Top

EJNMMI Research

Published in:

Open Access 01-12-2016 | Original research

A dual tracer ⁶⁸Ga-DOTANOC PET/CT and ¹⁸F-FDG PET/CT pilot study for detection of cardiac sarcoidosis

Authors: Lars C. Gormsen, Ate Haraldsen, Stine Kramer, Andre H. Dias, Won Yong Kim, Per Borghammer

Published in: EJNMMI Research | Issue 1/2016

Abstract

Background

Cardiac sarcoidosis (CS) is a potentially fatal condition lacking a single test with acceptable diagnostic accuracy. ¹⁸F-FDG PET/CT has emerged as a promising imaging modality, but is challenged by physiological myocardial glucose uptake. An alternative tracer, ⁶⁸Ga-DOTANOC, binds to somatostatin receptors on inflammatory cells in sarcoid granulomas. We therefore aimed to conduct a proof-of-concept study using ⁶⁸Ga-DOTANOC to diagnose CS. In addition, we compared diagnostic accuracy and inter-observer variability of ⁶⁸Ga-DOTANOC vs. ¹⁸F-FDG PET/CT.

Methods

Nineteen patients (seven female) with suspected CS were prospectively recruited and dual tracer scanned within 7 days. PET images were reviewed by four expert readers for signs of CS and compared to the reference standard (Japanese ministry of Health and Welfare CS criteria).

Results

CS was diagnosed in 3/19 patients. By consensus, 11/19 ¹⁸F-FDG scans and 0/19 ⁶⁸Ga-DOTANOC scans were rated as inconclusive. The sensitivity of ¹⁸F-FDG PET for diagnosing CS was 33 %, specificity was 88 %, PPV was 33 %, NPV was 88 %, and diagnostic accuracy was 79 %. For ⁶⁸Ga-DOTANOC, accuracy was 100 %. Inter-observer agreement was poor for ¹⁸F-FDG PET (Fleiss’ combined kappa 0.27, NS) and significantly better for ⁶⁸Ga-DOTANOC (Fleiss’ combined kappa 0.46, p = 0.001).

Conclusions

Despite prolonged pre-scan fasting, a large proportion of ¹⁸F-FDG PET/CT images were rated as inconclusive, resulting in low agreement among reviewers and correspondingly poor diagnostic accuracy. By contrast, ⁶⁸Ga-DOTANOC PET/CT had excellent diagnostic accuracy with the caveat that inter-observer variability was still significant. Nevertheless, ⁶⁸Ga-DOTANOC PET/CT looks very promising as an alternative CS PET tracer.

Trial registration

Current Controlled Trials NCT01729169.

Available only for authorised users

Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med. 1997;336:1224–34. doi:10.1056/NEJM199704243361706.CrossRefPubMed

Patel MR, Cawley PJ, Heitner JF, Klem I, Parker MA, Jaroudi WA, et al. Detection of myocardial damage in patients with sarcoidosis. Circulation. 2009;120:1969–77. doi:10.1161/CIRCULATIONAHA.109.851352.CrossRefPubMedPubMedCentral

Silverman KJ, Hutchins GM, Bulkley BH. Cardiac sarcoid: a clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation. 1978;58:1204–11.CrossRefPubMed

Sharma OP, Maheshwari A, Thaker K. Myocardial sarcoidosis. Chest. 1993;103:253–8.CrossRefPubMed

Chiu CZ, Nakatani S, Zhang G, Tachibana T, Ohmori F, Yamagishi M, et al. Prevention of left ventricular remodeling by long-term corticosteroid therapy in patients with cardiac sarcoidosis. Am J Cardiol. 2005;95:143–6. doi:10.1016/j.amjcard.2004.08.083.CrossRefPubMed

Ishikawa T, Kondoh H, Nakagawa S, Koiwaya Y, Tanaka K. Steroid therapy in cardiac sarcoidosis. Increased left ventricular contractility concomitant with electrocardiographic improvement after prednisolone. Chest. 1984;85:445–7.CrossRefPubMed

