Small-molecule PET tracers targeting carbonic anhydrase IX (CAIX) have recently been developed for patients with clear cell renal cell carcinoma (ccRCC). Here, we report the preclinical results and first-in-human study of a CAIX-targeting theranostic pair, [68Ga]Ga/[177Lu]Lu-NYM096, for patients with metastatic ccRCC, aiming to assess its safety, tolerability, dosimetry, and preliminary efficacy. Methods: The in vivo biodistribution of [68Ga]Ga-NYM096 was evaluated in mice bearing OS-RC-2 xenografts. The therapeutic efficacy of [177Lu]Lu-NYM096 was assessed with a dose escalating from 8.1 to 74 MBq. Patients with metastatic ccRCC who had disease progression after standard therapy were prospectively enrolled. Serial whole-body [68Ga]Ga-NYM096 PET/CT scans were performed to evaluate biodistribution and dosimetry. Patients with positive CAIX expression entered the therapeutic phase and received [177Lu]Lu-NYM096 following a standard 3-plus-3 dose escalation design that started from 1.85 GBq. Serial whole-body planar imaging was performed after the first therapy cycle. Safety, dosimetry, and preliminary efficacy were evaluated. Results: High tumor accumulation of [68Ga]Ga/[177Lu]Lu-NYM096 was observed in OS-RC-2 xenograft tumor models. Moreover, [177Lu]Lu-NYM096 was well tolerated and demonstrated a significant dose-dependent tumor suppression effect. In the 2 patients, [68Ga]Ga-NYM096 demonstrated excellent tumor uptake, with an SUVmax of 330.0 at 1 h postinjection. Subsequent [177Lu]Lu-NYM096 treatment demonstrated no evidence of nephrotoxicity, hepatotoxicity, or pancreatic toxicity. Patient 1 experienced grade 1 gastric side effects and anemia, whereas patient 2 developed grade 3 radiation-induced gastritis. Follow-up [68Ga]Ga-NYM096 PET/CT evaluations showed evidence of tumor response to [177Lu]Lu-NYM096 treatment. Conclusion: This is early evidence that the CAIX-targeting theranostic pair [68Ga]Ga/[177Lu]Lu-NYM096 is feasible, offering a strategy for patients with end-stage ccRCC. The gastric toxicity proposes a significant challenge for CAIX-targeting radiopharmaceutical therapy.

This study aims to investigate the prevalence, pattern, physiological basis, and influencing factors of sympathetic ganglia uptake on [18F]AlF-NOTA-LM3 PET/CT. [18F]AlF-NOTA-LM3 PET/CT images from 101 patients were retrospectively reviewed to evaluate the presence of sympathetic ganglia uptake. Clinical data and normal-organ uptake were investigated to identify influencing factors. Uptake patterns were compared between sympathetic ganglia and metastatic lymph nodes. Immunohistochemical (IHC) staining for SSTR2 was performed on a stellate ganglion and other specimens. Positive sympathetic ganglia were observed in 76.2

This study aimed to compare the diagnostic performance of CAIX-targeted [68Ga]Ga-NY104 PET/CT versus standard [18F]FDG PET/CT in metastatic clear cell renal cell carcinoma (ccRCC). In this prospective single-center trial (NYCRM), 45 patients with histologically confirmed metastatic ccRCC underwent paired [68Ga]Ga-NY104 and [18F]FDG PET/CT scans within 7 days. Lesions were evaluated using a standardized composite reference (histopathology, imaging, and follow-up). Primary endpoints were lesion- and region-level sensitivity/specificity; secondary endpoints included SUVmax, tumor-to-background ratios (TBR), and clinical management impact. Among 682 analyzed lesions, [68Ga]Ga-NY104 demonstrated superior sensitivity (94.4

