2- versus BRCA1-associated epithelial ovarian cancer (EOC), whereas the impact of chemotherapy is not yet clear. In a nationwide cohort, we examined the results of primary treatment, progression-free survival (PFS), treatment-free interval (TFI), and OS of BRCA1 versus BRCA2 EOC patients. METHODS: Two hundred and forty-five BRCA1- and 99 BRCA2-associated EOC patients were identified through all Dutch university hospitals. Analyses were carried out with the Pearson's Chi-square test, Kaplan-Meier, and Cox regression methods. RESULTS: BRCA1 patients were younger at EOC diagnosis than BRCA2 patients (51 versus 55 years; P < 0.001), without differences regarding histology, tumor grade, and International Federation of Gynecology and Obstetrics (FIGO) stage. Complete response rates after primary treatment, including chemotherapy, did not differ between BRCA1 (86%) and BRCA2 patients (90%). BRCA1 versus BRCA2 patients had a shorter PFS (median 2.2 versus 3.9 years, respectively; P = 0.006), TFI (median 1.7 versus 2.8 years; P = 0.009), and OS (median 6.0 versus 9.7 years; P = 0.04). Differences could not be explained by age at diagnosis, FIGO stage or type of treatment. CONCLUSIONS: PFS and OS were substantially longer in BRCA2- than in BRCA1-associated EOC patients. While response rates after primary treatment were similarly high in both groups, TFI, as surrogate for chemosensitivity, was significantly longer in BRCA2 patients.

Increased risk for ovarian cancer and borderline ovarian tumours in subfertile women with endometriosis.

STUDY QUESTION: Is ovarian or extra-ovarian endometriosis associated with an increased risk of ovarian cancer and borderline ovarian tumours (BOT)? SUMMARY ANSWER: We found a 3- to 8-fold increased risk of ovarian tumours associated with endometriosis: the magnitude of the risk increase depended on the definition of endometriosis. WHAT IS KNOWN ALREADY: There is increasing evidence of an association between endometriosis and increased risk of ovarian cancer. However, most reports were based on self-reported diagnosis of endometriosis. STUDY DESIGN, SIZE, DURATION: We conducted a nationwide historic cohort study among women with subfertility problems between 1980 and 1995. For this analysis we selected all cohort members with endometriosis, and a comparison group of subfertile women (male factor or idiopathic) without endometriosis (total cohort of 8904 women). Median follow-up time was 15.2 for the entire study population. PARTICIPANTS/MATERIALS, SETTING, METHODS: For this analysis we selected all cohort members with (n = 3657) and without (n = 5247) evidence of endometriosis. Seventy-eight per cent of diagnoses of endometriosis were confirmed by pathology report, and 22% was self-reported endometriosis (positive predictive value of 73%). We linked the cohort with the Dutch Pathology Database and the Netherlands Cancer Registry to assess the occurrence of ovarian cancer and BOT between January 1989 and June 2007. MAIN RESULTS AND THE ROLE OF CHANCE: We observed a substantially increased risk of all ovarian malignancies combined in women with endometriosis when we based the definition of endometriosis on self-report, medical records information at subfertility treatment and/or the nationwide pathology database (hazard ratio (HR) 8.2; 95% confidence interval (CI) 3.1-21.6). The HR associated with endometriosis was 12.4 (95% CI 2.8-54.2) for ovarian cancer and 5.5 (95% CI 1.5-20.2) for BOT. When we excluded information from the pathology database, HRs were 3.0 (95% CI 1.5-6.1) for all ovarian tumours, 4.3 (95% CI 1.6-11.2) for ovarian cancer and 1.9 (95% CI 0.6-5.8) for BOT. Both ovarian and extra-ovarian endometriosis carried a significantly increased risk for ovarian cancer and BOT. LIMITATIONS, REASONS FOR CAUTION: We did not have information on oral contraceptive use and parity for 23.4 and 3.4%, of women in the analytic cohort, respectively. Furthermore, a limitation of our study, and also of other studies, is that the date of diagnosis of endometriosis is usually made long after the onset of the disease. Also, the number of cases in the cohort is small (n = 34), resulting in wide CIs. WIDER IMPLICATIONS OF THE FINDINGS: The fact that endometriosis was assessed before diagnosis of ovarian malignancy and the high degree of medical confirmation in our study likely contribute to the validity of our estimate of a 3- to 8-fold increased risk of ovarian tumours associated with endometriosis. The risk of ovarian malignancies associated with endometriosis was much higher in analyses including information on endometriosis from the nationwide pathology database, implying that risk estimates from studies using self-reported information on endometriosis may be too low due to non-differential misclassification bias. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: None.

