Анемия при хронических заболеваниях: ключевые механизмы патогенеза у пациентов со злокачественными новообразованиями и возможные подходы к классификации

В.Т. Сахин1, Е.Р. Маджанова1, Е.В. Крюков3, А.В. Сотников2, А.В. Гордиенко2, О.А. Рукавицын3

1 ФГКУ «1586 Военный клинический госпиталь» Минобороны России, ул. Маштакова, д. 4, Московская область, Подольск, Российская Федерация, 142110

2 ФГБВОУ ВО «Военно-медицинская академия им. С.М. Кирова» Минобороны России, ул. Академика Лебедева, д. 6, Санкт-Петербург, Российская Федерация, 194044

3 ФГБУ «Главный военный клинический госпиталь им. акад. Н.Н. Бурденко» Минобороны России, Госпитальная пл., д. 3, Москва, Российская Федерация, 105229

Для переписки: Валерий Тимофеевич Сахин, канд. мед. наук, ул. Маштакова, д. 4, Московская область, Подольск, Российская Федерация, 142110; тел.: +7(916)314-31-11; e-mail: SahinVT@yandex.ru

Для цитирования: Сахин В.Т., Маджанова Е.Р., Крюков Е.В. и др. Анемия при хронических заболеваниях: ключевые механизмы патогенеза у пациентов со злокачественными новообразованиями и возможные подходы к классификации. Клиническая онкогематология. 2019;12(3):344-9

doi: 10.21320/2500-2139-2019-12-3-344-349


РЕФЕРАТ

Цель. Изучить влияние гепцидина, растворимого рецептора трансферрина (sTfR), цитокинов на обмен железа и развитие анемии у пациентов со злокачественными новообразованиями; на основании полученных данных предложить рабочий вариант классификации анемии при хронических заболеваниях (АХЗ) по ведущему патогенетическому фактору.

Материалы и методы. В исследование включено 63 пациента со II–IV стадией злокачественных новообразований. Больных с анемией было 41 (34 мужчины, 7 женщин, средний возраст 67,1 ± 9,9 года), без анемии — 22 (17 мужчин, 5 женщин, средний возраст 60,2 ± 14,9 года). Выполнен сравнительный анализ показателей обмена железа, С-реактивного белка (СРБ), гепцидина, sTfR, а также провоспалительных (интерлейкин-6 [ИЛ-6], фактор некроза опухолей α [ФНО-α]) и противовоспалительных (ИЛ-10) цитокинов у больных со злокачественными (солидными) новообразованиями с анемией и без нее. Проведен корреляционный анализ между ИЛ-6, ИЛ-10, ФНО-α, гепцидином, sTfR и показателями гемограммы.

Результаты. У больных с анемией в сравнении с контрольной группой выявлены более низкие концентрации железа, общей железосвязывающей способности (ОЖСС), коэффициента насыщения трансферрина железом (КНТ) и более высокие концентрации СРБ, гепцидина, sTfR, ИЛ-6, ИЛ-10, ФНО-α (< 0,05). Показано негативное влияние на уровень эритроцитов ИЛ-6 (r = –0,58), ФНО-α (r = –0,32), гепцидина (r = –0,57). Установлена отрицательная взаимосвязь между концентрацией гемоглобина и ИЛ-6 (r = –0,57), ИЛ-10 (r = –0,64), ФНО-α (r = –0,65), гепцидина (r = –0,3), sTfR (r = –0,57). Выявлена корреляция между концентрациями гепцидина и ИЛ-6 (r = 0,58), ИЛ-10 (r = 0,33), ФНО-α (r = –0,4), а также между концентрациями sTfR и ИЛ-10 (r = 0,58), ФНО-α (r = –0,53). Установлена взаимосвязь между концентрацией ИЛ-6 и уровнями железа (r = –0,38), ОЖСС (r = –0,56), КНТ (r = –0,31), ферритина (r = 0,56), трансферрина (r = –0,72), СРБ (r = 0,86); между концентрациями ИЛ-10 и железа (r = –0,63), КНТ (r = –0,67), трансферрина (r = –0,7), ферритина (r = 0,55), СРБ (r = 0,65), ОЖСС (r = –0,71). Показано наличие корреляции между уровнями ФНО-α и ОЖСС (r = –0,36), трансферрина (r = –0,5).

