Improving susceptibility of neuroendocrine tumors to radionuclide therapies: personalized approaches towards complementary treatments.

Radionuclide therapies are an important tool for the management of patients with neuroendocrine neoplasms (NENs). Especially [131I]MIBG and [177Lu]Lu-DOTA-TATE are routinely used for the treatment of a subset of NENs, including pheochromocytomas, paragangliomas and gastroenteropancreatic tumors. Some patients suffering from other forms of NENs, such as medullary thyroid carcinoma or neuroblastoma, were shown to respond to radionuclide therapy; however, no general recommendations exist. Although [131I]MIBG and [177Lu]Lu-DOTA-TATE can delay disease progression and improve quality of life, complete remissions are achieved rarely. Hence, better individually tailored combination regimes are required. This review summarizes currently applied radionuclide therapies in the context of NENs and informs about recent advances in the development of theranostic agents that might enable targeting subgroups of NENs that previously did not respond to [131I]MIBG or [177Lu]Lu-DOTA-TATE. Moreover, molecular pathways involved in NEN tumorigenesis and progression that mediate features of radioresistance and are particularly related to the stemness of cancer cells are discussed. Pharmacological inhibition of such pathways might result in radiosensitization or general complementary antitumor effects in patients with certain genetic, transcriptomic, or metabolic characteristics. Finally, we provide an overview of approved targeted agents that might be beneficial in combination with radionuclide therapies in the context of a personalized molecular profiling approach.

Size-dependent therapeutic efficiency of 223Ra-labeled calcium carbonate carriers for internal radionuclide therapy of breast cancer.

The size of drug carriers strongly affects their biodistribution, tissue penetration, and cellular uptake in vivo. As a result, when such carriers are loaded with therapeutic compounds, their size can influence the treatment outcomes. For internal α-radionuclide therapy, the carrier size is particularly important, because short-range α-emitters should be delivered to tumor volumes at a high dose rate without any side effects, i.e. off-target irradiation and toxicity. In this work, we aim to evaluate and compare the therapeutic efficiency of calcium carbonate (CaCO3) microparticles (MPs, >2 µm) and nanoparticles (NPs, <100 nm) labeled with radium-223 (223Ra) for internal α-radionuclide therapy against 4T1 breast cancer. To do this, we comprehensively study the internalization and penetration efficiency of these MPs and NPs, using 2D and 3D cell cultures. For further therapeutic tests, we develop and modify a chelator-free method for radiolabeling of CaCO3 MPs and NPs with 223Ra, improving their radiolabeling efficiency (>97%) and radiochemical stability (>97%). After intratumoral injection of 223Ra-labeled MPs and NPs, we demonstrate their different therapeutic efficiencies against a 4T1 tumor. In particular, 223Ra-labeled NPs show a tumor inhibition of approximately 85%, which is higher compared to 60% for 223Ra-labeled MPs. As a result, we can conclude that 223Ra-labeled NPs have a more suitable biodistribution within 4T1 tumors compared to 223Ra-labeled MPs. Thus, our study reveals that 223Ra-labeled CaCO3 NPs are highly promising for internal α-radionuclide therapy.

Development of Nanocarrier-Based Radionuclide and Photothermal Therapy in Combination with Chemotherapy in Melanoma Cancer Treatment.

Conventional cancer therapy methods have serious drawbacks that are related to the nonspecific action of anticancer drugs that leads to high toxicity on normal cells and increases the risk of cancer recurrence. The therapeutic effect can be significantly enhanced when various treatment modalities are implemented. Here, we demonstrate that the radio- and photothermal therapy (PTT) delivered through nanocarriers (gold nanorods, Au NRs) in combination with chemotherapy in a melanoma cancer results in complete tumor inhibition compared to the single therapy. The synthesized nanocarriers can be effectively labeled with 188Re therapeutic radionuclide with a high radiolabeling efficiency (94-98%) and radiochemical stability (>95%) that are appropriate for radionuclide therapy. Further, 188Re-Au NRs, mediating the conversion of laser radiation into heat, were intratumorally injected and PTT was applied. Upon the irradiation of a near-infrared laser, dual photothermal and radionuclide therapy was achieved. Additionally, the combination of 188Re-labeled Au NRs with paclitaxel (PTX) has significantly improved the treatment efficiency (188Re-labeled Au NRs, laser irradiation, and PTX) compared to therapy in monoregime. Thus, this local triple-combination therapy can be a step toward the clinical translation of Au NRs for use in cancer treatment.

