Beta-emitting Radioisotope Research Articles

An inter-comparison between MCNPX and EGSnrc Monte Carlo codes in grid radiotherapy characterization using beta-emitting radionuclides

IntroductionThe applicability of MCNPX and EGSnrc Monte Carlo codes in dosimetric characterization of spatially fractionated radiotherapy (SFRT or grid radiotherapy, in other words) of superficial tumors using beta-emitting radionuclides has been assessed in the current study. Materials and methodsA grid block including 63 cubic holes was modeled by each Monte Carlo code. Then, the grid block was separately filled by four widely adopted beta-emitting radioisotopes for radionuclide-therapy purposes including 32P, 90Y, 166Ho, and 188Re. Finally, the depth dose distribution and transverse dose profiles at different depths were separately calculated for each radionuclide using both MCNPX and EGSnrc Monte Carlo codes. Obtained results were quantitatively compared by gamma analysis as well as an R-squared statistical test to evaluate the compatibility of acquired dosimetry results by each code. ResultsSimilar dosimetry results were obtained by both Monte Carlo codes, where no significant difference was observed among the obtained data by each code. The uniformity of dose distribution improved with increasing the depth inside the phantom for all radionuclides under investigation. ConclusionFrom the results, it can be concluded that MCNPX and EGSnrc Monte Carlo codes have similar performance in dosimetric characterization of grid radiotherapy using beta-emitting radionuclides. Small differences between the results acquired by employed codes originate from associated statistical uncertainty with the Monte Carlo data as well as differences in considered condense history scheme (CHS) during the electron transport inside the medium.

Optimal production and purification of n.c.a.143Pr as a promising palliative agent for the treatment of metastatic bone pain

This study proposes the beta-emitting radioisotope 143Pr as a promising candidate for palliative treatment of metastatic bone pain due to its desirable physical decay characteristics. An optimized process was developed for the production and purification of non-carrier-added 143Pr using a medium flux research reactor. Calculations were performed to determine the optimal irradiation time and cooling period for irradiating 1 mg of natural cerium oxide to indirectly produce 143Pr through the decay of 143Ce. Following irradiation and cooling, extraction chromatography was employed to efficiently isolate 143Pr from the irradiated target material. A column containing Ln-resin was used along with nitric acid as the mobile phase and an optional oxidation step with NaBrO3/ascorbic acid to separate 143Pr from impurities such as 143Ce and 141Ce. Radionuclidic purity of over 99.995% was achieved as confirmed through gamma spectroscopy, demonstrating effective separation of 143Pr. Additional quality control analyses established the chemical and radiochemical purity of the purified 143Pr nitrate product. With a half-life of 13.6 days and maximum beta energy of 0.937 MeV, 143Pr exhibits favorable properties for palliative bone pain therapy. This study therefore provides a viable method for producing high-purity 143Pr through the optimized irradiation and purification processes described. Further investigation is warranted to explore potential clinical applications of 143Pr for palliation of metastatic bone cancer pain.

Epidemiology of Neuroendocrine Neoplasms and Results of Their Treatment with [177Lu]Lu-DOTA-TATE or [177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE-A Six-Year Experience in High-Reference Polish Neuroendocrine Neoplasm Center.

