The efficacy and safety of zoledronic acid and strontium-89 in treating non-small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Zoledronic acid (ZA) and strontium-89 have been widely used to treat lung cancer with bone metastases. The authors perform this meta-analysis to better evaluate the clinical outcome of ZA and strontium-89 for non-small cell lung cancer (NSCLC) patients. METHODS: We carried out standard meta-analysis and network meta-analysis based on a comprehensive data retrieval of EMBASE, PubMed, and Cochrane Library databases (up to March 2019). Random and fixed effects models were used where indicated and between-study heterogeneity was assessed. The primary endpoints were overall survival (OS) and skeletal-related events (SREs). The second endpoints were progression-free survival (PFS) and overall response rate (ORR). RESULTS: Seven randomized clinical trials, including 1426 NSCLC patients with seven studies of zoledronic acid and two studies of strontium-89, met the inclusion criteria. Compared with the control group, ZA is associated with a OS benefit (1-year survival rate: RR = 1.76, 95% CI 1.36-2.27; and 24-month survival rate: RR = 2.38, 95% CI 1.35-4.19) and a reduction of SREs (RR = 0.57, 95% CI 0.40-0.84) for the patients with bone metastases. No statistical differences were found in PFS and ORR. Network meta-analysis for the patients with bone metastases showed that ZA + strontium-89 and ZA harbored significantly clinical benefits than strontium-89 and placebo in terms of 1-year survival rate and SREs. Both head-to-head study and network meta-analysis showed that strontium-89 had no statistical impact on OS and SREs compared with placebo. CONCLUSION: Our analysis demonstrates that ZA +strontium-89 can be considered a priority for NSCLC patients with bone metastases, followed by ZA.

Application of 82 Sr/82 Rb generator in neurooncology.

INTRODUCTION: The applicability of "Rubidium Chloride, 82 Rb from Generator" radiopharmaceutical for brain tumors (BT) diagnostics is demonstrated on the basis of the application experience of the radiopharmaceutical in neurooncology. EXPERIMENTAL: A total of 21 patients with various brain tumors and nonneoplastic abnormal brain masses were investigated. RESULTS AND DISCUSSIONS: The results of the imaging and differential diagnostics of malignant and benign tumors, nonneoplastic abnormal brain masses and lesions revealed the prevalence of high uptake of the radiopharmaceutical in the malignant tumors in comparison with benign glioma and arteriovenous malformations in which 82 Rb-chloride accumulates in the vascular phase but does not linger further. The ultra-short half-life of radionuclide 82 Rb (76 s) along with a low absorbed radiation dose with 82 Rb-chloride by intravenous administration create a new possibility of successive use of two or more radiopharmaceuticals for the examination of the same patient. For instance, PET examination with 18 F-FDG, 11 C-methionine, 11 C-choline, or any other radiopharmaceutical can be carried out in just 7-15 min. after 82 Rb-chloride injection. CONCLUSION: Research demonstrated an effectiveness of 82 Rb-chloride application as a diagnostic agent in neurooncology. A method of dosing and administration of the generator-produced radiopharmaceutical has been worked out. It is possible to do up to 600 PET sessions using one Russian 82 Rb generator GR-01. The generator is proved to be reliable and easy to use. The interest in 82 Rb-chloride as a tumor-seeking radiopharmaceutical rose due to the active application of the modern devices PET/CT in the routine clinical practice.

DNA damage induced by Strontium-90 exposure at low concentrations in mesenchymal stromal cells: the functional consequences.

