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Background/Aim: Pelvic inflammatory disease (PID) is a risk factor for epithelial ovarian cancer (EOC). Chlamydia trachomatis infection, a major cause of PID, may persist in some women. Serum IgG antibodies to chlamydial TroA and HtrA are more common in ascending or repeat chlamydial infection than in uncomplicated infection. The aim of this study was to explore the role of C. trachomatis infection in EOC by analyzing chlamydial TroA, HtrA and major outer membrane protein (MOMP) IgG serum antibody responses. Patients and Methods: The study is based on the review of Oulu University Hospital medical records of 162 women diagnosed with EOC between March 2008 and May 2018. Serum IgG antibody responses to recombinant C. trachomatis TroA, HtrA and MOMP were analyzed using enzyme-linked immunoassay. Complete response to the first line therapy and the three-year survival were the study endpoints. Results: Altogether, 16.7%, 11.1% and 12.3% women were C. trachomatis TroA, HtrA and MOMP IgG positive, respectively. Women with these antibodies were more likely to have a complete response to the first-line treatment, compared to women without these antibodies (63.0% vs. 34.1% for TroA IgG, 50.0% vs. 37.5% for HtrA IgG and 50% vs. 37.3% for MOMP IgG, respectively). The presence of these antibodies predicted better three-year survival. Conclusion: Women with EOC and positive markers of persistent C. trachomatis infection have better response to the first-line treatment and seem to have better three-year survival.

Background: Use of metformin and statins have been associated with improved prognosis of colon cancer (CC) in patients with type 2 diabetes (T2D). We examined the survival from CC in relation to the use of metformin, other oral antidiabetic medications (ADM), insulin, and statins in T2D patients. Materials and Methods: A cohort (n = 2252) of persons with pre-existing T2D diagnosed with incident CC between 1998 and 2011 was identified from several Finnish registers. Cox models were fitted for cause-specific mortality rates to obtain adjusted estimates of the hazard ratios (HR) with 95% confidence intervals (CI) in relation to use of ADM and statins before the CC diagnosis. Cox models were also fitted for mortality in relation to post-diagnostic use of the medications treating these as time-dependent exposures, and starting follow-up 1 year after the CC diagnosis. Results: Pre- and post-diagnostic metformin use was weakly associated with the risk of CC-related death (HR 0.75; 95% CI 0.58–0.99, and HR 0.78; 95% CI 0.54–1.14, respectively) compared to the use of other oral ADMs. Pre- and post-diagnostic statin use predicted a reduced risk of CC-related death (HR 0.83; 95% CI 0.71– 0.98, and HR 0.69; 95% CI 0.54–0.89, respectively). Conclusions: Additional evidence was found for use of statins being associated with an improved survival from CC in patients with pre-existing T2D, but for metformin use the evidence was weaker.

Tiivistelmä JOHDANTO: Oulun yliopistollisen sairaalan perinnöllisyyspoliklinikan ja gynekologisen onkologian yhteisprojektina on ollut 1990-luvulta lähtien tavoittaa perinnöllistä rinta- ja munasarjasyöpäalttiutta kantavia sukuja. Selvitimme BRCA1/2-alttiusmutaation toteamisen jälkeen kantajanaisten seurantatapahtumat. MENETELMÄT: Tutkimme vuosina 1992–2016 alttiusmutaatiovastauksen saaneiden naisten mutaatiokirjoa, syöpäsairastavuutta, seurantaa ja riskiä pienentäviä toimenpiteitä Pohjois-Suomessa. Tarkemmat tiedot hankittiin henkilöistä, jotka eivät olleet sairastaneet rinta- tai munasarjasyöpää ennen mutaatiovastausta. Tutkimus toteutettiin takautuvana rekisteritutkimuksena, jonka aineisto kerättiin sairauskertomuksista. TULOKSET: BRCA1-mutaatio oli 63 naisella (54 %) ja BRCA2-mutaatio 54:llä (46 %). Tarkemmin tarkastelluista henkilöistä valtaosa osallistui seurantatutkimuksiin. Mutaatiovastauksen jälkeen kuudella todettiin rintasyöpä ja kahdella munasarjasyöpä. Riskiä pienentävä munasarjojen poistoleikkaus oli mastektomiaa suositumpi. PÄÄTELMÄT: Tutkimus on ensimmäinen pohjoissuomalaisia BRCA1/2-sukuja kartoittava julkaisu. Suurin osa alttiusmutaatioista oli perustajamutaatioita. Seurantojen toteutuminen vaihteli paljon, mutta on sittemmin yhtenäistynyt kansallisten suositusten ansiosta.

