Markku Santala

Synthesis and breakdown of fibrillar collagens: concomitant phenomena in ovarian cancer.

The synthesis and degradation of type I and type III interstitial collagens releases several antigenic metabolites, whose measurement allows the metabolism of connective tissue to be evaluated under a variety of different conditions. In this study we investigated the influence of benign and malignant ovarian neoplasms on the metabolism of these collagens. The study population comprised patients with benign (n = 53), borderline (n = 6) or malignant (n = 36) ovarian neoplasms. We quantified the serum, cyst fluid and peritoneal/ascitic fluid concentrations of the amino-terminal propeptide of type I (PINP) and III (PIIINP) procollagens, indicators of the synthesis of type I and III collagen, respectively and the cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), an indicator of type I collagen degradation. Macrophage colony-stimulating factor 1 (CSF-1) concentration was also assayed as its serum level is increased in ovarian cancer and CSF-1 may be involved in the regulation of collagen metabolism. The concentration of each antigen was significantly higher in patients with malignant tumour than with benign neoplasm in each comparison, except for ICTP in peritoneal fluid and for CSF-1 in cyst fluid. The high ascitic fluid concentration of PINP, PIIINP or CSF-1 correlated with malignancy, and the low cyst fluid concentration of any of the four markers was indicative of benign tumour. Levels of CSF-1 did not correlate with the levels of any of the markers of collagen turnover. The concentration of PINP in ascites was about 50 times higher and in cyst fluid about eight times higher than that in the serum from patients with malignant tumour, whereas the respective ratios for ICTP were only 2.5 and 1.3. In such patients, the ratio of ascitic fluid to serum concentration was also about 80-fold higher for PIIINP and about 20-fold higher for PINP than for ICTP. The different distributions of PIIINP, PINP and ICTP suggests dominance of synthetic processes or retarded elimination of PIIINP and PINP in ovarian cancer. In advanced malignancies, the accumulation of PINP and PIIINP in abdominal space, possibly due to increased synthesis and/or failed resorption, may promote ascites formation. This study shows that both accelerated synthesis and breakdown of fibrillar collagens are characteristic of ovarian malignancy, and suggests that measurements of cyst fluid or ascitic fluid concentrations of collagen metabolites or CSF-1 could be used in the differential diagnosis of benign and malignant ovarian neoplasms.

Feasibility of endometrial assessment after thermal ablation

OBJECTIVEnTo evaluate the feasibility of endometrial assessment after endometrial thermal ablation.nnnSTUDY DESIGNnProspective observational study. A total of 57 women (age 47-52 years), who had undergone endometrial thermal ablation as a treatment for heavy menstrual bleeding (HMB) 3-10 years (mean 6 years) earlier, were examined with transvaginal ultrasound and saline sonohysterography. Endometrial samples were collected with a Pipelle device. Visualisation of endometrium, access to uterine cavity, change in cavity length, success in outpatient endometrial sampling and success in sonohysterography were evaluated.nnnRESULTSnEndometrial thickness was 4.5mm in amenorrhoeic women (n=17), 5.6mm in eumenorrhoeic women (n=37) and 6.6mm in hypermenorrhoeic women (n=3). An endometrial sample was successfully taken in 44 (77%) women, and in 13 (23%) women endometrial sample taking failed. The length of the uterine cavity compared to the length measured before endometrial thermal ablation was 0.5-5 cm (mean 2 cm) shorter in 34 women, unchanged in four women and longer in five women. The uterine cavity distended regularly in only nine (16%) women. In 14 (25%) women the cavity distended irregularly or only partly, and in 24 (42%) women the uterine cavity did not distend at all, but appeared as a narrow tube. In 10 (18%) women the sonohysterography catheter did not enter the uterine cavity at all.nnnCONCLUSIONnEndometrial assessment is compromised after previous endometrial thermal ablation. Both endometrial sampling and sonohysterography fail quite often, causing problems in diagnosis of abnormal bleeding. Intrauterine adhesions may also decrease the reliability of the endometrial sampling.

Matrix Metalloproteinases 2 and 9 and Their Tissue Inhibitors in Low Malignant Potential Ovarian Tumors

Objectives: This study aimed to analyze the expression of matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) and their tissue inhibitors TIMP-1 and TIMP-2 in low malignant potential (LMP) ovarian tumors and to compare these values with those recorded for benign and malignant ovarian neoplasms. Methods: A total of 53 ovarian tumors (16 benign, 15 LMP and 22 malignant) were evaluated by immunohistochemistry for the expression of MMP-2, MMP-9, TIMP-1 and TIMP-2. Results: MMP-2 expression was found in 56% of the benign, 40% of the LMP, and 90% of the malignant ovarian tumors (benign vs. malignant, p = 0.021; LMP vs. malignant, p = 0.002). The expression of MMP-9, TIMP-1 and TIMP-2 was lower in the benign and LMP tumors compared with the malignant ones. Conclusion: The data suggest that, in relation to the expression of MMP-2, MMP-9, TIMP-1 and TIMP-2, LMP ovarian tumors are more similar to benign than to malignant ovarian tumors.

