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PURPOSE: Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [68Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [177Lu]Lu-LNC1010 than with [177Lu]Lu-DOTATATE in treating metastatic NPC. METHODS: We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [68Ga]Ga/[177Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [68Ga]Ga/[177Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC. RESULTS: LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [68Ga]Ga/[177Lu]Lu-LNC1010 than [68Ga]Ga/[177Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [177Lu]Lu-LNC1010 than [177Lu]Lu-DOTATATE. In preclinical PRRT studies, [177Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [177Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [177Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC. CONCLUSION: [177Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [177Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [177Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.
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Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.
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Inhibidores de Puntos de Control Inmunológico , Animales , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Endopeptidasas/genética , Células 3T3 NIH , Radiofármacos/uso terapéutico , Serina Endopeptidasas/genética , Serina Endopeptidasas/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Inmunoterapia , Gelatinasas/genética , Gelatinasas/inmunología , Lutecio/farmacología , Línea Celular TumoralRESUMEN
Early detection of pulmonary fibrosis is a critical yet insufficiently met clinical necessity. This study evaluated the effectiveness of FAPI-LM3, a 68Ga-radiolabeled heterobivalent molecular probe that targets fibroblast activating protein (FAP) and somatostatin receptor 2 (SSTR2), in the early detection of pulmonary fibrosis, leveraging its potential for early disease identification. A bleomycin-induced early pulmonary fibrosis model was established in C57BL/6 mice for 7 days. FAP and SSTR2 expression levels were quantitatively assessed in human idiopathic pulmonary fibrosis lung tissue samples and bleomycin-treated mouse lung tissues by using western blotting, real-time quantitative PCR (RT-qPCR), and immunofluorescence techniques. The diagnostic performance of FAPI-LM3 was investigated by synthesizing monomeric radiotracers 68Ga-FAPI-46 and 68Ga-DOTA-LM3 alongside the heterobivalent probe 68Ga-FAPI-LM3. These imaging radiopharmaceuticals were used in small-animal PET to compare their uptake in fibrotic and normal lung tissues. Results indicated significant upregulation of FAP and SSTR2 at both RNA and protein levels in fibrotic lung tissues compared with that in normal controls. PET imaging demonstrated significantly enhanced uptake of the 68Ga-FAPI-LM3 probe in fibrotic lung tissues, with superior visual effects compared to monomeric tracers. At 60 min postinjection, early stage fibrotic tissues (day 7) demonstrated low-to-medium uptake of monomeric probes, including 68Ga-DOTA-LM3 (0.45 ± 0.04% ID/g) and 68Ga-FAPI-46 (0.78 ± 0.09% ID/g), whereas the uptake of the heterobivalent probe 68Ga-FAPI-LM3 (1.90 ± 0.10% ID/g) was significantly higher in fibrotic lesions than in normal lung tissue. Blockade experiments confirmed the specificity of 68Ga-FAPI-LM3 uptake, which was attributed to synergistic targeting of FAP and SSTR2. This study demonstrates the potential of 68Ga-FAPI-LM3 for early pulmonary fibrosis detection via molecular imaging, offering significant benefits over monomeric tracers 68Ga-FAPI-46 and 68Ga-DOTA-LM3. This strategy offers new possibilities for noninvasive and precise early detection of pulmonary fibrosis.
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Radioisótopos de Galio , Ratones Endogámicos C57BL , Tomografía de Emisión de Positrones , Radiofármacos , Receptores de Somatostatina , Animales , Ratones , Receptores de Somatostatina/metabolismo , Humanos , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Radiofármacos/química , Fibrosis Pulmonar/diagnóstico por imagen , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/inducido químicamente , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/metabolismo , Masculino , Bleomicina , Endopeptidasas/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Fibrosis Pulmonar Idiopática/metabolismo , Proteínas de la Membrana/metabolismo , Serina Endopeptidasas/metabolismo , QuinolinasRESUMEN
Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China's engagement with FAPI tracers, aiming to guide future research endeavors.
