Value of Semi-Quantitative Parameters of 68Ga-FAPI-04 PET/CT in Primary Malignant and Benign Diseases: A Comparison with 18F-FDG.

Objectives: We aimed to compare the value of the semiquantitative parameters of 68Ga-labeled FAP inhibitor (68Ga-FAPI)-04 positron emission tomography/computed tomography (PET/CT) and 18F-fluorodeoxyglucose (18F-FDG) in diagnosing primary malignant and benign diseases. Materials and Methods: 18F-FDG and 68Ga-FAPI-04 PET/CT images of 80 patients were compared. Semiquantitative parameters, including maximum standardized uptake value (SUVmax), mean SUV (SUVmean), peak SUV (SUVpeak), peak SUV by lean body mass (SULpeak), metabolic tumor volume (or tumor volume of FAPI; FAPI-TV), and TLG (or total lesion activity of FAPI; FAPI-TLA), were automatically obtained using the IntelliSpace Portal image processing workstation with a threshold of 40% SUVmax. The liver blood pool was measured as the background, and the tumor-to-background ratio (TBRliver) was calculated. Results: In all malignant lesions, FAPI-TV and FAPI-TLA were higher in 68Ga-FAPI-04 PET/CT than in 18F-FDG. In the subgroup analysis, 68Ga-FAPI-04 had higher FAPI-TV and FAPI-TLA and lower SUVmax than 18F-FDG had in group A, including gynecological tumor, esophageal, and colorectal cancers. However, six semiquantitative parameters were higher in group B (the other malignant tumors). For the benign diseases, SUVmax, SUVmean, SUVpeak, and SULpeak were lower in 68Ga-FAPI-04 PET/CT than in 18F-FDG. 68Ga-FAPI-04 PET/CT showed a lower liver background and a higher TBRliver than 18F-FDG did. 68Ga-FAPI-04 PET/CT had higher accuracy, sensitivity, and specificity than 18F-FDG had. Conclusion: More accurate semiquantitative parameters and lower abdominal background in 68Ga-FAPI-04 PET/CT make it more competitive in the differential diagnosis of malignant and benign diseases than in 18F-FDG.

Noninvasive Assessment of HER2 Expression Status in Gastric Cancer Using 18F-FDG Positron Emission Tomography/Computed Tomography-Based Radiomics: A Pilot Study.

Purpose: Immunohistochemistry (IHC) is the main method to detect human epidermal growth factor receptor 2 (HER2) expression levels. However, IHC is invasive and cannot reflect HER2 expression status in real time. The aim of this study was to construct and verify three types of radiomics models based on 18F-fuorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging and to evaluate the predictive ability of these radiomics models for the expression status of HER2 in patients with gastric cancer (GC). Patients and Methods: A total of 118 patients with GC were enrolled in this study. 18F-FDG PET/CT imaging was performed prior to surgery. The LIFEx software package was applied to extract PET and CT radiomics features. The minimum absolute contraction and selection operator (least absolute shrinkage and selection operator [LASSO]) algorithm was used to select the best radiomics features. Three machine learning methods, logistic regression (LR), support vector machine (SVM), and random forest (RF) models, were constructed and verified. The Synthetic Minority Oversampling Technique (SMOTE) was applied to address data imbalance. Results: In the training and test sets, the area under the curve (AUC) values of the LR, SVM, and RF models were 0.809, 0.761, 0.861 and 0.628, 0.993, 0.717, respectively, and the Brier scores were 0.118, 0.214, and 0.143, respectively. Among the three models, the LR and RF models exhibited extremely good prediction performance. The AUC values of the three models significantly improved after SMOTE balanced the data. Conclusions: 18F-FDG PET/CT-based radiomics models, especially LR and RF models, demonstrate good performance in predicting HER2 expression status in patients with GC and can be used to preselect patients who may benefit from HER2-targeted therapy.

