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αvβ3 imaging can accurately distinguish between mature teratoma and necrosis in 18F-FDG-negative residual masses after treatment of non-seminomatous testicular cancer: a preclinical study

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Abstract

Purpose

We assessed whether imaging αvβ3 integrin could distinguish mature teratoma from necrosis in human non-seminomatous germ cell tumour (NSGCT) post-chemotherapy residual masses.

Methods

Human embryonal carcinoma xenografts (six/rat) were untreated (controls) or treated to form mature teratomas with low-dose cisplatin and all-trans retinoic acid (ATRA) over a period of 8 weeks. In another group, necrosis was induced in xenografts with high-dose cisplatin plus etoposide (two cycles).18F-Fluorodeoxyglucose (18F-FDG) small animal positron emission tomography (SA PET) imaging was performed in three rats (one control and two treated for 4 and 8 weeks with cisplatin+ATRA). Imaging of αvβ3 expression was performed in six rats bearing mature teratomas and two rats with necrotic lesions on a microSPECT/CT device after injection of the tracer [99mTc]HYNIC-RGD [6-hydrazinonicotinic acid conjugated to cyclo(Arg-Gly-Asp-D-Phe-Lys)]. Correlative immunohistochemistry studies of human and mouse αvβ3 expression were performed.

Results

Cisplatin+ATRA induced differentiation of the xenografts. After 8 weeks, some glandular structures and mesenchymal cells were visible; in contrast, control tumours showed undifferentiated tissues. SA PET imaging showed that mature teratoma had very low avidity for 18F-FDG [mean standardised uptake value (SUVmean) = 0.48 ± 0.05] compared to untreated embryonal carcinoma (SUVmean = 0.92 ± 0.13) (p = 0.005). αvβ3 imaging accurately distinguished mature teratoma (tumour to muscle ratio = 4.29 ± 1.57) from necrosis (tumour to muscle ratio = 1.3 ± 0.26) (p = 0.0002). Immunohistochemistry studies showed that αvβ3 integrin expression was strong in the glandular structures of mature teratoma lesions and negative in host stroma.

Conclusion

Imaging αvβ3 integrin accurately distinguished mature teratoma from necrosis following cisplatin-based treatment in human NSGCT xenografts.

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References

  1. Kollmannsberger C, Honecker F, Bokemeyer C. Treatment of germ cell tumors–update 2006. Ann Oncol 2006;17 Suppl 10:x31–5.

    Article  PubMed  Google Scholar 

  2. De Santis M, Becherer A, Bokemeyer C, Stoiber F, Oechsle K, Sellner F, et al. 2-18Fluoro-deoxy-D-glucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric SEMPET trial. J Clin Oncol 2004;22:1034–9.

    Article  PubMed  Google Scholar 

  3. Hartmann JT, Schmoll HJ, Kuczyk MA, Candelaria M, Bokemeyer C. Postchemotherapy resections of residual masses from metastatic non-seminomatous testicular germ cell tumors. Ann Oncol 1997;8:531–8.

    Article  CAS  PubMed  Google Scholar 

  4. Krege S, Beyer J, Souchon R, Albers P, Albrecht W, Algaba F, et al. European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008;53:478–96.

    Article  PubMed  Google Scholar 

  5. Krege S, Beyer J, Souchon R, Albers P, Albrecht W, Algaba F, et al. European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II. Eur Urol 2008;53:497–513.

    Article  PubMed  Google Scholar 

  6. Hartmann JT, Candelaria M, Kuczyk MA, Schmoll HJ, Bokemeyer C. Comparison of histological results from the resection of residual masses at different sites after chemotherapy for metastatic non-seminomatous germ cell tumours. Eur J Cancer 1997;33:843–7.

    Article  CAS  PubMed  Google Scholar 

  7. Bourguet P, Blanc-Vincent MP, Boneu A, Bosquet L, Chauffert B, Corone C, et al. Summary of the standards, options and recommendations for the use of positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDP-PET scanning) in oncology (2002). Br J Cancer 2003;89 Suppl 1:S84–91.

