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To compare long-term oncological outcomes in early-stage cervical cancer (CC) patients treated with minimally invasive radical hysterectomy (MIRH) versus abdominal radical hysterectomy (ARH), with a focus on recurrence patterns, tumor sizes, and conization. This single-institution, retrospective study consisted of stage IA1-IB1 (FIGO 2009) squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma of the cervix, who underwent radical hysterectomy between 2000 and 2017. Of the 582 patients included, 353 (60.7%) underwent ARH, and 229 (39.3%) MIRH. The median follow-up was 14.4 years in the ARH group and 6.1 years in the MIRH group (p < 0.0001). Among the 96 stage IA patients, only 3 (3.1%) experienced recurrence. Among stage IB1 patients, the risk of recurrence, after adjusting for standard prognostic variables, was twofold higher in the MIRH group versus the ARH group (HR 2.73, 95% CI: 1.56–4.80), and the relative difference was similar in terms of risk of cancer-specific survival (CSS) (HR 3.04, 95% CI: 1.28–7.20) and overall survival (OS) (HR 2.35, 95% CI: 1.21–4.59). In stage IB1 ≤ 2 cm patients without conization MIRH was associated with reduced time to recurrence (TTR) (HR 4.00, 95% CI: 1.67–9.57), CSS (HR 3.71, 95% CI: 1.19–11.58) and OS (HR 3.02, 95% CI: 1.24–7.34). Intraperitoneal combined recurrences accounted for 12 of 30 (40.0%) recurrences in the MIRH group but were not identified after ARH (p = 0.0001). MIRH was associated with reduced TTR, CSS and OS versus ARH in stage IB1 CC patients. The risk of peritoneal recurrence was high, even for tumors ≤2 cm without conization. • In stage IA CC, similar oncological survival outcomes were observed for MIRH and ARH. • In stage IB1 CC, MIRH yielded a significantly shorter TTR, CSS and OS than ARH. • In stage IB1 CC ≤2 cm, MIRH yielded a significantly shorter TTR, CSS and OS than ARH when conization was not performed. • Intraperitoneal combined recurrences accounted for 40.0% of all recurrences after MIRH compared to 0.0% after ARH. • No intraperitoneal combined recurrences were observed in patients who underwent conization with clean margins. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The EORTC 55971 trial compared primary debulking surgery (PDS) versus neo-adjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). The impact of both treatment arms on quality of life (QOL) is reported. Methods: Patients with stages IIIc or IV ovarian cancer completed the EORTC QLQ-C30 before treatment, at the third and sixth cycle of chemotherapy, and at 6- and 12-month follow-up. Results: Data of 404 patients (N =201 PDS arm; N =203 IDS arm) were included in the QOL analysis. Between treatment arms no statistically significant differences were found in any of the QOL functioning scales. Patients showed a clinically relevant improvement (>10 points) on the global health/QOL, role functioning, emotional functioning and social functioning scales during and after treatment independent of the type of treatment. Clinically relevant differences from baseline to the follow-up assessments were noted for fatigue, pain, insomnia, appetite loss, constipation, diarrhea indicating symptom control in both treatment arms. Institutions with good QOL compliance were associated with better outcomes. There was a statistical significant difference in the overall debulking status with 39.9% optimal debulking surgery in institutions with good QOL compliance compared to 19.9% in institutions with poor QOL compliance (p =0.0011). Overall survival (median 32.30 versus 23.29months; p =0.0006) and progression free survival (median 12.35 versus 9.92months; p =0.0002) were also significantly better. Conclusions: Survival and QOL after NACT followed by surgery was similar to survival and QOL after PDS followed by chemotherapy. However, institutions with good QOL compliance had better survival outcomes. [Copyright &y& Elsevier]

Introduction. Pharmacokinetic analysis of dynamic contrast enhanced magnetic resonance images (DCEMRI) allows for quantitative characterization of vascular properties of tumors. The aim of this study is twofold, first to determine if tumor regions with similar vascularization could be labeled by clustering methods, second to determine if the identified regions can be associated with local cancer relapse. Materials and methods. Eighty-one patients with locally advanced cervical cancer treated with chemoradiotherapy underwent DCEMRI with Gd-DTPA prior to external beam radiotherapy. The median follow-up time after treatment was four years, in which nine patients had primary tumor relapse. By fitting a pharmacokinetic two-compartment model function to the temporal contrast enhancement in the tumor, two pharmacokinetic parameters, Ktrans and ύύe, were estimated voxel by voxel from the DCEMR-images. Intratumoral regions with similar vascularization were identified by k-means clustering of the two pharmacokinetic parameter estimates over all patients. The volume fraction of each cluster was used to evaluate the prognostic value of the clusters. Results. Three clusters provided a sufficient reduction of the cluster variance to label different vascular properties within the tumors. The corresponding median volume fraction of each cluster was 38%, 46% and 10%. The second cluster was significantly associated with primary tumor control in a log-rank survival test (p-value: 0.042), showing a decreased risk of treatment failure for patients with high volume fraction of voxels. Conclusions. Intratumoral regions showing similar vascular properties could successfully be labeled in three distinct clusters and the volume fraction of one cluster region was associated with primary tumor control. [ABSTRACT FROM AUTHOR]

Purpose: To compare the severe late effects (Grade 3 or greater) for two groups of cervical cancer patients treated with the same external beam radiotherapy and two high-dose-rate intracavitary brachytherapy regimens and to investigate the influence of the dose delivered each week. Methods and Materials: For 120 patients, intracavitary brachytherapy was delivered with 33.6 Gy in eight fractions to Point A (HD group), and for 119, intracavitary brachytherapy was delivered with 29.4 Gy in seven fractions to Point A (LD group). The cumulative incidence of severe gastrointestinal and genitourinary late effects were calculated for both dose groups using Kaplan-Meier survival analysis. This method was also used to explore whether the number of weeks with different dose levels could predict the cumulative incidence of late effects. Results: The actuarial rate of developing severe gastrointestinal morbidity at 7 years was 10.7% and 8.3% for HD and LD groups, respectively. The rate for genitourinary morbidity was 6.6% for the HD group and 5.0% for the LD group, respectively. No significant difference was found between the two groups. The analyses showed that a marginally significant increase occurred in severe gastrointestinal complications as the number of weeks with a physical dose >20 Gy increased in the HD group (p = .047). Conclusion: To establish dose–response relationships for late complications, three-dimensional imaging and dose–volume histogram parameters are needed. We found some indications that 20 Gy/wk is an upper tolerance level when the dose to the International Commission on Radiation Units and Measurements rectum point is 81 Gyα/β=3 (isoeffective [equivalent] dose of 2-Gy fractions). However, additional investigations using three-dimensional data are needed. [Copyright &y& Elsevier]

Purpose: The aim of this cross-sectional study is to investigate the associations between pelvic radiotherapy (RT) and markers of intestinal absorption in cervical cancer survivors (CCSs). We compared patient data with normative data from a reference population and explored the associations between cobalamin status and clinically significant diarrhea and depression. Methods and Materials: Fifty-five CCSs treated with RT in 1994–1999 were included in 2005 in a follow-up questionnaire study exploring physical and psychological symptoms. Blood tests, including serum (S)-vitamin B12, S-methylmalonic acid, S-folate, erythrocyte-folate, and plasma homocysteine, were analyzed. Differences in median values between CCSs and reference populations were evaluated by using Wilcoxon tests. Associations between variables were examined by means of multiple regression analyses. Results: Median S-vitamin B12 level was significantly lower and median S-methylmalonic acid level was significantly higher in CCSs compared with the reference population (p < 0.001). Correction for renal function verified a likely cobalamin deficiency in 20% of CCSs (11 of 55). Diarrhea or depression was not significantly related to any of the mentioned markers of cobalamin or folate status. Fifteen percent of CCSs (8 of 55) had subnormal S-calcium values. Conclusions: Significant cobalamin deficiency was observed in 11 (20%) and low calcium level was observed in 8 CCSs (15%) 6–12 years after pelvic RT. Neither diarrhea nor depression was associated with this deficiency. Routine monitoring of S-vitamin B12 level is recommended, and regular intake of cobalamin should be considered in CCSs treated with RT. [Copyright &y& Elsevier]

Objectives. To examine the prognostic significance of the protein expression of E-cadherin, α-, β-, and γ-catenin in early squamous cervical carcinoma (SCC).Methods. We studied 219 patients who underwent radical hysterectomy and bilateral lymphadenectomy at our institution for stage IB SCC between 1987 and 1993. Immunohistochemistry using monoclonal antibodies against E-cadherin, α-, β-, and γ-catenin was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolapse served as controls.Results. Membrane expression for E-cadherin, α-, β-, and γ-catenin was decreased and low expression (≤50% positive cells) was found in 198/219 (90%), 154/219 (70%), 157/219 (72%), and 181/219 (83%) tumors, respectively, and high (>50% positive cells) in 21/219 (10%), 65/219 (30%), 62/219 (28%), and 38/219 (17%) tumors, respectively. In univariate analysis, all classical clinicopathological parameters but none of the investigated proteins were associated with prognosis. In multivariate analysis, only deep stromal invasion was independently related to survival.Conclusion. E-cadherin, α-, β-, and γ-catenin were not independently associated with prognosis in stage IB SCC. [Copyright &y& Elsevier]