Factors associated with dizygotic twinning after IVF treatment with double embryo transfer.

BACKGROUND: Dizygotic twin pregnancies after IVF treatment are the result of multiple embryos transferred into the uterine cavity, followed by successful double implantation. Factors that increase the chance of multiple implantation after IVF are relatively unknown. The present study aimed to investigate whether features of body composition, such as maternal height, weight and body mass index (BMI) are associated with an increased chance of dizygotic twinning after IVF with double embryo transfer (DET). METHODS: This study was conducted using data from a large Dutch nationwide cohort that comprised 19 861 women who had IVF or ICSI treatment between 1983 and 1995 (OMEGA study). First 'fresh' IVF and ICSI cycles with DET resulting in a delivery of a singleton or twin (living as well as stillborn) were selected. A multivariable logistic regression analysis was performed, with the delivery of a singleton or twin as the dependent variable and height, weight, BMI, maternal age, number of retrieved oocytes, use of alcohol, smoking, highest level of education and parity as independent variables. RESULTS: Of the 6598 women who completed their first IVF or ICSI cycle, 2375 had DET, resulting in 496 deliveries of 371 singletons and 125 twins. Multivariable regression analysis revealed that tall women (>1.74 cm) and women with a high number of retrieved oocytes (>8) had an increased chance of dizygotic twinning [OR: 1.8 (95% CI: 1.0-3.4) and OR: 2.2 (95% CI: 1.3-3.8), respectively]. CONCLUSIONS: Our data demonstrate that tall stature and increased number of retrieved oocytes independently increase the chance of dizygotic twinning after IVF with DET.

Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients.

BACKGROUND: Because it is insufficiently clear whether BRCA-associated epithelial ovarian cancer (EOC) is more chemosensitive than sporadic EOC, we examined response to chemotherapy, progression-free survival (PFS) and overall survival (OS) in BRCA1- and BRCA2-associated versus sporadic EOC patients. METHODS: Data about patient characteristics, response to and outcome after primary therapy, including chemotherapy, were collected from 99 BRCA1, 13 BRCA2 and 222 sporadic patients. Analyses were carried out using a chi-square test and Kaplan-Meier and Cox regression methods. RESULTS: Complete response (CR) or no evidence of disease (NED) was observed in 87% of the BRCA1 patients, progressive disease (PD) in 2%, being 71% and 15%, respectively, in sporadic EOC patients (P = 0.002). In BRCA2 patients, 92% had CR/NED, and none PD (P = 0.27). Median PFS in BRCA1, BRCA2 and sporadic patients was 2.1 [95% confidence interval (CI) 1.9-2.5] years (P = 0.006), 5.6 (95% CI 0.0-11.5) years (P = 0.008) and 1.3 (95% CI 1.1-1.5) years, respectively. Median OS in the three groups was 5.9 (95% CI 4.7-7.0) years (P < 0.001), >10 years (P = 0.008), and 2.9 (95% CI 2.2-3.5) years, respectively. A trend for a longer PFS and OS in BRCA2 compared with BRCA1 patients was observed. CONCLUSION: Compared with sporadic EOC patients, both BRCA1- and BRCA2-associated patients have improved outcomes after primary therapy, including chemotherapy.

Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort.

BACKGROUND: Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown. METHODS: We identified a nationwide historic cohort of 19,146 women who received IVF treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997-1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group. RESULTS: After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population [standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16-2.56]. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62-6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25-14.33 and 2.14; 95% CI = 1.07-4.25, respectively, adjusted for age, parity and subfertility cause). CONCLUSIONS: Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.

A reduced size of the ovarian follicle pool is associated with an increased risk of a trisomic pregnancy in IVF-treated women.

