Evaluation of Month-24 Efficacy and Safety of Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration: The MERLOT Randomized Clinical Trial.

Importance: Although anti-vascular endothelial growth factor (VEGF) treatment offers better outcomes than the natural history of neovascular age-related macular degeneration (ARMD), a less burdensome, less expensive, and more durable treatment is needed. Objective: To assess the efficacy and safety of epimacular brachytherapy (EMB) for chronic, active, neovascular ARMD. Design, Setting, and Participants: The Macular Epiretinal Brachytherapy vs Ranibizumab (Lucentis) Only Treatment (MERLOT) pivotal device trial was conducted at 24 National Health Service hospitals across the UK. Patients who had neovascular ARMD and received intravitreal ranibizumab were enrolled between November 10, 2009, and January 30, 2012. Eligible patients were randomized 2:1 and were stratified by lens status and angiographic lesion type to receive either EMB plus as-needed ranibizumab or as-needed ranibizumab monotherapy. Participants were followed up monthly for 24 months and then assessed at a final visit at month 36. Masking of participants and clinicians was not possible, but best-corrected visual acuity (BCVA) and imaging were analyzed by masked assessors. Analysis followed the intent-to-treat approach. Interventions: Pars plana vitrectomy with 24 Gy EMB plus as-needed ranibizumab vs as-needed ranibizumab monotherapy. Main Outcomes and Measures: Coprimary outcomes were the number of as-needed ranibizumab injections and the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA with a noninferiority margin of -5 ETDRS letters. Secondary outcomes were the percentage of participants losing fewer than 15 ETDRS letters and gaining 0 or more or 15 or more ETDRS letters and the mean change in angiographic total lesion size, choroidal neovascularization size, and foveal thickness on optical coherence tomography. Results: Of 363 participants, 329 (90.6%) completed 24 months of follow-up (222 participants in the EMB group and 107 in the ranibizumab group). The mean (SD) age of the combined groups was 76.5 (7.4) years. The mean (SD) number of ranibizumab injections was 9.3 (6.7) in the EMB group and 8.3 (4.5) in the ranibizumab group, with a difference of 1.0 injection (95% CI, -0.3 to 2.3; P = .13). The mean (SD) BCVA change was -11.2 (15.7) ETDRS letters in the EMB group and -1.4 (10.9) ETDRS letters in the ranibizumab group, with a difference of 9.8 ETDRS letters (95% CI, -6.7 to -12.9). In the EMB group, 65.6% of participants (160 of 244) lost fewer than 15 ETDRS letters vs 86.6% (103 of 119) in the ranibizumab group, with a difference of 21% (95% CI, 12.4%-29.5%; P < .001). Microvascular abnormalities occurred in 20 of 207 eyes (9.7%) in the EMB group and 1 of 97 eyes (1.0%) in the ranibizumab group. These abnormalities occurred outside the foveal center, and there were no unexpected safety concerns. Conclusions and Relevance: The MERLOT trial found that despite the acceptable safety of EMB, it did not reduce the number of ranibizumab injections and was associated with worse visual acuity than anti-VEGF treatment alone; these results do not support EMB use as an adjunct treatment for chronic, active neovascular ARMD. Trial Registration: ClinicalTrials.gov Identifier: NCT01006538.

Internal exposure rate conversion coefficients and absorbed fractions of mouse for 137Cs, 134Cs and 90Sr contamination in body.

