Experience with olaparib in a patient with luminal HER2-positive metastatic breast cancer

Hereditary breast cancer (BC) accounts for about 5-10% of cases. BRCA-associated tumors have been identified as a separate group of malignant neoplasms with distinctive clinical manifestations and specific treatment features. Understanding of biological mechanisms leading to cancer in BRCA1/2 mutation carriers and discovery of potential molecular targets, such as poly (ADP-ribose) polymerase (PARP), involved in base excision repair mechanisms, led to the development of a new class of targeted drugs belonging to the PARP inhibitors group. PARP inhibition leads to the preservation of single-stranded DNA breaks, the arrest of the replication fork, and the realization of the “synthetic lethality” phenomenon due to the inability to repair double-stranded DNA breaks by homologous recombination in cells with mutations in the BRCA1/2 genes. Two randomized trials OlympiAD and EMBRACA evaluated and proved the effectiveness of PARP inhibitors in patients with metastatic BRCA-mutated HER2-negative breast cancer in comparison with standard chemotherapy. At the same time, data on the potential use of PARP inhibitors for the treatment of BRCA-mutated HER2-positive breast cancer patients are extremely limited. This article presents a clinical example of the use of olaparib in a patient with BRCA-mutated HER2-positive metastatic breast cancer

ЭФФЕКТИВНОСТЬ ТАРГЕТНОЙ ТЕРАПИИ ALK-ПОЗИТИВНЫХ ОПУХОЛЕЙ НА ПРИМЕРЕ ИСПОЛЬЗОВАНИЯ ПРЕПАРАТА КРИЗОТИНИБ У БОЛЬНОГО РАСПРОСТРАНЕННЫМ РАКОМ ЖЕЛУДКА

Although many currently known molecular targets are characterized by organ specificity, they can be found in various types of tumors. Molecular diagnostic techniques can be used to help select patients who are most likely to benefit from target therapy. Case presentation. We describe the case of a 38-year-old patient with advanced gastric cancer with peritoneal dissemination. On december 11, 2014, the patient underwent palliative subtotal gastrectomy followed by 18 cycles of chemotherapy (xelOx) and radiotherapy. On February 2, 2017, percutaneous transhepatic cholangiostomy of the left lobe bile duct was performed. in May 2017, the stent was inserted into the common bile duct due to bile duct stenosis. three months later, disease progression (multiple liver metastases) occurred, and chemotherapy with paclitaxel was given in a weekly schedule. therapy with crizotinib was administered 3 months after determining the alK mutation. the duration of treatment was 8 months with satisfactory tolerability. Conclusion. target therapy with krizotinib seems to be an effective treatment for alK-positive tumors.Многие известные на данный момент молекулярные мишени характеризуются достаточной органной специфичностью, но могут быть выявлены в различных типах опухолей. Своевременное использование молекулярных методов диагностики позволит осуществить отбор пациентов, применение таргетной терапии у которых приведет к получению наилучшего результата в отношение контроля над заболеванием. Описание клинического случая. Пациенту, 38 лет, в декабре 2014 г. по поводу распространенного  низкодифференцированного аденогенного рака антрального отдела желудка с диссеминацией по брюшине по витальным показаниям выполнена паллиативная субтотальная резекция желудка. В послеоперационном периоде проведены 18 курсов ПХТ по схеме xelOx с последующей ДлТ на область ворот печени. В феврале 2017 г. выполнена чрескожная чреспеченочная холангиостомия левого долевого протока, в мае 2017 г. в связи с развитиями картины стеноза – стентирование общего желчного протока. Через 3 мес диагностировано прогрессирование заболевания в виде билобарного метастатического поражения печени. начата МХТ препаратом паклитаксел в еженедельном режиме. Через 3 мес после определения в опухоли перестройки alK консилиумом врачей больному рекомендована терапия кризотинибом. Длительность лечения при удовлетворительной переносимости составила 8 мес. Заключение. имеющийся на данный момент опыт применения препарата кризотиниб позволяет рассматривать его как эффективное средство в лечении alK-позитивных опухолей

