Dose-Limiting Bone Marrow Toxicities After Peptide Receptor Radionuclide Therapy Are More Prevalent in Women Than in Men.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) can cause dose-limiting toxicities (DLTs) of the bone marrow, liver, and kidneys. It is yet unknown whether women and men are equally at risk of these DLTs. METHODS: Neuroendocrine tumor patients treated with 177Lu-DOTATATE between 2000 and 2015 in our phase II trial with available laboratory data were included. For all DLTs, the highest Common Terminology Criteria for Adverse Events (version 4.03) grades that occurred from the start of PRRT until 3 months after the last cycle were scored. RESULTS: At baseline, women (n = 439) had a significantly lower body mass index, Karnofsky Performance Score, hemoglobin level, and creatinine clearance and a significantly higher platelet level than men (n = 534). Both groups received a median activity of 29.6 GBq (800 mCi). After the start of PRRT, women more frequently developed grade ≥2 thrombocytopenia compared with men (25% vs 18%, P = 0.004) due to a significant increase in grade ≥3 thrombocytopenia (11% vs 6%, P = 0.008). Furthermore, the incidence of grade ≥3 anemia was higher in women (7% vs 3%, P = 0.002). In the multivariable regression model, female sex (odds ratio, 2.50; 95% confidence interval, 1.67-3.74) was confirmed to be an independent risk factor for grade ≥2 thrombocytopenia, among baseline platelet count, bone metastases, uptake on 111In-DTPA-octreotide scan, Karnofsky Performance Score, alkaline phosphatase, lymphocytes, albumin, and renal function. CONCLUSIONS: Female neuroendocrine tumor patients more often experienced PRRT-induced toxicities of platelets and hemoglobin than males, but this did not lead to a lower cumulative activity.

Quantitative encapsulation and retention of 227Th and decay daughters in core-shell lanthanum phosphate nanoparticles.

Targeted alpha therapy (TAT) offers great promise for treating recalcitrant tumors and micrometastatic cancers. One drawback of TAT is the potential damage to normal tissues and organs due to the relocation of decay daughters from the treatment site. The present study evaluates La(227Th)PO4 core (C) and core +2 shells (C2S) nanoparticles (NPs) as a delivery platform of 227Th to minimize systemic distribution of decay daughters, 223Ra and 211Pb. In vitro retention of decay daughters within La(227Th)PO4 C NPs was influenced by the concentration of reagents used during synthesis, in which the leakage of 223Ra was between 0.4 ± 0.2% and 20.3 ± 1.1% in deionized water. Deposition of two nonradioactive LaPO4 shells onto La(227Th)PO4 C NPs increased the retention of decay daughters to >99.75%. The toxicity of the nonradioactive LaPO4 C and C2S NP delivery platforms was examined in a mammalian breast cancer cell line, BT-474. No significant decrease in cell viability was observed for a monolayer of BT-474 cells for NP concentrations below 233.9 µg mL-1, however cell viability decreased below 60% when BT-474 spheroids were incubated with either LaPO4 C or C2S NPs at concentrations exceeding 29.2 µg mL-1. La(227Th)PO4 C2S NPs exhibit a high encapsulation and in vitro retention of radionuclides with limited contribution to cellular cytotoxicity for TAT applications.

EFFECT OF ADDITIONAL ACUTE IRRADIATION ON CYTOMORPHOLOGICAL ABNORMALITIES OF ERYTHROCYTES OF THE PRUSSIAN CARP (CARASSIUS GIBELIO BLOCH) FROM WATER BODY CONTAMINATED WITH RADIONUCLIDES. / VPLYV DODATKOVOGO GOSTROGO OPROMINENNIa NA TsYTOMORFOLOGIChNI PORUShENNIa ERYTROTsYTIV KARASIa SRIBLIaSTOGO (CARASSIUS GIBELIO BLOCH) IZ ZABRUDNENOÏ RADIONUKLIDAMY VODOY̆MY.