The aim of this study was to determine parameters for estimating the internal exposure of all organs in mouse experiments from the radioactivity concentration in organs. The estimation of internal exposure rate conversion coefficients and absorbed fractions for 137Cs, 134Cs and 90Sr by the Particle and Heavy Ion Transport code System (PHITS) with a voxel-based mouse phantom is presented. The geometry of the voxel phantom is constructed from computer tomography images of a mouse 9 cm in length weighing 23.9 g. The voxel-based mouse phantom has the following organs: brain, skull, heart, lungs, liver, stomach, spleen, kidneys, bladder, testis and tissue (tissue and other organs). Gamma- and beta-rays from 137Cs, 134Cs and 90Sr sources in each source organ are generated and scored for every target organ. The internal exposure rate conversion coefficients and absorbed fractions are calculated from deposition energies in each target organ from each source organ and are used to generate an internal exposure rate conversion coefficient matrix and an absorbed fraction matrix. The absorbed fractions of beta-rays in the source organs are roughly 0.5-0.8 for 137Cs and 134Cs, and the absorbed fractions of gamma-rays are <0.04 for 137Cs and <0.03 for 134Cs. The internal exposure rate conversion coefficient matrix is defined using the absorbed fractions. The calculated internal exposure rate coefficient matrix is tested under a uniform radioactivity concentration of 1 Bq/kg for 137Cs, 134Cs and 90Sr. The estimated internal exposure rates in the mouse whole body for 137Cs, 134Cs and 90Sr are 3.28 × 10-3, 2.55 × 10-3 and 1.20 × 10-2 µGy/d, respectively. These values are very similar to those for an ellipsoid frog (31.4 g) and an ellipsoid crab egg mass (12.6 g) reported in ICRP Publication 108.

Effects of 90Sr on Tree Swallow Nestlings Near Groundwater Contaminant Plumes.

Discharge of groundwater contaminant plumes has created elevated concentrations of Sr in some aquatic sediments at Chalk River Laboratories. Tree swallows (Tachycenita bicolor) feed and supply their nestlings almost exclusively with airborne insects that developed as larvae in aquatic sediments. To monitor the uptake and test for potential detriment due to Sr in a terrestrial animal, we measured the gross beta concentrations in the bone of 12-d-old tree swallow nestlings in areas having sediments with elevated levels of gross beta (Sr and Y) and in several control areas where sediment gross beta was primarily due to naturally occurring K. Nesting behavior and reproductive success of the tree swallows were similar regardless of the gross beta concentrations in sediments near their nest boxes. Radiation can damage DNA and cause micronuclei to form in cells, so we examined the frequency of micronuclei in erythrocytes of nestlings. The formation of micronuclei in the erythrocytes of the nestlings was also similar wherever nestlings were analyzed. The results revealed no significant increases even near sediments with the highest gross beta levels. At Perch Lake, where Chalk River Laboratories has a large area of Sr-contaminated sediments, the bones of 12-d-old nestlings contained gross beta concentrations as high as 29 Bq g. This would produce a skeletal dose rate of 9 µGy h, which is one-fourth of the threshold dose rate of 40 µGy h, above which detriment could occur. Failing to find any indication of detriment in the field study, we irradiated wild eggs in the lab and returned them to their nest for natural incubation, hatching, and feeding by the parents. There was an increase in formation of micronuclei following a dose of 3.2 Gy, and the other results were consistent with existing literature.

The potential for disease initiation by inhaled beta-emitting nuclear particles.

There were many anecdotal reports of injuries to humans, animals and plants following the Three Mile Island, Chernobyl and Fukushima accidents that were indicative of radiation exposures that delivered a dose of at least 0.5 Sieverts, but studies that attempted to relate observed increases of cancer rates and other injuries with exposure to the radioactive releases from these accidents have failed to find an association. To resolve this dissonance, it was assumed that an analysis of knowledge about accident releases and health effects gathered from one of these accidents could lead to the identification of an unrecognized exposure that could be inferred to have caused a specific observed injury that required a dose of at least 0.5 Sieverts. Because there is considerably more useful knowledge of reactor releases of radionuclides and observed health effects related to the Three Mile Island accident, that knowledge is analyzed. A relationship is inferred to exist between exposure to particulates in plumes released from the station vent stack and severe prolonged immunosuppression, a known effect of an exposure that delivers a dose of at least 0.5 Sieverts. More than ninety percent of the particulates were comprised of Strontium 89 nuclides, essentially pure beta emitters. Because Strontium is a metal, the nuclides in the particulates were configured as stable crystals which, when coming to rest in body tissue, functioned as intense point sources of chronic beta irradiation. The inference led to the hypothesis "particulates comprised of Strontium 89 nuclides provided the exposure that caused the health effects that were observed following the Three Mile Island accident". The hypothesis was tested for validity against two requirements; that only the humans beneath the plumes, who would have inhaled the particulates, expressed the abrupt and persistent rise in the health parameter Deaths from all Causes that would result from the severe prolonged immunosuppression that follows a 0.5 Sievert dose, and that they expressed the excess cancers that would be expected following organ doses of 0.5 or more Sieverts. These effects were found. The Hypothesis is therefore valid and leads to knowledge of the heretofore unknown mechanisms and effects of low LET beta irradiation by a particulate.

