A study of the long term changes in the electromagnetic environment using data from continuous monitoring sensors in Greece.

Owing to the advancement of wireless technologies, there is a strong public perception of increasing exposure to Radiofrequency (RF) electromagnetic fields (EMF). The aim of this study is to determine the evolution of EMF in the environment, and consequently, human exposure to them, over a period of about two decades, spanning from the end of 2003 until February 2022. The study is based on data collected by two non-ionizing radiation monitoring networks in Greece. The networks consist of fixed EMF sensors that register the RMS electric field value every 6 min, on a 24 h basis. We used the Seasonal-Trend decomposition method using (LOESS), known as the STL method to decompose the time series into trend, seasonal, and noise components. Additionally, since the sensors include frequency filters for separating the cellular frequencies, the recorded data were used to identify the exposure contribution by cellular networks in comparison to other EMF sources. The study indicates that RF-EMF do not explicitly decrease or increase but rather fluctuate over time. Similarly, the contribution of mobile cellular networks to the total field change over time.

Electromagnetic Fields Exposure Assessment in Europe Utilizing Publicly Available Data.

The ever-increasing use of wireless communication systems during the last few decades has raised concerns about the potential health effects of electromagnetic fields (EMFs) on humans. Safety limits and exposure assessment methods were developed and are regularly updated to mitigate health risks. Continuous radiofrequency EMF monitoring networks and in situ measurement campaigns provide useful information about environmental EMF levels and their variations over time and in different microenvironments. In this study, published data from the five largest monitoring networks and from two extensive in situ measurement campaigns in different European countries were gathered and processed. Median electric field values for monitoring networks across different countries lay in the interval of 0.67-1.51 V/m. The median electric field value across different microenvironments, as evaluated from in situ measurements, varied from 0.10 V/m to 1.42 V/m. The differences between networks were identified and mainly attributed to variations in population density. No significant trends in the temporal evolution of EMF levels were observed. The influences of parameters such as population density, type of microenvironment, and height of measurement on EMF levels were investigated.

Competing Metal-Ligand Interactions in Tris(cyclopentadienyl)-cyclohexylisonitrile Complexes of Trivalent Actinides and Lanthanides.

The structure and bonding properties of 16 complexes formed by trivalent f elements (M=U, Np, Pu and lanthanides except for Pm and Pr) with cyclopentadienyl (Cp) and cyclohexylisonitrile (C≡NCy) ligands, (Cp)3M(C≡NCy), were studied by a joint experimental (XRD, NMR) and theoretical (DFT) analysis. For the large La(III) ion, the bis-adduct (Cp)3La(C≡NCy)2 could also be synthesized and characterized. The metal-ligand interactions, focusing on the comparison of the actinides and lanthanides as well as on the competition of the two different ligands for M, were elucidated using the Quantum Theory of Atoms in Molecules (QTAIM) and Natural Bond Orbital (NBO) models. The results point to interactions of comparable strengths with the anionic Cp and neutral C≡NCy ligands in the complexes. The structural and bonding properties of the actinide complexes reflect small but characteristic differences with respect to the lanthanide analogues. They include larger ligand-to-metal charge transfers as well as metal-ligand electron-sharing interactions. The most significant experimental marker of these covalent interactions is the C≡N stretching frequency.

Dosing 225Ac-DOTATOC in patients with somatostatin-receptor-positive solid tumors: 5-year follow-up of hematological and renal toxicity.

PURPOSE: The aim of this retrospective analysis is to estimate the most appropriate single cycle and cumulative doses of 225Ac-DOTATOC in patients treated for somatostatin-receptor-expressing cancers. METHODS: 225Ac-DOTATOC was administered to thirty-nine patients with various somatostatin-receptor-positive tumors. Baseline and follow-up 68Ga-DOTATOC PET/CT, lab tests, and renal scintigraphy were obtained. Patients received long-term follow-up either at the local cancer center or in close collaboration with external oncologists. Acute and chronic hematological toxicity was evaluated quantitatively over time. Long-term follow-up of creatinine was used to approximate the annual loss of estimated GFR (eGFR). RESULTS: Dose-dependent acute hematological toxicity was seen at single doses above 40 MBq or repeated doses greater than approximately 20 MBq 225Ac-DOTATOC at 4 month intervals. Treatment-related kidney failure occurred in 2 patients after a delay of >4 years but was independent of administered radioactivity, and other clinical risk factors were important contributors to renal decline. In general, the annual decline of eGFR among patients did not follow a clear dose-effect relationship even in patients with previous ß-therapy. An average eGFR-loss of 8.4ml/min (9.9%) per year was observed which is similar to the experience with ß-therapy studies. CONCLUSION: Treatment activities of approx. 20 MBq per cycle (4 monthly repetition) and cumulative doses up to 60-80 MBq generally avoided both acute and chronic grade 3/4 hematotoxicity in patients with advanced stage malignancies. Chronic renal toxicity was observed at these doses, but pre-existing renal risk factors were important co-factors. These data represent a starting point for additional research to more precisely define safety thresholds of 225Ac-DOTATOC.

