Standard Radio-Iodine Labeling Protocols Impaired the Functional Integrity of Mesenchymal Stem/Stromal Cell Exosomes.

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.

Radiolabeled Liposomes for Nuclear Imaging Probes.

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.

Radiochemical Feasibility of Mixing of 99mTc-MAA and 90Y-Microspheres with Omnipaque Contrast.

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.

Frequent neck US in papillary thyroid cancer likely detects non-actionable findings.

BACKGROUND: American Thyroid Association (ATA) low-intermediate-risk papillary thyroid cancer (PTC) patients without structural and biochemical evidence of disease on initial post-treatment evaluation have a low risk of recurrence. Studies have shown that with current ultrasound scans (US) and thyroglobulin assays, recurrences mostly occurred 2-8 years after initial therapy. The ATA recommends that neck US be done 6-12 months after surgery to establish patient's response to therapy, then periodically depending on risk of recurrence. The lack of clarity in recommendations on timing of follow-up US and fear of recurrence leads to frequent tests. OBJECTIVES: To evaluate the utility of routine neck US in ATA low-intermediate-risk PTC patients with no structural disease on neck US and non-stimulated thyroglobulin <1.0 ng/mL after initial therapy. METHODS: A retrospective study of 93 patients from Singapore, Saudi Arabia and Argentina with ATA low (n = 49) to intermediate (n = 44) risk PTC was conducted between 1998 and 2017. The outcome was to measure the frequency of identifying structural disease recurrence and non-actionable US abnormalities. RESULTS: Over a median follow-up of 5 years, five of the 93 patients (5.4%) developed structural neck recurrence on US at a median of 2.5 years after initial treatment. Indeterminate US abnormalities were detected in 19 of the 93 patients (20.4%) leading to additional tests, which did not detect significant disease. CONCLUSION: In ATA low-intermediate-risk PTC with no suspicious findings on neck US and a non-stimulated thyroglobulin of <1.0 ng/mL after initial therapy, frequent US is more likely to identify non-actionable abnormalities than clinically significant disease.

Reconfiguring the radiology leadership team for crisis management during the COVID-19 pandemic in a large tertiary hospital in Singapore.

The coronavirus 2019 (COVID-19) outbreak poses a serious public health risk. To date, the disease has affected almost all countries in the world. The enormous scale of the outbreak and the relative lack of knowledge and information regarding a new virus, as well as the unpredictability of events, make it challenging for leadership teams to respond. This paper shares how we have reconfigured our radiology leadership team into a smaller disease outbreak task force (DOTF) to respond and coordinate all related efforts during this ongoing COVID-19 pandemic. The DOTF format is modelled after the military with domain groups looking at manpower, intelligence, operations, and logistics matters on a daily basis so that timely decisions can be made and action plans executed promptly. In managing the DOTF, discipline, flexibility, and teamwork are key principles, and these are built upon a strong foundation of focus on infection prevention and control, and patient and staff safety as well as staff well-being. The DOTF has positioned us well to confront the many challenges to date. We believe it will also help us navigate the complex issues that will arise with future surges in cases and in formulating strategies to manage exit from the present and future lockdowns. KEY POINTS: • In a pandemic, regular and directed meetings by a smaller leadership core group are required, for prompt decision making and execution of action plans. • The military format, with domain groups to look at manpower, intelligence, operations, and logistics matters, is useful in managing a pandemic. • Discipline, flexibility, and teamwork with strong focus on infection prevention and control, and patient and staff safety as well as staff well-being are key principles for leadership teams managing a pandemic.

Facing a disruptive threat: how can a nuclear medicine service be prepared for the coronavirus outbreak 2020?

