Asparaginase-like protein 1 expression in curettage independently predicts lymph node metastasis in endometrial carcinoma: a multicentre study.

OBJECTIVE: Correct preoperative identification of high-risk patients is important to optimise surgical treatment and improve survival. We wanted to explore if asparaginase-like protein 1 (ASRGL1) expression in curettage could predict lymph node metastases and poor outcome, potentially improving preoperative risk stratification. DESIGN: Multicentre study. SETTING: Ten hospitals in Norway, Sweden and Belgium. POPULATION: Women diagnosed with endometrial carcinoma. METHODS: ASRGL1 expression in curettage specimens from 1144 women was determined by immunohistochemistry. MAIN OUTCOME MEASURES: ASRGL1 status related to disease-specific survival, lymph node status, preoperative imaging parameters and clinicopathological data. RESULTS: ASRGL1 expression had independent prognostic value in multivariate survival analyses, both in the whole patient population (hazard ratio (HR) 1.63, 95% CI 1.11-2.37, P = 0.012) and in the low-risk curettage histology subgroup (HR 2.54, 95% CI 1.44-4.47, P = 0.001). Lymph node metastases were more frequent in women with low expression of ASRGL1 compared with women with high ASRGL1 levels (23% versus 10%, P < 0.001), and low ASRGL1 level was found to independently predict lymph node metastases (odds ratio 2.07, 95% CI 1.27-3.38, P = 0.003). CONCLUSIONS: Low expression of ASRGL1 in curettage independently predicts lymph node metastases and poor disease-specific survival. TWEETABLE ABSTRACT: Low ASRGL1 expression in curettage predicts lymph node metastasis and poor survival in endometrial carcinoma.

DNA ploidy in curettage specimens identifies high-risk patients and lymph node metastasis in endometrial cancer.

BACKGROUND: Preoperative risk stratification is essential in tailoring endometrial cancer treatment, and biomarkers predicting lymph node metastasis and aggressive disease are aspired in clinical practice. DNA ploidy assessment in hysterectomy specimens is a well-established prognostic marker. DNA ploidy assessment in preoperative curettage specimens is less studied, and in particular in relation to the occurrence of lymph node metastasis. METHODS: Curettage image cytometry DNA ploidy in relation to established clinicopathological variables and outcome was investigated in 785 endometrial carcinoma patients prospectively included in the MoMaTEC multicentre trial. RESULTS: Diploid curettage status was found in 72.0%, whereas 28.0% were non-diploid. Non-diploid status significantly correlated with traditional aggressive postoperative clinicopathological features, and was an independent predictor of lymph node metastasis among FIGO stage I-III patients in multivariate analysis (OR 1.94, P=0.033). Non-diploid status was related to shorter disease-specific survival (5-year DSS of 74.4% vs 88.8% for diploid curettage, P<0.001). When stratifying by FIGO stage and lymph node status, the prognostic effect remained. However, in multivariate regression analysis, preoperative histological risk classification was a stronger predictor of DSS than DNA ploidy. CONCLUSIONS: Non-diploid curettage is significantly associated with aggressive clinicopathological phenotype, lymph node metastasis, and poor survival in endometrial cancer. The prognostic effect was also observed among subgroups with (presumably) less aggressive traits, such as low FIGO stage and negative lymph node status. Our results indicate curettage DNA ploidy as a possible supplement to existing parameters used to tailor surgical treatment.

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.

Chromogranin A and pancreastatin-like immunoreactivity in normal pregnancies.

