Molecular Imaging and Biology最新文献

Background: Pafolacianine (Cytalux^®) represents the first FDA-approved tumor-specific fluorescence imaging agent, demonstrating efficacy in ovarian cancer through folate receptor-α (FR-α) targeting. Given the need for improved intraoperative margin assessment in head and neck squamous cell carcinoma (HNSCC), where positive surgical margins occur in 10-30% of cases, we investigated the potential utility of pafolacianine for fluorescence-guided surgery in HNSCC models.

Objective: To evaluate the feasibility of visualizing HNSCC using pafolacianine in vitro, in vivo, and clinical tissue analysis, with comparison to fluorescence-guided surgery agents that have been successful in patients.

Methods: HNSCC cell lines (FaDu, UMSCC47) were treated with escalating concentrations of pafolacianine (0-500 nM) and assessed for binding at 1 and 24 h. Nude mice bearing HNSCC xenografts (FaDu, UMSCC47) received intraperitoneal injection of pafolacianine (10 nmol) with fluorescence imaging at multiple timepoints. Immunohistochemistry analysis of patient samples (n = 8 tumor, n = 8 normal) evaluated FR-α and FR-β expression. Panitumumab-IRDye800CW served as a positive control for comparison.

Results: In vitro analysis demonstrated minimal pafolacianine binding across all HNSCC cell lines, with fluorescence intensities similar to or lower than the FR-α-negative A549 control cell line. In vivo imaging revealed poor tumor localization with mean fluorescence intensity (MFI) of 7.39 (FaDu) and 6.97 (UMSCC47), substantially lower than non-target tissues including skin. Immunohistochemistry analysis showed no statistically significant difference in FR-α expression between tumor and normal tissue (p > 0.05). For comparison, panitumumab-IRDye800CW demonstrated robust tumor targeting with MFI of 32.14 (FaDu) and 14.98 (UMSCC47).

Conclusions: This study demonstrates that pafolacianine exhibits limited utility for fluorescence-guided surgery in HNSCC due to insufficient FR-α expression and poor tumor-to-background contrast. These negative findings provide crucial evidence against the clinical translation of pafolacianine for HNSCC applications and highlight the importance of target expression validation in precision medicine approaches.

Clinical relevance: Negative studies such as this are essential for evidence-based clinical decision-making, preventing unnecessary resource allocation and potential patient exposure to ineffective interventions. These findings inform the broader fluorescence-guided surgery field and support continued investigation of alternative targeting strategies for HNSCC.

Purpose: Wound healing process in lung injury involves the activation of the mitogen-activated protein kinase (MAPK) pathway. In this study, we investigated the role of the MAPK pathway in wound healing in a murine model of emphysema using hyperpolarized ¹²⁹Xe (HP ¹²⁹Xe) magnetic resonance imaging (MRI).

Procedures: Porcine pancreatic elastase was administered intratracheally to 25 mice to induce lung injury. Temporal changes in pulmonary gas exchange function were monitored using HP ¹²⁹Xe MRI, revealing a significant decline in function one day after elastase administration. Treatments with ethyl pyruvate (EP) and nicorandil (Nic), which upregulate and downregulate the MAPK pathway, respectively, were initiated in 12 and 7 of the 25 mice, respectively, and continued for 20 days. Over the 21-day period, HP ¹²⁹Xe MRI was performed to monitor the disease progression and treatment efficacy through changes in the metrics of gas exchange and fractional ventilation.

Results: HP ¹²⁹Xe MRI showed that EP significantly improved gas exchange function 14 days after elastase administration, whereas Nic did not show any improvement. Ventilatory function also improved in the EP group, but not in the Nic group, 14 days after elastase administration. Histological analysis showed that EP repaired tissue damage to a level similar to that observed in healthy mice, whereas Nic did not.

Conclusions: In the present study, we provide some insight into the role of the MAPK pathway in wound healing in elastase-induced lung injury, as assessed using the HP ¹²⁹Xe MRI protocol.

Background: CD38 is an excellent biomarker and therapeutic target for multiple myeloma due to its high expression on cancerous cells in comparison to healthy cells.

Purpose: We aimed to adapt Isatuximab as a PET imaging agent to detect CD38 positive multiple myeloma.