[18F]Florbetazine ([18F]FBZ) is a novel Aβ tracer with imaging characteristics similar to [11C]PiB. This study aimed to establish Centiloid conversion equations for [18F]FBZ and to evaluate its quantification precision relative to [11C]PiB across different image-processing pipelines and effective image resolutions (EIRs). Methods: Paired [11C]PiB and [18F]FBZ PET scans were acquired in 53 participants. Centiloid conversion equations for [18F]FBZ standardized uptake value ratio (SUVR), derived from both the standard SPM pipeline and a FreeSurfer pipeline, were calculated following the Level-2 analysis proposed by Klunk et al. The variance ratio of Centiloids derived from [18F]FBZ SUVR to those derived from standard [11C]PiB SUVR in YCs was computed to compare quantification precision. Additionally, the linear relationships between [18F]FBZ and [11C]PiB SUVR were evaluated under different EIRs. Results: The Centiloid conversion equation for [18F]FBZ SUVR using the standard SPM pipeline was: Centiloid=98.6 × [18F]FBZ SUVRstd–99.8 (variance ratio=0.92). For the FreeSurfer pipeline, the conversion was: Centiloid=110.1 × [18F]FBZ SUVRfs–108.1 (variance ratio=0.55). Robust linear correlations between [11C]PiB and [18F]FBZ SUVR were observed across EIRs with the SPM pipeline, whereas regression parameters varied across EIRs with the FreeSurfer pipeline. Conclusion: [18F]Florbetazine SUVR can be reliably converted to Centiloid units. Compared with [11C]PiB, [18F]FBZ demonstrated equal or improved quantification precision, supporting its broader use in clinical and research Aβ imaging.

Primary leptomeningeal melanomatosis is a rare and aggressive variant of primary central nervous system melanoma. Diagnosis is often challenging due to nonspecific radiologic features. We hereby report the 18F-FDG PET/CT and MRI findings in a case of primary leptomeningeal melanomatosis in a 47-year-old woman with a previously unidentified diastematomyelia. Spinal MRI showed diffuse abnormal signal. 18F-FDG PET/CT showed hypermetabolism most notably in the lumbar and caudal portion of the spinal cord, which was helpful to identify an appropriate site for biopsy.

CAIX-targeted PET/CT imaging has demonstrated utility for detecting primary clear-cell renal cell carcinoma (ccRCC), but current monoclonal antibody tracers require delayed imaging, limiting same-day evaluation. This study was designed to evaluate the performance of same-day [68Ga]Ga-NY104 PET/CT for detecting ccRCC in patients with indeterminate renal masses (IDRMs). This prospective, single-centre phase II trial included fifty-five patients with IDRMs. The primary outcome was the diagnostic sensitivity for detecting ccRCC, using histopathology as the reference standard. Semiquantitative PET parameters, including SUVmax, lesion-to-normal cortex ratio, lesion-to-blood pool ratio, and lesion-to-liver ratio, were also assessed. CAIX immunohistochemistry was performed in available specimens. Visual interpretation yielded a sensitivity of 92.3

Objectives: Early and noninvasive detection of fibrotic interstitial lung disease (fILD) is a critical but unmet clinical necessity. This study aimed to evaluate the feasibility of using 99mTc-HYNIC-Glu(PEG4-oncoFAPi)2 (denoted as 99mTc-H-PoFP2), a novel 99mTc-labeled radiopharmaceutical that targets fibroblast activation protein (FAP), for single-photon emission computed tomography (SPECT) imaging of pulmonary fibrosis in a mouse model and preliminary clinical studies. Methods:99mTc-H-PoFP2 could be conveniently afforded using a kit formula with high radiochemical purity and stability. The binding specificity and affinity of 99mTc-H-PoFP2 for FAP were validated by an in vitro binding assay. The in vivo characteristics of 99mTc-H-PoFP2 were also determined. Results:99mTc-H-PoFP2 was eliminated quickly via the urinary system, leading to low normal tissue uptake and a high target/background ratio. SPECT imaging demonstrated significantly enhanced uptake of the 99mTc-H-PoFP2 in bleomycin-induced fibrotic lung tissues, with visual effects superior to those of normal mice. Thus, a pilot clinical study of 99mTc-H-PoFP2 SPECT/CT imaging was conducted in 12 patients diagnosed with fILD. The physiological biodistribution of 99mTc-H-PoFP2 in patients was predominantly observed in the kidneys, bladder, liver, and pancreas, with relatively minor accumulation in the thyroid, salivary glands, and spleen. fILD patients exhibited elevated pulmonary 99mTc-H-PoFP2 uptake in the affected lung regions. Furthermore, the uptake of 99mTc-HPoFP2 demonstrated moderate correlations with the results of pulmonary function tests (PFTs). A higher gender-age-physiology (GAP) index was associated with elevated standardized uptake value maximum (SUVmax) and target-to-background ratio (TBR) values. Conclusions: Collectively, this study demonstrates the potential of 99mTc-HPoFP2 for SPECT imaging and assessing fILD by targeting FAP overexpressed in fibrotic lung tissues. This strategy offers new possibilities for noninvasive and precise assessment of pulmonary fibrosis.

