Non-invasive visualization of liver fibrosis with [68Ga]Ga-DOTA-FAPI-04 PET from preclinical insights to clinical translation.

PURPOSE: The reversibility of early liver fibrosis highlights the need for improved early detection and monitoring techniques. Fibroblast activation protein (FAP) is a promising theranostics target significantly upregulated during fibrosis. This preclinical and preliminary clinical study investigated a FAP-targeted probe, gallium-68-labeled FAP inhibitor 04 ([68Ga]Ga-DOTA-FAPI-04), for its capability to visualize liver fibrosis. METHODS: The preclinical study employed [68Ga]Ga-DOTA-FAPI-04 micro-positron emission tomography (PET)/computed tomography (CT) on carbon tetrachloride-induced mice model (n = 34) and olive oil-treated control group (n = 26), followed by validation of the probe's biodistribution. Hepatic uptake was correlated with fibrosis and inflammation levels, quantified through histology and serum assays. FAP and α-smooth muscle actin expression were determined by immunohistochemistry, as well as immunofluorescence. The subsequent clinical trial enrolled 26 patients with suspected or confirmed liver fibrosis to undergo [68Ga]Ga-DOTA-FAPI-04 PET/magnetic resonance imaging or PET/CT. Key endpoints included correlating [68Ga]Ga-DOTA-FAPI-04 uptake with histological inflammation grades and fibrosis stages, and evaluating its diagnostic and differential efficacy compared to established serum markers and liver stiffness measurement (LSM). RESULTS: [68Ga]Ga-DOTA-FAPI-04 mean uptake in mice livers was notably higher than in control mice, increasing from week 6 [0.70 ± 0.11 percentage injected dose per cubic centimeter (%ID/cc)], peaking at week 10 (0.97 ± 0.15%ID/cc) and slightly reducing at week 12 (0.89 ± 0.28%ID/cc). The hepatic biodistribution and FAP expression showed a consistent trend. In the patient cohort, hepatic [68Ga]Ga-DOTA-FAPI-04 uptake presented moderate correlations with inflammation grades (r = 0.517 to 0.584, all P < 0.05) and fibrosis stages (r = 0.653 to 0.698, all P < 0.01). The average SUVmax to background ratio in the liver showed superior discriminative ability, especially between stage 0 and stage 1, outperforming LSM (area under curve 0.984 vs. 0.865). CONCLUSION: [68Ga]Ga-DOTA-FAPI-04 PET shows significant potential for non-invasive visualization and dynamic monitoring of liver fibrosis in both preclinical experiment and preliminary clinical trial, especially outperforming other common clinical indicators in the early stage. TRIAL REGISTRATION: NCT04605939. Registered October 25, 2020, https://clinicaltrials.gov/study/NCT04605939.

Landscape of Nuclear Medicine in China and Its Progress on Theranostics.

Nuclear medicine in China started in 1956 and, with the rapid development of the economy and continuous breakthroughs in precision medicine, has made significant progress in recent years. Almost 13,000 staff members in nearly 1,200 hospitals serve more than 3.9 million patients each year. Over the past decade, the radiopharmaceutical industry has developed rapidly, with the initial formation of a complete industrial chain of production of various radiopharmaceuticals for both clinical use and basic research. Advanced equipment such as PET/CT scanners is being manufactured domestically and even installed abroad. Recently, research into screening and synthesizing new target probes and their translation into the clinic has gained more attention, with various new tracers with potential clinical value being thoroughly studied. Simultaneously, 68Ga- and 177Lu-labeled tumor-targeted probes and others have been implemented for theranostics in an increasing number of hospitals and would be helped by approval from the National Medical Products Administration. Over the next 10-20 y, with the launch of the Mid- and Long-Term Development Plan for Medical Isotopes (2021-2035) by the Chinese government, there is great potential for nuclear medicine in China. With the rise in independent innovation in manufacturing, the shortage of radiopharmaceuticals will be effectively curtailed. We anticipate that the scale of nuclear medicine will at least double by 2035, covering all high-grade hospitals and leading to the aim of "one county, one department" in China.

Different Ectopic Endocrine Tumors on Renal Hilum Detected by 68 Ga-DOTATATE PET.

ABSTRACT: Renal hilum is a very rare location for primary adrenocortical adenoma or pheochromocytoma. We report 68 Ga-DOTATATE PET/CT findings of primary renal hilar adrenocortical adenoma in one patient and 68 Ga-DOTATATE PET/MR findings of pheochromocytoma in another patient.

