Эпидемиологический обзор первично-множественных злокачественных новообразований предстательной железы, почки и мочевого пузыря

Background. In recent years, an increase in the incidence of multiple primary malignancies has been observed. Multiple primary malignancies are an independent occurrence and development of two or more neoplasms of different histological origin in one patient.Aim. To evaluate epidemiological, clinical and morphological aspects of primary multiple malignant neoplasms of the prostate, kidney, and bladder.Materials and methods. Data analysis of the work report of the Saratov region oncological service in 2019, presented by the Regional Clinical Oncological Dispensary, patient case histories in the archive of the medical information system was performed.We performed a comparative analysis of the literature sources and data we obtained based to the following criteria: topographic anatomical combination of tumor locations, distribution of tumor combinations depending on time of occurrence (synchronous, metachronous), dynamics of urogenital multiple primary malignancies diagnosis in 2012-2019, distribution by gender and age, combination of stages of tumor process in both tumors, distribution by combination of histological types.Results. Between 2012 and 2019, 783 cases of multiple primary tumors with lesions in the urogenital system were identified. We studied 186 cases with a combination of two malignant neoplasms in the prostate, kidney, and bladder. Tumors developed synchronously in 36 % of patients, metachronously in 64 %. Mean patient age was 75 years. Half of the cases were in the group of localized stages - 90 (48.4 %), with the most common combination of TI-TII stages observed in 46 (24.7 %) cases. Combinations of acinar adenocarcinoma of the prostate with urothelial carcinoma of the bladder (34.7 %), clear cell renal carcinoma (27.8 %), papillary urothelial carcinoma of the bladder (12.5 %) were the most common according to histological diagnosis of primary multiple tumors of the urogenital system.Conclusion. Over the recent years we can observe a steady growth of diagnosable urogenital multiple primary malignancies. Morphological verification of the tumor and revelation of the most frequent histological types allows to assume the presence of the common mechanisms of development and the influence of tumor microenvironment on the growth of both tumors in a multiple primary malignancies pair.Введение. В последние годы отмечено увеличение частоты первично-множественных злокачественных новообразований. Первично-множественные злокачественные новообразования - независимое возникновение и развитие у 1 больного 2 или более образований, которые имеют разное гистологическое происхождение.Цель исследования - оценка эпидемиологических и клинико-морфологических аспектов первично-множественных злокачественных новообразований предстательной железы, почки и мочевого пузыря.Материалы и методы. Проведен анализ данных на основании отчета по итогам работы онкологической службы Саратовской области в 2019 г., представленным Областным клиническим онкологическим диспансером, историй болезни, находящихся в архиве медицинской информационной системы.Выполнен сравнительный анализ источников литературы и полученных нами данных по следующим критериям: топографо-анатомическое сочетание локализаций опухолей, распределение сочетания опухолей в зависимости от времени возникновения (синхронное, метахронное), динамика диагностики первично-множественных злокачественных новообразований мочеполовой системы за 2012-2019 гг., распределение по полу и возрасту, сочетание стадий опухолевого процесса в обеих опухолях, распределение по сочетанию гистологических типов.Результаты. За период 2012-2019 гг. выявлено 783 случая первично-множественных опухолей с поражением органов мочеполовой системы. Изучено 186 случаев с сочетанием 2 злокачественных новообразований в следующих органах: предстательной железе, почке, мочевом пузыре. Опухоли развивались синхронно у 36 % пациентов, метахронно - у 64 %. Средний возраст пациентов составил 75 лет. Половина случаев относилась к группе локализованных стадий - 90 (48,4 %), причем самым распространенным было сочетание стадии TI-TII - 46 (24,7 %). При гистологической диагностике первично-множественных опухолей мочеполовой системы преобладали сочетания ацинарной аденокарциномы предстательной железы с уротелиальной карциномой мочевого пузыря (34,7 %), светлоклеточным раком почки (27,8 %), папиллярной уротелиальной карциномой мочевого пузыря (12,5 %).Заключение. За последние годы наблюдается постоянный рост диагностируемых первично-множественных злока-чественных новообразований мочеполовой системы. Морфологическая верификация опухоли и выявление наиболее часто встречающихся гистологических типов позволяют предположить наличие общих механизмов развития и влияния опухолевого микроокружения на рост обеих опухолей из пары первично-множественных злокачественных новообразований