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Proteínas de la Membrana , Neoplasias , Investigación Biomédica Traslacional , Animales , Humanos , China , Endopeptidasas , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/metabolismo , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Tomografía de Emisión de Positrones , Trazadores RadiactivosRESUMEN
Recognizing the significance of SPECT in nuclear medicine and the pivotal role of fibroblast activation protein (FAP) in cancer diagnosis and therapy, this study focuses on the development of 99mTc-labeled dimeric HF2 with high tumor uptake and image contrast. The dimeric HF2 was synthesized and radiolabeled with 99mTc in one pot using various coligands (tricine, TPPTS, EDDA, and TPPMS) to yield [99mTc]Tc-TPPTS-HF2, [99mTc]Tc-EDDA-HF2, and [99mTc]Tc-TPPMS-HF2 dimers. SPECT imaging results indicated that [99mTc]Tc-TPPTS-HF2 exhibited higher tumor uptake and tumor-to-normal tissue (T/NT) ratio than [99mTc]Tc-EDDA-HF2 and [99mTc]Tc-TPPMS-HF2. Notably, [99mTc]Tc-TPPTS-HF2 exhibited remarkable tumor accumulation and retention in HT-1080-FAP and U87-MG tumor-bearing mice, thereby surpassing the monomeric [99mTc]Tc-TPPTS-HF. Moreover, [99mTc]Tc-TPPTS-HF2 achieved acceptable T/NT ratios in the hepatocellular carcinoma patient-derived xenograft (HCC-PDX) model, which provided identifiable contrast and imaging quality. In conclusion, this study presents proof-of-concept research on 99mTc-labeled FAP inhibitor dimers for the visualization of multiple tumor types. Among these candidate compounds, [99mTc]Tc-TPPTS-HF2 showed excellent clinical potential, thereby enriching the SPECT tracer toolbox.
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Compuestos de Organotecnecio , Tomografía Computarizada de Emisión de Fotón Único , Animales , Humanos , Ratones , Tomografía Computarizada de Emisión de Fotón Único/métodos , Compuestos de Organotecnecio/química , Compuestos de Organotecnecio/farmacocinética , Compuestos de Organotecnecio/síntesis química , Línea Celular Tumoral , Diseño de Fármacos , Radiofármacos/química , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Tecnecio/química , Distribución Tisular , Dimerización , Ratones Desnudos , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/química , Endopeptidasas/metabolismo , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/químicaRESUMEN
ABSTRACT: SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) are rare and aggressive neoplasms commonly found in male smokers and portend a poor prognosis. In this case, we reported 18 F-FDG and 68 Ga-FAPI-46 PET/CT findings in an occult SMARCA4-dUT located in the left pulmonary hilum along with mediastinal lymph node metastases. 68 Ga-FAPI-46 PET/CT showed superiority over 18 F-FDG for detecting SMARCA4-dUT lesions. This case highlighted that 68 Ga-FAPI-46 PET/CT may be a promising imaging modality in the evaluation of SMARCA4-dUT, particularly for detecting the occult SMARCA4-dUT arising in uncommon sites.