Feasibility of One-Day PET/CT Scanning Protocol with 68Ga-DOTA-FAPI-04 and 18F-FDG for the Detection of Ovarian Cancer Recurrence and Metastasis.

Objective: The objective of this study was to investigate the feasibility of 1-d 68Ga-DOTA-FAPI-04 and 18F-FDG (2-deoxy-2[18F]fluoro-d-glucose) positron emission tomography/computed tomography (PET/CT) for detecting ovarian cancer recurrence and metastasis. Materials and Methods: Fifty-two patients who underwent 18F-FDG and 68Ga-DOTA-FAPI-04 PET/CT were divided into 1- and 2-d groups. Image acquisition, injection time, and total waiting time were compared. For the 68Ga-DOTA-FAPI-04 PET/CT scans, low-dose CT scans and low injection dosages were employed, and total radiation dose was assessed for both protocols. The comparative analysis included assessment of patient-based detection rates and lesion-based diagnostic efficacy. Results: The total waiting time was significantly shorter in the 1-d group than in the 2-d group (p = 0.000). The radiation doses stemming from internal radiation and external radiation between the groups showed no differences (p = 0.151 vs. 0.716). In the patient-based analysis, the detection rates for local recurrence, peritoneal, lymph node, and other metastases were not significantly different in both protocols (p ∈ [0.351, 1.000]). For the lesion-based analysis, no differences were noted in terms of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy (p ∈ [0.371, 1.000]). Conclusions: The 1-d PET/CT protocol reduced waiting time and exhibited equivalent detectability compared with the 2-d protocol, suggesting its clinical value.

Baseline 18F-FDG PET/CT radiomics for prognosis prediction in diffuse large B cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in adults. Standard treatment includes chemoimmunotherapy with R-CHOP or similar regimens. Despite treatment advancements, many patients with DLBCL experience refractory disease or relapse. While baseline 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) parameters have shown promise in predicting survival, they may not fully capture lesion heterogeneity. This study aimed to assess the prognostic value of baseline 18F-FDG PET radiomics features in comparison with clinical factors and metabolic parameters for assessing 2-year progression-free survival (PFS) and 5-year overall survival (OS) in patients with DLBCL. RESULTS: A total of 201 patients with DLBCL were enrolled in this study, and 1328 radiomics features were extracted. The radiomics signatures, clinical factors, and metabolic parameters showed significant prognostic value for individualized prognosis prediction in patients with DLBCL. Radiomics signatures showed the lowest Akaike information criterion (AIC) value and highest Harrell's concordance index (C-index) value in comparison with clinical factors and metabolic parameters for both PFS (AIC: 571.688 vs. 596.040 vs. 576.481; C-index: 0.732 vs. 0.658 vs. 0.702, respectively) and OS (AIC: 339.843 vs. 363.671 vs. 358.412; C-index: 0.759 vs. 0.667 vs. 0.659, respectively). Statistically significant differences were observed in the area under the curve (AUC) values between the radiomics signatures and clinical factors for both PFS (AUC: 0.768 vs. 0.681, P = 0.017) and OS (AUC: 0.767 vs. 0.667, P = 0.023). For OS, the AUC of the radiomics signatures were significantly higher than those of metabolic parameters (AUC: 0.767 vs. 0.688, P = 0.007). However, for PFS, no significant difference was observed between the radiomics signatures and metabolic parameters (AUC: 0.768 vs. 0.756, P = 0.654). The combined model and the best-performing individual model (radiomics signatures) alone showed no significant difference for both PFS (AUC: 0.784 vs. 0.768, P = 0.163) or OS (AUC: 0.772 vs. 0.767, P = 0.403). CONCLUSIONS: Radiomics signatures derived from PET images showed the high predictive power for progression in patients with DLBCL. The combination of radiomics signatures, clinical factors, and metabolic parameters may not significantly improve predictive value beyond that of radiomics signatures alone.