OBJECTIVE: Assessment of the effect of additional acute irradiation (AAI) in sub-lethal range on the peculiarities of formation of qualitative composition of red blood and adaptive possibilities of the hematopoietic system of fish in reservoirs within the Chernobyl Exclusion Zone (CEZ), contaminated with radionuclides. MATERIALS AND METHODS: We studied the Prussian carp Carassius gibelio Bloch (2-3 years old) from Vershyna Lake (impacted reservoir in the CEZ) and Dibrova Lake (reference reservoir), where the average absorbed dose rate (ADR) was, respectively, 110.80 and 0.07 µGy/h. The fish were exposed by a single X-ray dose at the unit RUM-17 (ADR - 0.89 Gy/min) at dose of 2.5, 5.0 and 10.0 Gy. Morphological and cytogenetic studies of red blood cells were per- formed dynamically for the 1st, 7th and 30th day after irradiation. The blood was taken from the tail vein and stained by Pappenheim's method. Cytomorphological abnormalities of erythrocytes were analyzed for 3000 cells (‰). RESULTS: In blood of fish from the impacted reservoir (Vershyna Lake) on the 1st day after AAI, the average number of all types of deformations of erythrocytes cells increased in 2.1 times, and in fish of the reference reservoir (Dibrova Lake) - in 5.2 times. General spectrum of erythrocyte disturbances in fish of Vershyna Lake has increased from 4 to 6 types (in 1.5 times), and Dibrova Lake - from 2 to 5 types (in 2.5 times). However, further observations of the dynamics of morphological disorders of fish's blood cells from Vershyna Lake on the 7th and the 30th day after AAI showed a significant increase in pathological processes in comparison with the reference reservoir, namely - an increase in the number of gross damage of DNA molecules - amitosis (on average in 14.8 times), erythrocytes with septum in the nucleus (in 1.9 times), as well as structural disorders in the cells - protuberances (in 10.5 times), cells with vacuolate cytoplasm (in 8.6 times). CONCLUSIONS: The red blood cells of the fish of the impacted reservoir show a greater vulnerability to AAI, which manifests itself in an increase in the number of erythrocytes with pathology of mitosis and may indicate a violation of the genetic structures of cells due to long-term radiation exposure.

Assessment of the effects of repeated doses of potassium iodide intake during pregnancy on male and female rat offspring using metabolomics and lipidomics.

Preparedness for nuclear accident responsiveness includes interventions to protect pregnancies against prolonged exposure to radioactive iodine. The aim of this study was to investigate a new design consisting of repeated administration of potassium iodide (KI, 1 mg/kg) for 8 days in late pregnancy gestational day 9-16 (GD9-GD16) in rats. The later-life effects of this early-life iodine thyroid blocking (ITB) strategy were assessed in offspring two months afterbirth. Functional behavioral tests including forced swimming test (FST) and rotarod test (RRT) in rats of both genders showed lower FST performance in KI-treated females and lower RRT performance in KI-treated male pups. This performance decline was associated with metabolic disruptions in cortex involving amino acid metabolism, tyrosine metabolism, as well as docosahexaenoic acid (DHA) lipids and signaling lipids in males and females. Beyond these behavior-associated metabolic changes, a portion of the captured metabolome (17-25%) and lipidome (3.7-7.35%) remained sensitive to in utero KI prophylactic treatment in both cortex and plasma of post-weaning rats, with some gender-related variance. Only part of these disruptions was attributed to lower levels of TSH and T4 (males only). The KI-induced metabolic shifts involved a broad spectrum of functions encompassing metabolic and cell homeostasis and cell signaling functions. Irrespective Regardless of gender and tissues, the predominant effects of KI affected neurotransmitters, amino acid metabolism, and omega-3 DHA metabolism. Taken together, data demonstrated that repeated daily KI administration at 1 mg/kg/day for 8 days during late pregnancy failed to protect the mother-fetus against nuclear accident radiation. Abbreviations: CV-ANOVA: Cross-validation analysis of variance; DHA: Docosahexaenoic acid; FST: Forced swimming test; FT3: plasma free triiodothyronine; FT4: plasma free thyroxine; GD: Gestational day; ITB: Iodine thyroid blocking; KI: potassium iodide; LC/MS: Liquid chromatography coupled with mass spectrometry; MTBE: Methyl tert-butyl ether; m/z: mass-to-charge ratio; PLS-DA: Partial least squares-discriminant analysis; PRIODAC: Repeated stable iodide prophylaxis in accidental radioactive releases; RRT: Rotarod test; TSH: Thyroid-stimulating hormone; VIP: Variable importance in projection.