Neuroendocrine neoplasms (NENs) are a group of neoplasms arising from neuroendocrine cells. The worldwide incidence and prevalence of the NENs are estimated to be 6/100,000 and 35/100,000, respectively. Those numbers are increasing every decade, requiring higher and higher diagnosis and treatment costs. Radioligand therapy (RLT) using beta-emitting radioisotopes is an efficient and relatively safe method of treatment, typically used as a second-line treatment. RLT tolerability is higher than other available pharmacotherapies (chemotherapy or tyrosine kinase inhibitors). Recent studies show an increase in overall survival among patients treated with RLT. The present study aimed to learn the epidemiology of NENs in Poland and assess the effectiveness of RLT in a high-reference center. A prospective analysis of 167 patients treated with RLT in one of Poland's highest-reference NEN centers was performed. The analysis covered 66 months of observation (1 December 2017-30 May 2023), during which 479 RLT single administrations of radioisotope were given. The standard procedure was to give four courses of [177Lu]Lu-DOTA-TATE alone, or tandem therapy-[177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE. Grading analysis showed that most patients had non-functioning G2 NEN with a mean Ki-67 of 6.05% (SD ± 6.41). The most common primary tumor location was the pancreas. Over two-thirds of patients did undergo surgery due to primary tumors or distant metastases. The majority of patients were using lanreotide as a chronically injected somatostatin analog. Median progression-free survival (PFS) on somatostatin analogs was 21.0 (IQR = 29.0) months. Directly after the last course of RLT, disease stabilization was noted in 69.46% of patients, partial regression was noted in 20.36% of patients, complete regression was noted in 0.60% of patients, and progression was noted in 9.58% of patients. In long-term follow-up, the median observation time among patients who underwent four treatment cycles (n = 108) was 29.8 (IQR = 23.9) months. Stabilization of the disease was observed in 55.56% of the patients and progression was observed in 26.85% of the patients, while 17.59% of patients died. Median PFS was 29.3 (IQR 23.9), and the median OS was 34.0 months (IQR 16.0). The mean age of NEN diagnosis is the sixth decade of life. It takes almost three years from NEN diagnosis to the start of RLT. In long-term observation, RLT leads to disease stabilization in over half of the patients with progressive disease. No differences in PFS or OS depend on the radioisotope used for RLT. In Poland, organized coordination of NEN treatment in high-reference centers ensures the continuity of patient care.

Determination of pharmacokinetics and tissue distribution of a novel lutetium-labeled PSMA-targeted ligand, 177Lu-DOTA-PSMA-GUL, in rats by using LC–MS/MS

Prostate specific membrane antigen (PSMA) is known to be overexpressed in prostate cancer cells, providing as a diagnostic and therapeutic target for prostate cancer. A lutetium-labeled PSMA targeted ligand, 177Lu-DOTA-PSMA-GUL is a novel radiopharmaceutical, which has been developed for the treatment of prostate cancer. While the GUL domain of 177Lu-DOTA-PSMA-GUL binds to the antigen, the beta-emitting radioisotope, 177Lu-labeled DOTA, interacts with prostate cancer cells. However, the in vivo pharmacokinetics of intact 177Lu-DOTA-PSMA-GUL has never been characterized. This study aimed to evaluate the pharmacokinetics and tissue distribution of the radiopharmaceutical in rats by using its stable isotope-labeled analog, 175Lu-DOTA-PSMA-GUL. A sensitive liquid chromatography-tandem mass spectrometry (LC–MS/MS) analysis of 175Lu-DOTA-PSMA-GUL was developed and validated. Following intravenous injection, the plasma concentration–time profiles of 175Lu-DOTA-PSMA-GUL showed a multi-exponential decline with the average elimination half-life of 0.30 to 0.33 h. Systemic exposure increased with the dose and renal excretion is the major elimination route. Tissue distribution of 175Lu-DOTA-PSMA-GUL was most substantial in kidneys, followed by the prostate. The developed LC–MS/MS assay and the in vivo pharmacokinetic data of 175Lu-DOTA-PSMA-GUL would provide helpful information for further clinical studies to be developed as a novel therapeutic agent for prostate cancer.

177Lu-DOTA-TLX591 safety, biodistribution and dosimetry study (ProstACT-SELECT).