Multiple Intrahepatic Inflammatory Myofibroblastic Tumor on 68 Ga-FAPI and 18 F-FDG PET/CT.

ABSTRACT: A 31-year-old man with multiple intrahepatic inflammatory myofibroblastoma tumor was referred to nuclear medicine department to assess its malignant potential. Multiple lesions in the liver exhibited 68 Ga-FAPI uptake at different degrees. Instead, there was no abnormal 18 F-FDG activity in the other hepatic lesions under the normal liver background except for the puncture site. This case reflects tumor heterogeneity of the disease and shows the potential value of 68 Ga-FAPI PET/CT for the evaluation of hepatic inflammatory myofibroblastoma tumor.

18F-labeled FGFR1 peptide: a new PET probe for subtype FGFR1 receptor imaging.

Introduction: The fibroblast growth factor receptor (FGFR) family is highly expressed in a variety of tumor types and represents a new target for cancer therapy. Different FGFR subtype aberrations have been found to exhibit highly variable sensitivity and efficacy to FGFR inhibitors. Methods: The present study is the first to suggest an imaging method for assessing FGFR1 expression. The FGFR1-targeting peptide NOTA-PEG2-KAEWKSLGEEAWHSK was synthesized by manual solid-phase peptide synthesis and high-pressure liquid chromatography (HPLC) purification and then labeled with fluorine-18 using NOTA as a chelator. In vitro and in vivo experiments were conducted to evaluate the stability, affinity and specificity of the probe. Tumor targeting efficacy and biodistribution were evaluated by micro-PET/CT imaging in RT-112, A549, SNU-16 and Calu-3 xenografts. Results: The radiochemical purity of [18F]F-FGFR1 was 98.66% ± 0.30% (n = 3) with excellent stability. The cellular uptake rate of [18F]F-FGFR1 in the RT-112 cell line (FGFR1 overexpression) was higher than that in the other cell lines and could be blocked by the presence of excess unlabeled FGFR1 peptide. Micro-PET/CT imaging revealed a significant concentration of [18F]F-FGFR1 in RT-112 xenografts with no or very low uptake in nontargeted organs and tissues, which demonstrated that [18F]F-FGFR1 was selectively taken up by FGFR1-positive tumors. Conclusion: [18F]F-FGFR1 showed high stability, affinity, specificity and good imaging capacity for FGFR1-overexpressing tumors in vivo, which provides new application potential in the visualization of FGFR1 expression in solid tumors.

Value of pre-treatment 18F-FDG PET/CT radiomics in predicting the prognosis of stage III-IV colorectal cancer.

Background and purpose: To investigate the value of radiomics features extracted from pre-treatment 18F-FDG PET/CT in predicting the outcomes of stage III-IV colorectal cancer (CRC), which may assist in clinical management strategies and precise treatment of stage III-IV CRC. Materials and methods: 124 patients with pathologically confirmed stage III-IV CRC who underwent pre-treatment 18F-FDG PET/CT scans were enrolled in this study. The least absolute shrinkage and selection operator Cox regression (LASSO-Cox) was used to select radiomics features, and the radiomics scores (Rad-scores) were calculated to build radiomics models. The performance of radiomics models was represented by the concordance index (C-index) and compared with clinical models and complex model. The bootstrap resampling method was used to create validation sets. Additionally, nomograms were developed based on complex models. Results: The C-indices of the radiomics model for predicting PFS and OS were 0.712 (95%CI: 0.680-0.744) and 0.758 (0.728-0.789), respectively. In the clinical model, these values were 0.690 (0.664-0.0.717) and 0.738 (0.709-0.767), respectively. However, in the complex model were 0.734 (0.705-0.762) and 0.780 (0.754-0.807), respectively. The Kaplan-Meier curves demonstrated that the radiomics model could effectively separate patients with stage III-IV stage CRC into high- and low-risk groups (p < 0.001). Multivariate Cox regression analysis confirmed the independent prognostic value of Rad-scores. Conclusion: Pre-treatment 18F-FDG PET/CT radiomics features can stratify the risk of patients with stage III-IV CRC and accurately predict their outcomes. These findings could be clinically valuable for precision treatment and management decisions in stage III-IV CRC.

