Enhanced glucose metabolism mediated by CD147 is associated with 18 F-FDG PET/CT imaging in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most deadly thoracic tumors. Reprogrammed glycolytic metabolism is a hallmark of cancer cells and significantly affects several cellular functions. In the current study, we aimed to investigate cluster of differentiation 147 (CD147)-mediated glucose metabolic regulation in LUAD and its association with 18 F-FDG PET/CT imaging. METHODS: The expression profile and prognostic potential of CD147 in LUAD were analyzed using UALCAN and a Kaplan-Meier plotter. Tissue immunohistochemical analyses and PET metabolic parameters were used to identify the relationship between CD147 expression and reprogrammed glycolysis. The role of CD147 in glucose metabolic reprogramming was assessed by radioactive uptake of 18 F-FDG through γ-radioimmunoassays in vitro and micro-PET/CT imaging in vivo. Western blotting assays were used to determine the expression level of monocarboxylate transporter 1 (MCT1) and MCT4 in established human LUAD cell lines (ie, HCC827 and H1975) with different CD147 expression levels via lentiviral transduction. RESULTS: CD147 was highly expressed in LUAD. A significant positive correlation existed between CD147 expression and PET metabolic parameters(SUVmax,SUVmean, SUVpeak). CD147 could promote radioactive uptake of 18 F-FDG in vitro and in vivo, suggesting the ability of CD147 to enhance glycolytic metabolism. Furthermore, as an obligate chaperone for MCT1 and MCT4, CD147 positively correlated with MCT1 and MCT4 expression in LUAD tissues and established cell lines with different CD147 expression. CONCLUSIONS: Our study revealed that CD147 is a promising novel target for LUAD treatment and CD147-mediated glucose metabolism demonstrated its contribution to the predictive role of 18 F-FDG PET/CT imaging for targeted therapeutic efficacy.

CD147-mediated glucose metabolic regulation contributes to the predictive role of 18 F-FDG PET/CT imaging for EGFR-TKI treatment sensitivity in NSCLC.

The aim of this study is to investigate the role of CD147 in glucose metabolic regulation and its association with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment sensitivity prediction using 18 F-fluorodeoxyglucose (18 F-FDG) PET/CT imaging in non-small cell lung cancer (NSCLC). In this study, four human NSCLC cell lines with different EGFR-TKI responses were used to detect p-EGFR/EGFR and CD147 expression via Western blotting and flow cytometric analyses. Radioactive uptake of 18 F-FDG by established stable NSCLC cell lines (HCC827, H1975) with different levels of CD147 expression and the corresponding xenografts was assessed through γ-radioimmunoassays in vitro and micro-PET/CT imaging in vivo to study the role of CD147 in glucose metabolic reprogramming. Correlation analyses were performed to investigate the association between CD147 expression and PD-L1 expression in stable NSCLC cell lines. Higher CD147 expression was found in EGFR-TKI-sensitive NSCLC cell lines than in relatively resistant NSCLC cell lines (HCC827>PC9>A549>H1975). CD147 could promote 18 F-FDG uptake by HCC827 and H1975 cells in vitro and in vivo through an EGFR-initiated Akt/mTOR-dependent signaling pathway. Programmed cell death-ligand 1 (PD-L1) expression was positively correlated with CD147 expression in human NSCLC cell lines. EGFR-TKI treatment sensitivity prediction in NSCLC using 18 F-FDG PET/CT imaging significantly correlated with CD147-mediated glucose metabolic regulation via the Akt/mTOR-dependent pathway. Moreover, PD-L1 expression in NSCLC cell lines could be regulated by CD147, suggesting a potential immunosuppression induced by the upregulation of tumor glucose metabolism.

Quantitative 18F-FDG PET analysis in survival rate prediction of patients with non-small cell lung cancer.