Заключение. Описан многокомпонентный патогенез анемии у больных со злокачественными новообразованиями. Важное значение имеют дефицит железа и нарушение эритропоэза. Предложен рабочий вариант классификации АХЗ на основании ведущего патогенетического фактора развития анемии (АХЗ с преимущественным дефицитом железа, АХЗ с нарушениями регуляторных механизмов эритропоэза, АХЗ с недостаточной продукцией эритропоэтина).

Ключевые слова: рак, анемия, обмен железа, интерлейкин-6, интерлейкин-10, фактор некроза опухолей α, гепцидин, растворимый рецептор трансферрина.

Получено: 21 января 2019 г.

Принято в печать: 18 июня 2019 г.

Читать статью в PDF 


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Патогенетические особенности анемии у больных с солидными опухолями

В.Т. Сахин1, Е.Р. Маджанова1, Е.В. Крюков3, А.В. Сотников2, А.В. Гордиенко2, О.А. Рукавицын3

1ФГКУ «1586 Военный клинический госпиталь» Минобороны России, ул. Маштакова д. 4, Московская область, Подольск, Российская Федерация, 142110

2ФГБВОУ ВПО «Военно-медицинская академия им. С.М. Кирова» Минобороны России, ул. Академика Лебедева, д. 6, Санкт-Петербург, Российская Федерация, 194044

3ФГКУ «Главный военный клинический госпиталь им. Н.Н. Бурденко» Минобороны России, Госпитальная пл., д. 3, Москва, Российская Федерация, 105229

Для переписки: Валерий Тимофеевич Сахин, канд. мед. наук, ул. Маштакова, д. 4, Московская область, Подольск, Российская Федерация, 142110; Тел.:+7(916)314-31-11; e-mail: SahinVT@yandex.ru

Для цитирования: Сахин В.Т., Маджанова Е.Р., Крюков Е.В. и др. Патогенетические особенности анемии у больных с солидными опухолями. Клиническая онкогематология. 2017;10(4):514–8.

DOI: 10.21320/2500-2139-2017-10-4-514-518


РЕФЕРАТ

Цель. Изучить значение нарушений обмена железа и влияние некоторых цитокинов на развитие анемии у пациентов с солидными опухолями.

Материалы и методы. В исследование включено 42 пациента со злокачественными новообразованиями. Среди них пациентов с анемией было 24 (19 мужчин, 5 женщин; средний возраст 67,7 ± 10 лет), без анемии — 18 (15 мужчин, 3 женщины; средний возраст 65,7 ± 14 лет). Диагноз анемии установлен в соответствии с критериями ВОЗ (у мужчин: число эритроцитов менее 4 × 1012/л, гемоглобин менее 130 г/л, гематокрит менее 39 %; у женщин: число эритроцитов менее 3,8 × 1012/л, гемоглобин менее 120 г/л, гематокрит менее 36 %).

Результаты. Выполнен сравнительный анализ показателей обмена железа у пациентов с анемией и без таковой. Установлены более низкие значения сывороточного железа и коэффициента насыщения трансферрина железом у пациентов с анемией (< 0,05). Пациенты с анемией в сравнении с пациентами без таковой имели более низкий уровень железа и коэффициент насыщения трансферрина железом (< 0,05). Общая железосвязывающая способность сыворотки, уровень ферритина, трансферрина, С-реактивного белка, непрямого билирубина в исследуемых группах не имели статистически значимых различий (> 0,05). У пациентов с анемией отмечалось более высокое содержание интерлейкинов (ИЛ-6 и ИЛ-10) (< 0,05). Для ИЛ-6 показана отрицательная корреляция умеренной силы с уровнем эритроцитов (r = –0,58), гемоглобина (r = –0,57), гематокрита (r = –0,52) и прямая корреляция с уровнем лейкоцитов (r = 0,42). Между ИЛ-10 и уровнем эритроцитов, лейкоцитов, тромбоцитов, MCV, MCH также установлены слабые связи (r < 0,3). Для ИЛ-10 выявлена сильная отрицательная корреляция с MCHC (r = –0,71) и отрицательная корреляция умеренной силы с уровнем гемоглобина (r = –0,64) и гематокрита (r = –0,32). Наличие взаимосвязей между уровнями ИЛ-6, ИЛ-10 и уровнями гемоглобина, эритроцитов и некоторых цветовых индексов может свидетельствовать об их влиянии на развитие анемии у данной категории пациентов.

