Эффективность химиотерапии по схеме GemCap + митотан во 2-й и последующих линиях лечения метастатического адренокортикального рака

Background. Combination of gemcitabine, metronomic capecitabine and mitotane (GemCap + m) is the most studied regimen in second and subsequent lines of therapy for advanced adrenocortical cancer (ACC). Previously published studies do not give a definitive answer to the question- what plays a key role in realizing the response to treatment: chemotherapy or mitotane in therapeutic concentration.Aim. Evaluation the efficacy and safety of GemCap + m combination with the standard dosing regimen of capecitabine in patients with metastatic ACC.Materials and methods. This retrospective single-center clinical study included patients over 18 years of age with histologically confirmed ACC with disease progression after completion of platinum-containing therapy. They received chemotherapy regimen gemcitabine 800 mg/m2 for days 1, 8 and capecitabine 1000 mg/m2 orally 2 times at days 1–14 of the 21-day cycle with mitotane. we evaluated objective response, stabilization of disease, 6-months disease control rate and median progression-free and overall survival. Radiological assessment according to RECIST 1.1 criteria was carried out every 6–8 weeks of treatment.Results. The study included 25 patients. mitotane concentration above 14 ng/mL was achieved in 22 (88 %) patients, of which 21 (84 %) reached therapeutic concentration in previous treatment lines. 80 % of patients received treatment as 2nd line, 20 % as 3rd and subsequent lines. The objective responses and disease stabilization was observed in 1 (4 %) and 11 (44 %) of patients, respectively. Disease control for at least 6 months rate was 24 %. median progression-free and overall survival were 3.2 months and 12.17 months, respectively. Toxicity grade 3–4 was observed in 28 % of patients. gemcitabine dose reductions due to thrombocytopenia grade 1–2 were required in 2 cases (8 %), no capecitabine reductions were necessary.Conclusion. This study demonstrates the effectiveness of a new dose regimen of chemotherapy GemCap + m in the second and subsequent lines of therapy for metastatic ACC. The progression of the disease against the background of previous lines of therapy at a therapeutic concentration of mitotane in the majority of patients indicates the effectiveness of the chemotherapeutic component of gemCap in a cohort of patients resistant to platinum and mitotane.Введение. В терапии 2-й и последующих линий метастатического адренокортикального рака (АКР) наиболее изученной является комбинация гемцитабина, метрономного капецитабина и митотана (GemCap + m). Опубликованные ранее работы, посвященные изучению данного режима, не дают однозначного ответа на вопрос, что играет ключевую роль в реализации ответа на лечение: химиотерапия или митотан в терапевтической концентрации.Цель исследования – изучение эффективности и безопасности комбинации GemCap + m со стандартным режимом дозирования капецитабина у больных метастатическим АКР.Материалы и методы. В данное ретроспективное одноцентровое клиническое исследование включались пациенты старше 18 лет с гистологически подтвержденным АКР с прогрессированием заболевания после завершения платиносодержащей терапии. Пациенты получали лечение по схеме гемцитабин 800 мг/м2 в 1-й и 8-й дни и капецитабин 1000 мг/м2 внутрь 2 раза в сутки в 1–14-й дни 21-дневного цикла на фоне приема митотана. Нами были оценены частота ответа на лечение, медианы выживаемости без прогрессирования и общей выживаемости. Радиологическая оценка эффективности терапии по критериям RECIST 1.1 проводилась каждые 6–8 нед лечения.Результаты. В исследование включено 25 пациентов. концентрация митотана выше 14 нг/мл была достигнута у 22 (88 %) пациентов, из них у 21 (84 %) – до включения в исследование. большинство пациентов (80 %) получили лечение в качестве 2-й линии, 20 % – в качестве 3-й и последующих. у 1 (4 %) пациента наблюдался частичный ответ, у 11 (44 %) – стабилизация заболевания. Частота клинической эффективности составила 24 % (n = 6), медиана выживаемости без прогрессирования и общей выживаемости – 3,2 и 12,17 мес соответственно. Нежелательные явления III–Iv степени зарегистрированы у 28 % пациентов. Редукция дозы гемцитабина в связи с тромбоцитопенией I–II степени потребовалась в 2 (8 %) случаях; редукция дозы капецитабина не требовалась.Выводы. В данной работе продемонстрирована эффективность нового дозового режима химиотерапии по схеме GemCap + m во 2-й и последующих линиях лечения метастатического АКР. у большинства пациентов в нашем исследовании прогрессирование заболевания отмечалось на фоне предыдущих линий терапии при уже достигнутой терапевтической концентрации митотана, что свидетельствует об эффективности именно химиотерапевтической составляющей GemCap при резистентности к препаратам платины и митотану