BACKGROUND: The increased risk of a trisomic pregnancy with a woman's age arises from an increased rate of meiotic non-disjunction in the oocytes. It has been hypothesized that the increase in meiotic errors is related to the decreasing number of oocytes with age. Our aim was to assess the relation between trisomic pregnancy and three parameters of oocyte quantity. METHODS: In a Dutch nationwide database on in vitro fertilization (IVF) treatment from 1983 to 1995, we identified 28 women with a trisomic pregnancy conceived via or within 1 year from IVF treatment. We selected five age-matched controls with a healthy child for each trisomy case. We performed a case-control study to examine whether trisomy cases more often had a history of ovarian surgery and a lower response to ovarian hyperstimulation than controls. Subsequently, cases and controls were followed to compare the incidence of signs of menopause at the end of the study period as self-reported by questionnaire. RESULTS: Logistic regression analysis showed an association between trisomic pregnancy and a history of ovarian surgery [odds ratio (OR) 3.3; 95% confidence interval (CI): 1.0-10.5; P = 0.04] and between trisomic pregnancy and retrieval of < or = 4 oocytes during IVF treatment (OR 4.0; 95% CI: 1.4-11.5; P = 0.01). The adjusted OR for signs of menopause associated with trisomic pregnancy was 5.7 (95% CI: 1.1-29.9; P = 0.04). CONCLUSIONS: Our results suggest that IVF-treated women with a reduced ovarian follicle pool are at increased risk of a trisomic pregnancy, independent of their age. Our findings support the hypothesis that follicle pool size and not chronological age determines a woman's trisomy risk. Since a questionnaire was used, we cannot fully exclude the possibility of selection bias in this study.

Assessment of posterior compartment prolapse: a comparison of evacuation proctography and 3D transperineal ultrasound.

INTRODUCTION: Evacuation proctography (EP) is considered to be the gold standard investigation for the diagnosis of posterior compartment prolapse. 3D transperineal ultrasound (3DTPUS) imaging of the pelvic floor is a noninvasive investigation for detection of pelvic floor abnormalities. This study compared EP with 3DTPUS in diagnosing posterior compartment prolapse. METHOD: In a prospective observational study, patients with symptoms related to posterior compartment prolapse participated in a standardized interview, clinical examination, 3DTPUS and EP. Both examinations were analysed separately by two experienced investigators, blinded against the clinical data and against the results of the other imaging technique. After the examinations, all patients were asked to fill out a standardized questionnaire concerning their subjective experience. RESULTS: Between 2005 and 2007, 75 patients were included with a median age of 59 years (range 22-83). The Cohen's Kappa Index for enterocole was 0.65 (good) and for rectocele it was 0.55 (moderate). The level of correlation for intussusception was fair (kappa = 0.21). CONCLUSION: This study showed moderate to good agreement between 3DTPUS and EP for detecting enterocele and rectocele.

The prediction of progression-free and overall survival in women with an advanced stage of epithelial ovarian carcinoma.

OBJECTIVE: Prognosis in women with ovarian cancer mainly depends on International Federation of Gynecology and Obstetrics stage and the ability to perform optimal cytoreductive surgery. Since ovarian cancer has a heterogeneous presentation and clinical course, predicting progression-free survival (PFS) and overall survival (OS) in the individual patient is difficult. The objective of this study was to determine predictors of PFS and OS in women with advanced stage epithelial ovarian cancer (EOC) after primary cytoreductive surgery and first-line platinum-based chemotherapy. DESIGN: Retrospective observational study. SETTING: Two teaching hospitals and one university hospital in the south-western part of the Netherlands. POPULATION: Women with advanced stage EOC. METHODS: All women who underwent primary cytoreductive surgery for advanced stage EOC followed by first-line platinum-based chemotherapy between January 1998 and October 2004 were identified. To investigate independent predictors of PFS and OS, a Cox' proportional hazard model was used. Nomograms were generated with the identified predictive parameters. MAIN OUTCOME MEASURES: The primary outcome measure was OS and the secondary outcome measures were response and PFS. RESULTS: A total of 118 women entered the study protocol. Median PFS and OS were 15 and 44 months, respectively. Preoperative platelet count (P = 0.007), and residual disease <1 cm (P = 0.004) predicted PFS with a optimism corrected c-statistic of 0.63. Predictive parameters for OS were preoperative haemoglobin serum concentration (P = 0.012), preoperative platelet counts (P = 0.031) and residual disease <1 cm (P = 0.028) with a optimism corrected c-statistic of 0.67. CONCLUSION: PFS could be predicted by postoperative residual disease and preoperative platelet counts, whereas residual disease, preoperative platelet counts and preoperative haemoglobin serum concentration were predictive for OS. The proposed nomograms need to be externally validated.

