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Contrast Media & Molecular Imaging
Volume 2018 (2018), Article ID 8194678, 6 pages
https://doi.org/10.1155/2018/8194678
Clinical Study

Comparing the Differential Diagnostic Values of 18F-Alfatide II PET/CT between Tuberculosis and Lung Cancer Patients

1Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University (Wuxi No. 4 People’s Hospital), Wuxi, China
2Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Institute of Nuclear Medicine, Wuxi, China

Correspondence should be addressed to Chunjing Yu

Received 31 October 2017; Revised 27 December 2017; Accepted 31 December 2017; Published 19 February 2018

Academic Editor: Yuebing Wang

Copyright © 2018 Xiaoqing Du et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose. To compare the differential diagnostic values of 18F-Alfatide II PET/CT between tuberculosis and lung cancer patients and in patients with sarcoidosis and common inflammation. Methods. Nine inflammation patients (4 tuberculosis, 3 sarcoidosis, and 2 common inflammation) and 11 lung cancer patients were included in this study. All patients underwent 18F-FDG and 18F-Alfatide II PET/CT within 2 weeks, followed by biopsy and surgery. The maximized standard uptake value (SUVmax) and the mean standard uptake value (SUVmean) were evaluated. Results. The active tuberculosis lesions showed a high accumulation of 18F-FDG, but varying degrees of accumulation of 18F-Alfatide II, including negative results. The SUVmax of 18F-Alfatide II in malignant lesions was significantly higher than that in tuberculosis (4.08 ± 1.51 versus 2.63 ± 1.34, = 0.0078). Three patients with sarcoidosis showed negative results in 18F-Alfatide II PET/CT. Conclusions. The expression of is much lower in tuberculosis as compared to that in lung cancer, and accumulation of 18F-Alfatide II varied even in lesions of the same patient. The negative results of sarcoidosis patients led to the speculation that was not expressed in those lesions.

1. Introduction

Lung cancer is one of the largest malignant tumors with fast-growing morbidity and mortality. 18F-FDG PET/CT has been verified as a crucial tool for detecting, identifying, and staging lung cancer. However, the specificity of 18F-FDG PET/CT in lung cancer is controversial as some benign lesions such as tuberculosis and sarcoidosis also show a high accumulation of 18F-FDG. Thus, a new tracer with higher specificity in differentiating lung cancer and inflammation is essential.

The expression of integrin β3 on the surface of cancer cells and neovascularization endothelial cells is upregulated in cancer, inflammation, and wound [1]. 18F-Alfatide II is an annular dimer RGD (Arg-Gly-Asp) tracer targeting integrin β3. Previous studies reported that the uptake of Alfatide in lung cancer and tuberculosis lesions is markedly different [2, 3]. Thus, additional clinical data is needed to illustrate whether this new tracer is beneficial for the differentiation of tuberculosis from lung cancer.

The present study investigated the differential diagnostic value of 18F-Alfatide II PET/CT between tuberculosis and lung cancer patients. Also, the angiogenesis in sarcoidosis and chronic inflammations was investigated.

2. Materials and Methods

2.1. Radiopharmaceutical Preparation

The kit was provided by Jiangsu Institute of Nuclear Medicine. Synthesis of 18F-Alfatide II has been described previously [4].

2.2. Patients

The local institutional review board approved the 18F-Alfatide II PET/CT compliment protocol. Written informed consent was obtained from each patient. The cohort consisted of 9 patients [5 men and 4 women; aged 25–71 (55 ± 16) years] with suspected inflammations and 11 patients [10 men, 1 women; aged 48–78 (66 ± 9) years] with suspected lung cancer.

2.3. PET/CT Acquisition and Image Analysis

18F-FDG and 18F-Alfatide II PET/CT were performed at an interval of 2 weeks. Patients were required to fast at least 6 h before 18F-FDG (5.55 MBq/kg) intravenous injection. The acquisitions were conducted at 60 min after the injection. The patients were placed in a supine position on the scanner bed. Imaging data were acquired from the skull to the thigh, using PET/CT scanner, at 1.5 min/bed position. Low-dose CT was performed for attenuation correction and lesion localization. 18F-Alfatide II PET/CT was performed on the next day without any specific preparation before the examination. 18F-Alfatide II (248.27 ± 45.14 MBq) was injected intravenously in all patients. The acquisition procedure and parameters were identical to that as 18F-FDG PET/CT. Regions of interest (ROIs) were drawn manually on the site of lesions based on the corresponding CT images.