Гипоксические белки VEGF A и CA IX и резистентность клеток сарком мягких тканей к химиопрепаратам: пилотный опыт ex vivo анализа

Introduction. The identification of predictive factors is a cornerstone task of modern oncology. The development of new targeted drugs determines the need for prediction of chemosensitivity of each patient to the prescribed therapy, in this regard, the search for biomarkers of predictive response to therapy is actively conducted.The study objective to investigate the relationship between tumor cell resistance and the expression levels of CA IX (carbonic anhydrase IX) and VEGF A (vascular endothelial growth factor А) in patient-derived cultures of soft tissue sarcomas.Materials and methods: ex vivo soft tissue sarcoma cell culture, resazurin test, immunoblotting.Results. We obtained 46 ex vivo samples of soft tissue sarcoma cultures for which chemosensitivity to doxorubicin, ifosfamide, docetaxel, gemcitabine, and their combinations was assessed by the resazurin cytotoxicity test. We analyzed the relationship between the expression of hypoxic proteins VEGF A and CA IX and the resistance to drugs. A correlation between the CA IX expression in hypoxia and cell resistance to ifosfamide and its combination with doxorubicin was found. Soft tissue sarcomas with high VEGF A index were resistant to doxorubicin, docetaxel, and its combination with gemcitabine (p <0.05).Conclusion. The data obtained on patient-derived cultures indicate the relationship between hypoxic signaling and resistance of soft tissue sarcomas to chemotherapeutics.Введение. Поиск предиктивных факторов является краеугольной задачей современной онкологии. Разработка большого числа новых таргетных препаратов определяет необходимость четкого предсказания хемочувствительности конкретного пациента к назначаемой терапии. В связи с этим активно ведется поиск биомаркеров прогноза ответа на терапию.Цель исследования – изучение взаимосвязи между резистентностью опухолевых клеток и уровнем экспрессии CA IX (карбоангидразы IX) и VEGF A (фактора роста эндотелия сосудов А) в ex vivo культурах сарком мягких тканей.Материалы и методы. В исследование были включены ex vivo культуры сарком мягких тканей, использованы резазуриновый тест, иммуноблоттинг.Результаты. Получено 46 ex vivo образцов культур сарком мягких тканей, для которых с помощью резазуринового теста на цитотоксичность определена хемочувствительность к доксорубицину, ифосфамиду, доцетакселу, гемцитабину и их комбинациям. Проведен анализ связи экспрессии гипоксических белков VEGF A и CA IX с резистентностью к химиопрепаратам. Обнаружена корреляция уровня экспрессии CA IX в гипоксии с резистентностью клеток к ифосфамиду и его комбинации с доксорубицином. Образцы сарком мягких тканей, обладающие высоким индексом VEGF A, были резистентны к доксорубицину, доцетакселу и его комбинации с гемцитабином (p <0,05).Заключение. Полученные на ex vivo культурах данные свидетельствуют о взаимосвязи гипоксического сигналинга и резистентности сарком мягких тканей к химиотерапии

RARE FORMS OF UTERINE LEIOMYOMAS (description of a case)