Methods: In vitro studies confirmed the specificity of [⁸⁹Zr]Zr-DFO-Isatuximab in CD38 + OPM-2 and MM.1S cells. Upregulation of CD38 was performed using pomalidomide and ricolinostat. Athymic nude mice were implanted with OPM-2 tumors and PET/CT images were collected 24 h, 3d, and 7d post-injection. Dosimetry data was collected from male and female mice and calculated using OLINDA. Three productions of [⁸⁹Zr]Zr-DFO-Isatuximab were produced using GMP techniques and validated for use in the clinic.

Results: Upregulation of CD38 was observed in vitro in CD38 + cells when treated with either pomalidomide or ricolinostat. In vivo evaluation of [⁸⁹Zr]Zr-DFO-Isatuximab showed high selectivity in OPM-2 xenografts. Blocking with an excess of unlabeled Isatuximab reduced the tumor accumulation of [⁸⁹Zr]Zr-DFO-Isatuximab by 45.5-48.5% confirming the in vivo specificity of this radiotracer. Dosimetry calculations were performed and showed an estimated effective dose of 0.359 mSv/MBq in females and 0.327 mSv/MBq in males. Three clinical grade [⁸⁹Zr]Zr-DFO-Isatuximab doses using good manufacturing practices were synthesized which passed all quality control requirements and were stable up to 6 h, thus validating this compound for use in future clinical trials.

Conclusion: [⁸⁹Zr]Zr-DFO-Isatuximab showed high specificity to CD38 positive cells, had estimated effective doses comparable to other clinically relevant ⁸⁹Zr-labeled antibodies, and can be prepared using GMP practices for clinical use.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) represents a highly aggressive malignancy with a 5-year survival rate below 10% and poor prognosis. Early diagnosis of PDAC remains a significant challenge due to its nonspecific symptomatology, insufficient reliable biomarkers, aggressive tumor progression with early metastatic spread, and limited effective screening protocols. Recent research indicates cannabinoid type 2 receptor (CB2R) overexpression in PDAC, leading to the development of [¹⁸F]JR-1004 as a potential CB2R-targeted PET probe to address diagnostic challenges in this aggressive malignancy.

Procedures: The probe development utilized computer-aided drug design, incorporating modifications to a triaryl sulfonamide CB2R inverse agonist lead compound. Essential pharmacophoric elements (central sulfonamide, flanking aromatic rings) were preserved, while the para-methoxy group underwent conversion to a tosylate precursor for radiolabeling. Radiolabeling with ¹⁸F was performed using a JiRui OnePlatform 3.1 s synthesizer (synthesis time: 70 min).

Results: The radiochemical purity and yield achieved values exceeding 95% and 16.7%, respectively. In vitro studies confirmed [¹⁸F]JR-1004's specific binding affinity in CB2R-overexpressing cells, with uptake significantly reduced by a CB2R antagonist administration. PET imaging in PDAC mouse models revealed significant accumulation in tumor regions, with receptor specificity validated through CB2R blocking studies. Biodistribution analysis revealed primary probe metabolism through the hepatobiliary system, with maximal uptake in the liver and pancreas. The probe's targeting profile demonstrates notable improvements for PDAC detection compared to the relatively nonspecific uptake patterns of [¹⁸F]FDG PET in pancreatic imaging.

Conclusions: This investigation presents an innovative molecular imaging approach for early PDAC diagnosis, exhibiting considerable potential for clinical implementation.

Purpose: Accurate staging of prostate cancer is essential for therapeutic decision-making. While PSMA PET-CT reports offer rich clinical data, their unstructured format hinders large-scale analysis. Recent advances in large language models (LLMs) offer new opportunities to extract structured information from narrative radiology reports. However, their ability to perform multi-step clinical reasoning, particularly for cancer staging, remains underexplored.

Methods: In this feasibility study, 80 anonymized, Turkish-language PSMA PET-CT reports were independently interpreted by two LLMs-Gemini 2.5 Pro (Google) and ChatGPT 4o (OpenAI). Using a structured prompt containing an embedded knowledge base (AJCC/CHAARTED criteria) and few-shot examples, both LLMs generated classifications for T, N, M, and overall clinical stage/disease volume. Outputs were benchmarked against expert classifications by a senior nuclear medicine specialist. Performance was evaluated using accuracy, precision, recall, F1-score, and Cohen's kappa.