PET/CT Scanner was from Siemens (Biograph True Point PET/CT).

Visual analysis was used to evaluate the preliminary accumulation of 18F-Alfatide II and 18F-FDG in tuberculosis and lung cancer. Maximum standard uptake value (SUVmax), mean standard uptake value (SUVmean), and lesion/muscle (L/M) ratio recorded the uptake of the lesions in this study. The uptake of the right hip muscle was selected as a reference for lesions. All lesions were divided into different regions of head-neck, chest, abdomen, and pelvis. The largest lesion of each region was chosen to measure the uncountable lesions.

Two physicians evaluated the images independently, and the discrepancies were resolved by consultation.

2.4. Pathological Analysis and Follow-Up

Inflammation Group. Number 1 patient was confirmed as thoracic tuberculosis by biopsy. Number 2–4 patients, receiving PPD test, T-SPOT test, and antituberculosis treatment, were followed up for 16, 17, and 33 months, respectively; they were confirmed as lung tuberculosis, lymph node tuberculosis, and lung tuberculosis mixed with tuberculous pleurisy. Number 5 patient was confirmed as sarcoidosis by bronchoscope puncture biopsy. Number 6-7 patients, receiving no treatment and followed up for 17 and 28 months, respectively, were diagnosed as sarcoidosis. Number 8 patient was shown to have chronic inflammation accompanied by fibrosis as assessed by percutaneous lung biopsy. Number 9 patient was diagnosed with inflammation caused by common infection after 20 months’ follow-up based on CT (Table 1).

Table 1: Patient demographics (inflammation group).

Malignancy Group. Eight patients received surgery. One patient did not undergo surgery since the pulmonary trunk was invaded by cancer, and two patients were not recommended surgery as distant metastasis detected by PET/CT and MRI. All patients were confirmed by pathology; one distant metastasis patient received bronchoscopy biopsy, while the other underwent clavicle lymph node excision (Table 2).

Table 2: Patient demographics (malignancy group).
2.5. Statistical Analysis

Mean ± standard deviation (m ± SD) was used to express all quantitative data. Differences in SUVmax/SUVmean between patients with different diseases were compared and assessed by -test or Mann–Whitney test. All statistical analyses were carried out using SAS 9.2. < 0.05 indicated statistical significance.

3. Results

3.1. Safety

Patients did not report any subjective effects following the injected dose of 18F-Alfatide II. No adverse events were noted during the examination of 18F-Alfatide II PET/CT or follow-up (at least 6 months).

3.2. Visual Analysis Results

The accumulation of 18F-Alfatide II in tuberculosis was much lower than that of 18F-FDG (Figures 1 and 2), while no accumulation was observed in sarcoidosis lesions (Figure 3). Additionally, 2 chronic inflammations showed a high accumulation of 18F-Alfatide II.

Figure 1: -FDG (a) and -Alfatide II (b) PET/CT images of a thoracic tuberculosis patient. T2, T3, and T4 showed intense -FDG uptake and mild -Alfatide II uptake. The white arrows indicate tuberculosis lesions in T4.
Figure 2: -FDG (a) and -Alfatide II (b) PET/CT images of a lymph node tuberculosis patient. Lymph nodes tuberculosis lesions showed intense -FDG uptake and no -Alfatide II uptake. The white arrows indicate tuberculosis lesions in porta hepatis lymph nodes.
Figure 3: -FDG (a) and -Alfatide II (b) PET/CT images of a sarcoidosis patient. All lesions showed intense -FDG uptake and no -Alfatide II uptake. The white arrows indicate sarcoidosis lesions in mediastinum and hilus pulmonis.

All lung cancer patients in this study showed a high accumulation of 18F-Alfatide II, including brain and bone metastasis. The results were similar to that in the previous reports [5].

