Peeter Padrik

Time-gated luminescence assay using nonmetal probes for determination of protein kinase activity-based disease markers.

A novel nonmetal optical probe ARC-1063 whose long-lifetime luminescence is induced by association with the target protein kinase is used for the measurement of the concentration of catalytic subunit of protein kinase A (PKAc) in complicated biological solutions. High affinity (K(D) = 10 pM toward PKAc) and unique optical properties of the probe enable its application for the measurement of picomolar concentrations of PKAc in the presence of high concentrations of other proteins. The described assay is applicable in the high-throughput format with the instrument setups designed for lanthanide-based time-gated (time-resolved) luminescence methods. The assay is used for demonstration that extracellular PKAc (ECPKA) is present in plasma samples of all healthy persons and cancer patients but great care must be taken for procedures of treatment of blood samples to avoid disruption, damage, or activation of platelets in the course of plasma (or serum) preparation and conservation.

Sex differences in cancer survival in Estonia: a population-based study

BackgroundIn Estonia, women have much longer life expectancy than men. The aim of this study was to examine sex differences in cancer survival in Estonia and to explore the role of age at diagnosis, stage at diagnosis and tumour subsite.MethodsUsing data from the population-based Estonian Cancer Registry, we examined the relative survival of adult patients diagnosed with nine common cancers in Estonia in 1995–2006 and followed up through 2011. Excess hazard ratios (EHR) of death associated with female gender adjusted for age, stage at diagnosis and tumour subsite were estimated.ResultsA total of 20 828 male and 13 166 female cases were analysed. The main data quality indicators were similar between men and women. Women had more cases with unknown extent of disease at diagnosis. Overall, the age-adjusted 5-year relative survival ratio was higher among women than men for all studied sites, but the difference was significant for cancers of mouth and pharynx (22% units), lung (5% units), skin melanoma (17% units) and kidney (8% units). The increase in survival over time was larger for women than men for cancers of mouth and pharynx, colon, rectum, kidney and skin melanoma. In multivariate analysis, women had a significantly lower EHR of death within five years after diagnosis for five of the nine cancers studied (cancers of mouth and pharynx, stomach, lung, skin melanoma and kidney). Adjustment for stage and subsite explained some, but not all of the women’s advantage.ConclusionsWe found a significant female survival advantage in Estonia for cancers of mouth and pharynx, stomach, lung, kidney and skin melanoma. The differences in favour of women tended to increase over time as from the 1990s to the 2000s, survival improved more among women than among men. A large part of the women’s advantage is likely attributable to biological factors, but other factors, such as co-morbidities, treatment compliance or health behaviour, are also probable contributors to gender survival disparities in Estonia and merit further investigation. Our findings have implications for public health, early detection and cancer care in Estonia.

Identifying women at risk for delayed presentation of breast cancer: a cross-sectional study in Estonia

BackgroundSurvival from breast cancer remains lower in Estonia than in most other European countries. More advanced stage and larger tumors that have impact on survival may be a result of delay in seeking help for breast cancer symptoms. The aim of this study was to identify determinants of delayed presentation among breast cancer patients in Estonia.MethodsThe study population included women with primary breast cancer diagnosed in Estonia in 2008–2010. All data were collected using structured personal interviews carried out by trained nurses in the hospital setting. Only patients with self-discovered symptoms were included in this analysis. Patient delay was measured as time elapsing from symptom self-discovery to first medical consultation. The effect of different factors on the likelihood of prolonged delay (>90xa0days) was evaluated using logistic regression.ResultsAmong 703 eligible patients, median patient delay was 16xa0days (interquartile range 5–54xa0days). Seventeen percent of the patients had their first medical consultation more than three months after self-detection of symptoms. In multivariate analysis, the risk of prolonged delay was significantly associated with age 65xa0years and over (OR 2.27, 95% CI 1.23–4.20), current smoking (OR 2.09, 95% CI 1.21–3.61), symptoms other than painless breast lump or breast pain (OR 1.84, 95% CI 1.08–3.16), no history of mammograms (OR 1.83, 95% CI 1.13–2.95), having received no information on breast cancer during past year (OR 1.77, 95% CI 1.05–2.99), and previous benign breast problems (OR 1.65, 95% CI 1.01–2.67). Non-significant risk increase was seen with lower education.ConclusionsThis study provides evidence that factors associated with delayed presentation of breast cancer in Eastern Europe are similar to those observed in Western countries. The results suggest that educational messages to general population should aim at increasing awareness of “non-lump” symptoms of breast cancer and encouraging women of all ages to present in a timely manner. Women at risk for delayed presentation such as smokers and women with no history of mammograms could be identified in the primary care setting.