PURPOSE: The aim of this short communication is to outline our experience in policies and processes of a nuclear medicine service during the COVID-19 outbreak in Singapore. METHODS: We describe the key considerations of policies and processes that have been implemented in our nuclear medicine service since the first case of COVID-19 was confirmed in Singapore General Hospital on 23 January 2020, up to the present time. RESULTS: Infection control, screening of patients and visitors, segregation of risk groups, segregation of staff and service continuity plans, communication and staff welfare, using electronic platforms for multi-disciplinary meetings and tele-reporting are discussed. CONCLUSION: Since our hospital received the first patient with COVID-19 in Singapore, our centre has managed 16 COVID-19 cases to date. There has not been any healthcare worker in our institution who has contracted COVID-19 through patient contact. We have highlighted for discussion some of the policies and processes to prepare a nuclear medicine service for the COVID-19 threat.

Clinicopathologic Characteristics and Survival of Patients with Gastroenteropancreatic Neuroendocrine Neoplasm in a Multi-Ethnic Asian Institution.

BACKGROUND: Epidemiological evidence suggests there are differences in gastroenteropancreatic neuroendocrine neoplasm (GEPNEN) among population groups. We aimed to contribute to the current evidence by evaluating the clinicopathological characteristics of GEPNEN in a multi-ethnic Asian group. MATERIALS AND METHODS: This was a retrospective chart review of patients diagnosed with GEPNEN at a tertiary medical institution at Singhealth Outram Campus, Singapore, between 1995 and 2015. RESULTS: Two hundred ninety-five patients were included in the evaluation, comprising Chinese (74.6%), Malay (4.4%), Indian (9.5%) and other (11.5%) ethnic backgrounds. The median age at diagnosis was 59 years; 52.5% were males. Distribution of disease stage at diagnosis was: localised (42.4%), regional (15.3%) and distant (38.0%). The three most common primary tumour sites were located in the pancreas (38.6%), rectum (19.7%) and stomach (9.5%), which varied significantly with ethnic background and age at diagnosis. Malay patients were younger (median 42 years) at diagnosis than Chinese (60 years). Patients with an appendiceal neuroendocrine neoplasm (NEN) (48 years) were younger compared to oesophageal NEN (66 years). Disease stage correlated with primary tumour site and grade (p < 0.001). Median overall survival (OS) for all GEPNEN was 10.2 years. Age at diagnosis, disease stage and grading were prognostic factors of OS in multivariable analyses. CONCLUSION: Our findings correspond with other studies that focus on GEPNEN incidences in Asian countries, with the pancreas, rectum and stomach being the most common primary tumour sites. Our findings suggest racial differences in primary tumour site and age at diagnosis. Further prospective population-based registries are required to understand these epidemiological differences.

Addressing bone quality and bone density after renal transplantation: A prospective evaluation of the evolution of trabecular bone score and bone mineral density over the first 5 years following renal transplantation in Asian patients.

The evolution of trabecular bone score (TBS) and bone mineral density (BMD) over the first 5 years after renal transplantation was prospectively evaluated in 164 patients. Dual energy X-ray absorptiometry (DXA) scans were performed at 0, 6, 12, 24, and 60 months. Cumulative steroid dose, serum 25(OH)D, calcium, parathyroid hormone, and total ALP levels at these time points were checked. Incident fractures were identified from X-rays/vertebral fracture assessments. Mean (SD) age, TBS, and lumbar spine BMD at baseline were 47.11 (9.53), 1.424 (0.097), and 0.935 (0.183) gm/cm2 , respectively. Baseline TBS was lower in tertiary 1.38 (0.07) vs secondary hyperparathyroidism 1.43 (0.01) vs post-parathyroidectomy 1.46 (0.11); P = .035. Trabecular bone score and BMD significantly decreased from baseline->6 months, changes after that at consecutive time points were non-significant. 11% had incident fractures during the follow-up period, majority being metatarsal with no vertebral or hip fractures noted. This first prospective evaluation of TBS and BMD evolution at multiple time points over 5 years suggest that microarchitectural and bone density deteriorations post-renal transplantation stabilize after 6 months. Stabilization of these parameters could partially account for the absence of major fractures noted in this Asian population. Possible genetic and ethnic differences in fracture risk between Asian and Caucasian renal transplant patients have to be explored through large population-based studies.

