There is a growing worldwide interest in the detection and targeted treatment of cancer with radiotheranostics as part of precision medicine. This article reviews some of the developments in theranostics, namely, approved radiopharmaceuticals, agents in late-stage clinical trials, emerging radionuclides and targets, as well as operational and regulatory challenges. Other areas of development include use of novel ligands, new indications, and combinations with other systemic therapies. We aim to provide an overview of radiopharmaceutical therapies in use and in clinical development and consider some of the challenges in East and Southeast Asia, including an innovative yet highly regulated environment in Singapore.

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a severe complication of SSc, characterised by progressive fibrosis and inflammation. Current diagnostic tools do not accurately differentiate progressors from non-progressors, limiting timely intervention. 68Ga-FAPI-46 is a positron emission tomography (PET) tracer targeting fibroblast activation protein alpha (FAP), a marker of activated fibroblasts, with high affinity and retention. Optimal imaging timepoints and PET parameters for 68Ga-FAPI-46 PET/CT imaging in fibroinflammatory disorders remain undefined. This exploratory study investigated early versus late 68Ga-FAPI-46 PET parameters in evaluating SSc-ILD. Early (10 min) and late (60 min) 68Ga-FAPI-46 PET parameters were compared between progressive (n = 8) and non-progressive SSc-ILD (n = 14), defined by INBUILD trial criteria. PET parameters were correlated with pulmonary function test (PFT) and HRCT parameters. Optimal thresholds for identified PET parameters were determined by closest-to-(0,1) criterion. Early total lesion FAPI uptake (median TL-FAPI10min 1245 vs. 714, p = 0.020) and affected lung volume (median AV10min 514 ml vs. 368 ml, p = 0.042) were significantly higher in progressors than non-progressors. Early PET parameters showed stronger, more consistent correlations with PFT and quantitative HRCT parameters than late PET parameters. Volume-based compared to intensity-based PET parameters more consistently correlated with PFT and quantitative HRCT parameters. TL-FAPI10min threshold of 928 had the best diagnostic performance (AUC 0.80). This exploratory study showed that 68Ga-FAPI-46 PET/CT imaging, specifically early volume-based PET parameters, was associated with patients with recent disease progression of SSc-ILD. Prospective validation in treatment-response studies is needed to confirm the clinical utility of these PET parameters and their identified preliminary thresholds.

AIM:Asia-Pacific guidelines recommend selective internal radiation therapy (SIRT) as an alternative to transarterial chemoembolization for patients with intermediate or advanced hepatocellular carcinoma (HCC) and, in more limited circumstances, for metastatic colorectal cancer (mCRC). This multicenter, single-arm, prospective, observational registry evaluated safety and efficacy of SIRT with 90Y resin microspheres for HCC or mCRC in Asia. PATIENTS & METHODS:Adults (n = 202) with HCC or mCRC eligible for, and scheduled to receive, SIRT with 90Y resin microspheres at participating centers were recruited. Dosimetry methods used were body surface area or partition model at the physician's discretion. The primary endpoints were overall response rate (ORR), frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), and liver function baseline changes. RESULTS:ORR at 3 or 6 months was 56% (HCC) and 33% (mCRC). 491 TEAEs were reported in 125 patients and 71 SAEs were reported in 29 patients. Performance status was maintained or improved in most patients 6 months after SIRT. CONCLUSION:SIRT may offer clinicians a targeted, single-use approach for HCC or mCRC palliative care or for tumor down-sizing or down-staging in Asia. Controlled trials of SIRT using personalized dosimetry could further define a role for SIRT in these populations.

INTRODUCTION:Prostate cancer is the second most common cancer and the leading cause of cancer-related deaths in men. Patients with metastatic castration-resistant prostate cancer (mCRPC) with diffuse bone metastases have limited treatment options due to severe hematological toxicity risks. This study evaluates the safety and efficacy of [177Lu]Lu-PSMA radioligand therapy (RLT) in this high-risk group within an Asian population. METHODS:We conducted a retrospective analysis of 48 mCRPC patients with PSMA-avid diffuse bone metastases treated with [177Lu]Lu-PSMA-RLT between May 9, 2018 and Jan 10, 2023. Patients received up to 4 to 6 initial therapy cycles, with additional cycles considered for those who responded initially but later progressed. Primary and secondary endpoints included overall survival (OS), PSA progression-free survival (PFS), PSA response, clinical response, and toxicity assessment. RESULTS:Median OS was 9.3 months. Any PSA response was observed in 75% of patients. Notably, 48% achieved a ≥50% PSA reduction, correlating with a longer median OS (11.6 vs. 8.6 months, p = 0.03). Median PSA PFS was 3.2 months, with improved outcomes observed in patients achieving ≥50% PSA reduction (6.0 vs. 1.8 months, p < 0.0001). Pain relief was reported in 43% of patients, with a median pain score reduction of 5 points. The most common adverse effect was hepatotoxicity, with anemia in 27%, neutropenia in 27%, and thrombocytopenia in 21%. CONCLUSION:[177Lu]Lu-PSMA-RLT demonstrates clinically meaningful benefits in survival and symptom management with an acceptable safety profile for mCRPC patients with extensive bone metastases. These findings support [177Lu]Lu-PSMA-RLT as a viable treatment option for this challenging population.