Congenital Mesoblastic Nephroma Mimic Wilms Tumor on 18 F-FDG PET/CT and PET/MR.

ABSTRACT: Congenital mesoblastic nephroma is an extremely rare, low-grade malignant renal tumor in children. A 10-month-old boy and a 4-month-old girl were admitted to our hospital with a huge abdominal mass. For staging of the mass, 18 F-FDG PET/CT and PET/MR were performed showing a huge heterogeneous abdominal mass accompanied by extensive heterogeneous aggregation. Both of them were highly suspected to be Wilms tumor, the most common renal malignant tumor in children. However, histopathological examination after surgery confirmed congenital mesodermal nephroma.

Coexistence of FDG-Avid and FDG-Negative Aneurysms in a Patient With Fever of Unknown Origin.

ABSTRACT: A 68-year-old man with intermittent fever of unknown origin for 5 months underwent 18F-FDG PET/CT to detect causative lesion. An 18F-FDG-avid lesion was revealed in the left pelvic iliac vessel region and was highly suggestive of malignancy. One and a half months later, a giant left internal iliac artery aneurysm was identified by CT angiography, corresponding to the 18F-FDG-avid lesion. Combined with elevated inflammatory markers, he was finally diagnosed as having inflammatory internal iliac artery aneurysm. An abdominal aortic aneurysm with low 18F-FDG uptake was also identified.

The diagnostic value of dual-layer CT in the assessment of lymph nodes in lymphoma patients with PET/CT as a reference standard.

This study aimed to evaluate the diagnostic performances of dual-layer CT (DLCT) for the identification of positive lymph nodes (LNs) in patients with lymphoma and retrospectively included 1165 LNs obtained by biopsy from 78 patients with histologically proven lymphoma, who underwent both pretreatment DLCT and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). According to 18F-FDG PET/CT findings as a reference standard, cases were categorized into the LN-negative and LN-positive groups. LNs were then randomly divided at a ratio of 7:3 into the training (n = 809) and validation (n = 356) cohorts. The patients' clinical characteristics and quantitative parameters including spectral curve slope (λHU), iodine concentration (IC) on arterial phase (AP) and venous phase (VP) images were compared between the LN-negative and LN-positive groups using Chi-square test, t-test or Mann-Whitney U test for categorical variables or quantitative parameters. Multivariate logistic regression analysis with tenfold cross-validation was performed to establish the most efficient predictive model in the training cohort. The area under the curve (AUC) was used to evaluate the diagnostic value of the predictive model, and differences in AUC were determined by the DeLong test. Moreover, the predictive model was validated in the validation cohort. Repeatability analysis was performed for LNs using intraclass correlation coefficients (ICCs). In the training cohort, long diameter (LD) had the highest AUC as an independent factors compared to other parameter in differentiating LN positivity from LN negativity (p = 0.006 to p < 0.001), and the AUC of predictive model jointly involving LD and λHU-AP was significantly elevated (AUC of 0.816, p < 0.001). While the AUC of predictive model in the validation cohort was 0.786. Good to excellent repeatability was observed for all parameters (ICC > 0.75). The combination of DLCT with morphological and functional parameters may represent a potential imaging biomarker for detecting LN positivity in lymphoma.

Comparison of efficacies of haploidentical transplantation and matched sibling donor transplantation in treating T-cell lymphoblastic lymphoma.