Tris-{hydridotris(1-pyrazolyl)borato}actinide Complexes: Synthesis, Spectroscopy, Crystal Structure, Bonding Properties and Magnetic Behaviour.

The isostructural compounds of the trivalent actinides uranium, neptunium, plutonium, americium, and curium with the hydridotris(1-pyrazolyl)borato (Tp) ligand An[η3 -HB(N2 C3 H3 )3 ]3 (AnTp3 ) have been obtained through several synthetic routes. Structural, spectroscopic (absorption, infrared, laser fluorescence) and magnetic characterisation of the compounds were performed in combination with crystal field, density functional theory (DFT) and relativistic multiconfigurational calculations. The covalent bonding interactions were analysed in terms of the natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) models.

Supply and Clinical Application of Actinium-225 and Bismuth-213.

The recent development of 225Ac-PSMA617 for therapy of prostate cancer has strikingly demonstrated the clinical potential of targeted alpha therapy. Further promising applications of the alpha emitters 225Actinium and its daughter nuclide 213Bismuth include the therapy of brain tumors, bladder cancer, neuroendocrine tumors, and leukemia. This paper will provide a brief overview on the current status of the clinical development of compounds labelled with 225Ac or 213Bi and describe the various production routes that are in place or are under development to meet the increasing demand for these radionuclides.

Safety and efficacy of targeted alpha therapy with 213Bi-DOTA-substance P in recurrent glioblastoma.

Treatment options for recurrent glioblastoma multiforme (GBM) are very limited. GBM cells express high levels of the GPCR neurokinin type 1 receptor (NK-1R), and a modified substance P can be used as its ligand for the tumor cell targeting. Targeted alpha therapy with DOTA-Substance P labeled with the short range alpha emitter 213Bi allows for selective irradiation and killing of tumor cells. MATERIAL AND METHODS: Twenty patients with recurrent GBM were included into the study following a standard therapy. 1-2 intracavitary or intratumoral port-a-cath systems were stereotactically inserted. Patients were treated with 1-7 doses of 213Bi-DOTA-Substance P (213Bi-DOTA-SP) in 2-month intervals. 68Ga-DOTA-Substance P (68Ga-DOTA-SP) was co-injected with 213Bi-DOTA-SP to assess the biodistribution using PET/CT. Therapeutic response was monitored with performance status and MRI imaging. RESULTS: Treatment with activity up to 11.2 GBq 213Bi-DOTA-SP was well tolerated with only mild and transient adverse reactions. The median progression free survival was 2.7 months. The median overall survival from the first diagnosis was 23.6 months and median survival after recurrence was 10.9 months. The median survival time from the start of 213Bi-DOTA-SP was 7.5 months. CONCLUSIONS: Treatment of recurrent GBM with 213Bi-DOTA-SP is safe and well tolerated. The median overall survival after recurrence of 10.9 months compares favorably to the available alternative treatment options. Once the supply of high activity 225Ac/213Bi radionuclide generators is secured, targeted alpha therapy with 213Bi-DOTA-SP may evolve as a promising novel option to treat recurrent GBM.

An Overview of Targeted Alpha Therapy with 225Actinium and 213Bismuth.

Background: Recent reports of the remarkable therapeutic efficacy of 225Ac-labeled PSMA- 617 for therapy of metastatic castration-resistant prostate cancer have underlined the clinical potential of targeted alpha therapy. Objective and Conclusion: This review describes methods for the production of 225Ac and its daughter nuclide 213Bi and summarizes the current clinical experience with both alpha emitters with particular focus on recent studies of targeted alpha therapy of bladder cancer, brain tumors, neuroendocrine tumors and prostate cancer.

Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with 213Bi-substance P analogue.

BACKGROUND: Glioblastoma multiforme (GBM), the most common malignant brain tumor, mainly manifests as a primary de novo and less frequently as a secondary glial neoplasm. GBM has been demonstrated to overexpress the NK-1 receptor and substance P can be used as a ligand for targeted therapy. Alpha emitters, e.g. 213Bi, that deposit their high energy within a short range allow the selective irradiation of tumor cells while sparing adjacent neuronal structures. MATERIAL AND METHODS: Among 50 glioma patients of different subtypes that have to date been treated with targeted alpha therapy at the Medical University Warsaw, we report here the data on nine patients with secondary GBM. Following surgery, chemo- and radiotherapy, recurrent GBM was treated by intracavitary injection of 1-6 doses of 0.9-2.3 GBq 213Bi- DOTA-[Thi8,Met(O2)11]-substance P (213Bi-DOTA-SP) in 2-month intervals. 68Ga-DOTA-[Thi8,Met(O2)11]-substance P (68Ga-DOTA-SP) was co-injected with the therapeutic doses to assess biodistribution using PET/CT. Therapeutic response was monitored with MRI. RESULTS: Treatment with activities ranging from 1.4 to 9.7 (median 5.8) GBq 213Bi- DOTA-SP was well tolerated with only mild transient adverse reactions, mainly headaches due to a transient perfocal edema reaction. The median progression free survival and overall survival time following the initiation of alpha therapy was 5.8 and 16.4 months, respectively. The median overall survival time from the first diagnosis was 52.3 months. Two out of nine patients are still alive 39 and 51 months, respectively, after the initiation of the therapy. CONCLUSIONS: Targeted alpha therapy of secondary GBM with 213Bi-DOTA-SP is safe and well tolerated and may evolve as a promising novel therapeutic option for secondary GBM.

Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study.

PURPOSE: Patients with carcinoma in situ (CIS) of the bladder refractory to bacillus Calmette-Guérin (BCG) treatment are usually treated with cystectomy. Therefore, new treatment options with preservation of the urinary bladder are needed. The objective of the study was to investigate the feasibility, safety and efficacy of a novel targeted alpha-emitter immunotherapy for CIS after BCG treatment failure. METHODS: A pilot study was conducted in 12 patients (age range 64-86 years, ten men, two women) with biopsy-proven CIS of the bladder refractory to BCG treatment. The patients were treated intravesically with a single instillation (one patient was treated twice) of the alpha-emitter 213Bi coupled to an anti-EGFR antibody (366-821 MBq). The primary aims of the study were to determine the feasibility of treatment with the 213Bi-immunoconjugate and evaluation of adverse effects. Therapeutic efficacy was monitored by histological mapping of the urinary bladder 8 weeks after treatment and at different time points thereafter. RESULTS: The study proved that intravesical instillation of the 213Bi-immunoconjugate targeting EGFR is feasible. No adverse effects were observed and all blood and urine parameters determined remained in their normal ranges. Therapeutic efficacy was considered satisfactory, in that three of the 12 patients showed no signs of CIS 44, 30 and 3 months after treatment. CONCLUSION: Intravesical instillation of 213Bi-anti-EGFR monoclonal antibody was well tolerated and showed therapeutic efficacy. Repeated instillation and/or instillation of higher activities of the 213Bi-immunoconjugate might lead to better therapeutic outcomes. A phase I clinical trial is planned.

In vitro evaluation of 225 Ac-DOTA-substance P for targeted alpha therapy of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most malignant form of brain tumors with dismal prognosis despite treatment by surgery combined with radiotherapy and chemotherapy. The neuropeptide Substance P (SP) is the physiological ligand of the neurokinin-1 receptor, which is highly expressed in glioblastoma cells. Thus, SP represents a potential ligand for targeted alpha therapy. In this study, a protocol for the synthesis of SP labeled with the alpha emitter 225 Ac was developed and binding affinity properties were determined. The effects of 225 Ac-DOTA-SP were investigated on human glioblastoma cell lines (T98G, U87MG, U138MG) as well as GBM stem cells. A significant dose-dependent reduction in cell viability was detected up to 6 days after treatment. Also, colony-forming capacity was inhibited at the lower doses tested. In comparison, treatment with the conventional agent temozolomide showed higher cell viability and colony-forming capacity. 225 Ac-DOTA-SP treatment caused induction of late apoptosis pathways. Cells were arrested to G2/M-phase upon treatment. Increasing doses and treatment time caused additional S-phase arrest. Similar results were obtained using human glioblastoma stem cells, known to show radioresistance. Our data suggest that 225 Ac-DOTA-SP is a promising compound for treatment of GBM.