A 30-year-old woman presented with progressive edema and mild diarrhea. Laboratory examination revealed hypoalbuminemia. She underwent 99mTc-antimony sulphide colloid (99mTc-ASC) lymphoscintigraphy to evaluate potential loss of protein through gastrointestinal tract caused by lymphatic leakage and detect abnormalities in the lymphatic systems. The images showed abnormal leakage of radiotracers in the bowel, suggestive of protein loss through the gastrointestinal tract. Abnormal visualization of the lower part of thoracic duct and bilateral venous angle was also demonstrated on 99mTc-ASC scintigraphy. It suggested secondary intestinal lymphangiectasis caused by lymphatic obstruction and reflux. Enhanced CT reconstruction of the small intestine revealed roughness and thickening of intestinal wall, consistent with the diagnosis of protein-losing enteropathy.

The pathogenesis of connective tissue disease-associated interstitial lung disease (CTD-ILD) involves complex interactions between inflammatory cell infiltration and fibroblast activation, which are pivotal in driving the disease progression. The aim of the study was to assess the feasibility of 99mTc-HFAPI imaging for visualizing active fibrotic process and 18F-FDG imaging for visualizing inflammatory process in CTD-ILD patients. A total of 54 CTD-ILD patients were enrolled. Visual analysis revealed that nearly half of the patients exhibited high tracer uptake on 99mTc-HFAPI imaging, whereas most patients showed low or moderate uptake on 18F-FDG imaging. 8 patients showed high uptake in both scans. 15 patients showed low or moderate 18F-FDG uptake but high 99mTc-HFAPI uptake. No patients demonstrated high 18F-FDG uptake coupled with low 99mTc-HFAPI uptake were observed among these 54 patients. Correlation analysis between 99mTc-HFAPI parameters and pulmonary function testing (PFT) results showed 99mTc-HFAPI uptake was significantly negatively correlated with forced vital capacity (FVC) [whole lung (wl) SUVmean: R=-0.45, p < 0.005; metabolic active volume (MAV): R=-0.41, p < 0.005; total lesion (TL): R=-0.45, p < 0.005] and diffusion capacity for carbon monoxide (DLCO) (wlSUVmean: R=-0.58, p < 0.005; MAV: R=-0.62, p < 0.005; TL: R=-0.65, p < 0.005). Significantly positive correlations were observed between 99mTc-HFAPI parameters and disease extent on HRCT (wlSUVmean: R = 0.51, p < 0.005; MAV: R = 0.53, p < 0.005; TL: R = 0.64, p < 0.005). In contrast, 18F-FDG parameters demonstrated weak or mild correlations with both PFT results and disease extent on HRCT. 99mTc-HFAPI imaging shows promising utility in assessing active fibrosis in CTD-ILD patients, demonstrating superior performance over 18F-FDG. The potential added value of dual-tracer imaging for characterization fibrotic and inflammatory processes might provide more insights of CTD-ILD.