Objectives. To examine the prognostic significance of the protein expression of cyclin E, cyclin A and cyclin D3, and of the proliferation markers Ki-67 and BM28 in early squamous cervical carcinoma (SCC).Methods. Tissue blocks from 221 patients who underwent radical hysterectomy and bilateral lymphadenectomy at our institution for stage IB SCC between 1987 and 1993 were available for this study. Immunohistochemistry using monoclonal antibodies against cyclin E, cyclin A, cyclin D3, Ki-67 and BM28 was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolapse served as controls.Results. Cyclin E, cyclin A, Ki-67 and BM28 expression was increased in SCC and high expression was observed in 81.5% (180/221), 35% (78/221), 25.5% (56/221) and 92% (204/221) of tumors, respectively. Cyclin D3 was decreased in SCC and low expression was found in 50.5% (111/220) of tumors. In univariate analysis, all classical clinicopathological parameters but none of the investigated proteins were associated with prognosis. In multivariate analysis, only deep stromal invasion was independently related to survival.Conclusion. Cyclin E, cyclin A and cyclin D3 and the proliferation markers Ki-67 and BM28 are not independently associated with prognosis in stage IB SCC. [Copyright &y& Elsevier]

Reports that ovarian cancer is the second most common gynecological cancer. Discussion of epithelial ovarian carcinoma; Aetiology; Pathogenesis; Pathology; Diagnosis; Treatment; Surgery; Chemotherapy; Conclusions.

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide biomarkers of the outcome of locally-advanced cervical carcinoma (LACC). There is, however, no agreement on how DCE-MR recordings should be analyzed. Previously, we have analyzed DCE-MRI data of LACC using non-model-based strategies. In the current study, we analyzed DCE-MRI data of LACC using the Tofts pharmacokinetic model, and the biomarkers derived from this analysis were compared with those derived from the non-model-based analyses.Methods: Eighty LACC patients given cisplatin-based chemoradiotherapy with curative intent were included in the study. Treatment outcome was recorded as disease-free survival (DFS) and overall survival (OS). DCE-MRI series were analyzed voxelwise to produce Ktrans and ve frequency distributions, and ROC analysis was used to identify the parameters of the frequency distributions having the greatest potential as biomarkers. The prognostic power of these parameters was compared with that of the non-model-based parameters LETV (low-enhancing tumor volume) and TVIS (tumor volume with increasing signal).Results: Poor DFS and OS were associated with low values of Ktrans, whereas there was no association between treatment outcome and ve. The Ktrans parameters having the greatest prognostic value were p35-Ktrans (the Ktrans value at the 35 percentile of a frequency distribution) and RV-Ktrans (the tumor subvolume with Ktrans values below 0.13 min- 1). Multivariate analysis including clinical parameters and p35-Ktrans or RV-Ktrans revealed that RV-Ktrans was the only independent prognostic factor of DFS and OS. There were significant correlations between RV-Ktrans and LETV and between RV-Ktrans and TVIS, and the prognostic power of RV-Ktrans was similar to that of LETV and TVIS.Conclusions: Biomarkers of the outcome of LACC can be provided by analyzing DCE-MRI series using the Tofts pharmacokinetic model. However, these biomarkers do not appear to have greater prognostic value than biomarkers determined by non-model-based analyses. [ABSTRACT FROM AUTHOR]

Background: There is significant evidence that DCE-MRI may have the potential to provide clinically useful biomarkers of the outcome of locally advanced cervical carcinoma. However, there is no consensus on how to analyze DCE-MRI data to arrive at the most powerful biomarkers. The purpose of this study was to analyze DCE-MRI data of cervical cancer patients by using the Brix pharmacokinetic model and to compare the biomarkers derived from the Brix analysis with biomarkers determined by non-model-based analysis [i.e., low-enhancing tumor volume (LETV) and tumor volume with increasing signal (TVIS)] of the same patient cohort. Material and methods: DCE-MRI recordings of 80 patients (FIGO stage IB–IVA) treated with concurrent cisplatin-based chemoradiotherapy were analyzed voxel-by-voxel, and frequency distributions of the three parameters of the Brix model (ABrix, kep, and kel) were determined. Moreover, risk volumes were calculated from the Brix parameters and termed RV-ABrix, RV-kep, and RV-kel, where the RVs represent the tumor volume with voxel values below a threshold value determined by ROC analysis. Disease-free survival (DFS) and overall survival (OS) were used as measures of treatment outcome. Results: Significant associations between the median value or any other percentile value of ABrix, kep, or kel and treatment outcome were not found. However, RV-ABrix, RV-kep, and RV-kel correlated with DFS and OS. Multivariate analysis revealed that the prognostic power of RV-ABrix, RV-kep, and RV-kel was independent of well-established clinical prognostic factors. RV-ABrix, RV-kep, and RV-kel correlated with each other as well as with LETV and TVIS. Conclusion: Strong biomarkers of the outcome of locally advanced cervical carcinoma can be provided by subjecting DCE-MRI series to pharmacokinetic analysis using the Brix model. The prognostic power of these biomarkers is not necessarily superior to that of biomarkers identified by non-model-based analyses. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer antigen 125 (CA-125) is a protein found at a high concentration in the blood of patients with specific types of cancer, mainly ovarian cancer. In 2004, the Gynecologic Cancer Intergroup (GCIG) proposed criteria defining response to treatment, as well as disease progression, based on the CA-125 concentration. Ever since, for the follow-up of ovarian cancer patients, the CA-125 concentration and/or CT-scans are used. This paper aims to compare different summaries of CA-125 evolution in the 3 to 6 months following treatment initiation in newly diagnosed advanced ovarian cancer and explore their prognostic capacity to predict overall survival. Based on individual patient data from the GCIG meta-analysis, we propose the most appropriate timeframe between follow-up and the prediction horizon in order to obtain robust, dynamic, individual predictions. (1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients' monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy. [ABSTRACT FROM AUTHOR]

Background:Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide prognostic biomarkers for cervix carcinoma. We have shown previously that the early phase of the signal intensity-versus-time curve (SITC) may have significant prognostic power. The purpose of the present investigation was to explore the prognostic value of the late phase of the SITC. Material and methods:DCE-MRI data of 80 patients (FIGO stage IB–IVA) treated with concurrent chemoradiotherapy were examined. Four parameters were calculated from the late-phase SITC: tumor volume with decreasing signal, tumor fraction with decreasing signal, tumor volume with increasing signal (TVIS), and tumor fraction with increasing signal. Results:Multivariate analysis involving clinical parameters and late-phase SITC parameters suggested that TVIS is a strong independent prognostic factor for both disease-free and overall survival. When early-phase SITC parameters were included in the multivariate analysis, the early-phase SITC, but not the late-phase SITC, was found to have independent prognostic value. Conclusion:The late-phase SITC can provide prognostic factors for the outcome of cervix carcinoma, that is, a large tumor volume with increasing late-phase SITCs is associated with poor outcome. However, the prognostic power of the late-phase SITC is not as strong as that of the early-phase SITC. [ABSTRACT FROM AUTHOR]

• In cervical cancer, multiparametric MR images were fused into hypoxia images. • Imaging-based hypoxic fraction (HF) identified low-risk patients with 95% precision. • Integration of MRI (HF) and FDG-PET (SUV) improved detection of high-risk patients. • A candidate multimodal imaging biomarker, HF/SUV 50 , was defined. • HF/SUV 50 is based on standard diagnostic images and feasible in clinical practice. MRI, applying dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) sequences, and 18F-fluorodeoxyglucose (18F-FDG) PET/CT provide information about tumor aggressiveness that is unexploited in treatment of locally advanced cervical cancer (LACC). We investigated the potential of a multimodal combination of imaging parameters for classifying patients according to their risk of recurrence. Eighty-two LACC patients with diagnostic MRI and FDG-PET/CT, treated with chemoradiotherapy, were collected. Thirty-eight patients with MRI only were included for validation of MRI results. Endpoints were survival (disease-free, cancer-specific, overall) and tumor control (local, locoregional, distant). Ktrans, reflecting vascular function, apparent diffusion coefficient (ADC), reflecting cellularity, and standardized uptake value (SUV), reflecting glucose uptake, were extracted from DCE-MR, DW-MR and FDG-PET images, respectively. By applying an oxygen consumption and supply-based method, ADC and Ktrans parametric maps were voxel-wise combined into hypoxia images that were used to determine hypoxic fraction (HF). HF showed a stronger association with outcome than the single modality parameters. This association was confirmed in the validation cohort. Low HF identified low-risk patients with 95% precision. Based on the 50th SUV-percentile (SUV 50), patients with high HF were divided into an intermediate- and high-risk group with high and low SUV 50 , respectively. This defined a multimodality biomarker, HF/SUV 50. HF/SUV 50 increased the precision of detecting high-risk patients from 41% (HF alone) to 57% and showed prognostic significance in multivariable analysis for all endpoints. Multimodal combination of MR- and FDG-PET/CT-images improves classification of LACC patients compared to single modality images and clinical factors. [ABSTRACT FROM AUTHOR]