OBJECTIVE: To investigate the differences in efficacy and safety between haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) and matched sibling donor HSCT (MSD-HSCT) in patients with T-cell lymphoblastic lymphoma (T-LBL). METHODS: In this retrospective analysis, we enrolled 38 patients who had undergone allogeneic HSCT at our institution between 2013 and 2021. The study participants included 28 patients who underwent HID-HSCT and 10 patients who underwent MSD-HSCT. We compared the patient characteristics and treatment effectiveness and safety between the two groups and evaluated potential prognostic variables for patients with T-LBL. RESULTS: The median follow-up durations in the HID-HSCT and MSD-HSCT groups were 23.5 (range: 4-111) and 28.5 (range: 13-56) months, respectively. All patients showed full-donor chimerism after hematopoietic stem cell transplantation (HSCT). Except for two patients in the HID-HSCT cohort who developed poor graft function, all patients showed neutrophil and platelet engraftments after HSCT. The cumulative incidences of grades III-IV acute graft-versus-host disease were 37.5% and 28.57% in the HID-HSCT and MSD-HSCT groups, respectively (p = 0.84). The cumulative incidences of limited (34.13% vs. 28.57%, p = 0.82) and extensive (31.22% vs. 37.50%, p = 0.53) chronic graft-versus-host disease did not differ between the two cohorts. In the HID-HSCT and MSD-HSCT cohorts, the estimated 2-year overall survival rates were 70.3% (95% confidence interval [CI]: 54.9%-90.0%) and 56.2% (95% CI: 31.6%-100%), respectively (p = 1.00), and the estimated 2-year progression-free survival (PFS) rates were 48.5% (95% CI: 32.8%-71.6%) and 48.0% (95% CI: 24.6%-93.8%), respectively (p = 0.94). Furthermore, the Cox proportional-hazards model showed that a positive positron emission tomography/computed tomography (PET/CT) status before HSCT in patients who had completed chemotherapy was an independent risk factor for PFS in the multivariate analysis (p = 0.0367). CONCLUSION: This study showed that HID-HSCT had comparable effectiveness and safety to MSD-HSCT in treating T-LBL. HID-HSCT could serve as an alternate treatment option for T-LBL in patients without an eligible identical donor. Achievement of the PET/CT-negative status before HSCT may contribute to better survival.

Q.Clear reconstruction for reducing the scanning time for 68 Ga-DOTA-FAPI-04 PET/MR imaging.

PURPOSE: This study aims to determine whether Q.Clear positron emission tomography (PET) reconstruction may reduce tracer injection dose or shorten scanning time in 68Gallium-labelled fibroblast activation protein inhibitor (68 Ga-FAPI) PET/magnetic resonance (MR) imaging. METHODS: We retrospectively collected cases of 68 Ga-FAPI whole-body imaging performed on integrated PET/MR. PET images were reconstructed using three different methods: ordered subset expectation maximization (OSEM) reconstruction with full scanning time, OSEM reconstruction with half scanning time, and Q.Clear reconstruction with half scanning time. We then measured standardized uptake values (SUVs) within and around lesions, alongside their volumes. We also evaluated image quality using lesion-to-background (L/B) ratio and signal-to-noise ratio (SNR). We then compared these metrics across the three reconstruction techniques using statistical methods. RESULTS: Q.Clear reconstruction significantly increased SUVmax and SUVmean within lesions (more than 30%) and reduced their volumes in comparison with OSEM reconstruction. Background SUVmax also increased significantly, while background SUVmean showed no difference. Average L/B values for Q.Clear reconstruction were only marginally higher than those from OSME reconstruction with half-time. SNR decreased significantly in Q.Clear reconstruction compared with OSEM reconstruction with full time (but not half time). Differences between Q.Clear and OSEM reconstructions in SUVmax and SUVmean values within lesions were significantly correlated with SUVs within lesions. CONCLUSIONS: Q.Clear reconstruction was useful for reducing PET injection dose or scanning time while maintaining the image quality. Q.Clear may affect PET quantification, and it is necessary to establish diagnostic recommendations based on Q.Clear results for Q.Clear application.

Berberin sustained-release nanoparticles were enriched in infarcted rat myocardium and resolved inflammation.

Inflammatory regulation induced by macrophage polarization is essential for cardiac repair after myocardial infarction (MI). Berberin (BBR) is an isoquinoline tetrasystemic alkaloid extracted from plants. This study analyzes the most likely mechanism of BBR in MI treatment determined via network pharmacology, showing that BBR acts mainly through inflammatory responses. Because platelets (PLTs) can be enriched in the infarcted myocardium, PLT membrane-coated polylactic-co-glycolic acid (PLGA) nanoparticles (BBR@PLGA@PLT NPs) are used, which show enrichment in the infarcted myocardium to deliver BBR sustainably. Compared with PLGA nanoparticles, BBR@PLGA@PLT NPs are more enriched in the infarcted myocardium and exhibit less uptake in the liver. On day three after MI, BBR@PLGA@PLT NPs administration significantly increases the number of repaired macrophages and decreases the number of inflammatory macrophages and apoptotic cells in infarcted rat myocardium. On the 28th day after MI, the BBR@PLGA@PLT group exhibits a protective effect on cardiac function, reduced cardiac collagen deposition, improved scar tissue stiffness, and an excellent angiogenesis effect. In addition, BBR@PLGA@PLT group has no significant impact on major organs either histologically or enzymologically. In summary, the therapeutic effect of BBR@PLGA@PLT NPs on MI is presented in detail from the perspective of the resolution of inflammation, and a new solution for MI treatment is proposed.