New PSMA-Targeting Ligands: Transformation from Diagnosis (Ga-68) to Radionuclide Therapy (Lu-177).

Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported 68Ga-imaging agent, [68Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA)2 led to P17-087 (4) and P17-088 (7). Both agents showed excellent PSMA binding affinity (IC50 = 10-30 nM) comparable to that of recently FDA-approved [177Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [177Lu]Lu-4 exhibited very high tumor uptake and a fast blood clearance similar to those of [177Lu]Lu-PSMA-617. Conversely, [177Lu]Lu-7, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [177Lu]Lu-4 and [177Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA)2 and the switch from the imaging isotope gallium-68 to the therapeutic isotope lutetium-177 have successfully transformed a PSMA-targeting agent from diagnosis to promising radionuclide therapeutic agents.

An alternative radiochemical separation strategy for isolation of Ac and Ra isotopes from high energy proton irradiated thorium targets for further application in Targeted Alpha Therapy (TAT).

Targeted Alpha Therapy (TAT) has shown very high potential for the treatment of cancers that were not responsive to other therapy options (e.g., ß- therapy and chemotherapy). The main constraint to the widespread use of TAT in clinics is the limited availability of alpha-emitting radionuclides. One of the most promising candidates for TAT is 225Ac (t1/2 = 9.92 days), which can be used directly in combination with selective biomolecules (e.g., antibodies, peptides, etc.) or be a generator source of 213Bi (t1/2 = 45.6 min), another shorter-lived TAT radionuclide. Several strategies are currently under investigation to increase the supply of 225Ac. One of the most attractive options is the irradiation of natural thorium-232 targets with high-energy protons (≥100 MeV). However, there are several challenges associated with this production method including the development of an efficient radiochemical purification method. During irradiation of natural thorium with proton energy above 100 MeV, several Ra isotopes (223,224,225Ra) are produced. 223Ra (t1/2 = 11.43 days) is used for the treatment of bone metastases and can also be used as a generator source for 211Pb. Additionally, 225Ra (t1/2 = 14.9 days) can be a valuable source of isotopically pure 225Ac. In the present work, we address the radiochemical separation aspects of isolating Ac and Ra isotopes from irradiated thorium targets.

A feasibility study of the therapeutic application of a mixture of 67/64 Cu radioisotopes produced by cyclotrons with proton irradiation.