Placenta is a neuroendocrine organ, and we therefore wanted to study the occurrence of the general neuroendocrine marker chromogranin A (CgA) and its split product pancreastatin. CgA and pancreastatin-like immunoreactivity (PST-LI) were determined by ELISA and RIA methods, respectively, in homogenates from term placentas, sera from pregnant women, nonpregnant women, umbilical cords, and in amniotic fluids. In placental homogenates, the mean level of CgA was 7.1 +/- 8.6 pmol/g wet wt (mean +/- SD), whereas PST-LI was not detectable. CgA immunoreactivity was demonstrated by immunofluorescence studies of isolated trophoblasts and decidual cells from term placentas. In trophoblasts, CgA was colocalized with human chorionic gonadotropin (hCG) and human placental lactogen. By Northern blotting, a distinct band corresponding to CgA messenger RNA (mRNA) was demonstrated in the placental cell line, whereas, in placental homogenates, a mRNA band of a slightly larger size was found. Median CgA level in maternal sera at term tended to be higher (median: 469 pmol/L, range 61-980 pmol/L, P < 0.1) than at 6-11 weeks (286 pmol/L, 61-653 pmol/L) or in sera from nonpregnant women (306 pmol/L, 204-469 pmol/L). In umbilical cord sera, median CgA level was significantly higher (898 pmol/L, 102-2245 pmol/L, P < 0.05) than in term sera. Median serum level of PST-LI was significantly higher at term (38 pmol/L, 0-131 pmol/L) than at 6-11 weeks (9 pmol/L (0-85 pmol/L, P < 0.05), than in nonpregnant women (6 pmol/L, 0-52 pmol/L, P < 0.05), and in umbilical cord sera (12 pmol/L, 0-76 pmol/L, P < 0.05). In amniotic fluid, median CgA value was significantly higher at term (1163 pmol/L, 714-1673 pmol/L) than at 14-17 weeks (551 pmol/L, 82-980 pmol/L, P < 0.01), whereas median level of PST-LI was significantly higher at 14-17 weeks (32 pmol/L, 6-97 pmol/L) than at term (0 pmol/L, 0-15 pmol/L, P < 0.01). To our knowledge, this is the first report describing the presence of CgA and PST-LI in placenta and amniotic fluid and the occurrence CgA mRNA in placental tissue and in a placental cell line. The presence of CgA in placenta may indicate a physiological role in pregnancy.

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.

A phase II study of biweekly administration of paclitaxel in patients with recurrent epithelial ovarian cancer.

The purpose of this study was to assess the efficacy and toxicity of single agent paclitaxel administered biweekly to patients with relapse of epithelial ovarian cancer previously treated with platinum-based regimen. Forty patients received an initial paclitaxel dose of 134 mg/m2 administered intravenously over three hours every two weeks. 283 cycles were given. All 40 patients were evaluable for toxicity, which mainly consisted of granulocytopenia, myalgia/arthralgia, and peripheral neuropathy. Two patients developed severe hypersensitivity reactions. Dose escalation was possible by one level in 11 patients and by two levels in 12 patients, dose reductions were not necessary. Thirty-five patients were evaluated for response. Five obtained complete response (14%), eight obtained partial response (23%), and nine had stable disease (26%), while 11 patients showed progression (31%). The overall response rate was 37% (95% confidence interval 22-57%). The median duration of responses (complete and partial) was six months. Overall median time to progression and overall median survival for eligible patients (n = 35) was 4.3 months and 11 months, respectively. We conclude that biweekly administration of paclitaxel in recurrent epithelial ovarian carcinoma was active with manageable toxicity.

A discordant histological risk classification in preoperative and operative biopsy in endometrial cancer is reflected in metastatic risk and prognosis.