Заключение. Установлено наличие функционального дефицита железа у пациентов с анемией; показаны несколько причин развития анемии и значимая роль интерлейкинов в ее патогенезе.

Ключевые слова: рак, анемия, обмен железа, интерлейкин-6, интерлейкин-10.

Получено: 21 марта 2017 г.

Принято в печать: 22 июля 2017 г.

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ЛИТЕРАТУРА

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Нарушенный метаболизм метионина в злокачественных клетках — потенциальная мишень для противоопухолевой терапии

В.С. Покровский1, Д.Ж. Давыдов1, Н.В. Ануфриева2, Д.Д. Жданов3, Е.М. Трещалина1, Т.В. Демидкина2, Е.А. Морозова2

1 ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, лаборатория комбинированной терапии опухолей, Каширское ш., д. 24, Москва, Российская Федерация, 154478

2 ФГБУН «Институт молекулярной биологии им. В.А. Энгельгардта» РАН, ул. Вавилова, д. 32, Москва, Российская Федерация, 119991

3 ФГБУ «НИИ биомедицинской химии им. В.Н. Ореховича», Погодинская ул., д. 10, стр. 8, Москва, Российская Федерация, 119121

Для переписки: Вадим Сергеевич Покровский, д-р мед. наук, Каширское ш., д. 24, Москва, Российская Федерация, 154478; тел.: 8(499)324-14-09; e-mail: vadimpokrovsky@yandex.ru

Для цитирования: Покровский В.С., Давыдов Д.Ж., Ануфриева Н.В. и др. Нарушенный метаболизм метионина в злокачественных клетках — потенциальная мишень для противоопухолевой терапии. Клиническая онкогематология. 2017;10(3):324–32.

DOI: 10.21320/2500-2139-2017-10-3-324-332


РЕФЕРАТ

В обзоре представлены особенности клеточного метаболизма метионина, а также известные данные о механизмах развития метиониновой зависимости в злокачественных клетках. Рассмотрены возможности использования безметиониновой диеты для контроля опухолевого роста у больных с различными формами рака. Сгруппированы и обобщены новейшие сведения о метионин-γ-лиазе — ферменте, обеспечивающем элиминацию метионина из плазмы. Раскрыта его роль в качестве потенциального противоопухолевого фермента. Обобщены сведения о продуцентах метионин-γ-лиазы, активности данного фермента, полученного из различных источников, и сведения о моделях опухолей и клеточных культурах, проявляющих метиониновую зависимость.

Ключевые слова: метионин-γ-лиаза, метионин, метиониновая зависимость, злокачественные клетки, рак, противоопухолевые ферменты, противоопухолевая терапия.

Получено: 16 декабря 2016 г.

Принято в печать: 6 марта 2017 г.

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Хромотрипсис в онкологии: обзор литературы и собственное наблюдение

Н.Н. Мамаев1, Т.Л. Гиндина1, Э.Г. Бойченко2

1 НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, ГБОУ ВПО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова», ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022

2 Детская городская больница № 1, ул. Авангардная, д. 14, Санкт-Петербург, Российская Федерация, 198205

Для переписки: Татьяна Леонидовна Гиндина, канд. мед. наук, ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022; тел.: + 7(812)233-12-43; e-mail: cytogenetics.bmt.lab@gmail.com

Для цитирования: Мамаев Н.Н., Гиндина Т.Л., Бойченко Э.Г. Хромотрипсис в онкологии: обзор литературы и собственное наблюдение. Клиническая онкогематология. 2017;10(2):191–205.