BACKGROUND:Numerous studies have shown that long non-coding RNAs (lncRNAs) play key roles during multiple cancer processes, such as cell proliferation, apoptosis, migration and invasion. The previous studies found that NKILA interacted with and suppressed the nuclear translocation of NF-KappaB, which influenced metastasis and prognosis in breast cancer. However the clinical significance and biological role of NKILA in non-small cell lung cancer (NSCLC) remains unknown. METHODS:We examined expression levels of NKILA in 106 pairs of NSCLC tissues and cell lines. The expression level of NKILA after TGF-β1 stimulation also was examined by qRT-PCR and validated by Chromatin immunoprecipitation (ChIP). Gain-of-function and loss-of-function assays were performed to examine the effect of NKILA on proliferation, migration and invasion of NSCLC cells. RNA immunoprecipitation (RIP), western blot and rescue experiments were carried out to reveal the interrelation between NKILA, NF-κB and EMT signal pathway. RESULTS:The expression of NKILA was down-regulated in NSCLC cancer tissues compared with matched adjacent noncancerous tissues, and lower NKILA expression in tumor tissues were significantly correlated with lymph node metastasis and advanced TNM stage. We found that the expression of NKILA was mainly regulated by classical TGF-β signal pathway in NSCLC cells rather than NF-κB pathway reported in breast cancer. Gain and loss of function assays found that NKILA inhibited migration, invasion and viability of NSCLC cells. Mechanistic study showed that NKILA attenuated Snail expression via inhibiting the phosphorylation of IκBα and NF-κB activation, subsequently suppressed the expression of markers of epithelial-mesenchymal transition process. CONCLUSIONS:The present study found that the expression of NKILA was downregulated in tumor tissues of NSCLC, which improved the metastasis of NSCLC patients. In vitro studies further clarified that the expression of NKILA was regulated through classical TGF-β signal pathway, which subsequently inhibited migration and invasion of NSCLC cells through interfering NF-κB/Snail signal pathway in NSCLC cells.

ObjectiveTo evaluate whether improved progression-free survival (PFS) from radiotherapy (RT) translates into an overall survival (OS) benefit for diffuse large B-cell lymphoma (DLBCL).MethodsA systematic literature search identified randomized controlled trials (RCTs) and retrospective studies that compared combined-modality therapy (CMT) with chemotherapy (CT) alone. Weighted regression analyses were used to estimate the correlation between OS and PFS benefits. Cohen's kappa statistic assessed the consistency between DLBCL risk-models and PFS patterns. Furthermore, the benefit trend of RT was analyzed by fitting a linear regression model to the pooled hazard ratio (HR) according to the PFS patterns.ResultsFor both 7 RCTs and 52 retrospective studies, correlations were found between PFS HR (HRPFS) and OS HR (HROS) at trial level (r = 0.639–0.876), and between PFS and OS rates at treatment-arm level, regardless of CT regimens (r = 0.882–0.964). Incorporating RT increased ∼18% of PFS, and revealed a different OS benefit profile. Patients were stratified into four PFS patterns (> 80%, > 60%–80%, > 40%–60%, and ≤ 40%), which was consistent with risk-stratified subgroups (kappa > 0.6). Absolute gain in OS from RT ranged from ≤ 5% at PFS > 80% to ∼21% at PFS ≤ 40%, with pooled HROS from 0.70 (95% CI, 0.51–0.97) to 0.48 (95% CI, 0.36–0.63) after rituximab-based CT. The OS benefit of RT was predominant in intermediate- and high-risk patients with PFS ≤ 80%.ConclusionWe demonstrated a varied OS benefit profile of RT to inform treatment decisions and clinical trial design.

