Do we need dosimetry for optimization of theranostics in CNS tumors?

Radiopharmaceutical theranostic treatments have grown exponentially worldwide, and internal dosimetry has attracted attention and resources. Despite some similarities with chemotherapy, radiopharmaceuticals treatments are essentially radiotherapy treatments, as the release of radiation into tissues is the determinant of the observed clinical effects. Therefore, absorbed dose calculations are key to explain dose-effect correlations and to individualize radiopharmaceutical treatments. The present article introduces the basic principles of internal dosimetry and provides an overview of available locoregional and systemic radiopharmaceutical treatments for CNS tumors. The specific characteristics of dosimetry as applied to these treatments are highlighted, along with their limitations and most relevant results. Dosimetry is performed with higher precision and better reproducibility than in the past, and dosimetric data should be systematically collected, as treatment planning and verification may help exploit the full potential of theranostic of CNS tumors.

Immunological effects of radiopharmaceutical therapy.

Radiation therapy (RT) is a pillar of cancer therapy used by more than half of all cancer patients. Clinically, RT is mostly delivered as external beam radiation therapy (EBRT). However, the scope of EBRT is limited in the metastatic setting, where all sites of disease need to be irradiated. Such a limitation is attributed to radiation-induced toxicities, for example on bone marrow and hematologic toxicities, resulting from a large EBRT field. Radiopharmaceutical therapy (RPT) has emerged as an alternative to EBRT for the irradiation of all sites of metastatic disease. While RPT can reduce tumor burden, it can also impact the immune system and anti-tumor immunity. Understanding these effects is crucial for predicting and managing treatment-related hematological toxicities and optimizing their integration with other therapeutic modalities, such as immunotherapies. Here, we review the immunomodulatory effects of α- and ß-particle emitter-based RPT on various immune cell lines, such as CD8+ and CD4+ T cells, natural killer (NK) cells, and regulatory T (Treg) cells. We briefly discuss Auger electron-emitter (AEE)-based RPT, and finally, we highlight the combination of RPT with immune checkpoint inhibitors, which may offer potential therapeutic synergies for patients with metastatic cancers.

Distribution and in situ bioaccumulation test of radioecologically relevant metals in boreal freshwater sediments.

Sediments act as important sinks for metals and their radionuclides in aquatic environments and play a crucial role in their transfer and uptake to aquatic organisms. Traditional radioecological models use radionuclide concentrations in water to predict concentrations in aquatic organisms. In this study, we investigated the distribution of radioecologically important metals (Ba, Co, Ni, Sr, U) among sediment, porewater and hypolimnion over seasons. We also studied the uptake of these metals to benthic organisms and importance of sediment as an uptake source by conducting a 28-day in situ bioaccumulation experiment with oligochaete worms (Lumbriculus variegatus). The studied metals were chosen based on common occurrence of their radioactive isotopes in nuclear fuel cycle. Measurements of total elemental concentration were used as proxies to study the behavior of specific radionuclides. Sediment and water samples were collected from two small lakes connected to a former uranium mine in Eastern Finland, and from a nearby reference lake connected to a different drainage area. Environmental characteristics and concentrations measured from sediment, porewater and overlying water indicated only minor changes between seasons. Measured metals were highly associated with sediment particles, rather than porewater or hypolimnion. Both the distribution of metals and in situ experiment indicated the importance of sediment as the main source of bioaccumulation. Significant differences in Ba, Ni and U concentrations between treatments containing contaminated sediment and reference sediment were noted, regardless of water concentrations. Additionally, as U contaminated lakes lacked seasonal overturn during our monitoring period, metal distribution and environmental conditions remained unchanged in deeper parts of those lakes. Lastly, the results of this in situ bioaccumulation experiment are in line with the findings of our previous laboratory study using sediments from these same lakes.

Advancements in microbial-mediated radioactive waste bioremediation: A review.