Screening Internal Contamination of Inhaled and Ingested Radionuclides with Hand-held Survey Meters.

During the aftermath of a radiological accident or attack, the rapid identification of individuals who have internalized medically significant amounts of material is paramount to guide medical and public health decisions. This paper explores the utility of hand-held, pancake GM detectors to determine if an individual has inhaled Sr, Cs, Pu, Pu, or Am in quantities requiring treatment. Additionally, ingestion of Sr or Cs was considered. Both Sr and Cs were modeled in equilibrium with their progeny, but the progeny of Pu, Pu, and Am were excluded. Treatment thresholds are defined using the National Council on Radiation Protection & Measurements' (NCRP) clinical decision guides (CDGs). Using Monte Carlo N-Particle (MCNP) modeling software, a human phantom and detector were modeled to determine the activity required to achieve a detector reading of twice background 1, 7, or 30 d post-ingestion or post-inhalation. Modeling found that inhaled Pu, Pu, and Am are detectable only if the contaminated individual inhaled thousands-fold more material than the CDG. This lack of detectability means that hand-held GM detectors are inappropriate for initial screening for americium or plutonium and that more intensive screening is necessary to confirm suspected contamination. Cesium-137, by contrast, could be detected at levels 10- to 100-fold lower than the amount requiring treatment, allowing quick differentiation between contaminated and uncontaminated individuals. Surprisingly, Sr was detectable within a factor of 2 of the amount requiring treatment. Detection of Sr was due primarily to bremsstrahlung radiation from beta interactions with calcium in bone. While rapid screening could identify individuals contaminated by Cs and possibly with Sr, further screening of identified individuals is necessary to establish medical need. However, these contaminated individuals could still be prioritized for further testing and possible presumptive treatment. Based on the findings of this study, concepts of operation for the use of hand-held survey meters should be developed for the screening of individuals potentially internally contaminated with Cs and Sr.

Comparison of Homogeneous and Particulate Lung Dose Rates For Small Mammals.

Small, highly radioactive fragments of material incorporated into metallic matrices are commonly found at nuclear weapons test and accident sites and can be inhaled by wildlife. Inhaled particles often partition heterogeneously in the lungs, with aggregation occurring in the periphery of the lung, and are tenaciously retained. However, dose rates are typically calculated as if the material were homogeneously distributed throughout the entire organ. Here the authors quantify the variation in dose rates for alpha-, beta-, and gamma-emitting radionuclides with particle sizes from 0.01-150 µm (alpha) and 1-150 µm (beta, gamma) and considering three averaging volumes-the entire lung (64 cm), a 10-cm volume of tissue, and a 1-cm volume of tissue. Dose rates from beta-emitting particles (e.g., Sr) were approximately one order of magnitude higher than those from gamma-emitting radionuclides (e.g., Cs). Self-shielding within the particle, which reduces the dose rate to the surrounding tissue, was negligible for gammas and minor for betas. For alpha-emitting particles (e.g., Pu), self-shielding in larger particles is substantial, with >90% of emissions captured within particles of +20 µm diameter; but for smaller sizes of the respirable range of 0.01 to 5 µm, an average of 85% of the energy escapes the particle and is deposited in the surrounding tissues. These data provide more detail on respirable particles, which may remain lodged deep in the lung where they represent a considerable contribution to long-term lung dose rates. For practical dose rate calculation purposes, a graph of particle size vs. dose rates for plutonium-containing hot particles is provided. This study demonstrates one possible approach to dose assessments for biota in environments contaminated by radioactive particles, which may prove useful for those engaged in environmental radioprotection.