Predicting PD-L1 expression status in patients with non-small cell lung cancer using [18F]FDG PET/CT radiomics.

BACKGROUND: In recent years, immune checkpoint inhibitor (ICI) therapy has greatly changed the treatment prospects of patients with non-small cell lung cancer (NSCLC). Among the available ICI therapy strategies, programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors are the most widely used worldwide. At present, immunohistochemistry (IHC) is the main method to detect PD-L1 expression levels in clinical practice. However, given that IHC is invasive and cannot reflect the expression of PD-L1 dynamically and in real time, it is of great clinical significance to develop a new noninvasive, accurate radiomics method to evaluate PD-L1 expression levels and predict and filter patients who will benefit from immunotherapy. Therefore, the aim of our study was to assess the predictive power of pretherapy [18F]-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT)-based radiomics features for PD-L1 expression status in patients with NSCLC. METHODS: A total of 334 patients with NSCLC who underwent [18F]FDG PET/CT imaging prior to treatment were analyzed retrospectively from September 2016 to July 2021. The LIFEx7.0.0 package was applied to extract 63 PET and 61 CT radiomics features. In the training group, the least absolute shrinkage and selection operator (LASSO) regression model was employed to select the most predictive radiomics features. We constructed and validated a radiomics model, clinical model and combined model. Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were used to evaluate the predictive performance of the three models in the training group and validation group. In addition, a radiomics nomogram to predict PD-L1 expression status was established based on the optimal predictive model. RESULTS: Patients were randomly assigned to a training group (n = 233) and a validation group (n = 101). Two radiomics features were selected to construct the radiomics signature model. Multivariate analysis showed that the clinical stage (odds ratio [OR] 1.579, 95% confidence interval [CI] 0.220-0.703, P < 0.001) was a significant predictor of different PD-L1 expression statuses. The AUC of the radiomics model was higher than that of the clinical model in the training group (0.706 vs. 0.638) and the validation group (0.761 vs. 0.640). The AUCs in the training group and validation group of the combined model were 0.718 and 0.769, respectively. CONCLUSION: PET/CT-based radiomics features demonstrated strong potential in predicting PD-L1 expression status and thus could be used to preselect patients who may benefit from PD-1/PD-L1-based immunotherapy.

Value of Presurgical 18F-FDG PET/CT Radiomics for Predicting Mediastinal Lymph Node Metastasis in Patients with Lung Adenocarcinoma.

Objective: The aim of this study was to develop an F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) radiomic model for predicting mediastinal lymph node metastasis (LNM) in presurgical patients with lung adenocarcinoma. Methods: The study enrolled 320 patients with lung adenocarcinoma (288 internal and 32 external cases) and extracted 190 radiomic features using the LIFEx package. Optimal radiomic features to build a radiomic model were selected using the least absolute shrinkage and selection operator algorithm. Logistic regression was used to build the clinical and complex (combined radiomic and clinical variables) models. Results: Ten radiomic features were selected. In the training group, the area under the receiver operating characteristic curve of the complex model was significantly higher than that of the radiomic and clinical models [0.924 (95% CI: 0.887-0.961) vs. 0.863 (95% CI: 0.814-0.912; p = 0.001) and 0.838 (95% CI: 0.783-0.894; p = 0.000), respectively]. The sensitivity, specificity, accuracy, and positive and negative predictive values of the radiomic model were 0.857, 0.790, 0.811, and 0.651 and 0.924, respectively, which were better than that of visual evaluation (0.539, 0.724, 0.667, and 0.472 and 0.775, respectively) and PET semiquantitative analyses (0.619, 0.732, 0.697, and 0.513 and 0.808, respectively). Conclusions: 18F-FDG PET/CT radiomics showed good predictive performance for LNM and improved the N-stage accuracy of lung adenocarcinoma.