Pharmacological treatment of inhalation injury after nuclear or radiological incidents: The Chinese and German approach.

Inhalation injury is often associated with burns and significantly increases morbidity and mortality. The main toxic components of fire smoke are carbon monoxide, hydrogen cyanide, and irritants. In the case of an incident at a nuclear power plant or recycling facility associated with fire, smoke may also contain radioactive material. Medical treatments may vary in different countries, and in this paper, we discuss the similarities and differences in the treatments between China and Germany. Carbon monoxide poisoning is treated by 100% oxygen administration and, if available, hyperbaric oxygenation in China as well as in Germany. In addition, antidotes binding the cyanide ions and relieving the respiratory chain are important. Methemoglobin-forming agents (e.g., nitrites, dimethylaminophenol) or hydroxocobalamin (Vitamin B12) are options. The metabolic elimination of cyanide may be enhanced by sodium thiosulfate. In China, sodium nitrite with sodium thiosulfate is the most common combination. The use of dimethylaminophenol instead of sodium nitrite is typical for Germany, and hydroxocobalamin is considered the antidote of choice if available in cases of cyanide intoxications by fire smoke inhalation as it does not further reduce oxygen transport capacity. Systematic prophylactic use of corticosteroids to prevent toxic pulmonary edema is not recommended in China or Germany. Stable iodine is indicated in the case of radioiodine exposure and must be administered within several hours to be effective. The decorporation of metal radionuclides is possible with Ca (DTPA) or Prussian blue that should be given as soon as possible. These medications are used in both countries, but it seems that Ca (DTPA) is administered at lower dosages in China. Although the details of the treatment of inhalation injury and radionuclide(s) decorporation may vary, the general therapeutic strategy is very similar in China and Germany.

Usefulness of continuous probability distributions of rates for modelling radionuclide biokinetics in humans and animals.

Modelling the biokinetics of radionuclide excretion or retention is important in nuclear medicine and following accidental/malicious radioactivity releases. Sums of discrete exponential decay rates are often used, but we hypothesized that continuous probability distributions (CPD) of decay rates can describe the data more parsimoniously and robustly. We tested this hypothesis on diverse human and animal data sets involving various radionuclides (including plutonium, strontium, caesium) measured in the laboratory and in regions contaminated by the Fukushima and Chernobyl nuclear accidents. We used four models on each data set: mono-exponential (ME) with one discrete decay rate, bi-exponential (BE) with two rates, gamma-exponential (GE) with a Gamma distribution of stretched-exponential rates, and power-decay (PD) with a Gamma distribution of power-decay rates. Information-theoretic model selection suggested that radionuclide biokinetics, e.g. for plutonium in humans, are often better described by CPD models like GE and PD, than by discrete rates (ME and BE). Extrapolation of models fitted to data at short times to longer times was frequently more robust for CPD formalisms. We suggest that using a set of several CPD and discrete-rate models, and comparing them by information-theoretic methods, is a promising strategy to enhance the analysis of radionuclide excretion and retention kinetics.

Evaluation of chromosomal aberrations induced by 188Re-dendrimer nanosystem on B16f1 melanoma cells.