Режим паклитаксел, ифосфамид, цисплатин (TIP) при несеминомных герминогенных опухолях неблагоприятного и промежуточного прогноза с неудовлетворительным снижением уровня онкомаркеров: исследование II фазы

Purpose: To evaluate efficacy of TIP (paclitaxel, ifosfamid, cisplatin) in the 1st line treatment of germ cell tumors patients with unfavorable decline of serum tumor markers after 1 cycle of the standard regimen of chemotherapy.Patients and methods: In this phase II multicenter, nonrandomized trial, patients were enrolled from 4 centers of the Russian Federation. Patients were included if they were older than 18 years, had evidence of testicular, retroperitoneal, or mediastinal nonseminoma based on histologic findings or clinical evidence (high serum human chorionic gonadotropin or alpha-fetoprotein levels) that matched International Germ Cell Cancer Consensus Group (IGCCCG) intermediate and poor prognosis criteria. All patients got one cycle of BEP regimen (bleomycin 30 mg on days 1, 3, 5, etoposide 100 mg / m2 on days 1–5, cisplatin 20 mg / m2 on days 1–5). Patients with unfavorable serum tumor markers decline after the first cycle of chemotherapy at day 18–21 received four cycles of TIP regimen (paclitaxel 120 mg / m2 on days 1–2, ifosfamide 1500 mg / m2 on days 2–5, and cisplatin 25 mg / m2 om days 2–5, granulocyte-colony stimulating factor 5 mg / kg on days 6–15). In the presence of a residual tumor larger than 1 cm and the technical possibility of its removal, surgical treatment was performed. The primary endpoint was 1-year progression-free survival.Results: Between 2017 and 2021, 28 patients were included in our study: seven patients with an intermediate prognosis according to IGCCCG classification and twenty-one with poor risk. Median follow-up was 15,5 months (range, 4,4–38,3 months). The 1-year progression-free survival and overall survival in intention-to-treat population were 76,6 % and 81,0 %, respectively. One-year progression-free survival and overall survival according IGCCCG classification were 100 % and 100 % for an intermediate risk patients and 68 % and 73,8 % for a poor risk, respectively. The favorable response rate (complete response + partial response with normalization STM) was observed in 19 (68 %) patients. During the follow-up period, disease progression was noted in 9 (32 %) patients, 7 (25 %) patients died, including one from an aggressive growing mature teratoma syndrome. Eleven (39 %) patients underwent surgical treatment: retroperitoneal lymph node dissection (55 %), mediastinal lymph node dissection (36 %), pulmonary resection (9 %). Pathological complete response was achieved in 6 (55 %) patients, mature teratoma — 2 (18 %), viable tumour — 3 (27 %). TIP showed acceptable safety profile and only in one case tumor lysis syndrome was observed.Conclusions: The TIP regimen may improve the results of treatment in the first line with unfavorable decrease of serum tumor markers after the first cycle of chemotherapy, which requires further study in a randomized trial.Цель исследования: Оценка эффективности режима TIP (паклитаксел, ифосфамид, цисплатин) у пациентов c диссеминированными герминогенными опухолями при неудовлетворительном снижении уровня маркеров после первого курса ХТ.Материалы и методы: В многоцентровое нерандомизированное исследование II фазы вошли пациенты из 4 центров Российской Федерации c диагнозом герминогенной несеминомной опухоли яичка или внегонадной природы, промежуточным или неблагоприятным прогнозом согласно классификации IGCCCG. Всем пациентам был проведен 1 курс химиотерапии (ХТ) по схеме ВЕР (блеомицин 30 мг в день 1, 3, 5, этопозид 100 мг / м2 в дни 1–5, цисплатин 20 мг / м2 в дни 1–5). Пациенты с неудовлетворительной скоростью снижения опухолевых маркеров к 18–21 дню получили 4 курса TIP (паклитаксел 120 мг / м2 в дни 1–2, ифосфамид 1500 мг / м2 в дни 2–5, цисплатин 25 мг / м2 в дни 2–5 + Г-КСФ с 6 по 15 дни). При наличии резидуальной опухоли размером более 1 см и технической возможности ее удаления, выполнялось хирургическое лечение. Первичной конечной точкой являлась однолетняя выживаемость без прогрессирования.Результаты исследования: С 2017 по 2021 годы в исследование включено 28 пациентов: 7 пациентов с промежуточным прогнозом и 21 с неблагоприятным. Медиана наблюдения за пациентами составила 15,5 месяцев (диапазон 4,4–38,3 месяцев). Одногодичная выживаемость без прогрессирования и общая выживаемость без учета риска по IGCCCG составили 76,6 % и 81 % соответственно. Одногодичная выживаемость без прогрессирования и общая выживаемость с учетом классификации: для промежуточного прогноза — 100 % и 100 %, для неблагоприятного — 68 % и 73,8 % соответственно. За период наблюдения прогрессирование заболевания отмечено у 9 (32 %) больных, 7 (25 %) пациентов умерло от основного заболевания, включая один случай агрессивно протекающего синдрома растущей зрелой тератомы в средостении. Хирургическое лечение было выполнено 11 (39 %) больным. Патоморфологический полный ответ отмечен у 6 (21,4 %) пациентов, зрелая тератома у 2 (7,1 %), жизнеспособная опухоль у 3 (10,7 %) больных. Режим TIP продемонстрировал удовлетворительный профиль токсичности, несмотря на это у 1 пациента развился синдром лизиса опухоли.Заключение: Режим TIP может улучшить результаты лечения в первой линии при неудовлетворительном снижении опухолевых маркеров после одного курса ХТ, что требует дальнейшего изучения в рандомизированном исследовании