Case Report: 68Ga-FAPI PET/CT, a more advantageous detection mean of gastric, peritoneal, and ovarian metastases from breast cancer.

Breast cancer is the most common malignant tumor in adult women. Its common metastatic sites are lymph nodes, bones, lungs, the liver, and the brain. It is so rare for a patient with breast cancer to have metastases of the gastrointestinal tract, peritoneum, and ovary at the same time that the clinical reporting rate is low. We present a case of a 61-year-old woman who underwent right mastectomy and chemoradiotherapy 3 years ago because of mixed invasive ductal-lobular breast cancer. This time, she came to the hospital due to the symptom of stomach discomfort for 2 weeks. The gastroscopy biopsy result showed gastric metastasis from breast cancer. Then, 18F-FDG imaging and 68Ga-FAPI PET/CT imaging were performed for further diagnosis; 68Ga-FAPI PET/CT demonstrated a significantly elevated FAPI activity in the thickened gastric wall, peritoneum, and bilateral adnexal areas, which was superior to that of 18F-FDG. Finally, a biopsy of suspicious lesions was taken for pathological and histochemical examination, which confirmed that, in addition to the gastric metastasis, the peritoneum and bilateral ovaries were all consistent with metastatic breast cancer.

68Ga-DOTATATE PET/CT imaging for insulinoma in MEN1 patient with endogenous hyperinsulinemic hypoglycemia: A case report.

RATIONALE: Multiple endocrine neoplasia type 1 (MEN1) syndrome is a rare and complicated disease that is associated with several endocrine tumors. Here, we report a case of MEN1 associated with insulinoma, parathyroid, and pituitary tumors by 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT). PATIENT CONCERNS: A 49-year-old woman presented with intermittent hypoglycemia for more than a year and developed indistinct consciousness without an apparent trigger. DIAGNOSES: Biochemical results showed abnormally high serum insulin and parathyroid hormone levels. She underwent an Abdominal magnetic resonance imaging revealed a small nodule in the uncinate process of the pancreas, but it did not clarify the nature of the small nodule. Pituitary magnetic resonance imaging scan revealed a micropituitary tumor, and parathyroid imaging showed no abnormalities. 18F-FDG PET/CT showed no apparent abnormal 18F-FDG uptake in the whole body. In contrast, 68Ga-DOTATATE PET/CT imaging showed pathological radiotracer uptake in the pancreatic uncinate process, accompanied by mild radiotracer uptake in the pituitary gland, and no apparent abnormal radiotracer uptake in the parathyroid area. INTERVENTIONS: The patient underwent echoendoscopy for pancreatic uncinate process lesions and surgical resection. OUTCOMES: Histological analysis was suggested of insulinoma of pancreatic neuroendocrine tumor, the Ki-67 index was low (only 1% being positive). LESSONS: This case demonstrates that 68Ga-DOTATATE can be used for the detection of MEN1-related tumors and preoperative localization of small and low-grade insulinomas by PET/CT.

Pre-Clinical Study of the [18F]AlF-Labeled HER2 Affibody for Non-Invasive HER2 Detection in Gastric Cancer.