PURPOSE: To study the rhenium-188 labeling of polyamidoamine (PAMAM) generation 4 (G4) dendrimer and its evaluation on biodistribution and chromosomal aberrations in melanoma cells induced by ionizing radiation as potential treatment agent. MATERIALS AND METHODS: Dendrimers were first conjugated with Suc-HYNIC (succinimidyl 6-hydrazinopyridine-3-carboxylic acid hydrochloride). Dendrimer-HYNIC was then incubated with 188ReO4-. Biodistribution was performed administrating 188Re-dendrimer to normal (NM) or melanoma-bearing mice (MBM). Chromosome aberration test was conducted in order to measure treatment capacity of 188Re-dendrimer in melanoma cells. RESULTS: Radiolabeling yield of dendrimer was approx. 70%. Biodistribution studies in NM showed blood clearance with hepatic and renal depuration. MBM showed a similar pattern of biodistribution with tumor uptake of 6% of injected dose. Aberrant metaphases quantified in control cells were 7%, increasing to 29.5% in cells treated with 15µCi (0.555 MBq) of 188Re-dendrimer for 24 h. CONCLUSIONS: 188Re-dendrimer can produce double-stranded breaks in DNA induced by ionizing radiation in melanoma cells in vitro.

Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats.

Manganese in its divalent state (Mn2+) has features that make it a unique tool for tracing neuronal pathways. It is taken up and transported by neurons in an activity-dependent manner and it can cross synapses. It also acts as a contrast agent for magnetic resonance imaging (MRI) enabling visualization of neuronal tracts. However, due to the limited sensitivity of MRI systems relatively high Mn2+ doses are required. This is undesirable, especially in long-term studies, because of the known toxicity of the metal. In order to overcome this limitation, we propose 52Mn as a positron emission tomography (PET) neuronal tract tracer. We used 52Mn for imaging dopaminergic pathways after a unilateral injection into the ventral tegmental area (VTA), as well as the striatonigral pathway after an injection into the dorsal striatum (STR) in rats. Furthermore, we tested potentially noxious effects of the radioactivity dose with a behavioral test and histological staining. 24 h after 52Mn administration, the neuronal tracts were clearly visible in PET images and statistical analysis confirmed the observed distribution of the tracer. We noticed a behavioral impairment in some animals treated with 170 kBq of 52Mn, most likely caused by dysfunction of dopaminergic cells. Moreover, there was a substantial DNA damage in the brain tissue after applying 150 kBq of the tracer. However, all those effects were completely eliminated by reducing the 52Mn dose to 20-30 kBq. Crucially, the reduced dose was still sufficient for PET imaging.

Mutagenic potential assessment associated with human exposure to natural radioactivity.

Lucrécia city, known to harbor a high cancer rate, is located in a semiarid region characterized by the presence of mineral reservoirs, facing a high exposure to metal and natural radioactivity. The present study aimed to assess the environmental scenario at a semiarid region located in Northeastern Brazil. Metal concentration, alpha and beta radiation, and cyanobacteria content in tap water along with indoor radon and gamma emitters (U, K and Th) concentrations were measured. In addition, mutagenic and nuclear instability effects were assessed using buccal micronucleus cytome assay. The study included five samplings corresponding to a period between 2007 and 2009. Drinking water from Lucrécia city presented levels of Mn, Ni and Cr along with cyanobacteria in concentrations one to four times higher than regulatory guidelines considered. Furthermore, high levels of all the tested radionuclides were found. A high percentage of the houses included in this study presented indoor radon concentrations over 100 Bq m-3. The mean annual effective dose from Lucrécia houses was six times higher than observed in a control region. The levels of exposure in most of the Lucrécia houses were classified as middle to high. A significant mutagenic effect, represented as an increase of micronuclei (MN) frequency and nuclear abnormalities as nuclear buds (NB), binucleated cells (BN), and pyknotic cells (PYC) were found. The results obtained highlight the role of high background radioactivity on the observed mutagenic effect and could help to explain the exacerbated cancer rate reported in this locality.