3.3. Preliminary Diagnostic Value of 18F-FDG PET/CT and 18F-Alfatide II PET/CT in Tuberculosis

The SUVmax of tuberculosis was calculated as 7.53 ± 2.88 and 2.63 ± 1.34 for 18F-FDG and 18F-Alfatide II, respectively. The SUVmean of tuberculosis was 4.58 ± 1.73 and 1.86 ± 1.0, respectively.

3.4. Preliminary Diagnostic Value of 18F-FDG PET/CT and 18F-Alfatide II PET/CT in Chronic Inflammation

The SUVmax of two patients with chronic inflammation was 10.80 and 1.62 for 18F-FDG and 9.13 and 5.75 for 18F-Alfatide II, respectively. The SUVmean was 5.33, 0.99 and 5.12, 2.65, respectively.

3.5. Preliminary Diagnostic Value of 18F-FDG PET/CT and 18F-Alfatide II PET/CT in Sarcoidosis

The SUVmax of 18F-FDG and 18F-Alfatide II in sarcoidosis was calculated as 8.82 ± 5.17 and 1.77 ± 0.69, respectively, while SUVmean was 5.34 ± 3.08 and 1.28 ± 0.63, respectively.

3.6. Preliminary Diagnostic Value of 18F-FDG PET/CT and 18F-Alfatide II PET/CT in Lung Cancer

The SUVmax of 18F-FDG and 18F-Alfatide II in lung cancer was 12.04 ± 4.67 and 4.08 ± 1.51, respectively, while SUVmean was 4.55 ± 1.98 and 1.99 ± 0.81, respectively.

3.7. Difference between the SUVmax of Malignant Lesions and Tuberculosis Lesions

The lesion-to-lesion analysis showed that the SUVmax of 18F-Alfatide II in malignant lesions was 4.08 ± 1.51, which was significantly higher than that in tuberculosis (2.63 ± 1.34, = 0.0078).

3.8. Difference between the SUVmean of Malignant Lesions and Tuberculosis Lesions

The SUVmean of 18F-Alfatide II in malignant lesions was 1.99 ± 0.81 without any statistically significant difference from that of tuberculosis (1.86 ± 1.0, = 0.3820).

3.9. Preliminary Diagnostic Value of 18F-FDG and 18F-Alfatide II PET/CT in Inflammations (Active TB, Chronic Inflammation, and Sarcoidosis) and Lung Cancer

See Table 3.

Table 3: SUVmax and SUVmean of lesions.

4. Discussion

Integrin is overexpressed not only in various tumor cells and tumor neovasculature [6] but also in chronic inflammatory diseases, such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) [7, 8]. Previous studies reported that angiogenesis and chronic inflammation are interrelated [7, 9]. Jackson et al. [10] suggested that several resident cells (fibroblasts, monocytes-macrophages, neutrophils, and lymphocytes) can promote angiogenesis when the microenvironment becomes hypoxic or inflammatory, thereby facilitating the migration of inflammatory cells to inflammatory sites and the supply of nutrients and oxygen to the proliferating tissue. The frequent dual functionality of angiogenic factors such as and VEGF reflects the close relationship between angiogenesis and inflammation [11]. Cao et al. [12] demonstrated specific uptake of in the chronic inflammation of mouse ear using 64Cu-DOTA-RGD tetramer PET imaging.

Chin et al. [13] carried out a PET imaging study with 18F-FPP(RGD)2 in a healthy woman volunteer, and no unusual or adverse patient symptoms were found on the day of imaging as well as during follow-up. Wan et al. [2] did not record any adverse events associated with 18F-Alfatide in the first subject during the study, in which nine lung cancer patients were investigated. No adverse events occurred in all patients during or after the 18F-Alfatide II PET/CT imaging in the current study. All these investigations revealed that using RGD tracers labeled by 18F is safe for patients.

