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Stanniocalcin-1 (STC-1) is a glycoprotein hormone involved in diverse biological processes, including regulation of calcium phosphate homeostasis, cell proliferation, apoptosis, inflammation, oxidative stress responses, and cancer development. The role of STC-1 in endometrial cancer (EC) is yet to be elucidated. In this study, we investigated the protein expression pattern of STC-1 in a tissue microarray (TMA) cohort of hysterectomy specimens from 832 patients with EC. We then evaluated the prognostic value of STC-1 expression regarding the clinicopathologic features and patients survival over a period of 140 months. Our results revealed that in EC tissue samples, STC-1 is mainly localized in the endometrial epithelium, although some expression was also observed in the stroma. Decreased STC-1 expression was associated with factors relating to a worse prognosis, such as grade 3 endometrioid tumors ( p = 0.030), deep myometrial invasion ( p = 0.003), lymphovascular space invasion ( p = 0.050), and large tumor size ( p = 0.001). Moreover, STC-1 expression was decreased in tumors obtained from obese women ( p = 0.014) and in women with diabetes mellitus type 2 (DMT2; p = 0.001). Interestingly, the data also showed an association between DNA mismatch repair (MMR) deficiency and weak STC-1 expression, specifically in the endometrial epithelium ( p = 0.048). No association was observed between STC-1 expression and disease-specific survival. As STC-1 expression was particularly low in cases with obesity and DMT2 in the TMA cohort, we also evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n = 111). The analysis showed no difference in STC-1 expression in either the epithelium or the stroma in women undergoing metformin therapy compared to metformin non-users. Overall, our data may suggest a favorable role for STC-1 in EC behavior; however, further studies are required to elucidate the detailed mechanism and possible applications to cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Khatun, Urpilainen, Ahtikoski, Arffman, Pasanen, Puistola, Tapanainen, Andersson, Butzow, Loukovaara and Piltonen.)

Ovarian adult-type granulosa cell tumors (AGCTs) require prolonged follow-up, but evidence regarding the optimal follow-up marker is lacking. The objective of our study was to validate the clinical usefulness of serum anti-Müllerian hormone (AMH) and the current marker inhibin B as single and combined markers of AGCTs. We conducted a longitudinal, partially prospective cohort study of 123 premenopausal and postmenopausal AGCT patients with a median follow-up time of 10.5 years (range 0.3-50.0 years). Serum AMH and inhibin B levels were measured from 560 pretreatment and follow-up serum samples by using immunoenzymometric assays. We found that serum AMH and inhibin B levels were significantly elevated in patients with primary or recurrent AGCTs. The levels of both markers positively correlated to tumor size (p < 0.05). AMH and inhibin B performed similarly in receiving operator characteristic analyses; area under the curve (AUC) values were 0.92 [95% confidence interval (CI) 0.88-0.95] for AMH, and 0.94 (95% CI 0.90-0.96) for inhibin B. AMH was highly sensitive (92%) and specific (81%) in detecting a macroscopic AGCT. However, in AUC comparison analyses, the combination of the markers was superior to inhibin B alone. In conclusion, serum AMH is a sensitive and specific marker of AGCT, and either AMH or inhibin B can be monitored during follow-up. However, combining AMH and inhibin B in AGCT patient follow-up improves the detection of recurrent disease., (© 2015 UICC.)

Background: Oxidative stress is a widely seen phenomenon in several carcinomas. Increasing evidence also suggests that it has a significant role in the development of epithelial ovarian carcinoma (EOC). 8-Hydroxydeoxyguanosine (8-OHdG) is one of the main indicators of oxidative stress and increased expression of 8-OHdG has previously been seen in EOC. DJ-1 is an oncoprotein connected to oxidative stress regulation, but its role in ovarian cancer is not well known. We investigated redox status in different histotypes of EOC by measuring serum 8-OHdG and DJ-1 concentrations and their associations with known prognostic factors., Methods: Serum samples from newly diagnosed EOC patients were collected in 1996-2009 and stored at the Department of Obstetrics and Gynecology, Oulu University Hospital. Serum 8-OHdG and DJ-1 levels were measured by using commercially available ELISA kits. Clinical data was gathered retrospectively from the patients` files. Results were analyzed by using SPSS software., Results: In total, 112 patient samples were analyzed (38 serous, 20 mucinous, 34 endometrioid and 20 clear-cell). High serum 8-OHdG levels were associated with poor overall survival (OS) (p = 0.019), poor disease-free survival (DFS) (p = 0.020), platinum resistance (p = 0.002), serous histology versus other (p = 0.033), stage III-IV versus I-II (p = 0.009) and suboptimal surgical outcome (p = 0.012). Regarding histotypes, in the endometrioid EOC group in particular, serum 8-OHdG levels were significantly associated with poor DFS (p = 0.005), suboptimal surgical outcome (p = 0.025), and platinum resistance (p = 0.007). The prognostic significance of 8-OHdG in patients with endometrioid cancer in terms of DFS was confirmed in Cox regression analysis. High DJ-1 levels were associated with high histological grade (p = 0.029) and nonsignificantly associated with serous histology vs. other histology (p = 0.089)., Conclusions: An elevated serum 8-OHdG level is a significant predictor of poor prognosis, especially in cases of the endometrioid subtype of ovarian carcinoma. High 8-OHdG levels are associated with all traditional factors of poor prognosis in ovarian cancer and they also predict earlier development of platinum resistance. These results could be valuable when deciding the primary treatment mode for EOC patients.