[Application of the EPR and FISH Methods to Dose Reconstruction for People Exposed in the Techa River Area].

Release of liquid radioactive waste into the Techa River from the Mayak Production Association during 1949-1956 resulted in a significant exposure of about 30000 people who lived in downstream settlements. The residents were exposed to internal and external radiation. The article discusses the capability of two methods that were used 50 years after the termination of radioactive discharges for the dose reconstruction, namely EPR measurements of tooth enamel, and FISH measurements of stable chromosome aberrations in circulating lymphocytes. The Main issue in the application of these methods for the dose reconstruction was local irradiation from strontium radioisotopes incorporated in teeth and bones. The EPR and FISH assays were supported by measurements of the 90Sr content in the skeleton and teeth in order to estimate and subtract internal doses from incorporated 89, 90Sr. The resulting dose estimates obtained from EPR and FISH mea- surements were found to be consistent The settlement-averaged values in the upper-Techa Region varied from 550-570 mGy to 130-160 mGy and showed a reduction with the distance from the release site. The EPR- and FISH-based dose estimates were in agreement with the doses calculated with the dosimetry system TRDS that uses data on radionuclide contamination of the Techa River floodplain and individual residential histories.

[Assessment of the Status of Effector and Regulatory Components of Immune System in Chelyabinsk Region Residents Exposed to Radiation Due to Residence in the Area Contaminated as a Result of the Radiation Accident at Mayak PA and in Their Offspring].

Immune status was studied in the framework of the current work and the results of the analysis of concentration of 26 characteristic parameters of innate and acquired immunity in 140 individuals from 56 trios (fathers, mothers and their Ist generation offspring that were included in 2 groups) are presented. Fathers and mothers of the children under study in the main groip Were exposed due to a long-term residence (from childhood to maturity) in the areas of Chelyabinsk region contaminated as a result of the-accident at Mayak PA (contamination included long-lived isotopes - 9°Sr and, to a smaller extent, ¹³7Cs and ²³9Pu) and then migrated into Ozyorsk prior to the conception of their children (75 individuals, 33 family trios). Comparison group (control) included parents and their offspring who are Ozyorsk residents never residing in the areas contaminated by radionuclides (65 individuals, 23 family trios). All the investigated individuals from the compared groups were of the corresponding age and gender and had never worked at nuclear facilities. Blood samples were obtained in the periods that excluded oncological, acute infectious and inflammatory diseases of any acute stages of chronic processes. Concentration of immune cells was measured by flow cytometer (Beckman Coulter, USA) using special monoclonal antibodies of the same manufacturer in a licensed medical center "Familia" (Chelyabinsk). The objective of the work is to assess the immune status in parents who migrated from contaminated areas prior to the conception of children and in their 1st generation offspring not exposed to radiation. Alterations of the immune status in the form of increase or, to a smaller extent, decrease of concentration of lymphocytes with effector and/or regulatory functions (B-1, T-helpers, NK, T-NK, late precursors of T-1 and T-1 of late activation) in blood of exposed parents and their offspring were detected in comparison with the results in the control group; that could possibly be related to the stimulation effect of low doses that support activation, proliferation and development of compensatory imbalance in the immune system and immunodeficiency in parents of the main group and in their offspring. In order to reveal the mechanisms of the detected alterations the interrelation between immune damage and incidence, of diseases among the cohorts involved in the current work will be studied further.

[Apoptosis of Peripheral Blood Lymphocytes in the Members of the Techa River Cohort Chronically Exposed to Radiation].