Tuberculosis is a major global health problem with an estimated 8.6 million new cases worldwide in 2012 [14]. The tuberculous granuloma is an organized collection of differentiated macrophages surrounded by T-lymphocytes, B-lymphocytes, dendritic cells, fibroblasts, and extracellular matrix components [15]. Some studies demonstrated expression in lung granulomas and lymph nodes of sarcoid patients [16]. Rojas et al. [17] found that the mycobacterial glycolipid phosphatidylinositol mannoside interacts directly with integrin VLA-5 on CD4+ T-lymphocytes, resulting in fibronectin binding and T-cell migration. Several studies have reported increased levels of VEGF in granulomatous disease, such as pulmonary tuberculosis [1821] and Crohn’s disease [22]. Hur et al. [23] reported that median concentration of serum VEGF-A was significantly higher in tuberculosis patients than that in the latent tuberculosis infection and control groups. Four patients with active tuberculosis showed varying degree of accumulation of 18F-Alfatide II in this study, including negative results, and even the positive lesions showed a low accumulation of 18F-Alfatide II than that of 18F-FDG. Kang et al. [3] reported that tuberculosis granuloma and the surrounding vasculature epithelium showed baseline expression as assessed by immunohistochemistry. The diversity in the current study revealed different expression of in all tuberculosis lesions.

All lung cancer lesions and the metastases in the brain and bone showed an increased RGD uptake. A significant difference was noted in SUVmax between the lung cancer and tuberculosis groups, which indicated that RGD PET/CT might differentiate lung cancer from tuberculosis.

Sarcoidosis is an immunological, granulomatous disorder affecting multiple systems. The presence of noncaseating granulomas in involved organs is a pathological feature [24]. The common sites of the disease are lung, mediastinum, and hilus pulmonis lymph node [25, 26]. The precise pathogenesis is yet unknown, which might include various factors: environmental, occupational exposure, the presence of infectious agents, and genetic susceptibility [2729]. Various studies suggested that angiogenic factors contribute to the pathogenesis of sarcoidosis [30, 31]. Agostini et al. [32] and Antoniou et al. [31] indicated the presence of angiogenesis in the pathogenesis of granulomatous and pulmonary fibrosis. Tzouvelekis et al. [33] revealed an abundant expression of VEGF and ING4 within the granulomatous tissue, localized in the epithelioid and giant cells. Three sarcoidosis patients, in this study, showed negative results in 18F-Alfatide II PET/CT, thereby indicating the lack of expression in sarcoidosis. Kambouchner et al. [34] proposed the presence of an avascular microenvironment within sarcoid lesions. Tzouvelekis et al. [33] speculated that abundant expression of VEGF might be implicated in the inflammatory than the angiogenic cascade of sarcoidosis. Murdoch et al. supported this speculation with respect to the pleiotropic properties of VEGF in promoting the Th1-dependent immunity via facilitation of monocyte recruitment and T-cell migration to sites of ongoing inflammation [35]. The results from the current study were in agreement with the theory by Kambouchner et al. and Tzouvelekis et al.

Furthermore, the present study comprised 2 common infection patients: one patient showed high accumulation of 18F-Alfatide II as well as 18F-FDG, while the other showed a high accumulation of 18F-Alfatide II compared to 18F-FDG. Winter et al. [36] speculated that integrin was a potential marker of inflammation and angiogenesis in atherosclerotic lesions. Srivatsa et al. and Hansson both observed persistently high levels of expression between 7 and 21 days following injury in the neointima, media, and adventitia [37, 38]. Other studies demonstrated the expression of integrin on activated macrophages by different methods [3941]. When acute inflammation transforms into subacute and chronic inflammation, macrophages are gradually increased in number in lesions than the neutrophils. Thus, the high accumulation of 18F-Alfatide II in the 2 patients in this study indicated the chronic inflammatory stage, which was confirmed by fibrosis tested by percutaneous lung biopsy in one lesion. Storgard et al. [42] reported that the treatment with cyclic RGD peptide c(RGDfV), an integrin antagonist, significantly inhibited the disease progression in an experimental RA model. Taken together, 18F-Alfatide II PET/CT may not only detect chronic inflammation but also allow the evaluation of angiogenesis and neovascularization during chronic inflammation and guide the selection of patients for antiangiogenesis therapy.

Nevertheless, the present study has some deficiencies. (1) Early experimental design was not perfect; for example, we did not recruit lymphoma patients to compare with sarcoidosis in 18F-Alfatide II PET/CT. (2) The number of patients was small. (3) Further investigations are essential.