The role of molecular classification in patients with low/intermediate risk endometrial cancer (EC) is uncertain. Higher precision in diagnostics will inform the unsettled debate on optimal adjuvant treatment. We aimed to determine the association of molecular profiling with patterns of relapse and survival. This retrospective cohort study included patients referred to The Norwegian Radium Hospital, Oslo University Hospital from 2006–2017. Patients with low/intermediate risk EC were molecularly classified as pathogenic polymerase epsilon (POLE)-mutated, mismatch repair deficient (MMRd), p53 abnormal, or no specific molecular profile (NSMP). The main outcomes were time to recurrence (TTR) and cancer-specific survival (CSS). Of 626 patients, 610 could be molecularly classified. Fifty-seven patients (9%) had POLE-mutated tumors, 202 (33%) had MMRd tumors, 34 (6%) had p53 abnormal tumors and 317 (52%) had NSMP tumors. After median follow-up time of 8.9 years, there was a statistically significant difference in TTR and CSS by molecular groups. Patients with p53 abnormal tumors had poor prognosis, with 10 of the 12 patients with relapse presenting with para-aortic/distant metastases. Patients with POLE mutations had excellent prognosis. In the NSMP group, L1CAM expression was associated with shorter CSS but not TTR. The differences in outcome by molecular groups are driven by differences in relapse frequency and -patterns and demand a higher precision in diagnostics, also in patients with low/intermediate risk EC. Tailored adjuvant treatment strategies need to consider systemic treatment for patients with p53 abnormal tumors and de-escalated treatment for patients with POLE mutated tumors. • Clarifying the role of molecular classification in low/intermediate risk endometrial cancer. • Time to relapse and survival differed signifi cantly by molecular groups. • roboPatients with p53 abnormal tumors had poor outcome. • roboPatients with POLE mutated tumors had excellent survival. • pmMolecular classification is crucial for tailoring of adjuvant treatment. [ABSTRACT FROM AUTHOR]

Background. The histopathological classification and staging system for uterine sarcoma (US) were revised in 2003 and 2009, respectively. However, there is currently no consensus on the significance of various prognostic factors. Therefore the available clinicopathological data on US are summarized in this review. Methods. Articles on uterine sarcoma published in English from 1970 to 2011 were identified systematically by computer-based searches in Medline and the Cochrane Library. Results. Prognosis of US is poor, with a five-year survival rate as low as 30%. The most common histological types are leiomyosarcoma (LMS, 63%), endometrial stromal sarcoma (ESS, 21%), adenosarcoma (6%), undifferentiated sarcoma (5%) and other types (5%). Carcinosarcoma is a mixed tumor, which is today regarded as a subset of endometrial carcinoma. Disease stage is the most important prognostic factor for all types of US. However, the prognosis of stage I LMS is also significantly related to tumor size and mitotic index (MI), and stage I ESS is related to MI and tumor cell necrosis (TCN). In adenosarcoma, TCN is the only significant histopathological prognostic factor. Information on the use of preoperative imaging for staging purposes is lacking. Total hysterectomy is the cornerstone of US treatment. The ovary can be preserved in premenopausal women with early-stage LMS and ESS, and routine lymphadenectomy is not necessary unless enlarged lymph nodes are present. As tumor-free resection margins at primary surgery are the most important prognostic factor for survival, sarcoma surgery should be centralized. Adjuvant treatment has changed from radiation therapy to chemotherapy over the last decades, without any change in survival. Conclusion. There are differences in survival between histological types of US. LMS and ESS can be divided into different prognostic groups and should be treated separately. [ABSTRACT FROM AUTHOR]

Objective: To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and primary peritoneal cancer. This quality assurance project was performed within the EORTC-GCG 55971/NCIC-CTG OV13 study comparing primary debulking surgery followed by chemotherapy with neoadjuvant chemotherapy and interval debulking surgery. Methods: Four hundred and seventy nine pathology reports from 40 institutions in 11 different countries were checked for the following quality indicators: macroscopic description of all specimens, measuring and weighing of major specimens, description of tumour origin and differentiation. Results: All specimens were macroscopically described in 92.3% of the reports. All major samples were measured and weighed in 59.9% of the reports. A description of the origin of the tumour was missing in 20.5% of reports of the primary debulking group and in 23.4% of the interval debulking group. Assessment of tumour differentiation was missing in 10% of the reports after primary debulking and in 20.8% of the reports after interval debulking. Completeness of reports is positively correlated with accrual volume and adversely with hospital volume or type of hospital (academic versus non-academic). Quality of reports differs significantly by country. Conclusion: This audit of ovarian cancer pathology reports reveals that in a substantial number of reports basic pathologic data are missing, with possible adverse consequences for the quality of cancer care. Specialisation by pathologists and the use of standardised synoptic reports can lead to improved quality of reporting. Further research is needed to better define pre- and post-operative diagnostic criteria for ovarian cancer treated with neoadjuvant chemotherapy. [Copyright &y& Elsevier]

Background: The Sexual Activity Questionnaire (SAQ) has been used in several trials of gynecological diseases and breast cancer, but normative data are lacking. The SAQ is the first patient self-administered questionnaire used to assess female sexuality in Norway, and we wanted to examine the psychometrics of the SAQ, reasons for sexual inactivity, and scorings on the SAQ function scale (SAQ-F). Methods: From public official address lists 2800 women aged 20–69 years were invited to take part in an anonymous questionnaire study, including the SAQ. Altogether 1165 women (42%) responded, and the response rates varied with age. Descriptive statistics and principal component analysis (PCA) of the SAQ were performed. Results: PCA confirmed a three-factor structure of the SAQ-F: habit, pleasure, and discomfort from sexual intercourse. The internal consistency of the SAQ-F showed a Cronbach's coefficient alpha of 0.86. “No current partner” was the main reason for sexual inactivity in all age groups. Tiredness as a reason for nonactivity was a significantly more cited cause among women in the age group 35–55 years compared with the younger and older groups. The prevalence of pleasure from sexual intercourse dropped significantly with increasing age. Normative findings on the SAQ-F are presented as percentiles in relation to age groups. Conclusions: The SAQ is a short and discrete screening tool for sexual function, with good psychometric properties. Changes with age as to pleasure, habit, and discomfort confirmed construct validity of the SAQ-F, and the findings were used to produce age-related percentile scores of the SAQ-F considered helpful for clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: Objectives. : To analyze expressions of the EphB2 and EphB4 receptors in ovarian carcinomas and explore their clinicopathological correlations and prognostic value. Methods. : 115 patients with advanced ovarian carcinoma FIGO IIB to IV were involved. RT-PCR and immunohistochemistry were used to examine the expressions of EphB2/B4 receptor mRNA and protein. Correlations between protein expression and clinicopathological factors were also analyzed. Results. : Ovarian carcinoma patients with age elder than 60 years had higher EphB2 expression than younger patients. Expression of EphB2 and EphB4 protein did not significantly correlate with any other clinical variables, including FIGO stage, residual tumor, histological type and differentiation grade. No significant correlation between mRNA and protein expression level for both of these receptors was seen. It was found that patients with strong immunostaining for EphB2 (P = 0.03) or EphB4 (P = 0.003) receptors had poorer survival, and patients with strong immunostaining for EphB4 receptor showed poorer response to chemotherapy (P = 0.036). Conclusions. : These studies suggest that EphB2 and B4 receptors are of prognostic value and EphB4 receptor may be an independent predictor of chemotherapy response in ovarian cancer patients. [Copyright &y& Elsevier]

