Samu Kurki

Breast cancer in neurofibromatosis type 1: overrepresentation of unfavourable prognostic factors

Background:An increased breast cancer incidence and poor survival have been reported for women with neurofibromatosis 1 (NF1). To explain the poor survival, we aimed to link the histopathology and clinical characteristics of NF1-associated breast cancers.Methods:The Finnish Cancer Registry and the Finnish NF Registry were cross-referenced to identify the NF1 patients with breast cancer. Archival NF1 breast cancer specimens were retrieved for histopathological typing and compared with matched controls.Results:A total of 32 breast cancers were diagnosed in 1404 NF1 patients during the follow-up. Women with NF1 had an estimated lifetime risk of 18.0% for breast cancer, and this is nearly two-fold compared with that of the general Finnish female population (9.74%). The 26 successfully retrieved archival NF1 breast tumours were more often associated with unfavourable prognostic factors, such as oestrogen and progesterone receptor negativity and HER2 amplification. However, survival was worse in the NF1 group (P=0.053) even when compared with the control group matched for age, diagnosis year, gender and oestrogen receptor status. Scrutiny of The Cancer Genome Atlas data set showed that NF1 mutations and deletions were associated with similar characteristics in the breast cancers of the general population.Conclusions:These results emphasise the role of the NF1 gene in the pathogenesis of breast cancer and a need for active follow-up for breast cancer in women with NF1.

Sleep During Menopausal Transition: A 6-Year Follow-Up

Study Objectives Menopausal transition is associated with increased dissatisfaction with sleep, but the effects on sleep architecture are conflicting. This prospective 6-year follow-up study was designed to evaluate the changes in sleep stages and sleep continuity that occur in women during menopausal transition. Methods Sixty women (mean age 46.0 years, SD 0.9) participated. All women were premenopausal at baseline, and at the 6-year follow-up, women were in different stages of menopausal transition. Polysomnography was used to study sleep architecture at baseline and follow-up. The effects of aging and menopause (assessed as change in serum follicle-stimulating hormone [S-FSH]) on sleep architecture were evaluated using linear regression models. Results After controlling for body mass index, vasomotor, and depressive symptoms, aging of 6 years resulted in shorter total sleep time (B -37.4, 95% confidence interval [CI] -71.5 to (-3.3)), lower sleep efficiency (B -6.5, 95%CI -12.7 to (-0.2)), as well as in increased transitions from slow-wave sleep (SWS) to wakefulness (B 1.0, 95%CI 0.1 to 1.9), wake after sleep onset (B 37.7, 95%CI 12.5 to 63.0), awakenings per hour (B 1.8, 95%CI 0.8 to 2.8), and arousal index (B 2.3, 95%CI 0.1 to 4.4). Higher S-FSH concentration in menopausal transition was associated with increased SWS (B 0.09, 95%CI 0.01 to 0.16) after controlling for confounding factors. Conclusions A significant deterioration in sleep continuity occurs when women age from 46 to 52 years, but change from premenopausal to menopausal state restores some SWS.

Role of ultrasensitive prostate-specific antigen in the follow-up of prostate cancer after radical prostatectomy