PURPOSE: 64 Cu and 67 Cu radioisotopes have nuclear characteristics suitable for nuclear medicine applications. The production of 64 Cu is already well established. However, the production of 67 Cu in quantities suitable to conduct clinical trials is more challenging as it leads to the coproduction of other Cu isotopes, in particular 64 Cu. The aim of this study is to investigate the possibility of using a CuCl2 solution with a mixture of 67/64 Cu radioisotopes for therapeutic purposes, providing an alternative solution for the cyclotron production problem. METHODS: Copper radioisotopes activities were calculated by considering proton beam irradiation of the following targets: (i) 70 Zn in the energy range 70-45 MeV; (ii) 68 Zn in the energy range 70-35 MeV; (iii) a combination of 70 Zn (70-55 MeV) and 68 Zn (55-35 MeV). The contribution of each copper radioisotope to the human-absorbed dose was estimated with OLINDA/EXM software using the biokinetic model for CuCl2 published by ICRP 53. The total absorbed dose generated by the 67/64 CuCl2 mixture, obtained through different production routes, was calculated at different times after the end of the bombardment (EOB). A simple spherical model was used to simulate tumors of different sizes containing uniformly distributed 67/64 Cu mixture and to calculate the absorbed dose of self-irradiation. The biological damage produced by 67 Cu and 64 Cu was also evaluated through cellular dosimetry and cell surviving fraction assessment using the MIRDcell code, considering two prostate cancer cell lines with different radiosensitivity. RESULTS: The absorbed dose to healthy organs and the effective dose (ED) per unit of administered activity of 67 CuCl2 are higher than those of 64 CuCl2 . Absorbed dose values per unit of administered activity of 67/64 CuCl2 mixture increase with time after the EOB because the amount of 67 Cu in the mixture increases. Survival data showed that the biological damage caused per each decay of 67 Cu is greater than that of 64 Cu, assuming that radionuclides remain accumulated in the cell cytoplasm. Sphere model calculations demonstrated that 64 Cu administered activity must be about five times higher than that of 67 Cu to obtain the same absorbed dose for tumor mass between 0.01 and 10 g and about 10 times higher for very small spheres. Consequently, the 64 CuCl2 -absorbed dose to healthy organs will reach higher values than those of 67 CuCl2 . The supplemental activity of the 67/64 CuCl2 mixture, required to get the same tumor-absorbed dose produced by 67 CuCl2 , triggers a dose increment (DI) in healthy organs. The waiting time post-EOB necessary to keep this DI below 10% (t10% ) depends on the irradiation methods employed for the production of the 67/64 CuCl2 mixture. CONCLUSIONS: A mixture of cyclotron produced 67/64 Cu radioisotopes proved to be an alternative solution for the therapeutic use of CuCl2 with minimal DI to healthy organs compared with pure 67 Cu. Irradiation of a 70 Zn+68 Zn target in the 70-35 MeV proton energy range for 185 h appears to be the best option from among all the production routes investigated, as it gives the maximum amount of activity, the shortest t10% (10 h), and less than 1% of 61 Cu and 60 Cu impurities.

Hydroxypyridinones as a Very Promising Platform for Targeted Diagnostic and Therapeutic Radiopharmaceuticals.

Hydroxypyridinones (HOPOs) have been used in the chelation therapy of iron and actinide metals. Their application in metal-based radiopharmaceuticals has also been increasing in recent years. This review article focuses on how multidentate HOPOs can be used in targeted radiometal-based diagnostic and therapeutic radiopharmaceuticals. The general structure of radiometal-based targeted radiopharmaceuticals, a brief description of siderophores, the basic structure and properties of bidentate HOPO, some representative HOPO multidentate chelating agents, radiopharmaceuticals based on HOPO multidentate bifunctional chelators for gallium-68, thorium-227 and zirconium-89, as well as the future prospects of HOPO multidentate bifunctional chelators in other metal-based radiopharmaceuticals are described and discussed in turn. The HOPO metal-based radiopharmaceuticals that have shown good prospects in clinical and preclinical studies are gallium-68, thorium-227 and zirconium-89 radiopharmaceuticals. We expect HOPO multidentate bifunctional chelators to be a very promising platform for building novel targeted radiometal-based diagnostic and therapeutic radiopharmaceuticals.

High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

Targeted radionuclide therapies (TRT) using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.

Can intermediate-energy sources lead to elevated bone doses for prostate and head & neck high-dose-rate brachytherapy?

PURPOSE: Several radionuclides with high (60Co, 75Se) and intermediate (169Yb, 153Gd) energies have been investigated as alternatives to 192Ir for high-dose-rate brachytherapy. The purpose of this study was to evaluate the impact of tissue heterogeneities for these five high- to intermediate-energy sources in prostate and head & neck brachytherapy. METHODS AND MATERIALS: Treatment plans were generated for a cohort of prostate (n = 10) and oral tongue (n = 10) patients. Dose calculations were performed using RapidBrachyMCTPS, an in-house Geant4-based Monte Carlo treatment planning system. Treatment plans were simulated using 60Co, 192Ir, 75Se, 169Yb, and 153Gd as the active core of the microSelectron v2 source. Two dose calculation scenarios were presented: (1) dose to water in water (Dw,w), and (2) dose to medium in medium (Dm,m). RESULTS: Dw,w overestimates planning target volume coverage compared with Dm,m, regardless of photon energy. The average planning target volume D90 reduction was ∼1% for high-energy sources, whereas larger differences were observed for intermediate-energy sources (1%-2% for prostate and 4%-7% for oral tongue). Dose differences were not clinically relevant (<5%) for soft tissues in general. Going from Dw,w to Dm,m, bone doses were increased two- to three-fold for 169Yb and four- to five-fold for 153Gd, whereas the ratio was close to ∼1 for high-energy sources. CONCLUSIONS: Dw,w underestimates the dose to bones and, to a lesser extent, overestimates the dose to soft tissues for radionuclides with average energies lower than 192Ir. Further studies regarding bone toxicities are needed before intermediate-energy sources can be adopted in cases where bones are in close vicinity to the tumor.