A prognostication system based on clinical parameters and [18F]-FDG PET/CT in patients with newly diagnosed multiple myeloma.

PURPOSE: This study aimed to assess prognosis of patients with newly diagnosed multiple myeloma (NDMM) by combining [18F]-FDG positron emission tomography (PET)/CT parameters and clinical indices. METHODS: Clinical data and PET/CT parameters of 133 NDMM patients were retrospectively analyzed for associations between clinical indices and PET/CT parameters. Independent predictors of progression-free survival (PFS) and overall survival (OS) were determined. A new prognostic prediction system (NPPS) was constructed based on our findings. Prediction effectiveness was compared among the NPPS, International Staging System (ISS), Revised ISS (R-ISS), and R2-ISS. RESULTS: Prevalence of elevated ß2-microglobulin, serum creatinine (sCr), serum calcium (sCa), and C-reactive protein concentrations was higher in patients with higher SUVmax (≥ 5.3). Prevalence of elevated sCa, sCr, and extramedullary disease (EMD) was higher in patients with a higher number of focal lesions (≥ 10). SUVmax, serum free-light chain (sFLC) ratio, and EMD were independent predictors of PFS and OS. The NPPS used SUVmax, sFLC ratio, and EMD could effectively predict OS and was more effective at prognostication than the ISS, R-ISS, and R2-ISS. CONCLUSIONS: [18F]-FDG PET/CT parameters play a significant role in predicting prognosis in NDMM patients. The NPPS based on SUVmax, sFLC ratio, and EMD outperformed the ISS, R-ISS, and R2-ISS in prognostication.

68Ga-FAPI PET visualize heart failure: from mechanism to clinic.

PURPOSE: Heart failure (HF) is a chronic progressive clinical syndrome associated with structural and/or functional heart abnormalities. Active fibroblasts and ventricular remodelling play an essential role in HF progression. 68Ga-labelled fibroblast activation protein (FAP) inhibitor (68Ga-FAPI) binds to FAP. This study aimed to examine the feasibility of using 68Ga-FAPI positron emission tomography (PET)/computed tomography (CT) to visualize changes in cardiac fibrosis and function over time in the HF setting. METHODS: After establishing an isoproterenol (ISO)-induced HF rat model (14 consecutive days of intraperitoneal ISO injections), echocardiography and 68Ga-FAPI PET/CT were performed weekly in experimental and control groups. Rat hearts were examined weekly for biodistribution analysis; autoradiography; and haematoxylin and eosin, FAP immunofluorescence and Masson's trichrome staining analysis. Rat blood was sampled weekly for enzyme-linked immunosorbent assay analysis of various plasma indicators. A preliminary clinical study was also performed in seven HF patients who underwent both 13N-amino (NH3) perfusion and 68Ga-FAPI cardiac PET imaging. RESULTS: In the animal experiments, myocardial 68Ga-FAPI uptake, expression of FAP and myocardial contractility peaked on day 7 after the initial ISO injection. Only slight fibrotic changes were observed on histopathological examination. 68Ga-FAPI uptake and ventricular wall motion decreased over time as cardiac fibrosis and degree of myocardial injury gradually increased. In the human HF patient study, 68Ga-FAPI PET imaging identified varying degrees of 68Ga-FAPI uptake in the myocardium that did not precisely match with 13N-NH3 myocardial perfusion. CONCLUSION: As HF progresses, 68Ga-FAPI uptake is high in the early stages and then gradually decreases. Although preliminary, our findings suggest that 68Ga-FAPI PET can be used to demonstrate active myocardial fibrosis. Active myocardial FAP expression is followed by myocardial remodelling and fibrosis. Detection of early active FAP expression may assist treatment decision making in HF patients. CLINICAL TRIAL REGISTRATION: NCT04982458.

Diagnosis and prognostic predictive value of delineation methods from 18F-FDG PET/CT and PET/MR in pancreatic lesion.