OBJECTIVE Prostate-specific antigen (PSA) is an important tool in the follow-up of prostate cancer after radical prostatectomy (RP). However, the relevance of ultrasensitive PSA (uPSA) after RP is not well defined. The aim of this study was to investigate the value of uPSA in follow-up after RP and to determine whether ultrasensitive PSA doubling time (uDT) correlates with traditional PSA doubling time (tDT). PATIENTS AND METHODS In total, 604 consecutive patients undergoing open RP and pelvic lymphadenectomy between 2004 and 2008 (minimum 5y of follow-up) were studied. To evaluate the postsurgical uPSA level, scatter plot statistics were used. To correlate uDT and tDT in patients with a biochemical recurrence (PSA ≥0.2ng/ml), at least 2 uPSA and 2 PSA measurements without salvage treatment were required and a weighted Cohen kappa statistic and receiver operating characteristic curve were used to test agreement across the categories. RESULTS There were 229 patients without biochemical recurrence who did not have 3 rising PSA values after nadir within ultrasensitive area. Their highest uPSA value was between 0.003 and 0.1ng/ml. In 97.4% of patients, the highest uPSA value was less than 0.03ng/ml, and in 89% of these patients, the values were less than 0.02ng/ml. The median uDT and tDT were 10.2 and 11.4 months, respectively. The weighted Cohen kappa statistic between these 2 groups was 0.30 (95% CI:-0.09 to 0.50), demonstrating a poor agreement of PSA doubling time across categories. The predictive capability of uDT was tested with tDT <9 months. A receiver operating characteristic curve area under the curve value was 0.737 (95% CI:-0.577 to 0.897) demonstrating a fair agreement between the groups. CONCLUSIONS uPSA values>0.03ng/ml seems to be valid and can be used in a clinical setting. There was a poor to fair agreement between tDT and uDT. The accuracy of uDT improves when it approaches the traditional PSA threshold of 0.1ng/ml. Also according to our results, there is no prognostic benefit of uDT calculation.

Risk of osteoporotic fractures in multiple sclerosis patients in southwest Finland

Increased risk of osteoporotic fractures in multiple sclerosis (MS) patients compared with general population has been reported. The purpose of this study was to assess the risk of osteoporotic and other low‐energy fractures in an MS cohort from a large hospital district in southwest Finland. Age‐adjusted total and gender‐specific prevalence for definite MS per 100 000 in a population of 472 139 was calculated as a point prevalence in December 31, 2012.

Common comorbidities and survival in MS: Risk for stroke, type 1 diabetes and infections

BACKGROUND Survival in MS has increased during the era of disease modifying therapies, but life expectancy in MS patients is still reduced by several years. Increased risk for common comorbidities related to brain health, such as risk for circulatory diseases have been reported in MS and could affect survival. In this paper, we studied age- and gender adjusted risks for circulatory diseases and related disorders, and their impact on overall MS survival in population of Southwest Finland. MATERIALS AND METHODS The ICD-10 codes for hospital visits were searched from the administrative data pool from 1.1.2004 up to 31.12.2012 for the resident MS and control cases at the Hospital District of Southwest Finland. The MS population under study consisted of prevalent cases in 1.1.2004 and new cases from 1.1.2004 followed up to death or 31.12.2012. Patient documents were scrutinized to confirm the MS diagnosis (G 35) by the McDonald´s criteria and to confirm the diagnoses and causes of death for the cerebro- and cardiovascular diagnoses under study. The randomly chosen 10-fold control population was matched by birth year and gender to calculate the coincident risks (odds ratio, OR) with 95% confidence intervals (95% CI) and another separate control population from the same patient pool was used to verify the stability of the results. P-values were calculated using Pearsons χ2 test. The Kaplan- Meier analysis log rank test was applied to study survival. RESULTS During the follow-up 1074 confirmed MS cases were treated in the hospital district, including the deceased cases after 1.1.2004 (5.9%). The probability of survival was 82.4 years among MS and 85.6 years among the control cases, log rank p < 0.001. The survival disadvantage within MS was associated with comorbidity for circulatory disease codes in ICD -10: I06-I71, log rank p < 0.001. The specific risk for ischemic and haemorrhagic stroke was significant with high OR of 1.49 (95% CI 1.03- 2.35) and 2.5 (1.24-5.06) respectively. The two-fold risk for type 1 diabetes in MS was significant, OR 2.1 (1.3-3.36). The main causes of death among the MS cases were infections and the coincident high risk for several infections was significant. There was no difference in the risk for acute myocardial infarct, transient ischemic attack, atrial fibrillation, hypertension, or obesity in comparison with the control cases. CONCLUSIONS Given the high risk for stroke in this MS population and the observed complexity among the coincident common risk factors for circulatory diseases, the high risk for type 1 diabetes and common infections raise a need to recognize patients at risk with these conditions and with the other known risk factors such as metabolic syndrome and smoking. The survival disadvantage related to circulatory diseases observed in general population is true also in MS and should be recognized to reduce the burden of disease and premature mortality in MS.

