Real-world safety and effectiveness of radium-223 in patients with metastatic castration-resistant prostate cancer: Interim analyses of the prospective, observational RAPIT study.

Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride (223Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223Ra was prescribed as part of routine practice by investigators. Patients with prior 223Ra treatment were excluded. The primary objective was to assess 223Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223Ra injections and earlier 223Ra use had longer OS than those receiving fewer injections and later 223Ra use. 223Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases.

Safety and effectiveness of the radium-223-taxane treatment sequence in patients with metastatic castration-resistant prostate cancer in a global observational study (REASSURE).

BACKGROUND: Radium-223 and taxane chemotherapy each improve survival of patients with metastatic castration-resistant prostate cancer (mCRPC). Whether the radium-223-taxane sequence could extend survival without cumulative toxicity was explored. METHODS: The global, prospective, observational REASSURE study (NCT02141438) assessed real-world safety and effectiveness of radium-223 in patients with mCRPC. Using data from the prespecified second interim analysis (data cutoff, March 20, 2019), hematologic events and overall survival (OS) were evaluated in patients who were chemotherapy-naive at radium-223 initiation and subsequently received taxane chemotherapy starting ≤90 days ("immediate") or >90 days ("delayed") after the last radium-223 dose. RESULTS: Following radium-223 therapy, 182 patients received docetaxel (172 [95%]) and/or cabazitaxel (44 [24%]); 34 patients (19%) received both. Seventy-three patients (40%) received immediate chemotherapy and 109 patients (60%) received delayed chemotherapy. Median time from last radium-223 dose to first taxane cycle was 3.6 months (range, 0.3-28.4). Median duration of first taxane was 3.7 months (range, 0-22.0). Fourteen patients (10 in the immediate and four in the delayed subgroup) had grade 3/4 hematologic events during taxane chemotherapy, including neutropenia in two patients in the delayed subgroup and thrombocytopenia in one patient in each subgroup. Median OS was 24.3 months from radium-223 initiation and 11.8 months from start of taxane therapy. CONCLUSIONS: In real-world clinical practice settings, a heterogeneous population of patients who received sequential radium-223-taxane therapy had a low incidence of hematologic events, with a median survival of 1 year from taxane initiation. Thus, taxane chemotherapy is a feasible option for those who progress after radium-223. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02141438. PLAIN LANGUAGE SUMMARY: Radium-223 and chemotherapy are treatment options for metastatic prostate cancer, which increase survival but may affect production of blood cells as a side effect. We wanted to know what would happen if patients received chemotherapy after radium-223. Among the 182 men treated with radium-223 who went on to receive chemotherapy, only two men had severe side effects affecting white blood cell production (neutropenia) during chemotherapy. On average, the 182 men lived for 2 years after starting radium-223 and 1 year after starting chemotherapy. In conclusion, patients may benefit from chemotherapy after radium-223 treatment without increasing the risk of side effects.

Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials.

BACKGROUND: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases. METHODS: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory). RESULTS: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610-1.072), p = 0.1389; rPFS 0.956 (0.759-1.205), p = 0.7039; OS 0.889 (0.660-1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379-0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%. CONCLUSIONS: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014.

Alpha-Emitter Radium-223 Induces STING-Dependent Pyroptosis to Trigger Robust Antitumor Immunity.

Radium-223 (223 Ra) is the first-in-class alpha-emitter to mediate tumor eradication, which is commonly thought to kill tumor cells by directly cleaving double-strand DNA. However, the immunogenic characteristics and cell death modalities triggered by 223 Ra remain unclear. Here, it is reported that the 223 Ra irradiation induces the pro-inflammatory damage-associated molecular patterns including calreticulin, HMGB1, and HSP70, hallmarks of tumor immunogenicity. Moreover, therapeutic 223 Ra retards tumor progression by triggering pyroptosis, an immunogenic cell death. Mechanically, 223 Ra-induced DNA damage leads to the activation of stimulator of interferon genes (STING)-mediated DNA sensing pathway, which is critical for NLRP3 inflammasome-dependent pyroptosis and subsequent DCs maturation as well as T cell activation. These findings establish an essential role of STING in mediating alpha-emitter 223 Ra-induced antitumor immunity, which provides the basis for the development of novel cancer therapeutic strategies and combinatory therapy.