The aim was to utilize three segmentation methods on 18F-FDG PET/CT and PET/MR images of pancreatic neoplasm patients, and further compare the effectiveness in differentiating benign from malignant, TNM-stage and prognosis. We conducted a retrospective analysis of 51 patients with pancreatic neoplasm who had undergone 18F-FDG PET/CT and PET/MR before treatment. The patients were categorized into malignant and benign groups. For each patient, the lesion was segmented by 3 thresholds and we recorded TNM-stage, treatment strategy, time to death, and the performance status of survivors. We used receiver operating characteristic (ROC) analysis to compare the diagnostic performance of different threshold delineations between benign and malignant, as well as TNM-stage of adenocarcinoma patients. The optimal model of prognostic value was also assessed by Cox proportional hazards regression analysis and Kaplan-Meier survival analysis. For both PET/CT and PET/MR, SUVmax had the best diagnostic efficacy in identifying malignant tumors. The background method of PET/MR exhibited the outstanding performance in M-stage (sensitivity/specificity, 92.90%/88.20%), with the weighted factor being whole-body total lesion glycolysis (WBTLG). In multivariate analysis, WBTLG (Exp [B] = 1.009; P = 0.009), and surgery (Exp [B] = 15.542; P = 0.008) were independent predictive factors associated with prognosis. This study found that SUVmax from PET/CT had the best diagnostic efficacy in identifying malignancy, while PET/MR showed higher specificity and accuracy for M-stage. The treatment strategy and WBTLG were independent prognostic factors in pancreatic neoplasm patients. PET/MR using the background method was identified as the optimal predictive model for prognosis.

Development and Evaluation of a Peptide Heterodimeric Tracer Targeting CXCR4 and Integrin αvß3 for Pancreatic Cancer Imaging.

Nowadays, pancreatic cancer is still a formidable disease to diagnose. The CXC chemokine receptor 4 (CXCR4) and integrin αvß3 play important roles in tumor development, progression, invasion, and metastasis, which are overexpressed in many types of human cancers. In this study, we developed a heterodimeric tracer 68Ga-yG5-RGD targeting both CXCR4 and integrin αvß3, and evaluated its feasibility and utility in PET imaging of pancreatic cancer. The 68Ga-yG5-RGD could accumulate in CXCR4/integrin αvß3 positive BxPC3 tumors in a high concentration and was much higher than that of 68Ga-yG5 (p < 0.001) and 68Ga-RGD (p < 0.001). No increased uptake of 68Ga-yG5-RGD was found in MX-1 tumors (CXCR4/integrin αvß3, negative). In addition, the uptake of 68Ga-yG5-RGD in BxPC3 was significantly blocked by excess amounts of AMD3100 (an FDA-approved CXCR4 antagonist) and/or unlabeled RGD (p < 0.001), confirming its dual-receptor targeting properties. The ex vivo biodistribution and immunohistochemical results were consistent with the in vivo imaging results. The dual-receptor targeting strategy achieved improved tumor-targeting efficiency and prolonged tumor retention in BxPC3 tumors, suggesting 68Ga-yG5-RGD is a promising tracer for the noninvasive detection of tumors that express either CXCR4 or integrin αvß3 or both, and therefore may have good prospects for clinical translation.

Early-life vitamin B12 orchestrates lipid peroxidation to ensure reproductive success via SBP-1/SREBP1 in Caenorhabditis elegans.

Vitamin B12 (B12) deficiency is a critical problem worldwide. Such deficiency in infants has long been known to increase the propensity to develop obesity and diabetes later in life through unclear mechanisms. Here, we establish a Caenorhabditis elegans model to study how early-life B12 impacts adult health. We find that early-life B12 deficiency causes increased lipogenesis and lipid peroxidation in adult worms, which in turn induces germline defects through ferroptosis. Mechanistically, we show the central role of the methionine cycle-SBP-1/SREBP1-lipogenesis axis in programming adult traits by early-life B12. Moreover, SBP-1/SREBP1 participates in a crucial feedback loop with NHR-114/HNF4 to maintain cellular B12 homeostasis. Inhibition of SBP-1/SREBP1-lipogenesis signaling and ferroptosis later in life can reverse disorders in adulthood when B12 cannot. Overall, this study provides mechanistic insights into the life-course effects of early-life B12 on the programming of adult health and identifies potential targets for future interventions for adiposity and infertility.