Metformin and statin use have been associated with an improved prognosis for colorectal cancer in persons with type 2 diabetes (T2D). Data regarding rectal cancer (RC) have been inconclusive; therefore, we investigated the issue with high-quality data and a robust study design. We identified 1271 eligible patients with T2D and incident RC between 1998 and 2011 from the Diabetes in Finland (FinDM) database. Cox models were fitted for cause-specific mortality rates to obtain adjusted estimates of the hazard ratios (HR) with 95% confidence intervals (CI) in relation to use of antidiabetic medication (ADM) and statins before the RC diagnosis and for post-diagnostic use in a time-dependent exposure manner. No sufficient evidence was found for either pre- or post-diagnostic metformin use and RC mortality (HR 0.96, 95% CI 0.67–1.38, and 0.70, 95% CI 0.45–1.10, respectively) when compared to other oral ADMs. Both pre- and post-diagnostic statin use appeared to be inversely associated with mortality from RC (HR 0.77 95% CI 0.63–0.94, and 0.57, 95% CI 0.42–0.78, respectively). Our study was inconclusive as to the association of metformin use with the prognosis of RC, but statin use was found to predict reduced mortality, both from RC and from other causes of death in persons with T2D.

Background: Metformin and statins may have anticancer effects, with plausible cellular mechanisms. However, the association of these agents with the risk of colorectal cancer is unclear. Patients and Methods: This was a retrospective cohort study on a large population (N = 316,317) of patients with type 2 diabetes. Data were obtained from the Diabetes in Finland database (FinDM). In a full cohort analysis, hazard ratios (HRs) with their 95% confidence intervals (CIs) for ever use versus never use were estimated using a multiple Poisson regression model. A nested case–control design within the cohort was used to examine the association of colon cancer (CC) with the defined daily dose of medication. The data were analyzed by conditional logistic regression. The analyses were adjusted for the patient’s age, sex, and duration of diabetes. Results: In total, 1351 CC cases were diagnosed during 1996–2011. The results revealed insufficient evidence for an association between metformin (HR, 1.01; 95% CI, 0.90–1.14), other oral antidiabetic medications (HR, 1.05; 95% CI, 0.93–1.19), insulin (HR, 1.02; 95% CI, 0.86–1.22), or statins (HR, 0.94; 95% CI, 0.84–1.05) and the incidence of CC in the full cohort analysis. The results from the case–control study were similar, with no consistent trend in the incidence of CC according to the cumulative dose of metformin or the other studied medications. Conclusion: This study found insufficient evidence for an association between metformin, insulin, other oral type 2 diabetes medications, or statins and the incidence of CC.

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 detail

Preclinical studies have suggested statins have antiproliferative and anti-metastatic effects on endometrial cancer cells. Similarly, most previous epidemiological studies have reported a better prognosis of endometrial cancer in patients who used statins. In this study, we explored the role of statins in the prognosis of endometrial cancer in women with type 2 diabetes in a hospital-based cohort. This retrospective cohort consisted of 119 women with type 2 diabetes who were diagnosed and treated for endometrial cancer at Oulu University Hospital, Finland, between 2007 and 2014. The patients were classified as statin users (n = 58) and nonusers (n = 61) based on the type of medication they were using at the time of endometrial cancer diagnosis. Statin use showed no association with progression-free survival or overall survival in the whole cohort nor the subgroups with type I or type II histology, in lower or higher body mass index groups, or at an early or advanced stage. The results remained similar in the multivariate analysis after adjusting for the patient’s age, cancer stage, and histology. Furthermore, statin use seemed not to have any association with most of the prognostic factors at the time of endometrial cancer diagnosis.

We investigated the survival of female patients with pre-existing type 2 diabetes (T2D) diagnosed with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of breast, in relation to the use of metformin, other antidiabetic medication (ADM) and statins. The study cohort consisted of 3,165 women (2,604 with IDC and 561 with ILC). The cumulative mortality from breast cancer (BC) and from other causes was calculated using the Aalen-Johansen estimator. The cause-specific mortality rates were analysed by Cox models, and adjusted hazard ratios (HRs) were estimated for the use of different medications. No evidence of an association of metformin use with BC mortality was observed in either IDC (HR 0.92, 95% confidence interval [CI] 0.64–1.31) or ILC (HR 0.68, 95% CI 0.32–1.46) patients, when compared to other oral ADMs. The mortality from other causes was found to be lower amongst the IDC patients using metformin (HR 0.64, 95% CI 0.45–0.89), but amongst ILC patients the evidence was inconclusive (HR 1.22, 95% CI 0.64–2.32). Statin use was consistently associated with reduced mortality from BC in IDC patients (HR 0.77, 95% CI 0.62–0.96) and ILC patients (HR 0.59, 95% CI 0.37–0.96), and also mortality from other causes in IDC patients (HR 0.81, 95% CI 0.67–0.96) and in ILC patients (HR 0.66, 95% CI 0.43–1.01). We found no sufficient evidence for the possible effects of metformin and statins on the prognosis of BC being different in the two histological subtypes.