Description of a transient proximal tubulopathy induced by amino acids perfusion in peptide receptor radionuclide therapy: A case report.

RATIONALE: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a targeted internal radiotherapy method used to treat tumors expressing somatostatin receptors. Concomitant amino acids perfusion is systematically performed in order to inhibit the proximal tubular uptake of the radionuclide and thus prevent nephrotoxicity. PATIENT CONCERNS:: a 67-year-old woman with an intestinal neuroendocrine tumor with multiple lymphadenopathies and liver metastases. The patient displayed a carcinoid syndrome with flushes including facial erythrosis and paresthesia. During the treatment, the patient exhibited emesis and severe cramps. DIAGNOSIS: We describe incomplete proximal tubulopathy induced by an amino acid therapy with [177Lu]-DOTA0-Tyr3-octreotate, which was reversible after treatment discontinuation. This diagnosis relies on metabolic acidosis, hypophosphatemia due to renal loss, tubular proteinuria and generalized aminoaciduria. Serum creatinine remained stable during and after the procedure. INTERVENTIONS: PRRT with radiolabeled somatostatin analog ([177Lu]-DOTA0-Tyr3-octreotate). In order to prevent PRRT induced nephrotoxicity, we used a solution of 20 amino acids including 22 g/L Lysine and 16.8 g/L Arginine. Metoclopramide was successfully used to control vomiting. During the treatment and at the time of cramps, the blood sample showed hypophosphatemia at 0.3 mmol/L justifying intravenous phosphate supplementation. The cramps disappeared after this infusion. OUTCOMES: Hypophosphatemia with low TmPO4/GFR was observed as well as an increase in ß2-microglobulinuria, urinary polyclonal light chains, and amino aciduria involving all amino acids. All these disturbances disappeared the day after the treatment and there was no acute kidney injury after 5 PRRT sessions. Six months after PRRT discontinuation, the patient had neither renal failure nor proximal tubulopathy. Aminoacid induced tubulopathy involves the main ligands of the megalin receptor. It has recently been demonstrated that cilastatin is a megalin inhibitor in the proximal tubule and therefore could represent an attractive alternative to amino acids for this purpose. LESSONS: This case report is a description of a nephroprotective strategy in which partial, and transient tubulopathy is induced, in order to decrease proximal absorption of a tubulotoxic molecule. This little known strategy could be used to prevent proximal tubular injury caused by others megalin-mediated nephrotoxicity medication.

Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer has extremely high risk of relapse due to the lack of targeted therapies, intra- and inter-tumoral heterogeneity, and the inherent and acquired resistance to therapies. In this study, we evaluate the potential of prostate-specific membrane antigen (PSMA) as target for radio-ligand therapy (RLT). METHODS: Tube formation was investigated after incubation of endothelial HUVEC cells in tumor-conditioned media and monitored after staining using microscopy. A binding study with 68Ga-labeled PSMA-addressing ligand was used to indicate targeting potential of PSMA on tumor-conditioned HUVEC cells. For mimicking of the therapeutic application, tube formation potential and vitality of tumor-conditioned HUVEC cells were assessed following an incubation with radiolabeled PSMA-addressing ligand [177Lu]-PSMA-617. For in vivo experiments, NUDE mice were xenografted with triple-negative breast cancer cells MDA-MB231 or estrogen receptor expressing breast cancer cells MCF-7. Biodistribution and binding behavior of [68Ga]-PSMA-11 was investigated in both tumor models at 30 min post injection using µPET. PSMA- and CD31-specific staining was conducted to visualize PSMA expression and neovascularization in tumor tissue ex vivo. RESULTS: The triple-negative breast cancer cells MDA-MB231 showed a high pro-angiogenetic potential on tube formation of endothelial HUVEC cells. The induced endothelial expression of PSMA was efficiently addressed by radiolabeled PSMA-specific ligands. 177Lu-labeled PSMA-617 strongly impaired the vitality and angiogenic potential of HUVEC cells. In vivo, as visualized by µPET, radiolabeled PSMA-ligand accumulated specifically in the triple-negative breast cancer xenograft MDA-MB231 (T/B ratio of 43.3 ± 0.9), while no [68Ga]-PSMA-11 was detected in the estrogen-sensitive MCF-7 xenograft (T/B ratio of 1.1 ± 0.1). An ex vivo immunofluorescence analysis confirmed the localization of PSMA on MDA-MB231 xenograft-associated endothelial cells and also on TNBC cells. CONCLUSIONS: Here we demonstrate PSMA as promising target for two-compartment endogenous radio-ligand therapy of triple-negative breast cancer.

Evaluación del riesgo radiológico en la radiosinoviortesis y el tratamiento mielosupresor de la policitemia vera / Radiological risk assessment in radiosynoviorthesis and the myelosupressor treatment of polycythemia vera

Introducción: La aplicación del método de la matriz de riesgo para la evaluación del riesgo radiológico en la medicina permite identificar de manera proactiva debilidades en las etapas del proceso y hacer un plan de acciones de mejora para la seguridad y calidad. Objetivo: Evaluar los riesgos radiológicos de la radiosinoviortesis y el tratamiento mielosupresor con Fósforo-32 de la policitemia vera. Método: Se utilizó el método de matriz de riesgo y se realizó el análisis y tratamiento de los riesgos radiológicos por medio del código cubano SECURE-MR-FMEA 3.0. Resultados: El 17 por ciento del riesgo alto se eliminó con las medidas adicionales adoptadas; predominaron las consecuencias medias para los trabajadores y el público, 30 por ciento y el 14 por ciento, respectivamente. Las defensas más importantes fueron: levantamiento radiológico inicial de las áreas del departamento; revisión independiente del proyecto con las regulaciones de seguridad aplicables; inspección de trabajos de construcción civil y montaje de equipos antes de iniciar la operación del departamento; capacitación de los médicos nucleares en los tratamientos; existencia de protocolos de tratamiento; análisis de lecciones aprendidas de incidentes radiológicos; levantamiento radiológico periódico de las áreas del servicio y procedimiento de emergencia para reducir la dosis en órganos críticos en caso de administración errónea de radiofármacos. Se creó una base de datos de incidentes utilizada como referencia para el modelo utilizado. El factor humano fue la causa mayor de los sucesos radiológicos analizados (88 por ciento). Conclusiones: Estos resultados facilitan la toma de decisiones para el mejor desempeño de la radiosinoviortesis y el tratamiento de la policitemia vera con Fósforo-32 en Cuba. Se sugiere elaborar el plan de mejora de la seguridad con especial atención a las operaciones de administración del radiofármaco en ambos casos.(AU)

Introduction: The application of risk matrix for ionizing radiation medicine allow identify in proactive way the weakness of the process' step, which implies in the design of safety and quality improvement plan for this. Method: Risk matrix method applied for radiosynoviorthesis and the myelosupressor treatment with Phosphorus-32 of polycythemia vera. The Cuban code SECURE-MR-FMEA 3.0 is used. Results: It was eliminated the 17 percent of the high risk with additional measures, and the medium consequences for workers and public are 30 percent and 14 percent, respectively. The most important identified safety measures were the initial radiological monitoring from different nuclear medicine department areas; the project revision based on the applicable safety regulations; a survey of civil construction works and equipment assembly before work began; training of nuclear medicine doctors in related aspects of nuclear medicine treatments; existence of treatment protocols; the analysis of learned lessons from radiological incidents; the periodical radiological monitoring from different services areas and the emergency procedure for the cases of mistake in the radiopharmaceuticals administration. Human factor was the major cause in analyzed radiological events (88 percent). Conclusions: These results facilitate taking decisions for the best performance of radiosynoviorthesis and the myelosupressor treatment with Phosphorus-32 of polycythemia vera in Cuba. It is recommended to elaborate the safety improvement plan from these and focussing in the radiopharmaceutical administration operations in both cases.(AU)

Meaningful differences and validity for the NCCN/FACT-P Symptom Index: An analysis of the ALSYMPCA data.