TPS5109 Background: The cell surface glycoprotein prostate-specific membrane antigen (PSMA) has proven to be an ideal therapeutic target in prostate cancer (PC) as it is highly expressed by malignant prostate cells.1,2 177Lu-DOTA-HuJ591-CHO (TLX591) is a radioimmunoconjugate comprised of the humanized IgG1 mAb rosopatamab, linked to the low energy beta-emitting radioisotope lutetium-177 (177Lu) via the bifunctional chelating agent DOTA-NHS ester. Chinese Hamster Ovary (CHO) cell line has been selected for the manufacture of the recombinant mAb. There is a strong rationale for investigation of TLX591 as a potential radioligand therapy for the treatment of PC, supported by previous clinical evidence of the safety of the antibody, as unconjugated and as a DOTA conjugate, and of the specificity of the antibody for PC tumors. 3,4,5,6. This multicenter Phase 1 radiomics study (ClinicalTrials.gov Identifier: NCT04786847) is designed to evaluate the safety, tolerability, biodistribution and dosimetry of TLX591 administered with best SoC to patients with PSMA-expressing, metastatic castration-resistant prostate cancer (mCRPC) progressing despite prior treatment with a novel androgen axis drug (NAAD). At the time of this abstract the study has commenced recruitment in Australia. This trial is sponsored by Telix Pharmaceuticals. Methods: The study will consist of 2 cohorts: Cohort 1: Five patients will be recruited for evaluation of biodistribution of TLX591 administered in combination with SoC. These patients will receive a single tracer (27 mCi) intravenous (IV) infusion of TLX591, and SPECT images and pharmacokinetic blood samples acquired at several time points until Day 13. A qualitative comparison of biodistribution of tracer level TLX591, as demonstrated by SPECT, with 68Ga-PSMA-11 on PET imaging will be performed to ensure equivalent (or improved) radiopharmaceutical tumour targeting. Dosimetry analysis will also be performed. If safety is confirmed by independent DSMB review, each individual patient in Cohort 1 will proceed 14 days following the initial tracer dose to a second administration of TLX591. SoC therapy will continue according to standard practice. Cohort 2: All further enrolled patients will receive two administrations of 76 mCi TLX591 for further evaluation of safety, tolerability and biodistribution, and efficacy in combination with SoC. 1. Pan M-H et al. 2009 2. Dorff TB et al., 2019 3. Tagawa, Milowsky et al., 2013 4. Tagawa et al., 2019 5. Tagawa, Whang et al., 2014 6. Niaz et al., 2020. Clinical trial information: NCT04786847.

177Lu-doxycycline as potential radiopharmaceutical: electrochemical characterization, radiolabeling, and biodistribution in tumor-bearing mice

Purpose Recent studies with doxycycline as adjuvant therapy to conventional chemotherapy have shown promising results in cancer therapy. The current study aimed to examine the capability of 177Lu-labeled tetracycline ligand, doxycycline hyclate, to use as an anticancer agent. Materials and methods Doxycycline was radiolabeled with beta-emitting radioisotope 177Lu. Complex formation and it interaction with DNA was investigated electrochemicaly. Binding of 177Lu-doxycycline to CT 26 cell line was done. Biodistribution of 177Lu-doxycycline was examined in healthy Wistar rats and in CT26 colon carcinoma tumor bearing mice by i.v. and i.p. administration, respectively. Results Doxycycline hyclate was successfully radiolabeled with 177Lu in high radiolabeling yield (>99%). The radiolabeled complex was stable in vitro in saline and human serum over 72 h. Non-radioactive Lu-doxycycline complex formation was demonstrated electrochemically as well. Intercalative interactions of the doxycycline and Lu-doxycycline with DNA were proved using simultaneously spectrophotometric and electrochemical methods. The binding of the radiolabeled complex with plasma proteins was 4.0 ± 0.4%. Partition coefficient showed the lipophilic nature of the complex similarly to free ligand. Binding curve demonstrates binding from 0.1 nM concentrations of 177Lu-doxycycline, with half-binding estimated ∼100 nM. Biodistribution studies of 177Lu-doxycycline in CT26 colon tumor bearing mice showed satisfactory accumulation rate in the tumor (2.88 ± 0.85% ID/g) 3 h after intraperitoneal injection. Both the hepatobiliary system and the urinary system were prominent as excretory routes of the radiolabeled complex. Conclusion Considering obtained results, 177Lu-doxycycline complex, due to its excellent electrochemical and biological characteristics, with emphasis on the binding ability to DNA via intercalative interaction as well as significant accumulation in the tumor, is suitable for further in vivo studies to investigate its potential use in cancer treatment.

Radioimmunotherapy of glioblastoma multiforme - Current status and future prospects.

