Overexpression of epidermal growth factor receptor (EGFR) is common in colorectal cancer. However, cetuximab as an EGFR-targeting drug is useful only for a subset of patients and currently no single predictor other than V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status has been established. In the present study, we investigated cetuximab accumulation in colorectal tumors and major organs using 111 In-DOTA-cetuximab. We also evaluated the potential of positron emission tomography (PET) imaging of 64 Cu-DOTA-cetuximab. Colorectal tumor xenografts with a different EGFR expression level and KRAS mutation status were subjected to in vivo biodistribution study and PET imaging at 48 h post-injection of radiolabeled cetuximab. The EGFR expression levels on colorectal tumors were determined by ex vivo immunoblotting and ELISA. We found that KRAS wild-type tumors had significantly higher In-DOTA-cetuximab accumulation than KRAS mutant tumors (P < 0.001). Based on KRAS mutation status, a strong correlation was found between Cu-DOTA-cetuximab allowed clear visualization of tumors. Both radiolabeled cetuximab had effectively visualized cetuximab accumulation in colorectal tumors with a wide variety of EGFR expression levels and different KRAS mutation status as commonly encountered in the clinical setting. Our findings suggest that this radioimmunoimaging therefore can be clinically translated as an in vivo tool to predict cetuximab accumulation in colorectal cancer patients prior to cetuximab therapy. (Cancer Sci 2012; 103: 600-605) I n 2008, colorectal cancer was the third most commonly diagnosed cancer worldwide, the third most common in men and the second in women. Additionally, colorectal cancer was the fourth leading cause of death from cancer with an 8% mortality rate. By 2020, the number of newly diagnosed cases of colorectal cancer is expected to grow by approximately one-third.( 1) Approximately 25% and 19% of European and American patients, respectively, present with metastases at initial diagnosis, and 89% of them die within 5 years following the diagnosis. (2,3) Therefore, to enhance the efficacy of conventional chemotherapy for advanced or metastatic colorectal carcinoma, current guidelines recommend using targeted therapy.(2,4) One of these targeted drugs is cetuximab (Erbitux), which is a chimeric monoclonal antibody (mAb) specialized in targeting the extracellular domain of epidermal growth factor receptor (EGFR) and disrupting its downstream signaling by preventing EGFR ligands binding. Since its approval in 2004, cetuximab has been widely used in clinical practice as a single agent or with other modalities for treatment of metastatic or advanced colorectal carcinoma. However, some clinical trials revealed that cetuximab can be beneficial to only approximately 31.5% of patients. (5) In the presence of EGFR ligands, EGFR has been shown to play an essential role in carcinogenesis, by initiating downstream signaling of several prosurvival cascades, such as the RAS and PI3K pathw...
BackgroundThis study aimed to determine the prognostic value of positron emission tomography (PET) metabolic parameters—namely metabolic tumor volume (MTV), total lesion glycolysis (TLG), and total lesion retention (TLR)—on fluorine-18 (18F) fluorodeoxyglucose (FDG) and L- [3-18F]-α-methyltyrosine (18F-FAMT) PET/CT in patients with non-small-cell lung cancer (NSCLC).MethodsThe study group comprised 112 NSCLC patients who underwent 18F-FDG and 18F-FAMT PET/CT prior to any therapy. The MTV, TLG, TLR, and maximum standardized uptake value (SUVmax) of the primary tumors were determined. Automatic MTV measurement was performed using PET volume computer assisted reading software. (GE Healthcare). Cox proportional hazards models were built to assess the prognostic value of MTV, TLG (for 18F-FDG), TLR (for 18F-FAMT), SUVmax, T stage, N stage, M stage, clinical stage, age, sex, tumor histological subtype, and treatment method (surgery or other therapy) on overall survival (OS).ResultsHigher TNM, higher clinical stage, inoperable status, and higher values for all PET parameters (both 18F-FAMT and 18F-FDG PET) were significantly associated (P < 0.05) with shorter OS. Multivariate analysis revealed that a higher MTV of 18F-FAMT (hazard ratio [HR]: 2.88, CI: 1.63–5.09, P < 0.01) and advanced clinical stage (HR: 5.36, CI: 1.88–15.34, P < 0.01) were significant predictors of shorter OS.ConclusionsMTV of 18F-FAMT is of prognostic value for OS in NSCLC cases and can help guide decision-making during patient management.
The accurate depiction of both biologic and anatomic profiles of tumors has long been a challenge in PET imaging. An inflammation, which is innate in the carcinogenesis of oral squamous cell carcinoma (OSCC), frequently complicates the image analysis because of the limitations of 18 F-FDG and maximum standardized uptake values (SUV max ). New PET parameters, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as well as 18 Ffluoro-α-methyltyrosine ( 18 F-FAMT), a malignancy-specific amino acid-based PET radiotracer, are considered more comprehensive in tumor image analysis. Here, we showed the substantial effects of the intratumoral inflammatory process on 18 F-FDG uptake and further study the possibility of MTV and TLG to predict both tumor biology (proliferation activity) and anatomy (pathologic tumor volume). Methods: 18 F-FDG and 18 F-FAMT PET images from 25 OSCC patients were analyzed. SUV max on the tumor site was obtained. PET volume computerized-assisted reporting was used to generate a volume of interest to obtain MTV and TLG for 18 F-FDG and total lesion retention (TLR) for 18 F-FAMT. The whole tumor dissected from surgery was measured and sectioned for pathologic analysis of tumor inflammation grade and Ki-67 labeling index. Results: The high SUV max of 18 F-FDG was related to the high inflammation grade. The SUV max ratio of 18 F-FDG to 18 F-FAMT was higher in inflammatory tumors (P , 0.05) whereas the corresponding value in tumors with a low inflammation grade was kept low. All 18 F-FAMT parameters were correlated with Ki-67 labeling index (P , 0.01). Pathologic tumor volume predicted from MTV of 18 F-FAMT was more accurate (R 5 0.90, bias 5 3.4 ± 6.42 cm 3 , 95% confidence interval 5 0.77-6.09 cm 3 ) than that of 18 F-FDG (R 5 0.77, bias 5 8.1 ± 11.17 cm 3 , 95% confidence interval 5 3.45-12.67 cm 3 ). Conclusion: 18 F-FDG uptake was overestimated by additional uptake related to the intratumoral inflammatory process, whereas 18 F-FAMT simply accumulated in tumors according to tumor activity as evaluated by Ki-67 labeling index in OSCC.