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Proteínas Nucleares , Tomografía Computarizada por Tomografía de Emisión de Positrones , Factores de Transcripción , Humanos , Masculino , Factores de Transcripción/genética , Proteínas Nucleares/genética , Proteínas Nucleares/deficiencia , ADN Helicasas/genética , Carcinoma/diagnóstico por imagen , Radioisótopos de Galio , Persona de Mediana Edad , Isótopos de GalioRESUMEN
The timely identification of individuals at high risk for peptic ulcers (PUs) is vital in preventing gastrointestinal bleeding after antiplatelet therapy. This study was designed to determine PU risk factors and develop a risk assessment model for PU detection in the general Chinese population. In a prospective dataset, clinical data from individuals undergoing gastroscopic evaluation between April 2019 and May 2022 were recorded. PUs were defined as mucosal defects exceeding 5 mm confirmed via gastroscopy. Participants were categorized into development (April 2019 to April 2021) and validation (May 2021 to May 2022) sets based on chronological order. LASSO-derived logistic regression analysis was employed to create a score, which was further validated via temporal validation. A total of 902 patients were ultimately enrolled, 204 (22.6%) of whom had PUs based on endoscopic findings. In the development cohort (n = 631), seven independent risk factors emerged: male sex (OR = 2.35, P = 0.002), white blood cell (WBC) count (OR = 1.16, P = 0.010), red blood cell (RBC) count (OR = 0.49, P < 0.001), globulin level (OR = 0.92, P = 0.004), albumin level (OR = 0.94, P = 0.020), pepsinogen I (PGI) level (OR = 1.01, P < 0.001), and positive Helicobacter pylori (HP) antibody (OR = 2.50, P < 0.001). Using these factors, a nomogram (HAMPROW score [hazard ratio (HP) antibody, albumin, male, PGI, RBC, globulin, and WBC]) was developed for individual PU prediction. The ability of the HAMPROW score to predict survival was confirmed with AUCs of 0.854 (95% CI 0.816-0.891) and 0.833 (95% CI 0.771-0.895) in the development and validation sets, respectively. In conclusion, the HAMPROW score can be used to screen for PUs effectively in the general Chinese population, facilitating personalized early detection of high risk of gastrointestinal bleeding before antiplatelet therapy.
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Globulinas , Infecciones por Helicobacter , Helicobacter pylori , Úlcera Péptica , Humanos , Masculino , Úlcera Péptica Hemorrágica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Estudios Prospectivos , Úlcera Péptica/complicaciones , Hemorragia Gastrointestinal/inducido químicamente , Albúminas/uso terapéutico , China/epidemiología , Supuración/inducido químicamente , Supuración/complicaciones , Infecciones por Helicobacter/tratamiento farmacológicoRESUMEN
Extensive research has been conducted on radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) and p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH2 (LM3) peptides for imaging of FAP and somatostatin receptor 2 (SSTR2)-positive tumors. In this study, we designed and synthesized a FAPI-LM3 heterobivalent molecule radiolabeled with 68Ga and evaluated its effectiveness in both tumor xenografts and patients with nasopharyngeal carcinoma (NPC). Methods: The synthesis of FAPI-LM3 was based on the structures of FAPI-46 and LM3. After radiolabeling with 68Ga, its dual-receptor-binding affinity was evaluated in vitro and in vivo. Preclinical studies, including small-animal PET and biodistribution evaluation, were conducted on HT-1080-FAP and HT-1080-SSTR2 tumor xenografts. The feasibility of 68Ga-FAPI-LM3 PET/CT in a clinical setting was evaluated in patients with NPC, and the results were compared with those of 18F-FDG. Results: 68Ga-FAPI-LM3 showed high affinity for both FAP and SSTR2. The tumor uptake of 68Ga-FAPI-LM3 was significantly higher than that of 68Ga-FAPI-46 and 68Ga-DOTA-LM3 in HT-1080-FAP-plus-HT-1080-SSTR2 tumor xenografts. In a clinical study involving 6 NPC patients, 68Ga-FAPI-LM3 PET/CT showed significantly higher uptake than did 18F-FDG in primary and metastatic lesions, leading to enhanced lesion detectability and tumor delineation. Conclusion: 68Ga-FAPI-LM3 exhibited FAPI and SSTR2 dual-receptor-targeting properties both in vitro and in vivo, resulting in improved tumor uptake and retention compared with that observed with monomeric 68Ga-FAPI and 68Ga-DOTA-LM3. This study highlights the clinical feasibility of 68Ga-FAPI-LM3 PET/CT for NPC imaging.