Ratner SJ, Fenoglio Jr JJ, Ursell PC. Utility of endomyocardial biopsy in the diagnosis of cardiac sarcoidosis. Chest. 1986;90:528–33.CrossRefPubMed

Smedema JP, Snoep G, van Kroonenburgh MP, van Geuns RJ, Dassen WR, Gorgels AP, et al. Evaluation of the accuracy of gadolinium-enhanced cardiovascular magnetic resonance in the diagnosis of cardiac sarcoidosis. J Am Coll Cardiol. 2005;45:1683–90. doi:10.1016/j.jacc.2005.01.047.CrossRefPubMed

Youssef G, Leung E, Mylonas I, Nery P, Williams K, Wisenberg G, et al. The use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis: a systematic review and metaanalysis including the Ontario experience. J Nucl Med. 2012;53:241–8. doi:10.2967/jnumed.111.090662.CrossRefPubMed

10.

Birnie DH, Sauer WH, Bogun F, Cooper JM, Culver DA, Duvernoy CS, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm. 2014;11:1305–23. doi:10.1016/j.hrthm.2014.03.043.CrossRefPubMed

11.

van der Vusse GJ, Glatz JF, Stam HC, Reneman RS. Fatty acid homeostasis in the normoxic and ischemic heart. Physiol Rev. 1992;72:881–940.PubMed

12.

Tahara N, Tahara A, Nitta Y, Kodama N, Mizoguchi M, Kaida H, et al. Heterogeneous myocardial FDG uptake and the disease activity in cardiac sarcoidosis. JACC Cardiovasc Imaging. 2010;3:1219–28. doi:10.1016/j.jcmg.2010.09.015.CrossRefPubMed

13.

Langah R, Spicer K, Gebregziabher M, Gordon L. Effectiveness of prolonged fasting 18f-FDG PET-CT in the detection of cardiac sarcoidosis. J Nucl Cardiol. 2009;16:801–10. doi:10.1007/s12350-009-9110-0.CrossRefPubMed

14.

Inglese E, Leva L, Matheoud R, Sacchetti G, Secco C, Gandolfo P, et al. Spatial and temporal heterogeneity of regional myocardial uptake in patients without heart disease under fasting conditions on repeated whole-body 18F-FDG PET/CT. J Nucl Med. 2007;48:1662–9. doi:10.2967/jnumed.107.041574.CrossRefPubMed

15.

ten Bokum AM, Hofland LJ, de Jong G, Bouma J, Melief MJ, Kwekkeboom DJ, et al. Immunohistochemical localization of somatostatin receptor sst2A in sarcoid granulomas. Eur J Clin Invest. 1999;29:630–6.CrossRefPubMed

16.

Prasad V, Baum RP. Biodistribution of the Ga-68 labeled somatostatin analogue DOTA-NOC in patients with neuroendocrine tumors: characterization of uptake in normal organs and tumor lesions. Q J Nucl Med Mol Imaging. 2010;54:61–7.PubMed

17.

Boy C, Heusner TA, Poeppel TD, Redmann-Bischofs A, Unger N, Jentzen W, et al. 68Ga-DOTATOC PET/CT and somatostatin receptor (sst1-sst5) expression in normal human tissue: correlation of sst2 mRNA and SUVmax. Eur J Nucl Med Mol Imaging. 2011;38:1224–36. doi:10.1007/s00259-011-1760-x.CrossRefPubMed

18.

Reiter T, Werner RA, Bauer WR, Lapa C. Detection of cardiac sarcoidosis by macrophage-directed somatostatin receptor 2-based positron emission tomography/computed tomography. Eur Heart J. 2015. doi:10.1093/eurheartj/ehv278.PubMed

19.

Fleiss JL. Measuring nominal scale agreement among many raters. Psychol Bull. 1971;76:5.CrossRef

20.