Photothermal and photodynamic therapy of tumors with plasmonic nanoparticles: challenges and prospects

Cancer remains one of the leading causes of death in the world. For a number of neo-plasms, the efficiency of conventional chemo-and radiation therapies is insufficient because of drug resistance and marked toxicity. Plasmonic photothermal therapy (PPT) using local hyperthermia induced by gold nanoparticles (AuNPs) has recently been extensively explored in tumor treatment. However, despite attractive promises, the current PPT status is limited by laboratory experiments, academic papers, and only a few preclinical studies. Unfortunately, most nanoformulations still share a similar fate: great laboratory promises and fair preclinical trials. This review discusses the current challenges and prospects of plasmonic nanomedicine based on PPT and photodynamic therapy (PDT). We start with consideration of the fundamental principles underlying plasmonic properties of AuNPs to tune their plasmon resonance for the desired NIR-I, NIR-2, and SWIR optical windows. The basic principles for simulation of optical cross-sections and plasmonic heating under CW and pulsed irradiation are discussed. Then, we consider the state-of-the-art methods for wet chemical synthesis of the most popular PPPT AuNPs such as silica/gold nanoshells, Au nanostars, nanorods, and nanocages. The photothermal efficiencies of these nanoparticles are compared, and their applications to current nanomedicine are shortly discussed. In a separate section, we discuss the fabrication of gold and other nanoparticles by the pulsed laser ablation in liquid method. The second part of the review is devoted to our recent experimental results on laser-activated interaction of AuNPs with tumor and healthy tissues and current achievements of other research groups in this application area. The unresolved issues of PPT are the significant accumulation of AuNPs in the organs of the mononuclear phagocyte system, causing potential toxic effects of nanoparticles, and the possibility of tumor recurrence due to the presence of survived tumor cells. The prospective ways of solving these problems are discussed, including developing combined antitumor therapy based on combined PPT and PDT. In the conclusion section, we summarize the most urgent needs of current PPT-based nanomedicine

The assessment of effectiveness of plasmonic resonance photothermal therapy in tumor-bearing rats after multiple intravenous administration of gold nanorods

To assess the effectiveness of plasmonic photothermal therapy (PPT) multiple intravenous strategy of gold nanorods (GNRs) administration was used before laser exposure. The model of alveolar liver cancer PC-1 was used in male outbred albino rats, which were intravenously administrated by single and multiple injections of GNRs and then were treated by PPT. The gold dosage was 400 μg (single injection group), 800 μg (double injection group), 1200 μg (triple injection group), and absorption maximum of gold nanorods suspension was at the wavelength of 808 nm. 24 hours after last injection the tumors were irradiated by the 808-nm diode laser during 15 min at power density 2.3 W/cm2. Temperature control of the tumor heating was provided by IR imager. 24 hours after the PPT the half of animals from each group was withdrawn from the experiments and the sampling tumor tissue for morphological study was performed. In survived animals the growth of tumors was evaluated during 21 days after the PPT. The antitumor effects of PPT after triple intravenous injection were comparable with those obtained at direct intratumoral administration of similar total dose of GNRs. The effectiveness of PPT depended on gold accumulation in tumor, probably, due to sufficient vascularizTation of tumor tissue

The morphological changes in transplanted tumors of rats at plasmonic photothermal therapy

The aim of work was to study the morphological changes in transplanted liver tumors of rats after plasmonic photothermal therapy (PPTT). The gold nanorods functionalized with thiolated polyethylene glycol were injected intravenously to rats with transplanted liver cancer PC-1. A day after injection the tumors were irradiated by the infrared 808-nm diode laser. The withdrawal of the animals from the experiment and sampling of tumor tissue for morphological study were performed 24 hours after the laser exposure. The standard histological and immunohistochemical staining with antibodies to proliferation marker Ki-67 and apoptosis marker BAX were used for morphological study of transplanted tumors. The plasmonic photothermal therapy had pronounced damaging effect in rats with transplanted liver tumors expressed in degenerative and necrotic changes in the tumor cells. The decrease of proliferation marker Ki-67 and increase of expression of apoptosis marker BAX were observed in tumor cells after PPTT