Glioblastoma multiforme (GBM) or grade IV astrocytoma is the most diagnosed form of primary brain tumours in adults. Radioimmunotherapy (RIT), mostly in combination with conventional therapies, is presented in the current review as a therapeutic strategy of high potential in the management of GBM. A systematic literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) to identify clinical studies that employed a form of radioimmunotherapy using alpha- or beta-emitting radioisotopes. The available literature on RIT in GBM and high-grade gliomas is presented and discussed. The results suggest that this promising treatment approach merits further investigation in future clinical studies.

Using cyclotron radiation emission for ultra-high resolution x-ray spectroscopy

Cyclotron radiation emission spectroscopy (CRES) is an approach to measuring the energy of an electron trapped in an externally applied magnetic field. The bare electron can come from different interactions, including photoelectric absorption, Compton scatters, beta decay, and pair production. CRES relies on measuring the frequency of the electron’s cyclotron motion, and because the measurement times extend over 106–107 cycles, the energy resolution is on the order of a single electronvolt. To date, CRES has only been performed on internal beta-emitting radioisotopes, but the technology can be applied to x-ray spectrometery through appropriate selection of a target gas and sufficient intensity of the distinct x-ray source. The applications of this technology range from high-precision measurements of atomic energy levels to calibrations of basic science experiments, to trace element identification. In this work we explore the use of CRES for x-ray spectroscopy within the rubric of measuring the energy levels of argon. Though the energy levels of argon are well established, we adopt this motivation as an example question around which a detector may be designed. The issues we explore include target material, density, electron trapping depth, noise levels, and overall efficiency. We also discuss spectral deconvolution and how the multiple peaks obtained from a single target/source pair can be used to enhance the robustness of the measurement.

Imaging and dosimetric characteristics of 67 Cu

In recent years the use of beta-emitting radiopharmaceuticals for cancer therapy has expanded rapidly following development of therapeutics for neuroendocrine tumors, prostate cancer, and other oncologic malignancies. One emerging beta-emitting radioisotope of interest for therapy is 67Cu (t1/2: 2.6 d) due to its chemical equivalency with the widely-established positron-emitting isotope 64Cu (t1/2: 12.7 h). In this work we evaluate both the imaging and dosimetric characteristics of 67Cu, as well as producing the first report of SPECT/CT imaging using 67Cu. To this end, 67Cu was produced by photon-induced reactions on isotopically-enriched 68Zn at the Low-Energy Accelerator Facility (LEAF) of Argonne National Laboratory, followed by bulk separation of metallic 68Zn by sublimation and radiochemical purification by column chromatography. Gamma spectrometry was performed by efficiency-calibrated high-purity germanium (HPGe) analysis to verify absolute activity calibration and establish radionuclidic purity. Absolute activity measurements corroborated manufacturer-recommended dose-calibrator settings and no radionuclidic impurities were observed. Using the Clinical Trials Network anthropomorphic chest phantom, SPECT/CT images were acquired. Medium energy (ME) SPECT collimation was found to provide the best image quality from the primary 185 keV gamma emission of 67Cu. Reconstructed images of 67Cu were similar in quality to images acquired using 177Lu. Recovery coefficients were calculated and compared against quantitative images of 99mTc, 177Lu, and 64Cu within the same anthropomorphic chest phantom. Production and clinical imaging of 67Cu appears feasible, and future studies investigating the therapeutic efficacy of 67Cu-based radiopharmaceuticals are warranted.

Calculation of dose point kernel values for monoenergetic electrons and beta emitting radionuclides: Intercomparison of Monte Carlo codes