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Neoplasias Nasofaríngeas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Animales , Humanos , Radioisótopos de Galio , Fluorodesoxiglucosa F18 , Carcinoma Nasofaríngeo/diagnóstico por imagen , Distribución Tisular , Tomografía de Emisión de Positrones , Neoplasias Nasofaríngeas/diagnóstico por imagenAsunto(s)
Tumores Neuroendocrinos , Compuestos Organometálicos , Humanos , Tumores Neuroendocrinos/diagnóstico por imagen , Radioisótopos de Galio , Bazo/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Imagen por Resonancia Magnética , Receptores de SomatostatinaRESUMEN
Fibroblast activation protein is overexpressed in the stroma of several cancer types. 18F-fibroblast activation protein inhibitor (FAPI)-74 is a PET tracer with high selectivity for fibroblast activation protein and has shown high accumulation in human tumors in clinical studies. However, the use of 18F-FAPI-74 for PET imaging of gastrointestinal cancer has not been systematically investigated. Herein, we investigated the diagnostic accuracy of 18F-FAPI-74 (18F-LNC1005) PET/CT in gastric, liver, and pancreatic cancers and compared the results with those of 18F-FDG PET/CT. Methods: This prospective study analyzed patients with confirmed gastric, liver, or pancreatic malignancies who underwent concurrent 18F-FDG and 18F-FAPI-74 PET/CT between June 2022 and December 2022. PET/CT findings were confirmed by histopathology or radiographic follow-up. 18F-FDG and 18F-FAPI-74 uptake and tumor-to-background ratios were compared using the Wilcoxon signed-rank test. The McNemar test was used to compare the diagnostic accuracy of the 2 scans. Results: Our cohort consisted of 112 patients: 49 with gastric cancer, 39 with liver cancer, and 24 with pancreatic cancer. Among them, 69 patients underwent PET/CT for initial staging and 43 for recurrence detection. Regarding lesion-based diagnostic accuracy, 18F-FAPI-74 PET/CT showed higher sensitivity than did 18F-FDG in the detection of primary tumors (gastric cancer, 88% [22/25] vs. 60% [15/25], P = 0.016; liver cancer, 100% [22/22] vs. 82% [18/22], P = 0.125; pancreatic cancer, 100% [22/22] vs. 86% [19/22], P = 0.250), local recurrence (92% [23/25] vs. 56% [14/25]; P = 0.021), involved lymph nodes (71% [41/58] vs. 40% [23/58]; P < 0.001), and bone and visceral metastases (98% [350/358] vs. 47% [168/358]; P < 0.001). Compared with 18F-FDG, 18F-FAPI-74 PET/CT upstaged 17 patients' TNM staging among all treatment-naïve patients (17/69, 25%) and changed the clinical management of 4 patients (4/43, 9%) in whom recurrence or metastases were detected. Conclusion: 18F-FAPI-74 PET/CT is superior to 18F-FDG PET/CT in detecting primary tumors, local recurrence, lymph node involvement, and bone and visceral metastases in gastric, pancreatic, and liver cancers, with higher uptake in most primary and metastatic lesions.
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Neoplasias Gastrointestinales , Neoplasias Hepáticas , Neoplasias Pancreáticas , Quinolinas , Neoplasias Gástricas , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Fluorodesoxiglucosa F18 , Neoplasias Gástricas/diagnóstico por imagen , Estudios Prospectivos , Tomografía de Emisión de Positrones , Neoplasias Gastrointestinales/diagnóstico por imagen , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Fibroblastos , Radioisótopos de GalioRESUMEN
PURPOSE: This translational study aimed to determine the maximum tolerated dose (MTD), safety, dosimetry, and therapeutic efficacy of 177Lu-PSMA-EB-01 (denoted as [177Lu]Lu-LNC1003) in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: A total of 13 patients with mCRPC were recruited in this study. A standard 3 + 3 dose escalation protocol was performed. The following dose levels were ultimately evaluated: 1.11, 1.85, and 2.59 GBq/cycle. Patients received [177Lu]Lu-LNC1003 therapy for up to two cycles at a 6-week interval. RESULTS: Patients received fractionated doses of [177Lu]Lu-LNC1003 ranging from 1.11 to 2.59 GBq per cycle. Myelosuppression was dose-limiting at 2.59 GBq, and 1.85 GBq was determined to be the MTD. The total-body effective dose for 177Lu-LNC1003 was 0.35 ± 0.05 mSv/MBq. The salivary glands were found to receive the highest estimated radiation dose, which was calculated to be 3.61 ± 2.83 mSv/MBq. The effective doses of kidneys and red bone marrow were 1.88 ± 0.35 and 0.22 ± 0.04 mSv/MBq, respectively. The