Elevated Serum ICTP Concentrations Reflect Poor Prognosis in Patients with Ovarian Carcinoma

The effect of ovarian carcinoma on the circulating concentration of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP) was studied in 17 patients before and during treatment. ICTP is a complex peptide released from type I collagen, which is the main organic component of bone matrix but also induced in ovarian carcinoma tissue and the peritoneal cavity by the tumour. CA 125 and the aminoterminal propeptide of type III procollagen (PIIINP) were also measured. The preoperative CA 125, PIIINP and ICTP concentrations were pathological in 16 (94%), nine (53%) and seven (41%) patients, respectively. There was a positive correlation between the PIIINP and ICTP levels in serum. After surgery and one course of cytotoxic chemotherapy, the median CA 125 concentration decreased whereas those of PIIINP and ICTP increased. During monitoring of the treatment response, patients with regressive disease showed lower CA 125 concentrations than those with stable or progressive disease. For PIIINP and ICTP there was no clear difference between these response categories, but altogether, simultaneously increasing serum CA 125, PIIINP and ICTP concentrations were consistently associated with poor prognosis.

Endometrial thermal balloon ablation has a beneficial long-term effect on menorrhagia.

Background. More data on the long‐term results of thermal balloon endometrial ablation are needed. Methods. A retrospective observational study of 190 women who underwent endometrial thermal balloon ablation in the treatment of menorrhagia. The mean follow‐up period was 6 years. Results. Of the 172 women analysed after exclusion, 28 (16%) had a hysterectomy during follow‐up. Women with regular menstrual periods had the best outcome. Some 152 (89%) women filled in a questionnaire concerning their satisfaction with the procedure, and 76% were satisfied. Amenorrhoea was reported by 14% and eumenorrhoea by 54% of the women who completed the questionnaire. Conclusion. Endometrial thermal balloon ablation has good long‐term efficacy and can be considered an applicable alternative in the treatment of menorrhagia, especially for women who have regular periods and are over 40 years of age.

Immunoreactivity for TIMP-2 is associated with a favorable prognosis in endometrial carcinoma

Tissue inhibitors of metalloproteinases are important regulators of metalloproteinase activity, and the balance of active enzyme and inhibitor is a critical determinant of tumor cell invasiveness. This study aimed to evaluate the prognostic and clinical implications of the two main inhibitors of matrix metalloproteinases, TIMP-1 and TIMP-2, in endometrial carcinoma. The material consisted of 241 patients with primary endometrial carcinoma. The median follow-up time was 77xa0months. Expressions of TIMP-1 and TIMP-2 proteins were examined in paraffin-embedded tumor sections by immunohistochemical methods. Positive staining for TIMP-1 and -2 was observed in 88% and 86% of the primary tumors, respectively. The Kaplan–Meier analysis showed that the 5-year cancer-specific survival rate of the patients with TIMP-2 positive immunostaining was 89% and that of the TIMP-2 negative patients 78%. Positive immunoreaction for TIMP-2 correlated with favorable cancer-specific and overall survival. When including only endometrioid adenocarcinomas, a similar trend towards favorable survival was seen. Excluding stage IA carcinomas, the difference became again statistically significant. For TIMP-1, there was no statistically significant association with overall or cancer-specific survival. The Cox regression analysis showed stage, grade and TIMP-2 to be significant predictors of survival. We suggest that TIMP-2 may have a more important role in endometrial carcinoma progression than TIMP-1 and might serve as a potential marker for favorable prognosis in this type of cancer.

Increased matrix metalloproteinases 2 and 9 and tissue inhibitor of matrix metalloproteinase 2 expression is associated with progression from vulvar intraepithelial neoplasia to invasive carcinoma.