90Sr is one of the radionuclides released after nuclear accidents that can significantly impact human health in the long term. 90Sr accumulates mostly in the bones of exposed populations. Previous research has shown that exposure induces changes in bone physiology both in humans and in mice. We hypothesize that, due to its close location with bone marrow stromal cells (BMSCs), 90Sr could induce functional damage to stromal cells that may explain these biological effects due to chronic exposure to 90Sr. The aim of this work was to verify this hypothesis through the use of an in vitro model of MS5 stromal cell lines exposed to 1 and 10 kBq.mL-1 of 90Sr. Results indicated that a 30-minute exposure to 90Sr induced double strand breaks in DNA, followed by DNA repair, senescence and differentiation. After 7 days of exposure, MS5 cells showed a decreased ability to proliferate, changes in cytokine expression, and changes in their ability to support hematopoietic progenitor proliferation and differentiation. These results demonstrate that chronic exposure to a low concentration of 90Sr can induce functional changes in BMSCs that in turn may explain the health effects observed in following chronic 90Sr exposure.

ß-Radiation Stress Responses on Growth and Antioxidative Defense System in Plants: A Study with Strontium-90 in Lemna minor.

In the following study, dose dependent effects on growth and oxidative stress induced by ß-radiation were examined to gain better insights in the mode of action of ß-radiation induced stress in plant species. Radiostrontium (9°Sr) was used to test for ß-radiation induced responses in the freshwater macrophyte Lemna minor. The accumulation pattern of 90Sr was examined for L. minor root and fronds separately over a seven-day time period and was subsequently used in a dynamic dosimetric model to calculate ß-radiation dose rates. Exposing L. minor plants for seven days to a 9°Sr activity concentration of 25 up to 25,000 kBq·L⁻¹ resulted in a dose rate between 0.084 ± 0.004 and 97 ± 8 mGy·h⁻¹. After seven days of exposure, root fresh weight showed a dose dependent decrease starting from a dose rate of 9.4 ± 0.5 mGy·h⁻¹. Based on these data, an EDR10 value of 1.5 ± 0.4 mGy·h⁻¹ was estimated for root fresh weight and 52 ± 17 mGy·h⁻¹ for frond fresh weight. Different antioxidative enzymes and metabolites were further examined to analyze if ß-radiation induces oxidative stress in L. minor.

The osmotic resistance, and zeta potential responses of human erythrocytes to transmembrane modification of Ca2+ fluxes in the presence of the imposed low rate radiation field of 90Sr.

PURPOSE: To investigate the effects of the imposed low dose rate ionizing field on membrane stability of human erythrocytes under modulation of transmembrane exchange of Ca(2+). MATERIALS AND METHODS: Osmotic resistance of human erythrocytes was determined by a measure of haemoglobin released from erythrocytes when placed in a medium containing serial dilutions of Krebs isotonic buffer. The zeta potential as indicator of surface membrane potential was calculated from value of the cellular electrophoretic mobility. The irradiation of erythrocyte suspensions carried out by applying suitable aliquots of (90)Sr in incubation media. RESULTS: Irradiation of human erythrocytes by (90)Sr (1.5-15.0 µGy·h(-1)) induced a reversible increase of hyposmotic hemolysis and negative charge value on the outer membrane surface as well as changed responses these parameters to modification of Ca(2+) fluxes with calcimycin and nitrendipine. CONCLUSIONS: Findings indicate that the low dose rate radionuclides ((90)Sr) field modifies both Ca(2+)-mediated, and Ca(2+)-independent cellular signalling regulating mechanical stability of erythrocyte membrane. A direction of that modification presumably depends on the initial structure of membranes, and it is determined by the quality and quantitative parameters of changes in membrane structure caused by concrete operable factors.

[The non-hormonal treatment of metastatic prostate cancer]. / Le traitement non hormonal de la maladie métastatique du cancer de la prostate.

AIM: To describe drugs used in the non-hormonal treatment of metastatic prostate cancer. MATERIAL: Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned. RESULTS: The metabolic radiotherapy although under-used for this indication, kept a place at the beginning of the disease. Radium-223 chloride seems to have to occupy an important place in the coming years. The chemotherapy, the only recourse until very recently in the castration-resistant prostate cancer, must redefine its place partially. The denosumab provide an interesting alternative to bisphosphonates. CONCLUSION: The non-hormonal treatment of the metastatic disease of the prostate cancer is changing rapidly with the emergence of new molecules. Urologist must know perfectly these new drugs.

