Covalent targeted radioligands potentiate radionuclide therapy.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted ß- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

The status of nuclear medicine in China: the first official national survey.

AIM/INTRODUCTION: The National Nuclear Medicine Quality Control Center of China conducted the first official survey to investigate the nationwide situation of nuclear medicine in 2020. The survey aimed to unveil the current nuclear medicine situation and its quality control in China. MATERIALS AND METHODS: The web-based survey was conducted and the data was collected via the National Clinical Improvement System (NCIS) of China from 1st April to 31st May 2021. RESULTS: A total of 808 institutes across 30 provinces responded to the national survey. For human resources, there are 4460 physicians, 3077 technologists, 339 physicists, and 309 radiochemists. There are 887 single-photon imaging instruments, including 823 SPECT or SPECT/CT, and 365 PET instruments including 314 PET/CT. Six hundred twenty-four institutes perform SPECT examinations and 319 institutes perform PET examinations. 60% of SPECT scans are bone scintigraphy. A total of 97% of PET scans use an [18F]F-FDG tracer. Furthermore, 587 institutes provide radionuclide therapy services but only 280 institutes have admission rooms. The top three radionuclide therapies are [131I] therapy of hyperthyroidism with 546 institutes, [89Sr] therapy of bone metastasis with 400 institutes, and [131I] therapy of differentiated thyroid cancer with 286 institutes. Finally, for the frequency of equipment quality control per year, there are about 67 times self-test within the department for SPECT instruments and 111 times for PET instruments on average in each province. There are about three failures of SPECT and five failures of PET on average per year in each province. There are 408 institutes (of 624 SPECT institutes) performing quality control of SPECT radiopharmaceuticals, 216 (of 319) for PET radiopharmaceuticals, and 373 (of 587) for radionuclide therapy. CONCLUSION: These results of the first official survey towards current status of nuclear medicine in China are the foundation for the establishment of the quality control management system.

Chemokine Receptor 4-Targeted PET/CT With 68 Ga-Pentixather Detects More Lesions Than 68 Ga-Pentixafor PET/CT in Multiple Myeloma.

ABSTRACT: An 83-year-old woman with newly diagnosed multiple myeloma (MM) was enrolled in our 68 Ga-pentixather and 68 Ga-pentixafor PET/CT trial for evaluation of tumor burden. 68 Ga-pentixather PET/CT detected more focal bone lesions, and the uptake levels of focal bone lesions on 68 Ga-pentixather PET/CT were higher than those on 68 Ga-pentixafor PET/CT. This suggests that 68 Ga-pentixather PET/CT may be an alternative imaging modality and more sensitive in detecting MM lesions than 68 Ga-pentixafor PET/CT.

18 F-Florbetapir PET/CT and 68 Ga-FAPI PET/CT in a Case of Light Chain Amyloidosis With Predominant Multiple Tumor-Like Deposits.

ABSTRACT: A 66-year-old man presented with multiple masses in different regions, including the left groin, back subcutaneous area, and lungs. Pathological examination confirmed localized amyloid deposits after 3 surgeries. Serum-free λ light chains were elevated. To evaluate systemic involvement, the patient underwent 18 F-Florbetapir PET/CT and 68 Ga-FAPI-04 PET/CT. Both scans showed increased uptake in multiple masses and nodules throughout the body. This report presents a rare case of light chain (AL) amyloidosis, primarily characterized by multiple localized tumor-like deposits with high activity on 18 F-Florbetapir PET/CT and 68 Ga-FAPI-04 PET/CT.

Phase I, first-in-human study of XTR004, a novel 18F-labeled tracer for myocardial perfusion PET: Biodistribution, radiation dosimetry, pharmacokinetics, and safety after a single injection at rest.