Tracing the Evolution of Prostate Brachytherapy in the 20th Century.

BACKGROUND: Prostate brachytherapy (BT) techniques have evolved over the past century. This paper aimed to preserve our collective memory of history and the early development of its technique. We searched articles in PubMed and Google Scholar using keywords referring to authors, dates, and BT technical details, including different radioactive sources and country-specific publications. We reviewed the work published by Holm and Aronowitz. The digital library Internet Archives was used to retrieve original journal articles, science newspaper printings, and government reports, which allowed us to situate the development of BT in its sociopolitical context in Europe and the USA. Our search was conducted in English, French, and German languages. SUMMARY: Early BT methods were developed by European physicians with early access to radium. Technical advancements were made by HH Young, who brought this practice to the USA, where Barringer pioneered the use of radon seeds and low-dose interstitial brachytherapy. While centralized radiotherapy centers, such as Memorial Hospital in New York, emerged for training and research, the high cost of radium and opposing interests made brachytherapy harder to implement in Germany. After World War II, the introduction of man-made radioisotopes allowed experiments with colloidal solutions and new seeds, including I-125. In the 1980s, transrectal ultrasound allowed for more accurate radioactive seed insertion and replaced the transrectal finger guidance.

The value of baseline 18F-sodium fluoride and 18F-choline PET activity for identifying responders to radium-223 treatment in castration-resistant prostate cancer bone metastases.

OBJECTIVES: To investigate whether baseline 18F-sodium fluoride (NaF) and 18F-choline PET activity is associated with metastatic castration-resistant prostate cancer (mCRPC) global and individual bone metastases' DWI MR imaging response to radium-223 treatment. METHODS: Thirty-six bone-only mCRPC patients were prospectively recruited from three centers. Whole-body (WB)-MRI with DWI and 18F-NaF and 18F-choline PET/CT were performed at therapy baseline and 8-week intervals. In each patient, bone disease median global (g)ADC change between baseline and follow-up was calculated. Additionally, up to five bone target lesions per patient were delineated and individual median ADC change recorded. An ADC increase > 30% defined response per-patient and per-lesion. For the same targets, baseline 18F-NaF and 18F-choline PET SUVmax were recorded. Mean SUVmax across patient targets was correlated with gADC change and lesion SUVmax with per-lesion ADC change. RESULTS: A total of 133 lesions in 36 patients (14 responders) were analyzed. 18F-NaF PET per-patient mean SUVmax was significantly higher in responders (median = 56.0 versus 38.7 in non-responders; p = 0.008), with positive correlation between SUVmax and gADC increase (rho = 0.42; p = 0.015). A 48.7 SUVmax threshold identified responders with 77% sensitivity and 75% specificity. Baseline 18F-NaF PET per-lesion SUVmax was higher in responding metastases (median = 51.6 versus 31.8 in non-responding metastases; p = 0.001), with positive correlation between baseline lesion SUVmax and ADC increase (rho = 0.39; p < 0.001). A 36.8 SUVmax threshold yielded 72% sensitivity and 63% specificity. No significant association was found between baseline 18F-choline PET SUVmax and ADC response on a per-patient (p = 0.164) or per-lesion basis (p = 0.921). CONCLUSION: 18F-NaF PET baseline SUVmax of target mCRPC bone disease showed significant association with response to radium-223 defined by ADC change. CLINICAL RELEVANCE STATEMENT: 18F-sodium fluoride PET/CT baseline maximum SUV of castration-resistant prostate cancer bone metastases could be used as a predictive biomarker for response to radium-223 therapy. KEY POINTS: • 18F-sodium fluoride PET baseline SUVmax of castration-resistant prostate cancer bone metastases showed significant association with response to radium-223. • Baseline 18F-sodium fluoride PET can improve patient selection for radium-223 therapy. • Change in whole-body DWI parameters can be used for response correlation with baseline 18F-sodium fluoride PET SUVmax in castration-resistant prostate cancer bone metastases.

Radiological Analyses of 226Ra and 238U in Surface Water and Sediments from the Jackpile Member of the Morrison Formation, Pueblo of Laguna, New Mexico.