Background: Despite the excellent prognosis of Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage I, type I endometrial cancers, a substantial number of patients experience recurrence and die from this disease. We analyzed the value of immunohistochemical L1CAM determination to predict clinical outcome., Methods: We conducted a retrospective multicenter cohort study to determine expression of L1CAM by immunohistochemistry in 1021 endometrial cancer specimens. The Kaplan-Meier method and Cox proportional hazard model were applied for survival and multivariable analyses. A machine-learning approach was used to validate variables for predicting recurrence and death., Results: Of 1021 included cancers, 17.7% were rated L1CAM-positive. Of these L1CAM-positive cancers, 51.4% recurred during follow-up compared with 2.9% L1CAM-negative cancers. Patients bearing L1CAM-positive cancers had poorer disease-free and overall survival (two-sided Log-rank P < .001). Multivariable analyses revealed an increase in the likelihood of recurrence (hazard ratio [HR] = 16.33; 95% confidence interval [CI] = 10.55 to 25.28) and death (HR = 15.01; 95% CI = 9.28 to 24.26). In the L1CAM-negative cancers FIGO stage I subdivision, grading and risk assessment were irrelevant for predicting disease-free and overall survival. The prognostic relevance of these parameters was related strictly to L1CAM positivity. A classification and regression decision tree (CRT)identified L1CAM as the best variable for predicting recurrence (sensitivity = 0.74; specificity = 0.91) and death (sensitivity = 0.77; specificity = 0.89)., Conclusions: To our knowledge, L1CAM has been shown to be the best-ever published prognostic factor in FIGO stage I, type I endometrial cancers and shows clear superiority over the standardly used multifactor risk score. L1CAM expression in type I cancers indicates the need for adjuvant treatment. This adhesion molecule might serve as a treatment target for the fully humanized anti-L1CAM antibody currently under development for clinical use.

Aims: To clarify the role of oxidative stress during breast carcinogenesis by studying the expression of 8-hydroxydeoxyguanosine (8-OHdG) (a marker of oxidative DNA damage) and 4-hydroxy-2-nonenal (HNE) (a marker of lipid peroxidation) during the different phases of breast carcinogenesis., Methods and Results: The study material consisted of a total of 219 patients: 31 with usual ductal hyperplasia (UDH), 25 with atypical ductal hyperplasia (ADH), 30 with ductal carcinoma in situ (DCIS) and 133 with invasive carcinoma. The expression of 8-OHdG and HNE were evaluated immunohistochemically. Both 8-OHdG (77.4%) and HNE (45.8%) expression was already seen in UDH lesions. Interestingly, the trend of these two immunostainings during breast carcinogenesis was diverse. 8-OHdG expression diminished significantly in invasive breast carcinomas compared to non-invasive lesions (P < 0.005 when set against non-invasive cohorts). Also within the same lesions, 8-OHdG expression was the most intensive in benign cells. Conversely, HNE immunostaining was strongest in invasive breast carcinomas (UDH versus invasive cohort, P = 0.015)., Conclusions: 4-hydroxy-2-nonenal as a marker of lipid peroxidation increases during breast carcinogenesis, reflecting the role of oxidative stress in the pathogenesis of breast cancer. However, 8-OHdG shows diminished levels in carcinomas, possibly resulting from the induction of DNA repair in these invasive lesions., (© 2011 Blackwell Publishing Limited.)

Background: 8-Hydroxydeoxyguanosine (8-OHdG) is a marker of oxidative stress in DNA. This study was undertaken to reveal whether serum 8-OHdG could be a prognostic factor in epithelial ovarian carcinoma (EOC)., Patients and Methods: Preoperative serum 8-OHdG levels were examined by enzyme-linked immunosorbent assay in 84 stage I-IV EOC patients. Immunohistochemical (IHC) 8-OHdG expression was determined in 78 of these patients., Results: Strong 8-OHdG immunostaining predicted poor survival. High serum 8-OHdG (>140 pg/ml) was associated with poor ovarian cancer-specific survival (p<0.05) in patients with grade 1-2 EOC (p<0.05), but was not observed among the grade 3 patients. High 8-OHdG levels both in the serum and in the tumour tissue was associated with traditional factors of poor prognosis and serous histology., Conclusion: Both serum and IHC 8-OHdG assessment may serve as prognostic tools in EOC and the role of oxidative stress as a carcinogenic factor in ovarian cancer pathogenesis is also suggested.