INTRODUCTION: In endometrial cancer, tissue for histological evaluation is obtained preoperatively (endometrial biopsy) and operatively (hysterectomy specimen). We investigated if a discordant risk classification based on preoperative and operative biopsy is reflected in metastatic risk and prognosis. PATIENTS AND METHODS: One thousand three hundred and seventy-four patients were prospectively included in a multicentre setting (Molecular Markers for Treatment of Endometrial Cancer (MoMaTEC) study). Preoperative and operative specimens were classified as high risk if non-endometrioid histology or endometrioid grade 3; otherwise low risk. Disease specific survival differences were calculated by means of Kaplan-Meier and Cox proportional hazard models. RESULTS: Discordant risk was found in 207 (16%) cases. Lymph node metastases were detected in 7% and 23% of patients with concordant low and high risk respectively versus 14% and 20% in the discordant groups (p<0.001). Five-year disease specific survival in the discordant groups proved intermediate (75-80%) to concordant low (94%) or high (58%) risk. Both operative and preoperative biopsy high-risk results have independent prognostic impact on disease specific survival with adjusted hazard ratios of 2.4 (95% confidence interval (95% CI) 1.5-3.9) and 2.1 (95% CI 1.3-3.2) respectively by Cox analysis. CONCLUSIONS: Discordant risk in preoperative biopsy and hysterectomy identifies an intermediate group with respect to disease spread and prognosis. Preoperative biopsy results remain important also with the hysterectomy histology available.

[Pelvic joint syndrome as the cause of chronic pelvic pain in women]. / Bekkenleddsyndromet som årsak til kroniske underlivssmerter hos kvinner.

We describe four cases of women with chronic pelvic pain caused by the pelvic joint syndrome. In three of the cases the women suffered from severe pelvic girdle relaxation during their last pregnancy. In one case the symptoms occurred after a trauma to the pelvis. We emphasize the need to obtain a meticulous medical history when investigating women with pelvic pain and the importance of an extended pelvic examination, especially when the gynecological examination is normal.

Comparison of 'pattern recognition' and logistic regression models for discrimination between benign and malignant pelvic masses: a prospective cross validation.

OBJECTIVES: To test prospectively the diagnostic performance of two logistic regression models for calculation of individual risk of malignancy in adnexal tumors (the 'Tailor model' and the 'Timmerman model'), and to compare them to that of 'pattern recognition' (subjective evaluation of the gray-scale ultrasound image and color Doppler ultrasound examination). DESIGN: Consecutive women with a pelvic mass judged clinically to be of adnexal origin underwent preoperative ultrasound examination including color and spectral Doppler examination. The same examination techniques and definitions as those used in the studies in which the logistic regression models had been created were used. The Tailor model was tested in 133 women (35 of whom hada malignancy) and the Timmerman model in 82 women (29 of whom had a malignancy). A subset of 79 women (28 of whom had a malignancy) was used to compare the performance of the Tailor model and the Timmerman model by calculating and comparing the areas under the receiver operating characteristics curves of the two models. Sensitivity and specificity with regard to malignancy were calculated for all three methods. RESULTS: Pattern recognition performed better than the two logistic regression models (sensitivity around 85%, specificity around 90%). Using a risk of malignancy of > 50% to indicate malignancy (as suggested in the original publications), the sensitivity of the Tailor model was 69% and the specificity 88% (n = 133). The corresponding values for the Timmerman model were 62% and 79% (n = 82). The receiver operating characteristics curves showed the two logistic regression models to have similar diagnostic properties (area under the curve, 0.87 vs. 0.84; P = 0.25; n = 79). The diagnostic performance of the mathematical models was much poorer in this study than in those in which the models had been created. CONCLUSION: The poor diagnostic performance of the mathematical models can probably be explained by subtle differences in definitions and examination technique and by differences between the original tumor populations and the study population. For mathematical models to be generally useful, they probably need to be created on the basis of a very large number of tumors, and the variables in the model must be unequivocally defined and the examination technique meticulously standardized.

[Chlamydia trachomatis and ectopic pregnancy. A causal relationship]. / Chlamydia trachomatis og extrauterine svangerskap. Ein kausal samanhang.