The aim of the present study was to investigate the prognostic value of quantitative [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) parameters for patients with non-small cell lung cancer (NSCLC). The present study conducted a retrospective review of the medical records of 203 patients with NSCLC, of which 193 patients underwent baseline 18F-FDG PET/CT prior to initial therapy. Multivariate analyses using Cox's proportional hazards regression were performed for the assessment of the association between initial PET/CT measurements and overall survival (OS). The multivariate models were adjusted for sex, age, smoking status, disease stage, standardized uptake value (SUV), standardized uptake value corrected for lean body mass (SUL), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and standard deviation of SUV (SD). Kaplan-Meier (K-M) estimator curves were constructed following the formation of three approximately equal-sized groups using tertiles for each PET/CT measurement (n=65, 64 and 64). OS curves were plotted using K-M estimator curves. Results demonstrated significant associations between OS and MTVPET volume computerized assisted reporting (PETVCAR), MTV2.5, MTV25%, MTV42% and TLGPETVCAR; however, no significant associations were identified between OS and MTV50%, MTV75%, TLG2.5, all SUV and SUL. Subgroup analyses according to pathology demonstrated that there were statistically significant associations between OS and stage (P<0.001), MTV50% (P=0.002) and MTV42% (P=0.004) in the adenocarcinoma group, and SULmean (P=0.010), MTV25% (P=0.005) and MTV42% (P=0.001) in the squamous cell carcinoma group; however, no significant differences were identified between any other group. Furthermore, there was a significant association between OS and MTV42% (P=0.02) and MTV50% (P=0.04) in the early-stage group; however, no significant differences were identified in the advanced-stage group. K-M estimator curve analyses demonstrated that the pathology (P=0.01), stage (P<0.001) and all PET metabolic parameters with the exception of SD were significantly associated with OS (P<0.05). No significant associations were demonstrated between SD and OS. In conclusion, 18F-FDG PET/CT MTVPETVCAR, MTV2.5, MTV25%, MTV42% and TLGPETVCAR exhibit prognostic values with regard to OS. Overall, selection of appropriate metabolic parameters may predict NSCLC prognosis.

Measurement and Evaluation of Quantitative Performance of PET/CT Images before a Multicenter Clinical Trial.

To ensure the reliability of the planned multi-center clinical trial, we assessed the consistence and comparability of the quantitative parameters of the eight PET/CT units that will be used in this trial. PET/CT images were scanned using a PET NEMA image quality phantom (Biodex) on the eight units of Discovery PET/CT 690 from GE Healthcare. The scanning parameters were the same with the ones to be used in the planned trial. The 18F-NaF concentration in the background was 5.3 kBq/ml, while the ones in the spheres of diameter 37 mm, 22 mm, 17 mm and 10 mm were 8:1 as to that of the background and the ones in the spheres of diameter 28 mm and 13 mm were 0 kBq/ml. The consistency of hot sphere recovery coefficient (HRC), cold sphere recovery coefficient (CRC), hot sphere contrast (QH) and cold sphere contrast (Qc) among these 8 PET/CTs was analyzed. The variation of the main quantitative parameters of the eight PET/CT systems was within 10%, which is acceptable for the clinical trial.

[Current Status and Progress in Molecular Imaging of Non-small Cell Lung 
Cancer for Molecular Targeted EGFR-TKI Treatment Sensitivity and 
Treatment Tolerance Prediction].

More than 80% of lung cancer is non-small cell lung cancer (NSCLC), and the epidermal growth factor receptor (EGFR)-mediated signaling pathway is closely related to the occurrence and development of NSCLC. Small molecule EGFR-tyrosine kinase inhibitors (EGFR-TKI) targeting EGFR have been used in the clinical treatment of NSCLC, and positron emission tomography/computed tomgraphy (PET/CT) imaging can noninvasively monitor the expression and mutation status of EGFR in patients with NSCLC. 18F-FDG PET/CT imaging has predictive value for the activation of EGFR mutation and EGFR-TKI treatment efficacy, and in vivo can be directly observed drugs and systemic tumor targeting EGFR combined with the specific circumstances, by PET/CT imaging before and after treatment, to achieve dynamic monitoring, guide the therapy before treatment and treatment of sensitive population screening process, to achieve NSCLC EGFR-TKI precise treatment is essential.

Application and Indication of Carcinoembryonic Antigen Triggered 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Scanning in the Detection of Relapse of Colorectal Cancer Patients After Curative Therapy.