The effects of prolonged oral administration of gold nanoparticles on the morphology of hematopoietic and lymphoid organs

Currently, the usage of gold nanoparticles as photosensitizers and immunomodulators for plasmonic photothermal therapy has attracted a great attention of researches and end-users. In our work, the influence of prolonged peroral administration of gold nanoparticles (GNPs) with different sizes on the morphological changes of hematopoietic and lymphoid organs was investigated. The 24 white outbred male rats weighing 180-220 g were randomly divided into groups and administered orally for 30 days the suspension of gold nanospheres with diameters of 2, 15 and 50 nm at a dosage of 190 μg/kg of animal body weight. To prevent GNPs aggregation in a tissue and enhance biocompatibility, they were functionalized with thiolated polyethylene glycol. The withdrawal of the animals from the experiment and sampling of spleen, lymph nodes and bone marrow tissues for morphological study were performed a day after the last administration. In the spleen the boundary between the red and white pulp was not clearly differ in all experimental groups, lymphoid follicles were significantly increased in size, containing bright germinative centers represented by large blast cells. The stimulation of lymphocyte and myelocytic series of hematopoiesis was recorded at morphological study of the bone marrow. The number of immunoblasts and large lymphocytes was increased in all structural zones of lymph nodes. The more pronounced changes were found in the group with administration of 15 nm nanoparticles. Thus, the morphological changes of cellular components of hematopoietic organs have size-dependent character and indicate the activation of the migration, proliferation and differentiation of immune cells after prolonged oral administration of GNPs

The inflammation markers in serum of tumor-bearing rats after plasmonic photothermal therapy

We report on plasmonic photothermal therapy of rats with inoculated cholangiocarcinoma through the intratumoral injection of PEG-coated gold nanorods followed by CW laser light irradiation. The length and diameter of gold nanorods were 41±8 nm and 10±2 nm, respectively; the particle mass-volume concentration was 400 μg/mL, which corresponds to the optical density of 20 at the wavelength 808 nm. The tumor-bearing rats were randomly divided into three groups: (1) without any treatment (control); (2) with only laser irradiation of tumor; (3) with intratumoral administration of gold nanorods and laser irradiation of tumors. An hour before laser irradiation, the animals were injected intratumorally with gold nanorod solutions in the amount of 30% of the tumor volume. The infrared 808-nm laser with power density of 2.3 W/cm2 was used for plasmonic photothermal therapy (PTT). The withdraw of animals from the experiment was performed 24 h after laser exposure. The content of lipid peroxidation products and molecular markers of inflammation (TNF-α, IGF-1, VEGF-C) was determined by ELISA test in serum of rats. The standard histological techniques with hematoxylin and eosin staining were used for morphological examination of tumor tissues. It was revealed that the significant necrotic changes were noted in tumor tissue after plasmonic photothermal therapy, which were accompanied by formation of inflammatory reaction with release of proinflammatory cytokines and lipid peroxidation products into the bloodstream

Liposomes loaded with hydrophilic magnetite nanoparticles: Preparation and application as contrast agents for magnetic resonance imaging

© 2015 Elsevier B.V.. Magnetic fluid-loaded liposomes (MFLs) were fabricated using magnetite nanoparticles (MNPs) and natural phospholipids via the thin film hydration method followed by extrusion. The size distribution and composition of MFLs were studied using dynamic light scattering and spectrophotometry. The effective ranges of magnetite concentration in MNPs hydrosol and MFLs for contrasting at both T2 and T1 relaxation were determined. On T2 weighted images, the MFLs effectively increased the contrast if compared with MNPs hydrosol, while on T1 weighted images, MNPs hydrosol contrasting was more efficient than that of MFLs. In vivo magnetic resonance imaging (MRI) contrasting properties of MFLs and their effects on tumor and normal tissues morphology, were investigated in rats with transplanted renal cell carcinoma upon intratumoral administration of MFLs. No significant morphological changes in rat internal organs upon intratumoral injection of MFLs were detected, suggesting that the liposomes are relatively safe and can be used as the potential contrasting agents for MRI