The purpose of the present research was to estimate the intensity of the apoptotic death of lymphocytes during the period of carcinogenic effect realization in the residents of the Techa riverside villages. The investigation included analyses of the frequency of lymphocytes at the early and late stages of apoptosis and necrosis of peripheral blood lymphocytes using the method of FITC Annexin V, lymphocyte counts at the stage of DNA fragmentation using the TUNEL method, and the number of CD95(+)-lymphocytes. In the capacity of additional tests, loading tests involving in vitro irradiation at the dose of 1 Gy of a suspension of lymphocytes and incubations for 5 and 24 hours were used. Activation of the initial apoptotic and necrotic death of peripheral blood lymphocytes was revealed in the persons chronically exposed to low-intensity radiation within the range from 0.01 to 4.23 Gy. Exposed patients demonstrated a decrease in the number of CD95(+)-cells as compared to unexposed patients. The results of the cell death studies in the persons residing in the Techa riverside villages testify indirectly to the genomic instability of the peripheral blood lymphocytes.

Method for rapid screening analysis of Sr-90 in edible plant samples collected near Fukushima, Japan.

A screening method for measuring (90)Sr in edible plant samples by focusing on (90)Y in equilibrium with (90)Sr is reported. (90)Y was extracted from samples with acid, co-precipitated with iron hydroxide, and precipitated with oxalic acid. The dissolved oxalate precipitate was loaded on an extraction chromatography resin, and the (90)Y-enriched eluate was analyzed by Cherenkov counting with a TDCR liquid scintillation counter. (90)Sr ((90)Y) concentration was determined in plant samples collected near the damaged Fukushima Daiichi Nuclear Power Plants with this method.

Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration (MERLOT): A Phase 3 Randomized Controlled Trial.

PURPOSE: To assess the safety and efficacy of epimacular brachytherapy (EMB) for patients with chronic, active, neovascular age-related macular degeneration (AMD). DESIGN: Phase 3 randomized controlled trial. PARTICIPANTS: Patients (n = 363) with neovascular AMD already receiving intravitreal ranibizumab injections. INTERVENTION: Either pars plana vitrectomy with 24-gray EMB and ongoing pro re nata (PRN) ranibizumab (n = 224) or ongoing PRN ranibizumab monotherapy (n = 119). MAIN OUTCOME MEASURES: The coprimary outcomes, at 12 months, were the number of PRN ranibizumab injections and Early Treatment of Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (VA). Secondary outcomes included the proportion of participants losing fewer than 15 ETDRS letters, angiographic total lesion size, choroidal neovascularization (CNV) size, and optical coherence tomography (OCT) foveal thickness. A predefined subgroup analysis tested the influence of baseline ocular characteristics on the response to EMB. RESULTS: The mean number of PRN ranibizumab injections was 4.8 in the EMB arm and 4.1 in the ranibizumab monotherapy arm (P = 0.068). The mean VA change was -4.8 letters in the EMB arm and -0.9 letters in the ranibizumab arm (95% confidence interval of difference between groups, -6.6 to -1.8 letters). The proportion of participants losing fewer than 15 letters was 84% in the EMB arm and 92% in the ranibizumab arm (P = 0.007). In the EMB arm, the mean total lesion size increased by 1.2 mm(2) versus 0.4 mm(2) in the ranibizumab arm (P = 0.27). The CNV size decreased by 0.5 mm(2) in the EMB arm and by 1.3 mm(2) in the ranibizumab arm (P = 0.27). The OCT foveal thickness decreased by 1.0 µm in the EMB arm and by 15.7 µm in the ranibizumab arm (P = 0.43). Most subgroups favored ranibizumab monotherapy, some significantly so. One participant showed retinal vascular abnormality attributed to radiation, but otherwise safety was acceptable. CONCLUSIONS: These results do not support the use of EMB for chronic, active, neovascular AMD. Safety is acceptable out to 12 months, but radiation retinopathy can occur later, so further follow-up is planned.