Objectives. To analyze the expressions of the protein and mRNA of EphA2 and EphrinA-1 in squamous cell cervical carcinomas and explore their prognostic value in cervical carcinoma.Methods. Immunohistochemistry was used to assess the protein expressions of EphA2 and EphrinA-1 in 206 patients with squamous cervical carcinoma FIGO stage Ia-IVb. Frozen tissues from 20 cases in which the tumors showed variable EphA2 and EphrinA-1protein expressions were used for laser capture microdissection (LCM). About 50 cancer cells in each frozen section were captured with the LCM method and processed for RT-PCR detection of EphA2 and EphrinA-1 mRNA.Results. Among the 206 squamous cervical carcinomas, 23 (11.2%) showed negative, 94(45.6%) weakly positive, 72 (35.0%) moderately positive, and 17 (8.3%) strongly positive for EphA2 immunostaining. For EphrinA-1 protein expression, 17 tumors (8.3%) showed negative, 95 (46.1%) weakly positive, 71(34.5%) moderately positive, and 23 (11.2%) strongly positive. EphA2 and EphrinA-1 often colocalized in the same tumor areas and vascular endothelial cells. Variable amount of mRNA expressions of EphA2 and EphrinA-1 were observed in the 20 tumors analyzed. There was no significant correlation between the overexpressions of EphA2/EphrinA-1 and age and FIGO stage. High level of EphA2 was significantly associated with overall survival in univariate and multivariate analysis. Moderate to high EphrinA-1 protein expression was significantly associated with overall survival in multivariate analysis. The combined high level of expression of EhpA2 and moderate to high level of expression of EphrinA-1 was a strong predictor of overall survival.Conclusions. High levels of EphA2 together with moderate to high level of EphrinA-1 protein expressions in squamous cervical carcinoma were predictive for a shorter overall survival and these proteins may be valuable prognostic markers. [Copyright &y& Elsevier]

Development of cervical carcinomas is strongly associated with presence of human papilloma virus (HPV). Recently we found that young patients with breast cancer had a higher frequency of skewed X inactivation in peripheral blood cells, indicating an effect of X-linked genes on breast cancer development. In this study, we investigated the frequency of skewed X-inactivation pattern in blood and tumor biopsies from patients with cervical cancer. No difference in the frequency of skewed X inactivation in blood was found between 142 patients and 437 age-matched controls. Elderly females have a higher frequency of skewed X inactivation in blood cells than younger females. An age effect was confirmed in this study for blood cells in both patients and controls. A tendency to an age effect was also found in the tumor biopsies. The correlation between X inactivation in blood and biopsies was 0.39 (P<0.001), showing that the X inactivation in biopsies to some degree reflects skewing in blood. Furthermore, of eight patients with a skewing of &ges;75% in biopsies, seven patients had a skewing in the same direction in their blood cells (P = 0.03). Our results indicate that if X-inactivation analysis is to be used in clonality studies of cervical cancers, it is essential to consider both the age and the X-inactivation pattern in blood cells. [Copyright &y& Elsevier]

Fibroblast growth factor receptor 3 (FGFR3) seems to play an inhibitory role in bone development, as activating mutations in the gene underlie disorders such as achondroplasia and thanatophoric dysplasia. Findings from multiple myeloma (MM) indicate that FGFR3 also can act as an oncogene, and mutation of codon 249 in the fibroblast growth factor receptor 3 (FGFR3) gene was recently detected in 3/12 primary cervical carcinomas. We have analysed 91 cervical carcinomas for this specific S249C mutation using amplification created restriction site methodology (ACRS), and detected no mutations. Immunohistochemistry was performed on 73 of the tumours. Reduced protein staining was seen in 43 (58.8%) samples. Six of the tumours (8.2%) revealed increased protein staining compared with normal cervical tissue. These patients had a better prognosis than those with reduced or normal levels, although not statistically significant.This report weakens the hypothesis of FGFR3 as an oncogene of importance in cervical carcinomas. [ABSTRACT FROM AUTHOR]

Background: Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations.Methods: We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial (NCT00003636) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic.Findings: Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0-9·6; EORTC, 9·2 years [IQR 7·3-10·4]; CHORUS, 5·9 years [IQR 4·3-7·4]). Median age was 63 years (IQR 56-71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8-13·0). 55 (5%) women had FIGO stage II-IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1-51·3] and 26·9 months [12·7-50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86-1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7-53·7) and 23·6 months (10·5-46·9), respectively (HR 1·20, 95% CI 1·06-1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1-47·6] and 21·2 months [10·0-36·4], respectively; HR 0·76, 95% CI 0·58-1·00; p=0·048; median progression-free survival 10·6 months [7·9-15·0] and 9·7 months [5·2-13·2], respectively; HR 0·77, 95% CI 0·59-1·00; p=0·049).Interpretation: Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC-IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status.Funding: National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer). [ABSTRACT FROM AUTHOR]

Purpose: The poor outcome of locally advanced cervical cancer has been associated with extensive hypoxia and high interstitial fluid pressure (IFP) in the primary tumor. In the present study, measures of tumor hypoxia and IFP were provided using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) and related to the treatment outcomes.Methods and Materials: The data from 54 cervical cancer patients treated with concurrent cisplatin-based chemoradiotherapy were studied. A low-enhancing tumor volume (LETV) and peritumoral fluid flow velocity (v0) were used as measures of tumor hypoxia and IFP, respectively.Results: Poor disease-free survival and overall survival were associated with large LETV and high v0. The multivariate analysis results suggested that the prognostic power of v0 and LETV is independent of established clinical prognostic factors and that the prognostic power of v0 is strong compared with that of LETV. The outcomes was especially poor for patients with a high v0 combined with a large LETV and especially good for those with a low v0 combined with a small LETV, with 5-year disease-free survival and overall survival of 13% versus 100%, respectively.Conclusions: The outcome of locally advanced cervical carcinoma seems to be influenced strongly by the tumor IFP and to a lesser extent by tumor hypoxia. DCE-MRI might have the power to provide important biomarkers for the outcome of cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Chromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation.Methods: Machine learning algorithms analysed the chromatin organisation in 461 000 images of tumour cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at the Aker University Hospital (Oslo, Norway). The resulting marker of chromatin heterogeneity, termed Nucleotyping, was subsequently independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study (UK); 391 patients with stage II colorectal cancer in the QUASAR 2 trial; 246 patients with stage I ovarian carcinoma; 354 patients with uterine sarcoma; 307 patients with prostate carcinoma; and 791 patients with endometrial carcinoma. The primary outcome was cancer-specific survival.Findings: In all patient cohorts, patients with chromatin heterogeneous tumours had worse cancer-specific survival than patients with chromatin homogeneous tumours (univariable analysis hazard ratio [HR] 1·7, 95% CI 1·2-2·5, in the discovery cohort; 1·8, 1·0-3·0, in the Gloucester validation cohort; 2·2, 1·1-4·5, in the QUASAR 2 validation cohort; 3·1, 1·9-5·0, in the ovarian carcinoma cohort; 2·5, 1·8-3·4, in the uterine sarcoma cohort; 2·3, 1·2-4·6, in the prostate carcinoma cohort; and 4·3, 2·8-6·8, in the endometrial carcinoma cohort). After adjusting for established prognostic patient characteristics in multivariable analyses, Nucleotyping was prognostic in all cohorts except for the prostate carcinoma cohort (HR 1·7, 95% CI 1·1-2·5, in the discovery cohort; 1·9, 1·1-3·2, in the Gloucester validation cohort; 2·6, 1·2-5·6, in the QUASAR 2 cohort; 1·8, 1·1-3·0, for ovarian carcinoma; 1·6, 1·0-2·4, for uterine sarcoma; 1·43, 0·68-2·99, for prostate carcinoma; and 1·9, 1·1-3·1, for endometrial carcinoma). Chromatin heterogeneity was a significant predictor of cancer-specific survival in microsatellite unstable (HR 2·9, 95% CI 1·0-8·4) and microsatellite stable (1·8, 1·2-2·7) stage II colorectal cancer, but microsatellite instability was not a significant predictor of outcome in chromatin homogeneous (1·3, 0·7-2·4) or chromatin heterogeneous (0·8, 0·3-2·0) stage II colorectal cancer.Interpretation: The consistent prognostic prediction of Nucleotyping in different biological and technical circumstances suggests that the marker of chromatin heterogeneity can be reliably assessed in routine clinical practice and could be used to objectively assist decision making in a range of clinical settings. An immediate application would be to identify high-risk patients with stage II colorectal cancer who might have greater absolute benefit from adjuvant chemotherapy. Clinical trials are warranted to evaluate the survival benefit and cost-effectiveness of using Nucleotyping to guide treatment decisions in multiple clinical settings.Funding: The Research Council of Norway, the South-Eastern Norway Regional Health Authority, the National Institute for Health Research, and the Wellcome Trust. [ABSTRACT FROM AUTHOR]