Background/Aim: Preclinical studies on metformin use and endometrial cancer have been promising but epidemiological studies have reported variable results. This study aimed to assess if metformin use is associated with endometrial cancer aggressiveness and survival in women with type 2 diabetes (T2D). Patients and methods: This retrospective hospital-based cohort consisted of women with T2D who were treated for endometrial cancer at the Oulu University Hospital, Finland, between 2007 and 2014. Results: The sample size was 121 patients: 58 metformin users and 63 metformin non-users. Intriguingly, type 2 histology, deep myometrial invasion and the presence of lymphovascular invasion were more common in the metformin user group. However, metformin use showed no association with overall survival and progression-free survival. Conclusion: Metformin use was associated with poorer prognostic factors in endometrial cancer patients with T2D.

In recent decades, great interest in the off-label use of metformin has arisen as a result of its broad effects on different signaling pathways, with only a few side effects, and low cost. Metformin has been shown to have multiple, dose-dependent preclinical anticancer effects, which can be roughly divided into either direct effects via inhibition of mitochondrial respiratory chain complex I, or indirect effects through lowered glucose, insulin and insulin-like growth factor levels. Further details on in vitro and in vivo anticancer effects specifically in ovarian cancer are continuously reported. Preclinically metformin has clear chemosensitizing effects in ovarian cancer and it is an effective negative regulator of angiogenesis. There are also some epidemiological studies on metformin use in ovarian cancer, but the results of these studies are not as promising as those preclinical studies would indicate. Most preclinical studies have involved metformin concentrations that are many times higher than the pharmacological doses used in patients, which might confound the clinical use of metformin as regards the above-mentioned aspects. In this review we evaluate preclinical and clinical evidence concerning metformin in ovarian cancer treatment.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a major regulator of the oxidative stress response and it is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1). The Keap1–Nrf2 axis has a fundamental role in carcinogenesis. In previous studies, the widely used diabetes drug metformin has appeared to have a critical role in the regulation of Nrf2 function. In this study, we assessed the expression of Nrf2 and Keap1 immunohistochemically in 157 patients with type 2 diabetes who underwent breast cancer surgery with curative intent. In total, 78 (49.7%) of these patients were taking metformin alone or combined with other oral anti-diabetic medication at the time of breast cancer diagnosis. We found that high-level cytoplasmic Nrf2 expression predicted dismal overall survival and breast cancer–specific survival, but only in the patients who were not taking metformin at the time of diagnosis. Similarly, low-level nuclear Keap1 expression had an adverse prognostic value in terms of overall survival and breast cancer–specific survival in patients without metformin. On the other hand, high-level nuclear Keap1 expression was associated with prolonged overall survival and breast cancer–specific survival. The results may be explained in terms of non-functioning or displaced Keap1, although more mechanistic pre-clinical and prospective clinical studies are warranted.

Patients with type 2 diabetes (T2D) are at a greater risk of some cancer types, possible together with worse prognosis. Various types of antidiabetic medication have been reported to have different relationships to cancer prognosis. Metformin seems to reduce mortality in some forms of cancer and it has effects on cell cycle arrest and apoptosis in vitro. T2D is a risk factor of coronary heart disease, which is widely treated with statins. Statins are associated with both reduced incidence and better prognosis in some cancers. Epidemiological studies on the associations between metformin and statin use and breast and ovarian cancer have reported inconclusive results. The aim of the present epidemiological study was to find out whether metformin and statin use are associated with reduced incidence and mortality in ovarian and/or breast cancer. The source population for the study was drawn from the Finnish nationwide diabetes database (FinDM; n = 244,322), supplemented with other Finnish registry data. The data from FinDM was combined with data from the Finnish Cancer Registry. The use of metformin and/or statins was found not to be associated with the incidence of either ovarian (n=303) or breast cancer (n=2,300) in women with type 2 diabetes. The use of insulin seemed to be associated with a higher incidence of breast cancer. Metformin use was not observed to be associated with mortality from ovarian or breast cancer but mortality from other causes seemed to be lower in breast cancer patients among metformin users compared with the users of other types of oral antidiabetic medication. Prediagnostic statin use seemed to be associated with decreased mortality from breast cancer and other causes in breast cancer patients, but in ovarian cancer, an association with reduced mortality was seen only in connection with ovarian cancer itself. On the basis of our study results, it would not be reasonable to initiate metformin or statin treatment solely in order to avo, Tiivistelmä Tyypin 2 diabetesta sairastavilla potilailla on yleensä suurentunut riski sairastua maksa-, haima- ja suolistosyöpiin, ja tämä heikentää ainakin näiden syöpien ennustetta. Diabeteslääkkeillä on todettu olevan toisistaan poikkeava vaikutus syöpäennusteeseen. Metformiini vaikuttaa alentavan kuolleisuutta, ja solutöissä sillä on todettu olevan vaikutuksia solusyklin pysähtymiseen ja ohjelmoituun solukuolemaan. Tyypin 2 diabetes on riskitekijä sydän- ja verisuonisairauksiin, ja sen vuoksi diabetespotilaiden hoitoon kuuluu usein kolesterolia alentavat statiinit. Statiinien käyttö on yhdistetty joidenkin syöpäsairauksien vähenemiseen ja niiden parempaan ennusteeseen. Epidemiologiset tutkimukset metformiinin ja statiinien käytön välisestä yhteydestä munasarja- ja rintasyöpiin ovat kuitenkin epäyhtenäisiä. Tutkimuksen tarkoituksena oli selvittää, onko metformiinin ja statiinien käytöllä yhteyttä munasarja- ja rintasyöpätapausten vähenemiseen ja niiden paranemisennusteeseen. Lähdeaineistona on käytetty erilaisia suomalaisia rekistereitä yhdistävää kansallista diabetes-tietokantaa (FinDM; n = 244 322), jonka tiedot on yhdistetty Suomen Syöpärekisteriin. Metformiinin ja statiinien käytöllä ei todettu olevan yhteyttä munasarjasyövän (n = 303) tai rintasyövän (n = 2 300) ilmaantuvuuteen tyypin 2 diabetesta sairastavilla naisilla. Insuliinin käytöllä oli sen sijaan yhteys korkeampaan rintasyövän ilmaantuvuuteen. Metformiinin käytöllä ei todettu olevan yhteyttä munasarja- tai rintasyöpäkuolleisuuteen. Rintasyöpää sairastavilla naisilla muista syistä johtuva kuolleisuus oli metformiinin käyttäjillä kuitenkin matalampaa verrattaessa muihin suun kautta otettavien diabeteslääkkeiden käyttäjiin. Ennen syöpädiagnoosia aloitettu statiinien käyttö vaikutti vähentävän kuolleisuutta sekä rintasyöpään että muihin syihin rintasyöpäpotilailla. Munasarjasyövän suhteen yhteys todettiin ainoastaan munasarjasyöpäkuolleisuudessa. Tutkimuksemme mukaan ei ole perusteltua aloittaa metformi