Análisis de la radiactividad en aguas del Balneario de San Nicolás (Almería) / Radioactivity analysis of San Nicolás Spa water

Se ha realizado el estudio radiológico del agua del manantial del Balneario de San Nicolás en la provincia de Almería. Este estudio ha consistido en la determinación cuantitativa de los radionucleidos naturales más importantes desde el punto de vista de la protección radiológica existentes en las aguas del balneario. La medida del contenido radiactivo de las aguas constituye un tema cuyo estudio resulta de gran interés. Las aguas con elementos radiactivos disueltos pueden producir, como consecuencia directa de su consumo, dosis de irradiación interna tanto por ingestión como por inhalación de estos elementos. Debido a esto es necesario, en algunos casos, proceder al análisis y posterior evaluación de la dosis asociada a este consumo (AU)

Radio activity analysis of San Nicolás Spa water was carried out by the CIEMAT Laboratory of Environmental Radioactivity. With this aim the most important natural radionuclides were determined in water from spring water. The measurement and knowledge of radioactivity level in water is an interesting and convenient topic. The consumption of water which has dissolved some radionuclides could lead to internal irradiation both by ingestion and by inhalation. Therefore it is necessary, in some cases, to determine the water radioactivity level in order to assess the dose (AU)

Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model.

Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy ß-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL.

Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer.

The standard treatment for ductal carcinoma in situ (DCIS) of the breast is surgical resection, followed by radiation. Here, we tested localized therapy of DCIS in mice using the immunoconjugate 225Ac linked-trastuzumab delivered through the intraductal (i.duc) route. Trastuzumab targets HER-2/neu, while the alpha-emitter 225Ac (half-life, 10 days) delivers highly cytotoxic, focused doses of radiation to tumors. Systemic 225Ac, however, elicits hematologic toxicity and at high doses free 213Bi, generated by its decay, causes renal toxicity. I.duc delivery of the radioimmunoconjugate could bypass its systemic toxicity. Bioluminescent imaging showed that the therapeutic efficacy of intraductal 225Ac-trastuzumab (10-40 nCi per mammary gland; 30-120 nCi per mouse) in a DCIS model of human SUM225 cancer cells in NSG mice was significantly higher (p<0.0003) than intravenous (120 nCi per mouse) administration, with no kidney toxicity or loss of body weight. Our findings suggest that i.duc radioimmunotherapy using 225Ac-trastuzumab deserves greater attention for future clinical development as a treatment modality for early breast cancer.

Multibiomarker toxicity characterization of uranium mine drainages to the fish Carassius auratus.

The release of acidic effluents, naturally enriched in metals and radionuclides, is the main legacy of uranium mines. Generally, metals dissolved by these acidic effluents can cause significant alterations in exposed organisms, with distinct toxicological outcomes. In this study, 72 individuals of the freshwater fish species Carassius auratus were exposed in situ for different periods (8, 16, 24, and 48 h) to water from a pond (treatment pond (TP)) with a chemically treated effluent and a reference pond (PRP), in the vicinity of the Cunha Baixa uranium mine (Portugal). Comparing the water of the two ponds, the PRP pond was characterized by higher pH and oxygen values and lower conductivity and hardness values. Regarding total metal concentrations, among others, magnesium (56,000 µg/L), sodium (17,400 µg/L), zinc (86 µg/L), manganese (6340 µg/L), and uranium (1380 µg/L) concentrations in the TP pond were above the values obtained for the PRP pond. The values of manganese and uranium exceeded the values of quality criteria established for surface waters for cyprinids and for irrigation purposes. After exposure to pond water, significant differences were recorded for several biomarkers: (i) between ponds for acetylcholinesterase (AChE) with higher activities for animals from the PRP and glutathione-S-transferase (GST) activities that were particularly enhanced in animals from the TP pond; (ii) between ponds and exposure periods for lactate dehydrogenase (LDH) activity, since organisms from PRP pond presented always higher values than those from the TP pond, and among these, organisms exposed for the longer period presented a further depression in LDH activity; and (iii) between exposure periods for erythrocyte micronucleus. GSTs and LDH were the most sensitive biomarkers within the timeframe of the in situ assay performed. Despite the alleged efficacy of the chemical treatment (evidenced by a significantly lower pH), some metals persisted in the treated effluent (TP pond), potentially contributing to the induction of oxidative stress or increased conjugation metabolic activity in fish.