OBJECTIVE: This study aimed to explore the characteristics of patients with colorectal cancer (CRC) following curative therapy that may benefit from fluorine-18-2-uoro-2-deoxy-D-glucose positron emission tomography/computed tomography (F-FDG PET/CT) scanning, evaluate the application of carcinoembryonic antigen (CEA)-triggered F-FDG PET/CT scanning, and provide referential indicators. METHODS: This retrospective study included 56 CRC patients who received a PET/CT scan as a primary examination because of rising CEA levels after curative therapy and who had not received any other radiological examinations previously. RESULTS: The rate of recurrence or metastasis was 75.0% by PET/CT scan but was 69.6% with follow-up treatment. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 94.9%, 70.6%, 87.5%, 88.1%, and 85.7%, respectively. TNM (tumor, node, metastasis) stage, body mass index, and CEA level were significant prognostic factors. CONCLUSIONS: Positron emission tomography/CT can be selectively applied as a primary examination in CRC patients with asymptomatic elevation of CEA. High CEA levels, increased body mass index, and advanced TNM staging are risk factors for relapse.

Pretreatment metabolic parameters measured by 18F-FDG-PET to predict the outcome of first-line chemotherapy in extensive-stage small-cell lung cancer.

OBJECTIVE: Patients' pretreatment metabolic burden, as measured by radiotracer fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT), has been shown to predict treatment outcome in various malignancies. However, its predictive role in extensive-stage small cell lung cancer (SCLC) has not been definitively determined. This retrospective study investigated the viability of using common pretreatment metabolic parameters, obtained through F-FDG-PET/CT, to predict outcomes of first-line chemotherapy in extensive-stage SCLC. PARTICIPANTS AND METHODS: The study population comprised 154 consecutive patients with extensive-stage SCLC who underwent a pretreatment F-FDG-PET/CT scan and received standard first-line chemotherapy between January 2011 and December 2015. RESULTS: Ten (6.5%) and 66 (42.9%) patients achieved a complete or a partial response, respectively (considered an objective response); 35 (22.7%) and 43 (27.9%) experienced stable or progressive disease. The metabolic tumor volume (MTV) was a significant factor for predicting an objective response. For predicting disease control (objective response or stable disease), MTV and total lesion glycolysis (TLG) were nonindependent factors. CONCLUSION: Greater MTV and TLG could indicate a poorer response to first-line chemotherapy for patients with extensive-stage SCLC, but the predictive efficiency was not high enough for routine reliance. For patients who are not suitable to receive first-line chemotherapy, MTV and TLG may help guide clinical decisions.

Advantages and disadvantages of F-18 fluorodeoxyglucose positron emission tomography/computed tomography in carcinoma of unknown primary.

Carcinoma of unknown primary is a type of malignant disease where the primary carcinoma cannot be identified by conventional examination, which presents challenges in diagnosis and therapy. This study aims to evaluate the detailed clinical value and indications of using fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (F-18 FDG PET/CT) in a large sample. A total of 449 patients who were selected under strict standards were retrospectively included in this study. F-18 FDG PET/CT accurately detected the primary carcinoma in 115 of 449 patients whose primaries could not be detected by conventional examination (25.6%), with additional 27 false-positive patients. The most common primary site was the lung (34.8%). In addition, except for in metastatic melanoma (1/19, 5.3%) and axillary metastasis patients (2/49, 4.1%), F-18 FDG PET/CT had a comparative performance in detecting primary carcinoma in other pathological types and anatomical locations. The scan is able to guide treatment strategy modifications to some extent (130/449, 29.0%). We strongly recommend the use of F-18 FDG PET/CT in the early phase of examination. It is also recommended as a supplementary radiological method, and certain patients may benefit from its application in cases where regular examination is inconclusive. However, in metastatic melanoma or axillary metastasis patients where the primary site cannot be identified by routine examination, regular application of F-18 FDG PET/CT for the sole purpose of detecting the primary carcinoma should not be encouraged.

Predictive efficacy of (11)C-PD153035 PET imaging for EGFR-tyrosine kinase inhibitor sensitivity in non-small cell lung cancer patients.