The global production of radioactive wastes is expected to increase in the coming years as more countries have resorted to adopting nuclear power to decrease their reliance on fossil-fuel-generated energy. Discoveries of remediation methods that can remove radionuclides from radioactive wastes, including those discharged to the environment, are therefore vital to reduce risks-upon-exposure radionuclides posed to humans and wildlife. Among various remediation approaches available, microbe-mediated radionuclide remediation have limited reviews regarding their advances. This review provides an overview of the sources and existing classification of radioactive wastes, followed by a brief introduction to existing radionuclide remediation (physical, chemical, and electrochemical) approaches. Microbe-mediated radionuclide remediation (bacterial, myco-, and phycoremediation) is then extensively discussed. Bacterial remediation involves biological processes like bioreduction, biosorption, and bioprecipitation. Bioreduction involves the reduction of water-soluble, mobile radionuclides to water-insoluble, immobile lower oxidation states by ferric iron-reducing, sulfate-reducing, and certain extremophilic bacteria, and in situ remediation has become possible by adding electron donors to contaminated waters to enrich indigenous iron- and sulfate-reducing bacteria populations. In biosorption, radionuclides are associated with functional groups on the microbial cell surface, followed by getting reduced to immobilized forms or precipitated intracellularly or extracellularly. Myco- and phycoremediation often involve processes like biosorption and bioaccumulation, where the former is influenced by pH and cell concentration. A Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis on microbial remediation is also performed. It is suggested that two research directions: genetic engineering of radiation-resistant microorganisms and co-application of microbe-mediated remediation with other remediation methods could potentially result in the discovery of in situ or ex situ microbe-involving radioactive waste remediation applications with high practicability. Finally, a comparison between the strengths and weaknesses of each approach is provided.

Does long-term radiation exposure in Chornobyl impact the reproductive structures of Nuphar lutea (Linné) Smith?

The 1986 Chornobyl Nuclear Power Plant accident caused radioactive contamination of water bodies within the Pripyat River floodplain, resulting in the accumulation of radionuclides by macrophytes, which are fundamental species in water ecosystems. Yellow water lily Nuphar lutea (L.) Smith., a macrophyte playing a significant role in the formation of vegetation cover in aquatic ecosystems, is commonly considered as a bioindicator of water pollution. In this study, we investigate the potential of N. lutea as an indicator of radionuclide contamination in water bodies, particularly through changes in its reproductive structures, such as pollen viability, morphology of pollen grains, seeds, and fruits. Our findings reveal that pollen viability remains stable at total absorbed dose rates below 14.4 µGy/h, with only 1-4% of sterile grains. However, beyond this threshold the percentage of sterile grains increases nearly fivefold, pointing to high internal plant exposure to 90Sr. A similar trend was observed in the allometry and size of pollen grains, where small and flattened grains are formed in the reservoir with the highest external radiation dose rate (≥14.4 µGy/h). On the other hand, while morphometric parameters of fruits are influenced by radiation, their variation appears to be the result of a combination of physicochemical factors and the trophic status of a water body. Our research highlights the adverse impact of long-term radiation exposure on the male reproductive system of N. lutea and shows the potential of using the pollen grains sterility as an indicators of heavily radionuclide-contaminated water bodies. Additionally, we observed gradual changes in a pollen allometric length-to-width coefficient as the radiation dose level increases.

Synthesis and immunotherapy efficacy of a PD-L1 small-molecule inhibitor combined with its 131I-iodide labelled isostructural compound.

Although antibody-based immune checkpoint blockades have been successfully used in antitumor immunotherapy, the low response rate is currently the main problem. In this work, a small-molecule programmed cell death-ligand (PD-L1) inhibitor, LG-12, was developed and radiolabeled with 131I to obtain the chemically and biologically identical radiopharmaceutical [131I]LG-12, which aimed to improve the antitumor effect by combination of LG-12 and [131I]LG-12. LG-12 showed high inhibitory activity to PD-1/PD-L1 interaction. The results of cell uptake and biodistribution studies indicated that [131I]LG-12 could specifically bind to PD-L1 in B16-F10 tumors. It could induce immunogenic cell death and the release of high mobility group box 1 and calreticulin. The combination of [131I]LG-12 and LG-12 could significantly inhibit tumor growth and resulted in enhanced antitumor immune response. This PD-L1 small-molecule inhibitor based combination strategy has great potential for tumor treatment.

Angiogenic biomarkers of response to treatment with peptide receptor radionuclide therapy in neuroendocrine tumours.