Noninvasive Monitoring of Reparative Fibrosis after Myocardial Infarction in Rats Using 68Ga-FAPI-04 PET/CT.

Noninvasively monitoring activated fibroblasts is of great value for understanding the dynamic process of myocardial fibrosis after myocardial infarction (MI). This study aimed to evaluate the feasibility of 68Ga-labeled fibroblast activation protein inhibitor 04 (68Ga-FAPI-04) for monitoring reparative fibrosis and reactive fibrosis after MI. MI models were prepared by ligation of the left anterior descending (LAD) coronary artery and validated by electrocardiogram and 18F-FDG PET/CT 1 day after MI and hematoxylin and eosin (HE) staining. 68Ga-FAPI-04 PET/CT scans (1, 3, 6, 9, 12, 15, 18, 21, 28, and 35 days after MI) were carried out in MI rats and sham-operated rats without ligation of LAD. Blocking experiments were carried out on MI rats on day 7 after MI with 68Ga-FAPI-04 and excessive FAPI-04. Autoradiography, HE staining, Masson's trichrome staining, and immunofluorescence staining were carried out for ex vivo validation. The infarcted area with decreased or defective myocardial metabolic activity in 18F-FDG PET/CT correspondingly showed high 68Ga-FAPI-04 uptake in the MI rats. The myocardial tracer uptake was significantly different between MI and sham-operated rats from day 1 to 28 after MI and reached peak value 6 days after MI (0.806 ± 0.257%ID/cc vs 0.199 ± 0.012%ID/cc, P < 0.05). Tracer uptake at the infarcted myocardium and normal tissues in MI rats decreased significantly after blocking. Obvious tracer uptake was confirmed by autoradiography, and immunofluorescence staining showed FAP+ cells in the infarcted myocardium and border zone. Masson's trichrome staining of the heart sections of MI rats at different times suggested the presence of myocardial fibrosis. 68Ga-FAPI-04 uptake was not observed in the distal uninjured myocardium throughout the observation period. In conclusion, 68Ga-FAPI-04 PET could noninvasively monitor the activated fibroblasts in the early stage post acute MI and may be helpful for evaluating the degree of reparative fibrosis, while reactive fibrosis monitoring still needs further study.

Gallium-68-labeled fibroblast activation protein inhibitor PET in gastrointestinal cancer: insights into diagnosis and management.

PURPOSE: Gallium-68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) is an emerging promising tumor tracer. This study aims to evaluate the diagnostic efficiency of 68Ga-FAPI PET in gastrointestinal cancer, and to determine its potential impact on clinical management. METHODS: Patients with malignancies were prospectively enrolled in a clinical trial to evaluate the diagnostic value of 68Ga-FAPI PET. One hundred twenty patients with gastrointestinal malignancies (121 68Ga-FAPI PET scans) between June 2020 and May 2021 were retrospectively analyzed. Initial staging of untreated patients and restaging of treated patients were evaluated. The treatment scheme promoted by imaging was determined according to NCCN guidelines. Final diagnosis and treatment reference standards were determined by a dedicated multidisciplinary team. The diagnostic performance and treatment guidance of 68Ga-FAPI PET were compared with those of conventional imaging (CI) and 18F-FDG PET. RESULTS: The diagnostic accuracy of 68Ga-FAPI PET was much higher than that of CI and 18F-FDG PET (95.0% vs. 65.1% and 69.0%, respectively, both p < 0.001). 68Ga-FAPI PET revised diagnosis in 30.3% and 26.2% of patients compared with CI and 18F-FDG PET. The accordance rate of 68Ga-FAPI PET-guided treatment in comparison with the reference standard was significantly higher than that of CI and 18F-FDG PET (96.7% vs. 75.2% and 76.2%, respectively, both p < 0.001). 68Ga-FAPI PET changed treatment in 22.9% and 23.8% of patients compared with CI and 18F-FDG PET. CONCLUSIONS: 68Ga-FAPI PET showed remarkable diagnostic performance in gastrointestinal cancer, resulting in more accurate staging and guidance for timely treatment revision, thereby having a critical impact on clinical management. TRIAL REGISTRATION: NCT04554719. Registered September 8, 2020-retrospectively registered, http://clinicaltrails.gov/show/NCT04554719.

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-4-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth. METHODS: Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-4-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated. RESULTS: Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. CONCLUSION: mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-4-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.