The proper functioning of mitochondria requires preserving the membrane potential (ΔΨm) within a narrow window. Significant deviation from the membrane potential of mitochondria is a well-established indicator of mitochondrial dysfunction. Various pathological conditions, such as cancer, diabetes, and cardiotoxicity, have been linked to mitochondrial dysfunction, highlighting the need for reliable methods to assess membrane potential in vivo. Hence, there is a need to explore radiolabeled lipophilic cations that accumulate within mitochondria in proportion to the potential gradient. The lipophilic organic cation triphenylphosphonium (TPP) has gained attention as a promising tracer for non-invasive imaging of mitochondrial function. It has been labeled with various radioisotopes, such as F-18, for imaging mitochondrial membrane potential in cancer through positron emission tomography (PET). The first attempt to quantify membrane potential in living organisms by examining the biodistribution of the 11C-labeled TPP derivative was reported more than 30 years ago. Herein, a series of TPP derivatives, together with TPP, have been radiolabeled with 64Cu for imaging gliomas, which are characterized by high mitochondrial content. 2-(diphenylphosphoryl)-ethyldiphenylphosphonium (TPEP) has demonstrated superior tumor uptake and favorable tumor-to-background ratios, leading to its selection for further assessment as a magnetic resonance imaging contrast agent. Building on these findings, we developed 68Ga-labeled TPP and TPEP as novel PET tracers for rhabdomyosarcoma. To assess how the choice of targeting moiety and bifunctional chelator influences tracer performance, biodistribution studies were conducted in mitochondrial-rich rhabdomyosarcoma patient-derived xenografts. These results support further development of 68Ga-TPP-based agents for mitochondrial-targeted oncologic imaging applications.

Introduction: Transarterial radioembolisation (RE) using yttrium-90 (Y-90) microspheres is a widely used locoregional therapy for a broad spectrum of hepatocellular carcinoma (HCC) given its favourable safety profile. We evaluated the real-world outcomes of unresectable HCC treated with resin Y-90 RE and the relationship between tumour absorbed dose and subsequent curative therapy with survival. Methods: Included were consecutive patients treated with Y-90 resin microspheres RE for unresectable HCC between January 2008 and May 2019 at the National Cancer Centre Singapore/Singapore General Hospital. The outcomes were stratified by tumour burden, distribution, presence of portal vein invasion (PVI) and liver function to improve prognostication. Results: The median overall survival (OS) evaluated on 413 included patients was 20.9 months (95% CI: 18.2-24.0). More than half of the patients (214/413, 51.8%) had HCC beyond up-to-seven criteria, and 37.3% had portal vein invasion (154/413, 37.3%). Majority (71.7%) had dosimetry calculated based on the partition model. Patients who received >= 150 Gy to tumour had significantly better outcomes (OS 32.2 months, 95% CI: 18.3-46.4) than those who did not (OS 17.5 months, 95% CI: 13.7-22.7, p < 0.001). Seventy patients (17%) received curative therapies after tumour was downstaged by Y-90 RE and had better OS of 79.7 months (95% CI: 40.4 - NE) compared to those who did not receive curative therapies (OS 17.1 months; 95% CI: 13.5-20.4, p < 0.001). RE-induced liver injury was observed in 5.08% of the patients while 3.2% of the patients had possible radiation pneumonitis but none developed Grade 3-4 toxicity. For HCC without PVI, OS differed significantly with performance status, albumin-bilirubin grade, tumour distribution, and radiation dose; for HCC with PVI, Child-Pugh class and AFP were significant predictors of survival. Conclusions: Treatment outcomes for unresectable HCC using Y-90 RE were favourable. Incorporating tumour burden and distribution improved prognostication. Patients who received tumour absorbed dose above 150 Gy had better OS. Patients who subsequently received curative therapies after being downstaged by Y-90 RE had remarkable clinical outcomes.