OBJECTIVES: This study assessed the imaging characteristics, pharmacokinetics and safety of XTR004, a novel 18F-labeled Positron Emission Tomography (PET) myocardial perfusion imaging tracer, after a single injection at rest in humans. METHODS: Eleven healthy subjects (eight men and three women) received intravenous XTR004 (239-290 megabecquerel [MBq]). Safety profiles were monitored on the dosing day and three follow-up visits. Multiple whole-body PET scans were conducted over 4.7 h to evaluate biodistribution and radiation dosimetry. Blood and urine samples collected for 7.25 h were metabolically corrected to characterize pharmacokinetics. RESULTS: In the first 0-12 min PET images of ten subjects, liver (26.81 ± 4.01), kidney (11.43 ± 2.49), lung (6.75 ± 1.76), myocardium (4.72 ± 0.67) and spleen (3.1 ± 0.84) exhibited the highest percentage of the injected dose (%ID). Myocardial uptake of XTR004 in the myocardium initially reached 4.72 %ID and 7.06 g/mL, and negligibly changed within an hour (Δ: 7.20%, 5.95%). The metabolically corrected plasma peaked at 2.5 min (0.0013896 %ID/g) and halved at 45.2 min. Whole-body effective dose was 0.0165 millisievert (mSv)/MBq. Cumulative urine excretion was 8.18%. Treatment-related adverse events occurred in seven out of eleven subjects (63.6%), but no severe adverse event was reported. CONCLUSIONS: XTR004 demonstrated a favorable safety profile, rapid, high, and stable myocardial uptake and excellent potential for PET myocardial perfusion imaging (MPI). Further exploration of XTR004 PET MPI for detecting myocardial ischemia is warranted.

Gallium-68 labeled somatostatin receptor antagonist PET/CT in over 500 patients with neuroendocrine neoplasms: experience from a single center in China.

PURPOSE: Somatostatin receptor antagonists have shown promising performance for imaging neuroendocrine neoplasms. However, there is a lack of studies exploring the diagnostic performance of SSTR antagonists or comparing them with agonists in a large cohort of patients with NENs. This study aimed to retrospectively review all SSTR antagonist PET/CT scans conducted at Peking Union Medical College Hospital since November 2018 in patients with confirmed or suspected NENs. METHODS: Four types of SSTR antagonists were utilized, including [68Ga]Ga-NODAGA-LM3, [68Ga]Ga-DOTA-LM3, [68Ga]Ga-NODAGA-JR11, and [68Ga]Ga-DOTA-JR11. The reference standard was based on a combination of histopathology, clinical evaluation, imaging results, and follow-up. Patient-based sensitivity, specificity, and accuracy were evaluated. The SUVmax and tumor-to-liver ratio (TLR) of the hottest lesions was recorded and compared between antagonists and [68Ga]Ga-DOTATATE. RESULTS: A total of 622 antagonist scans from 549 patients were included in the analysis. The patient-level sensitivity, specificity, and accuracy of antagonist imaging (all tracers combined) were 91.0% (443/487), 91.9% (57/62), and 91.1% (500/549), respectively. In 181 patients with a comparative [68Ga]Ga-DOTATATE PET/CT scan, the patient-level sensitivity, specificity, and accuracy were 87.5% (147/168), 76.9% (10/13), and 86.7% (157/181), respectively. For the hottest lesions, SSTR antagonists all tracers combined demonstrated an overall comparable SUVmax to [68Ga]Ga-DOTATATE (40.1 ± 32.5 vs. 39.4 ± 23.8, p = 0.772). While [68Ga]Ga-NODAGA-LM3 showed significantly higher uptake than [68Ga]Ga-DOTATATE (57.4 ± 38.5 vs. 40.0 ± 22.8, p<0.001), [68Ga]Ga-NODAGA-JR11 (39.7 ± 26.5 vs. 34.3 ± 23.9, p = 0.108) and [68Ga]Ga-DOTA-LM3 (38.9 ± 32.1 vs. 37.2 ± 22.1, p = 0.858) showed comparable uptake to [68Ga]Ga-DOTATATE, and [68Ga]Ga-DOTA-JR11 showed lower uptake (28.9 ± 26.1 vs. 44.0 ± 25.7, p = 0.001). All antagonists exhibited significantly higher TLR than [68Ga]Ga-DOTATATE (12.1 ± 10.8 vs. 5.2 ± 4.5, p<0.001). CONCLUSION: Gallium-68 labeled SSTR antagonists could serve as alternatives to SSTR agonists for imaging of NENs. Among various antagonists, [68Ga]Ga-NODAGA-LM3 seems to have the best imaging profile.

Preclinical evaluation of the theranostic potential of 89Zr/177Lu-labeled anti-TROP-2 antibody in triple-negative breast cancer model.

BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most lethal malignant tumors among women, characterized by high invasiveness, high heterogeneity, and lack of specific therapeutic targets such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Trophoblast cell-surface antigen-2 (TROP-2) is a transmembrane glycoprotein over-expressed in 80% of TNBC patients and is associated with the occurrence, progress, and poor prognosis of TNBC. The TROP-2 targeted immunoPET imaging allows non-invasive quantification of the TROP-2 expression levels of tumors, which could help to screen beneficiaries most likely to respond to SG and predict the response. This study aimed to develop a 89Zr/177Lu-radiolabeled anti-TROP-2 antibody (NY003) for immunoPET and SPECT imaging, as well as radioimmunotherapy (RIT) in TROP-2 (+)TNBC tumor-bearing model. Based on the camelid antibody, we developed a TROP-2 targeted recombinant antibody NY003. NY003 was conjugated with DFO and DTPA for 89Zr and 177Lu radiolabelling, respectively. The theranostic potential of [89Zr]Zr-DFO-NY003/[177Lu]Lu-DTPA-NY003 was evaluated through immunoPET, SPECT imaging, and RIT studies in the subcutaneous TROP-2 positive TNBC xenograft mice model. RESULTS: The high binding affinity of NY003 to TROP-2 was verified through ELISA. The radiochemical purity of [89Zr]Zr-DFO-NY003/[177Lu]Lu-DTPA-NY003 exceeded 95% and remained stable within 144h p.i. in vitro. ImmunoPET and SPECT imaging showed the specific accumulation of [89Zr]Zr-DFO-NY003/[177Lu]Lu-DTPA-NY003 in MDA-MB-231 tumors and gradually increased with the time tested, significantly higher than that in control groups (P < 0.05). The strongest anti-tumor efficacy was observed in the high-dose of [177Lu]Lu-DTPA-NY003 group, followed by the low-dose group, the tumor growth was significantly suppressed by [177Lu]Lu-DTPA-NY003, the tumor volumes of both high- and low-dose groups were smaller than the control groups (P < 0.05). Ex vivo biodistribution and histological staining verified the results of in vivo imaging and RIT studies. CONCLUSION: As a drug platform for radiotheranostics, 89Zr/177Lu-radiolabeled anti-TROP-2 antibody NY003 could not only non-invasively screen the potential beneficiaries for optimizing SG ADC treatment but also suppressed the growth of TROP-2 positive TNBC tumors, strongly supporting the theranostic potential of [89Zr]Zr-DFO-NY003/[177Lu]Lu-DTPA-NY003.

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

Clinical Value of 68Ga-Pentixafor PET/CT in Subtype Diagnosis of Primary Aldosteronism Patients with Adrenal Micronodules.

Our objective was to investigate the clinical value of 68Ga-pentixafor PET/CT in subtype diagnosis of primary aldosteronism (PA) patients with adrenal micronodules less than 1 cm in diameter and compare it with the routine clinical methods. Methods: We used prospective enrollment of PA patients with adrenal micronodules identified by adrenal CT scans to undergo 68Ga-pentixafor PET/CT. Patients were divided into surgically eligible and ineligible groups based on surgical pathology and postoperative follow-up or adrenal venous sampling (AVS) results. Patient management was discussed by a multidisciplinary team. The semiquantitative parameters of PET/CT included SUVmax for adrenal lesion and SUV ratios for lesion to liver and lesion to normal adrenal gland. Results: In total, 123 PA patients with adrenal micronodules were examined using 68Ga-pentixafor PET/CT, and 104 patients who underwent surgery or successful AVS were included in the analysis (48 ± 10 y old). The sensitivity, specificity, and accuracy of visual analysis using 68Ga-pentixafor PET/CT to identify surgically eligible patients were 90.2%, 72.7%, and 86.5%, respectively, which were significantly higher than those of adrenal CT (73.1%, 53.8%, and 68.3%, respectively) and yielded consistent results in different CT morphologic or age subgroups. In 36 patients who had both AVS and 68Ga-pentixafor PET/CT, the tests showed a 66.7% concordance rate. However, PET/CT was significantly more concordant with surgical outcomes than was AVS in 17 patients who underwent adrenalectomy (82.4% vs. 68.86%). Among the 183 adrenal micronodules included in the study, the semiquantitative diagnostic thresholds for 92 lesions eligible for surgical treatment were an SUVmax of at least 4.55, an SUV ratio of at least 2.17 for lesion to liver, and an SUV ratio of at least 1.90 for lesion to normal adrenal gland. All patients benefited from surgical removal of 68Ga-pentixafor-avid microlesions. Conclusion: In PA patients with adrenal micronodules, 68Ga-pentixafor PET/CT demonstrated promising diagnostic accuracy in classification and appeared to perform better than adrenal CT. Furthermore, there was also a suggestion of some potential in predicting postoperative efficacy compared with AVS, although these observations require further investigation and verification in larger cohorts.