Background: Potential tissue and serum biomarkers were assessed for predicting efficacy of bevacizumab in ovarian cancer (OC)., Patients and Methods: Twenty patients with OC received chemotherapy alone (control group) or in combination with bevacizumab (study group) in this non-randomised study. Pre- and post-treatment serum concentrations of vascular endothelial growth factor (VEGF), 8-hydroxydeoxyguanosine (8-OHdG) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured in all patients. In addition, immunohistochemical expressions VEGF receptors (R1, R2), hypoxia-inducible factor 1alpha (HIF-1 alpha), matrix metalloproteinases (-2, -9) and TIMP-2 were analysed in tumours from bevacizumab-treated patients., Results: 8-OHdG and HIF-1alpha immunostainings were more highly expressed among patients with progression-free survival (PFS) >23 months than in patients with PFS <12 months. Similarly, MMP-9 was more frequently highly expressed in those with long versus short PFS. Serum VEGF concentrations decreased substantially in all bevacizumab-treated patients versus only 20% of the control group., Conclusion: Our results indicate differences in MMP-9 and HIF-1alpha expression in relation to duration of PFS and effects on serum VEGF when bevacizumab is used in combination with chemotherapy.

Objectives: Previous studies have suggested the importance of reactive oxygen species in all the steps of carcinogenesis. Antioxidant enzymes are considered as the most specific and efficient way to protect cells from reactive oxygen species. The purpose of the current study was to identify the role of oxidative stress and major antioxidant enzymes in ovarian carcinomas., Methods: The material consisted of 68 invasive ovarian carcinomas which were studied by immunohistochemistry with antibodies to antioxidant enzymes peroxiredoxins (Prxs) I-VI and thioredoxin and oxidative stress markers nitrotyrosine and 8-hydroxydeoxyguanosine (8-OHdG). Both the intensity and the extent of the stainings were assessed, and the nuclear and cytoplasmic expressions were evaluated separately., Results: The study revealed the hydroxyl radical-derived oxidative stress marker in DNA, 8-OHdG, to be a powerful prognostic factor in ovarian carcinoma (Kaplan-Meier survival log-rank-analysis P = 0.003; risk of death to ovarian carcinoma 2.69; 95% confidence interval 1.35-5.35. 8-OHdG was also associated with poor differentiation (P = 0.053), higher stage (P < 0.001), and non-optimal surgical outcome (P = 0.002). High cytoplasmic Prx IV immunostaining was associated with a better prognosis (P = 0.024), and elevated cytoplasmic expression rates of Prxs V (P = 0.043) and VI (P = 0.032) were associated with a higher stage., Conclusions: To conclude, it appears that hydroxyl radical-derived oxidative stress, but not nitric oxide radical-derived oxidative stress, plays a significant role in ovarian carcinogenesis. Immunohistochemical assessment of 8-OHdG could provide a useful prognostic marker in ovarian cancer.

Objective: We investigated the clinical utility of macrophage colony-stimulating factor 1 versus CA 125 and the aminoterminal propeptide of type III procollagen in endometrial carcinoma., Study Design: Serum levels of the three substances were measured in 159 patients with untreated endometrial adenocarcinoma and in 24 patients treated with cytotoxic chemotherapy for recurrent endometrial adenocarcinoma., Results: Initial concentrations of colony-stimulating factor 1, CA 125, and the aminoterminal peptide of type III procollagen were above the normal range in 73%, 11%, and 27%, respectively, of the patients. Colony-stimulating factor 1 levels correlated with those of the aminoterminal peptide of type III procollagen (r = 0.3, p = 0.002) and CA 125 (r = 0.20, p = 0.036) in the total group and with those of the aminoterminal peptide of type III procollagen in stage I and II patients (r = 0.3, p = 0.0023). Colony-stimulating factor 1 levels correlated significantly with tumor grade, whereas those of CA 125 and the aminoterminal peptide of type III procollagen correlated more closely with clinical stage. Mean colony-stimulating factor 1 levels (9.6 vs 7.7 ng/ml, p = 0.04) and the frequency of elevated CA 125 levels (31% vs 8%, p = 0.048) were higher in patients with poor prognosis than in those with good prognosis. Colony-stimulating factor 1, the aminoterminal peptide of type III procollagen, and CA 125 levels were useful in monitoring clinical behavior of the disease in 88%, 79%, and 63% of the cases, respectively. Levels of all three markers rose with disease progression, whereas colony-stimulating factor 1 and the aminoterminal peptide of type III procollagen fell with clinical responses to therapy., Conclusion: Elevated serum colony-stimulating factor 1 levels were the most accurate indicator of the presence and activity (progression, stabilization, or regression) of primary or recurrent disease. Accuracy was not further enhanced by measurement of CA 125 or the aminoterminal peptide of type III procollagen levels.

The concentration of the aminoterminal propeptide of type III procollagen (PIIINP) in serum is a measure of the activity of the metabolism of type III collagen, which is a major constituent of soft connective tissues and of the connective tissue stroma of solid tumours. In advanced ovarian carcinoma, serum PIIINP serves as a tumour-associated antigen, its changes reflecting and preceding changes in the clinical behaviour of the malignancy. Elevated values of serum PIIINP are also observed in endometrial and cervical malignancies, though less frequently than in ovarian tumours. Very high concentrations of PIIINP are found in ovarian carcinoma ascites, suggesting an ongoing fibro-proliferative reaction in the peritoneal cavity as a response to the tumour.