Prognostic Factors of Immunotherapy in Metastatic Renal Cell Carcinoma

The prognosis of the majority of patients with metastatic renal cell carcinoma is poor, and there is no internationally recognized standard therapy for these patients. Patients are treated with interferon alpha or interleukin-2 monotherapy, or combinations outside of clinical trials and a subgroup of patients responds to these therapies. Because immunotherapy induces adverse effects in almost every patient, it is necessary to avoid treating patients who will not, in the end, benefit from the treatment. It is therefore sensible to carefully select patients prior to the initiation of immunotherapy. Determining prognostic factors of survival or of rapid progression under treatment would be of help for selecting patients for immunotherapy. This article reviews current data about prognostic and predictive factors from immunotherapy studies in metastatic renal cell carcinoma comparing all analyzed factors with those that demonstrated an independent prognostic significance in multivariate analyses.

Polygenic prediction of breast cancer: comparison of genetic predictors and implications for screening

Background Published genetic risk scores for breast cancer (BC) so far have been based on a relatively small number of markers and are not necessarily using the full potential of large-scale Genome-Wide Association Studies. This study aims to identify an efficient polygenic predictor for BC based on best available evidence and to assess its potential for personalized risk prediction and screening strategies. Methods Four different genetic risk scores (two already published and two newly developed) and their combinations (metaGRS) are compared in the subsets of two population-based biobank cohorts: the UK Biobank (UKBB, 3157 BC cases, 43,827 controls) and Estonian Biobank (EstBB, 317 prevalent and 308 incident BC cases in 32,557 women). In addition, correlations between different genetic risk scores and their associations with BC risk factors are studied in both cohorts. Results The metaGRS that combines two genetic risk scores (metaGRS2 - based on 75 and 898 Single Nucleotide Polymorphisms, respectively) has the strongest association with prevalent BC status in both cohorts. One standard deviation difference in the metaGRS2 corresponds to an Odds Ratio = 1.6 (95% CI 1.54 to 1.66, p = 9.7*10-135) in the UK Biobank and accounting for family history marginally attenuates the effect (Odds Ratio = 1.58, 95% CI 1.53 to 1.64, p = 9.1*10-129). In the EstBB cohort, the hazard ratio of incident BC for the women in the top 5% of the metaGRS2 compared to women in the lowest 50% is 4.2 (95% CI 2.8 to 6.2, p = 8.1*10-13). The different GRSs are only moderately correlated with each other and are associated with different known predictors of BC. The classification of genetic risk for the same individual may vary considerably depending on the chosen GRS. Conclusions We have shown that metaGRS2 that combines on the effects of more than 900 SNPs provides best predictive ability for breast cancer in two different population-based cohorts. The strength of the effect of metaGRS2 indicates that the GRS could potentially be used to develop more efficient strategies for breast cancer screening for genotyped women.

лечение несветлоклеточного почечно-клеточного рака

Появление низкомолекулярных ингибиторов рецепторов фактора роста эндотелия сосудов (VEGF) и мишени рапамицина млекопитающих (mTOR) существенно улучшило ситуацию с лечением диссеминированного почечно-клеточного рака (ПКР). Для локализованных стадии несветлоклеточного ПКР стандартом лечения остается резекция почки либо нефрэктомия. Поскольку светлоклеточныи рак почки составляет более 80% всех случаев ПКР, данные об эффективности системного лечения при диссеминированном несветлоклеточном ПКР ограничены. Сунитиниб и сорафениб можно рассматривать как возможные варианты лечения, несмотря на их ограниченную эффективность. На основании результатов анализа исследования III фазы, темсиролимус также может рассматриваться как вариант лечения несветлоклеточного ПКР. В проспективных исследованиях продолжается изучение новых лекарственных средств, направленных против новых мишенеи.