Surface water and sediments from the Jackpile mine, St. Anthony mine, Rio Paguate, Rio Moquino, and Mesita Dam areas near Pueblo of Laguna, New Mexico, were analyzed for 226Ra and U using gamma (γ) spectroscopy and inductively coupled plasma mass spectroscopy, respectively. Activity ratios for 226Ra/238U for solid samples range from 0.34 ± 0.13 to 16 ± 2.9, which reflect uranium transport and accumulation (<1), relatively pristine material in secular equilibrium (1), and removal of uranium by weathering (>1). Concentrations ranging from 80 to 225 µg L-1 U were detected in unfiltered water samples near the Jackpile mine. Water samples upstream and downstream from the mine contained concentrations ranging from 12 to 15 µg L-1 U. Water samples collected from the North Pit standing pond in the Jackpile mine contained as much as 1560 pCi L-1 of 226Ra, and passing the water through a 0.2 µM filter did not substantially reduce the activity of 226Ra in the water. 234Th and 226Ra are in secular equilibrium in this water, while radon gas was lost from the water. The results of the current study provide insight into the distribution of U-series radionuclides in the Pueblo of Laguna area, including detection of high levels of radioactivity in water at some locations within the Jackpile mine.

Influence of rock type and geophysical properties on radon flux density.

The most significant source of human exposure to ionizing radiation is the radioactive gas radon (basically 222Rn) and its daughter decay products, creating more than half of the effective dose from all natural sources. Radon enters buildings mainly from dense rocks, which are below building foundations at depths of 1 m and more. In this paper long-term measurements of radon flux density are analyzed, with radon exhalation from the surface of the most common rocks-loams, sandy loams, clays, clay shales, several types of sandy-gravel-pebble deposits, clay and rocky limestone. The influence of geophysical properties of rocks on radon flux density due to exhalation from surfaces of those rocks was studied. Based on the results obtained, a method of local assessment of the hazard from radon and its progeny in buildings is proposed, which is based on the geophysical properties of rocks below the foundations of those buildings.

Targeted Radium Alpha Therapy in the Era of Nanomedicine: In Vivo Results.

Targeted alpha-particle therapy using radionuclides with alpha emission is a rapidly developing area in modern cancer treatment. To selectively deliver alpha-emitting isotopes to tumors, targeting vectors, including monoclonal antibodies, peptides, small molecule inhibitors, or other biomolecules, are attached to them, which ensures specific binding to tumor-related antigens and cell surface receptors. Although earlier studies have already demonstrated the anti-tumor potential of alpha-emitting radium (Ra) isotopes-Radium-223 and Radium-224 (223/224Ra)-in the treatment of skeletal metastases, their inability to complex with target-specific moieties hindered application beyond bone targeting. To exploit the therapeutic gains of Ra across a wider spectrum of cancers, nanoparticles have recently been embraced as carriers to ensure the linkage of 223/224Ra to target-affine vectors. Exemplified by prior findings, Ra was successfully bound to several nano/microparticles, including lanthanum phosphate, nanozeolites, barium sulfate, hydroxyapatite, calcium carbonate, gypsum, celestine, or liposomes. Despite the lengthened tumor retention and the related improvement in the radiotherapeutic effect of 223/224Ra coupled to nanoparticles, the in vivo assessment of the radiolabeled nanoprobes is a prerequisite prior to clinical usage. For this purpose, experimental xenotransplant models of different cancers provide a well-suited scenario. Herein, we summarize the latest achievements with 223/224Ra-doped nanoparticles and related advances in targeted alpha radiotherapy.

Radiological risk and impact on soil microbial diversity of radionuclides in agricultural topsoils downstream of a decommissioned hydrometallurgical uranium plant.