Immune System Modifications Induced in a Mouse Model of Chronic Exposure to (90)Sr.

Strontium 90 ((90)Sr) remains in the environment long after a major nuclear disaster occurs. As a result, populations living on contaminated land are potentially exposed to daily ingesting of low quantities of (90)Sr. The potential long-term health effects of such chronic contamination are unknown. In this study, we used a mouse model to evaluate the effects of (90)Sr ingestion on the immune system, the animals were chronically exposed to (90)Sr in drinking water at a concentration of 20 kBq/l, for a daily ingestion of 80-100 Bq/day. This resulted in a reduced number of CD19(+) B lymphocytes in the bone marrow and spleen in steady-state conditions. In contrast, the results from a vaccine experiment performed as a functional test of the immune system showed that in response to T-dependent antigens, there was a reduction in IgG specific to tetanus toxin (TT), a balanced Th1/Th2 response inducer antigen, but not to keyhole limpet hemocyanin (KLH), a strong Th2 response inducer antigen. This was accompanied by a reduction in Th1 cells in the spleen, consistent with the observed reduction in specific IgG concentration. The precise mechanisms by which (90)Sr acts on the immune system remain to be elucidated. However, our results suggest that (90)Sr ingestion may be responsible for some of the reported effects of internal contamination on the immune system in civilian populations exposed to the Chernobyl fallout.

Concurrent use of strontium-89 with external beam radiotherapy for multiple bone metastases: early experience.

OBJECTIVE: The aim of the present study was to consider the safety and efficacy of concurrent use of strontium-89 (Sr-89) with external beam radiotherapy (EBRT) for multiple bone metastases, including lesions that require urgent therapy. METHODS: A retrospective review was performed of a consecutive series of patients who received Sr-89 for multiple bone metastases. Forty-five patients with multiple bone metastases received Sr-89 injection. Since 17 of the 45 patients had osteolytic bone lesions requiring emergent EBRT, they underwent concurrent use of Sr-89 with EBRT (concurrent group). The remaining 28 patients, none of whom had osteolytic lesions requiring urgent EBRT, were given Sr-89 injection only (singularity group). The injection of Sr-89 was to be given during EBRT, or on the day before the first day of EBRT. The dose of EBRT was 30 Gy in 10 fractions or 40 Gy in 20 fractions. Adverse events were evaluated according to hematological toxicity as measured by the Common Terminology Criteria for Adverse Events (V4.0). To assess efficacy, we checked changes in the pain scale and analgesic drug dosages, and the presence or absence of serious complications from bone metastases. RESULTS: Fifteen of 17 patients (88.2%) in the concurrent group and 17 of 28 patients (60.7%) in the singularity group reported bone pain relief. A statistically significant difference was found between the two groups, and severe complications (spinal cord compression and pathological fracture) from bone metastases could be prevented in all patients in the concurrent group. Severe hematological toxicity (grade 3 or higher) was not observed in the two groups. There was no statistical difference between the two groups. No one required additional intervention. The adverse events were tolerable. CONCLUSIONS: The results of our study suggest that concurrent use of Sr-89 with EBRT for multiple bone metastases can be performed safely if it is carried out with care, and that it may be an effective therapy in cases requiring emergency treatment.

A Comprehensive Metabolomic Investigation in Urine of Mice Exposed to Strontium-90.

Internal emitters such as Strontium-90 ((90)Sr) pose a substantial health risk during and immediately after a nuclear disaster or detonation of an improvised device. The environmental persistency and potency of (90)Sr calls for urgent development of high-throughput tests to establish levels of exposure and to help triage potentially exposed individuals who were in the immediate area of the disaster. In response to these concerns, our team focused on developing a robust metabolomic profile for (90)Sr exposure in urine using a mouse model. The sensitivity of modern time-of-flight mass spectrometry (TOFMS) combined with the separation power of ultra performance liquid chromatography (UPLC) was used to determine perturbations in the urinary metabolome of mice exposed to (90)Sr. The recently developed statistical suite, MetaboLyzer, was used to explore the mass spectrometry data. The results indicated a significant change in the urinary abundances of metabolites pertaining to butanoate metabolism, vitamin B metabolism, glutamate and fatty acid oxidation. All of these pathways are either directly or indirectly connected to the central energy production pathway, the tricarboxylic acid (TCA) cycle. To our knowledge, this is the first in vivo metabolomics to evaluate the effects of exposure to (90)Sr using the easily accessible biofluid, urine.