Endometrial cancer (EC) is the fifth most common female cancer worldwide and its incidence is increasing. The prognosis of EC is fairly good. Histologically, ECs are categorized into endometrioid and non-endometrioid subtypes. Lately, the idea of repurposing existing medications for the prevention and co-treatment of EC has evoked interest in the scientific community. The results of preclinical studies involving various forms of antidiabetic medication (ADM) such as metformin, or cholesterol-lowering statins have been promising. In the previous epidemiological studies, the results of metformin and/or statin use and the risk and prognosis of EC have indicated either neutral or beneficial effects. At least some of these studies have several limitations, including a potential for several types of bias, and missing information on the dose and timing of medication, cancer-specific mortality or the histology of EC. The aim of this study was to find reliable further evidence on whether the use of metformin or statins could have beneficial effects on the risk and prognosis of EC in women with type 2 diabetes (T2D). Endometrioid and non-endometrioid EC were analyzed separately based on data from the Finnish Cancer Registry (FCR). In our study cohort of 92 366 women obtained from a nationwide diabetes database (FinDM) (1996 to 2011), the incidence rates of endometrioid (n = 590 cases) and non-endometrioid (n = 57 cases) EC were not found to differ between metformin users and users of other forms of oral ADM when adjusted for age, duration of T2D and use at any time of other forms of medication under study. We found insufficient evidence that metformin affects the prognosis of patients diagnosed with endometrioid (n = 1215) or non-endometrioid (n = 105) EC (1998 to 2011) after adjusting for year, age and stage at diagnosis of EC, and duration of T2D. However, in patients with endometrioid EC, mortality from other (predominantly cardiovascular) causes of death was decr, Tiivistelmä Kohdun runko-osan syöpä on naisten viidenneksi yleisin syöpä, ja todettujen tapauksien määrä kasvaa. Syövän paranemisennuste on melko hyvä. Histologisesti syöpä jaetaan endometrioidi-muotoon ja ei-endometrioidi -muotoon. Alun perin muihin tarkoituksiin kehitettyjen lääkkeiden käyttö kohdun runko-osan syövän ehkäisyssä ja hoitoyhdistelmissä on ollut viime aikoina tieteellisen mielenkiinnon kohteena. Prekliinisten tutkimusten tulokset diabeteslääke metformiinin ja hyperkolesterolemian hoitoon käytettyjen statiinien osalta ovat olleet lupaavia. Aiemmissa epidemiologisissa tutkimuksissa metformiinin tai statiinien käytön vaikutukset kohdun runko-osan syövän riskiin ja ennusteeseen ovat olleet vaihtelevia. Osassa tutkimuksista on ollut ongelmia liittyen tilastollisten harhojen riskiin, puutteellisiin tietoihin lääkityksen kestosta ja kumulatiivisista annoksista sekä spesifisestä syöpäkuolleisuudesta ja syövän histologiasta. Kansalliseen diabetestietokantaan (FinDM) perustuvan tutkimuksemme tavoitteena oli selvittää, onko metformiinin tai statiinien käytöllä (Kelan lääkekorvaustilastot) kohdun runko-osan syövän riskiä vähentävää tai ennustetta parantavaa vaikutusta tyypin 2 diabetesta sairastavilla naisilla. Endometrioidit-syövät ja ei-endometrioidit -syövät analysoitiin erikseen Suomen Syöpärekisterin tietoihin perustuen. Kohortissamme (n = 92 366) ei todettu eroa endometrioidin (n = 590) tai ei-endometrioidin (n = 57) kohdun runko-osan syövän ilmaantuvuudessa metformiinia tai muita oraalisia diabeteslääkkeitä käyttävien naisten välillä (1996–2011), kun ikä, diabeteksen kesto ja muiden lääkitysten käyttö vakioitiin. Emme löytäneet näyttöä metformiinin käytön yhteydestä syöpäkuolleisuuteen endometrioidissa (n = 1 215) tai ei-endometrioidissa (n = 105) alatyypeissä verrattuna muihin diabeteslääkityksiin (1998–2011), kun ikä, syövän diagnoosivuosi ja levinneisyys sekä diabeteksen kesto vakioitiin. Endometrioidiin syöpään sairastuneilla metformiinia käyttävillä n