Introduction: Gynecological cancer patients are routinely followed up for five years after primary treatment. However, the value of such follow up has been debated, as retrospective studies indicate that first recurrence is often symptomatic and occurs within two to three years of primary treatment. We prospectively investigated time to first recurrence, symptoms at recurrence, diagnostic procedures, and recurrence treatment in gynecological cancer patients after primary curative treatment.Material and Methods: Clinicians from 21 hospitals in Norway interviewed 680 patients with first recurrence of gynecological cancer (409 ovarian, 213 uterine, and 58 cervical cancer patients) between 2012 and 2016. A standardized questionnaire was used to collect information on self-reported and clinical variables.Results: Within two years of primary treatment, 72% of ovarian, 64% of uterine, and 66% of cervical cancer patients were diagnosed with first recurrence, and 54, 67, and 72%, respectively, had symptomatic recurrence. Of symptomatic patients, 25-50% failed to make an appointment before their next scheduled follow-up visit. Computer tomography was the most common diagnostic procedure (89% of ovarian, 76% of uterine, and 62% of cervical cancer patients), and recurrence treatment in terms of chemotherapy was most frequently planned (86% of ovarian, 46% of uterine, and 62% of cervical cancer patients).Conclusions: A majority of patients experienced symptomatic recurrence, but many patients failed to make an appointment earlier than scheduled. Most first recurrences occurred within two years of primary treatment; the mean annual incidence rate for years 3-5 after primary treatment was <7%. New models for follow up of gynecological cancer patients could be considered. [ABSTRACT FROM AUTHOR]

Background: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to optimise their use.Methods: Blood samples were collected during and following treatment and, where appropriate, upon progression from ovarian cancer patients in ICON7, a randomised phase III trial of carboplatin and paclitaxel with or without bevacizumab. Plasma concentrations of 15 circulating angio-biomarkers were measured using a validated multiplex ELISA, analysed through a novel network analysis and their relevance to the PFS then determined.Results: Samples (n=650) were analysed from 92 patients. Bevacizumab induced correlative relationships between Ang1 and Tie2 plasma concentrations, which reduced after initiation of treatment and remained decreased until progressive disease occurred. A 50% increase from the nadir in the concentration of circulating Tie2 (or the product of circulating Ang1 and Tie2) predicted tumour progression. Combining Tie2 with GCIG-defined Ca125 data yielded a significant improvement in the prediction of progressive disease in patients receiving bevacizumab in comparison with Ca125 alone (74.1% vs 47.3%, P<1 × 10(-9)).Conclusions: Tie2 is a vascular progression marker for bevacizumab-treated ovarian cancer patients. Tie2 in combination with Ca125 provides superior information to clinicians on progressive disease in patients with VEGFi-treated ovarian cancers. [ABSTRACT FROM AUTHOR]

Hypoxia is an adverse factor in cervical cancer, and hypoxia-related gene expression could be a powerful biomarker for identifying the aggressive hypoxic tumors. Reverse transcription quantitative PCR (RT-qPCR) is a valuable method for gene expression studies, but suitable reference genes for data normalization that are independent of hypoxia status and clinical parameters of cervical tumors are lacking. In the present work, we aimed to identify reference genes for RT-qPCR studies of hypoxia in squamous cervical cancer. From 422 candidate reference genes selected from the literature, we used Illumina array-based expression profiles to identify 182 genes not affected by hypoxia in cervical cancer, i.e. genes regulated by hypoxia in eight cervical cancer cell lines or correlating with the hypoxia-associated dynamic contrast-enhanced magnetic resonance imaging parameter ABrix in 42 patients, were excluded. Among the 182 genes, nine candidates (CHCHD1, GNB2L1, IPO8, LASP1, RPL27A, RPS12, SOD1, SRSF9, TMBIM6) that were not associated with tumor volume, stage, lymph node involvement or disease progression in array data of 150 patients, were selected for further testing by RT-qPCR. geNorm and NormFinder analyses of RT-qPCR data of 74 patients identified CHCHD1, SRSF9 and TMBIM6 as the optimal set of reference genes, with stable expression both overall and across patient subgroups with different hypoxia status (ABrix) and clinical parameters. The suitability of the three reference genes were validated in studies of the hypoxia-induced genes DDIT3, ERO1A, and STC2. After normalization, the RT-qPCR data of these genes showed a significant correlation with Illumina expression (P<0.001, n = 74) and ABrix (P<0.05, n = 32), and the STC2 data were associated with clinical outcome, in accordance with the Illumina data. Thus, CHCHD1, SRSF9 and TMBIM6 seem to be suitable reference genes for studying hypoxia-related gene expression in squamous cervical cancer samples by RT-qPCR. Moreover, STC2 is a promising prognostic hypoxia biomarker in cervical cancer. [ABSTRACT FROM AUTHOR]

Background and purpose Several investigators have indicated that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has the potential to provide biomarkers for personalized treatment of cervical carcinoma. However, some clinical studies have suggested that treatment failure is associated with low tumor signal enhancement, whereas others have reported associations between high signal enhancement and poor outcome. The purpose of this investigation was to clear up these conflicting reports and to provide a method for identifying biomarkers that easily can be implemented in routine DCE-MRI diagnostics. Methods The study involved 85 patients (FIGO stage IB through IVA) treated with concurrent chemoradiotherapy. Low-enhancing tumor volume (LETV) and low-enhancing tumor fraction (LETF), defined as the volume and fractional volume of low-enhancing voxels, respectively, were calculated from signal intensities recorded within 1 min after contrast administration by using two methods reported to give conflicting conclusions. Results Multivariate analysis involving tumor volume, lymph node status, FIGO stage, and LETV or LETF revealed that LETV and LETF provided independent prognostic information on treatment outcome, independent of the method of calculation. Conclusion Low signal enhancement is associated with poor prognosis in cervical carcinoma, and biomarkers predicting poor outcome can be provided by short-term DCE-MRI without advanced image analysis. [ABSTRACT FROM AUTHOR]

Background and purpose High tumor interstitial fluid pressure (IFP) is associated with poor outcome in locally advanced carcinoma of the uterine cervix. We have recently developed a noninvasive assay of the IFP of tumors, and in this assay, the outward interstitial fluid flow velocity at the tumor surface ( v 0 ) is measured by Gd-DTPA-based DCE-MRI and used as a parameter for IFP. Here, we investigated the independent prognostic significance of v 0 in cervical cancer patients given cisplatin-based concurrent chemoradiotherapy with curative intent. Patients The study involved 62 evaluable patients from a cohort of 74 consecutive patients (Stage IB through IIIB) with a median follow-up of 5.5 years. Results The actuarial disease-free survival (DFS) and overall survival (OS) at 5 years were 67% and 76%, respectively. Significant associations were found between v 0 dichotomized about the median value and DFS and OS, both in the total patient cohort and a subcohort of 40 Stage IIB patients. Multivariate analysis involving stage, tumor volume, lymph node status, and v 0 revealed that only v 0 provided independent prognostic information about DFS and OS. Conclusion This investigation demonstrates a strong, independent prognostic impact of the pretreatment peritumoral fluid flow velocity in cervical cancer. [ABSTRACT FROM AUTHOR]

Background We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. Methods We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. Results Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. Conclusion Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients. Trial registration Trial identification number (Clinical Trials.gov): NCT01965080. Nordic Society of Gynecological Oncology: NSGO-EC-0302. EudraCT number: 2004-001103-35. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer (EC) is the most common gynaecologic malignancy in developed countries. Most patients are sufficiently treated with removal of uterus, tubes and ovaries. It depends on the estimated risk of metastases at diagnosis if more extensive surgery (removal of lymph nodes, peritoneum and/or omentum), to detect small metastases, is indicated. Metastases are associated with a higher risk of recurrence and justify adjuvant treatment (i.e., radiotherapy and/or chemotherapy). Recently it is advised to also subdivide EC into four molecular subgroups. Each subgroup is highly associated to a certain risk of recurrence and helps to decide for adjuvant treatment. What surgery should be performed in each of the subgroups is currently unknown. Moreover, it is uncertain if integration of other factors into the molecular classification could help to improve the risk classification. This review summarizes different aspects of surgery. Moreover, the relation between metastases and other factors including molecular classification are evaluated. Endometrial cancer (EC) is the most common gynaecologic malignancy in developed countries. The main challenge in EC management is to correctly estimate the risk of metastases at diagnosis and the risk to develop recurrences in the future. Risk stratification determines the need for surgical staging and adjuvant treatment. Detection of occult, microscopic metastases upstages patients, provides important prognostic information and guides adjuvant treatment. The molecular classification subdivides EC into four prognostic subgroups: POLE ultramutated; mismatch repair deficient (MMRd); nonspecific molecular profile (NSMP); and TP53 mutated (p53abn). How surgical staging should be adjusted based on preoperative molecular profiling is currently unknown. Moreover, little is known whether and how other known prognostic biomarkers affect prognosis prediction independent of or in addition to these molecular subgroups. This review summarizes the factors incorporated in surgical staging (i.e., peritoneal washing, lymph node dissection, omentectomy and peritoneal biopsies), and its impact on prognosis and adjuvant treatment decisions in an era of molecular classification of EC. Moreover, the relation between FIGO stage and molecular classification is evaluated including the current gaps in knowledge and future perspectives. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To assess the prognostic value of pharmacokinetic parameters derived from pre-chemoradiotherapy dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of cervical cancer patients. Materials and methods: Seventy-eight patients with locally advanced cervical cancer underwent DCE-MRI with Gd-DTPA before chemoradiotherapy. The pharmacokinetic Brix and Tofts models were fitted to contrast enhancement curves in all tumor voxels, providing histograms of several pharmacokinetic parameters (Brix: ABrix , kep , kel , Tofts: Ktrans , νe ). A percentile screening approach including log-rank survival tests was undertaken to identify the clinically most relevant part of the intratumoral parameter distribution. Clinical endpoints were progression-free survival (PFS) and locoregional control (LRC). Multivariate analysis including FIGO stage and tumor volume was used to assess the prognostic significance of the imaging parameters. Results: ABrix , kel , and Ktrans were significantly (P <0.05) positively associated with both clinical LRC and PFS, while νe was significantly positively correlated with PFS only. kep showed no association with any endpoint. ABrix was positively correlated with Ktrans and νe , and showed the strongest association with endpoint in the log-rank testing. kel and Ktrans were independent prognostic factors in multivariate analysis with LRC as endpoint. Conclusions: Parameters estimated by pharmacokinetic analysis of DCE-MR images obtained prior to chemoradiotherapy may be used for identifying patients at risk of treatment failure. [Copyright &y& Elsevier]