Targeted radionuclide therapy (TRT) and beta-emitting seeds brachytherapy (BSBT) exploit the characteristics of energy deposited by beta-emitting radionuclides. Monte Carlo (MC) modelling of electron transport is crucial for calculations of absorbed dose for TRT and BSBT. However, computer codes capable of providing consistent results are still limited. Since experimental validations show several difficulties, the estimation of electron dose point kernel (DPK) is often used to verify the accuracy of different MC codes. In this work, we compared DPK calculations for various point, isotropic and monoenergetic electron sources and several beta-emitting radioisotopes using the codes MCNP, EGSnrc, PENELOPE and TOPAS with different simulation options. The simulations were performed using latest versions of EGSnrc and Penelope, TOPAS version 3.3.1 and MCNP version 6.1 Monte Carlo codes. In our simulations, the geometrical model consists of a point electron source placed at the center of a water sphere emitting isotropically. The water sphere was divided into 28 shells and the energy deposition was scored within these shells. The radius of the outermost shell was 1.2R0, where R0 is the continuous slowing down approximation (CSDA) range. Five monoenergetic beta sources with energies of 0.05, 0.1, 0.5, 1 and 3 MeV were studied. Six beta-emitting radionuclides were also simulated: Lu-177, Sm-153, Ho-166, Sr-89, I-131 and Y-90. Monoenergetic electron simulations showed large deviations among the codes, larger than 13% depending on the electron energy and the distance from the source. In the cases where beta spectra of radionuclides were simulated, all MC codes showed differences from EGSnrc (used as reference value - RV) less than 3% within rE90 range (radius of the sphere in which 90% of the energy of the spectrum electrons would be deposited). TOPAS showed results comparable to EGSnrc and PENELOPE. DPK values for 0.1 MeV monoenergetic electrons, calculated using MCNP6, led to differences higher than ±5% from RV despite our attempts to tune electron transport algorithms and physics parameters.

Lutetium Lu-177 Dotatate Flare Reaction

PurposeLutetium Lu-177 dotatate is the first peptide receptor radionuclide therapy approved by the US Food and Drug Administration. Well-designed studies in Europe have shown dramatic effectiveness in improving progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors, which are progressive and generally metastatic. This therapy is a molecular targeted therapy linking a beta-emitting radioisotope to dotatate, which binds tightly to somatostatin receptors on neuroendocrine tumors cells. Various adverse effects of this therapy have been reported in the literature, including potential toxicity to renal, hepatic, and hematologic tissues and risk of second malignancy. Our study sought to explore acute adverse effects in this patient population. Methods and MaterialsWe tracked adverse effects and patient experience in our first year of therapy experience with this new agent. ResultsIn our first 12 patients who received Lutetium Lu-177 dotatate, tumor flare reactions occurred in 5 patients due to worsening symptoms of bone or soft tissue metastasis. This flare reaction can be mitigated with short course of corticosteroid therapy or other strategies. ConclusionsFlare reaction is common in patients with progressive metastatic gastroenteropancreatic neuroendocrine tumors and can be managed successfully with several strategies.

Role of theranostics in thoracic oncology.

Theranostics is a re-emerging field of medicine that aims to create targeted agents that can be used for diagnostic and/or therapeutic indications. In the past, theranostics has been used to treat neoplasms, such as thyroid cancer and neuroblastomas. More recently, theranostics has seen a resurgence with advent of new therapeutic antibodies and small molecules which can be transformed into Theranostic agents through radioconjugating with a radioactive isotope. Positron emitting radioisotopes can be used for diagnostic purposes while alpha- and beta-emitting radioisotopes can be used for therapy. The technique of radiolabeling an existing therapeutic agent (small molecule or antibody) leverages the existing qualities of that drug, and potentiates therapeutic effect by conjugating it with a cytotoxic-energy bearing radioisotope (e.g., 131-iodine, 177-lutetium). Theranostics have been used for a few decades now, starting with 131-iodine for therapy of autoimmune thyroiditis (Graves’ disease, Hashimoto’s thyroiditis) as well as for thyroid cancer. Additionally, 131-iodine-meta-iodobenzylguanidine (131-I-MIBG) initially had been used for gastroenteropancreatic neuroendocrine (carcinoid) tumors. However, recently clinical trials have start enrolling patients to evaluate efficacy of 131-I-MIBG in patients with small cell carcinoma of the lung. In the era of precision medicine and personalized targeted therapeutics, Theranostics can play a key pivotal in improving diagnostic and therapeutic specificity by increasing potency of these targeted small molecules and antibodies with radioisotopes. In this review, we will review various clinically relevant Theranostics agent and their utility in thoracic disorders, notably within oncology.

Prostate-specific membrane antigen theranostics in advanced prostate cancer: an evolving option.