BACKGROUND: Neuroendocrine tumours (NETs) are a heterogeneous group of tumours, which is characterized by rich vascularization. The role of angiogenesis in NETs has been widely researched. Peptide receptor radionuclide therapy (PRRT) is an effective treatment method for patients with disease progression in NETs. Due to the heterogeneousness of NETs, the response to treatment varies. Currently, the finding of efficient markers helpful in assessing the response to treatment in NETs is crucial. The aim of this study was to assess chromogranin A (CgA) and angiogenic factors in gastro-entero-pancreatic (GEP) and broncho-pulmonary (BP) NET patients treated with PRRT. MATERIAL AND METHODS: The study group included 40 patients with GEP NETs and BP NETs who completed four cycles of PRRT. Serum levels of CgA and angiogenic factors such as vascular endothelial growth factor (VEGF), its receptors (VEGF-R1, VEGF-R2, VEGF-R3), were assessed before and after four cycles of PRRT. All tests were determined using ELISA. RESULTS: The concentration of CgA, VEGF-R1 and VEGF-R2 decreased significantly, whereas VEGF-R3 increased significantly after PRRT. PRRT did not affect VEGF, it was similar before and after the radioisotope treatment. Based on AUROC, only for VEGF-R1 AUC was a consequence of 0.7 which can be considered as a good response to PRRT treatment. CONCLUSIONS: VEGF-R1 may be a potential biomarker useful in assessing the effectiveness of PRRT in NET patients.

Precise Localization of Urine Leak After Renal Transplantation on Radionuclide Renography: Added Value of the Unclamped Drainage Tube and SPECT-CT.

Identifying and localizing the site of post-renal transplantation urine leaks is important for patient management and treatment planning. Renal scintigraphy is a proven modality for confirming urine leaks after complicated post-renal transplantation. Routinely, renogram studies are performed with a clamped extraperitoneal drain. This results in the spread of radioactivity in the abdominal region, which makes localization of the leak site difficult in the planar images. Here we are trying to give an insight into minimalizing the accumulated urine volume by an unclamped extraperitoneal drain in order to precisely localize the site of the leak.

Analysis of bone single-photon emission CT/CT and diffusion-weighted MR imaging in medication-related osteonecrosis of the jaw: focusing on the correlation between standardized uptake values and apparent diffusion coefficient values.

The purpose of this study is to investigate bone SPECT/CT and diffusion-weighted MR imaging (DWI) in medication-related osteonecrosis of the jaw (MRONJ), focusing on the correlation between standardized uptake values (SUVs) and apparent diffusion coefficient (ADC) values. Twenty-nine patients with MRONJ who underwent SPECT/CT and DWI were included in this study. SUVs (maximum and mean) with SPECT/CT, and ADC values (maximum, mean and minimum) with DWI were analyzed on characteristics in MRONJ, such as stage, location, medication and underlying disease, by Mann-Whitney U test. Furthermore, the correlation between SUVs and ADC values for characteristics in MRONJ were assessed by Spearman's rank correlation test for nonparametric data. A p-value lower than 0.05 was considered as statistically significant. SUVs and ADC values have no significant differences for all characteristics in MRONJ. Negative correlations were found in all cases and in stage 2 cases, and no correlations were found in stage 3 cases. In addition, negative correlations were found in maxillary cases, mandibular cases, non-bisphosphonate cases, osteoporosis cases, and malignant tumor cases. In conclusion, this study found multiple correlations between SUVs and ADC values in MRONJ, especially in stage 2. Suggesting that ADC values and SUVs may change with disease progression and the possibility of predicting MRONJ progression by SUVs and ADC values.

Biophysical modeling of low-energy ion irradiations with NanOx.

BACKGROUND: Targeted radiotherapies with low-energy ions show interesting possibilities for the selective irradiation of tumor cells, a strategy particularly appropriate for the treatment of disseminated cancer. Two promising examples are boron neutron capture therapy (BNCT) and targeted radionuclide therapy with α $\alpha$ -particle emitters (TAT). The successful clinical translation of these radiotherapies requires the implementation of accurate radiation dosimetry approaches able to take into account the impact on treatments of the biological effectiveness of ions and the heterogeneity in the therapeutic agent distribution inside the tumor cells. To this end, biophysical models can be applied to translate the interactions of radiations with matter into biological endpoints, such as cell survival. PURPOSE: The NanOx model was initially developed for predicting the cell survival fractions resulting from irradiations with the high-energy ion beams encountered in hadrontherapy. We present in this work a new implementation of the model that extends its application to irradiations with low-energy ions, as the ones found in TAT and BNCT. METHODS: The NanOx model was adapted to consider the energy loss of primary ions within the sensitive volume (i.e., the cell nucleus). Additional assumptions were introduced to simplify the practical implementation of the model and reduce computation time. In particular, for low-energy ions the narrow-track approximation allowed to neglect the energy deposited by secondary electrons outside the sensitive volume, increasing significantly the performance of simulations. Calculations were performed to compare the original hadrontherapy implementation of the NanOx model with the present one in terms of the inactivation cross sections of human salivary gland cells as a function of the kinetic energy of incident α $\alpha$ -particles. RESULTS: The predictions of the previous and current versions of NanOx agreed for incident energies higher than 1 MeV/n. For lower energies, the new NanOx implementation predicted a decrease in the inactivation cross sections that depended on the length of the sensitive volume. CONCLUSIONS: We reported in this work an extension of the NanOx biophysical model to consider irradiations with low-energy ions, such as the ones found in TAT and BNCT. The excellent agreement observed at intermediate and high energies between the original hadrontherapy implementation and the present one showed that NanOx offers a consistent, self-integrated framework for describing the biological effects induced by ion irradiations. Future work will focus on the application of the latest version of NanOx to cases closer to the clinical setting.