ПАТОМОРФОЗ РАКА ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫ ПРИ ЛЕЧЕНИИ ВЫСОКОИНТЕНСИВНЫМ СФОКУСИРОВАННЫМ УЛЬТРАЗВУКОМ (HIFU)

The purpose of the study was to evaluate the efficiency of prostate cancer (PC) treatment using high-intensity focused ultrasound (HIFU) on the basis of morphometric and immunohistochemical (IHC) analyses of postoperative prostate biopsy specimens. The study subjects were 40 patients with localized and locally advanced PC. The postoperative morphological analysis was made on the basis of standard hematoxylineosin staining and morphometric and IHC studies using the following antibodies: PCNA, Bcl-2, AMACR, Е-cadherin, and ANDR (Dako). Pre- and post-HIFU therapy histological examination of the routinely hematoxylin-eosin-stained specimens showed that the therapeutic pathomorphism of the tumor corresponded to grades III and IV. It was established that the IHC study should be used as an additional crite-rion for the efficiency of PC therapy after HIFU ablation. In spite of positive clinical, laboratory, instrumental, and objective changes, the patients with high AMACR and Bcl-2 levels and decreased Е-cadherin expression may be considered as a group at risk for prolonged malignant growth or recurrent PC.Цель исследования – оценка эффективности лечения рака предстательной железы (РПЖ) с использованием высокоинтенсивного сфокусированного ультразвука (HIFU) на основании морфометрического и иммуногистохимического (ИГХ) анализа послеоперационных биоптатов предстательной железы. Объектом исследования явились 40 пациентов с локализованным и местно-распространенным РПЖ. Морфологический анализ после лечения проводили на основании стандартной окраски срезов гематоксилин-эозином, морфометрического и ИГХ-исследования с помощью следующих антител: PCNA, Bcl-2, AMACR, Е-кадгерин, ANDR (Dako). При гистологическом изучении материала до и после HIFU-терапии при стандартной окраске гематоксилин-эозином лечебный патоморфоз опухоли соответствовал III и IV степеням. Было выявлено, что в  качестве дополнительного критерия эффективности лечения РПЖ после HIFU аблации необходимо применение ИГХ-исследования. Пациенты с высоким уровнем AMACR, Bcl-2 и сниженной экспрессией Е-кадгерина, несмотря на положительную динамику клинико-лабораторных, инструментальных и объективных показателей, могут рассматриваться как группа риска продолженного злокачественного роста либо развития рецидива РПЖ

Тканевая экспрессия аутофагиального маркера LC3B как потенциальный биомаркер рецидива рака предстательной железы после лечения высокоинтенсивным сфокусированным ультразвуком (пилотное исследование)