To determine the correlation of (11)C-PD153035 uptake with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) sensitivity and phosphorylated EGFR (pEGFR) expression in non-small cell lung cancer (NSCLC) cell lines with different EGFR-TKI sensitivities and in their corresponding xenografts. Four human NSCLC cell lines (HCC827, PC9, A549, and H1975) in the logarithmic phase were co-incubated with (11)C-PD153035 to analyze the correlation of (11)C-PD153035 uptake with EGFR-TKI sensitivity, and EGFR/pEGFR expression. Nude mice xenograft models bearing the four NSCLCs were prepared. (11)C-PD153035 positron-emission tomography (PET)-computed tomography (CT) was used to image the xenografts and observe radioactive uptakes. Correlation of the in vivo uptakes with EGFR-TKI sensitivity, and EGFR/pEGFR expression was analyzed. HCC827 and PC9 cells, which were highly sensitive to EGFR-TKIs, exhibited higher (11)C-PD153035 uptakes than the other cells. A549 cells, which were moderately sensitive to EGFR-TKIs, showed higher uptake than the EGFR-TKI-resistant H1975 cells, which showed little or no uptake. Radioactive uptakes were positively correlated with pEGFR expression in all cells. PET-CT showed that radioactivity was highest in HCC827 xenografts. The radioactivity in PC9 xenografts was higher than that in A549 and H1975 xenografts. Tumor vs. non-tumor tissue ratio values were positively correlated with pEGFR expression in HCC827 and PC9 xenografts, but not in A549 and H1975 xenografts. In conclusion, (11)C-PD153035 can serve as an EGFR imaging agent in vitro and in vivo, and predicts sensitivity to EGFR-TKIs. This will provide an experimental basis for clinical applications of (11)C-PD153035 and individualized NSCLC therapy.

Comparison of the diagnostic performance of 18F-fluorothymidine versus 18F-fluorodeoxyglucose positron emission tomography on pulmonary lesions: A meta analysis.

A pulmonary lesion is an extremely common and clinically challenging disorder worldwide, and an accurate diagnosis of lung cancer is crucial for early treatment and management. The aim of the present study was to perform a comprehensive meta analysis to compare the diagnostic performance of 18F-fluorothymidine (18F-FLT) positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) PET in evaluating patients with pulmonary lesions. Relevant studies were identified using the PubMed, EMBASE and Cochrane library databases. The pooled estimated sensitivity, specificity, positive-likelihood ratio, negative-likelihood ratio, and diagnostic odds ratio (DOR) for 18F-FLT PET versus 18F-FDG PET were calculated as the main outcome measures. Summary receiver operating characteristic curves were also constructed by Meta-Disk 1.4 software using a Mose's constant of linear model. The meta analysis showed that 18F-FLT PET had a higher specificity (0.70; 95% CI, 0.61-0.77), but lower sensitivity (0.81; 95% CI, 0.74-0.87) compared to 18F-FDG PET (0.50; 95% CI, 0.41-0.58 for specificity; 0.92; 95% CI 0.86-0.95 for sensitivity). For DOR, 18F-FLT PET (12.58; 95% CI, 6.81-23.24) was higher compared to 18F-FDG PET (10.72; 95% CI, 5.51-20.87). The area under the curve was 0.8592 and 0.9240 for 18F-FLT PET and 18F-FDG PET, respectively (Z=0.976, P>0.05). In conclusion, 18F-FLT PET and 18F-FDG PET had good diagnostic performance for the overall assessment of pulmonary lesions, and 18F-FLT PET had a higher specificity compared to 18F-FDG PET, but was less sensitive than 18F-FDG PET. Therefore, 18F-FLT and 18F-FDG together could add diagnostic confidence for pulmonary lesions.

[Clinical significance of (18)F-FDG PET/CT evaluation of response to treatment in T-cell lymphoma].

OBJECTIVE: To investigate the usefulness of (18)F-FDG PET/CT imaging in restaging, evaluating the treatment outcome, monitoring relapse and predicting prognosis of T-cell lymphoma. METHODS: Retrospective analysis of PET/CT image results of thirty-four patients with T-cell lymphoma, and to evaluate its clinical significance in restaging, treatment efficiency, relapse monitor and prognosis prediction. RESULTS: Clinical restaging among the 20 stage I and II patients, 6 were ascended, 9 descended and 5 unchanged. Restaging among the other 14 stage III and IV patients, 3 were ascended, 4 descended and 7 unchanged. There were 12 patients in complete remission (CR), 11 in partial remission (PR), 2 in stable disease (SD) and 9 in progressive disease (PD) among all the 34 patients. There is obvious statistical difference of the standardized uptake value (SUV) between the efficacy group and the inefficacy group after treatment of 6 courses at least in 25 patients among all the 34 patients (P = 0.009). There is obvious statistical difference of the SUV value before and after treatment in 8 patients among all the 34 patients (P = 0.000). There is obvious statistical difference in the survival time between the efficacy group and the inefficacy group after treatment of 6 courses at least in 25 patients among all the 34 patients (P = 0.015). CONCLUSIONS: (18)F-FDG PET/CT imaging plays an very important role in guiding clinical restaging, evaluating the treatment outcome, monitoring relapse and predicting prognosis of T-cell lymphoma. It is helpful to establish personalized treatment planning.