Human epidermal growth factor receptor 2 (HER2) is an important biomarker in gastric cancer (GC) and directly influences the therapeutic effect. Fluorine is firmly bound to Al3+ forming [18F]AlF-1,4,7-triazacyclononanetriacetic acid (NOTA)-HER2 affibody is a promising radiolabeled tracer that can monitor the changes of HER2 expression combining the advantages of simple preparation and the properties of 18F. The aim of this study was to develop a quick method for the synthesis of [18F]AlF-NOTA-HER2 affibody and evaluate its utility for HER2+ GC imaging in mouse models. Moreover, 68Ga-NOTA-HER2 affibody imaging was also performed to highlight the superiority of [18F]AlF-NOTA-HER2 affibody imaging in resolution. The HER2 affibody was conjugated with NOTA and labeled using 18F based on the complexation of [18F]AlF by NOTA. Its quality control and stability were performed by high-pressure liquid chromatography (HPLC). The molecular specificity and binding affinity of the novel radiotracer were evaluated in the GC cell line with HER2 overexpression (NCI-N87) and negative expression (MKN74). Distribution studies and PET/CT imaging were performed in mouse models. 68Ga-NOTA-HER2 affibody PET/CT imaging was also performed. [18F]AlF-NOTA-HER2 affibody was efficiently prepared within 30 min with a non-decay-corrected maximum yield of 32.69% and a radiochemical purity of more than 98%. [18F]AlF-NOTA-HER2 affibody was highly stable in incubation medium for 4 h in vitro and in the blood of nude mice at 30 min post-injection (p.i.). In vitro studies revealed specific binding and high binding affinity of the probe in NCI-N87 cells, while no binding was seen in MKN74 cells. PET imaging showed that NCI-N87 xenografts were differentiated from MKN74 xenografts with excellent contrast and low abdominal background, which was confirmed by the distribution results. High-level accumulation of the [18F]AlF-NOTA-HER2 affibody in HER2+ tumors was blocked by excess unlabeled NOTA-HER2 affibody. [18F]AlF-NOTA-HER2 affibody has a higher image resolution than that of 68Ga-NOTA-HER2 affibody. [18F]AlF-NOTA-HER2 affibody could be produced facilely with high radiochemical yield and may serve as a novel molecular probe with tremendous clinical potential for the non-invasive whole-body detection of the HER2 status in GC with good image contrast and resolution. This method could provide an in vivo understanding of GC biology that will ultimately guide the accurate diagnosis and treatment of GC.

Developing a clinical and PET/CT volumetric prognostic index for risk assessment and management of NSCLC patients after initial therapy.

BACKGROUND: Currently, individual clinical prognostic variables are used sequentially with risk-stratification after TNM staging in clinical practice for the prognostic assessment of patients with NSCLC, which is not effective for estimating the collective impact of multiple individual variables on patient outcomes. Here, we developed a clinical and PET/CT volumetric prognostic (CPVP) index that integrates the prognostic power of multiple clinical variables and metabolic tumor volume from baseline FDG-PET, for use immediately after definitive therapy. PATIENTS AND METHODS: This retrospective cohort study included 998 NSCLC patients diagnosed between 2004 and 2017, randomly assigned to two cohorts for modeling the CPVP index using Cox regression models examining overall survival (OS) and subsequent validation. RESULTS: The CPVP index generated from the model cohort included pretreatment variables (whole-body metabolic tumor volume [MTVwb], clinical TNM stage, tumor histology, performance status, age, race, gender, smoking history) and treatment type. A clinical variable (CV) index without MTVwb and PET/CT volumetric prognostic (PVP) index without clinical variables were also generated for comparison. In the validation cohort, univariate Cox modeling showed a significant association of the index with overall survival (OS; Hazard Ratio [HR] 3.14; 95% confidence interval [95% CI] = 2.71 to 3.65, p < 0.001). Multivariate Cox regression analysis demonstrated a significant association of the index with OS (HR = 3.13, 95% CI = 2.66 to 3.67, p < 0.001). The index showed greater prognostic power (C-statistic = 0.72) than any of its independent variables including clinical TNM stage (C-statistic ranged from 0.50 to 0.69, all p < 0.003), CV index (C-statistic = 0.68, p < 0.001) and PVP index (C-statistic = 0.70, p = 0.006). CONCLUSIONS: The CPVP index for NSCLC patients has moderately strong prognostic power and is more prognostic than its individual prognostic variables and other indices. It provides a practical tool for quantitative prognostic assessment after initial treatment and therefore may be helpful for the development of individualized treatment and monitoring strategy for NSCLC patients.