[Simulation of Radionuclide Behaviour in Terrestrial Ecosystems in Studies of Ecological Consequences of Accident at Chernobyl NPP].

The article analyzes the results of using the imitation modeling method for the study, prediction and recon- struction processes of radionuclide. behaviour in terrestrial ecosystems after the Chernobyl accident. Also discussed are some additional issues associated with the application of this method and perspectives of radio- ecological modeling.

[Composition and Density of Soil Fauna in the Region with Enhanced Radioactivity Level (Komi Republic, Vodnyi)].

Studies on the influence of high levels of radiation on soil fauna were carried out in 2012 in the territory formed as a result of the activity of the enterprise for extraction and production of radium from reservoir water and waste of uranium ore from 1931 to 1956. At present the local radioactive pollution in this area is caused by the presence of heavy natural radionuclides 226Ra, 238U and products of their disintegration in soils. The oppression of soil invertebrate.fauna in pine forests and meadows with high levels of radionuclides and heavy metals is revealed. Also shown is the decrease in the number and density of different taxonomic groups of invertebrates, reduction of the diversity and spectrum of trophic groups and vital forms in the area with a high content of radionuclides in soil. Our results are in agreement with the results obtained by the similar studies showing negative influence of high-level ionizing radiation on soil fauna.

First retrieval of hourly atmospheric radionuclides just after the Fukushima accident by analyzing filter-tapes of operational air pollution monitoring stations.

No observed data have been found in the Fukushima Prefecture (FP) for the time-series of atmospheric radionuclides concentrations just after the Fukushima Daiichi Nuclear Power Plant (FD1NPP) accident. Accordingly, current estimates of internal radiation doses from inhalation, and atmospheric radionuclide concentrations by atmospheric transport models are highly uncertain. Here, we present a new method for retrieving the hourly atmospheric (137)Cs concentrations by measuring the radioactivity of suspended particulate matter (SPM) collected on filter tapes in SPM monitors which were operated even after the accident. This new dataset focused on the period of March 12-23, 2011 just after the accident, when massive radioactive materials were released from the FD1NPP to the atmosphere. Overall, 40 sites of the more than 400 sites in the air quality monitoring stations in eastern Japan were studied. For the first time, we show the spatio-temporal variation of atmospheric (137)Cs concentrations in the FP and the Tokyo Metropolitan Area (TMA) located more than 170 km southwest of the FD1NPP. The comprehensive dataset revealed how the polluted air masses were transported to the FP and TMA, and can be used to re-evaluate internal exposure, time-series radionuclides release rates, and atmospheric transport models.

[Radiation doses and allozyme variability in the population of the northern red-backed vole (Clethrionomys rutilus) from the east urals radioactive trace zone].

The paper estimates the external (due to radionuclides accumulated in the soil) and internal (due to incorporated radionuclides) exposure of rodents that live in the head of the East Urals Radioactive Trace (EURT). It is shown that in the last decades the dose rates were lower than the values that lead to doubling the number of mutations in the allozyme loci in mammals. The variability ofthe eight allozyme loci in populations of northern red-backed voles from the EURT zone and their neighboring plots, as well as the territories of the Urals and Trans-Urals with background levels of radioactive contamination, are analyzed. No differences in the pattern and frequency of allozymes that would distinguish the EURT samples from a number of other populations of the Urals, were found. In the control sample "Sysert", "unique" for the Ural populations of northern red-backed voles, alleles of the loci Got and Sod were marked, conspecific to a closely related species--the bank vole. This fact can be regarded as evidence of recent cross-species hybridization.