To review current data for the role of prostate specific membrane antigen (PSMA) radioligand therapy (RLT) for patients with advanced prostate cancer. This review provides an update for multidisciplinary teams on the current and potential future applications of theranostics in prostate cancer. Narrative review focussing on PSMA as a target for RLT, and data using RESULTS: RLT with PSMA is an exciting therapeutic alternative to the existing management options already in use for patients with metastatic castrate-resistant prostate cancer (mCRPC). To date, most evidence exists regarding small-molecule PSMA inhibitors bound to beta-emitting radioisotopes such as 177Lu (Lu-PSMA). Prospective phase II data supports the safety and efficacy of Lu-PSMA in men with heavily pre-treated progressive mCRPC, and several late-phase randomised trials of Lu-PSMA are underway, with many more in the pipeline. Early results are encouraging, indicating that the theranostic approach may play a vital role in management of advanced prostate cancer and perhaps even in much earlier disease states. PSMA RLT is a promising new treatment option for men with mCPRC, and may also have utility in less advanced prostate cancer.

Spectral Comparison of Neutron-Irradiated Natural and Enriched Ytterbium Targets for Lu-177 Production

Beta-emitting radioisotope 177 Lu has been suggested for radioimmunotherapy, peptide receptor radionuclide therapy, or another radionuclide therapy due to its excellent properties for destroying cancer cells. In this experimental investigation, natural ytterbium ( nat Yb) and enriched 176 Yb targets were irradiated with thermal neutrons at 1.2×10 14 cm -2 s -1 neutron flux for 95 hours. Using a high-purity germanium (HPGe) detector-based spectroscopy system, the post-irradiated targets were measured and the produced radioisotopes were identified according to their gamma ray emissions. Experimental results indicated that several radioisotopes such as 169 Yb and 175 Yb dominate the post-irradiated nat Yb target, though a relatively weak intensity of 177 Lu was also recorded. In contrast, 177 Lu radioisotope dominates the gamma rays observed in the post-irradiated enriched 176 Yb target following elution with HNO 3 solution. For the first time, evidence is found of 175 Yb impurity in the post-neutron-irradiated enriched 176 Yb 2 O 3 target as a result of 176 Yb(n,2n) 175 Yb nuclear reaction. This work recommends future 177 Lu radioisotope production using enriched 176 Yb 2 O 3 target.

Rhenium-188 Labeled Radiopharmaceuticals: Current Clinical Applications in Oncology and Promising Perspectives.

Rhenium-188 (188Re) is a high energy beta-emitting radioisotope with a short 16.9 h physical half-life, which has been shown to be a very attractive candidate for use in therapeutic nuclear medicine. The high beta emission has an average energy of 784 keV and a maximum energy of 2.12 MeV, sufficient to penetrate and destroy targeted abnormal tissues. In addition, the low-abundant gamma emission of 155 keV (15%) is efficient for imaging and for dosimetric calculations. These key characteristics identify 188Re as an important therapeutic radioisotope for routine clinical use. Moreover, the highly reproducible on-demand availability of 188Re from the 188W/188Re generator system is an important feature and permits installation in hospital-based or central radiopharmacies for cost-effective availability of no-carrier-added (NCA) 188Re. Rhenium-188 and technetium-99 m exhibit similar chemical properties and represent a “theranostic pair.” Thus, preparation and targeting of 188Re agents for therapy is similar to imaging agents prepared with 99mTc, the most commonly used diagnostic radionuclide. Over the last three decades, radiopharmaceuticals based on 188Re-labeled small molecules, including peptides, antibodies, Lipiodol and particulates have been reported. The successful application of these 188Re-labeled therapeutic radiopharmaceuticals has been reported in multiple early phase clinical trials for the management of various primary tumors, bone metastasis, rheumatoid arthritis, and endocoronary interventions. This article reviews the use of 188Re-radiopharmaceuticals which have been investigated in patients for cancer treatment, demonstrating that 188Re represents a cost effective alternative for routine clinical use in comparison to more expensive and/or less readily available therapeutic radioisotopes.

Outpatient treatment for haemophilic arthropathy with radiosynovectomy: Radiation dose to family members.