Objective. The expression of matrix metalloproteinases 2 (MMP‐2) and 9 (MMP‐9) and tissue inhibitors of matrix metalloproteinases 1 (TIMP‐1) and 2 (TIMP‐2) in vulvar intraepithelial neoplasia (VIN I–III) and in vulvar invasive carcinoma were evaluated. Design. A retrospective study. Setting. Oulu University Hospital, Finland. Sample. The study population consisted of 68 patients with vulvar neoplasia (13 VIN I, 5 VIN II, 6 VIN III and 44 squamous cell carcinomas). Methods. Paraffin‐embedded tissue samples were examined by immunohistochemistry. Main outcome measures. MMP‐2, MMP‐9, TIMP‐1 and TIMP‐2 expression in VIN compared to vulvar carcinoma. Results. In VIN I–III MMP‐2 expression was positive in 13%, MMP‐9 in 13%, TIMP‐1 in 50% and TIMP‐2 in 17% of patients. The positive expressions in patients with vulvar carcinoma were 52% for MMP‐2, 36% for MMP‐9, 41% for TIMP‐1 and 78% for TIMP‐2. Conclusions. We conclude that over‐expression of MMP‐2, MMP‐9 and TIMP‐2 may be associated with the progression from VIN to invasive vulvar squamous cell carcinoma.

Discrepant expression of carboxy- and aminoterminal propeptides of type I procollagen predicts poor clinical outcome in epithelial ovarian cancer

OBJECTIVEnThe metabolism and prognostic value of serum concentrations of the aminoterminal (PINP) and carboxyterminal (PICP) propeptides of type I collagen and the PICP:PINP ratio in relation to the carboxyterminal telopeptide of type I collagen (ICTP) in ovarian cancer were evaluated.nnnMETHODSnFifty patients with epithelial ovarian cancer were evaluated with serial measurements of serum concentrations of PICP, PINP, and ICTP before the operation and at 3-month intervals during the first year after the operation. For statistical analysis the patients were divided into two groups according to clinical outcome (alive vs dead) and clinical behavior (fast progression vs others).nnnRESULTSnThe serum PINP concentration before the operation was increased and the PICP/PINP ratio was lowered in patients with poor prognosis (PP) compared to those with good prognosis (GP) and in patients with fast progression compared to others. The serum PICP concentration did not differ between the groups. The circulating ICTP concentration was significantly higher in the PP-group than in the GP group. In Kaplan-Meier analysis the PICP:PINP ratio divided the PP and GP patients (P = 0.0004). In multivariate regression analysis, the independent prognostic variables were clinical stage (P = 0.014, 95% confidence interval (CI) 1.31-11.19) and preoperative serum ICTP concentration (P = 0.048, CI 1.01-5.91). When serum ICTP concentration was excluded from the equation, the PICP:PINP ratio (P = 0.012, CI 1.29-7.83), together with clinical stage (P = 0.013, CI 1.31-10.37), was found to be an independent prognostic variable. When the early and advanced stage patients were analyzed separately, the PICP:PINP ratio was a significant prognostic variable in multivariate analysis in early stage patients and in advanced stages during the first 4 years of follow-up.nnnCONCLUSIONSnA low PICP:PINP ratio was associated with fast progression and poor clinical outcome in ovarian cancer. Evaluation of the PICP:PINP ratio together with ICTP may be valuable in predicting the clinical outcome of ovarian cancer.

Cost-minimisation analysis of endometrial thermal ablation in a day case or outpatient setting under different anaesthesia regimens

OBJECTIVEnTo evaluate the cost difference between a daycase endometrial thermal ablation performed under general anaesthesia and an outpatient endometrial ablation using local anaesthetic.nnnSTUDY DESIGNnCalculations using real reported resource use in 20 daycase procedures and 16 outpatient procedures.nnnRESULTSnThe costs were 1865 euros for daycase procedure versus 1065 euros for outpatient procedure.nnnCONCLUSIONnThe cost of endometrial thermal ablation can be considerably minimised by taking the procedure out of the theatre and performing it under local anaesthetic instead of general anaesthesia. This setting makes endometrial thermal ablation cost-effective.

New endocrine tumor markers of gynecologic malignancies : A review

Any biological aberration that indicates the presence of a tumor may be considered a tumor marker (1). On the basis of this definition, Pap smear and cell flow cytometry are tumor markers. In clinical practice, the tumor marker usually defines any circulating substance that indicates the presence of tumor. Such tumor markers can be divided into three major categories: oncodevelopmental antigens, cancer-associated antigens and those representing biochemical or metabolic alterations, usually a reaction of the host against the tumor. No tumor specific marker has been identified and, therefore, the circulating tumor markers are maligancy-associated rather than tumor-specific. Many gynecologic tumors produce substances which are hormonally active and are therefore known as endocrine tumor markers. A classic example is human chorionic gonadotropin (hCG), which is produced by choriocarcinoma, other trophoblastic malignancies and some rare germ cell ovarian tumors containing syncytio-trophoblastic cells. There are also well known agents rarely used in clinical practice, such as estrogen for granulosa cell tumors, androgens for androblastomas, a-fetoprotein (AFP) for endodermal sinus tumors, thy-