Recent advances in near-infrared emitting lanthanide-doped nanoconstructs : mechanism, design and application for bioimaging

PSMA-Targeted Radiopharmaceuticals for Imaging and Therapy.

Bench to Bedside: Albumin Binders for Improved Cancer Radioligand Therapies.

In recent years, advancement in genetics has profoundly helped to gain a more comprehensive molecular, pathogenic, and prognostic picture of pheochromocytomas and paragangliomas (PPGLs). Newly discovered molecular targets, particularly those that target cell membranes or signaling pathways have helped move nuclear medicine in the forefront of PPGL precision medicine. This is mainly based on the introduction and increasing experience of various PET radiopharmaceuticals across PPGL genotypes quickly followed by implementation of novel radiotherapies and revised imaging algorithms. Particularly, 68Ga-labeled-SSAs have shown excellent results in the diagnosis and staging of PPGLs and in selecting patients for PRRT as a potential alternative to 123/131I-MIBG theranostics. PRRT using 90Y/177Lu-DOTA-SSAs has shown promise for treatment of PPGLs with improvement of clinical symptoms and/or disease control. However, more well-designed prospective studies are required to confirm these findings, in order to fully exploit PRRT's antitumoral properties to obtain the final FDA approval. Such an approval has recently been obtained for high-specific-activity 131I-MIBG for inoperable/metastatic PPGL. The increasing experience and encouraging preliminary results of these radiotherapeutic approaches in PPGLs now raises an important question of how to further integrate them into PPGL management (e.g. monotherapy or in combination with other systemic therapies), carefully taking into account the PPGLs locations, genotypes, and growth rate. Thus, targeted radionuclide therapy (TRT) should preferably be performed at specialized centers with an experienced interdisciplinary team. Future perspectives include the introduction of dosimetry and biomarkers for therapeutic responses for more individualized treatment plans, α-emitting isotopes, and the combination of TRT with other systemic therapies.

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Molecular imaging and radionuclide therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups.

Single Low-Dose Injection of Evans Blue Modified PSMA-617 Radioligand Therapy Eliminates Prostate-Specific Membrane Antigen Positive Tumors

This translational study is designed to assess the safety, dosimetry and therapeutic response to a single, low-dose of 177Lu-EB-PSMA-617 in comparison to 177Lu-PSMA-617 in patients with mCRPC. Following institutional review board approval and informed consent, nine patients with mCRPC were recruited. Four patients accepted intravenous injection of 0.80–1.1 GBq (21.5–30 mCi) of 177Lu-EB-PSMA-617, then underwent serial whole-body planar and SPECT/CT imaging at 2, 24, 72, 120 and 168 h. The other five patients accepted intravenous injection of 1.30–1.42 GBq (35–38.4 mCi) 177Lu-PSMA-617, then underwent the same imaging procedures at 0.5, 2, 24, 48, and 72 h. All patients were evaluated by 68Ga-PSMA-617 PET/CT before and one month after the treatment. Dosimetry evaluation was compared in both patient groups. When the bone metastasis tumors with comparable baseline SUVmax in the range of 10.0–15.0 were selected from the two groups for comparison, the accumulated radioactivity of 177Lu-EB-PSMA-617 was about 3.02-fold higher than that of 177Lu-PSMA-617. Imaging dose of 177Lu-EB-PSMA-617 treatment showed significant decrease of 68Ga-PSMA-617 uptake within a month, which was not observed in patients imaged with 177Lu-PSMA-617 (SUV change: −32.43 ± 0.14% vs. 0.21 ± 0.37%; P = 0.002). 177Lu-EB-PSMA-617 also had higher absorbed doses in the red bone marrow and kidneys than 177Lu-PSMA-617 (0.0547 ± 0.0062 vs. 0.0084 ± 0.0057 mSv/MBq for red bone marrow, P < 0.01; 2.39 ± 0.69 vs. 0.39 ± 0.06 mSv/MBq for kidneys, P < 0.01). This first-in-human study demonstrated that 177Lu-EB-PSMA-617 had higher accumulation in mCRPC and that low imaging dose appears to be effective in treating tumors with high 68Ga-PSMA-617 uptakes. Elevated uptakes of 177Lu-EB-PSMA-617 in kidneys and red bone marrow were well tolerated at the administered low dose. Further investigations with increased dose and frequency of administration are warranted.

First-in-human study of 177 Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer

Objective:177Lu-DOTA-EB-TATE is a theranostic agent based on octreotate that uses an Evans blue structure to bind albumin to improve the pharmacokinetics and pharmacodynamics. This pilot study aims to evaluate the efficacy of a single low-dose treatment using 177Lu-DOTA-EB-TATE in patients with advanced neuroendocrine neoplasm (NEN). Methods: With IRB approval and informed consent, 4 NEN patients were enrolled to undergo 177Lu-DOTA-EB-TATE treatment with a single low dose of 0.66 ± 0.06 GBq (17.8 ± 1.7 mCi); 3 other NEN patients were enrolled as controls to undergo 177Lu-DOTA-TATE treatment with administered activity of 3.98 ± 0.17 GBq (107.6 ± 4.6 mCi). One primary tumor and 62 metastatic lesions in the 7 patients were evaluated by 68Ga-DOTA-TATE PET/CT immediately before and one or three months after the treatment. Maximum SUV (SUVmax) of the tumors ≥2.0 cm in diameter were measured and percentage of change (ΔSUV) after treatment were calculated. Results: All 4 patients subjected to 177Lu-DOTA-EB-TATE treatment tolerated the administered activity without significant adverse effects and showed symptomatic remission. Among the patients, 40 tumors were found with diameter ≥2.0 cm, with the baseline SUVmax varied from 1.5-82.9 (35.9 ± 21.0) and the ΔSUVs before and three months after the treatment from -75.1-26.3% (-38.9 ± 25.5%). Twenty-nine (72.5%) of the tumors showed >15% decrease of SUVmax (ΔSUV = -75.1%--17.1%). There was a significant negative correlation between the baseline SUVmax and the ΔSUV after treatment (r = -0.852, P < 0.001). Compared with the control 177Lu-DOTA-TATE therapy, the 177Lu-DOTA-EB-TATE treatment using approximately 1/6 the dose showed no significant difference in ΔSUV (-7.9 ± 5.4% vs. -5.8 ± 3.9%, P = 0.189) as demonstrated by the tumors with comparable baseline SUVmax from 10.0-35.0. Conclusion: A single low-dose 177Lu-DOTA-EB-TATE treatment appears to be safe and effective in the treatment of NENs with high 68Ga-DOTA-TATE uptake. This pilot study merits further investigation with increased dose and frequency of 177Lu-DOTA-EB-TATE administration with potential advantages over 177Lu-DOTA-TATE.