Face validity and reliability of the first digital assessment scheme of pelvic floor muscle function conform the new standardized terminology of the International Continence Society.

AIMS: To test the face validity and reliability of a new digital pelvic floor muscle function (PFMF) assessment scheme that was designed on the basis of the recently standardized terminology of the International Continence Society. METHODS: Study participants comprised 41 women, age 18-85 years. Data on age and parity were obtained. Face validity of the new assessment scheme was tested by three senior and one junior pelvic physiotherapists, using the Delphi technique. PFMF of each woman was assessed four times by three specially trained pelvic physiotherapists. Examiners were blinded to parity and other findings. To test reliability, Kappa (K) was used for the dichotomous variables and Weighted Kappa (K(w)) for the items with more than two categories. RESULTS: Mean age of the women was 41 years (SD 10.5); 14 were nulliparous (34.1%), 6 primiparous (14.6%), and 21 multiparous (51.2%). The new assessment scheme showed satisfactory face validity and intra-observer reliability but low inter-observer reliability. CONCLUSIONS: The new assessment scheme based on the terminology of the ICS showed satisfactory face validity and intra-observer reliability. It can therefore be considered suitable for use in clinical practice. More detailed redefinition of the described outcome measures is necessary to improve the inter-observer reliability.

Molecular analysis of human endometrium: short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling.

Tibolone, a tissue-selective compound with a combination of estrogenic, progestagenic, and androgenic properties, is used as an alternative for estrogen or estrogen plus progesterone hormone therapy for the treatment of symptoms associated with menopause and osteoporosis. The current study compares the endometrial gene expression profiles after short-term (21 days) treatment with tibolone to the profiles after treatment with estradiol-only (E(2)) and E(2) + medroxyprogesterone acetate (E(2) + MPA) in healthy postmenopausal women undergoing hysterectomy for endometrial prolapse. The impact of E(2) treatment on endometrial gene expression (799 genes) was much higher than the effect of tibolone (173 genes) or E(2) + MPA treatment (174 genes). Furthermore, endometrial gene expression profiles after tibolone treatment show a weak similarity to the profiles after E(2) treatment (overlap 72 genes) and even less profile similarity to E(2) + MPA treatment (overlap 17 genes). Interestingly, 95 tibolone-specific genes were identified. Translation of profile similarity into biological processes and pathways showed that ER-mediated downstream processes, such as cell cycle and cell proliferation, are not affected by E2 + MPA, slightly by tibolone, but are significantly affected by E(2). In conclusion, tibolone treatment results in a tibolone-specific gene expression profile in the human endometrium, which shares only limited resemblance to E(2) and even less resemblance to E2 + MPA induced profiles.

Sentinel node procedure in vulvar squamous cell carcinoma: a histomorphologic review of 32 cases. The significance of anucleate structures on immunohistochemistry.

The sentinel lymph node (SLN) procedure is used in our institute in the setting of an observational multicenter study investigating the reliability of the sentinel node procedure in vulvar carcinoma (GROINSS-V: The Groningen International Study on Sentinel Nodes in Vulvar Cancer). One of our patients had a groin recurrence where the SLN had been reported as negative. After reviewing this SLN, it contained several anucleate, keratin-positive structures on immunohistochemistry, and in the same area on hematoxylin and eosin coloring, one single cell with a nucleus interpreted as a tumor cell. Our objective was to assess how frequently these anucleate structures occur and whether such nodes should be regarded as positive. The sentinel nodes from 32 patients with early-stage vulvar squamous cell carcinoma were reviewed. Seventy-seven SLN's were identified. In ten patients, the SLN was positive and a bilateral inguinofemoral lymph node dissection was subsequently performed. In two of these ten patients, both with a macrometastasis on SLN, further metastatic disease was present in the dissection specimen. Anucleate keratin-positive structures were seen on immunohistochemistry in 14 SLN's (18%), usually along with metastasis or single tumor cells, but in five nodes this was the only abnormality (mean follow-up period of 26.28 months). Anucleate keratin-positive structures are a common finding in immunohistochemical examination of SLN's. Our findings suggest that they are of no clinical significance and the SLN should be regarded as negative. When an atypical cell with a nucleus is present, the SLN should be classified as positive and further management should be accordingly.

Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases.

AIM OF THE STUDY: Results on tumour characteristics and survival of hereditary breast cancer (BC), especially on BRCA2-associated BC, are inconclusive. The prognostic impact of the classical tumour and treatment factors in hereditary BC is insufficiently known. METHODS: We selected 103 BRCA2-, 223 BRCA1- and 311 non-BRCA1/2 BC patients (diagnosis 1980-2004) from the Rotterdam Family Cancer Clinic. To correct for longevity bias, analyses were also performed while excluding index patients undergoing DNA testing 2 years after BC diagnosis. As a comparison group, 759 sporadic BC patients of comparable age at and year of diagnosis were selected. We compared tumour characteristics, the occurrence of ipsilateral recurrence (LRR) and contralateral BC (CBC) as well as distant disease-free (DDFS), BC-specific (BCSS) and overall survival (OS) between these groups. By multivariate modelling, the prognostic impact of tumour and treatment factors was investigated separately in hereditary BC. RESULTS: We confirmed the presence of the particular BRCA1-phenotype. In contrast, tumour characteristics of BRCA2-associated BC were similar to those of non-BRCA1/2 and sporadic BC, with the exception of a high risk of CBC (3.1% per year) and oestrogen-receptor (ER)-positivity (83%). No significant differences between BRCA2-associated BC and other BC subgroups were found with respect to LRR, DDFS, BCSS and OS. Independent prognostic factors for BC-specific survival in hereditary BC (combining the three subgroups) were tumour stage, adjuvant chemotherapy, histologic grade, ER status and a prophylactic (salpingo-)oophorectomy. CONCLUSIONS: Apart from the frequent occurrence of contralateral BC and a positive ER-status, BRCA2-associated BC did not markedly differ from other hereditary or sporadic BC. Our observation that tumour size and nodal status are prognostic factors also in hereditary BC implies that the strategy to use these factors as a proxy for ultimate mortality appears to be valid also in this specific group of patients.

Preoperative predictors for residual tumor after surgery in patients with ovarian carcinoma.

OBJECTIVES: Suboptimal debulking (>1 cm residual tumor) results in poor survival rates for patients with an advanced stage of ovarian cancer. The purpose of this study was to develop a prediction model, based on simple preoperative parameters, for patients with an advanced stage of ovarian cancer who are at risk of suboptimal cytoreduction despite maximal surgical effort. METHODS: Retrospective analysis of 187 consecutive patients with a suspected clinical diagnosis of advanced-stage ovarian cancer undergoing upfront debulking between January 1998 and December 2003. Preoperative parameters were Karnofsky performance status, ascites and serum concentrations of CA 125, hemoglobin, albumin, LDH and blood platelets. The main outcome parameter was residual tumor >1 cm. Univariate and multivariate logistic regression was employed for testing possible prediction models. A clinically applicable graphic model (nomogram) for this prediction was to be developed. RESULTS: Serum concentrations of CA 125 and blood platelets in the group with residual tumor >1 cm were higher in comparison to the optimally cytoreduced group (p < 0.0001 and <0.01, respectively). Serum albumin and hemoglobin levels were lower in the group with residual tumor (p < 0.0001 and <0.05, respectively). The frequency of preoperative ascites was higher in the group with residual tumor (p < 0.0005). The prediction model, consisting of CA 125 and albumin, for remaining with residual tumor showed an area under the receiver operating characteristics curve of 0.79. A nomogram for probability of residual tumor >1 cm based on serum levels of CA 125 and albumin was established. CONCLUSION: Postoperative residual tumor despite maximal surgical effort can be predicted by preoperative CA 125 and serum albumin levels. With a nomogram based on these two parameters, probability of postoperative residual tumor in each individual patient can be predicted. This proposed nomogram may be valuable in daily routine practice for counseling and to select treatment modality.

Mammography: interobserver variability in breast density assessment.