Containing only low levels of U-bearing minerals, U ores often have to undergo hydrometallurgical processing for the separation of other minerals. Hydrometallurgical operations, even after being shut down, could pose radiological risk to the ecosystem and human health due to the radionuclide contamination of surrounding environmental media. This study investigated the contamination of radionuclides in the agricultural topsoils downstream of a decommissioned hydrometallurgical U plant in southern China, and assessed the corresponding radiological risk and evaluated its impact on soil microbial communities. The values of geoaccumulation index and potential ecological risk index indicate that all soil samples were significantly contaminated with U and 226Ra, with their concentrations being 4.4-28.7 times and 4.4-114.8 times higher than the corresponding regional background values, respectively. The mean outdoor annual effective dose (OAED) in the sampling plot next to the drainage ditch downstream of the decommissioned plant was up to 3.9 and 8.2 times higher than the Chinese annual effective dose limit and global average, respectively, which is indicative of unacceptable radiological risk for the local farm workers. Soil microbial composition was obviously impacted by the soil physicochemical properties and radionuclides. Specifically, Cladophialophora, which belongs to the fungal genus, exhibited significantly positive correlations with the contents of total Cd, total U, organic U, residual U, and total K, while Methanosarcina, which belongs to the archaeal genus, exhibited significantly positive correlations with the contents of 226Ra and residual U. Soil pH and total N content were significantly correlated with the abundance of several bacterial genera and the dominant archaeal genus (i.e., Candidatus Nitrocosmicus). These findings demonstrate the existence of potentially significant radiological risk associated with the radionuclides released from historical hydrometallurgical processing of U ores to the surrounding environment, and the need for proper site management and remediation.

Assessment of radioactivity level and associated radiological hazard in fertilizer from Dhaka.

Miners, factory workers, traders, end-users, and foodstuff consumers all run the risk of encountering health hazards derived from the presence of elevated levels of radiation in fertilizers, as these groups often come into direct or indirect contact with fertilizers as well as raw materials throughout various linked processes such as mineral extractions, fertilizer production, agricultural practices. A total of 30 samples of various kinds of fertilizer produced in different factories in Dhaka megacity were analyzed to quantify the concentrations of primordial radionuclides using HPGe detector. Among the analyzed samples, average (range) concentration of 40K was found to be 9920 ± 1091 (8700 ± 957-11,500 ± 1265), 9100 ± 1001 (8600 ± 946-9600 ± 1056), 2565 ± 282 (2540 ± 279-2590 ± 285), and 3560 ± 392 (2620 ± 288-4500 ± 495) Bq/kg in the samples of Muriate of Potash Fertilizer, Sulphate of Potash Fertilizer, Humic Acid Fertilizer, and NPKS Fertilizer, respectively. Elevated concentration of 226Ra was found in Triple Super Phosphate Fertilizer with a mean (range) of 335 ± 37 (290 ± 32-380 ± 42) Bq/kg. The higher activity of 40K can be linked to the greater levels of elemental potassium in phosphate fertilizer. Elevated concentrations of radionuclides may also result from variations in chemical processes as well as the local geology of the mining areas where the raw materials were extracted for fertilizer production. Numerous fertilizer brands surpass prescribed limits for various hazardous parameters, presenting significant health risks to factory workers, farmers, and consumers of agricultural products. This study provides baseline information on the radioactivity of fertilizers, which could be used to develop mitigation methods, establish national fertilizer usage limits, justify regulatory frameworks, and raise public awareness of fertilizer overuse. The findings of the study could potentially help to explore the impact of fertilizer on the food chain.

Optimization of Radium-223 Treatment of Castration-resistant Prostate Cancer Based on the Burden of Skeletal Metastasis and Clinical Parameters.

BACKGROUND: Radium-223 dichloride (Ra-223) is now frequently used to treat prostate cancer that has metastasized to bone, although patient selection continues to be suboptimal for determining who will benefit most from this novel treatment modality. MATERIALS AND METHODS: Seventy-nine patients with metastatic castration-resistant prostate cancer (mCRPC) were treated with Ra-223 from 2012 to 2016. The burden of skeletal metastasis was determined for each using the Bone Scan Index (BSI) as a ratio of diseased to normal bone. Clinical, laboratory, and survival data were collected and examined for associations with BSI, and treatment tolerability was assessed. RESULTS: Chemotherapy-naïve patients were significantly more likely to complete the full course of treatment. Median follow-up was 31 months (range 0.7-38.8 months) and median overall survival was 15.4 months (range 9.5-20.6 months). Overall survival was significantly associated with findings on bone scans (P < .05). Patients with higher BSI tended toward poorer outcomes. Nearly half the patients with low baseline BSI survived 3 years or more following Ra-223 treatment. By contrast, only 20% of the patients with high baseline BSI lived for 1 year, and none lived for an additional 3. Baseline BSI was significantly associated with decreased hemoglobin, higher serum PSA and alkaline phosphatase levels, and treatment-associated reductions in platelet and absolute neutrophil counts. CONCLUSION: Our results suggest better outcomes to Ra-223 therapy for patients who are chemotherapy-naïve and who undergo treatment earlier in the course of their disease as reflected by low BSI and concordant laboratory parameters.