Solid-State Structure of Tris-Cyclopentadienide Uranium(III) and Plutonium(III).

The organometallic tris-cyclopentadienide actinide(III) (AnCp3 ) complexes were first reported about 50 years ago. However, up until now, only the NpCp3 solid state structure has been studied. Here we report on the solid state structures of UCp3 and PuCp3 which are isostructural to the Np analogue. The structural models are supported by theoretical calculations and compared to their lanthanide analogues. The observed trends in changes of bond lengths might be indicator for an increased covalency in the bonding in the tris-cyclopentadienide actinide(III) complexes (AnCp3 ) compared to their lanthanide homologues.

Reduction chemistry of neptunium cyclopentadienide complexes: from structure to understanding.

Neptunium complexes in the formal oxidation states II, III, and IV supported by cyclopentadienyl ligands are explored, and significant differences between Np and U highlighted as a result. A series of neptunium(iii) cyclopentadienyl (Cp) complexes [Np(Cp)3], its bis-acetonitrile adduct [Np(Cp)3(NCMe)2], and its KCp adduct K[Np(Cp)4] and [Np(Cp')3] (Cp' = C5H4SiMe3) have been made and characterised providing the first single crystal X-ray analyses of NpIII Cp complexes. In all NpCp3 derivatives there are three Cp rings in η5-coordination around the NpIII centre; additionally in [Np(Cp)3] and K[Np(Cp)4] one Cp ring establishes a µ-η1-interaction to one C atom of a neighbouring Np(Cp)3 unit. The solid state structure of K[Np(Cp)4] is unique in containing two different types of metal-Cp coordination geometries in the same crystal. NpIII(Cp)4 units are found exhibiting four units of η5-coordinated Cp rings like in the known complex [NpIV(Cp)4], the structure of which is now reported. A detailed comparison of the structures gives evidence for the change of ionic radii of ca. -8 pm associated with change in oxidation state between NpIII and NpIV. The rich redox chemistry associated with the syntheses is augmented by the reduction of [Np(Cp')3] by KC8 in the presence of 2.2.2-cryptand to afford a neptunium(ii) complex that is thermally unstable above -10 °C like the UII and ThII complexes K(2.2.2-cryptand)[Th/U(Cp')3]. Together, these spontaneous and controlled redox reactions of organo-neptunium complexes, along with information from structural characterisation, show the relevance of organometallic Np chemistry to understanding fundamental structure and bonding in the minor actinides.

Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding.

The aim of this study was to develop a treatment protocol for 225Ac-PSMA-617 α-radiation therapy in advanced-stage, metastatic castration-resistant prostate cancer patients with prostate-specific membrane antigen (PSMA)-positive tumor phenotype. Methods: A dosimetry estimate was calculated on the basis of time-activity curves derived from serially obtained 177Lu-PSMA-617 scans extrapolated to the physical half-life of 225Ac, assuming instant decay of unstable daughter nuclides. Salvage therapies empirically conducted with 50 (n = 4), 100 (n = 4), 150 (n = 2), and 200 kBq/kg (n = 4) of 225Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. Eight of 14 patients received further cycles in either 2- or 4-mo intervals with identical or deescalated activities. Results: Dosimetry estimates for 1 MBq of 225Ac-PSMA-617 assuming a relative biologic effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys, and 0.05 Sv for red marrow that are composed of 99.4% α, 0.5% ß, and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100 kBq/kg per cycle. At 100 kBq/kg, the duration of prostate-specific antigen decline was less than 4 mo, but if therapy was repeated every 2 mo patients experienced additive antitumor effects. Treatment activities of 50 kBq/kg were without toxicity but induced insufficient antitumor response in these high-tumor-burden patients. Remarkable antitumor activity by means of objective radiologic response or tumor marker decline was observed in 9 of 11 evaluable patients. Conclusion: For advanced-stage patients, a treatment activity of 100 kBq/kg of 225Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.

A Structurally Characterized Organometallic Plutonium(IV) Complex.