Ezrin expression combined with MSI status in prognostication of stage II colorectal cancer

Currently used factors predicting disease recurrence in stage II colorectal cancer patients are not optimal for risk stratification. Thus, new biomarkers are needed. In this study the applicability of ezrin protein expression together with MSI status and BRAF mutation status were tested in predicting disease outcome in stage II colorectal cancer. The study population consisted of 173 stage II colorectal cancer patients. Paraffin-embedded cancer tissue material from surgical specimens was used to construct tissue microarrays (TMAs) with next-generation technique. The TMA-slides were subjected to following immunohistochemical stainings: MLH1, MSH2, MSH6, PMS2, ezrin and anti-BRAF V600E antibody. The staining results were correlated with clinicopathological variables and survival. In categorical analysis, high ezrin protein expression correlated with poor disease-specific survival (p = 0.038). In univariate analysis patients having microsatellite instabile / low ezrin expression tumors had a significantly longer disease-specific survival than patients having microsatellite stable / high ezrin expression tumors (p = 0.007). In multivariate survival analysis, the presence of BRAF mutation was associated to poor overall survival (p = 0.028, HR 3.29, 95% CI1.14–9.54). High ezrin protein expression in patients with microsatellite stable tumors was linked to poor disease-specific survival (p = 0.01, HR 5.68, 95% CI 1.53–21.12). Ezrin protein expression is a promising biomarker in estimating the outcome of stage II colorectal cancer patients. When combined with microsatellite status its ability in predicting disease outcome is further improved.

Combined epithelial marker analysis of tumour budding in stage II colorectal cancer: ITGB4 marks aggressive tumour budding in colorectal cancer

Tumour budding predicts survival of stage II colorectal cancer (CRC) and has been suggested to be associated with epithelial‐to‐mesenchymal transition (EMT). However, the underlying molecular changes of tumour budding remain poorly understood. Here, we performed multiplex immunohistochemistry (mIHC) to phenotypically profile tumours using known EMT‐associated markers: E‐cadherin (adherence junctions), integrin β4 (ITGB4; basement membrane), ZO‐1 (tight junctions), and pan‐cytokeratin. A subpopulation of patients showed high ITGB4 expression in tumour buds, and this coincided with a switch of ITGB4 localisation from the basal membrane of intact epithelium to the cytoplasm of budding cells. Digital image analysis demonstrated that tumour budding with high ITGB4 expression in tissue microarray (TMA) cores correlated with tumour budding assessed from haematoxylin and eosin (H&E) whole sections and independently predicted poor disease‐specific survival in two independent stage II CRC cohorts (hazard ratio [HR] = 4.50 (95% confidence interval [CI] = 1.50–13.5), n = 232; HR = 3.52 (95% CI = 1.30–9.53), n = 72). Furthermore, digitally obtained ITGB4‐high bud count in random TMA cores was better associated with survival outcome than visual tumour bud count in corresponding H&E‐stained samples. In summary, the mIHC‐based phenotypic profiling of human tumour tissue shows strong potential for the molecular characterisation of tumour biology and for the discovery of novel prognostic biomarkers.

Early CD8+-recovery independently predicts low probability of disease relapse but also associates with severe GVHD after allogeneic HSCT

In this single-center study we retrospectively evaluated the impact of early reconstitution of different lymphocyte subsets on patient outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that CD8+ T-cell counts exceeding 50x106/l as early as on day 28 post-transplantation correlated significantly with decreased relapse risk, with three-year relapse rates of 17.0% and 55.6% (P = 0.002), but were also associated with severe acute and chronic GVHD. Incidence of grade III-IV acute GVHD was 30.5% for those with early CD8+ T-cell recovery compared to 2.1% for those with lower CD8+ T-cell counts on day 28 post-transplant (HR = 20.24, P = 0.004). Early CD8+ T-cell reconstitution did not, however, affect the overall survival. Multivariate analysis showed that slow CD8+ T-cell reconstitution was strongly associated with increased risk of relapse (HR = 3.44, P = 0.026). A weaker correlation was found between CD4+ reconstitution and relapse-risk, but there was no such association with CD19+ B-cells or NK-cells. In conclusion, the early CD8+ T-cell recovery on day 28 post-transplant is associated with the lower risk of relapse but also predicts the impending severe GVHD, and thus could be useful in guiding timely treatment decisions.