Response to Single Low-dose 177Lu-DOTA-EB-TATE Treatment in Patients with Advanced Neuroendocrine Neoplasm: A Prospective Pilot Study.

Abstract Background This pilot study is aimed to perform a pilot visualization study to investigate in vivo fibroblast activation in non-ischemic cardiomyopathies by 68 Ga-FAPI-04 PET/CT. Methods Twenty-nine consecutive patients with symptomatic non-ischemic cardiomyopathies who underwent 68 Ga-FAPI-04 PET/CT were prospectively recruited. Clinical characteristics and echocardiographic parameters were recorded. Cardiac uptake was quantified by standardized uptake values (SUV max , SUV mean , SUVR) and left ventricular metabolism volume. The relationship between 68 Ga-FAPI-04 uptake with clinical and echocardiography parameters was investigated. Results Heterogeneous 68 Ga-FAPI-04 uptake was observed in different subtypes of non-ischemic cardiomyopathies. Twenty-two (75.9%) patients showed elevated 68 Ga-FAPI-04 uptake in the left ventricle, and 10 (34.5%) patients also showed slightly diffuse elevated uptake in the right ventricle. Cardiac uptake values were significantly correlated with enlarged ventricular volume evaluated by echocardiography. Conclusion FAPI PET/CT presents a potential value for in vivo visualization and quantification of fibroblast activation on the molecular level. Further study is warranted for investigating the theranostic and prognostic value of elevated FAP signal. 

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Molecular imaging of fibroblast activation in multiple non-ischemic cardiomyopathies

Purpose The combination of PD-1/PD-L1 inhibitors and molecular targeted agents showed promising efficacy for unresectable hepatocellular carcinoma (uHCC). This study aimed to investigate the prognostic value of metabolic parameters from 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) in patients with uHCC underwent the combined therapies. Patients and Methods Patients with uHCC treated with a combination of immunotherapy and targeted therapy who underwent baseline 18F-FDG PET/CT between July 2018 and December 2021 were recruited retrospectively. The metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake values (SUVmax), and clinical and biological parameters were recorded. A multivariate prediction model was developed for overall survival (OS) using these parameters together with clinical prognostic factors. Results Seventy-seven patients were finally included. The median OS was 16.8 months. We found that a high MTV (≥39.65 cm3 as the median value) was significantly associated with OS (P<0.05). In multivariate analyses for OS, a high MTV, high Eastern Cooperative Oncology Group performance status (ECOG-PS, ≥1), Child-Pugh (B-C) grade, and the presence of bone metastasis were significantly associated with poor OS (HR 1.371, HR 3.73, HR 15.384, and HR 2.994, all P<0.05, respectively). A multivariate prognostic model including MTV and prognostic factors, such as ECOG-PS, Child-Pugh grade, and bone metastasis, further improved the identification of different OS subgroups. Conclusion High MTV is an adverse prognostic factor in patients with uHCC treated with a combination of immunotherapy and molecular targeted agents. Integrating PET/CT parameters with clinical prognostic factors could help to personalize immunotherapy.

Metabolic Tumor Volume Measured by 18F-FDG PET/CT is Associated with the Survival of Unresectable Hepatocellular Carcinoma Treated with PD-1/PD-L1 Inhibitors Plus Molecular Targeted Agents

A 47-year-old female with cardiac dysfunction and lymphadenopathy underwent 18FDG PET/CT and 68Ga-FAPI-04 imaging for tumor screening. Mild uptake in the left ventricular wall was detected on the oncology 18FDG PET/CT. True myocardiac-involvement could not be distinguished with physiological uptake. The following 68Ga-FAPI-04 showed intense heterogeneous uptake in the left ventricular wall, particularly in the septum and apex area, corresponding with the late gadolinium enhancement regions shown by cardiac MR. Intense uptake was also noted in the mediastinal and bilateral hilar lymph nodes. Endomyocardial biopsy demonstrated sarcoidosis.

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Jingnan Wang

Papers

First-in-human study of 177 Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer

Response to Single Low-dose 177Lu-DOTA-EB-TATE Treatment in Patients with Advanced Neuroendocrine Neoplasm: A Prospective Pilot Study.

Molecular imaging of fibroblast activation in multiple non-ischemic cardiomyopathies

Metabolic Tumor Volume Measured by 18F-FDG PET/CT is Associated with the Survival of Unresectable Hepatocellular Carcinoma Treated with PD-1/PD-L1 Inhibitors Plus Molecular Targeted Agents

In Vivo Fibroblast Activation of Systemic Sarcoidosis: A 68Ga-FAPI-04 PET/CT Imaging Study