Ishimaru S, Tsujino I, Takei T, Tsukamoto E, Sakaue S, Kamigaki M, et al. Focal uptake on 18F-fluoro-2-deoxyglucose positron emission tomography images indicates cardiac involvement of sarcoidosis. Eur Heart J. 2005;26:1538–43. doi:10.1093/eurheartj/ehi180.CrossRefPubMed

21.

Skali H, Schulman AR, Dorbala S. (18)F-FDG PET/CT for the assessment of myocardial sarcoidosis. Curr Cardiol Rep. 2013;15:352. doi:10.1007/s11886-013-0352-8.CrossRefPubMedCentral

22.

Morooka M, Moroi M, Uno K, Ito K, Wu J, Nakagawa T, et al. Long fasting is effective in inhibiting physiological myocardial 18F-FDG uptake and for evaluating active lesions of cardiac sarcoidosis. EJNMMI Res. 2014;4:1. doi:10.1186/2191-219X-4-1.CrossRefPubMedPubMedCentral

23.

Maurer AH, Burshteyn M, Adler LP, Gaughan JP, Steiner RM. Variable cardiac 18FDG patterns seen in oncologic positron emission tomography computed tomography: importance for differentiating normal physiology from cardiac and paracardiac disease. J Thorac Imaging. 2012;27:263–8. doi:10.1097/RTI.0b013e3182176675.CrossRefPubMed

24.

Kaneta T, Hakamatsuka T, Takanami K, Yamada T, Takase K, Sato A, et al. Evaluation of the relationship between physiological FDG uptake in the heart and age, blood glucose level, fasting period, and hospitalization. Ann Nucl Med. 2006;20:203–8.CrossRefPubMed

25.

Yokoyama R, Miyagawa M, Okayama H, Inoue T, Miki H, Ogimoto A, et al. Quantitative analysis of myocardial (18)F-fluorodeoxyglucose uptake by PET/CT for detection of cardiac sarcoidosis. Int J Cardiol. 2015;195:180–7. doi:10.1016/j.ijcard.2015.05.075.CrossRefPubMed

26.

Gormsen LC, Christensen NL, Bendstrup E, Tolbod LP, Nielsen SS. Complete somatostatin-induced insulin suppression combined with heparin loading does not significantly suppress myocardial 18F-FDG uptake in patients with suspected cardiac sarcoidosis. J Nucl Cardiol. 2013;20:1108–15. doi:10.1007/s12350-013-9798-8.CrossRefPubMed

27.

Thut DP, Ahmed R, Kane M, Djekidel M. Variability in myocardial metabolism on serial tumor (18)F-FDG PET/CT scans. Am J Nucl Med Mol Imaging. 2014;4:346–53.PubMedPubMedCentral

28.

Bartlett ML, Bacharach SL, Voipio-Pulkki LM, Dilsizian V. Artifactual inhomogeneities in myocardial PET and SPECT scans in normal subjects. J Nucl Med. 1995;36:188–95.PubMed

29.

Dweck MR, Jones C, Joshi NV, Fletcher AM, Richardson H, White A, et al. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation. 2012;125:76–86. doi:10.1161/CIRCULATIONAHA.111.051052.CrossRefPubMed

30.

Fujii H, Ide M, Yasuda S, Takahashi W, Shohtsu A, Kubo A. Increased FDG uptake in the wall of the right atrium in people who participated in a cancer screening program with whole-body PET. Ann Nucl Med. 1999;13:55–9.CrossRefPubMed

31.

Maurer AH, Burshteyn M, Adler LP, Steiner RM. How to differentiate benign versus malignant cardiac and paracardiac 18F FDG uptake at oncologic PET/CT. Radiographics. 2011;31:1287–305. doi:10.1148/rg.315115003.CrossRefPubMed

32.

Ahmadian A, Brogan A, Berman J, Sverdlov AL, Mercier G, Mazzini M, et al. Quantitative interpretation of FDG PET/CT with myocardial perfusion imaging increases diagnostic information in the evaluation of cardiac sarcoidosis. J Nucl Cardiol. 2014;21:925–39. doi:10.1007/s12350-014-9901-9.CrossRefPubMed

33.