Purpose: To address the possible association between the use of metformin, other forms of antidiabetic medication (ADM) and statins with the incidence of breast cancer in women with type 2 diabetes (T2D). Methods: Data were collected from a Finnish nationwide diabetes database (FinDM). The study cohort consisted of women diagnosed with T2D in 1996–2011 in Finland. In full-cohort analysis, Poisson regression was used to estimate hazard ratios (HRs) in relation to use of metformin, insulin, other forms of oral ADM and statins. In nested case–control analysis, up to 20 controls were matched for age and duration of diabetes to each case of breast cancer. Conditional logistic regression was used to estimate HRs in relation to medication use and cumulative use of different forms of ADM, and statins. Results: 2300 women were diagnosed with breast cancer during follow-up. No difference in breast cancer incidence was observed between metformin users [HR 1.02, 95% confidence interval (CI) 0.93–1.11] or statin users (HR 0.97, 95% CI 0.89–1.05) compared with non-users. In nested case–control analysis the results were similar. Use of insulin (HR 1.18, 95% CI 1.03–1.36) was associated with a slightly increased incidence of breast cancer. Conclusions: No evidence of an association between the use of metformin or statins and the incidence of breast cancer in women with T2D was found. Among insulin users, a slightly higher incidence of breast cancer was observed.

Aim: To determine the incidence and prognosis of non-endometrioid endometrial cancer (EC) in relation to the use of metformin, other antidiabetic medication (ADM) and statins in patients with type 2 diabetes (T2D). Materials and Methods: In order to analyze the incidence and prognosis of non-endometrioid EC, two cohorts were obtained from a nationwide diabetes database (FinDM); 57 non-endometrioid ECs were observed in a cohort of 92,366 women with newly-diagnosed T2D during the follow-up (1996 to 2011) to assess the incidence, and a retrospective cohort of 105 women with T2D diagnosed with non-endometrioid EC (1998 to 2011) was used to estimate cumulative mortality from EC and other causes of death. Hazard ratios (HRs) with 95% confidence intervals (CIs) for EC incidence were estimated in the full-cohort analysis and in the nested case–control analysis, matched for age and duration of T2D. Cumulative mortality was estimated by using the Aalen–Johansen estimator. Cause-specific mortality rates were analyzed by using Cox models regarding the pre-diagnostic use of different forms of ADM and statins. Results: In the nested case–control analysis, the use of metformin was not associated with the risk of non-endometrioid EC (HR=1.09, 95% CI=0.59–2.00), whereas statin use was associated with a lower risk (HR=0.47, 95% CI=0.26–0.84). The results from the full-cohort analysis supported these findings. Mortality from non-endometrioid EC was not different between users of metformin and other types of oral ADM (HR=1.56, 95% CI=0.40–6.07) but was observed to be lower in statin users (HR=0.41, 95% CI=0.20–0.82). Conclusions: Our findings were inconclusive regarding the association of metformin with the risk and prognosis of non-endometrioid EC. However, statin use was associated with a lower incidence and mortality from this disease.

Background: Ovarian cancer is one of the most lethal cancers and women with type 2 diabetes (T2D) have even poorer survival from it. We assessed the prognosis of ovarian cancer in women with type 2 diabetes treated with metformin, other forms of antidiabetic medication, or statins. Methods: Study cohort consisted of women with T2D diagnosed with ovarian cancer in Finland 1998–2011. They were identified from a nationwide diabetes database (FinDM), being linked to several national registers. Patients were grouped according to their medication in the three years preceding ovarian cancer diagnosis. The Aalen–Johansen estimator was used to describe cumulative mortality from ovarian cancer and from other causes in different medication groups. Mortality rates were analysed by Cox models, and adjusted hazard ratios (HR) with 95% confidence intervals (95% CIs) were estimated in relation to the use of different forms of medication. Main outcome measures were death from ovarian cancer and death from other causes. Results: During the accrual period 421 newly diagnosed ovarian cancers were identified in the FinDM database. No evidence was found for any differences in mortality from ovarian cancer or other causes between different antidiabetic medication groups. Pre-diagnostic use of statins was observed to be associated with decreased mortality from ovarian cancer compared with no such use (HR 0.72, 95% CI 0.56–0.93). Conclusions: Our findings are inconclusive as regards the association between metformin and ovarian cancer survival. However, some evidence was found for improved prognosis of ovarian cancer with pre-diagnostic statin use, requiring cautious interpretation, though.