[Chronic Radiation Syndrome Among the Population of the Techa River Basin].

Presented in the article is the analysis of the cases of the chronic radiation syndrome (CRS) diagnosed among members of the population exposed for multiple years to radiation due to radioactive contamination of the Techa River. The results of the more than 60-year period of observations have allowed us to assess not only the clinical manifestations of CRS during the period of its formation, but also the efficiency of the restoration processes going on in the human body after chronic radiation exposure, as well as its remote effects. The article discusses the problems of CRS diagnostics and especially its course in the cases of a combined (internal and external) radiation exposure when the red bone marrow becomes a critical organ. The analysis of CRS cases in dynamics for the exposed population characterized by a significant heterogeneity in terms of age, the initial health status and other factors modifying the person's radiosensitivity, allows us to regard the initial stage of CRS as a stereotypic dysregulating pathology.

Concurrent dendritic cell vaccine and strontium-89 radiation therapy in the management of multiple bone metastases.

BACKGROUND: In addition to its direct cytotoxic effects, radiation therapy renders tumor cells more susceptible to T cell-mediated cytotoxicity by modulating cell surface molecules involved in antigen presentation. The purpose of the present study was to determine the benefit of combined 89Sr radiation and dendritic cell (DC) vaccine therapy in bone metastasis patients. METHODS: Patients were treated with intravenous 89Sr at a dose of 40 µCi/kg of body weight on the first day after the peripheral blood mononuclear cell collection. Seven days later, patients received DCs once a week for 6 weeks. The first three vaccines were administered by intravenous infusion, and the last three vaccines were administered by 24-point intradermal injection. Clinical response was evaluated by the number of bone metastatic foci demonstrated on bone scintigraphy; cell-mediated cytotoxicity response was evaluated by delayed-type hypersensitivity (DTH) reaction. All treatment-related toxicities including vaccine-induced fever and 89Sr-associated hematological toxicity were carefully monitored. RESULTS: Twenty-six patients with histologically diagnosed with primary cancers and multiple bone metastases demonstrated on bone scintigraphy were studied. The overall survival rate was 58.3%. The total positive DTH rate was 50%. The efficiency rate for pain relief was 60% (6/10), for quantity of life was 80%, and for clinic responses was 90%. Out of 10 cases, the Grade 1 or 2 of hematological depression in 4, erythema in 1, and fever in 7 were observed. CONCLUSIONS: The study has important implications for that combined 89Sr radiation, and DC vaccine therapy can benefit cancer patients with bone metastasis.

Effects of ocular surface strontium-90 beta radiotherapy in dogs latently infected with canine herpesvirus-1.

Latent canine herpesvirus-1 (CHV-1) infections are common in domestic dogs, but stimuli causing viral reactivation and recrudescent disease are poorly understood. Immunosuppressive pharmaceuticals are currently the only experimentally established triggers for recurrent ocular CHV-1 infection in dogs; however, ocular CHV-1 shedding has been reported clinically following strontium-90 beta radiotherapy of the ocular surface and it has been speculated that radiotherapy can directly induce viral reactivation. Strontium-90 is used as a beta radiation source for the treatment of a variety of neoplastic and immune-mediated canine ocular surface diseases. In the present study, the effects of ocular surface strontium-90 beta radiotherapy in dogs latently infected with CHV-1 were evaluated. Ten mature dogs with experimentally induced latent CHV-1 infections were randomly divided into two groups: one group received a single fraction 50 Gy radiation dose in one application from a strontium-90 ophthalmic applicator and the second group received sham radiotherapy. Dogs were then monitored for 45 days for recurrent ocular CHV-1 infection using clinical and virological outcome measures. Clinical ophthalmic examinations, ocular sample CHV-1 PCR assays, and serum CHV-1 virus neutralizing antibody assays were performed at specified intervals. No abnormalities suggestive of recurrent CHV-1 ocular disease were observed on clinical examination in any dog during the study. Ocular viral shedding was not detected and CHV-1 virus neutralizing titers remained stable in all dogs. A single fraction 50 Gy radiation dose administered to the ocular surface by strontium-90 beta radiotherapy did not result in detectable recurrent ocular CHV-1 infection in mature dogs with experimentally induced latent infection.