Genomic instability and copy number alterations in cancer are generally associated with poor prognosis; however, recent studies have suggested that extreme levels of genomic aberrations may be beneficial for the survival outcome for patients with specific tumour types. We investigated the extent of genomic instability in predominantly high-grade serous ovarian cancers (SOC) using two independent datasets, generated in Norway (n = 74) and Australia (n = 70), respectively. Genomic instability was quantified by the Total Aberration Index (TAI), a measure of the abundance and genomic size of copy number changes in a tumour. In the Norwegian cohort, patients with TAI above the median revealed significantly prolonged overall survival (p<0.001) and progression-free survival (p<0.05). In the Australian cohort, patients with above median TAI showed prolonged overall survival (p<0.05) and moderately, but not significantly, prolonged progression-free survival. Results were confirmed by univariate and multivariate Cox regression analyses with TAI as a continuous variable. Our results provide further evidence supporting an association between high level of genomic instability and prolonged survival of high-grade SOC patients, possibly as disturbed genome integrity may lead to increased sensitivity to chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Knowledge of the molecular background of functional magnetic resonance (MR) images is required to fully exploit their potential in cancer management. We explored the prognostic impact of dynamic contrast-enhanced MR imaging (DCE-MRI) parameters in cervical cancer combined with global gene expression data to reveal their underlying molecular phenotype and construct a representative gene signature for the relevant parameter. On the basis of 78 patients with cervical cancer subjected to curative chemoradiotherapy, we identified the prognostic DCE-MRI parameter ABrix by pharmacokinetic analysis of pretreatment images based on the Brix model, in which tumors with low ABrix appeared to be most aggressive. Gene set analysis of 46 tumors with pairwise DCE-MRI and gene expression data showed a significant correlation between ABrix and the hypoxia gene sets, whereas gene sets related to other tumor phenotypes were not significant. Hypoxia gene sets specific for cervical cancer created in cell culture experiments, including both targets of the hypoxia inducible factor (HIF1α) and the unfolded protein response, were the most significant. In the remaining 32 tumors, low ABrix was associated with upregulation of HIF1α protein expression, as assessed by immunohistochemistry, consistent with increased hypoxia. On the basis of the hypoxia gene sets, a signature of 31 genes that were upregulated in tumors with low ABrix was constructed. This DCE-MRI hypoxia gene signature showed prognostic impact in an independent validation cohort of 109 patients. Our findings reveal the molecular basis of an aggressive hypoxic phenotype and suggest the use of DCE-MRI to noninvasively identify patients with hypoxia-related chemoradioresistance. [ABSTRACT FROM AUTHOR]

Background: Nuclear texture analysis gives information about the spatial arrangement of the pixel gray levels in a digitized microscopic nuclear image, providing texture features that may be used as quantitative tools for prognosis of human cancer. The aim of the study was to evaluate the prognostic value of adaptive nuclear texture features in early stage ovarian cancer. Methods: 246 cases of early stage ovarian cancer were included in the analysis. Isolated nuclei (monolayers) were prepared from 50 μm tissue sections and stained with Feulgen-Schiff. Local gray level entropy was measured within small windows of each nuclear image and stored in gray level entropy matrices. A compact set of adaptive features was computed from these matrices. Results: Univariate Kaplan-Meier analysis showed significantly better relapse-free survival (p < 0.001) for patients with low adaptive feature values compared to patients with high adaptive feature values. The 10-year relapse-free survival was about 78% for patients with low feature values and about 52% for patients with high feature values. Adaptive features were found to be of independent prognostic significance for relapse-free survival in a multivariate analysis. Conclusion: Adaptive nuclear texture features from entropy matrices contain prognostic information and are of independent prognostic significance for relapse-free survival in early stage ovarian cancer. [ABSTRACT FROM AUTHOR]

Abstract: DNA ploidy analysis is useful for prognostication in cancer patients, but the genomic details underlying ploidy changes are not fully understood. To improve this understanding, we compared DNA ploidy status with karyotypic and comparative genomic hybridization data on 51 endometrial adenocarcinomas. Out of 34 DNA diploid tumors evaluated by CGH, 16 (47%) showed imbalances, though only two had more than four copy number changes. Ten (29%) had aberrations involving chromosome 1, seven (21%) involving chromosome 10, while one tumor had a chromosome 8 aberration. Four of the seven DNA tetraploid tumors (57%) had imbalances detected by CGH with two (29%) having more than four. Six out of eight DNA aneuploid tumors showed imbalances by CGH, with five (63%) having more than four. The aberrations were observed on chromosomes 1 and 8 in five/eight (63%) cases while four imbalances (50%) involved chromosomes 5, 7 and X. Not surprisingly, we observed a significant correlation between increasing DNA ploidy complexity and increasing number of copy alterations. Gains of material from chromosomes 8 and 7 might be specifically correlated to DNA aneuploidy in endometrial adenocarcinomas since 63% and 50% of the aneuploid compared to 3% of the diploid tumors showed imbalances involving these chromosomes. [Copyright &y& Elsevier]

Abstract: Purpose: We have applied the sensitive and specific in situ proximity ligation assay (PLA) to characterize Tyr1068 phosphorylation of the epidermal growth factor receptor (EGFR) in cervical cancer in relation to the protein level and gene dosage. Materials and methods: Pretreatment tumor biopsies from 178 patients were analyzed. EGFR protein level was determined by immunohistochemistry, and Tyr1068 phosphorylation was detected with PLA in 97 EGFR positive tumors. EGFR gene dosage was derived from array comparative genomic hybridization of 86 cases. Results: EGFR was expressed in most tumors, whereas phosphorylation was seen in about half of the EGFR positive ones. A correlation was found between the expression of EGFR and phosphorylated EGFR (p =0.016, membrane; p =0.012, cytoplasm). However, tumor regions with high protein level without phosphorylation were occasionally seen and the percentage of EGFR positive cells was higher than the phosphorylated percentage (p <0.001). Moreover, an increase in the phosphorylation in both the membrane (p =0.014) and cytoplasm (p =0.002) was seen in 11 tumors with gain of EGFR. The protein level was not correlated with gene dosage. Conclusion: In contrast to gain of the EGFR chromosomal region, high EGFR protein level may not necessarily indicate Tyr1068 phosphorylation and thereby receptor activation in cervical cancer. [Copyright &y& Elsevier]