Synthesis of a novel 99mTc labeled GE11 peptide for EGFR SPECT imaging.

PURPOSE: This study investigated a novel SPECT agent for the noninvasive imaging of EGFR-overexpressing tumors. METHODS: The EGFR-targeting peptide GE11 was synthesized with the introduction of four amino acids (GGGC) to its C-terminal to act as a strong chelator and radiolabeled using 99mTc. The radiochemical yield of the 99mTc-peptide-GE11 were evaluated using RP-HPLC. Cellular assays of the probe were performed on two NSCLC cell lines: A549 (high expression) and H23 (low expression). Biodistribution and SPECT imaging were performed in BALB/c nude mice bearing A549 and H23 NSCLC xenografts. RESULTS: The 99mTc-peptide-GE11 was prepared at high efficiency with radiochemical yield of 98.40 ± 1.00 % and it showed favorable stability. The cellular uptake was significantly higher in A549 than in H23 at all time points (especially at 1 h, which was 10.34 ± 0.72 and 2.04 ± 0.18, respectively). A nearly 56% reduction in probe uptake was observed after pretreatment with excess unlabeled peptides. The performance of SPECT imaging and biodistribution demonstrated higher uptake of the 99mTc-peptide-GE11 in A549 xenograft than in H23 xenografts. CONCLUSION: The new SPECT tracer 99mTc-peptide-GE11 showed EGFR specificity, favorable pharmacokinetics and great potential for EGFR-targeted imaging.

Therapeutic efficacy and imaging assessment of the HER2-targeting chemotherapy drug ZHER2:V2-pemetrexed in lung adenocarcinoma Xenografts.

Chemotherapy has always been the first therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) with untreatable oncogenic mutations. However, chemotherapy has demonstrated limited success and is associated with severe side effects. This research aimed to investigate the antitumor efficacy and cytotoxic safety of the conjugate ZHER2:V2-pemetrexed, a novel targeted chemotherapeutic drug. In this context, human epidermal growth factor receptor 2 (HER2) + A549 lung xenografts were treated using ZHER2:V2-pemetrexed, pemetrexed or physiological saline. Therapeutic efficacy was monitored by single photon emission computed tomography (SPECT) imaging using the 99mTc-labeled ZHER2:V2-pemetrexed conjugate and further confirmed by performing apoptosis assays using flow cytometry analysis and hematoxylin-eosin (H&E) staining. To evaluate the expression of HER2 in tumor tissues, immunohistochemistry was performed, accompanied by quantitative analysis using flow cytometry. A toxicological evaluation was also conducted. Imaging with 99mTc-ZHER2:V2-pemetrexed demonstrated that in HER2+ A549 models, ZHER2:V2-pemetrexed showed better antineoplastic effects than pemetrexed. Compared with pemetrexed, the results from the pathological and flow cytometry analyses also revealed that ZHER2:V2-pemetrexed exhibits high antitumor activity against A549 tumors, inducing necrosis, apoptosis and cell cycle arrest. In addition, the clinical signs of toxicity in the ZHER2:V2-pemetrexed treated group were reduced compared with those in the pemetrexed treated group. These data revealed that the ZHER2:V2-pemetrexed conjugate encompasses promising targeted antitumor activity against HER2-positive lung adenocarcinoma, with reduced side effects compared with pemetrexed. Thus, the ZHER2:V2-pemetrexed conjugate may serve as a novel molecular agent with tremendous clinical breakthrough potential in the diagnosis and treatment of HER2-positive lung adenocarcinoma.

Value of pre-therapy 18F-FDG PET/CT radiomics in predicting EGFR mutation status in patients with non-small cell lung cancer.

