РАК ТОЛСТОЙ КИШКИ С МИКРОСАТЕЛЛИТНОЙ НЕСТАБИЛЬНОСТЬЮ У ПОЖИЛЫХ БОЛЬНЫХ: РОЛЬ ИММУНОДЕФИЦИТА И КЛИНИЧЕСКИЕ ОСОБЕННОСТИ

Background. Tumors demonstrating the phenomenon of microsatellite instability (MSI) represent a special category of colorectal cancer (CRC). Such neoplasms account for up to 20 % of CRC and are characterized by specific molecular and clinical manifestations, including high immunogenicity and sensitivity to immunotherapy. MSI phenotype occurs in two different groups of patients: young individuals with Lynch syndrome and patients older than 70 years with non-hereditary CRC. We assume that the development of sporadic MSI-positive tumors in elderly patients may be associated with age-dependent decrease in immune defense. The aim of the study was to investigate clinical and morphological characteristics in elderly patients with MSI-positive colorectal cancer. Material and methods. MSI status and mutations in the BRAF gene were tested in a group of 384 CRC patients older than 65 years by PCR-based techniques. A comparative analysis of clinico-pathological features was further conducted in the groups of 23 MSI-positive and 34 MSI-negative CRC cases. Results. MSI-positive phenotype was associated with the proximal tumor location, low degree of differentiation and the presence of the mucinous component in the tumor (p<0.0001, p=0.005, and p=0.0001, respectively). Patients with MSI-positive CRC containing BRAF mutations showed a significant prevalence of RhD-negative erythrocyte phenotype (53.3 % vs 11.8 %, p=0.004). In patients with MSI-positive carcinomas, the increased frequency of preoperative leukocytosis (p=0.009) and lymphopenia (p=0.014) was observed. Conclusion. The increased occurrence of Rh-negative erythrocyte phenotype and white blood formula changes in elderly patients with MSI-positive CRC may indicate the role of immune system disorders in the development of microsatellite-unstable carcinomas.Актуальность. Опухоли с феноменом микросателлитной нестабильности (microsatellite instability, MSI) представляют собой отдельную категорию рака толстой кишки (РТК). Подобные новообразования составляют до 20 % карцином этой локализации и характеризуются своеобразными молекулярными и клиническими проявлениями, в том числе высокой иммуногенностью и чувствительностью к иммунотерапии. Микросателлитная нестабильность встречается у двух разных групп пациентов – молодых больных с синдромом Линча и у пациентов старше 70 лет с ненаследственным РТК. Мы предполагаем, что развитию спорадических MSI-позитивных опухолей у пожилых пациентов может способствовать сопутствующее старению снижение иммунной защиты. Целью исследования стало изучение различных клинико-морфологических характеристик у пожилых больных с MSI-позитивным РТК. Материал и методы. Микросателлитная нестабильность и мутация V600E в гене BRAF оценивались методами, основанными на ПЦР, в группе из 384 больных РТК старше 65 лет. Сравнительный анализ клинических и патоморфологических особенностей выполнен у 23 пациентов с MSI-позитивными опухолями и 34 больных MSI-негативным РТК. Результаты. В группе больных РТК с MSI-позитивным фенотипом преобладают случаи локализации рака в правой половине ободочной кишки, низкая степень дифференцировки и наличие муцинозного компонента в опухоли (p<0,0001, p=0,005 и p=0,0001 соответственно). У пациентов с MSI-позитивным РТК, содержащим мутацию BRAF, значительно чаще встречается резус-отрицательный фенотип эритроцитов (53,3 % vs 11,8 %, p=0,004). У больных с MSI-позитивными карциномами отмечено увеличение частоты лейкоцитоза (p=0,009) и лимфопении (p=0,014) в периферической крови в предоперационном периоде. Заключение. Повышенная частота резус-негативного фенотипа эритроцитов и изменения в формуле белой крови у пожилых больных РТК с MSI-позитивным фенотипом могут свидетельствовать о роли нарушений иммунной системы в развитии микросателлит-нестабильных карцином

Встречаемость мутаций в генах BRCA1 и BRCA2 у больных раком поджелудочной железы

BRCA1 and BRCA2 may contribute in pancreatic cancer (PC) risk, however the selection criteria for BRCA1 testing are poorly defined. The analysis of Russian founder mutation BRCA1 5382insC in 150 PC patients identified 2 carriers. BRCA2 full-length sequencing of 8 DNA samples revealed 1 mutated allele (BRCA2 5197_5198delTC). All 3 carriers of BRCA1/2 mutations reported personal or familial history of BRCA-related cancers. Thus, BRCA1/2 testing is particularlyМутации в генах BRCA1 и BRCA2 могут играть роль в формировании риска рака поджелудочной железы (РПЖ), однако критерии включения пациентов в BRCA-диагностику остаются неясными. Присутствие повторяющейся мутации BRCA1 5382insC анализировалось у 150 больных РПЖ, при этом выявлено 2 носителя упомянутого аллеля. Полный анализ кодирующей области гена BRCA2 выполнен у 8 пациентов, обнаружен 1 дефектный вариант (BRCA2 5197_5198delTC). Все 3 больных с мутацией имели собственный или семейный анамнез BRCA-ассоциированных онкологических заболеваний. Таким образом, BRCA-тестирование случаев РПЖ целесообразно ограничить только теми пациентами, у которых имеются клинические признаки наследственного характера заболевани

