Evaluation of antihypertensive medications use and survival in patients with ovarian cancer: a population-based retrospective cohort study.

BACKGROUND: Despite declining mortality in most countries and in Lithuania, ovarian cancer burden has remained high. Studies have indicated that antihypertensive medications use may help to improve ovarian cancer survival, however findings remain controversial. The aim of the study was to analyse the association between post-diagnosis antihypertensive medications intake and cancer-specific survival in ovarian cancer patients. METHODS: This retrospective cohort study included 588 ovarian cancer cases diagnosed between 2013 and 2015. Hazard ratios (HR) and corresponding 95% confidence intervals (95%CI) were estimated using multivariable Cox proportional hazards models to assess associations between antihypertensive medications and ovarian cancer-specific mortality. RESULTS: In total, 279 (47%) patients died during the follow-up; 242 (87%) of them died due to ovarian cancer. The risk of ovarian cancer death was reduced in angiotensin-converting enzyme inhibitors (ACE inhibitors) users vs. non-users (HR 0.55, 95% CI: 0.36-0.83). Subgroup analysis showed better ovarian cancer survival in higher dose ACE inhibitors users (HR 0.46, 95% CI: 0.28-0.77, p for trend 0.002); the effect was also stronger in age 51-65 years, stage I-III, surgery or chemotherapy treatment, pre-diagnosis ACE inhibitor users' and pre-diagnosis hypertension subgroups. The risk of cancer-specific death was slightly lower among calcium-channel blocker and angiotensin-receptor blocker users and higher among beta-blocker users as compared to non-users, however chance and confounding could not be ruled out. We found no association between the use of centrally and peripherally acting antiadrenergic agents and diuretics and risk of ovarian cancer-specific mortality. CONCLUSIONS: Our findings imply that post-diagnosis use of ACE inhibitors may be associated with reduced ovarian cancer-specific mortality; however, further research is needed for the comprehensive assessment.

Effectiveness of the cervical cancer prevention programme: a case-control mortality audit in Lithuania.

The cervical cancer burden in Lithuania has remained high, and there are no previous effectiveness studies of cervical cancer prevention programme in the country. We investigated the effect of a prevention programme on the risk of mortality from cervical cancer in Lithuania by conducting a mortality audit study. The register-based case-control study included 715 cervical cancer deaths that occurred during 2010-2015 in Lithuania and their 2145 matched controls. Screening histories for cases and controls were obtained from the National Health Insurance Fund database. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression and corrected for self-selection bias. Index screening was associated with a 56% reduction in the cervical cancer death risk, OR: 0.44; 95% CI 0.26-0.74. The ORs for stage I and stage II+ cancers were 0.80; 95% CI 0.32-2.00 and 0.36; 95% CI 0.21-0.62, respectively. The preventive effect was statistically significant for women aged ≥40 years, while nonsignificant for younger. In women who died of cervical cancer, 71% were not invited and 88% were not screened within the recommended 36 months prior to index date. Among cases with index invitation, 32% had index screening compared to 70% in controls. In conclusion, participation in screening has been effective in reducing cervical cancer mortality in Lithuania. The study shows poor screening attendance, emphasizing the importance of greater efforts at the national level to improve the effectiveness of the screening.

Trends in Mortality Rates of Corpus Uteri and Ovarian Cancer in Lithuania, 1987-2016.

Background: The corpus uteri and ovarian cancers burden in Lithuania has remained high. The aim of this study was to investigate time trends in mortality rates of corpus uteri and ovarian cancer in Lithuania across age groups and time periods over a 30-year time span. Materials and Methods: Data on numbers of deaths from corpus uteri cancer during the period 1987-2016 and ovarian cancer during the period 1993-2016 were obtained from the WHO mortality database. Trends in age-standardized mortality rates (ASR, world standard), and age-specific rates were analyzed by calculating annual percentage change using Joinpoint regression. In addition, age-period-cohort analysis was performed for each cancer type. Results: Mortality from corpus uteri cancer decreased by -1.2% (95% CI: -1.8; -0.7) annually from 1987 to 2016. Decrease was most pronounced in youngest age group of 40-49 years; annual percentage change was -2.4 (95% CI: -4.0; -0.9). Mortality rates for ovarian cancers decreased by -1.2% (95% CI: -1.6; -0.8) annually from 1993 to 2016. Corpus uteri and ovarian cancer ASRs in 2016 were 3.5/100,000 and 7.4/100,000, respectively. The age-period-cohort analysis suggests that temporal trends in corpus uteri cancer mortality rates could be attributed to period and cohort effects. Conclusion: A reduction in mortality rate was observed for corpus uteri and ovarian cancer over the entire study period. Similar decreasing pattern for corpus uteri and ovarian cancer mortality indicate effect of shared factors.

A gene signature for immune subtyping of desert, excluded, and inflamed ovarian tumors.

PROBLEM: The current tumor immunology paradigm emphasizes the role of the immune tumor microenvironment and distinguishes several histologically and transcriptionally different immune tumor subtypes. However, the experimental validation of such classification is so far limited to selected cancer types. Here, we aimed to explore the existence of inflamed, excluded, and desert immune subtypes in ovarian cancer, as well as investigate their association with the disease outcome. METHOD OF STUDY: We used the publicly available ovarian cancer dataset from The Cancer Genome Atlas for developing subtype assignment algorithm, which was next verified in a cohort of 32 real-world patients of a known tumor subtype. RESULTS: Using clinical and gene expression data of 489 ovarian cancer patients in the publicly available dataset, we identified three transcriptionally distinct clusters, representing inflamed, excluded, and desert subtypes. We developed a two-step subtyping algorithm with COL5A2 serving as a marker for separating excluded tumors, and CD2, TAP1, and ICOS for distinguishing between inflamed and desert tumors. The accuracy of gene expression-based subtyping algorithm in a real-world cohort was 75%. Additionally, we confirmed that patients bearing inflamed tumors are more likely to survive longer. CONCLUSION: Our results highlight the presence of transcriptionally and histologically distinct immune subtypes among ovarian tumors and emphasize the potential benefit of immune subtyping as a clinical tool for treatment tailoring.