PURPOSE: To assess the predictive power of pre-therapy 18F-FDG PET/CT-based radiomic features for epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer. METHODS: Two hundred and forty-eight lung cancer patients underwent pre-therapy diagnostic 18F-FDG PET/CT scans and were tested for genetic mutations. The LIFEx package was used to extract 47 PET and 45 CT radiomic features reflecting tumor heterogeneity and phenotype. The least absolute shrinkage and selection operator (LASSO) algorithm was used to select radiomic features and develop a radiomics signature. We compared the predictive performance of models established by radiomics signature, clinical variables, and their combinations using receiver operating curves (ROCs). In addition, a nomogram based on the radiomics signature score (rad-score) and clinical variables was developed. RESULTS: The patients were divided into a training set (n = 175) and a validation set (n = 73). Ten radiomic features were selected to build the radiomics signature model. The model showed a significant ability to discriminate between EGFR mutation and EGFR wild type, with area under the ROC curve (AUC) equal to 0.79 in the training set, and 0.85 in the validation set, compared with 0.75 and 0.69 for the clinical model. When clinical variables and radiomics signature were combined, the AUC increased to 0.86 (95% CI [0.80-0.91]) in the training set and 0.87 (95% CI [0.79-0.95]) in the validation set, thus showing better performance in the prediction of EGFR mutations. CONCLUSION: The PET/CT-based radiomic features showed good performance in predicting EGFR mutation in non-small cell lung cancer, providing a useful method for the choice of targeted therapy in a clinical setting.

In vivo imaging characterization and anticancer efficacy of a novel HER2 affibody and pemetrexed conjugate in lung cancer model.

INTRODUCTION: In this study, a new agent consisting of HER2-specific affibody ZHER2:V2 and chemotherapy drug pemetrexed was synthesized to develop a new targeted drug. Its biological characteristics and anticancer efficacy were assessed in cells level and xenografts models by radiolabeling with technetium-99m. METHODS: After the ZHER2:V2-pemetrexed conjugate was synthesized, radiolabeling of the conjugate was performed using its C-terminal 4 amino acids (Gly-Gly-Gly-Cys) as the chelating moiety. The radiochemical yield of the [99mTc]Tc-ZHER2:V2-pemetrexed was identified by instant thin-layer chromatography (ITLC). Stability of the radiolabeled conjugate was investigated both in vitro and in vivo. In vitro binding affinity and cell internalization study of the probe were performed in A549 cells (HER2-positive). Tumor uptake was evaluated by in vitro uptake assay in A549 cells and H23 cells (HER2-negative), and by in vivo biodistribution and SPECT imaging in A549 and H23 tumor-bearing mice. The antitumor efficacy of the ZHER2:V2-pemetrexed conjugate was evaluated in cells and xenograft models. RESULTS: The ZHER2:V2-pemetrexed was successfully synthesized and conjugated with technetium-99 m, and acquired the radiochemical yield of 97.0 ±â€¯0.3%. The stability of [99mTc]Tc-ZHER2:V2-pemetrexed was good in both physiological saline and human serum. The radiolabeled agent displayed excellent HER2-binding specificity and affinity in vitro, and was gradually internalized into the cells. Biodistribution study revealed obvious tumor uptake in A549 xenografts (percentage injected dose per gram, 2.6 ±â€¯1.0%ID/g at 4 h postinjection), while the uptake in HER2-negative H23 tumors was much lower (0.2 ±â€¯0.1%ID/g at 4 h postinjection, P < 0.01). SPECT imaging exhibited an intensity in the A549 xenograft which could be blocked by excess ZHER2:V2-pemetrexed. Treatment with ZHER2:V2-pemetrexed significantly impaired the tumor growth (P < 0.05), with less weight loss than pemetrexed. CONCLUSION: [99mTc]Tc-ZHER2:V2-pemetrexed showed desirable property and HER2-specificity. The ZHER2:V2-pemetrexed conjugate could inhibit tumor growth of HER2-positive lung adenocarcinoma and may have the potential to become a targeted drug for lung cancer. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: The compound described herein performs HER2-targeting with favorable anticancer efficacy and offers the potential of novel targeting strategies for further tumor therapy.