One of the key features of good practice in medicine is the doctor-patient communication. Radiation protection standards for radiosynovectomy (RS) is limited. Yttrium-90 is a beta-emitting radioisotope used in RS to treat joint pain from haemophilic arthritis. ICRP 94 states that if a patient is treated with up to 200MBq, there is no need for further precautions when it comes to public exposure, however, activities can go up to 370MBq in RS for the knee. This study analysed 119 family members' safety (16.7% pregnant women). The ambient dose equivalent rate was measured within four distances. A survey was carried analysing risk groups and time spent next to patients. Results showed that family members should be advised to remain at 1.0m from the patient to decrease accumulated dose by 97.6%. The dose per activity factors estimated in this study is also a useful tool during the risk assessment and doctor/patient communication. Pamphlets were distributed with radiation protection recommendations. Ambient dose equivalent was low enough to show that RS is a safe procedure for family members, which is essential to promote adherence to RS in countries where it is needed but not performed due to lack of information on radiation safety.

Phase I/II dose-escalation trial of fractionated dose 177Lu-J591 plus 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC).

TPS339 Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. Prior studies of beta-emitting radiolabeled anti-PSMA antibody J591 demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable dose-limiting myelosuppression. Recent prospective trials have shown efficacy and safety of 177Lu-PSMA-617 in mCRPC. Studies demonstrate different binding sites of J591 and PSMA-617 and co-administration leads to non-competitive additive binding and delivery of payloads to PSMA+ cells. As the pharmacokinetics and biodistribution of the 2 agents is mostly non-overlapping (other than tumor) and given our prior dose-response data, we hypothesize that delivery of the combination will yield higher tumor delivery with less off-target toxicity (i.e. better responses without increased toxicity). Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) with metastatic disease on CT/MRI or bone scan without limit of # prior therapies (excluding bone-targeted beta-emitting radioisotopes) provided adequate organ function will be enrolled. Pre-treatment 88Ga-PSMA-11 will be performed, but results are not used for eligibility. Treatment includes fractionated 177Lu-J591 at a fixed moderate dose with escalating doses of 177Lu-PSMA-617 (7.4 – 18.5 GBq per cycle, fractionated D1 and D15) in a 3+3 dose-escalation study. Dose-limiting toxicity (DLT) is defined as attributable grade > 3 heme toxicity or grade > 2 non-heme toxicity. Following determination of recommended phase 2 dose (RP2D), the phase 2 portion will enroll in a 2-stage design. Primary endpoints: DLT and RP2D (ph 1) and PSA decline proportion (ph 2). Secondary endpoints include toxicity, radiographic response, PFS, rPFS, OS, CTC count changes. Correlatives include baseline/follow up PSMA imaging, whole body distribution of 177Lu, tissue and circulating genomic assessment, immunologic assessment, and patient reported outcomes (FACT-P and BPI-SF). Clinical trial information: NCT03545165.

Conceptual design of a personalized radiation therapy patch for skin cancer

Abstract Radiation therapy is a valuable option for treatment of skin cancer. In order to deliver the radiation dose to the superficial skin tumor, an X-ray source, electron beam radiation therapy or a radioisotope is applied. The effectiveness of these procedures is well established in the literature. Findings of some recent studies have indicated that beta particles can be of particular interest in suppressing skin tumor growth. Betaemitting radioisotopes are favorable because of the short penetration depth of their emitted particles. Beta radiation can induce significant damage in superficial skin tumor, and at the same time, result in enhanced protection of the underlying healthy tissues. In this study, we propose the design of a patch that can be used in beta radiation therapy of skin cancer patients. For that, we describe the components of this radioactive patch, as well as a proposal for the subsequent clinical application procedure. A scaffold was used as a substrate for embedding the desired beta-emitting radioisotope, and two layers of hydrogel to provide protection and shielding for the radioactively labelled scaffold. The proposed design could provide a universal platform for all beta-emitting radioisotopes. Depending on the depth of the tumor spread, a suitable beta emitter for that specific tumor can be selected and used. This is of particular and critical importance in cases where the tumor is located directly on top of the bone and for which the depth of penetration of radiation should be limited to only the tumor volume. The proposed design has the mechanical flexibility to adapt to curved body regions so as to allow the use in anatomically challenging areas of the body.