    Article  PubMed  Google Scholar 

  8. Spermon JR, Geus-Oei LF, Kiemeney LA, Witjes JA, Oyen WJ. The role of (18)fluoro-2-deoxyglucose positron emission tomography in initial staging and re-staging after chemotherapy for testicular germ cell tumours. BJU Int 2002;89:549–56.

    Article  CAS  PubMed  Google Scholar 

  9. Sanchez D, Zudaire JJ, Fernandez JM, Lopez J, Arocena J, Sanz G, et al. 18F-fluoro-2-deoxyglucose-positron emission tomography in the evaluation of nonseminomatous germ cell tumours at relapse. BJU Int 2002;89:912–6.

    Article  CAS  PubMed  Google Scholar 

  10. Kollmannsberger C, Oechsle K, Dohmen BM, Pfannenberg A, Bares R, Claussen CD, et al. Prospective comparison of [18F]fluorodeoxyglucose positron emission tomography with conventional assessment by computed tomography scans and serum tumor markers for the evaluation of residual masses in patients with nonseminomatous germ cell carcinoma. Cancer 2002;94:2353–62.

    Article  PubMed  Google Scholar 

  11. Johns Putra L, Lawrentschuk N, Ballok Z, Hannah A, Poon A, Tauro A, et al. 18F-fluorodeoxyglucose positron emission tomography in evaluation of germ cell tumor after chemotherapy. Urology 2004;64:1202–7.

    Article  CAS  PubMed  Google Scholar 

  12. Hain SF, O’Doherty MJ, Timothy AR, Leslie MD, Harper PG, Huddart RA. Fluorodeoxyglucose positron emission tomography in the evaluation of germ cell tumours at relapse. Br J Cancer 2000;83:863–9. doi:10.1054/bjoc.2000.1389.

    Article  CAS  PubMed  Google Scholar 

  13. Cremerius U, Effert PJ, Adam G, Sabri O, Zimmy M, Wagenknecht G, et al. FDG PET for detection and therapy control of metastatic germ cell tumor. J Nucl Med 1998;39:815–22.

    CAS  PubMed  Google Scholar 

  14. Cao F, Li Z, Lee A, Liu Z, Chen K, Wang H, et al. Noninvasive de novo imaging of human embryonic stem cell-derived teratoma formation. Cancer Res 2009;69:2709–13. doi:10.1158/0008-5472.CAN-08-4122.

    Article  CAS  PubMed  Google Scholar 

  15. Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer 2002;2:91–100. doi:10.1038/nrc727 10.1038/nrc727.

    Article  PubMed  Google Scholar 

  16. Howe A, Aplin AE, Alahari SK, Juliano RL. Integrin signaling and cell growth control. Curr Opin Cell Biol 1998;10:220–31.

    Article  CAS  PubMed  Google Scholar 

  17. Hynes RO, Lively JC, McCarty JH, Taverna D, Francis SE, Hodivala-Dilke K, et al. The diverse roles of integrins and their ligands in angiogenesis. Cold Spring Harb Symp Quant Biol 2002;67:143–53.

    Article  CAS  PubMed  Google Scholar 

  18. Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994;79:1157–64. doi:10.1016/0092-8674(94)90007-8.

    Article  CAS  PubMed  Google Scholar 

  19. Carreiras F, Lehmann M, Sichel F, Marvaldi J, Gauduchon P, Le Talaer JY. Implication of the alpha v beta 3 integrin in the adhesion of the ovarian-adenocarcinoma cell line IGROV1. Int J Cancer 1995;63:530–6.

    Article  CAS  PubMed  Google Scholar 

  20. Carreiras F, Thiébot B, Leroy-Dudal J, Maubant S, Breton MF, Darbeida H. Involvement of alphavbeta 3 integrin and disruption of endothelial fibronectin network during the adhesion of the human ovarian adenocarcinoma cell line IGROV1 on the human umbilical vein cell extracellular matrix. Int J Cancer 2002;99:800–8. doi:10.1002/ijc.1043310.1002/ijc.10433.