Distinct FDG PET/CT avidity among newly diagnosed intravascular large B-cell lymphoma patients: a descriptive observational study.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of aggressive B-cell non-Hodgkin lymphoma that poses a great diagnostic challenge due to its highly heterogenous clinical manifestations. Although 18F-fluorodeoxyglucose (FDG) is widely used as a diagnostic tool for patients suspected of having lymphoma, as it reveals FDG-avid lesions, the FDG avidity of IVLBCL has not been extensively characterized. Here, we present a comprehensive report of FDG avidity in IVLBCL and its association with clinicopathological features and survival. This descriptive observational study included consecutive patients aged at least 18 years diagnosed with IVLBCL in Peking Union Medical Hospital across 9 years. Among 50 screened IVLBCL patients, 42 had undergone 18F-FDG PET/CT to detect possible lesions for biopsy before pathological diagnosis; their FDG PET/CT (positron emission computed tomography, PET/CT) reports were retrospectively reviewed. The primary endpoint was the clinical description of FDG avidity of newly diagnosed intravascular large B-cell lymphoma and frequency. A total of 73.8% patients showed FDG-avid lesions, with a median SUVmax of 7.4 (range 1-27.7), which was lower than that for other aggressive lymphomas. Clinicopathological features were the same between the FDG-avid group and the non-FDG-avid group, except that the latter had a higher Ki-67 index (median 90% in the nonavid group vs. 80% in the avid group, P = 0.043). The overall survival rate was not different between the PET/CT groups. Our findings demonstrate that FDG PET/CT is a useful diagnostic tool for detecting FDG-avid lesions in IVLBCL patients. A random skin biopsy is essential for assisting in the diagnosis of IVLBCL, even for those with negative PET/CT.

Zinc Oxide-Loaded Cellulose-Based Carbon Gas Sensor for Selective Detection of Ammonia.

Cellulose-based carbon (CBC) is widely known for its porous structure and high specific surface area and is liable to adsorb gas molecules and macromolecular pollutants. However, the application of CBC in gas sensing has been little studied. In this paper, a ZnO/CBC heterojunction was formed by means of simple co-precipitation and high-temperature carbonization. As a new ammonia sensor, the prepared ZnO/CBC sensor can detect ammonia that the previous pure ZnO ammonia sensor cannot at room temperature. It has a great gas sensing response, stability, and selectivity to an ammonia concentration of 200 ppm. This study provides a new idea for the design and synthesis of biomass carbon-metal oxide composites.

Mesenteric Castleman Disease Misdiagnosed as Lymph Node Metastasis of Rectal Cancer on 18 F-FDG PET/CT.

ABSTRACT: Two years ago, a 64-year-old man underwent an 18 F-FDG PET/CT for staging rectal cancer. Besides the hypermetabolic rectal lesion, the image revealed a mesenteric lymph node with intense activity and multiple lung nodules with slight FDG uptake, which were highly suspected of metastases. After surgery and multiple cycles of chemotherapy, the follow-up 18 F-FDG PET/CT showed remission of all lesions except for the enlarged mesenteric lymph node with higher metabolic activity. Serum CEA remained normal during the follow-up. Postoperative pathology of the mesenteric lymph node confirmed Castleman disease.

Curcumin alleviates bisphenol AF-induced oxidative stress and apoptosis in caprine endometrial epithelial cells via the Nrf2 signaling pathway.