Matsui Y, Iwai K, Tachibana T, Fruie T, Shigematsu N, Izumi T, et al. Clinicopathological study of fatal myocardial sarcoidosis. Ann N Y Acad Sci. 1976;278:455–69.CrossRefPubMed

34.

Darlington P, Gabrielsen A, Sorensson P, Cederlund K, Eklund A, Grunewald J. Cardiac involvement in Caucasian patients with pulmonary sarcoidosis. Respir Res. 2014;15:15. doi:10.1186/1465-9921-15-15.CrossRefPubMedPubMedCentral

35.

Okumura W, Iwasaki T, Toyama T, Iso T, Arai M, Oriuchi N, et al. Usefulness of fasting 18F-FDG PET in identification of cardiac sarcoidosis. J Nucl Med. 2004;45:1989–98.PubMed

36.

Kwekkeboom DJ, Krenning EP, Kho GS, Breeman WA, Van Hagen PM. Somatostatin receptor imaging in patients with sarcoidosis. Eur J Nucl Med. 1998;25:1284–92.CrossRefPubMed

37.

Lebtahi R, Crestani B, Belmatoug N, Daou D, Genin R, Dombret MC, et al. Somatostatin receptor scintigraphy and gallium scintigraphy in patients with sarcoidosis. J Nucl Med. 2001;42:21–6.PubMed

38.

Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012;61:6–32. doi:10.1136/gutjnl-2011-300831.CrossRefPubMed

39.

Lapa C, Reiter T, Li X, Werner RA, Samnick S, Jahns R, et al. Imaging of myocardial inflammation with somatostatin receptor based PET/CT—a comparison to cardiac MRI. Int J Cardiol. 2015;194:44–9. doi:10.1016/j.ijcard.2015.05.073.CrossRefPubMed

40.

Blankstein R, Osborne M, Naya M, Waller A, Kim CK, Murthy VL, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol. 2014;63:329–36. doi:10.1016/j.jacc.2013.09.022.CrossRefPubMed

41.

Li J, Fine J. On sample size for sensitivity and specificity in prospective diagnostic accuracy studies. Stat Med. 2004;23:2537–50. doi:10.1002/sim.1836.CrossRefPubMed

42.

Crouser ED, Ono C, Tran T, He X, Raman SV. Improved detection of cardiac sarcoidosis using magnetic resonance with myocardial T2 mapping. Am J Respir Crit Care Med. 2014;189:109–12. doi:10.1164/rccm.201309-1668LE.PubMedPubMedCentral

Title: A dual tracer 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT pilot study for detection of cardiac sarcoidosis
Authors: Lars C. Gormsen
Ate Haraldsen
Stine Kramer
Andre H. Dias
Won Yong Kim
Per Borghammer
Publication date: 01-12-2016
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2016
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-016-0207-6

At a glance: The STEP trials

Springer Medicine

A dual tracer ⁶⁸Ga-DOTANOC PET/CT and ¹⁸F-FDG PET/CT pilot study for detection of cardiac sarcoidosis

Abstract

Background

Methods

Results

Conclusions

Trial registration

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2016

Impact of fasting on 18F-fluorocholine gastrointestinal uptake and detection of lymph node metastases in patients with prostate cancer

Impact of clinically tested NEP/ACE inhibitors on tumor uptake of [111In-DOTA]MG11—first estimates for clinical translation

Reproducibility of 18F-fluoromisonidazole intratumour distribution in non-small cell lung cancer

Pharmacokinetic modeling of [18F]fluorodeoxyglucose (FDG) for premature infants, and newborns through 5-year-olds

Dependence of treatment planning accuracy in peptide receptor radionuclide therapy on the sampling schedule

Fractal and multifractal analysis of PET/CT images of metastatic melanoma before and after treatment with ipilimumab