Preparation of Ca-alginate biopolymer beads and investigation of their decorporation characteristics for 85Sr, 238U and 234Th by in vitro experiments.

The aim of this work was to investigate whether Ca-alginate biopolymer beads (CaABBs) can be used to reduce the bioavailability of radionuclides in the gastrointestinal tract of humans. The uptake of strontium, uranium and thorium from a simulated gastrointestinal system was studied by in vitro techniques using CaABBs. This agent was prepared from Na-alginate through cross-linking with divalent calcium ions according to the egg-box model. The effects of process variables such as pH of the gastrointestinal juice, incubation time and solid-to-solution ratio for the removal of radionuclides from the gastrointestinal juice were investigated. The results suggest that CaABBs are a potent material for reducing the bioavailability of radionuclides with a high uptake efficiency in the gastrointestinal tract.

Radiation-induced impacts on the degradation of 2,4-D and the microbial population in soil microcosms.

In a soil microcosm experiment, the influence of low-level (137)Cs and (90)Sr contamination on the degradation of (14)C-ring-labeled 2,4-dichlorophenoxyacetic acid (2,4-D) was studied. Two differently treated soils (one native soil and one soil sterilized and reinoculated with a biotic soil aliquot) were artificially contaminated with various concentrations of (137)Cs and (90)Sr as nitrate salts. The cumulative doses increased up to 4 Gy for 30 days of incubation in soil microcosms. Changes in microbial community structure were observed with help of the denaturing gradient gel electrophoresis (DGGE). A radiation-induced impact appeared only in the microcosms treated with 30 times the maximum contamination appearing in the exclusion zone around reactor 4 in Chernobyl. In contrast to the less contaminated soils, the mineralization of 2,4-D was delayed for 4 days before it recovered. Slight shifts in the microbial communities could be traced to radiation effects. However, other parameters had a major impact on mineralization and community structure. Thus the sterilization and reinoculation and, of course, application of the 2,4-D were predominantly reflected in the (14)CO(2) emissions and the DGGE gel patterns.

[Compensatory adjustment of hemopoietic stem cell pool of CBA mice after acute intake of 90Sr].

It was investigated the functional status of stem cell pool (CFUs) of bone marrow, spleen and peripheral blood in mice (CBA) in early (1-30 days) and late (180-360 days) period after acute intake of 90Sr (29.6 kBq/g). Cumulative dose in red bone marrow due to incorporated 90Sr was 0.98-87.7 Gy. The kinetics, proliferative and differentiative potential of stem hemopoietic cells (CFUs) and productivity of hemopoietic tissues were significantly influenced by dose rate, absorbed dose and degree of suppresssion of bone marrow functions. The obtained results indicated that the sarcomogenous doses of 90Sr (29.6 kBq/g) resulted in realization of compensatory reactions in hemopoietic stem cell pool to support the life ability of irradiated animals: higher proliferative potential of CFUs and its repopulation, redistribution of cell subpopulations during differentiation and activation of spleens hemopoiesis.

Uptake of cesium-137 and strontium-90 from contaminated soil by three plant species; application to phytoremediation.

A field test was conducted to determine the ability of three plant species to extract 137Cs and 90Sr from contaminated soil. Redroot pigweed (Amaranthus retroflexus L.), Indian mustard [Brassica juncea (L.) Czern.], and tepary bean (Phaseolus acutifolius A. Gray) were planted in a series of spatially randomized cells in soil that was contaminated in the 1950s and 1960s. We examined the potential for phytoextraction of 90Sr and 137Cs by these three species. Concentration ratios (CR) for 137Cs for redroot pigweed, Indian mustard, and tepary bean were 2.58, 0.46, and 0.17, respectively. For 90Sr they were substantially higher: 6.5, 8.2, and 15.2, respectively. The greatest accumulation of both radionuclides was obtained with redroot pigweed, even though its CR for 90Sr was the lowest, because of its relatively large biomass. There was a linear relationship between the 137Cs concentration in plants and its concentration in soil only for redroot pigweed. Uptake of 90Sr exhibits no relationship to 90Sr concentrations in the soil. Estimates of time required for removal of 50% of the two contaminants, assuming two crops of redroot pigweed per year, are 7 yr for 90Sr and 18 yr for 137Cs.