    Article  CAS  PubMed  Google Scholar 

  21. Decristoforo C, Santos I, Pietzsch HJ, Kuenstler JU, Duatti A, Smith CJ, et al. Comparison of in vitro and in vivo properties of [99mTc]cRGD peptides labeled using different novel Tc-cores. Q J Nucl Med Mol Imaging 2007;51:33–41.

    CAS  PubMed  Google Scholar 

  22. Janssen M, Oyen WJ, Massuger LF, Frielink C, Dijkgraaf I, Edwards DS, et al. Comparison of a monomeric and dimeric radiolabeled RGD-peptide for tumor targeting. Cancer Biother Radiopharm 2002;17:641–6. doi:10.1089/10849780232097024410.1089/108497802320970244.

    Article  CAS  PubMed  Google Scholar 

  23. Jung KH, Lee KH, Paik JY, Ko BH, Bae JS, Lee BC, et al. Favorable biokinetic and tumor-targeting properties of 99mTc-labeled glucosamino RGD and effect of paclitaxel therapy. J Nucl Med 2006;47:2000–7.

    CAS  PubMed  Google Scholar 

  24. Sancey L, Ardisson V, Riou LM, Ahmadi M, Marti-Batlle D, Boturyn D, et al. In vivo imaging of tumour angiogenesis in mice with the alpha(v)beta (3) integrin-targeted tracer 99mTc-RAFT-RGD. Eur J Nucl Med Mol Imaging 2007;34:2037–47. doi:10.1007/s00259-007-0497-z10.1007/s00259-007-0497-z.

    Article  CAS  PubMed  Google Scholar 

  25. Su ZF, Liu G, Gupta S, Zhu Z, Rusckowski M, Hnatowich DJ. In vitro and in vivo evaluation of a technetium-99m-labeled cyclic RGD peptide as a specific marker of alpha(V)beta(3) integrin for tumor imaging. Bioconjug Chem 2002;13:561–70. doi:10.1021/bc0155566.

    Article  CAS  PubMed  Google Scholar 

  26. Ahmadi M, Sancey L, Briat A, Riou L, Boturyn D, Dumy P, et al. Chemical and biological evaluations of an (111)In-labeled RGD-peptide targeting integrin alpha(V) beta(3) in a preclinical tumor model. Cancer Biother Radiopharm 2008;23:691–700. doi:10.1089/cbr.2008.0528.

    Article  CAS  PubMed  Google Scholar 

  27. Haubner R, Beer AJ, Wang H, Chen X. Positron emission tomography tracers for imaging angiogenesis. Eur J Nucl Med Mol Imaging 2010;37 Suppl 1:S86–103. doi:10.1007/s00259-010-1503-4.

    Article  PubMed  Google Scholar 

  28. Andrews PW, Damjanov I, Simon D, Banting GS, Carlin C, Dracopoli NC, et al. Pluripotent embryonal carcinoma clones derived from the human teratocarcinoma cell line Tera-2. Differentiation in vivo and in vitro. Lab Invest 1984;50:147–62.

    CAS  PubMed  Google Scholar 

  29. Aide N, Poulain L, Briand M, Dutoit S, Allouche S, Labiche A, et al. Early evaluation of the effects of chemotherapy with longitudinal FDG small-animal PET in human testicular cancer xenografts: early flare response does not reflect refractory disease. Eur J Nucl Med Mol Imaging 2009;36:396–405. doi:10.1007/s00259-008-0984-x10.1007/s00259-008-0984-x.

    Article  CAS  PubMed  Google Scholar 

  30. Rosset A, Spadola L, Ratib O. OsiriX: an open-source software for navigating in multidimensional DICOM images. J Digit Imaging 2004;17:205–16. doi:10.1007/s10278-004-1014-610.1007/s10278-004-1014-6.