DOI: 10.21320/2500-2139-2017-10-2-191-205


РЕФЕРАТ

Представлено собственное наблюдение и обзор литературы, посвященный недавно открытому феномену хромотрипсиса в онкологии. Хромотрипсис — тип комплексных геномных изменений, при которых хромосома сначала разрывается на десятки и даже тысячи частей, а потом эти фрагменты соединяются в случайном порядке. Иногда в перестройке участвует несколько хромосом. В результате формируются мутантные зоны генома, провоцирующие развитие онкологических и врожденных заболеваний. Иными словами, использование определенных методических подходов (многоцветной флюоресцентной гибридизации in situ, метода SKY и некоторых других) позволяет увидеть под микроскопом распад на фрагменты двух или более хромосом и воссоединение этих фрагментов в новые необычные двух- или многоцветные структуры — хромосомные маркеры. Хромотрипсис — редкий феномен со своеобразной картиной, наблюдаемой в клонах клеток самых разнообразных опухолей, включая новообразования кроветворной и лимфоидной тканей. В литературе имеются указания о большей частоте этого феномена у больных с миелодиспластическим синдромом и опухолями костей. Важную роль в формировании хромотрипсиса играют мутации гена TP53. Использование секвенирования концевой спаренной ДНК или метода SNP в онкологии представляется перспективным как в теоретическом, так и клиническом плане. В первую когорту исследуемых должны включаться пациенты с мутациями генов TP53 и MLL, со сложными хромосомными нарушениями, гиперэкспрессией гена EVI1 и некоторые другие. В статье представлен феномен хромотрипсиса у девочки 8 мес. с М7-вариантом острого миелоидного лейкоза.

Ключевые слова: хромотрипсис, онкогематология, рак, мутации гена TР53.

Получено: 2 октября 2016 г.

Принято в печать: 6 января 2017 г.

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Анемии в онкологии: современные возможности поддерживающей терапии

А.В. Снеговой, В.Б. Ларионова, Л.В. Манзюк, И.Б. Кононенко

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, Каширское ш., д. 24, Москва, Российская Федерация, 115478

Для переписки: Антон Владимирович Снеговой, канд. мед. наук, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(499)324-41-09; e-mail: anvs2012@gmail.com

Для цитирования: Снеговой А.В., Ларионова В.Б., Манзюк Л.В., Кононенко И.Б. Анемии в онкологии: современные возможности поддерживающей терапии. Клиническая онкогематология. 2016;9(3):326-35.

DOI: 10.21320/2500-2139-2016-9-3-326-35


РЕФЕРАТ

Развитие анемии в период химио- или химиолучевой терапии злокачественных опухолей является серьезным нежелательным явлением, отрицательно влияющим на качество жизни и эффективность проводимого лечения. В связи с этим ведущие консенсусные комиссии NCCN, ESMO, ASCO, RUSSCO разработали и постоянно обновляют рекомендации по диагностике и лечению анемии у онкологических больных. В статье представлены современные данные о патогенезе и методах лечения анемии у онкологических больных, в т. ч. использование стимуляторов эритропоэза: рекомбинантных эритропоэтинов и внутривенных препаратов железа, витаминов, трансфузий эритроцитной массы.


Ключевые слова: рак, анемия, эритропоэтины, препараты железа для внутривенного введения, трансфузия эритроцитной массы.

Получено: 29 февраля 2016 г.

Принято в печать: 31 марта 2016 г.

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Влияние противоопухолевого лечения на репродуктивную систему женщин: методы защиты и сохранения функции яичников

М.В. Волочаева1, Р.Г. Шмаков1, Е.А. Демина2

1 ФГБУ «Научный центр акушерства, гинекологии и перинатологии им. В.И. Кулакова» МЗ РФ, Москва, Российская Федерация

2 ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» РАМН, Москва, Российская Федерация


РЕФЕРАТ

Последние исследования показали особую важность обсуждения вопроса защиты и сохранения функции яичников у женщин с онкологическими заболеваниями. В настоящее время, когда созданы во многом эффективные схемы лечения злокачественных опухолей, для ряда больных становится актуальным продолжение полноценной жизни после успешной противоопухолевой терапии. В обзоре рассматриваются методики защиты и сохранения функции яичников: фармакологическая, c применением вспомогательных репродуктивных технологий, в т. ч. криоконсервации и трансплантация ткани яичников, криоконсервации ооцитов и эмбрионов.


Ключевые слова: защита яичников, cохранение функции яичников, рак, криоконсервация ткани, криоконсервация ооцитов, криоконсервация эмбрионов.