Leiomyomas predominate among benign nonepithelial tumors of the corpus uteri. Leiomyoma is commonly an asymptomatic tumor and detectable in most cases at routine gynecological examinations. However, some forms of leiomyomas have a definite metastatic potential and, despite its benign morphological signs, may metastasize to the lung. Fatal cases resulting from tumor spread along the postcava to the right atrium are described

Draft of Russian Guidelines of Diagnosis and Treatment of Adrenal Cortical Cancer

Statement of hormonal activity and potential malignancy are the most important issues of diagnosis and selection of appropriate treatment way for patients with adrenal tumors. Adrenal cortical carcinoma (ACC) is rare disease with poor prognosis. Incidience of ACC is about 0.5-2 per million, and no more then 2-4% among adrenal tumors. This draft of guidelines of diagnosis and treatment of ACC is offered to common discussion among wide round of specialists

Draft of Russian Guidelines of Diagnosis and Treatment of Adrenal Cortical Cancer

Statement of hormonal activity and potential malignancy are the most important issues of diagnosis and selection of appropriate treatment way for patients with adrenal tumors. Adrenal cortical carcinoma (ACC) is rare disease with poor prognosis. Incidience of ACC is about 0.5-2 per million, and no more then 2-4% among adrenal tumors. This draft of guidelines of diagnosis and treatment of ACC is offered to common discussion among wide round of specialists

Soft Tissue Sarcoma Study: Association of Genetic Alterations in the Apoptosis Pathways with Chemoresistance to Doxorubicin

Soft tissue sarcomas (STS) are heterogeneous cancers with more than 100 histological subtypes, different in molecular alterations, which make its personalized therapy very complex. Gold standard of chemotherapy for advanced STS includes combinations of Doxorubicin and Ifosfamide or Gemcitabine and Docetaxel. Chemotherapy is efficient for less than 50% of patients and it is followed by a fast development of drug resistance. Our study was directed to the search of genetic alterations in cancer cells associated with chemoresistance of undifferentiated pleomorphic and synovial sarcomas to the abovementioned genotoxic drugs. We analyzed chemoresistance of cancer cells in vitro using primary STS cultures and performed genetic analysis for the components of apoptotic signaling. In 27% of tumors, we revealed alterations in TP53, ATM, PIK3CB, PIK3R1, NTRK1, and CSF2RB. Cells from STS specimens with found genetic alterations were resistant to Dox, excluding the only one case when TP53 mutation resulted in the substitution Leu344Arg associated with partial oligomerization loss and did not cause total loss of TP53 function. Significant association between alterations in the components of apoptosis signaling and chemoresistance to Dox was found. Our data are important to elaborate further the therapeutic strategy for STS patients with alterations in apoptotic signaling

Soft Tissue Sarcoma Study: Association of Genetic Alterations in the Apoptosis Pathways with Chemoresistance to Doxorubicin

Soft tissue sarcomas (STS) are heterogeneous cancers with more than 100 histological subtypes, different in molecular alterations, which make its personalized therapy very complex. Gold standard of chemotherapy for advanced STS includes combinations of Doxorubicin and Ifosfamide or Gemcitabine and Docetaxel. Chemotherapy is efficient for less than 50% of patients and it is followed by a fast development of drug resistance. Our study was directed to the search of genetic alterations in cancer cells associated with chemoresistance of undifferentiated pleomorphic and synovial sarcomas to the abovementioned genotoxic drugs. We analyzed chemoresistance of cancer cells in vitro using primary STS cultures and performed genetic analysis for the components of apoptotic signaling. In 27% of tumors, we revealed alterations in TP53, ATM, PIK3CB, PIK3R1, NTRK1, and CSF2RB. Cells from STS specimens with found genetic alterations were resistant to Dox, excluding the only one case when TP53 mutation resulted in the substitution Leu344Arg associated with partial oligomerization loss and did not cause total loss of TP53 function. Significant association between alterations in the components of apoptosis signaling and chemoresistance to Dox was found. Our data are important to elaborate further the therapeutic strategy for STS patients with alterations in apoptotic signaling