Solveig Tingulstad

Tumor necrosis factor, interleukin-1, and interleukin-6 in normal human pregnancy

OBJECTIVE Our purpose was to investigate the cytokines, tumor necrosis factor, interleukin-1, and interleukin-6 in normal human pregnancy and labor. STUDY DESIGN Bioassays were used to measure these factors in extraembryonic coelomic fluid, amniotic fluid, placenta, and maternal and cord serum. RESULTS Little or no tumor necrosis factor, interleukin-1, or interleukin-6 was found in coelomic fluid or amniotic fluid in the first trimester. Interleukin-6 appeared in second-trimester amniotic fluid. At term tumor necrosis factor was present (median 17 pg/ml) and increased with the onset of labor (median 58 pg/ml), as did interleukin-1 (median 188 to 680 pg/ml) and interleukin-6 (median 399 to 4800 pg/ml). Maternal serum interleukin-6 increased during pregnancy with a further increment with the onset of labor. Cord interleukin-6 also increased with labor but at a lower level. CONCLUSION The cytokines tumor necrosis factor, interleukin-1, and interleukin-6 may play a role in the onset of normal labor.

Evaluation of a risk of malignancy index based on serum CA125, ultrasound findings and menopausal status in the pre-operative diagnosis of pelvic masses

Objective To evaluate the ability of a risk of malignancy index (RMI), based on a serum CA125 level, ultrasound findings and menopausal status, to discriminate a benign from a malignant pelvic mass and to discriminate early stage (Figo Stage I) from Stages II, III and IV of ovarian cancer.

Survival and prognostic factors in patients with ovarian cancer.

OBJECTIVE To assess incidence during a 10-year study period and to identify and discuss clinical relevance for prognostic factors of survival within a cohort of Norwegian ovarian cancer patients. METHODS Incidence and prognostic factors of survival within a population-based cohort of ovarian cancer patients from one health region in Norway were examined over the 10-year period 1987 through 1996. A total of 571 histologically verified cases of primary ovarian cancer originally registered either in the Cancer Registry of Norway or in the hospitals discharge registers were included in the study. Pearson χ2 test was used in univariate analyses of cofactors by 5-year survival, and Kaplan-Meier survival curves were computed and tested statistically by the log rank test. A multivariable proportional hazard model (Cox) was applied to assess the prognostic significance of the different covariates. RESULTS The incidence and crude 5-year survival remained stable over the 10-year study period. The standardized incidence rate for the time periods 1987–1991 and 1992–1996 was 11.9/100,000 and 12.5/100,000, respectively. The crude 5-year survival rate for the cohort was 39%, whereas median survival was 32 months. Cox multivariable regression analysis showed that the only independent significant prognostic factors were International Federation of Gynecology and Obstetrics stage (P < .001), size of residual tumor at the end of primary surgery (P < .001), and age at diagnosis (P < .01). Variables such as time period, histologic type and grade, treating hospital, comorbidity, or CA 125 were insignificant in predicting 5-year survival. CONCLUSION The results underline the importance of improved surgical management of ovarian cancer, as residual tumor is the only prognostic factor achievable.

The effect of centralization of primary surgery on survival in ovarian cancer patients.

OBJECTIVE To examine the effect of centralized surgery on overall survival in patients with ovarian cancer and, in particular, patients with advanced disease (stage III/IV). METHODS In a historical prospective study design, patients referred from community hospitals to a teaching hospital for primary surgery during the 2-year period, 1995–1997, were included as cases. For each referred case, two controls, matched for International Federation of Gynecology and Obstetrics (FIGO) stage and age, were selected among patients who had had primary surgery at the referral hospitals (nonteaching) in the years, 1992–1995. Kaplan–Meier survival curves were computed and tested statistically by the log rank test. Cox proportional hazard model was applied for estimation of prognostic factors of survival. RESULTS There was no difference in postoperative mortality for stage I/II patients by level of care (community hospitals versus teaching hospital). However, for advanced stage disease (III + IV), the controls had significantly shorter crude survival than patients who had been operated on at the teaching hospital (5-year survival: 4% versus 26%; median survival: 12 months versus 21 months) (P = .01). Multivariable analyses showed that completed chemotherapy and size of residual tumor after primary surgery were independent prognostic factors of survival. Patients optimally operated on at the teaching hospital had significantly lower risk of death compared with all other groups, independently of chemotherapy. This indicates that the extent of cytoreductive surgery and the overall management undertaken in the teaching hospital are significant predictors of improved survival. CONCLUSION Centralization of primary ovarian cancer surgery in one health region in Norway has improved survival for patients with advanced disease. Patients with apparent advanced ovarian cancer should be referred to a subspecialty unit for primary surgery, and every effort should be made to attain as complete cytoreduction as possible.

The risk-of-malignancy index to evaluate potential ovarian cancers in local hospitals.