Results: For the composite task of classifying clinical stage and disease volume, Gemini 2.5 Pro achieved an accuracy of 93.8% (95% CI: 86.0-97.9) and a Cohen's kappa of 0.910 (95% CI: 0.834-0.986), while ChatGPT 4o achieved 91.3% accuracy (95% CI: 82.8-96.4) with a kappa of 0.874 (95% CI: 0.786-0.962). For T staging, Gemini showed a higher accuracy point estimate (95.0% [95% CI: 87.7-98.6] vs. 91.3% [95% CI: 82.8-96.4]), while both models excelled at the binary N and M classifications, achieving accuracies above 95% and kappa values indicating near-perfect agreement (κ > 0.900).

Conclusions: LLMs, when guided by expert-informed prompt engineering, can accurately stage prostate cancer from free-text PSMA PET-CT reports and may serve as a powerful assistive tool for data automation, research acceleration, and quality assurance.

Purpose: We aimed to compare the diagnostic performance of [⁶⁸Ga]Ga-FAPI-04 PET/CT, [¹⁸F]F-FDG PET/CT, enterography and intestinal ultrasound (IUS) in detecting inflamed segments in patients with Crohn's disease (CD), as well as in identifying CD-related complications.

Methods: This prospective study enrolled 16 patients with CD. Each patient underwent [⁶⁸Ga]Ga-FAPI-04 PET/CT, [¹⁸F]F-FDG PET/CT, enterography, and IUS within 14 days. Using endoscopic results as the reference standard, we assessed the diagnostic accuracy and agreement across these imaging modalities for detecting segmental lesions in the proximal upper gastrointestinal (GI) tract and ileocolon. Their performance in identifying CD-associated complications and mesenteric changes was also evaluated.

Results: [⁶⁸Ga]Ga-FAPI-04 PET/CT exhibited high sensitivity (73.3%, 95% CI: 0.610-0.829), specificity (97.8%, 95% CI: 0.887-0.996) and accuracy (84.0%, 95% CI: 0.758-0.897) for detecting segmental lesions in the terminal ileum and colon. These performance metrics were comparable to those of enterography, [¹⁸F]F-FDG PET/CT and IUS (all P > 0.05), with nearly perfect diagnostic agreement observed among these imaging modalities (all κ > 0.81; all P < 0.001). In the upper GI tract and proximal small intestine, its sensitivity (53.8%, 95% CI:0.291-0.768), specificity (92.1%, 95% CI:0.792-0.973) and accuracy (82.4%, 95% CI:0.697-0.904) were similar to [¹⁸F]F-FDG PET/CT and enterography, with good diagnostic agreement (both κ = 0.73; P < 0.001). However, its resolution was suboptimal for detecting mild lesions. Notably, [⁶⁸Ga]Ga-FAPI-04 PET/CT outperformed other imaging methods in detection rate and sensitivity for identifying CD-associated complications and mesenteric changes.

Conclusion: [⁶⁸Ga]Ga-FAPI-04 PET/CT may sever as a one-step, non-invasive diagnostic option for CD patients.

Purpose: Early detection and intervention in lung adenocarcinoma (LUAD) are critical for improving patient prognosis. This study explores the role of basic leucine zipper and W2 domains 1 (BZW1, BZAP45) in regulating malignant cellular behavior and glycolytic metabolism in LUAD.

Procedures: Bioinformatics and clinical information analysis was conducted to study BZW1 expression and its relationship with prognosis, glycolysis-related genes expression and PET/CT parameters of 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) in LUAD. BZW1 was knocked out in A549 cell line and verified. In vitro and in vivo studies were performed to analyze BZW1's impact on malignant behaviors and glycolysis. Non-targeted mass spectrometry analyzed xenograft tumor metabolites and potential biomarkers.

Results: Bioinformatic analyses identified BZW1 as a pivotal gene driving LUAD progression. The retrospective analysis revealed that BZW1 expression is elevated in LUAD tissues and is significantly correlated with clinical tumor parameters and metabolic parameters obtained from [¹⁸F]FDG PET/CT. In vitro assays demonstrated that BZW1 overexpression promotes LUAD cell proliferation, migration, and invasion. In vivo experiments with mouse xenograft models confirmed that BZW1 promotes tumor growth. Further analysis revealed that BZW1 may facilitate glycolysis and the Warburg effect by upregulating hypoxia inducible factor-1α (HIF-1α) and cellular Myelocytomatosis (c-Myc).