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

Background The maximum likelihood activity and attenuation (MLAA) reconstruction algorithm has been proposed to jointly estimate tracer activity and attenuation at the same time, and proven to be a promising solution to the CT attenuation correction (CT-AC) artifacts in PET images. This study aimed to perform a quantitative evaluation and clinical validation of the MLAA method. Methods A uniform cylinder phantom filled with 18 F-FDG solution was scanned to optimize the reconstruction parameters for the implemented MLAA algorithm. 67 patients who underwent whole-body 18 F-FDG PET/CT scan were retrospectively recruited. PET images were reconstructed using MLAA and clinical standard OSEM algorithm with CT-AC (CT-OSEM). The mean and maximum standardized uptake values (SUVmean and SUVmax) in regions of interest (ROIs) of organs, high uptake lesions and areas affected by metal implants and respiration motion artifacts were quantitatively analyzed. Results In quantitative analysis, SUVs in patient’s organ ROIs between two methods showed R 2 ranging from 0.91 to 0.98 and k ranging from 0.90 to 1.06, and the average SUVmax and SUVmean differences between two methods were within 10% range, except for the lung ROI, which was 10.5% and 16.73% respectively. The average SUVmax and SUVmean differences of a total of 117 high uptake lesions were 7.25% and 7.10% respectively. 20 patients were identified to have apparent respiration motion artifacts in the liver in CT-OSEM images, and the SUVs differences between two methods measured at dome of the liver were significantly larger than measured at middle part of the liver. 10 regions with obvious metal artifacts were identified in CT-OSEM images and the average SUVmean and SUVmax differences in metal implants affected regions were reported to be 52.90% and 56.20% respectively. Conclusions PET images reconstructed using MLAA are clinically acceptable in terms of image quality as well as quantification and it is a useful tool in clinical practice, especially when CT-AC may cause respiration motion and metal artifacts. Moreover, this study also provides technical reference and data support for the future iteration and development of PET reconstruction technology of SUV accurate quantification.

PDF file - 145K, Supplementary Tables S1. Characteristics of 29 HCC patients. Supplementary Table 2. Effects of cabozantinib on body weight, tumor burden, microvessel density, cell proliferation, and apoptosis of MHCC97 and HepG2 xenografts.

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

The emergence of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) revolutionized the treatment of advanced-stage non-small cell lung cancer (NSCLC). Detected in more than 50% of late-stage lung adenocarcinoma in Asian patients, the EGFR mutation was regarded as a golden mutation for Asians. However, resistance to TKIs seems inevitable and severely hinders patients from getting further benefits from treatment. Even though resistance caused by EGFR T790M could be effectively managed by third-generation EGFR-TKIs currently, resistance to third-generation EGFR-TKIs is still a troublesome issue faced by both clinicians and patients. Various efforts have been made to maximize the benefits of patients from EGFR-TKIs therapy. Thus, new requirements and challenges have been posed to clinicians of this era. In this review, we summarized the clinical evidence on the efficacy of third-generation EGFR-TKIs in patients with EGFR-mutated NSCLC. Then, we discussed advancements in sequential treatment aiming to delay the onset of resistance. Moreover, the resistance mechanisms and features were depicted to help us better understand our enemies. Lastly, we put forward future strategies, including recent approaches involving the utilization of antibody drug conjugates against resistance and research directions about shaping the evolution of NSCLC as a core idea in the management of NSCLC.

Background:Treatment with non-anthracycline (ANT)-based chemotherapy has increased survival in patients with extranodal natural killer/T-cell lymphoma (ENKTCL). However, the relative efficacy of various drug combinations has been contentious. We aimed to identify the most effective chemotherapy regimens for newly diagnosed ENKTCL.Methods:A network meta-analysis was performed to evaluate the differences in survival and treatment responses across various regimens. The primary objective was overall survival (OS), while secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and complete response (CR). We utilized a Bayesian framework to perform the network meta-analysis. Rank probabilities were assessed by the surface under the cumulative ranking curve (SUCRA). Node-splitting method was used to assess the inconsistency.Results:A total of 1,113 patients were enrolled across 10 studies. Chemotherapy regimens were grouped into five modalities, for which six types of direct comparisons were available. We identified the asparaginase (ASP)/gemcitabine (GEM)-based regimens superiority over ANT-based, non-ASP/ANT-based and ASP/methotrexate (MTX)-based regimens on OS. Although no significant differences were observed compared with ASP/not otherwise specified-based, ASP/GEM-based regimens were still the best option chemotherapy for OS. Moreover, the ASP/GEM-based regimens demonstrated advantages in PFS, ORR and CR.Conclusions:According to our network meta-analysis, it appears that ASP/GEM-based regimens could potentially serve as the most effective frontline chemotherapy option for ENKTCL.

PDF file - 54K, Sorafenib-resistant HCC specimens exhibit higher p-MET-positive rate compared with sorafenib-sensitive HCC specimens.

PDF file - 100K, Cabozantinib suppress colony-formation in HCC cells.

PDF file - 32K, Analysis of cyclin D1 expression and Apoptosis in HCC cells.