Background. The role of autophagy markers in prostate tumor recurrence has not been sufficiently investigated. We hypothesized that autophagy activation may be one mechanism by which prostate cancer cells survive exposure to high-intensity focused ultrasound (HIFU).Aim. To compare tissue expression of autophagic LC3B marker in prostate biopsies before and after treatment of localized prostate cancer by HIFU ablation.Materials and methods. 45 patients with localized morphologically confirmed prostate cancer were examined: group 1 – 25 patients of 65.6 ± 8.4 years without signs of recurrence or progression of the disease; group 2 – 20 patients of 67.5 ± 7.9 years with tumor recurrence proven during morphological examination. Immunohistochemical examination was performed by streptavidin-biotin method. In all cases, Anti-LC3B antibody ab48394 was used. The reaction results were quantified using the Histochemical score (Hs) system.Results. Prior to treatment, all patients of group 1 showed moderate cytoplasmic expression (Hs = 111 [111; 115]) of antibodies against LC3B in prostate adenocarcinoma cells, 5 % of patients – weak cytoplasmic expression in muscle connective stromal cells (Hs = 47 [43; 50]), 10 % of patients – weak positive LC3B reaction in the vessel wall (Hs = 28 [20; 35]). After treatment, the expression of LC3B in adenocarcinoma cells became negative, in the cytoplasm of muscle connective stromal cells weak (Hs = 75 [67.5; 80.0]), in the endothelium of the vascular wall even weaker (Hs = 55 [45.5; 60.0]) (p <0.001). Prior to treatment in group 2, LC3B expression in tumor tissue was moderate in 89 % of patients (Hs = 151.5 [137.5; 160.0]), weak in muscle connective stromal cells in 12 % of patients (Hs = 44 [35; 51.5]), and weak in the vascular wall in 5 % of patients (Hs = 30 [25; 35]). After treatment, LC3B expression in adenocarcinoma cells became pronounced (Hs = 260 [250; 285]), in muscle connective stromal cells – moderate (Hs = 118 [100; 130]), in the vascular wall – weak (Hs = 45 [30; 55]) (p <0.001). There was a significant correlation between tumor recurrence and LC3B overexpression (r = 0.51; p <0.001).Conclusion. The development of prostate cancer recurrence is associated with increased expression of autophagic LC3B protein. Increased LC3B expression, which is interpreted as evidence of autophagy activation and correlates with the risk of disease progression, is used by the tumor as an oncogenic advantage.Введение. Роль маркеров аутофагии при рецидиве опухоли предстательной железы недостаточно исследована. Мы предположили, что активация аутофагии может являться одним из механизмов, с помощью которого клетки рака предстательной железы выживают после воздействия высокоинтенсивным сфокусированным ультразвуком (HIFU).Цель исследования – сравнить тканевую экспрессию аутофагиального маркера LC3B в биоптатах предстательной железы до и после лечения локализованного рака предстательной железы методом HIFU-аблации.Материалы и методы. Обследованы 45 пациентов с локализованным раком предстательной железы, подтвержденным морфологически: 1-я группа – 25 пациентов (средний возраст 65,6 ± 8,4 года) без признаков рецидива или прогрессирования заболевания; 2-я группа – 20 пациентов (средний возраст 67,5 ± 7,9 года) с доказанным при морфологическом исследовании рецидивом опухоли. Иммуногистохимическое исследование проводили стрептавидин-биотиновым методом. Во всех случаях использовали антитело Anti-LC3B antibody ab48394. Результаты реакции подсчитывали по системе Histochemical score (Hs).Результаты. До лечения у всех пациентов 1-й группы зафиксирована умеренная цитоплазматическая экспрессия (Hs = 111 [111; 115]) антител к LC3B в клетках аденокарциномы предстательной железы, у 5 % – слабая цитоплазматическая экспрессия в клетках мышечно-соединительнотканной стромы (Hs = 47 [43; 50]), у 10 % – слабая положительная реакция LC3B в стенке сосудов (Hs = 28 [20; 35]). После лечения экспрессия LC3B в клетках аденокарциномы стала отрицательной, в цитоплазме клеток мышечно-соединительнотканной стромы – слабой (Hs = 75 [67,5; 80,0]), в эндотелии сосудистой стенки – еще слабее (Hs = 55 [45,5; 60,0]) (р <0,001). До лечения во 2-й группе у 89 % пациентов выявлена умеренная экспрессия LC3B в опухолевой ткани(Hs = 151,5 [137,5; 160,0]), у 12 % – слабая экспрессия в клетках мышечно-соединительнотканной стромы (Hs = 44 [35; 51,5]), у 5 % – слабая экспрессия в стенке сосудов (Hs = 30 [25; 35]). После лечения экспрессия LC3B в клетках аденокарциномы стала выраженной (Hs = 260 [250; 285]), в клетках мышечно-соединительнотканной стромы – умеренной (Hs = 118 [100; 130]), в сосудистой стенке – слабой (Hs = 45 [30; 55]) (р <0,001). Зафиксирована значимая ассоциация между рецидивом опухоли и гиперэкспрессией LC3B (r = 0,51; p <0,001).Заключение. Развитие рецидива рака предстательной железы связано с увеличением экспрессии аутофагиального белка LC3B. Повышенная экспрессия LC3B, которая интерпретируется как свидетельство активации аутофагии и коррелирует с риском прогрессирования заболевания, используется опухолью как онкогенное преимущество