Эффективность и безопасность винфлунина во 2-й линии терапии у больных распространенным переходно-клеточным раком мочевых путей в клинической практике

Objective: to investigate the safety of vinflunine, the rate and duration of its treatment response, progression-free and overall survival rates in patients receiving this drug in routine clinical practice for first-line chemotherapy (CT) – resistant disseminated transitional cell carcinoma of the urinary tract.Materials and methods. This retrospective observational multicenter study included data on 25 patients with verified disseminated transitional cell carcinoma of the urinary tract who took vinflunine for tumor progression after first-line CT performed in 11 Russian clinical centers in 23 March 2013 to 26 June 2016. The median age of the patients was 60 (44‒81) years. Their baseline somatic status was rated as ECOG 0 in 1 (4.0 %) patient, ECOG 1 in 13 (52.0 %) patients, EGOG 2 in 9 (36.0 %), and ECOG 3 in 2 (8.0 %). The most common sites of tumor foci were bones (n = 14, 56.0 %), lymph nodes of different groups (n = 14; 56.0 %), and lung (n = 9; 36.0 %).Results. Adverse reactions were recorded in 24 (96.0 %) cases. The most common types of toxicity were asthenia (n = 19; 76.0 %), anemia (n = 18; 72.0 %), neutropenia (n = 13; 52 %), and nausea (n = 12; 48.0 %). Most adverse events were grades I–II and well controlled. There were no deaths due to adverse events. The best treatment response was regarded as partial in 6 (24.0 %) patients; stabilization and progression were observed in 10 (40.0 %) and 9 (36.0 %) patients, respectively. The median duration of partial response was 5.1 (95 % confidence interval (CI), 0.6–15.0) months; that of stabilization was 3.4 (95 % CI, 1.2–6.3) months. In all the 25 cases, the median progression-free and overall survival rates were 3.7 (95 % CI, 2.1‒5.3) and 6.5 (95 % CI, 5.2‒7.8) months, respectively. The somatic status was a predictor of overall survival (p < 0.0001).Conclusion. The efficacy and safety of vinflunine in second-line therapy for first-line CT-resistant disseminated transitional cell carcinoma of the urinary tract in unselected patients agree with those previously observed in Phase III randomized trial.Цель исследования – изучение безопасности, частоты и длительности ответов, беспрогрессивной и общей выживаемости у больных, получавших винфлунин в рутинной клинической практике по поводу распространенного переходно-клеточного рака мочевых путей, резистентного к 1-й линии химиотерапии (ХТ).Материалы и методы. В ретроспективное наблюдательное многоцентровое исследование включены данные 25 больных верифицированным распространенным переходно-клеточным раком мочевых путей, получавших винфлунин по поводу прогрессии опухоли после проведения ХТ 1-й линии с 23.03.2013 по 26.06.2016 в 11 клинических центрах России. Медиана возраста – 60 (44–81) лет. Исходный соматический статус по шкале ECOG был расценен как 0 у 1 (4,0 %), 1 – у 13 (52,0 %), 2 – у 9 (36,0 %), 3 – у 2 (8,0 %) больных. Наиболее распространенными локализациями опухолевых очагов были кости (n =14; 56,0 %), лимфатические узлы различных групп (n =14; 56,0 %) и легкие (n = 9; 36,0 %).