Bisphenol AF (BPAF), a BPA-substitute, has been widely used in industrial compounds throughout the world. Several studies have shown that BPAF has endocrine interference and reproductive toxicity. However, the toxic effects of BPAF on pregnancy and placenta of goats are still unclear. Therefore, the objective of this study was to reveal the toxic effect of BPAF by using an in vitro culture model of caprine endometrial epithelial cells (EECs) and further attempted to alleviate the toxicity by curcumin pretreatment. The results showed that BPAF induces significant effects on EECs, including decreased cell viability and mitochondrial membrane potential (△ψm), elevating intracellular reactive oxygen species (ROS), promoting cell apoptosis through upregulating the expression of Bax, Cytochrome c, and downregulating the expression of Bcl-2. Meanwhile, BPAF induced dysregulation of oxidative stress by increasing the levels of malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) but decreasing the activities of superoxide dismutase (SOD). However, curcumin pretreatment could significantly attenuate BPAF-induced toxic effects in EECs. Further study revealed that BPAF treatment could activate mitogen-activated protein kinase (MAPK) pathway and nuclear factor-erythroid 2-related factor 2 (Nrf2) expression, but curcumin pretreatment significantly inhibited the activation of MAPK signal pathway and Nrf2 expression induced by BPAF. Overall, this study indicated that curcumin could prevent BPAF-induced EECs cytotoxicity, which provides a potential therapeutic strategy for female infertility associated with BPAF exposure.

Sustained Response to Ruxolitinib of Eosinophilia-Associated Myeloproliferative Neoplasm with Translocation t(8;9)(p21;p24).

The translocation t(8;9) produces the fusion gene PCM1-JAK2, resulting in the continuous activation of the JAK2 tyrosine kinase. Myelodysplastic/myeloproliferative neoplasms are the most common disease with t(8;9)/PCM1-JAK2. Individuals with this abnormality have similar features, and JAK2 kinase inhibitor (ruxolitinib) is an effective treatment of the condition. The long-term remission results of ruxolitinib are varied. It is important to determine the response to ruxolitinib. Here, we describe a patient who has been diagnosed with eosinophilia-associated myeloproliferative neoplasm with t(8;9)(p21;p24). This patient has achieved sustained response for >1 year since the administration of ruxolitinib.

[Progress of researches on acupuncture-moxibustion promoting wound repair].

Wound is a common surgical disease characterized by skin defect or functional limitation. Studies have found that acupuncture-moxibustion plays an important role in wound healing. In this paper, we reviewed the mechanisms of acupuncture-moxibustion in promoting wound repair. Outcomes display that acupuncture-moxibustion has an action in promoting wound restoration by improving wound flow perfusion, promoting angiogenesis, increasing the number of fibroblasts and regulating collagen synthesis. In addition, acupuncture can effectively promote wound healing by controlling the release of inflammatory cytokines, up-regulating the expression of growth factors such as vascular endothelial growth factor and transforming growth factor-ß1, and affecting phosphatidylinositol-3-kinase/protein kinase B, mitogen-activated protein kinase and advanced glycation end products/receptor for AGEs signaling pathways. Based on the above studies, it is highly recommended that future studies should pay more attention to the multi-mechanism coordinated regulation target center, and the therapeutic means and dose-effect relationship of acupuncture-moxibustion in tissue repair.

Comparing the clinical value of baseline [68 Ga]Ga-FAPI-04 PET/CT and [18F]F-FDG PET/CT in pancreatic ductal adenocarcinoma: additional prognostic value of the distal pancreatitis.