Ovarian cancer is the fifth leading cause of cancer-associated death in women in Finland. Although ovarian cancer is relatively common, the precise mechanism of its development is still unknown. Additionally, it appears that the modes of pathogenesis differ depending on histotype. Although the initial response to platinum-based chemotherapy is usually good, the majority of ovarian cancer patients relapse and develop platinum resistance. This is a major problem in the treatment of ovarian cancer. Reactive oxygen species (ROS) are metabolites of oxygen. They are continuously formed in normal cells as a by-product of aerobic respiration and they play an important role in normal cell functions. Oxidative stress occurs when ROS formation overrides the antioxidative defence system. Oxidative stress is associated with carcinogenesis. A small proportion of cancer cells are stem cells that survive initial chemotherapy. These cells are suspected of being associated with the development of platinum resistance. To evaluate the significance of oxidative stress in ovarian cancer we examined ROS-derived damage and antioxidant regulators in benign and borderline ovarian tumours and ovarian cancer samples by immunohistochemistry and analysis of serum samples. The existence of cancer stem cell markers was also assessed in ovarian cancer samples. The expression levels of various markers were compared with clinicopathological parameters. Our results confirm that oxidative stress (8-hydroxydeoxyguanosine) exists in benign tumours and antioxidant enzymes, such as peroxiredoxins and thioredoxin are widely expressed in benign and borderline tumours. Oxidative stress was associated with poor survival, higher stage and platinum resistance in ovarian cancer. Oxidative stress markers were more strongly expressed in certain histotypes of ovarian cancer, such as serous and endometrioid type. Cancer stem cell markers were found in ovarian cancer and they were associated with the developm, Tiivistelmä Munasarjasyöpä on yksi merkittävistä syöpäkuolleisuuden aiheuttajista naisilla Suomessa. Se on kohtalaisen yleinen, mutta sen perimmäinen syntymismekanismi on vielä epäselvä. Lisäksi näyttää siltä, että eri histologioilla syntymekanismit poikkeavat toisistaan. Vaikka yleensä platinapohjaisella solunsalpaajahoidolla saadaan hyvä vaste, suurimmalla osalla hoidetuista potilaista tauti uusii ja kehittyy vastustuskyky platinapohjaisille solunsalpaajille. Tämä on suuri ongelma munasarjasyövän hoidossa. Vapaat radikaalit ovat hapen johdannaisia. Niitä muodostuu jatkuvasti soluissa soluhengityksen sivutuotteena, ja niillä on tärkeä merkitys normaaleissa solun toiminnoissa. Jos vapaiden radikaalien tuotanto ylittää antioksidatiivisen puolustusjärjestelmän, syntyy oksidatiivinen stressitilanne. Oksidatiivisen stressin on todettu olevan yhteydessä useiden syöpien syntymiseen. Osaa syövän soluista kutsutaan kantasoluiksi. Nämä solut voivat selvitä solunsalpaajahoidoista ja niiden epäillään olevan yhteydessä vastustuskyvyn kehittymisessä platinapohjaisia sytostaatteja kohtaan. Tutkimuksessamme arvioimme oksidatiivisen stressin merkitystä munasarjakasvaimissa. Tutkimme vapaiden radikaalien aiheuttamia vaurioita ja antioksidatiivisia säätelijöitä hyvänlaatuisissa, rajalaatuisissa sekä munasarjasyöpä kasvaimissa immunohistokemiallisesti ja seeruminäytteistä. Lisäksi selvitimme syövän kantasolumerkkiaineiden esiintymistä munasarjasyövässä. Tutkittujen merkkiaineiden pitoisuuksia verrattiin kliinisiin potilastietoihin. Tutkimustuloksemme mukaan oksidatiivista stressiä (8-hydroxydeoxyguanosine) esiintyi jo hyvänlaatuisissa kasvaimissa. Myös antioksidatiiviset entsyymit, kuten peroksiredoksiinit ja tioredoksiini, esiintyivät jo hyvänlaatuisissa ja rajalaatuisissa kasvaimissa. Oksidatiivinen stressi oli yhteydessä huonompaan tautiennusteeseen ja platinakohtaisen vastustuskyvyn kehittymiseen. Oksidatiivista stressiä oli enemmän seroosissa ja endometrioidissa munasarjasyöpätyy