PURPOSE:Peptide receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NETs). It has been shown to be effective and well tolerated in patients with metastatic NETs in several centres in the USA, Europe, and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. METHODS:One hundred and seven (107) patients with metastatic NETs who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST 1.1 and qualitative analysis were examined. The overall and progression-free survival curves were also evaluated. RESULTS:The median progression-free survival was 49 months. Response assessment after completion of treatment showed that 33 (37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression-free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. CONCLUSION:Our results show that PRRT is safe and effective in the treatment of metastatic NET in the Asian population. There was a significant difference in the progression-free survival curves between low-grade and high-grade NET and in the progression-free and overall survival comparing the number of cycles received.

Mesenchymal stem/stromal cells (MSCs) are an extensively studied cell type in clinical trials due to their easy availability, substantial ex vivo proliferative capacity, and therapeutic efficacy in numerous pre-clinical animal models of disease. The prevailing understanding suggests that their therapeutic impact is mediated by the secretion of exosomes. Notably, MSC exosomes present several advantages over MSCs as therapeutic agents, due to their non-living nature and smaller size. However, despite their promising therapeutic potential, the clinical translation of MSC exosomes is hindered by an incomplete understanding of their biodistribution after administration. A primary obstacle to this lies in the lack of robust labels that are highly sensitive, capable of directly and easily tagging exosomes with minimal non-specific labeling artifacts, and sensitive traceability with minimal background noise. One potential candidate to address this issue is radioactive iodine. Protocols for iodinating exosomes and tracking radioactive iodine in live imaging are well-established, and their application in determining the biodistribution of exosomes has been reported. Nevertheless, the effects of iodination on the structural or functional activities of exosomes have never been thoroughly examined. In this study, we investigate these effects and report that these iodination methods abrogate CD73 enzymatic activity on MSC exosomes. Consequently, the biodistribution of iodinated exosomes may reflect the biodistribution of denatured exosomes rather than functionally intact ones.

AIM Lutetium-177 (Lu-177) prostate-specific membrane antigen radioligand therapy (PSMA-RLT) is a promising therapy for metastatic castration-resistant prostate cancer (mCRPC), but there is limited data of its efficacy and safety in Asian population. We aim to explore the clinical outcomes of Lu-177 PSMA-RLT in this population. METHODS We evaluated 84 patients with progressive mCRPC receiving Lu-177 PSMA-RLT between 9 May 2018 and 21 February 2022. Lu-177-PSMA-I&T was administered at 6-8-week intervals. Primary end point was overall survival (OS), and secondary end points included prostate-specific antigen (PSA) progression-free survival (PFS), PSA response rate, clinical response, toxicity assessment, and prognostic indicators. RESULTS The median OS and PSA PFS were 12.2 and 5.2 months, respectively. PSA decline of ≥50% was observed in 51.8% of patients. Patients achieving PSA response had longer median OS (15.0 vs. 9.5 months, p = .03) and PSA PFS (6.5 vs. 2.9 months, p < .001). Pain score improvement was seen in 19 out of 34 patients. A hematotoxicity of ≥grade 3 was observed in 13 out of 78 patients. Multivariable analyses showed that PSA velocity, alkaline phosphatase, hemoglobin (Hb), and the number of treatment cycles were independent prognostic indicators for OS. The retrospective design was the main limitation of the study. CONCLUSIONS Our study demonstrated a similar safety and efficacy of Lu-177 PSMA-RLT in Asian mCRPC patients compared to the existing literature. A PSA decline ≥50% was associated with longer OS and PSA PFS. Several prognostic indicators for patient outcomes were also identified.