Localization of megakaryocytes in normal mice and following administration of platelet antiserum, 5-fluorouracil, or radiostrontium: evidence for the site of platelet production.

The relative contributions of various organs to platelet production is controversial. In this study, serial histologic sections of bone marrow, spleen, liver, and lung from normal C57BL/6J mice and mice that had received three different agents which perturb normal murine thrombopoiesis (platelet antiserum, 5-fluorouracil, and radioactive strontium) were examined for the presence of megakaryocytes, utilizing morphologic and immunohistochemical techniques for their identification. In liver and lung tissue, megakaryocytes (including their naked nuclei or large cytoplasmic fragments) were rare in whole cross-sections (which included blood vessels) from normal and perturbed mice, even during periods of strong stimulation of thrombopoiesis. In contrast, megakaryocyte numbers were greatly increased in bone marrow and/or spleen tissue in these circumstances. We conclude that: 1) the bone marrow and spleen are the major thrombopoietic organs in the mouse, and 2) an insignificant fraction of thrombocytopoiesis occurs in the murine liver or lung, even during periods of greatly increased platelet production or following loss of the spleen and/or bone marrow.

Tratamiento del dolor por metástasis óseas en el cáncer de próstata y mama con Estroncio 89 / Pain treatment for bone metastase in prostate and breast cancer with Stronium 89

Se estudiaron los efectos de la inyección endovenosa del radioisótopo Estroncio 89, sobre la Escala de categoría numérica en reposo, Escala de categoría numérica en actividad (dinámico), Escala de Karnofsky, consumo de DAINES, opioides, y sobre sus efectos en los valores de PCA (Antígeno Prostático) Fosfatasa Alcalina, Fosfatemia, Calcemia, recuento de blancos, rojos y plaquetas y recuento de metástasis óseas, en 10 pacientes portadores de cáncer de próstata (8) y cáncer de mama (2). Se realizaron controles semanales de todos los parámetros durante 14 semanas, excepto el recuento de metástasis que se realizó en 2 oportunidades. En los resultados encontramos una disminución estadísticamente significativa en la Escala numérica en reposo, en la Escala numérica en actividad (Dinámico), y en la Escala de Karnofsky a partir de la 5ta. semana. El consumo de DAINES, mostró una tendencia descendente, siendo el consumo de opioides reducido a niveles significativos. Los glóbulos rojos, glóbulos blancos y plaquetas, descendieron luego de la 8va. semana, detectándose aumento del PCA (Antígeno Prostático) y la Fosfatasa Alcalina. Los números de metástasis no se modificaron. Se describen las características del fármaco, mecanismo de acción, dosificación, contraindicaciones y sus efectos adversos. Se discuten las distintas alternativas de tratamiento del dolor por metástasis óseas: hormonoterapia, cirugía, quimioterapia, radioterapia, farmacología. Se concluye que este procedimiento es una alternativa válida para disminuir consumo de analgésicos, aumentar la calidad de vida factible de realizar a pesar de haber sido irradiado el paciente, sin efectos secundarios, excepto por disminución de valores hemáticos no graves.