PURPOSE: Anatomical and molecular staging strategies are needed for the personalized treatment of localized pancreatic ductal adenocarcinoma (PDAC). This study evaluated the performance of [68 Ga]Ga-FAPI-04 and [18F]F-FDG PET/CT on the disease staging and prognostic value of patients with localized PDAC on contrast-enhanced (CE)-CT images. METHODS: Patients with suspected localized PDAC on CE-CT were recruited for static [68 Ga]Ga-FAPI-04 and 18[F]F-FDG and PET/CT, and select patients underwent simultaneous 60-min dynamic 68 Ga-FAPI-04 PET/CT. The diagnostic and staging performances of the static PET/CT results were evaluated by delineating regions of interest in the primary tumor, whole pancreas, and distal pancreas in both types of scans and then evaluating correlations between the PET/CT findings and clinicopathological characteristics. Furthermore, Kaplan-Meier and hazard ratio (log-rank) methods were used to evaluate the prognostic value of the combined dynamic [68 Ga]Ga-FAPI-04 and static [18F]F-FDG PET/CT method. RESULTS: We included 49 patients with histologically confirmed PDAC adenocarcinomas; 32 underwent 60-min dynamic [68 Ga]Ga-FAPI-04 PET/CT imaging simultaneously. The static [68 Ga]Ga-FAPI-04 method had significantly higher accuracy and uptake values than the static [18F]F-FDG method for primary PDAC lesions, metastatic lymph nodes, and distal metastases. Furthermore, 18.4% and 10.2% of the patients' stages changed after using the [68 Ga]Ga-FAPI-04 and [18F]F-FDG PET/CT methodologies, respectively, compared to the CE-CT-designated stage. The Ki values obtained from dynamic [68 Ga]Ga-FAPI-04 PET/CT did not differ between PDAC and distal obstructive pancreatitis lesions. Pathologically enlarged tumor size, poor differentiation, and perineural invasion were associated with increased [68 Ga]Ga-FAPI-04 uptake but not with [18F]F-FDG uptake. The preoperative prognostic performance of [68 Ga]Ga-FAPI-04 was better than that of [18F]F-FDG. Interestingly, combined [68 Ga]Ga-FAPI-04 and [18F]F-FDG uptake results in the whole pancreas could further stratify patients based on their postoperative prognosis. CONCLUSION: 6[68 Ga]Ga-FAPI-04 PET/CT was more sensitive and accurate than [18F]F-FDG PET/CT for tumor, node, and metastasis staging of PDAC identified on CE-CT. Additionally, [68 Ga]Ga-FAPI-04 uptake was significantly associated with pathologically aggressive tumor features. Combined [68 Ga]Ga-FAPI-04 and [18F]F-FDG PET/CT findings improved the prognostic value, potentially providing a non-invasive guide for clinical management. Finally, increased fibroblast activity in PDAC-induced obstructive pancreatitis may be associated with poor patient survival rates.

Comparison of Baseline 68Ga-FAPI and 18F-FDG PET/CT for Prediction of Response and Clinical Outcome in Patients with Unresectable Hepatocellular Carcinoma Treated with PD-1 Inhibitor and Lenvatinib.

Fibroblast activation protein contributes to immunosuppression and resistance to immunotherapies. This study aimed to compare baseline 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT and 18F-FDG PET/CT in response and survival prediction in unresectable hepatocellular carcinoma (uHCC) patients treated with the combination of programmed cell death 1 (PD-1) inhibitor and lenvatinib. Methods: In this prospective cohort study, 22 patients with uHCC who underwent baseline 18F-FDG and 68Ga-FAPI PET/CT and soon began taking a combination of PD-1 inhibitor and lenvatinib were recruited. Semiquantitative indices of baseline PET/CT were measured as 18F-FDG SUVmax, metabolic tumor volume, total lesion glycolysis, 68Ga-FAPI SUVmax, 68Ga-FAPI-avid tumor volume (FTV), and total lesion fibroblast activation protein expression (TLF). The primary endpoint was durable or nondurable clinical benefit after treatment, and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: The overall response rate of the combination therapy was 41% (9/22). Fifty percent of patients had durable clinical benefit. Median PFS and OS were 4.8 and 14.4 mo, respectively. Patients with nondurable clinical benefit showed a significantly higher FTV and TLF than those with durable clinical benefit, whereas 18F-FDG parameters overlapped. A higher 68Ga-FAPI-avid tumor burden (FTV > 230.46 cm3 or TLF > 961.74 SUVbody weight⋅cm3) predicted both shorter PFS (4.0 vs. 13.5 mo, P = 0.016) and shorter OS (7.8 mo vs. not reached, P = 0.030). Patients with a higher metabolic tumor burden (metabolic tumor volume > 206.80 cm3 or total lesion glycolysis > 693.53 SUVbody weight⋅cm3) showed a shorter OS although the difference did not reach statistical significance (P = 0.085). In multivariate analysis, a higher 68Ga-FAPI-avid tumor burden (hazard ratio [HR], 3.88 [95% CI, 1.26-12.01]; P = 0.020) and macrovascular invasion (HR, 4.00 [95% CI, 1.06-15.14]; P = 0.039) independently predicted a shorter PFS, whereas a higher 68Ga-FAPI-avid tumor burden (HR, 5.92 [95% CI, 1.19-29.42]; P = 0.035) and bone metastases (HR, 5.88 [95% CI, 1.33-25.93]; P = 0.022) independently predicted a shorter OS. Conclusion: Volumetric indices on baseline 68Ga-FAPI PET/CT were potentially independent prognostic factors to predict durable clinical benefit, PFS, and OS in uHCC patients treated with a combination of PD-1 and lenvatinib. Baseline 68Ga-FAPI PET/CT may facilitate uHCC patient selection before combination therapy.