Introduction: Despite advances in diagnosis and management, patients with advanced pheochromocytomas and paragangliomas (PPGL) face limited treatment options. This study aims to evaluate the safety and efficacy of peptide receptor radionuclide therapy (PRRT) in patients with advanced PPGL, based on a single-institution experience and provide a comprehensive review of the literature.Methods: A retrospective analysis was conducted on patients with advanced pheochromocytoma and paraganglioma who received PRRT at a single institution from April 2012 to March 2022. Clinical characteristics, treatment response, adverse events, and survival outcomes were assessed. A systematic literature review was also performed. Results: A total of 15 patients with advanced PPGL were included, the majority of whom had both metastatic and functional disease. Most patients received four infusions of 177Lu-DOTATATE (73%). The median therapeutic 177Lu-DOTATATE radioactivity for each infusion was 7.4 GBq. Only one patient was treated with one infusion of 90Y-DOTATATE (4.2 GBq) in addition to three infusions of Lu-177 DOTATATE. Overall, PRRT suggests a promising efficacy with disease control rate of 63.6% by RECIST v1.1. The median overall survival (OS) was not reached and the median progression free survival (PFS) was 25.9 months. In terms of safety, PRRT was well tolerated. Review of the literature revealed consistent findings, supporting the efficacy and safety of PRRT in PPGL. Conclusion: This study suggests that PRRT is a safe and effective therapeutic option for patients with PPGL. Our findings align with the existing literature, providing additional evidence to support the use of PRRT in this challenging patient population.

Quantitative nuclear imaging techniques are in high demand for various disease diagnostics and cancer theranostics. The non-invasive imaging modality requires radiotracing through the radioactive decay emission of the radionuclide. Current preclinical and clinical radiotracers, so-called nuclear imaging probes, are radioisotope-labeled small molecules. Liposomal radiotracers have been rapidly developing as novel nuclear imaging probes. The physicochemical properties and structural characteristics of liposomes have been elucidated to address their long circulation and stability as radiopharmaceuticals. Various radiolabeling methods for synthesizing radionuclides onto liposomes and synthesis strategies have been summarized to render them biocompatible and enable specific targeting. Through a variety of radionuclide labeling methods, radiolabeled liposomes for use as nuclear imaging probes can be obtained for in vivo biodistribution and specific targeting studies. The advantages of radiolabeled liposomes including their use as potential clinical nuclear imaging probes have been highlighted. This review is a comprehensive overview of all recently published liposomal SPECT and PET imaging probes.

Nuclear imaging is a powerful non-invasive imaging technique that is rapidly developing in medical theranostics. Nuclear imaging requires radiolabeling isotopes for non-invasive imaging through the radioactive decay emission of the radionuclide. Nuclear imaging probes, commonly known as radiotracers, are radioisotope-labeled small molecules. Nanomaterials have shown potential as nuclear imaging probes for theranostic applications. By modifying the surface of nanomaterials, multifunctional radio-labeled nanomaterials can be obtained for in vivo biodistribution and targeting in initial animal imaging studies. Various surface modification strategies have been developed, and targeting moieties have been attached to the nanomaterials to render biocompatibility and enable specific targeting. Through integration of complementary imaging probes to a single nanoparticulate, multimodal molecular imaging can be performed as images with high sensitivity, resolution, and specificity. In this review, nanomaterial nuclear imaging probes including inorganic nanomaterials such as quantum dots (QDs), organic nanomaterials such as liposomes, and exosomes are summarized. These new developments in nanomaterials are expected to introduce a paradigm shift in nuclear imaging, thereby creating new opportunities for theranostic medical imaging tools.

Radioembolisation is an established transarterial therapy for hepatocellular carcinoma and liver metastasis. Success of radioembolisation depends on meticulous angiography and accurate dosimetry. Intra-procedure catheter-directed CT-angiography is commonly performed to improve the efficacy and safety of radioembolisation. This review article will (1) introduce the differences between cone beam CT and hybrid angiography-CT, and (2) describe the benefits of catheter-directed CT-angiography in radioembolisation from both an interventional radiology and nuclear medicine perspective.

Yttrium-90 (90Y) microspheres are widely used for the treatment of liver-dominant malignant tumors. They are infused via catheter into the hepatic artery branches supplying the tumor under fluoroscopic guidance based on pre-therapy angiography and Technetium-99m macroaggregated albumin (99mTc-MAA) planning. However, at present, these microspheres are suspended in radiolucent media such as dextrose 5% (D5) solution. In order to monitor the real-time implantation of the microspheres into the tumor, the 90Y microspheres could be suspended in omnipaque contrast for allowing visualization of the correct distribution of the microspheres into the tumor. The radiochemical purity of mixing 90Y-microspheres in various concentrations of omnipaque was investigated. The radiochemical purity and feasibility of mixing 99mTc-MAA with various concentrations of a standard contrast agent were also investigated. Results showed the radiochemical feasibility of mixing 90Y-microspheres with omnipaque is radiochemically acceptable for allowing real-time visualization of radioembolization under fluoroscopy.