Advances in prostate cancer treatment: Radionuclide therapy for prostate cancer.

The optimal treatment of metastatic castration-resistant prostate cancer (mCRPC) continues to be challenging, given the multitude of life prolonging treatment options. Radionuclide therapy delivers concentrated doses of radiation via ionizing particles chelated to ligands or antibody-based molecules with specific tumor targets and is approved for patients with treatment resistant mCRPC. Variations of radionuclide therapies within the continuum of prostate cancer treatment are being investigated. Landmark phase III clinical trials of beta-emitting 177Lu-PSMA radionuclide therapy have demonstrated the utility of 177Lu-PSMA in the treatment of mCRPC. Further research into alpha-emitting radionuclide therapy and vectors may provide alternative treatments for patients with treatment resistant mCRPC. As radionuclide therapy treatment options evolve, assessing appropriate patient selection for radionuclide therapy is important and may be facilitated by advances in imaging and blood-based biomarkers. Exploration of other approved life prolonging therapies in combination with radionuclide therapy has shown increasing interest as a potential method of combatting radionuclide therapy resistance. In this chapter, we review various types of radionuclide therapies for mCRPC, patient selection for radionuclide therapy from outcome predictions, ongoing clinical trials of radiopharmaceuticals for treatment of prostate cancer, and the resistance mechanisms and challenges to radionuclide therapy.

Targeted radionuclide therapy for head and neck squamous cell carcinoma: a review.

Head and neck squamous cell carcinoma (HNSCC) is a type of head and neck cancer that is aggressive, difficult to treat, and often associated with poor prognosis. HNSCC is the sixth most common cancer worldwide, highlighting the need to develop novel treatments for this disease. The current standard of care for HNSCC usually involves a combination of surgical resection, radiation therapy, and chemotherapy. Chemotherapy is notorious for its detrimental side effects including nausea, fatigue, hair loss, and more. Radiation therapy can be a challenge due to the anatomy of the head and neck area and presence of normal tissues. In addition to the drawbacks of chemotherapy and radiation therapy, high morbidity and mortality rates for HNSCC highlight the urgent need for alternative treatment options. Immunotherapy has recently emerged as a possible treatment option for cancers including HNSCC, in which monoclonal antibodies are used to help the immune system fight disease. Combining monoclonal antibodies approved by the US Food and Drug Administration, such as cetuximab and pembrolizumab, with radiotherapy or platinum-based chemotherapy for patients with locally advanced, recurrent, or metastatic HNSCC is an accepted first-line therapy. Targeted radionuclide therapy can potentially be used in conjunction with the first-line therapy, or as an additional treatment option, to improve patient outcomes and quality of life. Epidermal growth factor receptor is a known molecular target for HNSCC; however, other targets such as human epidermal growth factor receptor 2, human epidermal growth factor receptor 3, programmed cell death protein 1, and programmed death-ligand 1 are emerging molecular targets for the diagnosis and treatment of HNSCC. To develop successful radiopharmaceuticals, it is imperative to first understand the molecular biology of the disease of interest. For cancer, this understanding often means detection and characterization of molecular targets, such as cell surface receptors, that can be used as sensitive targeting agents. The goal of this review article is to explore molecular targets for HNSCC and dissect previously conducted research in nuclear medicine and provide a possible path forward for the development of novel radiopharmaceuticals used in targeted radionuclide therapy for HNSCC, which has been underexplored to date.

Development and preclinical characterization of a novel radiotheranostic EphA2-targeting bicyclic peptide.