Novel nomogram developed for determining suitability of metastatic castration-resistant prostate cancer patients to receive maximum benefit from radium-223 dichloride treatment-Japanese Ra-223 Therapy in Prostate Cancer using Bone Scan Index (J-RAP-BSI) Trial.

PURPOSE: To develop a novel nomogram for determining radium-223 dichloride (Ra-223) treatment suitability for metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: This Japanese Ra-223 Therapy in Prostate Cancer using Bone Scan Index (J-RAP-BSI) Trial was a retrospective multicenter investigation enrolled 258 mCRPC patients in Japan with Ra-223 treatment between June 2016 and August 2020, with bone scintigraphy findings before treatment, clinical data, and survival outcome available. A nomogram was constructed using prognostic factors for overall survival (OS) based on a least absolute shrinkage and selection operator Cox regression model. A sub-analysis was also conducted for patients meeting European Medicines Agency (EMA) guidelines. RESULTS: Within a median of 17.4 months after initial Ra-223 treatment, 124 patients (48.1%) died from prostate cancer. Predictive factors included (1) sum of prior treatment history (score 0, never prior novel androgen receptor-targeted agents (ARTA) therapy, never prior taxane-based chemotherapy, and ever prior bisphosphonate/denosumab treatment), (2) Eastern Cooperative Oncology Group (ECOG) performance status, (3) prostate-specific antigen doubling time (PSADT), (4) hemoglobin, (5) lactate dehydrogenase (LDH), and (6) alkaline phosphatase (ALP) levels, and (7) automated bone scan index (aBSI) value based on bone scintigraphy. The nomogram using those factors showed good discrimination, with apparent and optimism-corrected Harrell's concordance index values of 0.748 and 0.734, respectively. Time-dependent area under the curve values at 1, 2, and 3 years were 0.771, 0.818, and 0.771, respectively. In 227 patients meeting EMA recommendation, the nomogram with seven factors showed good discrimination, with apparent and optimism-corrected Harrell's concordance index values of 0.722 and 0.704, respectively. Time-dependent area under the curve values at 1, 2, and 3 years were 0.747, 0.790, and 0.759, respectively. CONCLUSION: This novel nomogram including aBSI to select mCRPC patients to receive Ra-223 with significantly prolonged OS possibility was found suitable for assisting therapeutic decision-making, regardless of EMA recommendation.

Management of bone metastasis in prostate cancer.

Progression of bone metastases is the primary cause of death in prostate cancer, and skeletal-related events (SREs), including pathologic fractures, spinal cord compression, radiation, or surgery to bone can impair patients' quality of life. Over the past decade, the development of cytotoxic agents, androgen-receptor-axis-targeted therapies (ARATs), and radioligand therapies has prolonged overall survival of prostate cancer patients with bone metastases and reduced the risk of SREs. The use of bone-modifying agents has also contributed to the reduced risk of SREs. Initial use of a cytotoxic agent, docetaxel, or an ARAT agent with androgen deprivation therapy (ADT) is the current approach to metastatic castration-sensitive prostate cancer. However, there is no consensus on the optimal medication for upfront use in combination with ADT, or on specific patient selection. Recently, next-generation imaging modalities, such as whole-body magnetic resonance imaging and prostate-specific membrane antigen-positron emission tomography have been utilized to detect bone metastases at an early stage. In addition, metastasis-directed therapy, such as stereotactic body radiation therapy, has been attempted. In the future, patients with bone metastatic prostate cancer will be divided into subgroups and their treatment options will be tailored to their specific characteristics.