(18)F-FAMT PET/CT was useful and more specific than MRI or (18)F-FDG PET/CT in the detection of bone marrow invasion of OSCC and may contribute to minimize the extent of resection in oral surgery patient.
BackgroundThis meta-analysis aims to compare the diagnostic performance of l-3-18F-α-methyl tyrosine (18F-FAMT) positron emission tomography (PET) and 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) PET for malignancy detection.MethodsThe workflow of this study follows Cochrane Collaboration Guidelines of a systematic review of diagnostic test accuracy studies. An electronic search was performed for clinical diagnostic studies directly comparing 18F-FAMT and 18F-FDG PET for malignant tumors. Study quality, the risks of bias and sources of variation among studies were assessed using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) assessment tool. A separate meta-analysis was performed for diagnostic performance based on visual assessment and diagnostic cut-off values. Whenever possible, a bivariate random-effect model was used for analysis and pooling of diagnostic measures across studies.ResultsElectronic search revealed 56 peer-reviewed basic science investigations and clinical studies. Six eligible studies (272 patients) of various type of cancer were meta-analyzed. The 18F-FAMT diagnostic accuracy for malignancy was higher than 18F-FDG based on both visual assessment (diagnostic odd ratio (DOR): 8.90, 95% confidence interval (CI) [2.4, 32.5]) vs 4.63, 95% CI [1.8, 12.2], area under curve (AUC): 77.4% vs 72.8%) and diagnostic cut-off (DOR: 13.83, 95% CI [6.3, 30.6] vs 7.85, 95% CI [3.7, 16.8], AUC: 85.6% vs 80.2%), respectively. While the average sensitivity and specificity of 18F-FAMT and 18F-FDG based on visual assessment were similar, 18F-FAMT was significantly more specific than 18F-FDG (p < 0.05) based on diagnostic cut-off values.Conclusions 18F-FAMT is more specific for malignancy than 18F-FDG, while their sensitivity is comparable. 18F-FAMT PET is equal to 18F-FDG PET in diagnostic performance for malignancy detection in several cancer types.
BackgroundsOverexpression of epidermal growth factor receptor (EGFR) has been established as a valid therapeutic target of non-small cell lung cancer (NSCLC). However, the clinical benefit of cetuximab as an EGFR-targeting drug is still controversial, partially due to the lack of effective means to identify suitable patients. This study aimed to investigate the potential of radiolabeled cetuximab as a non-invasive tool to predict cetuximab accumulation in NSCLC tumor xenografts with varying EGFR expression levels.MethodsThe NSCLC tumors in model mice were subjected to in vivo biodistribution study and positron emission tomography (PET) imaging 48 h after injection of either 111In- or 64Cu-labeled cetuximab. The EGFR expression levels of NSCLC tumors were determined by ex vivo immunoblotting.ResultsWe found that tumors with high EGFR expression had significantly higher [111In]In-DOTA-cetuximab accumulation than tumors with moderate to low EGFR expression (P < 0.05). Strong correlations were found between [111In]In-DOTA-cetuximab tumor uptake and EGFR expression level (r = 0.893), and between [64Cu]Cu-DOTA-cetuximab tumor uptake with EGFR expression level (r = 0.915). PET imaging with [64Cu]Cu-DOTA-cetuximab allowed clear visualization of tumors.ConclusionOur findings suggest that this immuno-PET imaging can be clinically translated as a tool to predict cetuximab accumulation in NSCLC cancer patients prior to cetuximab therapy.
BONENAVI reading of BSIs and hot spot numbers was highly affected by acquisition time. In serial or follow-up examinations (in particular, for monitoring therapeutic efficacy), acquisition time should be fixed for each patient. Cautious interpretation should be made on segments with high physiological uptake. BONENAVI reading was prone to misinterpretation of artifacts. Visual assessment is necessary to rule out this possibility.
Therapeutic radiopharmaceuticals have been researched extensively in the last decade as a result of the growing research interest in personalized medicine to improve diagnostic accuracy and intensify intensive therapy while limiting side effects. Radiometal-based drugs are of substantial interest because of their greater versatility for clinical translation compared to non-metal radionuclides. This paper comprehensively discusses various components commonly used as chemical scaffolds to build radiopharmaceutical agents, i.e., radionuclides, pharmacokinetic-modifying linkers, and chelators, whose characteristics are explained and can be used as a guide for the researcher.
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