Erythropoietin-producing hepatocellular receptor A2 (EphA2), is a receptor tyrosine kinase involved in cell-cell interactions. It is known to be overexpressed in various tumors and is associated with poor prognosis. EphA2 has been proposed as a target for theranostic applications. Low molecular weight peptide-based scaffolds with low nanomolar affinities have been shown to be ideal in such applications. Bicyclic peptides have emerged as an alternative to traditional peptides for this purpose, offering affinities comparable to antibodies due to their constrained nature, along with high tissue penetration, and improved stability compared to linear counterparts. This study presents the development and comprehensive in vitro and in vivo preclinical evaluation of BCY18469, a novel EphA2-targeting bicyclic peptide-based radiotheranostic agent. Methods: The EphA2-targeting Bicycle® peptide BCY18469 was identified through phage-display and chemically optimized. BCY18469 was radiolabeled with 68Ga, 177Lu and 111In. The physicochemical properties, binding affinity and internalization as well as specificity of the peptide were evaluated in vitro. In vivo PET/MR and SPECT/CT imaging studies were performed using [68Ga]Ga-BCY18469 and [111In]In-BCY18469, respectively, along with biodistribution of [177Lu]Lu-BCY18469 up to 24 h post injection in HT1080- and PC-3-tumor bearing BALB/c nu/nu EphA2-overexpressing xenograft mouse models. Results: The EphA2-targeting bicyclic peptide BCY18469 showed high binding affinity toward human and mouse EphA2 (1.9 and 3.8 nM, respectively). BCY18469 specifically bound and internalized into EphA2-expressing HT1080 cells. Imaging studies showed high tumor enrichment at early time-points (SUV of 1.7 g/mL at 1 h p.i. and 1.2 g/mL at 2 h p.i. in PET/MRI, HT1080 xenograft) with tumor contrast as early as 5 min p.i. and kidney-mediated clearance. Biodistribution studies revealed high early tumor uptake (19.5 ± 3.5 %ID/g at 1 h p.i., HT1080 xenograft) with SPECT/CT imaging further confirming these findings (5.7 ± 1.5 %ID/g at 1 h p.i., PC-3 xenograft). Conclusion: BCY18469 demonstrated high affinity, specific targeting of EphA2, a favorable biodistribution profile, and clearance through renal pathways. These findings underscore the potentially important role of bicyclic peptides in advancing radiotheranostic approaches and encourage additional translational research.

The value of simplified models of radionuclide transport for the safety assessment of nuclear waste repositories: A benchmark study.

In order to assess sites for a deep geological repository for storing high-level nuclear waste safely in Germany, various numerical models and tools will be in use. For their interaction within one workflow, their reproducibility, and reliability version-controlled open-source solutions and careful documentation of model setups, results and verifications are of special value. However, spatially fully resolved models including all relevant physical and chemical processes are neither computationally feasible for large domains nor is the data typically available to parameterize such models. Thus, simplified models are crucial for the pre-assessment of possible sites to narrow down the list of suitable candidates for which detailed site investigations and fully resolved models will be done at a later stage. Still, the accuracy of these simplified models is of importance as the pre-assessment of suitable sites will be based on them. In this study, we compare the modelling capabilities of TransPyREnd, a one-dimensional transport code based on finite differences, specifically developed for the fast estimation of radionuclide transport by the German federal company for radioactive waste disposal (BGE), with OpenGeoSys, which is a modelling platform based on finite elements in up to three spatial dimensions. Both codes are used in the site selection procedure for the German nuclear waste repository. The comparison of the model results of TransPyREnd and OpenGeoSys is augmented by comparisons with an analytical solution for a homogeneous material. For the purpose of numerical benchmarking, we consider a geological profile located in southern Germany as an example where the hypothetical repository is located in a clay-stone formation. TransPyREnd and OpenGeoSys yield overall similar results. However, both codes use different discretizations which impact is the highest for strongly sorbing compounds, while the difference gets negligible for less sorbing and more diffusive compounds as higher diffusion tends to blur the initial conditions. Overall, the OpenGeoSys model is more exact whereas the TransPyREnd model has considerable faster run times. We found in our example, that significant substance amounts are only leaving the host rock formation, if apparent diffusion is high, for which case both codes give similar results, while relative differences are considerable for strongly sorbing compounds. However, in the latter case no significant substance amount of radionuclides leaves the host-rock formation, thus deeming the differences in the model results minor for the overall safety assessments of sites.

Identification of Wandering Masses and Tumor Heterogeneity on 68Ga-DOTATATE and 18F-FDG PET/CT in Metastatic Grade II Neuroendocrine Tumor with Increased Somatostatin Receptor Expression After Combined Chemotherapy and PRRT.