Molecular subtypes of serous ovarian cancer have been recently described. Using data from independent datasets including over 900 primary tumour samples, we show that deregulation of the Let-7 pathway is specifically associated with the C5 molecular subtype of serous ovarian cancer. DNA copy number and gene expression of HMGA2, alleles of Let-7, LIN28, LIN28B, MYC, MYCN, DICER1, and RNASEN were measured using microarray and quantitative reverse transcriptase PCR. Immunohistochemistry was performed on 127 samples using tissue microarrays and anti-HMGA2 antibodies. Fluorescence in situ hybridisation of bacterial artificial chromosomes hybridized to 239 ovarian tumours was used to measure translocation at the LIN28B locus. Short interfering RNA knockdown in ovarian cell lines was used to test the functionality of associations observed. Four molecular subtypes (C1, C2, C4, C5) of high-grade serous ovarian cancers were robustly represented in each dataset and showed similar pattern of patient survival. We found highly specific activation of a pathway involving MYCN, LIN28B, Let-7 and HMGA2 in the C5 molecular subtype defined by MYCN amplification and over-expression, over-expression of MYCN targets including the Let-7 repressor LIN28B, loss of Let-7 expression and HMGA2 amplification and over-expression. DICER1, a known Let-7 target, and RNASEN were over-expressed in C5 tumours. We saw no evidence of translocation at the LIN28B locus in C5 tumours. The reported interaction between LIN28B and Let-7 was recapitulated by siRNA knockdown in ovarian cancer cell lines. Our results associate deregulation of MYCN and downstream targets, including Let-7 and oncofetal genes, with serous ovarian cancer. We define for the first time how elements of an oncogenic pathway, involving multiple genes that contribute to stem cell renewal, is specifically altered in a molecular subtype of serous ovarian cancer. By defining the drivers of a molecular subtype of serous ovarian cancers we provide a novel strategy for targeted therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Primary debulking surgery before initiation of chemotherapy has been the standard of care for patients with advanced ovarian cancer. Methods: We randomly assigned patients with stage IIIC or IV epithelial ovarian carcinoma, fallopian-tube carcinoma, or primary peritoneal carcinoma to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery (so-called interval debulking surgery). Results: Of the 670 patients randomly assigned to a study treatment, 632 (94.3%) were eligible and started the treatment. The majority of these patients had extensive stage IIIC or IV disease at primary debulking surgery (metastatic lesions that were larger than 5 cm in diameter in 74.5% of patients and larger than 10 cm in 61.6%). The largest residual tumor was 1 cm or less in diameter in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. Postoperative rates of adverse effects and mortality tended to be higher after primary debulking than after interval debulking. The hazard ratio for death (intention-to-treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.84 to 1.13; P=0.01 for noninferiority), and the hazard ratio for progressive disease was 1.01 (90% CI, 0.89 to 1.15). Complete resection of all macroscopic disease (at primary or interval surgery) was the strongest independent variable in predicting overall survival. Conclusions: Neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy as a treatment option for patients with bulky stage IIIC or IV ovarian carcinoma in this study. Complete resection of all macroscopic disease, whether performed as primary treatment or after neoadjuvant chemotherapy, remains the objective whenever cytoreductive surgery is performed. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003636.) N Engl J Med 2010;363:943-53. [ABSTRACT FROM AUTHOR]

Integrative analysis of gene dosage, expression, and ontology (GO) data was performed to discover driver genes in the carcinogenesis and chemoradioresistance of cervical cancers. Gene dosage and expression profiles of 102 locally advanced cervical cancers were generated by microarray techniques. Fifty-two of these patients were also analyzed with the Illumina expression method to confirm the gene expression results. An independent cohort of 41 patients was used for validation of gene expressions associated with clinical outcome. Statistical analysis identified 29 recurrent gains and losses and 3 losses (on 3p, 13q, 21q) associated with poor outcome after chemoradiotherapy. The intratumor heterogeneity, assessed from the gene dosage profiles, was low for these alterations, showing that they had emerged prior to many other alterations and probably were early events in carcinogenesis. Integration of the alterations with gene expression and GO data identified genes that were regulated by the alterations and revealed five biological processes that were significantly overrepresented among the affected genes: apoptosis, metabolism, macromolecule localization, translation, and transcription. Four genes on 3p (RYBP, GBE1) and 13q (FAM48A, MED4) correlated with outcome at both the gene dosage and expression level and were satisfactorily validated in the independent cohort. These integrated analyses yielded 57 candidate drivers of 24 genetic events, including novel loci responsible for chemoradioresistance. Further mapping of the connections among genetic events, drivers, and biological processes suggested that each individual event stimulates specific processes in carcinogenesis through the coordinated control of multiple genes. The present results may provide novel therapeutic opportunities of both early and advanced stage cervical cancers. [ABSTRACT FROM AUTHOR]

Abstract: Aberrations in the Wnt/β-catenin signalling pathway are suggested as mediators of chromosomal instability and carcinogenesis. β-catenin acts both as a component of the membranous adhesion system, and as a transcription activator in the nucleus. β-Catenin immunoreactivity was evaluated in 353 uterine sarcomas (US) including 231 leiomyosarcomas (LMS), 82 endometrial stromal sarcomas (ESS), 22 adenosarcomas (AS) and 18 undifferentiated uterine sarcomas (UUS). Up-regulated membranous β-catenin was observed in 25% of the LMS (p =0.039), 21% of the ESS (p =0.072) and 39% of the UUS (p =0.025). Cytoplasmic β-catenin was up-regulated in 36% of the LMS (p =0.008) and 33% of the UUS (p =0.028). Nuclear β-catenin expression was observed in 23% of the LMS (p =0.051), 61% of ESS (p =0.628) and in the sarcoma component of 68% of the AS. In patients with LMS, membranous β-catenin was associated with poor crude survival in univariate (p =0.045), but not in multivariate analyses. In patients with ESS, nuclear β-catenin expression was related to spread of tumour (p =0.033), but not to survival. The observation of up-regulated β-catenin expression in US might suggest a so far undocumented role for the Wnt/β-catenin pathway in these malignancies. [Copyright &y& Elsevier]

Aims: To determine the frequency and survival of the various types of uterine sarcoma in the total population of Norway and evaluate histopathological prognostic factors in order to identify risk groups. Methods and results: Histopathological review of all uterine sarcoma cases reported to the Norwegian Cancer Registry during 1970–2000 was undertaken. Survival dates were provided by The Cancer Registry. Kaplan–Meier survival curves were generated. The log rank test was used for univariate analysis and a Cox proportional hazards regression model for multivariate evaluation of survival. Stage of disease was the most important prognostic factor for all tumour types. Tumour size and the mitotic index (MI) were significant prognostic factors ( P < 0.0001) in leiomyosarcomas confined to the uterus and allowed for separation into three risk groups with marked differences in prognosis. The prognosis of endometrial stromal sarcomas confined to the uterus was related to MI ( P < 0.0001) and tumour cell necrosis ( P < 0.004). Combining these parameters allowed for separation into three risk groups with marked difference in prognosis. In adenosarcomas, tumour cell necrosis was the only significant prognostic factor. Conclusions: There are marked differences in survival between uterine sarcoma types. Leiomyosarcomas and endometrial stromal sarcomas can be divided into different groups. [ABSTRACT FROM AUTHOR]

Purpose: Descriptions of late morbidity after radiotherapy in cervical cancer survivors (CCSs) are usually based on observations made by physicians, and rarely by patients themselves. We describe and compare physician-assessed morbidity with patient-rated symptoms more than 5 years after pelvic radiotherapy. Methods and Materials: In 147 CCSs treated between 1994 and 1999 at The Norwegian Radiumhospital, morbidity data were regularly documented by physicians at least for 5 years after radiotherapy. Information on patient-rated symptoms was collected by a questionnaire from 91 (62%) of the 147 survivors after a median follow-up time of 96 months (65–131 months). The results were compared with physician-assessed morbidity scores recorded at 5 years, and to selected normative data using descriptive statistics. Physician-assessed morbidity data were modeled using Kaplan-Meier method. Agreement between physician data and patient data was expressed using weighted kappa statistics. Results: The 5-year Kaplan-Meier estimates of physician-assessed intestinal, bladder, and vaginal morbidity Grade 3-4 were 15%, 13%, and 23%, respectively. The prevalence of patient-rated severe symptoms from these organs was much higher (intestines 45%, bladder 23%, and 58% vaginal discomfort among sexually active CCSs). Poor agreement was confirmed by low values of kappa: For bladder the concordance was slight (κ = 0.16) and for intestine it was fair (κ = 0.27). Stress incontinence, diarrhea, nausea, and sexual problems were significantly (p < 0.001) more prevalent when compared with a control sample from the general female population. Conclusions: Morbidity is common after pelvic radiotherapy. However, our data indicate that physicians underreport patients symptoms. It is important to incorporate patient-reported outcomes in the evaluation of treatment-related morbidity. [Copyright &y& Elsevier]

Background: High-resolution magic angle proton magnetic resonance spectroscopy (HR 1H MAS MRS) provides a broad metabolic mapping of intact tumor samples and allows for microscopy investigations of the samples after spectra acquisition. Experimental studies have suggested that the method can be used for detection of apoptosis, but this has not been investigated in a clinical setting so far. We have explored this hypothesis in cervical cancers by searching for metabolites associated with apoptosis that were not influenced by other histopathological parameters like tumor load and tumor cell density. Methods: Biopsies (n = 44) taken before and during radiotherapy in 23 patients were subjected to HR MAS MRS. A standard pulse-acquire spectrum provided information about lipids, and a spin-echo spectrum enabled detection of non-lipid metabolites in the lipid region of the spectra. Apoptotic cell density, tumor cell fraction, and tumor cell density were determined by histopathological analysis after spectra acquisition. Results: The apoptotic cell density correlated with the standard pulse-acquire spectra (p <0.001), but not with the spin-echo spectra, showing that the lipid metabolites were most important. The combined information of all lipids contributed to the correlation, with a major contribution from the ratio of fatty acid -CH2 to CH3 (p =0.02). In contrast, the spin-echo spectra contained the main information on tumor cell fraction and tumor cell density (p < 0.001), for which cholines, creatine, taurine, glucose, and lactate were most important. Significant correlations were found between tumor cell fraction and glucose concentration (p = 0.001) and between tumor cell density and glycerophosphocholine (GPC) concentration (p = 0.024) and ratio of GPC to choline (p < 0.001). Conclusion: Our findings indicate that the apoptotic activity of cervical cancers can be assessed from the lipid metabolites in HR MAS MR spectra and that the HR MAS data may reveal novel information on the metabolic changes characteristic of apoptosis. These changes differed from those associated with tumor load and tumor cell density, suggesting an application of the method to explore the role of apoptosis in the course of the disease. [ABSTRACT FROM AUTHOR]