tumor mean absorbed doses for bone and lymph node metastases were 8.52 and 9.51 mSv/MBq. Following the first treatment cycle, PSA decline was observed in 1 (33.3%), 4 (66.7%), and 2 (50.0%) patients at dose levels 1 (1.11 GBq), 2 (1.85 GBq), and 3 (2.59 GBq), respectively. Compared with the baseline serum PSA value, 1 (33.3%) at dose level 1 and 4 (66.6%) patients at dose level 2, presented a PSA decline after the second treatment cycle. CONCLUSION: This phase 1 trial revealed that the MTD of [177Lu]Lu-LNC1003 is 1.85 GBq. The treatment with multiple cycles at the dose of 1.11 GBq /cycle and 1.85 GBq /cycle was well tolerated. [177Lu]Lu-LNC1003 has higher tumor effective doses in bone and lymph nodes metastases while the absorbed dose in the red bone marrow should be closely monitored in future treatment studies with higher doses and multiple cycles. The frequency of administration also needs to be further explored to assess the efficacy and side effects of [177Lu]Lu-LNC1003 treatment. TRIAL REGISTRATION: 177Lu-PSMA-EB-01 in patients with metastatic castration-resistant prostate cancer (NCT05613738, Registered 14 November 2022). URL of registry https://classic. CLINICALTRIALS: gov/ct2/show/NCT05613738.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Antígeno Prostático Específico , Dosis Máxima Tolerada , Dipéptidos/uso terapéutico , Radiofármacos/uso terapéutico , Metástasis Linfática , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Lutecio/uso terapéutico , Resultado del TratamientoRESUMEN
ABSTRACT: Septic thrombophlebitis of the portal vein is a serious infectious disorder and is difficult to be diagnosed at an early stage. In this case, we presented 18 F-FDG and 68 Ga-FAPI-46 PET/CT findings in a 45-year-old man with acute appendicitis complicated by septic thrombophlebitis of the portal vein. 68 Ga-FAPI-46 PET/CT showed intense radiotracer uptake in the thrombosis of the portal vein, with higher SUV max and larger disease extent than 18 F-FDG PET/CT. This case demonstrated that 68 Ga-FAPI PET/CT may be a useful imaging modality for the diagnosis of this infectious condition.
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Apendicitis , Infecciones de los Tejidos Blandos , Tromboflebitis , Masculino , Humanos , Persona de Mediana Edad , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones , Apendicitis/complicaciones , Apendicitis/diagnóstico por imagen , Vena Porta/diagnóstico por imagen , Enfermedad Aguda , Radioisótopos de Galio , Tromboflebitis/complicaciones , Tromboflebitis/diagnóstico por imagenRESUMEN
PURPOSE: Fibroblast activation protein (FAP) is a promising target for tumor treatment. In this study, we aimed to investigate the safety and efficacy of the albumin binder-conjugated FAP-targeted radiopharmaceutical, 177Lu-EB-FAPI (177Lu-LNC1004), in patients with metastatic radioiodine-refractory thyroid cancer (mRAIR-TC). PATIENTS AND METHODS: This open-label, non-randomized, first-in-human, dose-escalation, investigator-initiated trial had a 3+3 design and involved a 6-week 177Lu-LNC1004 treatment cycle in patients with mRAIR-TC at 2.22 GBq initially, with subsequent cohorts receiving an incremental 50% dose increase until dose-limiting toxicity (DLT) was observed. RESULTS: 177Lu-LNC1004 administration was well tolerated, with no life-threatening adverse events observed. No patients experienced DLT in Group A (2.22 GBq/cycle). One patient experienced grade 4 thrombocytopenia in Group B (3.33 GBq/cycle); hence, another three patients were enrolled, none of whom experienced DLT. Two patients experienced grade 3 and 4 hematotoxicity in Group C (4.99 GBq/cycle). The mean whole-body effective dose was 0.17 ± 0.04 mSv/MBq. Intense 177Lu-LNC1004 uptake and prolonged tumor retention resulted in high mean absorbed tumor doses (8.50 ± 12.36 Gy/GBq). The mean effective half-lives for the whole-body and tumor lesions were 90.20 ± 7.68 and 92.46 ± 9.66 hours, respectively. According to RECIST, partial response, stable disease, and progressive disease were observed in 3 (25%), 7 (58%), and 2 (17%) patients, respectively. The objective response and disease control rates were 25% and 83%, respectively. CONCLUSIONS: FAP-targeted radioligand therapy with 177Lu-LNC1004 at 3.33 GBq/cycle was well tolerated in patients with advanced mRAIR-TC, with high radiation dose delivery to the tumor lesions, encouraging therapeutic efficacy, and acceptable side effects.