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Анемии и дефицит железа у онкологических больных

В.В. Птушкин

ФГБУ «ФНКЦ Детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздравсоцразвития, Москва, Российская Федерация


РЕФЕРАТ

Многочисленные исследования последних лет показали, что анемии являются частым осложнением онкологических заболеваний, и особенно при проведении химиотерапии. Снижение содержания гемоглобина в крови сопровождается слабостью, уменьшением толерантности к физической и умственной нагрузкам с закономерным ухудшением качества жизни. Кроме того, анемия ассоциируется с ухудшением показателей выживаемости онкологических больных. Опухолевая анемия помимо прочих механизмов может быть обусловлена продукцией провоспалительных цитокинов, обладающих негативным влиянием на различные этапы продукции эритроцитов в костном мозге, длительность их жизни и обмен железа. Применение эритропоэтинов у онкологических больных с анемией вызывает повышение уровня гемоглобина и сокращение потребности в заместительных гемотрансфузиях, однако повышает риск тромбозов. Повышение продукции провоспалительных цитокинов у онкологических пациентов снижает доступность железа для эффективного эритропоэза. В настоящем обзоре обобщены клинические последствия дефицита железа и анемии у онкологических больных, обсуждаются механизмы нарушения гомеостаза железа, а также диагностика этого состояния и его лечение. Представлены данные клинических исследований, в которых оценивается эффективность различных препаратов железа с или без сопутствующей терапии эритропоэтинами.


Ключевые слова: Анемия, рак, эритропоэтины, препараты железа, карбоксимальтозат железа, ферритин, трансферрин

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ЛИТЕРАТУРА

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Таксономическая структура и резистентность к антибиотикам возбудителей инфекций кровотока у онкогематологических больных

Багирова Н.С. 

ФГБНУ «Российский онкологический научный центр им. Н.Н. Блохина», Каширское ш., д. 24, Москва, Российская Федерация, 115478

Для переписки: Наталья Сергеевна Багирова, д-р мед. наук, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(499)324-18-60; e-mail: nbagirova@mail.ru

Для цитирования: Багирова Н.С. Таксономическая структура и резистентность к антибиотикам возбудителей инфекций кровотока у онкогематологических больных. Клиническая онкогематология. 2015;8(2):191–200.


РЕФЕРАТ

Актуальность и цели. В онкогематологии инфекции являются одной из основных причин летальности у больных. Меняющиеся эпидемиологические закономерности отражают не только появление новых возбудителей инфекций кровотока, но и рост резистентности патогенов к противомикробным препаратам. Очень важно проводить постоянный мониторинг таксономической структуры возбудителей инфекций кровотока и их резистентности к антимикробным препаратам в целях адекватной и своевременной терапии тяжелых инфекций. Цель — анализ таксономической структуры возбудителей, выделенных при диагностике бактериемии у взрослых онкогематологических больных с использованием современных приборов, и эффективности терапии тяжелых инфекций.

Методы. Проведено микробиологическое исследование образцов крови онкогематологических больных при подозрении на сепсис и другие тяжелые инфекции за период с 2005 по 2013 г. Диагностику бактериемии проводили с использованием геманализаторов-инкубаторов Bactec FX400 (Becton Dickinson, США) и Bact/Alert (BioMerieux, Франция), идентификацию штаммов — с использованием масс-спектрометра MALDI-TOF Microflex LT (Biotyper, Bruker Daltonics, Германия). Чувствительность к антимикробным препаратам определяли на автоматическом анализаторе Microscan Walk Away 40/96+ (Siemens, Германия) и Vitek 2 (BioMerieux, Франция). Представлены сравнительные данные зарубежных исследователей.

Результаты. Было получено 3794 гемокультуры, из которых в 600 (15,8 %) случаях отмечен рост. Только 210 (53,6 %) из 392 штаммов были расценены как возбудители истинной бактериемии. Статистически значимых различий в частоте выделения грамположительных кокков (47,6 %) и грамотрицательных палочек (39,5 %) не выявлено. Грибы регистрировались статистически значимо реже грамположительных кокков и грамотрицательных палочек (9 %; < 0,0001). Прочие микроорганизмы составили 3,8 %.

Заключение. Терапия и профилактика инфекционных осложнений у онкогематологических больных сопровождаются развитием нарастающей резистентности возбудителей к антибиотикам. Изменения в таксономической структуре возбудителей инфекций кровотока необходимо учитывать при назначении эмпирической и этиотропной терапии.


Ключевые слова: инфекции, рак, инфекции кровотока, бактериемия, антимикробная резистентность, онкогематологические заболевания, антимикробная терапия.

Получено: 12 января 2015 г.

Принято в печать: 30 января 2015 г.

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