Tratamiento del dolor por metástasis óseas en el cáncer de próstata y mama con Estroncio 89 / Pain treatment for bone metastase in prostate and breast cancer with Stronium 89

Se estudiaron los efectos de la inyección endovenosa del radioisótopo Estroncio 89, sobre la Escala de categoría numérica en reposo, Escala de categoría numérica en actividad (dinámico), Escala de Karnofsky, consumo de DAINES, opioides, y sobre sus efectos en los valores de PCA (Antígeno Prostático) Fosfatasa Alcalina, Fosfatemia, Calcemia, recuento de blancos, rojos y plaquetas y recuento de metástasis óseas, en 10 pacientes portadores de cáncer de próstata (8) y cáncer de mama (2). Se realizaron controles semanales de todos los parámetros durante 14 semanas, excepto el recuento de metástasis que se realizó en 2 oportunidades. En los resultados encontramos una disminución estadísticamente significativa en la Escala numérica en reposo, en la Escala numérica en actividad (Dinámico), y en la Escala de Karnofsky a partir de la 5ta. semana. El consumo de DAINES, mostró una tendencia descendente, siendo el consumo de opioides reducido a niveles significativos. Los glóbulos rojos, glóbulos blancos y plaquetas, descendieron luego de la 8va. semana, detectándose aumento del PCA (Antígeno Prostático) y la Fosfatasa Alcalina. Los números de metástasis no se modificaron. Se describen las características del fármaco, mecanismo de acción, dosificación, contraindicaciones y sus efectos adversos. Se discuten las distintas alternativas de tratamiento del dolor por metástasis óseas: hormonoterapia, cirugía, quimioterapia, radioterapia, farmacología. Se concluye que este procedimiento es una alternativa válida para disminuir consumo de analgésicos, aumentar la calidad de vida factible de realizar a pesar de haber sido irradiado el paciente, sin efectos secundarios, excepto por disminución de valores hemáticos no graves. (AU)

The role of vitamin D in toxic metal absorption: a review.

Vitamin D increases intestinal calcium and phosphate absorption. Not so well known, however, is that vitamin D stimulates the co-absorption of other essential minerals like magnesium, iron, and zinc; toxic metals including lead, cadmium, aluminum, and cobalt; and radioactive isotopes such as strontium and cesium. Vitamin D may contribute to the pathologies induced by toxic metals by increasing their absorption and retention. Reciprocally, lead, cadmium, aluminum, and strontium interfere with normal vitamin D metabolism by blocking renal synthesis of 1,25-dihydroxyvitamin D. This is the first review of the role of the vitamin D endocrine system in metal toxicology.

Time and dose-related changes in the thickness of pig skin after irradiation with single doses of 90Sr/90Y beta-rays.

Time-related changes in pig skin thickness have been evaluated using a non-invasive ultrasound technique after exposure to a range of single doses of 90Sr/90Y beta-rays. The reduction in relative skin thickness developed in two distinct phases: the first was between 12 and 20 weeks postirradiation. No further changes were then seen until 52 weeks postirradiation when a second phase of skin thinning was observed. This was complete after 76 weeks and no further changes in relative skin thickness were seen in the maximum follow up period of 129 weeks. The timings of these phases of damage were independent of the radiation dose, however, the severity of both phases of radiation-induced skin thinning were dose related.

Strontium-89--precursor targeted therapy for pain relief of blastic metastatic disease.

Strontium-89 is a radioactive calcium analog that provides an energetic beta particle for radiation therapy of osteoblastic disease. Strontium-89 is used as palliative therapy with the primary goal being pain relief. More than 500 patients with painful blastic metastatic disease were treated at University of Kansas Medical Center since the initiation of the first clinical trial there 15 years ago. Most patients have had metastatic prostate cancer to bone or breast cancer, as these tumors are commonly associated with bone pain as their primary clinical management problem. Improvement (decrease in pain, increase in physical activity level) was noted in 80% of patients with prostate carcinoma and 81% of patients with metastatic breast cancer to bone. Marrow toxicity levels were acceptable. The therapy can be repeated at 3-month intervals. Strontium-89 is a safe and effective systemic therapy for painful blastic metastatic disease. There is no longer any reason why the vast majority of persons with painful blastic metastatic disease should continue to hurt.