OBJECTIVE To assess the risk-of-malignancy index (a scoring system based on menopausal status, ultrasound features, and serum CA 125) at district hospitals for referral of women with suspected malignant pelvic masses for primary surgery at a central gynecologic oncology unit. METHODS All seven hospitals in Health Region IV, Norway, agreed to refer women with pelvic masses and risk-of-malignancy indices of 200 or more for centralized primary surgery. In total, 365 women 30 years of age or older, admitted consecutively at the local hospitals, were enrolled in the study from February 1, 1995, to January 31, 1997. RESULTS Compliance with the study was satisfactory; 84% (65 of 77) of women with risk-of-malignancy indices of at least 200 were referred for centralized primary surgery. Sensitivity and specificity to malignancy were 71% and 92%, respectively, which is in agreement with previous validation of the risk-of-malignancy index in teaching hospital settings. False negatives were due mainly to stage Ia (18 of 24) ovarian cancer, whereas 27 of 28 stage II-IV ovarian cancer cases were identified correctly. CONCLUSION The risk-of-malignancy index identified women with malignant pelvic masses efficiently. Our study showed the risk-of-malignancy index strategy in a practical setting to be able to centralize primary surgery for advanced ovarian cancer from local hospitals to a subspecialty unit. We recommend the risk-of-malignancy index for detection of patients with advanced ovarian cancer for centralized primary surgery.

Stathmin overexpression identifies high-risk patients and lymph node metastasis in endometrial cancer.

Purpose: Overexpression of the oncogen Stathmin has been linked to aggressive endometrial carcinoma and a potential for PI3Kinase inhibitors in this disease. We wanted to validate the prognostic value of Stathmin expression in a large prospective multicenter setting. As lymph node sampling is part of current surgical staging, we also aimed to test if Stathmin expression in endometrial curettage specimens could predict lymph node metastasis. Experimental Design: A total of 1,076 endometrial cancer patients have been recruited from 10 centers to investigate the biological tumor marker Stathmin in relation to clinicopathologic variables, including lymph node status and survival. Stathmin immunohistochemical staining was carried out in 477 hysterectomy and 818 curettage specimens. Results: Seventy-one percent of the patients (n = 763) were subjected to lymph node sampling, of which 12% had metastatic nodes (n = 94). Overexpression of Stathmin was detected in 37% (302 of 818) of the curettage and in 18% (84 of 477) of the hysterectomy specimens investigated. Stathmin overexpression in curettage and hysterectomy specimens were highly correlated and significantly associated with nonendometrioid histology, high grade, and aneuploidy. Stathmin analysis in preoperative curettage samples significantly correlated with, and was an independent predictor of, lymph node metastases. High Stathmin expression was associated with poor disease-specific survival (P ≤ 0.002) both in curettage and hysterectomy specimens. Conclusions: Stathmin immunohistochemical staining identifies endometrial carcinomas with lymph node metastases and poor survival. The value, as a predictive marker for response to PI3Kinase inhibition and as a tool to stratify patients for lymph node sampling in endometrial carcinomas, remains to be determined. Clin Cancer Res; 17(10); 3368–77. ©2011 AACR.

Hormone receptor loss in endometrial carcinoma curettage predicts lymph node metastasis and poor outcome in prospective multicentre trial

BACKGROUND Preoperative histologic examination of tumour tissue is essential when deciding if endometrial cancer surgery should include lymph node sampling. We wanted to investigate if biomarkers could improve prediction of lymph node metastasis and outcome. PATIENTS AND METHODS Curettage specimens from 832 endometrial carcinoma patients prospectively recruited from 10 centres in the MoMaTEC trial (Molecular Markers in Treatment of Endometrial Cancer) were investigated for hormone receptor and p53 status. RESULTS Eighteen per cent of tumours were double negative for oestrogen- and progesterone receptors (ER/PR loss), 24% overexpressed p53. Pathologic expression of all markers correlated with nodal metastases, high FIGO (Federation International of Gynecology and Obstetrics) stage, non-endometrioid histology, high grade and poor prognosis (all P<0.001). ER/PR loss independently predicted lymph node metastasis (odds ratios (OR) 2.0, 95% confidence interval (CI) 1.1-3.7) adjusted for preoperative curettage histology and predicted poor disease-specific survival adjusted for age, FIGO stage, histologic type, grade and myometrial infiltration (hazard ratio (HR) 2.3, 95% CI 1.4-3.9). For lymph node negative endometrioid tumours, ER/PR loss influenced survival independent of grade. CONCLUSION Double negative hormone receptor status in endometrial cancer curettage independently predicts lymph node metastasis and poor prognosis in a prospective multicentre setting. Implementing hormone receptor status to improve risk-stratification for selecting patients unlikely to benefit from lymphadenectomy seems justified.

Completeness and accuracy of registration of ovarian cancer in the cancer registry of Norway.