Результаты. Нежелательные явления были зарегистрированы в 24 (96,0 %) случаях. Наиболее распространенными видами токсичности являлись астения (n =19; 76,0 %), анемия (n =18; 72,0 %), нейтропения (n =13; 52,0 %), тошнота (n = 12; 48,0 %). Нежелательные явления в большинстве наблюдений имели I–II степени тяжести и хорошо контролировались. Смертности, обусловленной нежелательными явлениями, не зарегистрировано. Наилучший ответ на лечение расценен как частичный у 6 (24,0 %), стабилизация – у 10 (40,0 %), прогрессирование – у 9 (36,0 %) больных. Медиана длительности частичного ответа составила 5,1 (95 % доверительный интервал (ДИ) 0,6–15,0) мес, стабилизации – 3,4 (95 % ДИ 1,2–6,3) мес. Медиана беспрогрессивной и общей выживаемости всех 25 больных составила 3,7 (95 % ДИ 2,1–5,3) и 6,5 (95 % ДИ 5,2–7,8) мес соответствен- но. Соматический статус являлся фактором прогноза общей выживаемости (p < 0,0001).Заключение. Эффективность и безопасность применения винфлунина во 2-й линии терапии распространенного переходно-клеточного рака мочевых путей, резистентного к 1-й линии ХТ, у неотобранных больных соответствуют ранее полученным результатам рандомизированного исследования III фазы.

Firearm violence: a neglected Global Health issue.

Abstract Populations around the world are facing an increasing burden of firearm violence on mortality and disability. While firearm violence affects every country globally, the burden is significantly higher in many low- and middle-income countries. However, despite overwhelming statistics, there is a lack of research, reporting, and prioritization of firearm violence as a global public health issue, and when attention is given it is focused on high-income countries. This paper discusses the impact of firearm violence, the factors which shape such violence, and how it fits into global public health frameworks in order to illustrate how firearm violence is a global health issue which warrants evidence-based advocacy around the world

Economic development and road traffic fatalities in Russia: analysis of federal regions 2004–2011

© 2015, He et al. Background: The relationship between economic development and road safety at sub-national level has not been well established. This study aims to assess the relationships between economic growth (measured by gross regional product (GRP)) and road traffic fatalities (RTFs) and crash fatality ratio (CFR) at sub-national level in Russia. Methods: We used published secondary data on annual RTFs and CFR obtained from the traffic police and socioeconomic development indicators from the statistics department for each Russian federal region (referred to in Russia as “subject”) for 2004–2011. We used multivariate fixed effects models for longitudinal data to examine the GRP-RTF and the GRP-CFR relationships excluding regions with extreme values. Time (in years) and a set of relevant socioeconomic variables (territory, population, number of privately owned cars, number of public buses, length of public motor roads, number of physicians, and budget expenditure on health care and physical wellness) were also included as covariates in the models. Results: The RTF rates decreased monotonically over time as GRP per capita increased in 66 studied regions during 2004–2011. This relationship was mainly explained by the number of privately owned cars and partially explained by year dummy variables, number of buses, and number of physicians. CFR also decreased monotonically as GRP per capita increased in 67 studied regions. This relationship between economic growth and CFR was fully explained by secular time trends. The year dummy effects on CFR were not mediated by other socioeconomic variables included in the study. Conclusions: For the period of 2004–2011 in Russia, the reduction in RTFs is mostly explained by increasing the number of private cars, while the reduction of CFR is mostly associated with year-effects suggesting a process of diffusion of knowledge, which is not solely dominated by economic growth