Submarine Groundwater Discharge Exceeds River Inputs as a Source of Nutrients to the Great Barrier Reef.

Rivers are often assumed to be the main source of nutrients triggering eutrophication in the Great Barrier Reef (GBR). However, existing nutrient budgets suggest a major missing source of nitrogen and phosphorus sustaining primary production. Here, we used radium isotopes to resolve submarine groundwater discharge (SGD)-derived, shelf-scale nutrient inputs to the GBR. The total SGD was ∼10-15 times greater than average river inputs, with nearshore groundwater discharge accounting for ∼30% of this. Total SGD accounted for >30% of all known dissolved inorganic N and >60% of inorganic P inputs and exceeded regional river inputs. However, SGD was only a small proportion of the nutrients necessary to sustain primary productivity, suggesting that internal recycling processes still dominate the nutrient budget. With millions of dollars spent managing surface water nutrient inputs to reef systems globally, we argue for a shift in the focus of management to safeguard reefs from the impacts of excess nutrients.

Age-Dating of Foliage and Soil Organic Matter: Aligning 228Th:228Ra and 7Be:210Pb Radionuclide Chronometers over Annual to Decadal Time Scales.

The 228Th:228Ra ratios of foliage and organic soil horizons evolve with time following a predictable radioactive decay law and thus provide a new chronometer for absolute age-dating of plant and soil organic matter. Preferential uptake of 228Th (t0.5 = 1.9 years) and 228Ra (t0.5 = 5.9 years) by canopy tree species, ferns, and mosses, drives disequilibrium in the 232Th-228Ra-228Th radioactive decay series within forest vegetation and organic soils. With examples from northeastern USA, we verify a new 228Th:228Ra age model by demonstrating its concordance with the fallout radionuclide chronometer 7Be:210Pb in the 0 to 5-year time frame [R2 = 0.87, RMSE = 0.5 years]. At our locality, canopy tree species assimilate 228Th with a typical initial ratio (228Th:228Ra)0 ∼ 0.3, but in several instances, both deciduous and coniferous tree species show a preference for Th over Ra with (228Th:228Ra)0 exceeding 5. While the 228Th:228Ra system is restricted to organic soil horizons, concordance of 228Th:228Ra with established 7Be:210Pb and 241Am bomb-pulse chronometers establishes a coherent age-dating system of soil organic matter based on three independent chronometers and five particle reactive metals, and spanning 0-200 years in time scale that encompasses both organic and mineral soils to depths of up to 30 cm. Concordance indicates that these metals all follow common processes of organometallic colloid formation and migration and, in conjunction with 14C, may open new opportunities to understand soil pedogenic processes that regulate the storage of carbon and atmospheric metals such as Pb and Hg.

Tissue-Specific Toxicokinetics of Aqueous Radium-226 in an Estuarine Mussel, Geukensia demissa.

Radiological contamination of coastal habitats poses potential risk for native fauna, but the bioavailability of aqueous radium (Ra) and other dissolved metals to marine bivalves remains unclear. This study was the first to examine the tissue-specific disposition of aqueous 226Ra in a coastal mussel, specifically the Atlantic ribbed mussel Geukensia demissa. Most organ groups reached steady-state concentrations within 7 days during experimental exposure, with an average uptake rate constant of 0.0013 mL g-1 d-1. When moved to Ra-free synthetic seawater, mussels rapidly eliminated aqueous 226Ra (average elimination rate constant 1.56 d-1). The biological half-life for aqueous 226Ra ranged from 8.9 h for the gills and labial palps to 15.4 h for the muscle. Although previous field studies have demonstrated notable 226Ra accumulation in the soft tissues of marine mussels and that, for freshwater mussels, tissue-incorporated 226Ra derives primarily from the aqueous phase, our tissue-specific bioconcentration factors (BCFs) were on the order of (8.3 ± 1.5) × 10-4 indicating low accumulation potential of aqueous 226Ra in estuarine mussels. This suggests marine and estuarine mussels obtain 226Ra from an alternate route, such as particulate-sorbed Ra ingested during filter-feeding or from a contaminated food source.