Chemokine profiling in serum from patients with ovarian cancer reveals candidate biomarkers for recurrence and immune infiltration.

The management of advanced ovarian cancer is challenging due to the high frequency of recurrence, often associated with the development of resistance to platinum­based chemotherapy. Molecular analyses revealed the complexity of ovarian cancer with particular emphasis on the immune system, which may contribute to disease progression and response to treatment. Cytokines and chemokines mediate the cross­talk between cancer and immune cells, and therefore, present as potential biomarkers, reflecting the tumor microenvironment. A panel of circulating C­C motif chemokine ligand (CCL) and C­X­C motif chemokine ligand (CXCL) chemokines were examined in the serum of 40 high­grade patients with ovarian cancer prior to primary surgery. The level of immune infiltration in tumors was also analyzed. The preoperative levels of chemokines differ between patients. Elevated levels of circulating CXCL4 + CCL20 + CXCL1 combination can discriminate patients with shorter recurrence­free survival and overall survival. The presence of tumor­infiltrating T lymphocytes was detected in half of the patients. The mRNA expression analysis suggests the presence of antitumoral and immunosuppressive elements in the tumor microenvironment. The combination of circulating CXCL9 + CXCL10 can distinguish immune­infiltrated tumors that will lead to shorter recurrence­free survival. The results suggest that preoperative profiling of circulating chemokines in patients with ovarian cancer may provide valuable information regarding tumor recurrence and immune infiltration. The findings demonstrate that combinations have better prognostic utility than single chemokines, and may serve as patient stratification tools.

Trends in cervical cancer mortality rates in Lithuania, 1987-2016.

BACKGROUND: The aim of this study was to investigate time trends in cervical cancer mortality rates in Lithuania across age groups and time periods over a 30-year time span. METHODS: Data on numbers of deaths from cervical cancer during the period 1987-2016 were obtained from the WHO mortality database. Trends in age-standardised mortality rates (ASR, world standard), and age-specific rates were analysed by calculating annual percentage change (APC) using Joinpoint regression. In addition, age-period-cohort analysis was performed. RESULTS: Joinpoint regression analysis indicated that mortality from cervical cancer increased by 2.0% (95% CI: 1.2, 2.9) annually from 1987 to 2002 and decreased by 2.3% (95% CI: 3.2, 1.3) annually thereafter. In age groups 20-39 and 40-49 years after a sharp increase by 5.6% (95% CI: 2.6, 8.7) and 5.9% (95% CI: 2.7, 9.2), respectively, mortality rates declined since around 2000 with slopes of -4.8% (95% CI: -7.6, -1.9) and -2.7% (95% CI: -4.7, -0.6), respectively. Among women aged 50-59 years there was an increase in mortality (APC = 2.6%; 95% CI: 0.8, 4.5) followed by decrease with a not statistically significant slope (APC = -2.2%; 95% CI: -5.1, 0.7) since 2004. For older women mortality rates moderately declined during the entire time span. The age-period-cohort analysis suggests that temporal trends in cervical cancer mortality rates could be attributed to period and cohort effects. CONCLUSIONS: Opportunistic screening may have contributed to favourable recent changes in cervical cancer mortality rates in Lithuania, however not to the extent seen in most European countries.

Platinum sensitivity of ovarian cancer cells does not influence their ability to induce M2-type macrophage polarization.

PROBLEM: Development of platinum resistance in ovarian cancer is mediated by both cancer cells and tumor microenvironment. Activation of epithelial-mesenchymal transition program in cancer cells may lead to enrichment for resistant clones. These processes can be affected by tumor-associated macrophages, a highly plastic population of cells that participate in tumor progression and response to treatment by shaping the microenvironment. We aimed to study how platinum resistance influences the crosstalk between macrophages and ovarian cancer cells. METHOD OF STUDY: Using cisplatin-sensitive ovarian cancer cell line A2780, we developed and characterized cisplatin-resistant A2780Cis and cisplatin and doxorubicin co-resistant A2780Dox cell lines. Next, we set up an indirect coculture system with THP-1 cell line-derived M0-type-, M1-type- and M2-type-like polarized macrophages. We monitored the expression of genes associated with cellular stemness, multidrug resistance, and epithelial-mesenchymal transition in cancer cells, and expression profile of M1/M2 markers in macrophages. RESULTS: Development of drug resistance in ovarian cancer cell lines was accompanied by increased migration, clonogenicity, and upregulated expression of transcription factors, associated with cellular stemness and epithelial-mesenchymal transition. Upon coculture, we noted that the most relevant changes in gene expression profile occurred in A2780 cells. Moreover, M0- and M1-type macrophages, but not M2-type macrophages, showed significant transcriptional alterations. CONCLUSION: Our results provide the evidence for bidirectional interplay between cancer cells and macrophages. Independent of platinum resistance status, ovarian cancer cells polarize macrophages toward M2-like type, whereas macrophages induce epithelial-mesenchymal transition and stemness-related gene expression profile in cisplatin-sensitive, but not cisplatin-resistant cancer cells.