5. Conclusion

The accumulation of lung cancer and tuberculosis exhibits distinct difference, which might be valuable in differentiating the two diseases. Three sarcoidoses showed negative results, and thus, we speculated the lack of expression within sarcoidosis. 18F-Alfatide II might be valuable in the evaluation of angiogenesis and neovascularization during chronic inflammation, which could guide the selection of patients for antiangiogenesis therapy and evaluate the clinical effect of the treatment.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This work was supported by the Natural Science Foundation of China (81471691).

References

  1. J. A. Varner and D. A. Cheresh, “Integrins and cancer,” Current Opinion in Cell Biology, vol. 8, no. 5, pp. 724–730, 1996. View at Publisher · View at Google Scholar · View at Scopus
  2. W. Wan, N. Guo, D. Pan et al., “First experience of 18F-alfatide in lung cancer patients using a new lyophilized kit for rapid radiofluorination,” Journal of Nuclear Medicine, vol. 54, no. 5, pp. 691–698, 2013. View at Publisher · View at Google Scholar · View at Scopus
  3. F. Kang, S. Wang, F. Tian et al., “Comparing the diagnostic potential of 68Ga-Alfatide II and 18F-FDG in differentiating between non-small cell lung cancer and tuberculosis,” Journal of Nuclear Medicine, vol. 57, no. 5, pp. 672–677, 2016. View at Publisher · View at Google Scholar
  4. L. Lang, Y. Ma, D. O. Kiesewetter, and X. Chen, “Stability analysis of glutamic acid linked peptides coupled to NOTA through different chemical linkages,” Molecular Pharmaceutics, vol. 11, no. 11, pp. 3867–3874, 2014. View at Publisher · View at Google Scholar · View at Scopus
  5. S. Gao, H. Wu, W. Li et al., “A pilot study imaging integrin αvβ3 with RGD PET/CT in suspected lung cancer patients,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 42, no. 13, pp. 2029–2037, 2015. View at Publisher · View at Google Scholar · View at Scopus
  6. W. Cai and X. Chen, “Anti-angiogenic cancer therapy based on integrin αvβ3 antagonism,” Anti-Cancer Agents in Medicinal Chemistry, vol. 6, no. 5, pp. 407–428, 2006. View at Publisher · View at Google Scholar · View at Scopus
  7. S. Danese, M. Sans, C. de la Motte et al., “Angiogenesis as a novel component of inflammatory bowel disease pathogenesis,” Gastroenterology, vol. 130, no. 7, pp. 2060–2073, 2006. View at Publisher · View at Google Scholar · View at Scopus
  8. R. L. Wilder, “Integrin alpha V beta 3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases,” Annals of the Rheumatic Diseases, vol. 61, supplement 2, pp. ii96–ii99, 2002. View at Publisher · View at Google Scholar
  9. I. E. Koutroubakis, G. Tsiolakidou, K. Karmiris, and E. A. Kouroumalis, “Role of angiogenesis in inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 12, no. 6, pp. 515–523, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. J. R. Jackson, M. P. Seed, C. H. Kircher, D. A. Willoughby, and J. D. Winkler, “The codependence of angiogenesis and chronic inflammation,” The FASEB Journal, vol. 11, no. 6, pp. 457–465, 1997. View at Google Scholar · View at Scopus
  11. D. A. Walsh, “Angiogenesis and arthritis,” Rheumatology, vol. 38, no. 2, pp. 103–112, 1999. View at Publisher · View at Google Scholar · View at Scopus
  12. Q. Cao, W. Cai, Z.-B. Li et al., “PET imaging of acute and chronic inflammation in living mice,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 34, no. 11, pp. 1832–1842, 2007. View at Publisher · View at Google Scholar · View at Scopus
  13. F. T. Chin, B. Shen, S. Liu et al., “First experience with clinical-grade 18F-FPP (RGD)2: An automated multi-step radiosynthesis for clinical PET studies,” Molecular Imaging and Biology, vol. 14, no. 1, pp. 88–95, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. Eurosurveillance editorialt, “WHO publishes global tuberculosis report 2013,” Euro Surveill, vol. 18, no. 43, 2013. View at Google Scholar