Our objective was to determine the interobserver variability of breast density assessment according to the Breast Imaging Reporting and Data System (BI-RADS) and to examine potential associations between breast density and risk factors for breast cancer. Four experienced breast radiologists received instructions regarding the use of BI-RADS and they assessed 57 mammograms into BI-RADS density categories of 1-4. The weighted kappa values for breast density between pairs of observers were 0.84 (A, B) (almost perfect agreement); 0.75 (A, C), 0.74 (A, D), 0.71 (B, C), 0.77 (B, D), 0.65 (C, D) (substantial agreement). The weighted overall kappa, measured by the intraclass correlation coefficient (ICC), was 0.77 (95% CI: 0.69-0.85). Body mass index was inversely associated with high breast density. In conclusion, overall interobserver agreement in mammographic interpretation of breast density is substantial and therefore, the BI-RADS classification for breast density is useful for standardization in a multicentre study.

Recurrent endometrial cancer: a retrospective study.

OBJECTIVE: The value of follow-up after treatment for endometrial cancer will be discussed. STUDY DESIGN: We evaluated our clinical experience, including mode of detection, of patients with recurrent endometrial cancer treated in the Erasmus Medical Centre in Rotterdam over a 20-year period. Clinical data and histopathological features from 64 patients were analyzed. Survival was analyzed with a Kaplan-Meier curve. RESULTS: Twenty-two patients had a local recurrence, 30 had a distant recurrence and 12 had simultaneous local and distant recurrent disease. Ninety-five percent of the local recurrences and 67% of the distant recurrences were detected within three years. Twenty-seven patients had a screen-detected recurrence, 34 had an interval screening recurrence and two had a chance finding recurrence. The overall survival rate at two years was 70% and at five years 53%. Patients with a screen-detected recurrence had a 5-year survival rate of 62%, while patients with interval screening and chance finding recurrences had a 5-year survival rate of 47%. CONCLUSION: A follow-up program in the first three years after primary treatment of endometrial cancer is useful in detecting recurrent disease. We have no reason to use a different program of follow-up in patients with low risk primary disease.

Inadequate office endometrial sample requires further evaluation in women with postmenopausal bleeding and abnormal ultrasound results.

OBJECTIVE: To determine whether further histologic assessment can be omitted after office sampling produced a nondiagnostic specimen. METHODS: Data were retrieved from a prospective cohort study of 913 women presenting with postmenopausal bleeding. This study was limited to women with an endometrial thickness either 5 mm or greater or that could not be measured, and in whom an endometrial biopsy performed in the office yielded nondiagnostic results. RESULTS: Endometrial thickness was nonreassuring or unknown in 516 women, of whom 403 (78.1%) underwent office endometrial sampling. In 66 women the amount of tissue obtained was not sufficient for pathologic characterization. Further investigation revealed an endometrial malignancy in 3 of these 66 women and atypical hyperplasia in 1. CONCLUSION: In women with postmenopausal bleeding and a nonreassuring transvaginal ultrasound evaluation, a nondiagnostic office endometrial sample does not rule out endometrial cancer and further endometrial sampling is advisable.

Progesterone-induced miR-133a inhibits the proliferation of endometrial epithelial cells.

AIM: This study aimed to understand the role of miR-133a in progesterone actions, explore the regulative mechanism of the progesterone receptor, and investigate the effects of miR-133a on the progesterone-inhibited proliferation of mouse endometrial epithelial cells. METHODS: The expression of miR-133a induced by progesterone was detected by quantitative real-time PCR both in vivo and in vitro. Ishikawa subcell lines stably transfected with progesterone receptor subtypes were used to determine the receptor mechanism of progesterone inducing miR-133a. Specific miR-133a mimics or inhibitors were transfected into mouse uteri and primary cultured endometrial epithelial cells to overexpress or downregulate the miR-133a. The roles of miR-133a in the cell cycle and proliferation of endometrial epithelial cells were analysed by flow cytometry and Edu incorporation analysis. The protein levels of cyclinD2 in uterine tissue sections and primary cultured endometrial epithelial cells were determined by immunohistochemistry and Western blot analysis. RESULTS: Progesterone could induce miR-133a expression in a PRB-dependent manner in endometrial epithelial cells. miR-133a inhibited endometrial epithelial cell proliferation by arresting cell cycle at the G1 -S transition. Moreover, miR-133a acted as an inhibitor in downregulating cyclinD2 in endometrial epithelial cells. CONCLUSION: We showed for the first time that progesterone-induced miR-133a inhibited the proliferation of endometrial epithelial cells by downregulating cyclinD2. Our research indicated an important mechanism for progesterone inhibiting the proliferation of endometrial epithelial cells by inducing special miRNAs to inhibit positive regulatory proteins in the cell cycle.