In a case-control study, chlamydial antibody (IgG) was examined in sera from 58 women with ectopic pregnancy and 58 birth-giving controls matched for age (+/- 3 years) and parity. More patients than controls stated that they had previously been treated for salpingitis (p less than 0.05). In the index pregnancy, two cases and four controls were positive for C trachomatis in specimen from the cervix uteri. Chlamydial antibody was detected among 69% of the cases and 33% of the controls (p less than 0.01). These results were consistent with age, parity and information on previous treatment for salpingitis. The occurrence of a previous chlamydial infection, proven by IgG-antibodies, increases risk of an ectopic pregnancy by a factor of 4.6 (odds ratio 4.6, 95% CI 2.1-10.3).

[Surgical treatment of cervix cancer. A 6-year material from a regional hospital]. / Kirurgisk behandling av cancer cervicis uteri. Et seksårsmateriale fra et regionsykehus.

The results are reported for 75 patients treated with radical hysterectomy and pelvic lymphadenectomy (Wertheim-Meigs' operation) for cervical carcinoma. There was no per- or postoperative death. Ten patients suffered immediate postoperative complications. One case of lower limb lymphoedema was observed. 17 patients (23%) had pelvic lymph node metastases. In eight patients the disease has recurred (median observation time 43 months). Overall recurrence-free survival was 89%: for patients without lymph node metastases 91%, and for patients with metastases 82%. Using a prognostic score based on stage, presence of lymph node metastases, blood or lymph vessel invasion, low differentiation, and tumour-involved resection margins; two groups could be identified, with a recurrence-free survival of 94% (score < or = 2) and 75% (score > or = 3), respectively (p < 0.02).

CO2 laser conization for cervical intraepithelial neoplasia grade II-III: complications and efficacy.

AIMS: To examine per- and postoperative complication rates and efficacy of laser conization in the treatment of cervical intraepithelial neoplasia (CIN) grade II-III. MATERIAL AND METHODS: Eligible for analyses were all women treated with their first laser conization because of CIN II-III during the time-period January 1, 1983 to December 31, 1992. The study population comprises 1081 women who were permanent residents of one Norwegian county (Sør-Trøndelag). All analyses were performed in SPSS applying chi-square for trend, Mann-Whitney test, survival analyses and logistic regression. RESULTS: In total 86 women (8.0%) were observed with one or two (4:86) complications. Bleeding was most frequent (n = 66) followed by symptomatic cervical stenosis (n = 18). Most bleeding complications (74.2%) occurred one to two weeks postoperatively. Both bleeding complications and the occurrence of cervical stenosis were associated with cone height. Three emergency hysterectomies, two for bleeding and one for bladder perforation, were performed. Persistent disease was diagnosed in 1.9% (20:1053) of the women. All women with persistent disease were diagnosed among those with CIN III. Persistent disease was more than 20 times more common among women with disease-involved resection margins compared to those with free resection margins. CONCLUSIONS: Our evaluation of ten years' consistent use of conization by CO2 laser in the treatment of CIN II-III in an unselected population showed a low overall complication rate (8%) and very high efficacy (CIN II 100%, CIN III 98.1%) of the treatment.

[Preoperative identification of malignancy among women with a pelvic mass. Evaluation of a risk index based on ultrasound findings. CA 125 in serum and menopausal status]. / Preoperativ identifisering av malign tilstand blant kvinner med oppfylning i bekkenet. Evaluering av risikoindeks basert på ultralydfunn, CA 125 i serum og menopausestatus.

A risk of malignancy index (RMI) based on vaginal ultrasound, the tumour marker CA 125 level in serum, and menopausal status was calculated in 134 consecutive patients with a pelvic mass. 41 patients harboured a malignancy, while in 93 the condition was benign. The specificity according to the presence of a malignancy was 95% using the risk of malignancy index, compared with 78% when ultrasound was used alone, and 78% when CA 125 was used alone. The corresponding sensitivities were 73, 71 and 83% respectively. The majority of patients with a false negative index score had early stage ovarian cancer. Only one of the 21 patients with advanced ovarian cancer had a score below the limit of 200. The use of the risk malignancy index is a convenient method for pre-operative identification of cases of advanced ovarian cancer.