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Radioisótopos de Yodo , Neoplasias de la Tiroides , Humanos , Masculino , Radioisótopos de Yodo/uso terapéutico , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/tratamiento farmacológico , Radiofármacos/efectos adversos , Antígeno Prostático Específico , FibroblastosRESUMEN
BACKGROUND: Tacrolimus (TAC) and mycophenolic acid (MPA) are commonly used immunosuppressive therapies after renal transplant. Our objective was to quantify TAC and MPA concentrations in peripheral blood mononuclear cells (PBMCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) and to evaluate and validate the performance of the methodology. A prospective follow-up cohort study was conducted to determine whether intracellular concentrations were associated with adverse outcomes in renal transplants. METHODS: PBMCs were prepared using the Ficoll separation technique and purified with erythrocyte lysis. The cells were counted using Sysmex XN-3100 and then packaged and frozen according to a 50 µL volume containing 1.0 × 106 cells. TAC and MPA were extracted using MagnaBeads and quantified using an LC-MS/MS platform. The chromatography was run on a reversed-phase Waters Acquity UPLC BEH C18 column (1.7 µm, 50 mm × 2.1 mm) for gradient elution separation with a total run time of 4.5 min and a flow rate of 0.3 mL/min. Mobile phases A and B were water and methanol, respectively, each containing 2 mM ammonium acetate and 0.1% formic acid. Renal transplant recipients receiving TAC and MPA in combination were selected for clinical validation and divided into two groups: a stable group and an adverse outcome group. The concentrations were dynamically monitored at 5, 7, 14, and 21 days (D5, D7, D14, and D21) and 1, 2, 3, and 6 months (M1, M2, M3, and M6) after operation. RESULTS: Method performance validation was performed according to Food and Drug Administration guidelines, showing high specificity and sensitivity. The TAC and MPA calibration curves were linear (r2 = 0.9988 and r2 = 0.9990, respectively). Both intra-day and inter-day imprecision and inaccuracy were less than 15%. Matrix effects and recoveries were satisfactory. The TAC and MPA concentrations in 304 "real" PBMC samples from 47 renal transplant recipients were within the calibration curve range (0.12 to 16.40 ng/mL and 0.20 to 4.72 ng/mL, respectively). There was a weak correlation between PBMC-C0TAC and WB-C0TAC (p < 0.05), but no correlation was found for MPA. The level of immunosuppressive intra-patient variation (IPV) was higher in PBMC at 77.47% (55.06, 97.76%) than in WB at 34.61% (21.90, 49.85%). During the dynamic change in C0TAC, PBMC-C0TAC was in a fluctuating state, and no stable period was found. PBMC-C0TAC did not show a significant difference between the stable and adverse outcome group, but the level of the adverse outcome group was generally higher than that of the stable group. CONCLUSIONS: Compared with conventional therapeutic drug monitoring, the proposed rapid and sensitive method can provide more clinically reliable information on drug concentration at an active site, which has the potential to be applied to the clinical monitoring of intracellular immunosuppressive concentration in organ transplantation. However, the application of PBMC-C0TAC in adverse outcomes of renal transplant should be studied further.