BACKGROUND: The Functional Assessment of Cancer Therapy-Prostate (FACT-P) and the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy-Prostate Symptom Index-17 (NFPSI-17) are 2 commonly used measures for patient-reported outcomes in prostate cancer trials. Their use may be enhanced by a better understanding of how change scores on the measures should be interpreted. METHODS: Using data from the phase 3 Alpharadin in Symptomatic Prostate Cancer Patients trial, this study estimated important change scores on the FACT-P and the NFPSI-17 via a combination of distribution- and anchor-based methods. These data were also used to establish evidence for the validity of the NFPSI-17. RESULTS: The available data suggested the following important difference ranges: 2 to 4 points for the Prostate Cancer Subscale, 5.5 to 8.5 points for the Trial Outcome Index, 1 to 1.5 points for the 3-item Pain Scale, 1 to 2 points for the 4-item Pain Scale, 4 to 6 points for the NFPSI-17, 2 to 3.5 points for NFPSI-Disease-Related Symptoms-Physical, 0.5 points for NFPSI-Disease-Related Symptoms-Emotional, 1 to 1.5 points for NFPSI-Treatment Side Effects, and 0.5 to 1 point for NFPSI-Function/Well-Being. The internal consistency reliability of the NFPSI-17 and most of its subscales was good to excellent (>.70). Significant support was also found for the known groups validity of the NFPSI-17 (and most of its subscales) on the basis of the Eastern Cooperative Oncology Group performance status, the total alkaline phosphatase, the presence of a skeletal-related event during treatment, and the prostate-specific antigen response before the end of treatment. CONCLUSIONS: The secondary analysis supports the continued use of the FACT-P, the NFPSI-17, and its related subscales in future research on the quality of life of patients with symptomatic castration-resistant prostate cancer with bone metastases.

Improved freeze-dried kit for the preparation of 188ReN-DEDC/lipiodol for the therapy of unresectable hepatocellular carcinoma.

Rhenium-188-N-(DEDC)2/lipiodol (abbreviated as 188ReN-DEDC, where DEDC = monoanionic diethyldithiocarbamate) is a clinically proven radiopharmaceutical for the therapy of unresectable hepatocellular carcinoma (HCC) through trans arterial radioembolization (TARE). A two-vial freeze-dried kit for the preparation of [188ReN(DEDC)2] complex using sodium perrhenate (Na188ReO4) obtained from a commercial Tungsten-188/Rhenium-188 generator had been reported earlier. This method required addition of stipulated volume of glacial acetic acid into vial 1 by the user for efficient preparation of [188ReN]2+ intermediate. An error in this step can result in low radiochemical yield of [188ReN]2+ intermediate as well as sub-optimal pH of the reaction mixture for the second step, leading to poor radiochemical purity of 188ReN-DEDC complex. In the present work, a solution to this problem was found by including an oxalate buffer of pH = 3 in vial 1, eliminating the need for the addition of glacial acetic acid by the user. This modification not only made the kits more user-friendly, it resulted in significant improvement in the kinetics of formation of [188ReN]2+ intermediate, wherein > 95% radiochemical purity could be achieved within 5 min incubation at ambient temperature. Moreover, the novel route for the preparation of [188ReN]2+ intermediate may be applied to any radiopharmaceutical based on 188ReN-core.

Absorbed dose distributions from ophthalmic 106 Ru/106 Rh plaques measured in water with radiochromic film.