Single administration of Selective Internal Radiation Therapy versus continuous treatment with sorafeNIB in locally advanced hepatocellular carcinoma (SIRveNIB): study protocol for a phase iii randomized controlled trial.

BACKGROUND: Approximately 20 % of hepatocellular carcinoma (HCC) patients diagnosed in the early stages may benefit from potentially curative ablative therapies such as surgical resection, transplantation or radiofrequency ablation. For patients not eligible for such options, prognosis is poor. Sorafenib and Selective Internal Radiation Therapy (SIRT) are clinically proven treatment options in patients with unresectable HCC, and this study aims to assess overall survival following either SIRT or Sorafenib therapy for locally advanced HCC patients. METHODS: This investigator-initiated, multi-centre, open-label, randomized, controlled trial will enrol 360 patients with locally advanced HCC, as defined by Barcelona Clinic Liver Cancer stage B or stage C, without distant metastases, and which is not amenable to immediate curative treatment. Exclusion criteria include previous systemic therapy, metastatic disease, complete occlusion of the main portal vein, or a Child-Pugh score of >7. Eligible patients will be randomised 1:1 and stratified by centre and presence or absence of portal vein thrombosis to receive either a single administration of SIRT using yttrium-90 resin microspheres (SIR-Spheres®, Sirtex Medical Limited, Sydney, Australia) targeted at HCC in the liver by the trans-arterial route or continuous oral Sorafenib (Nexavar®, Bayer Pharma AG, Berlin, Germany) at a dose of 400 mg twice daily until disease progression, no further response, complete regression or unacceptable toxicity. Patients for both the Sorafenib and SIRT arms will be followed-up every 4 weeks for the first 3 months and 12 weekly thereafter. Overall survival is the primary endpoint, assessed for the intention-to-treat population. Secondary endpoints are tumour response rate, time-to-tumour progression, progression free survival, quality of life and down-staging to receive potentially curative therapy. DISCUSSION: Definitive data comparing these two therapies will help to determine clinical practice in the large group of patients with locally advanced HCC and improve outcomes for such patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01135056 , first received 24, May 2010.

Current role of selective internal radiation with yttrium-90 in liver tumors.

An expert panel met to review the evidence for selective internal radiation therapy (SIRT) using yttrium-90 microspheres in hepatocellular carcinoma and metastases from colorectal cancer and neuroendocrine tumors. There is now convincing evidence for the safety and efficacy of SIRT in these situations albeit mostly from retrospective cohort studies. There are a number of ongoing prospective randomized controlled clinical trials investigating the role of SIRT in liver tumors; however, data from these trials are still several years away (although the SIRFLOX study has been recently published). In this evolving environment, published evidence and the authors' experience were used to summarize the current and potential role of SIRT in the management of hepatocellular carcinoma of intermediate or advanced stage and in liver-dominant metastatic colorectal cancer and metastatic neuroendocrine tumors.

SPECT/CT in musculoskeletal infections.

This article provides a brief overview of the current state of hybrid single-photon emission computed tomography/computer tomography (SPECT/CT) imaging in musculoskeletal infections. SPECT/CT imaging, compared with conventional planar study and SPECT alone, provides improved anatomic localization of infection and more accurate delineation of the extent of infection. This article emphasizes three clinical aspects where SPECT/CT is found to be most useful: differentiating between soft tissue and bone infections, assessing suspected infected sites with underlying structural bone alterations, and defining infective focus when complex anatomy is involved. The accurate assessment of site of infection is vital for selecting the most appropriate therapeutic strategy. Other advantages of SPECT/CT imaging such as reducing the inconvenience of combination planar studies, providing additional CT information, and increasing interobserver agreement are also discussed.

The role of PET/CT in the evaluation of skeletal metastases.