MICROSATELLITE-UNSTABLE COLORECTAL CANCER IN ELDERLY PATIENTS: CLINICAL FEATURES AND THE ROLE OF IMMUNODEFICIENCY

Background. Tumors demonstrating the phenomenon of microsatellite instability (MSI) represent a special category of colorectal cancer (CRC). Such neoplasms account for up to 20 % of CRC and are characterized by specific molecular and clinical manifestations, including high immunogenicity and sensitivity to immunotherapy. MSI phenotype occurs in two different groups of patients: young individuals with Lynch syndrome and patients older than 70 years with non-hereditary CRC. We assume that the development of sporadic MSI-positive tumors in elderly patients may be associated with age-dependent decrease in immune defense. The aim of the study was to investigate clinical and morphological characteristics in elderly patients with MSI-positive colorectal cancer. Material and methods. MSI status and mutations in the BRAF gene were tested in a group of 384 CRC patients older than 65 years by PCR-based techniques. A comparative analysis of clinico-pathological features was further conducted in the groups of 23 MSI-positive and 34 MSI-negative CRC cases. Results. MSI-positive phenotype was associated with the proximal tumor location, low degree of differentiation and the presence of the mucinous component in the tumor (p<0.0001, p=0.005, and p=0.0001, respectively). Patients with MSI-positive CRC containing BRAF mutations showed a significant prevalence of RhD-negative erythrocyte phenotype (53.3 % vs 11.8 %, p=0.004). In patients with MSI-positive carcinomas, the increased frequency of preoperative leukocytosis (p=0.009) and lymphopenia (p=0.014) was observed. Conclusion. The increased occurrence of Rh-negative erythrocyte phenotype and white blood formula changes in elderly patients with MSI-positive CRC may indicate the role of immune system disorders in the development of microsatellite-unstable carcinomas

Occurrence of BRCA1 and BRCA2 mutation in pancreatic cancer patients

BRCA1 and BRCA2 may contribute in pancreatic cancer (PC) risk, however the selection criteria for BRCA1 testing are poorly defined. The analysis of Russian founder mutation BRCA1 5382insC in 150 PC patients identified 2 carriers. BRCA2 full-length sequencing of 8 DNA samples revealed 1 mutated allele (BRCA2 5197_5198delTC). All 3 carriers of BRCA1/2 mutations reported personal or familial history of BRCA-related cancers. Thus, BRCA1/2 testing is particularl

The effect of natural disturbances on forest biodiversity: an ecological synthesis

Disturbances alter biodiversity via their specific characteristics, including severity and extent in the landscape, which act at different temporal and spatial scales. Biodiversity response to disturbance also depends on the community characteristics and habitat requirements of species. Untangling the mechanistic interplay of these factors has guided disturbance ecology for decades, generating mixed scientific evidence of biodiversity responses to disturbance. Understanding the impact of natural disturbances on biodiversity is increasingly important due to human-induced changes in natural disturbance regimes. In many areas, major natural forest disturbances, such as wildfires, windstorms, and insect outbreaks, are becoming more frequent, intense, severe, and widespread due to climate change and land-use change. Conversely, the suppression of natural disturbances threatens disturbance-dependent biota. Using a meta-analytic approach, we analysed a global data set (with most sampling concentrated in temperate and boreal secondary forests) of species assemblages of 26 taxonomic groups, including plants, animals, and fungi collected from forests affected by wildfires, windstorms, and insect outbreaks. The overall effect of natural disturbances on α-diversity did not differ significantly from zero, but some taxonomic groups responded positively to disturbance, while others tended to respond negatively. Disturbance was beneficial for taxonomic groups preferring conditions associated with open canopies (e.g. hymenopterans and hoverflies), whereas ground-dwelling groups and/or groups typically associated with shady conditions (e.g. epigeic lichens and mycorrhizal fungi) were more likely to be negatively impacted by disturbance. Across all taxonomic groups, the highest α-diversity in disturbed forest patches occurred under moderate disturbance severity, i.e. with approximately 55% of trees killed by disturbance. We further extended our meta-analysis by applying a unified diversity concept based on Hill numbers to estimate α-diversity changes in different taxonomic groups across a gradient of disturbance severity measured at the stand scale and incorporating other disturbance features. We found that disturbance severity negatively affected diversity for Hill number q = 0 but not for q = 1 and q = 2, indicating that diversity-disturbance relationships are shaped by species relative abundances. Our synthesis of α-diversity was extended by a synthesis of disturbance-induced change in species assemblages, and revealed that disturbance changes the β-diversity of multiple taxonomic groups, including some groups that were not affected at the α-diversity level (birds and woody plants). Finally, we used mixed rarefaction/extrapolation to estimate biodiversity change as a function of the proportion of forests that were disturbed, i.e. the disturbance extent measured at the landscape scale. The comparison of intact and naturally disturbed forests revealed that both types of forests provide habitat for unique species assemblages, whereas species diversity in the mixture of disturbed and undisturbed forests peaked at intermediate values of disturbance extent in the simulated landscape. Hence, the relationship between α-diversity and disturbance severity in disturbed forest stands was strikingly similar to the relationship between species richness and disturbance extent in a landscape consisting of both disturbed and undisturbed forest habitats. This result suggests that both moderate disturbance severity and moderate disturbance extent support the highest levels of biodiversity in contemporary forest landscapes