Cancer is the leading cause of death worldwide. Despite the significant research effort, underlying mechanisms of carcinogenic processes are still poorly understood. In recent decades, a group of extremely reactive oxygen metabolites, reactive oxygen species (ROS), have been linked closely to carcinogenesis. Levels of ROS are constantly controlled by antioxidants to ensure stable redox balance in our cells. An aberrant cellular redox balance is thought to be connected to carcinogenesis by inflicting damage to cellular macromolecules and disturbing normal cellular signalling. In this work, the role of ROS in carcinogenesis was studied by observing the ROS-derived DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) in breast cancer and endometriosis-associated ovarian cancer. This marker was also measured in connection with endometriosis and PCOS to study the early stages of the carcinogenic process. In addition, peroxiredoxin antioxidant enzymes were studied in endometriosis-associated ovarian cancer to explore their impact on the carcinogenic process and relationship with ROS-derived DNA damage. There seems to be a decreasing trend in the expression of 8-OHdG in the development of breast cancer and endometriosis-associated ovarian cancer. In breast cancer, low levels of 8-OHdG in serum and in tumour tissue were found to be associated with more aggressive disease. In endometriosis-associated ovarian cancer, 8-OHdG and Prx II expressions in tissue decreased with malignant transformation from benign endometriosis tissue to ovarian cancer. Patients with PCOS were found to have lower levels of 8-OHdG in serum compared with healthy controls and metformin treatment further decreased 8-OHdG levels in obese patients. These results, together with observations is previous studies indicate that in breast cancer and endometriosis-associated ovarian cancer, a high level of ROS-derived DNA damage could be significant factor in the initiation stage of carcinogenesis, wherea, Tiivistelmä Syöpä on nykyisin maailman yleisin kuolinsyy. Vaikka syöpätutkimukseen kohdistetaan maailmanlaajuisesti huomattavia resursseja, syövän kehittymisen perimmäinen syy on edelleen heikosti tunnettu. Yhä kasvavan todistusaineiston perusteella happiradikaalien epäillään liittyvän läheisesti syövän kehittymiseen. Nämä erittäin reaktiiviset hapen aineenvaihduntatuotteet ovat välttämättömiä solujemme normaalille toiminnalle, mutta liian suurina määrinä ne voivat vaurioittaa solun rakenteita ja häiritä solun normaalia viestintää. Solut sisältävät useita antioksidantteja, joiden tärkeimpänä tehtävänä on kontrolloida happiradikaalien määrää ja näin ylläpitää solun hapetus–pelkistys-tasapaino. Tässä väitöskirjatutkimuksessa tutkittiin happiradikaalien yhteyttä syövän kehittymiseen tarkastelemalla niiden aiheuttaman DNA-vaurion merkkiainetta, 8-hydroksideoksiguanosiinia (8-OHdG), rintasyövässä ja endometrioosiin liittyvässä munasarjasyövässä sekä peroksiredoksiiniperheen antioksidanttientsyymejä endometrioosiin liittyvässä munasarjasyövässä. 8-OHdG:n avulla selvitettiin myös munasarjojen monirakkulaoireyhtymän (PCOS) ja endometrioosin yhteyttä syövän kehittymiseen. Lisäksi tutkittiin metformiinin vaikutusta happiradikaalien aiheuttamaan DNA-vaurioon. Väitöskirjatutkimuksen tulosten perusteella 8-OHdG:n määrä vähentyy rintasyövän edetessä ja endometrioosiin liittyvän munasarjasyövän kehittyessä. Matalat 8-OHdG-tasot syöpäkudoksessa ja verinäytteissä ovat yhteydessä aggressiivisempaan taudinkuvaan rintasyövässä. Endometrioosiin liittyvässä munasarjasyövässä kudoksen ilmentämä 8-OHdG ja Prx II vähentyi asteittain siirryttäessä hyvänlaatuisesta endometrioosista munasarjasyöpään. Munasarjojen monirakkulaoireyhtymässä potilaiden verinäytteiden 8-OHdG-tasot olivat merkittävästi matalammat terveisiin verrokkeihin verrattuna. Korkeilla happiradikaalipitoisuuksilla ja niistä aiheutuvalla DNA-vauriolla on väitöskirjatutkimuksen tulosten perusteella tärkeä rooli syövän syntyvaihe

Contains fulltext : 124525.pdf (publisher's version ) (Closed access), BACKGROUND: Despite the excellent prognosis of Federation Internationale de Gynecologie et d'Obstetrique (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 hum