Shot noise in radiobiological systems

As a model for human tissue, this report considers the rate of free radical generation in a dilute solution of water in which a beta-emitting radionuclide is uniformly dispersed. Each decay dissipates a discrete quantity of energy, creating a large number of free radicals in a short time within a small volume determined by the beta particle range. Representing the instantaneous dissipated power as a train of randomly-spaced pulses, the time-averaged dissipated power p¯ and rate of free radical generation g¯ are derived. The analogous result in the theory of electrical circuits is known as the shot noise theorem. The reference dose of X-rays Dref producing an identical rate of free radical generation and level of oxidative stress is shown a) to increase with the square root of the absorbed dose, D, and b) to be far larger than D. This finding may have important consequences for public health in cases where the level of shot noise exceeds some noise floor corresponding to equilibrium biological processes. An estimate of this noise floor is made using the example of potassium-40, a beta-emitting radioisotope universally present in living tissue.

Theranostics: radionuclide imaging and therapy in neuroendocrine tumours

Neuroendocrine tumours (NETs) are a heterogeneous group with significant variation in morphological characteristics and functional behaviour. This poses challenges in terms of both biochemical and imaging assessment. Somatostatin receptor (sst) overexpression is documented in several malignancies. The sst subtype 2 (sst2) is overexpressed in NETs [1] and can be targeted for both somatostatin receptor scintigraphy and therapy. In-111-octreotide (Octreoscan), a gamma imaging sst agent, binds with relatively high affinity to sst 2.This has good overall sensitivity in the detection of NETs (80-100%) [2]. However, sensitivity varies according to tumour type, grade, and location (e.g. sensitivity 24% in insulinomas) [3]. PET agents such as Ga-68-DOTA-labelled somatostatin analogues have been developed with higher receptor affinity when compared to gamma-based agents. This leads to improved target-to-background ratio and provides the improved imaging characteristics inherent of PET tracers. A 2012 meta-analysis demonstrated pooled sensitivity and specificity in detecting NETs of 93% and 91%, respectively [4] with higher detection rates compared to conventional sst imaging [5]. Whilst other PET tracers such as F-18-DOPA have shown utility and higher sensitivity than conventional sst scintigraphy, their role is limited to problem solving at present. F-18-FDG can, however, provide prognostic information with patients showing uptake having a progression free survival of 0% at 2 years compared with 75±10% in those without uptake [6]. Peptide receptor radionuclide therapy (PRRT) utilises primarily beta-emitting radioisotopes such as Lu-177 and Y-90 linked to somatostatin analogues such as DOTATATE and DOTATOC. Whilst phase 3 data comparing PRRT with other therapies is awaited, treatment with Y-90 and Lu-177 PRRT has been shown to have response rates of approximately 80% and to confer a survival advantage over historical controls [7]. Unsurprisingly, extensive hepatic involvement is an adverse factor for progression free survival, whereas high tumour uptake in pre-therapy imaging confers prolonged survival [8]. Due to the differences in beta particle energy and path length, it has been postulated that Lu-177 PRRT would be best suited to smaller tumour volumes compared with Y-90 which emits a more energetic particle with longer path length. Kunikowska and colleagues have now demonstrated that overall survival is significantly higher in patients treated with combination Y-90/Lu-177-DOTATATE compared with Y-90-DOTATATE alone [9]. Research into the role of sst antagonists is relatively new. Several studies have shown a significantly greater number of binding sites for antagonists when compared to agonists such as Lu-177-DOTATATE. Pilot studies have shown 1.7-10.6 times higher tumour dose with the antagonist Lu-177-DOTA-JR11 when compared to Lu-177-DOTATATE [10]. Encouraging results have also been obtained with the use of radiosensitising chemotherapeutic agents administered together with PRRT. A phase 2 study evaluating capecitabine with Lu-177-octreotate demonstrated a response rate of 94% with no significant increase in toxicity [11]. Further work is required, however, these advances are likely to play a significant role in the future.