Integrating radium-223 therapy into the management of metastatic prostate cancer care: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Few life-prolonging treatment options are available for patients with metastatic castration-resistant prostate cancer (mCRPC). This article provides an overview of the current systemic treatments available for mCRPC and reviews studies that investigate the optimal timing for the use of radium-223. The aim is to illustrate possible systemic treatment sequences to maximize benefit from radium-223 therapy. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER & HOW IS IT TREATED?: Prostate cancer is called mCRPC when it spreads to organs outside of the prostate (such as the lymph nodes, bones, liver, or lungs) and no longer responds to hormonal therapy. There are several treatment options available for mCRPC, such as abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, olaparib, rucaparib, sipuleucel-T, and 177Lu-PSMA. It is important to understand the risks and benefits associated with each treatment and whether current use may have an impact on future treatment options, including eligibility in certain clinical trials. Maintaining bone health is also an important part of prostate cancer care. WHAT IS RADIUM-223?: Radium-223 is a radioactive molecule that releases strong radiation within a very small range around itself. It mainly travels to the bone where the prostate cancer has spread and kills the cancer cells in that area. Results from a clinical study named ALSYMPCA showed that men who received radium-223 lived longer in addition to having less bone pain. The most common side effects of radium-223 are nausea, vomiting, and diarrhea. Radium-223 minimally suppresses the bone marrow, which means that it slightly reduces the levels of red and white blood cells.

A phase II randomized trial of metastasis-directed therapy with alpha emitter radium-223 in men with oligometastatic castration-resistant prostate cancer (MEDAL).

BACKGROUND: The significance of metastasis-directed therapy for oligometastatic prostate cancer has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multidisciplinary treatment for castration-resistant prostate cancer (CRPC). When oligometastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases. The progression of oligometastatic CRPC after targeted therapy may be due in part to the presence of micrometastatic lesions that, though undetected on imaging, were present prior to targeted therapy. Thus the systemic treatment of micrometastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect. Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays. Therefore, for oligometastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases. METHODS: This phase II, randomized trial of Metastasis-Directed therapy with ALpha emitter radium-223 in men with oligometastatic CRPC (MEDAL) is designed to assess the utility of radium-223 in combination with metastasis-directed radiotherapy in patients with oligometastatic CRPC confined to bone. In this trial, patients with oligometastatic CRPC with three or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone. The prior use of androgen receptor axis-targeted therapy and prostate-specific antigen doubling time will be used as allocation factors. The primary endpoint will be radiological progression-free survival against progression of bone metastases on WB-DWI. DISCUSSION: This will be the first randomized trial to evaluate the effect of radium-223 in combination with targeted therapy in oligometastatic CRPC patients. The combination of targeted therapy for macroscopic metastases with radiopharmaceuticals targeting micrometastasis is expected to be a promising new therapeutic strategy for patients with oligometastatic CRPC confined to bone. Trial registration Japan Registry of Clinical Trials (jRCT) (jRCTs031200358); Registered on March 1, 2021, https://jrct.niph.go.jp/latest-detail/jRCTs031200358.

Radiation dose and lifetime risk for radiation-induced cancer due to natural radioactivity in tap water from Jordan.

The purpose of this study was to investigate the radiological quality of drinking water in Ma'an governorate, which includes the archeological city of Petra and is one of Jordan's most important tourist destinations. To the best of the authors' knowledge, this is the first study in southern Jordan that investigates radioactivity in drinking water and its potential to cause cancer. A liquid scintillation detector was used to measure gross alpha and gross beta activities in tap water samples from Ma'an governorate. A high-purity Germanium detector was used to measure the activity concentrations of 226Ra and 228Ra. Gross alpha, gross beta, 226Ra, and 228Ra activities were < 110-724 mBq/l, < 220-362 mBq/l, < 11-241 mBq/l, and < 32-49 mBq/l, respectively. The results were compared to internationally recommended levels and literature values. Annual effective doses ([Formula: see text]) from 226 and 228Ra intake were calculated for infants, children, and adults. The highest doses were found for children while the lowest were found for infants. For each water sample, the lifetime risk of radiation-induced cancer (LTR) was calculated for the whole population. All of the LTR values were lower than the value recommended by the World Heath Organisation. It is concluded that there are no significant radiation-related health risks associated with consumption of tap water from the studied region.