Ovarian cancer is the leading cause of death from gynaecological cancers in the Western world. Ovarian cancer comprises of tumours with distinct behaviour and individually different responses to chemotherapy, even within the same histology. Unfortunately, there are no molecular markers in clinical use to either distinguish between patients with better and worse prognosis or to predict individual chemosensitivity. The comprehension of the molecular effects of chemotherapeutic drugs is a prerequisite for finding predictive molecular factors for chemoresponse and prognosis. Some proteins in molecular pathways contributing to DNA damage response, angiogenesis and oxidative stress have been implicated in ovarian cancer prognosis. In this study, the responses in p53 pathway and among angiogenesis-related factors to chemotherapeutic drugs were analysed in ovarian cancer cell lines. In OVCAR-3 cells with mutated p53, cisplatin but not docetaxel induced p14ARF, an important regulator of p53, at mRNA and protein level. Cisplatin also significantly increased the mRNA expression of angiogenesis-related factors TSP-1, BMP-4, ET-1 and PlGF-2 while an equivalent dose of docetaxel had only minor effects. In clinical ovarian carcinomas, the expression of BMP-4, TSP-1 and CD105 as well as the marker of oxidative stress derived DNA damage, 8-OHdG, and peroxiredoxin antioxidants were analysed by immunohistochemistry. High expression of BMP-4 and cytoplasmic peroxiredoxin IV were associated with better prognosis, while high 8-OHdG expression associated with shorter survival. Explant cultures of fresh ovarian tumour tissue were used for the evaluation of individual responses of p53 and Hdm2 after in vitro treatments of the explant cultures by carboplatin or docetaxel. Major differences between the individual tumours were found, especially in the responses of p53 to carboplatin. The results of this study suggest, that BMP-4, 8-OHdG and peroxiredoxin IV may serve as prognostic mar, Tiivistelmä Munasarjasyöpä on suurinta kuolleisuutta aiheuttava gynekologinen syöpä läntisessä maailmassa. Munasarjakasvaimet eroavat toisistaan niin käyttäytymiseltään kuin yksilölliseltä sytostaattihoitovasteeltaan, jopa sama histologisen tyypin sisällä. Kliinisessä käytössä ei valitettavasti ole sellaisia molekulaarisia merkkiaineita, jotka erottaisivat toisistaan paremman ja huonomman ennusteen kasvaimet tai ennustaisivat yksilöllistä solunsalpaajaherkkyyttä. Hoitovastetta ja potilaan prognoosia ennustavien merkkiaineiden löytämisen edellytys on kemoterapian molekyylitason vaikutusten ymmärtäminen. DNA vaurion tunnistamiseen, angiogeneesiin ja oksidatiiviseen stressiin liittyvien vaikutusreittien joillakin proteiineilla on ehdotettu olevan ennusteellista merkitystä munasarjasyövässä. Tässä väitöskirjatyössä analysoitiin munasarjasyöpäsoluja käyttäen p53 vaikutusreitin ja eräiden angiogeneesiin liittyvien tekijöiden vasteita sytostaateille. Mutatoitunutta p53 proteiinia kantavissa OVCAR-3 soluissa sisplatiini, toisin kuin dosetakseli, indusoi p53 proteiinin tärkeää säätelijää, p14ARF:a sekä mRNA- että proteiinitasolla. Sisplatiini lisäsi merkittävästi myös usean angiogeneesiin liittyvän tekijän (TSP-1, BMP-4, ET-1 ja PlGF-2) mRNA:ta. Dosetakselin vaikutukset vastaavalla annoksella olivat vähäiset. Kliinisissä munasarjasyövissä BMP-4, TSP-1 ja CD105 sekä oksidatiivisen stressin aiheuttaman DNA-vaurion merkkiaineen, 8-OHdG:n sekä peroksiredoksiiniantioksidanttien ilmeneminen analysoitiin immunohistokemiallisesti. BMP-4:n ja sytoplasmisen peroksiredoksiini IV:n vahva ilmentyminen liittyivät parempaan ennusteeseen, kun taas 8-OHdG:n vahva ilmentyminen liittyi huonompaan elinajan ennusteeseen. Tuoreen munasarjasyöpäkudoksen eksplanttiviljelyn avulla selvitettiin p53 ja Hdm2 proteiinien vasteita syöpäkudoksen karboplatiini- tai dosetakseli-käsittelyille. Selkeitä yksilökohtaisia eroja havaittiin erityisesti karboplatiinin aiheuttamissa p53 vasteissa niin eri potilaiden

The aim of this study was to evaluate the efficacy and toxicity of paclitaxel given at the same dose intensity and administered weekly (arm A) or every 3 weeks (arm B), and to assess the safety of intravenous steroids versus standard peroral premedication. Two hundred and eight patients with advanced ovarian cancer previously treated with no more than one platinum-containing regimen were randomized to receive either a weekly infusion of paclitaxel or an infusion every 3 weeks. The median delivered dose intensity was 77.6 mg/m2/week in the weekly arm, and 72.7 mg/m2/week in the every 3 weeks arm. WHO grade 3-4 hematological and non-hematological toxicity occurred more frequently in arm B. No difference in number of severe events of hypersensitivity, response rate, time to progression or survival between arms was observed. Weekly paclitaxel at a dose of 67 mg/m2/week was found to have a better safety profile and seemed to be as effective as the equivalently dosed schedule every 3 weeks. Intravenous steroids are a safe alternative to oral steroids.