Osseous metastatic disease from malignancy is a common occurrence with significant patient morbidity and mortality as well as increasing health care expenditures. Patient management plans frequently change with the identification of skeletal metastasis and the upstaging of disease status. Bone scintigraphy remains the current mainstay of diagnostic imaging procedures in nuclear medicine for the early detection of skeletal metastasis owing to their high sensitivity. Emerging positron tracers and the increasing use and availability of hybrid single-photon emission computed tomography and positron emission tomography (PET)/computed tomography machines enable physicians to diagnose metastatic disease in bones with superior accuracy. This review introduces the basics of PET and the commonly used positron tracers used to evaluate skeletal metastases.

Outcomes and prognostic predictors of Lu-177 PSMA radioligand therapy in metastatic castration-resistant prostate cancer (Asian Population Study).

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.

Safety and efficacy of peptide receptor radionuclide therapy in patients with advanced pheochromocytoma and paraganglioma: A single-institution experience and review of the literature.

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.

The Role of Catheter-Directed CT-Angiography in Radioembolisation.

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.

Nanomaterial Probes for Nuclear Imaging.

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.

Positron emission tomographic imaging in drug discovery.

Positron emission tomography (PET) is an extensively used nuclear functional imaging technique, especially for central nervous system (CNS) and oncological disorders. Currently, drug development is a lengthy and costly pursuit. Imaging with PET radiotracers could be an effective way to hasten drug discovery and advancement, because it facilitates the monitoring of key facets, such as receptor occupancy quantification, drug biodistribution, pharmacokinetic (PK) analyses, validation of target engagement, treatment monitoring, and measurement of neurotransmitter concentrations. These parameters demand careful analyses for the robust appraisal of newly formulated drugs during preclinical and clinical trials. In this review, we discuss the usage of PET imaging in radiopharmaceutical development; drug development approaches with PET imaging; and PET developments in oncological and cardiac drug discovery.

Selective Internal Radiation Therapy with Yttrium-90 Resin Microspheres Followed by Gemcitabine plus Cisplatin for Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Single-Arm Multicenter Clinical Trial.

Introduction: This investigator-initiated clinical trial aims to study the efficacy and safety of administering selective internal radiation therapy with resin yttrium-90 microspheres (SIRT) followed by standard chemotherapy in unresectable intrahepatic cholangiocarcinoma (ICC). Methods: A phase 2 single-arm multicenter study was conducted in patients with unresectable ICC (NCT02167711). SIRT was administered at dose of 120 Gy targeted at tumor followed by commencement of gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on days one and eight of a 21-day cycle. The primary endpoint was overall survival (OS), and the secondary endpoints include progression-free survival (PFS), response rate according to Response Evaluation Criteria in solid tumors 1.1, toxicity, and time from SIRT to commencement of chemotherapy. Results: Total 31 patients were screened and twenty-four were recruited. All patients completed SIRT and 16 of them underwent subsequent chemotherapy. The median cycle of chemotherapy was 5 (range: 1-8). The median OS was 13.6 months (95% CI: 5.4-21.6) for the intent-to-treat population. Among 16 patients undergoing chemotherapy, the median OS was 21.6 months (95% CI: 7.3-25.2) and the median PFS was 9 months (95% CI: 3.2-13.1). The response rate was 25% (95% CI: 3.8-46.2%), and the disease control rate was 75% (95% CI: 53.8-96.2%). No new safety signal was observed, with fewer than 10% of patients suffering from grade 3 or higher treatment-related adverse events. The median time from SIRT to chemotherapy was 29 (range: 7-42) days. Eight patients could not receive chemotherapy due to rapid progressive disease (n = 4), underlying treatment unrelated comorbidities (n = 2), and withdrawal of consent due to personal reasons (n = 2). Conclusions: Treatment of SIRT followed by standard gemcitabine and cisplatin chemotherapy is feasible and effective for unresectable ICC. Further studies are required to study the optimal sequence of SIRT and chemotherapy.