The blood-red plutonocene complex Pu(1,3-COT'')(1,4-COT'') (4; COT''=η8 -bis(trimethylsilyl)cyclooctatetraenyl) has been synthesized by oxidation of the anionic sandwich complex Li[Pu(1,4-COT'')2 ] (3) with anhydrous cobalt(II) chloride. The first crystal structure determination of an organoplutonium(IV) complex revealed an asymmetric sandwich structure for 4 where one COT'' ring is 1,3-substituted while the other retains the original 1,4-substitution pattern. The electronic structure of 4 has been elucidated by a computational study, revealing a probable cause for the unexpected silyl group migration.

Subtle Interactions and Electron Transfer between U(III) , Np(III) , or Pu(III) and Uranyl Mediated by the Oxo Group.

A dramatic difference in the ability of the reducing An(III) center in AnCp3 (An=U, Np, Pu; Cp=C5 H5 ) to oxo-bind and reduce the uranyl(VI) dication in the complex [(UO2 )(THF)(H2 L)] (L="Pacman" Schiff-base polypyrrolic macrocycle), is found and explained. These are the first selective functionalizations of the uranyl oxo by another actinide cation. At-first contradictory electronic structural data are explained by combining theory and experiment. Complete one-electron transfer from Cp3 U forms the U(IV) -uranyl(V) compound that behaves as a U(V) -localized single molecule magnet below 4 K. The extent of reduction by the Cp3 Np group upon oxo-coordination is much less, with a Np(III) -uranyl(VI) dative bond assigned. Solution NMR and NIR spectroscopy suggest Np(IV) U(V) but single-crystal X-ray diffraction and SQUID magnetometry suggest a Np(III) -U(VI) assignment. DFT-calculated Hirshfeld charge and spin density analyses suggest half an electron has transferred, and these explain the strongly shifted NMR spectra by spin density contributions at the hydrogen nuclei. The Pu(III) -U(VI) interaction is too weak to be observed in THF solvent, in agreement with calculated predictions.

Organometallic neptunium(III) complexes.

Studies of transuranic organometallic complexes provide a particularly valuable insight into covalent contributions to the metal-ligand bonding, in which the subtle differences between the transuranium actinide ions and their lighter lanthanide counterparts are of fundamental importance for the effective remediation of nuclear waste. Unlike the organometallic chemistry of uranium, which has focused strongly on U(III) and has seen some spectacular advances, that of the transuranics is significantly technically more challenging and has remained dormant. In the case of neptunium, it is limited mainly to Np(IV). Here we report the synthesis of three new Np(III) organometallic compounds and the characterization of their molecular and electronic structures. These studies suggest that Np(III) complexes could act as single-molecule magnets, and that the lower oxidation state of Np(II) is chemically accessible. In comparison with lanthanide analogues, significant d- and f-electron contributions to key Np(III) orbitals are observed, which shows that fundamental neptunium organometallic chemistry can provide new insights into the behaviour of f-elements.

225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently, we started the first-in-human treatment with an α-radionuclide-labeled PSMA ligand. Although the case series is still ongoing, we here report in advance about two patients in highly challenging clinical situations who showed a complete response to 225Ac-PSMA-617 therapy. METHODS: 68Ga-PSMA-11 PET/CT validated the presence of the PSMA-positive tumor phenotype. A 100-kBq activity of 225Ac-PSMA-617 per kilogram of body weight was administered bimonthly. Prostate-specific antigen response and hematologic toxicity were measured at least every 4 wk. Restaging was performed with 68Ga-PSMA-11 PET/CT. RESULTS: Both patients experienced a prostate-specific antigen decline to below the measurable level and showed a complete response on imaging. No relevant hematologic toxicity was observed. Xerostomia was the only mentionable clinical side effect. CONCLUSION: Targeted α-therapy with 225Ac-PSMA-617, although still experimental, obviously has strong potential to significantly benefit advanced-stage prostate cancer patients.

T-Bar Utilization for Concomitant Coronary Artery Bypass Graft Operation and Left Upper Lobectomy.

Management in patients with coexisting coronary artery disease and lung carcinoma is usually a two-stage operation, with the cardiac surgery procedure followed by pulmonary resection at a later time. Delayed tumor resection on the other hand may be detrimental. Off-pump coronary artery bypass grafting could facilitate concomitant lung resection at one stage via median sternotomy. T-bar retractor may be a useful tool in the surgical approach of this combined operation.