  15. C. L. Cosma, D. R. Sherman, and L. Ramakrishnan, “The secret lives of the pathogenic mycobacteria,” Annual Review of Microbiology, vol. 57, pp. 641–676, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. K. Shigehara, N. Shijubo, M. Hirasawa, S. Abe, and T. Uede, “Immunolocalization of extracellular matrix proteins and integrins in sarcoid lymph nodes,” Virchows Archiv, vol. 433, no. 1, pp. 55–61, 1998. View at Publisher · View at Google Scholar · View at Scopus
  17. R. E. Rojas, J. J. Thomas, A. J. Gehring et al., “Phosphatidylinositol mannoside from mycobacterium tuberculosis binds αvβ1 integrin (VLA-5) on CD4+ T cells and induces adhesion to fibronectin,” The Journal of Immunology, vol. 177, no. 5, pp. 2959–2968, 2006. View at Publisher · View at Google Scholar
  18. W. Matsuyama, T. Hashiguchi, K. Matsumuro et al., “Increased serum level of vascular endothelial growth factor in pulmonary tuberculosis,” American Journal of Respiratory and Critical Care Medicine, vol. 162, no. 3 I, pp. 1120–1122, 2000. View at Publisher · View at Google Scholar · View at Scopus
  19. S. W. Ra, J. Lyu, C.-M. Choi et al., “Distinguishing tuberculosis from Mycobacterium avium complex disease using an interferon-gamma release assay,” The International Journal of Tuberculosis and Lung Disease, vol. 15, no. 5, pp. 635–640, 2011. View at Publisher · View at Google Scholar · View at Scopus
  20. Y. Nishigaki, S. Fujiuchi, Y. Fujita et al., “Increased serum level of vascular endothelial growth factor in Mycobacterium avium complex infection,” Respirology, vol. 11, no. 4, pp. 407–413, 2006. View at Publisher · View at Google Scholar · View at Scopus
  21. C. Riou, B. Perez Peixoto, L. Roberts et al., “Effect of standard tuberculosis treatment on plasma cytokine levels in patients with active pulmonary tuberculosis,” PLoS ONE, vol. 7, no. 5, Article ID e36886, 2012. View at Publisher · View at Google Scholar · View at Scopus
  22. I. D. Pousa, J. Maté, X. Salcedo-Mora, M. T. Abreu, R. Moreno-Otero, and J. P. Gisbert, “Role of vascular endothelial growth factor and angiopoietin systems in serum of Crohn's disease patients,” Inflammatory Bowel Diseases, vol. 14, no. 1, pp. 61–67, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. Y.-G. Hur, Y. A. Kang, S.-H. Jang et al., “Adjunctive biomarkers for improving diagnosis of tuberculosis and monitoring therapeutic effects,” Infection, vol. 70, no. 4, pp. 346–355, 2015. View at Publisher · View at Google Scholar · View at Scopus
  24. R. P. Baughman, E. E. Lower, and R. M. Du Bois, “Sarcoidosis,” The Lancet, vol. 361, no. 9363, pp. 1111–1118, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. R. P. Baughman, S. Nagai, M. Balter et al., “Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG task force,” Sarcoidosis, Vasculitis and Diffuse Lung Diseases, vol. 28, pp. 56–64, 2011. View at Google Scholar
  26. G. W. Hunninghake, U. Costabel, M. Ando et al., “American thoracic society/european respiratory society/world association of sarcoidosis and other granulomatous disorders,” Sarcoidosis, Vasculitis and Diffuse Lung Diseases, vol. 16, pp. 149–173, 1999. View at Google Scholar
  27. A. Lazarus, “Sarcoidosis: epidemiology, etiology, pathogenesis, and genetics,” Disease-a-Month, vol. 55, no. 11, pp. 649–660, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. K. W. Thomas and G. W. Hunninghake, “Sarcoidosis,” Journal of the American Medical Association, vol. 289, no. 24, pp. 3300–3303, 2003. View at Publisher · View at Google Scholar · View at Scopus