FISH analysis of translocations induced by chronic exposure to Sr radioisotopes: second set of analysis of the Techa River Cohort.

Fluorescent in situ hybridisation analysis of stable translocations was performed for 26 residents living along the Techa River (Russia), who were predominantly (95%) exposed to ingested strontium radioisotopes ((89)Sr and (90)Sr) resulting in exposure of their red bone marrow (RBM). Analysis was conducted at the Urals Research Center for Radiation Medicine, Public Health England and Leiden University Medical Center. Each laboratory scored 1000 cells per donor, which resulted in ∼1000 genome equivalents (GE) per donor. The age-dependent spontaneous level of translocations for each donor was evaluated on the basis of data published by Sigurdson et al. (International study of factors affecting human chromosome. Mutat. Res. 2008;652: :112-121). Reconstruction of doses was performed with the 'Techa River Dosimetry System' developed in 2009. In the studied donors, the range of individual cumulated RBM dose was from 0.3 to 3.7 Gy. Analysis of the yield of stable translocations dependent on the individual RBM dose from (89,90)Sr showed a linear dose-response relationship of 0.007 ± 0.002 translocation/GE cell/Gy (R = 0.61, p = 0.001). This set of results was in a good agreement with the previous data reported for 18 donors by Vozilova et al. (Preliminary FISH-based assessment of external dose for residents exposed on the Techa River.

Fast determination of 9°Sr/9°Y activity in milk by Cherenkov counting.

Cherenkov counting of the 9°Sr/9°Y pure beta emitters is an attractive method for 9°Sr activity determination, but the color quenching effect may be significant, especially for strongly colored or semi-opaque media. A quench correction method based on the external source of some liquid scintillation systems (named ESAR - external source area ratio) was proposed and checked for aqueous solutions and was proved to be effective also for urine samples. In the present work, the application of the ESAR method for fast determination of 9°Sr/9°Y activity in milk samples is described.

[Atypical onset of therapy-related acute promyelocytic leukemia after combined modality therapy including (89)Sr for metastatic breast cancer].

A 51-year-old woman diagnosed as having left breast cancer with axillary lymph node and liver metastases seven years earlier was seen in our office because of severe pancytopenia. She had received chemotherapy including several cycles of doxorubicin plus cyclophosphamide and docetaxel followed by hormone therapy containing leuprorelin and tamoxifen over four years. For management of bone pain due to metastasis, she had also undergone stereotaxic radiation therapy of the neck one and a half years earlier and unsealed internal radiation therapy with (89)Sr injection five months prior to the current presentation, Subsequently, myelosuppression progressively worsened and she finally required a blood transfusion. Although bone marrow examination showed severe hypoplasia, but neither blastic nor dysplastic, a test for PML-RARA fluorescence in situ hybridization was positive. After administration of all-trans retinoic acid, hematogenesis improved within three weeks. Neither disseminated intravascular coagulation nor retinoic acid syndrome was observed during the course of her illness. This is the first report describing acute promyelocytic leukemia after administration of (89)Sr, to our knowledge, and with an atypical onset and progression. As the number of cancer survivors increases due to improvements in medical intervention, clinicians must take more notice of special characteristics of therapy-related leukemia modified by previous treatments.