Evaluation of the five-year Bloomberg Philanthropies Global Road Safety Program in the Russian Federation

© 2016 Road traffic injuries are a leading cause of morbidity and mortality in the world. In Russia, a road safety program was implemented in Lipetskaya and Ivanovskaya oblasts (regions) as part of a 10-country effort funded by Bloomberg Philanthropies. The program was focused on increasing seat belt and child restraint use and reducing speeding. The primary goals of this monitoring and evaluation study are to assess trends in seat belt use, child restraint use, and speed compliance in the two oblasts over the 5 years and to explore the overall impact of the program on road traffic injury and death rates. Primary data via roadside observations and interviews, and secondary data from official government sources were collected and analyzed for this study. Our results indicate significant improvements in seat belt wearing and child seat use rates and in prevalence of speeding in both intervention oblasts. The observations were consistent with the results from the roadside interviews. In Lipetskaya, restraint use by all occupants increased from 52.4% (baseline, October 2010) to 77.4% (final round, October 2014) and child restraint use increased from 20.9% to 54.1% during the same period. In Ivanovskaya, restraint use by all occupants increased from 48% (baseline, April 2012) to 88.7% (final round, October 2014) and child restraint use increased from 20.6% to 89.4% during the same period. In Lipetskaya, the overall prevalence of speeding (vehicles driving above speed limit) declined from 47.0% (baseline, July 2011) to 30.4% (final round, October 2014) and a similar pattern was observed in Ivanovskaya where the prevalence of speeding decreased from 54.6% (baseline, March 2012) to 46.6% (final round, October 2014). Through 2010–2014, the road traffic crash and injury rates per 100,000 population decreased in Lipetskaya oblast (191.5 and 246.9 in 2010 and 170.4 and 208.6 in 2014, respectively) and slightly increased in Ivanovskaya oblast (184.4 and 236.0 in 2010 and 186.7 and 243.4 in 2014, respectively). These road safety improvements are associated with the program that enabled a combined focus on policy reform, legislation, enforcement, advocacy, education, and data collection and use. However, the existence of other road safety efforts, lack of data from comparable regions, and unavailability of risk factor-specific data make it difficult to attribute these changes to the program

Monitoring the Decade of Action for Global Road Safety 2011–2020: An update

© 2016 Informa UK Limited, trading as Taylor & Francis Group. The United Nations Road Safety Collaboration (UNRSC) was set up in 2004 in response to the recognised need for the United Nations (UN) system to encourage efforts to address the global road safety crisis. In 2010, the UN General Assembly Resolution 64/255 declared 2011–2020 the Decade of Action for Road Safety with the overarching goal of stabilising and reducing the forecasted number of road traffic deaths by increasing activities at national, regional and global levels. In 2011, a Plan of Action for the Decade of Action, a tool to support the development of national and local plans of action, was launched. Countries are encouraged to implement activities according to the five pillars set out by the Plan of Action. The UNRSC, tasked to evaluate the overall impact of the Decade, developed and populated indicators for each pillar. Currently, 36 of 38 proposed indicators are populated by baseline data for 2010 from the second Global status report for road safety. However, gaps exist in data quality and availability on a global level. Therefore, there is an urgent need for improving data quality and availability to measure the progress of the Decade of Action