Exudation of proliferative macrophages in local inflammation in the peritoneum.

Thioglycollate (TG)-elicited peritoneal macrophages (m phi s) were highly proliferative and formed m phi colonies in vitro in the presence of m phi colony-stimulating factor (M-CSF), while resident peritoneal m phi s did not. To determine whether such proliferative m phi s are immigrant or locally activated resident m phi s, mice depleted of bone marrow cells and circulating monocytes by bone-seeking radiostrontium (89Sr) were injected intraperitoneally with TG. For control (88Sr) and splenectomized (Spx) mice, more than 4 x 10(4) m phi colony-forming cells (M-CFCs) per mouse were recovered in the peritoneal lavage fluid 5 days after TG injection. 89Sr-treated mice, on the other hand, had only 20% of those in the control mice. Splenectomized and 89Sr-treated (Spx/89Sr) mice showed further depletion of bone marrow cells and monocytes and, as expected, total numbers of peritoneal M-CFCs were severely depressed to less than 1% of those in the control mice. The results suggest that levels of peritoneal M-CFCs are strongly dependent on the presence of radiosensitive bone marrow cells and circulating monocytes, and resident peritoneal m phi s activated locally by inflammatory stimuli do not form m phi colonies under the defined conditions.

The role of Kupffer cells in glucan-induced granuloma formation in the liver of mice depleted of blood monocytes by administration of strontium-89.

In order to elucidate the role of Kupffer cells in granuloma formation in the liver of mice under a condition of severe monocytopenia induced by administration of strontium-89, granulomas were produced by particulate glucan injection and examined histopathologically, immunohistochemically, by [3H]thymidine autoradiography, and in culture experiments. Hepatic granulomas were smaller, less numerous, and more irregularly shaped in the monocytopenic mice than in the control mice. The granulomas were composed of multinuclear giant cells, epithelioid cells, Kupffer cells, and T lymphocytes, but not monocytes or granulocytes. Kupffer cells were heavily labeled with [3H]thymidine in the monocytopenic mice, particularly just before the stage of granuloma formation, and then clustered in the liver sinusoids. At 8 days, they formed granulomas, transformed into epithelioid cells, and transformed further into multinuclear giant cells. Although the culture of liver cell suspensions prepared from the livers of monocytopenic mice sustained diffuse proliferation of macrophages on a monolayer of mouse stromal cell line (ST2), no monocyte/macrophage colonies were formed. From these results, it is reasonable to conclude that Kupffer cells alone are activated in a condition without a supply of monocytes from peripheral blood; proliferate and cluster in the hepatic sinusoids; transform into peroxidase-negative macrophages, epithelioid cells, and multinuclear giant cells; and participate in granuloma formation in loco together with T lymphocytes.

Provirus integration and myc amplification in 90Sr induced osteosarcomas of CF1 mice.

In mice, endogenous retroviruses are known to be activated during the course of radiation osteosarcomagenesis. Using the Southern blotting procedure, we have studied the presence of somatically acquired proviruses in genomic DNA isolated from seven primary 90Sr induced osteosarcomas and one osteosarcoma cell line, 0-127a1, of the CF1 mouse strain. Specific hybridization probes demonstrated the presence of newly integrated ecotropic proviruses in four primary tumors. Probably, clonally integrated proviruses were present at distinct locations in different subpopulations of tumor cells, reflecting tumor heterogeneity. Genomic DNA isolated from cultured osteosarcoma cells contained different additional MCF-related proviruses. No proviruses were found integrated in the vicinity of c-myc, but a large domain containing the complete c-myc gene was found amplified in one primary tumor (greater than 22 kbp) and in 0-127a1 cells (greater than 39 kbp). Our data suggest that activated retroviruses are not essential for the development of radiogenic osteosarcomas in CF1 mice, but they might be responsible for the deregulated expression of a growth promoting gene in some bone tumor cells.