PURPOSE: Brachytherapy with 106 Ru/106 Rh plaques offers good outcomes for small-to-medium choroidal melanomas and retinoblastomas. The dose measurement of the plaques is challenging, due to the small range of the emitted beta particles and steep dose gradients involved. The scarce publications on film dosimetry of 106 Ru/106 Rh plaques used solid phantoms. This work aims to develop a practical method for measuring the absorbed dose distribution in water produced by 106 Ru/106 Rh plaques using EBT3 radiochromic film. METHODS: Experimental setups were developed to determine the dose distribution at a plane perpendicular to the symmetry axis of the plaque and at a plane containing the symmetry axis. One CCA and two CCX plaques were studied. The dose maps were obtained with the FilmQA Pro 2015 software, using the triple-channel dosimetry method. The measured dose distributions were compared to published Monte Carlo simulation and experimental data. RESULTS: A good agreement was found between measurements and simulations, improving upon published data. Measured reference dose rates agreed within the experimental uncertainty with data obtained by the manufacturer using a scintillation detector, with typical differences below 5%. The attained experimental uncertainty was 4.1% (k = 1) for the perpendicular setup, and 7.9% (k = 1) for the parallel setup. These values are similar or smaller than those obtained by the manufacturer and other authors, without the need of solid phantoms that are not available to most users. CONCLUSIONS: The proposed method may be useful to the users to perform quality assurance preclinical tests of 106 Ru/106 Rh plaques.

Unusual Case of Diffuse Penile Metastasis of Prostate Cancer on 68Ga PSMA PET/CT Imaging and 177Lu PSMA Posttherapy Scintigraphy.

An 85-year-old man with prostate cancer for metastatic workup underwent Gallium Prostate-Specific Membrane Antigen (Ga-PSMA) PET/CT (Ga-PSMA PET/CT), which revealed unusual tracer uptake in the shaft and glans of penis as well as multiple systemic metastases in liver, skeletal, and lymph nodes. The penile lesion was proved to be metastatic adenocarcinoma from prostate on fine needle aspiration cytology. The patient underwent Lutetium (Lu)-labeled PSMA radioligand therapy, which also revealed diffuse tracer uptake in the penile shaft as well as other metastatic sites.

Microdosimetric Evaluation of Current and Alternative Brachytherapy Sources-A Geant4-DNA Simulation Study.

PURPOSE: Radioisotopes such as 75Se, 169Yb, and 153Gd have photon energy spectra and half-lives that make them excellent candidates as alternatives to 192Ir for high-dose-rate brachytherapy. The aim of the present study was to evaluate the relative biological effectiveness (RBE) of current (192Ir, 125I, 103Pd) and alternative (75Se, 169Yb, 153Gd) brachytherapy radionuclides using Monte Carlo simulations of lineal energy distributions. METHODS AND MATERIALS: Brachytherapy sources (microSelectron v2 [192Ir, 75Se, 169Yb, 153Gd], SelectSeed [125I], and TheraSeed [103Pd]) were placed in the center of a spherical water phantom with a radius of 40 cm using the Geant4 Monte Carlo simulation toolkit. The kinetic energy of all primary, scattered, and fluorescence photons interacting in a scoring volume were tallied at various depths from the source. Electron tracks were generated by sampling the photon interaction spectrum and tracking all the interactions down to 10 eV using the event-by-event capabilities of the Geant4-DNA models. The dose mean lineal energy (y¯D) values were obtained through random sampling of transfer points and overlaying spherical scoring volumes within the associated volume of the tracks. The scoring volume diameter was determined by fitting the y¯D ratio for 125I to its observed RBE. RESULTS: y¯D increased with the increasing distance from the source for 192Ir, 75Se, and 169Yb, remained constant for 153Gd and 125I, and decreased for 103Pd. The diameter at which the y¯D ratio coincided with the RBE of 1.15 to 1.20 for 125I was ∼25 to 40 nm. The RBE (reference 1 MeV photons) at high doses and dose rates for 192Ir, 75Se, 169Yb, 153Gd, 125I, and 103Pd was 1.028 to 1.034, 1.05 to 1.07, 1.12 to 1.15, 1.16 to 1.21, 1.15 to 1.20, and 1.17 to 1.22, respectively. CONCLUSIONS: The radiation quality of the radionuclides under investigation was greater than that of high-energy photons. The present study has provided a set of values to modify the prescription doses for brachytherapy to account for the variation in radiation quality among radionuclides.