Background: A better understanding of the development of metastatic disease and the identification of molecular markers for cancer spread would be useful for the design of improved treatment strategies. This study was conducted to identify gene expressions associated with metastatic phenotypes of locally advanced cervical carcinomas and investigate whether gains or losses of these genes could play a role in regulation of the transcripts. Gene expressions and copy number changes were determined in primary tumors from 29 patients with and 19 without diagnosed lymph node metastases by use of cDNA and genomic microarray techniques, respectively. Results: Thirty-one genes that differed in expression between the node positive and negative tumors were identified. Expressions of eight of these genes (MRPL11, CKS2, PDK2, MRPS23, MSN, TBX3, KLF3, LSM3) correlated with progression free survival in univariate analysis and were therefore more strongly associated with metastatic phenotypes than the others. Immunohistochemistry data of CKS2 and MSN showed similar relationships to survival. The prognostic genes clustered into two groups, suggesting two major metastatic phenotypes. One group was associated with rapid proliferation, oxidative phosphorylation, invasiveness, and tumor size (MRPS23, MRPL11, CKS2, LSM3, TBX3, MSN) and another with hypoxia tolerance, anaerobic metabolism, and high lactate content (PDK2, KLF3). Multivariate analysis identified tumor volume and PDK2 expression as independent prognostic variables. Gene copy number changes of the differentially expressed genes were not frequent, but correlated with the expression level for seven genes, including MRPS23, MSN, and LSM3. Conclusion: Gene expressions associated with known metastatic phenotypes of cervical cancers were identified. Our findings may indicate molecular mechanisms underlying development of these phenotypes and be useful as markers of cancer spread. Gains or losses of the genes may be involved in development of the metastatic phenotypes in some cases, but other mechanisms for transcriptional regulation are probably important in the majority of tumors. [ABSTRACT FROM AUTHOR]

Abstract: Objectives.: To examine the expressions of the protein and mRNA of EPHA2 and EphrinA-1 in epithelial ovarian carcinomas/ovarian cancer cell lines and explore their prognostic value. Methods.: To validate the immunohistochemical method, two ovarian cancer cell lines (OVCAR3 and SKOV3) were examined with RT-PCR, Western blot, and immunohistochemistry for EphA2 and EphrinA-1 expressions. Tumors from 118 patients with advanced epithelial ovarian cancer were then evaluated for EPHA2 and Ephrin A-1 protein expression, and frozen tissues from 30 cases were used for laser capture microdissection (LCM) assistant RT-PCR RNA analysis. Results.: 11 (9.3%), 67 (56.8%), 26 (22.0%), and 14 (11.9%) tumors demonstrated negative, weak, moderate, and strong EphA2 protein expressions, respectively, while 3 (2.5%), 67 (56.8%), 32 (27.1%), and 16 (13.8%) tumors were negative, weak, moderate, and strong for Ephrin A-1 protein expression, respectively. Variable amount of mRNA expression was observed in the 30 tumors analyzed by the method of LCM assistant RT-PCR. There was a trend for association between higher levels of either EphA2 or Ephrin A-1 expression and higher histological grade (P = 0.05 for both factors). No significant correlation between the expressions of EphA2 or Ephrin A-1 and age, histological type, and FIGO stage was observed. Patients with higher levels of EphA2 protein expressions had significantly shorter survival. Cox multivariate analyses revealed that residual tumor after surgery, histological type, and EphA2 protein expression were of independent prognostic significance. Conclusions.: High level of EphA2 protein expression is significantly associated with a shorter patient survival and EphA2 receptor is a valuable prognostic marker for ovarian carcinoma. [Copyright &y& Elsevier]

Abstract: Objectives. : To test the Gynecologic Oncology Group (GOG) prognostic criteria (based on stromal invasion, tumor size and vascular invasion) for early squamous cervical carcinoma (SCC) in an independent population and to evaluate the prognostic value of a simpler model. Methods. : We studied 221 patients who underwent radical hysterectomy and bilateral lymphadenectomy for stage IB SCC between 1987 and 1993. Adjuvant treatment consisting of radiotherapy and/or chemotherapy was given in case of large tumor size, positive lymph nodes or invasion into the parametria. Histological slides from all patients were reviewed by one pathologist. Results. : The GOG criteria divided the patients from our population in a small low risk group (3-year relapse-free rate (RFR) of 100%), a small high risk group (RFR of 57%) and a bigger intermediate risk group (RFR of 80–90%). These results are in good agreement with those of the original publication. A risk model based on 2 of the 3 factors used by the GOG may perform as well as the 3-factor model, especially when allowing interaction. Tumors measuring >2 cm and invading into the outer third of the cervical wall had a 5-year DFS of 56% compared to 93% for tumors measuring ≤2 cm or invading to less then the outer third of the cervical wall. Conclusion. : The GOG criteria could be validated in this independent population. A model based on 2 of the 3 factors may perform as good. [Copyright &y& Elsevier]

Abstract: The CTNNB1 gene and its product β-catenin, a regulator of the Wnt signalling pathway, is often mutated and deregulated in human malignancies. Down stream targets of the Wnt signalling pathway are linked to genomic instability. In this study, the impact of β-catenin expression on genomic instability in ovarian carcinoma, as determined by DNA ploidy, was investigated. Expression of β-catenin was examined by immunohistochemistry in 253 ovarian carcinomas. The results were related to genomic instability and clinicopathological features of the patients. Membrane associated staining of β-catenin was detected in nearly all cases with no correlation to clinical parameters. Most of the samples also had cytoplasmic (84%), while only 13% had nuclear β-catenin localisation. A significant association between β-catenin expression (cytoplasmic and nuclear) and histological subtype and degree of differentiation was observed. Nuclear β-catenin was almost exclusively present in endometroid carcinomas. 53% of all endometroid tumours were positive for nuclear β-catenin expression (P &#60;0.0001). Mucinous carcinomas had the highest degree of cytoplasmic β-catenin expression (92%), followed by endometroid (92%), mixed (90%), serous (82%), unclassified adenocarcinomas (81%), carcinomas clear cell and (70%), (P =0.01). Tumours with differentiation grade 1 (16%) and 2 (24%) had higher nuclear β-catenin expression than grade 3 and clear cell carcinomas (6%) (P =0.012). Better prognostic outcome was found for patients with nuclear β-catenin localisation as compared to the cases without (P =0.027). In conclusion, the study showed no correlation between β-catenin expression in ovarian carcinoma and FIGO stage and genomic instability as determined by DNA ploidy status. However, nuclear β-catenin expression was strongly associated with endometroid histological subtype. Finally, in ovarian cancer, although β-catenin staining seems to be of prognostic importance with respect to nuclear staining in univariate analysis, only DNA ploidy status, histological grade and FIGO staging were of independent prognostic significance in multivariate analysis. [Copyright &y& Elsevier]

Background: While numerous studies have characterized primary ovarian tumors, little information is available regarding expression patterns of metastatic sites of this cancer. To define sets of genes that distinguish primary and metastatic ovarian tumors, we used cDNA microarrays to characterize global gene expression patterns in 38 effusions (28 peritoneal, 10 pleural) and 8 corresponding primary ovarian tumors, and searched for associations between expression patterns and clinical parameters. Results: We observed multidimensional variation in expression patterns among the cancers. Coordinate variation in expression of genes from two chromosomal regions, 8q and 19q, was seen in subsets of the cancers indicating possible amplifications in these regions. A set of 112 unique genes of known function was differentially expressed between primary tumors and effusions using supervised analysis. Relatively few differences were seen between effusions isolated from the pleural and peritoneal cavities or between effusions from patients diagnosed with stage III and stage IV cancers. A set of 84 unique genes was identified that distinguished high from lower grade ovarian cancers. The results were corroborated using immunocytochemistry, mRNA in situ hybridization, and immunoblotting. Conclusion: The extensive variation in expression patterns observed underscores the molecular heterogeneity of ovarian cancer, but suggests a similar molecular profile for ovarian carcinoma cells in serosal cavities. [ABSTRACT FROM AUTHOR]