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ABSTRACT: SMARCA4-deficient undifferentiated carcinoma is a new clinical entity characterized by SMARCA4 inactivation and has a dismal prognosis because of rapid growth. In this case, we reported 18 F-FDG and 68 Ga-FAPI-46 PET/CT imaging findings in a patient with SMARCA4-deficient undifferentiated carcinoma of stomach. 68 Ga-FAPI-46 PET/CT showed much higher tumor-to-background contrast of primary tumor and revealed more metastatic lesions than 18 F-FDG PET/CT. This case demonstrated the superiority of 68 Ga-FAPI PET/CT over 18 F-FDG for identifying both primary and metastatic lesions in SMARCA4-deficient undifferentiated carcinoma. This observation may add the information on the benefit of FAPI PET in oncology imaging.
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Carcinoma , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Fluorodesoxiglucosa F18 , Estómago , ADN Helicasas , Proteínas Nucleares , Factores de TranscripciónRESUMEN
Purpose: Recent studies suggest that 68Ga-FAPI PET/CT demonstrated superiority over 18F-FDG PET/CT in the evaluation of various cancer types, especially in gastric cancer (GC). By comprehensively reviewing and analysing the differences between 68Ga-FAPI and 18F-FDG in GC, some evidence is provided to foster the broader clinical application of FAPI PET imaging. Methods: In this review, studies published up to July 3, 2023, that employed radionuclide labelled FAPI as a diagnostic radiotracer for PET in GC were analysed. These studies were sourced from both the PubMed and Web of Science databases. Our statistical analysis involved a bivariate meta-analysis of the diagnostic data and a meta-analysis of the quantitative metrics. These were performed using R language. Results: The meta-analysis included 14 studies, with 527 patients, of which 358 were diagnosed with GC. Overall, 68Ga-FAPI showed higher pooled sensitivity (0.84 [95% CI 0.67-0.94] vs. 0.46 [95% CI 0.32-0.60]), specificity (0.91 [95% CI 0.76-0.98] vs. 0.88 [95% CI 0.74-0.96]) and area under the curve (AUC) (0.92 [95% CI 0.77-0.98] vs. 0.52 [95% CI 0.38-0.86]) than 18F-FDG. The evidence showed superior pooled sensitivities of 68Ga-FAPI PET over 18F-FDG for primary tumours, local recurrence, lymph node metastases, distant metastases, and peritoneal metastases. Furthermore, 68Ga-FAPI PET provided higher maximum standardized uptake value (SUVmax) and tumour-to-background ratios (TBR). For bone metastases, while 68Ga-FAPI PET demonstrated slightly lower patient-based pooled sensitivity (0.93 vs. 1.00), it significantly outperformed 18F-FDG in the lesion-based analysis (0.95 vs. 0.65). However, SUVmax (mean difference [MD] 1.79 [95% CI -3.87-7.45]) and TBR (MD 5.01 [95% CI -0.78-10.80]) of bone metastases showed no significant difference between 68Ga-FAPI PET/CT and 18F-FDG PET/CT. Conclusion: Compared with 18F-FDG, 68Ga-FAPI PET imaging showed improved diagnostic accuracy in the evaluation of GC. It can be effectively applied to the early diagnosis, initial staging, and detection of recurrence/metastases of GC. 68Ga-FAPI may have the potential of replacing 18F-FDG in GC in future applications.
Asunto(s)
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Fluorodesoxiglucosa F18 , Radioisótopos de Galio , Tomografía de Emisión de PositronesAsunto(s)
Muerte Celular Inmunogénica , Neoplasias , Humanos , Radiación Ionizante , Microambiente TumoralRESUMEN
ABSTRACT: Benign metastasizing leiomyomas (BMLs) are benign disseminated extrauterine tumors in patients with prior history of uterine leiomyomas and may occur years after hysterectomy. In this case, we presented 18 F-FDG and 68 Ga-FAPI PET/CT findings in a 37-year-old woman with benign leiomyoma metastasizing to lung and pelvis. The metastatic lesions demonstrated faint 18 F-FDG but elevated 68 Ga-FAPI activity, indicating the low level of glucose metabolism but excessive accumulation of activated fibroblasts in the BMLs. This case demonstrated that 68 Ga-FAPI PET/CT may be potentially useful in the evaluation of BMLs.