Completeness of reporting and accuracy of the diagnosis of ovarian cancer from one health region in Norway to the Cancer Registry were examined. Data kept by the Cancer Registry were evaluated against discharge diagnosis data from all 8 hospitals in the health region during the period of 1987–1996. The assessment of the accuracy of the diagnosis recorded in the Cancer Registry was based on review of all medical records in the hospital setting and on slide review of all histologic diagnoses. The overall completeness of reporting ovarian cancer to the Cancer Registry was 99.6%. The organ specific completeness of registration of histologic verified ovarian cancer within the Cancer Registry was 95.3%; 0.9% was erroneously coded and 3.5% had their diagnosis changed to ovarian cancer at re‐evaluation. Of all ovarian cancer cases registered at the Cancer Registry, 91% had a primary histologic diagnosis. Among 591 cases identified with a histologic diagnosis in the Cancer Registry, the accuracy of the diagnosis was estimated at 92%. Coding errors were found in 2% of these cases, while in 6% of the cases it was not possible to reproduce the original diagnosis of ovarian cancer at re‐evaluation. In order to provide data of high quality for cancer surveillance a cancer registry needs several data providers, such as histopathologic laboratory reports and clinical reports. In addition, assessment of reported data through stringent quality assurance procedures within the registry are necessary for reaching a nearly 100% completeness of registration as found for ovarian cancer in the Cancer Registry of Norway.

Revision of FIGO surgical staging in 2009 for endometrial cancer validates to improve risk stratification

OBJECTIVE Correct staging is a cornerstone in cancer treatment. The FIGO surgical staging for endometrial cancer was revised in 2009. We have evaluated if the revision improved stratification with respect to prognosis in a large prospective multicenter setting. METHODS 1268 endometrial cancer patients have been prospectively recruited in the MoMaTEC study for the investigation of clinical and histopathological data. RESULTS Restaging from FIGO 88 to FIGO 09 criteria increased the number of stage I cases from 932 to 979. The majority of the non-endometrioid tumors, down-staged to FIGO 09 stage I, were of serous histology. One third of the patients classified as stage II tumors based on FIGO 88 criteria (FIGO88 IIA) were down-staged to FIGO 09 IA (53%) and FIGO 09 IB (47%). The histological subtype for these cases was mainly endometrioid (86.1%) and high/intermediate grade (77.7%). Patients with FIGO 88 stages IA, IB, IIA and IIIA with positive cytology only, showed similar survival. In Cox multivariate survival analysis adjusting for histopathological variables we found that the revised FIGO 09 criteria improved prognostication. For FIGO stage I patients the adjusted HR was 3.9 (p=0.01, CI 1.35-11.36) for FIGO IB compared to FIGO IA. The independent prognostic impact for the FIGO 09 staging was also confirmed in a subset analysis of patients not subjected to lymphadenectomy and for the endometrioid subgroup. CONCLUSIONS The FIGO 2009 staging system has improved prediction of prognosis, and is less complex, compared to earlier versions. Careful assessment of myometrial invasion seems particularly important for patients not subjected to lymphadenectomy.

SNP285C modulates oestrogen receptor/Sp1 binding to the MDM2 promoter and reduces the risk of endometrial but not prostatic cancer

INTRODUCTION The MDM2 promoter polymorphism (SNP309T > G) extends a binding site for the transcription factor Sp1 and has been linked to elevated cancer risk and/or young age at cancer diagnosis, especially in females. Recently, we reported an adjacent polymorphism (SNP285G > C). SNP285C antagonises the effect of SNP309G by reducing Sp1 binding and lowers the risk of breast and ovarian cancer. METHODS We assessed the potential gender specificity in the effect of this polymorphism. We performed in silico predictions of transcription factor binding sites in the MDM2 promoter and analysed MDM2 SNP285 and SNP309 status in two independent cohorts of endometrial (n = 438 and 472) and 666 prostatic cancer patients, and compared to 3.140 healthy controls. RESULTS We identified three oestrogen-receptor binding elements (EREs) within the MDM2 intronic promoter, one of which overlapping the Sp1 binding-site harbouring SNP285. The SNP285C/309G haplotype was associated with a reduced Odds Ratio (OR) for endometrial cancer (OR1: 0.55; Confidence Interval (CI) 0.32-0.97; OR2: 0.65; CI 0.40-1.08, especially for ER+ tumours; OR: 0.48; CI 0.28-0.87) but not for prostatic cancer among SNP309TG heterozygotes. SNP309G (SNP309TG or SNP309GG genotype) was associated with a moderately increased risk of endometrial cancer (OR: 1.17; CI 1.00-1.37) compared to SNP309TT homozygotes. Removing individuals harbouring the SNP309G-counteracting SNP285C polymorphism from the analysis strengthened this association (OR: 1.20; CI 1.02-1.41). CONCLUSION The finding of an ERE overlapping with the Sp1-binding site affected by SNP285, taken together with the significant impact of SNP285 on the risk of breast, ovarian and now endometrial cancer but not prostatic cancer, suggests a gender specific effect of SNP285C on cancer risk.