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.

Primary treatment of cervical carcinoma. Ten years experience from one Norwegian health region.

OBJECTIVE: To study the primary care of cervical carcinoma with regard to clinical and pathological factors, treatment decisions, complications and survival. DESIGN: A historical cohort comprising all women hospitalized with invasive cervical carcinoma (n=293) during the period 1987-1996. RESULTS: Median age was 52 years (range 23-90). FIGO stage distribution was 62%, 15%, 18% and 5% in stages I, II, III and IV, respectively. Early stage disease correlated with young age. Histologic types were: squamous cell carcinoma 84%, adenocarcinoma 11%, adenosquamous carcinoma 4% and small cell/anaplastic carcinoma 1%. Primary therapies were: surgery 188 women (64%), radiotherapy 99 women (34%), chemotherapy two women (0.7%); four women not treated (1.3%). Complications after surgery in 25 women (13%), none were fatal. Acute or late complications after primary or postoperative radiotherapy in 39 women (25%), seven (4.6%) were late serious complications. Three women died from complications related to radiotherapy. Mean follow-up of surviving patients was 58 months. Overall disease specific five-year survival was 70%. Five-year survival in stages IA, IB, II and III was 100%, 88%, 58% and 20%, respectively. One-year survival in stage IV was 31%. Median survival in stages III and IV according to curative or palliative aim of treatment was 20 and 6 months, respectively (p<0.005). CONCLUSION: Satisfactory quality of diagnosis and therapy have been maintained through regional care for cervical cancer patients.

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. DESIGN: A prospective study. SETTING: Department of Gynaecology, Trondheim University Hospital, Trondheim, Norway. PARTICIPANTS: One hundred and seventy-three women, 30 years or older, consecutively admitted between February 1992 and February 1994 for primary laparotomy of a pelvic mass. MAIN OUTCOME MEASURES: The sensitivity, specificity and positive predictive value of serum CA125 level, ultrasound findings and menopausal status, separately and combined into the RMI, to diagnose ovarian cancer. RESULTS: The RMI was more accurate than any individual criterion in diagnosing cancer. Using a RMI cut-off level of 200 to indicate malignancy, the RMI derived from this dataset gave a sensitivity of 80%, specificity of 92% and positive predictive value of 83%. Applying RMI criteria developed by others, the following test performance was found: sensitivity 71%, specificity 96% and positive predictive value 89%. For the Stages II, III and IV of ovarian cancer the sensitivity increased to approximately 90% without any substantial loss in specificity. CONCLUSIONS: The risk of malignancy index is able to correctly discriminate between malignant and benign pelvic masses. It is a scoring system which can be introduced easily into clinical practice to facilitate the selection of patients for primary surgery at an oncological unit.

Predictive values of serum tumour markers tetranectin, OVX1, CASA and CA125 in patients with a pelvic mass.

Our objective was to compare the predictive value of the well-established tumour marker CA125 with the newer tumour markers tetranectin (TN), OVX1 and CASA in distinguishing benign and malignant pelvic masses in women. Participants included 185 women, 19 years or older, with a pelvic mass planned for surgical exploration. Significantly different CA125 levels were found between benign tumours and localised ovarian cancer (OC), advanced OC and other non-OCs. Significantly different TN levels were found between benign tumours and advanced OC (stage III/IV), between benign tumours and other cancers and between all OCs and other cancers. For CASA, significant differences were found between benign tumours and all OCs as well as advanced OC. No significant differences could be demonstrated for OVX1. Significant correlations for the 44 OC patients were found between CA125, TN and CASA. No significant correlations were found for OVX1, possibly because of the method used for collection and handling of serum samples. None of the new markers had any additional predictive value compared to CA125. TN and CASA levels correlated with FIGO stage and could be used to discriminate between benign and advanced OC. However, in comparison to the performance of CA125, the additional discriminative value of TN and CASA was minor.