  29. M. C. Iannuzi, B. A. Rybicki, and A. S. Tierstein, “Sarcoidosis,” The New England Journal of Medicine, vol. 357, pp. 2153–2165, 2007. View at Publisher · View at Google Scholar
  30. A. Cui, O. Anhenn, D. Theegarten et al., “Angiogenic and angiostatic chemokines in idiopathic pulmonary fibrosis and granulomatous lung disease,” Respiration, vol. 80, no. 5, pp. 372–378, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. K. M. Antoniou, A. Tzouvelekis, M. G. Alexandrakis et al., “Different angiogenic activity in pulmonary sarcoidosis and idiopathic pulmonary fibrosis,” CHEST, vol. 130, no. 4, pp. 982–988, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. C. Agostini, M. Facco, M. Siviero et al., “CXC chemokines IP-10 and Mig expression and direct migration of pulmonary CD8+/CXCR3+ T cells in the lungs of patients with HIV infection and T-cell alveolitis,” American Journal of Respiratory and Critical Care Medicine, vol. 162, no. 4 I, pp. 1466–1473, 2000. View at Publisher · View at Google Scholar · View at Scopus
  33. A. Tzouvelekis, P. Ntolios, A. Karameris et al., “Expression of hypoxia-inducible factor (HIF)-1a-vascular endothelial growth factor (VEGF)-inhibitory growth factor (ING)-4- axis in sarcoidosis patients,” BMC Research Notes, vol. 5, article 654, 2012. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Kambouchner, D. Pirici, J.-F. Uhl, L. Mogoanta, D. Valeyre, and J.-F. Bernaudin, “Lymphatic and blood microvasculature organisation in pulmonary sarcoid granulomas,” European Respiratory Journal, vol. 37, no. 4, pp. 835–840, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. C. Murdoch, A. Giannoudis, and C. E. Lewis, “Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues,” Blood, vol. 104, no. 8, pp. 2224–2234, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. P. M. Winter, A. M. Morawski, S. D. Caruthers et al., “Molecular imaging of angiogenesis in early-stage atherosclerosis with αvβ3-integrin-targeted nanoparticles,” Circulation, vol. 108, no. 18, pp. 2270–2274, 2003. View at Publisher · View at Google Scholar · View at Scopus
  37. S. S. Srivatsa, L. A. Fitzpatrick, P. W. Tsao et al., “Selective αvβ3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury: evidence for the functional importance of integrin αvβ3 and osteopontin expression during neointima formation,” Cardiovascular Research, vol. 36, no. 3, pp. 408–428, 1997. View at Publisher · View at Google Scholar · View at Scopus
  38. G. K. Hansson, “Inflammation, atherosclerosis, and coronary artery disease,” The New England Journal of Medicine, vol. 352, pp. 1685–1695, 2005. View at Google Scholar
  39. A. S. Antonov, F. D. Kolodgie, D. H. Munn et al., “Regulation of macrophage foam cell formation by αVβ3 integrin: potential role in human atherosclerosis,” The American Journal of Pathology, vol. 165, pp. 247–258, 2004. View at Publisher · View at Google Scholar
  40. J. Waldeck, F. Häger, C. Höltke et al., “Fluorescence reflectance imaging of macrophage-rich atherosclerotic plaques using an αvβ3 integrin-targeted fluorochrome,” Journal of Nuclear Medicine, vol. 49, no. 11, pp. 1845–1851, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. Y. Yao, Y. Jiang, Z. Sheng et al., “Analysis of in situ and ex vivo αVβ3 integrin expression during experimental carotid atherogenesis,” International Journal of Nanomedicine, vol. 7, pp. 641–649, 2012. View at Publisher · View at Google Scholar · View at Scopus
  42. C. M. Storgard, D. G. Stupack, A. Jonczyk, S. L. Goodman, R. I. Fox, and D. A. Cheresh, “Decreased angiogenesis and arthritic disease in rabbits treated with an αvβ3 antagonist,” The Journal of Clinical Investigation, vol. 103, no. 1, pp. 47–54, 1999. View at Publisher · View at Google Scholar · View at Scopus