Conclusions: These findings highlighted the role of BZW1 in LUAD metabolism and may promote tumor progression through modulating of glycolytic pathways. In conclusion, BZW1 is significantly associated with LUAD malignancy and [¹⁸F]FDG PET/CT derived metabolic parameters. It could provide a potential molecular target for the diagnosis and treatment of LUAD, offering new insights into precision oncology.

Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, remains a formidable challenge in aging populations. This review synthesizes current knowledge on its multifactorial pathogenesis, including mitochondrial dysfunction, oxidative stress, chronic inflammation, apoptosis, and satellite cell impairment. Neuromuscular alterations such as motor unit Remodeling and neuromuscular junction degeneration further exacerbate functional decline. Diagnostic approaches, ranging from DXA, CT, MRI, and ultrasound imaging to functional assessments like handgrip strength and gait speed, exhibit variability that complicates standardization. Therapeutic strategies are equally versatile. Resistance-based exercise and targeted nutritional support remain first-line, but late-phase trials of myostatin-neutralising antibodies (e.g., LY2495655, bimagrumab) and oral selective androgen-receptor modulators (SARMs; e.g., enobosarm, GSK2881078) now show dose-dependent gains in appendicular lean mass and preliminary functional benefits, signalling that combination regimens integrating lifestyle and drug therapy are imminent. Integration of these approaches with personalized medicine paradigms and AI-driven diagnostic tools holds promise for improved outcomes. This review also outlines critical research areas including mechanistic studies, diagnostic standardization, and translational gaps between preclinical models and clinical application. Addressing these challenges requires an interdisciplinary strategy that encompasses molecular, clinical, and public health perspectives to mitigate the personal and societal impacts of sarcopenia. Future efforts must focus on harmonizing diagnostic criteria, refining therapeutic regimens, and leveraging emerging technologies to develop targeted interventions that preserve muscle function and enhance quality of life in the aging population.

Purpose: Despite advancements in colorectal cancer (CRC) therapy, surgery remains the only curative option. Incomplete resection resulting in tumor cell positive surgical margins occurs in ~ 7% of CRC surgeries and is associated with recurrence and poor prognosis. Fluorescence-guided surgery (FGS) enhances tumor detection and enables real-time identification of tumor margins. Claudins, a large family of tight junction proteins, are being explored as cancer biomarkers and therapeutic targets due to their presence on the cell surface, tissue-specific expression, and selective upregulation in carcinomas. Claudin-1 (CLDN1) is overexpressed in CRC and associated with therapy resistance and metastasis, making it a promising target for fluorescence-based tumor detection.

Procedures: CLDN1 expression in CRC was analyzed using the Cancer Genome Atlas Colorectal Adenocarcinoma (TCGA-COAD) dataset. To enable in vivo tumor detection, a CLDN1 monoclonal antibody was conjugated to a near-infrared fluorescent dye (CLDN1-IR800). Sensitivity, specificity, and tumor-to-background ratio were tested in vitro and in vivo using CRC cell lines, patient-derived organoids, and an orthotopic, syngeneic model of CRC metastasis.

Results: This study demonstrates that CLDN1 is upregulated in 100% of CRC tumors compared to patient-matched normal adjacent colon in the TCGA-COAD dataset, with an average 40-fold increase in expression. CLDN1-IR800 showed specific binding and strong fluorescence in CLDN1-expressing CRC cells, with minimal signal in non-expressing cells or IgG-IR800 controls. In vivo, CLDN1-IR800 produced a significantly higher tumor-to-background ratio in CLDN1-expressing CRC cell line and patient-derived organoid xenografts compared to CLDN1-negative tumors or IgG-IR800-injected mice. Necropsy revealed significantly higher fluorescence in tumors than in other organs. In an orthotopic syngeneic mouse model, both primary and metastatic lesions were detectable. Ex vivo imaging confirmed signal in a panel of patient-derived organoids.

Conclusions: These findings demonstrate CLDN1's potential as a target for tumor detection and FGS in CRC.