Real-world features associated with cancer-related venous thromboembolic events

Background The incidence of venous thromboembolism (VTE) is 1–2/1000 individuals. Patients with cancer, especially during chemotherapy, are at enhanced risk, but real-world data on factors associated with VTE events are still scarce. Aim The aim of this retrospective study was to survey the incidence of VTE based on a large hospital database, and to identify comorbidities and features associated with VTE events. We focused on cancer-related VTE events and on factors indicating increased VTE risk during chemotherapy. Methods The cohort included patients treated at Turku University Hospital during years 2005–2013. Health information was derived and analysed from multiple electronic databases. The diagnoses of VTE and all comorbidities, including type of cancer, were based on International Classification of Diseases 10th Revision coding. For further analysis, we focused on 16 common types of cancers treated with chemotherapy. Age, gender, surgery, radiotherapy, distant metastasis, available laboratory values and platinum-based chemotherapy were evaluated for VTE group, and associations were estimated by Cox regression analyses. Results The entire database contained information from 495 089 patients, of whom 5452 (1.1%) had a VTE diagnosis. Among individuals with VTE, 1437 (26.4%) had diagnosis of coronary heart disease and 1467 (26.9%) had cancer diagnosis. Among 7778 patients with cancer treated with chemotherapy, 282 (3.6%) had a VTE, platinum-based chemotherapy being a major risk factor (HR 1.77, 95% CI 1.40 to 2.24, p<0.001). In multivariate analysis, elevated blood neutrophil counts (>3.25×109 cells/L, HR 1.96, 95% CI 1.33 to 2.89, p<0.001) and plasma creatinine (>62.5 μmol/L; HR 1.60, 95% CI 1.21 to 2.13, p=0.001) values were independent indicators of increased VTE risk during chemotherapy. Conclusions Longitudinal electronic health record analysis provides a powerful tool to gather meaningful real-world information to study clinical associations, like comorbidities, and to identify markers associated with VTE. The combination of various clinical and laboratory variables could be used for VTE risk evaluation and targeted prevention.

Formin Proteins FHOD1 and INF2 in Triple-Negative Breast Cancer: Association With Basal Markers and Functional Activities

Basal-like breast cancer is an aggressive form of breast cancer with limited treatment options. The subgroup can be identified immunohistochemically, by lack of hormone receptor expression combined with expression of basal markers such as CK5/6 and/or epidermal growth factor receptor (EGFR). In vitro, several regulators of the actin cytoskeleton are essential for efficient invasion of basal-like breast cancer cell lines. Whether these proteins are expressed in vivo determines the applicability of these findings in clinical settings. The actin-regulating formin protein FHOD1 participates in invasion of the triple-negative breast cancer cell line MDA-MB-231. Here, we measure the expression of FHOD1 protein in clinical triple-negative breast cancers by using immunohistochemistry and further characterize the expression of another formin protein, INF2. We report that basal-like breast cancers frequently overexpress formin proteins FHOD1 and INF2. In cell studies using basal-like breast cancer cell lines, we show that knockdown of FHOD1 or INF2 interferes with very similar processes: maintenance of cell shape, migration, invasion, and proliferation. Inhibition of EGFR, PI3K, or mitogen-activated protein kinase activity does not alter the expression of FHOD1 and INF2 in these cell lines. We conclude that the experimental studies on these formins have implications in the clinical behavior of basal-like breast cancer.