Value of post-therapy 177Lu-PSMA images for accurate interpretation of therapy response with 68Ga-PSMA PET/CT. / Valor de las imágenes de 177Lu-PSMA post-terapia para una interpretación precisa de la respuesta a la terapia con PET/TC con 68Ga-PSMA.

A 54-year-old man with progressive prostate cancer underwent a 68Ga-PSMA PET/CT, which showed lymph node and bone metastases. After 2-cycles of 177Lu-PSMA therapy, the repeated 68Ga-PSMA PET/CT showed decreased radiotracer uptake in lymph node and bones metastases, but there were new lesions which may be compatible with progression or tumour sink-effect. A review of 177Lu-PSMA-therapy images revealed that new lesions in the second PET/CT were the metastatic lesions that progressed after the first PET/CT, and subsequently showed a good response. The patient received additional cycles of 177Lu-PSMA therapy, and the disease regressed further, with a PSA of 0.06ng/ml. Response evaluation of new therapeutic diagnostics (theranostic) agents needs a review of not only diagnostic PET/CT images, but also post-therapy images and laboratory results.

Reductions in prostatic doses are associated with less acute morbidity in patients undergoing Pd-103 brachytherapy: Substantiation of the rationale for focal therapy.

PURPOSE: Interest in prostate dose reduction or focal treatment exists due to expected reductions in treatment morbidity. Prior analyses have not generally corroborated relationships between prostate or urethral dose and urinary toxicity after brachytherapy, but such analyses have been performed on cohorts all receiving the same prescribed dose. We analyzed patients treated to differing prescription doses to assess acute urinary morbidity with dose reduction. METHODS AND MATERIALS: Patients treated with Pd-103 to either 125 Gy or 90-100 Gy were compared using the International Prostate Symptom Score (IPSS) at 1-month postimplant. Patients in the 90-100 Gy cohort began external beam radiation therapy after their 1-month assessment; thus, toxicities were measured before contribution from external beam radiation therapy. Patient/treatment characteristics were compared to verify subgroup homogeneity. Dose and change in IPSS 1 month after treatment were assessed using a multivariate linear regression model. RESULTS: One hundred ninety-one and 41 patients were treated with 125 Gy versus 90-100 Gy, respectively. Preimplant and postimplant prostate volumes and initial IPSS were similar between groups. Higher prescription dose and increased pretreatment IPSS were independent predictors of increased 1-month IPSS. In addition, every 10 percentage point additional prostate volume receiving a given dose was associated with increase in IPSS after treatment for the same level of pretreatment IPSS. CONCLUSION: Lower prescription dose and decreased volume of high-dose regions to the prostate correlated with reduced acute urinary morbidity after brachytherapy. Our findings suggest that focal treatment approaches with modest dose reductions to subregions of the prostate may reduce acute morbidity and potentially expand the number of patients eligible for brachytherapy.

Measurement of dose in radionuclide therapy by using Cerenkov radiation.

This work aims to determine the relationship between Cerenkov photon emission and radiation dose from internal radionuclide irradiation. Water and thyroid phantoms were used to simulate the distribution of Cerenkov photon emission and dose deposition through Monte Carlo method. The relationship between Cerenkov photon emission and dose deposition was quantitatively analyzed. A neck phantom was also used to verify Cerenkov photon detection for thyroid radionuclide therapy. Results show that Cerenkov photon emission and dose deposition exhibit the same distribution pattern in water phantom, and this relative distribution relationship also existed in the thyroid phantom. Moreover, Cerenkov photon emission exhibits a specific quantitative relation to dose deposition. For thyroid radionuclide therapy, only a part of Cerenkov photon produced by thyroid could penetrate the body for detection; therefore, the use of Cerenkov radiation for measurement of radionuclide therapy dose may be more suitable for superficial tumors. This study demonstrated that Cerenkov radiation has the potential to be used for measuring radiation dose for radionuclide therapy.