[Growing characteristic of breast adenocarcinoma suicide gene cell line T47D-tk and construction of subcutaneous xenografts].

OBJECTIVE: To further identify the breast adenocarcinoma cell line T47D-tk stably expressing the suicide gene HSV1-tk, observe its growing characteristics, and establish an animal model of implanted breast adenocarcinoma. METHODS: Retroviral vector of HSV1-tk gene and breast carcinoma cell line T47D-tk stably expressing the HSV1-tk gene were established. Breast carcinoma cells of the lines T47D and T47D-tk were cultured, and observed by inverted microscope. Growth curve was drawn. Genomic DNA of T47D-tk cells was extracted, and amplified by PCR with HSV1-tk and HSV1-tk P2 as primers. Agarose gel electrophoresis was used to identify the HSV1tk gene. Suspensions of T47D and T47D-tk cells were inoculated subcutaneously at bilateral roots of foreleg of female BALB/c nude mice respectively. The growth of tumor was observed every day. RESULTS: PCR showed 1131 bp fragment in the T47D-tk genome, but not in the T47D genome. The numbers of growing T47D cells on days 3, and 7 were (10.00 +/- 1.30) x 10(3) and (19.25 +/- 0.66) x 10(3) respectively, not significantly different from those of the T47D-tk cells [(10.25 +/- 0.90) x 10(3) and (19.00 +/- 1.80) x 10(3) respectively, both P > 0.05]. The time needed for tumor formation after the inoculation of T47D cells was (9.67 +/- 0.33) d, not significantly different from that of the T47D-tk cells [(9.83 +/- 0.48) d, P > 0.05]. The tumor size 19 days after inoculation of the T47D cells was (72.17 +/- 25.88) mm(3), not significantly different from that of the T47D-tk cells [(70.66 +/- 22.16) mm(3), P > 0.05]. CONCLUSION: The T47D-tk cells have integrated the HSV1-tk gene without changing its growing characteristics. An animal model of implanted breast cancer has been successfully established. The T47D and T47D-tk subcutaneous xenografts offer the foundation for further study of gene imaging and gene therapy.

[Molecular imaging for PET-CT reporter gene in breast adenocarcinoma (HSV1-tk) of subcutaneous xenografts in living nude mice].

OBJECTIVE: To study the in vitro accumulation of (18)F-FHBG, its in vivo distribution and (18)F-FHBG PET-CT imaging for reporter gene (HSV1-tk) in nude mice with a xenograft of breast adenocarcinoma. METHODS: The in vitro uptake of (18)F-FHBG in tumor cells of T47D and T47D-tk and the distribution of (18)F-FHBG in normal Kunming mice and nude mice with breast adenocarcinoma xenograft were detected by well-type gamma counter. Reporter gene PET-CT imaging with (18)F-FHBG was performed in nude mice with a xenograft of breast adenocarcinoma. And the expression location of HSV1-tk gene could be monitored by observing the in vitro and in vivo accumulation of (18)F-FHBG. RESULTS: The in vitro uptake of (18)F-FHBG in T47D-tk cells (143.67 dpm/10(4) +/- 5.82 dpm/10(4) cells) was significantly higher than that in T47D cells (2.23 dpm/10(4) +/- 0.23 dpm/10(4) cells) at 60 and 120 min post-injection (P < 0.001) and reaches a plateau at 60 min. In normal Kunming mice, (18)F-FHBG was mainly distributed in liver, intestine, kidney and bladder while there was no obvious radioactive accumulation in brain. (18)F-FHBG accumulated at a significantly higher level in T47D-tk tumors than in T47D tumors and its accumulation yielded the best image effect at 2 h by PET-CT imaging in nude mice. CONCLUSION: The in vitro uptake of (18)F-FHBG in T47D-tk cells is significantly higher than that in T47D cells. (18)F-FHBG is mainly excreted by digestive tract and urinary tract in mice. It agrees with the expression pattern of HSV1-tk gene. (18)F-FHBG can determine the localization of HSV1-tk gene expression in an efficient way. This study will offer a monitoring method and scientific base for (18)F-FHBG reporter gene imaging and HSV1-tk gene therapy in tumors.