Neuroendocrine tumors (NETs) may manifest as large masses in the abdominopelvic region that exhibit mobility and shifting, potentially leading to diagnostic uncertainty both before and after treatment. A meticulous analysis of PET/CT scans is advantageous in accurately identifying the precise location of large abdominopelvic masses. Tumor heterogeneity may be present in NETs with large abdominopelvic masses and may be easily identified on dual-tracer (68Ga-DOTATATE and 18F-FDG) PET/CT scans. In this scenario, the combined use of chemotherapy and peptide receptor radionuclide therapy is a more effective treatment option than monotherapy. Here, we present a case of a NET with wandering, large, heterogeneous masses in the abdominopelvic regions that were identified using dual-tracer PET/CT. After the administration of temozolomide chemotherapy in a combined chemotherapy-peptide receptor radionuclide therapy approach, we observed an upregulation in the expression of somatostatin receptor in the abdominopelvic masses.

Efficient α and ß- radionuclide therapy targeting fibroblast activation protein-α in an aggressive preclinical mouse tumour model.

PURPOSE: Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with 225Ac or 131I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB). METHODS: We studied the biodistribution and tumour uptake of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [225Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [225Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB. RESULTS: The biodistribution showed high tumour uptake of [131I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [225Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [131I]I-GMIB-4AH29 or [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [225Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy. CONCLUSION: [225Ac]Ac-DOTA-4AH29 and [131I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [225Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy.

PRRT in high-grade digestive neuroendocrine neoplasms (NET G3 and NEC).

Peptide receptor radionuclide therapy (PRRT) has been primarily studied in low and intermediate-grade digestive neuroendocrine tumors (NET G1-G2). The documentation of a similar benefit for high-grade digestive neuroendocrine neoplasms (NEN) has been limited. This review evaluates the use of PRRT for high-grade digestive NEN (well-differentiated NET G3 and poorly differentiated neuroendocrine carcinomas [NEC]). We identified one phase III trial and seven retrospective studies reporting specifically on PRRT outcome of >10 digestive high-grade NEN patients. The retrospective single-arm studies indicate a benefit for PRRT in NET G3. The randomized phase III NETTER-2 trial demonstrates major PFS superiority of PRRT versus somatostatin analog therapy as the first-line treatment for the NET G3 subgroup. PRRT can now be considered a potential first-line treatment for somatostatin receptor-positive NET G3 patients, but whether it should be the first-line standard of care for all NET G3 patients is still not clarified. For NEC, scarce data are available, and pathologic distinction between NEC and NET G3 can be difficult when Ki-67 is below 55%. PRRT could be considered as a treatment for refractory NEC in very selected cases when there is a high uptake on somatostatin receptor imaging, Ki-67 is below 55%, and there is no rapid tumor progression.

PSMA and Sigma-1 receptor dual-targeted peptide mediates superior radionuclide imaging and therapy of prostate cancer.

Radionuclide therapy, in particular peptide receptor radionuclide therapy (PRRT), has emerged as a valuable means to combat malignant tumors. The specific affinity of ACUPA peptide toward prostate-specific membrane antigen (PSMA) renders the successful development of PRRT for prostate cancer. The clinical outcome of PRRT is, however, generally challenged by moderate tumor uptake and off-target toxicity. Here, we report on a novel design of Sigma-1 receptor and PSMA dual-receptor targeted peptide (S1R/PSMA-P) for superior radionuclide imaging and therapy of prostate cancer. S1R/PSMA-P was acquired with good purity and could efficiently be labeled with 177Lu to yield 177Lu-S1R/PSMA-P with high specific activity and radiostability. Interestingly, 177Lu-S1R/PSMA-P revealed greatly enhanced affinity to LNCaP cells over single-targeted control 177Lu-PSMA-617. The single photon emission computed tomography (SPECT) imaging demonstrated exceptional uptake and retention of 177Lu-S1R/PSMA-P in LNCaP tumor, affording about 2-fold better tumor accumulation while largely reduced uptake by most normal tissues compared to 177Lu-PSMA-617. The selective uptake in LNCaP tumor was also visualized by positron emission tomography (PET) with 68Ga-S1R/PSMA-P. In accordance, a single and low dosage of 177Lu-S1R/PSMA-P at 11.1 MBq effectively suppressed tumor growth without causing apparent side effects. This dual-targeting strategy presents an appealing radionuclide therapy for malignant tumors.