    Article  PubMed  Google Scholar 

  31. Kieffer N, Phillips DR. Platelet membrane glycoproteins: functions in cellular interactions. Annu Rev Cell Biol 1990;6:329–57.

    Article  CAS  PubMed  Google Scholar 

  32. Lutke Holzik MF, Hoekstra HJ, Mulder NH, Suurmeijer AJ, Sleijfer DT, Gietema JA. Non-germ cell malignancy in residual or recurrent mass after chemotherapy for nonseminomatous testicular germ cell tumor. Ann Surg Oncol 2003;10:131–5.

    Article  PubMed  Google Scholar 

  33. Aide N, Comoz F, Sevin E. Enlarging residual mass after treatment of a nonseminomatous germ cell tumor: growing teratoma syndrome or cancer recurrence? J Clin Oncol 2007;25:4494–6.

    Article  PubMed  Google Scholar 

  34. Spiess PE, Kassouf W, Brown GA, Kamat AM, Liu P, Gomez JA, et al. Surgical management of growing teratoma syndrome: the M. D. Anderson cancer center experience. J Urol 2007;177:1330–4.

    Article  PubMed  Google Scholar 

  35. Mizutani Y, Sato N, Kawauchi A, Nonomura N, Fukushima M, Miki T. Cisplatin-induced in vivo differentiation of human embryonal carcinoma. BJU Int 2002;89:454–8.

    Article  CAS  PubMed  Google Scholar 

  36. Wouda S, Timmer B, Mulder NH, Dam A, Koudstaal J, Oosterhuis JW. Retinoic acid and cisdiaminodichloroplatinum in the treatment of murine teratocarcinomas in vivo in a nullipotent model. J Immunother Emphasis Tumor Immunol 1993;13:261–6.

    CAS  PubMed  Google Scholar 

  37. Oosterhuis JW, Suurmeyer AJ, Sleyfer DT, Koops HS, Oldhoff J, Fleuren G. Effects of multiple-drug chemotherapy (cis-diammine-dichloroplatinum, bleomycin, and vinblastine) on the maturation of retroperitoneal lymph node metastases of nonseminomatous germ cell tumors of the testis. No evidence for de novo induction of differentiation. Cancer 1983;51:408–16.

    Article  CAS  PubMed  Google Scholar 

  38. Hong WK, Wittes RE, Hajdu ST, Cvitkovic E, Whitmore WF, Golbey RB. The evolution of mature teratoma from malignant testicular tumors. Cancer 1977;40:2987–92.

    Article  CAS  PubMed  Google Scholar 

  39. Castedo SM, de Jong B, Oosterhuis JW, Idenburg VJ, Seruca R, Buist J, et al. Chromosomal changes in mature residual teratomas following polychemotherapy. Cancer Res 1989;49:672–6.

    CAS  PubMed  Google Scholar 

  40. Reinhardt MJ, Müller-Mattheis VG, Gerharz CD, Vosberg HR, Ackermann R, Müller-Gärtner HW. FDG-PET evaluation of retroperitoneal metastases of testicular cancer before and after chemotherapy. J Nucl Med 1997;38:99–101.

    CAS  PubMed  Google Scholar 

  41. Pfannenberg C, Aschoff P, Dittmann H, Mayer F, Reischl G, von Weyhern C, et al. PET/CT with 18F-FLT: does it improve the therapeutic management of metastatic germ cell tumors? J Nucl Med 2010;51:845–53.

    Article  PubMed  Google Scholar 

  42. Connor S, Guest P. Conversion of multiple solid testicular teratoma metastases to fatty and cystic liver masses following chemotherapy: CT evidence of “maturation”. Br J Radiol 1999;72:1114–6.

    CAS  PubMed  Google Scholar 

  43. Panicek DM, Toner GC, Heelan RT, Bosl GJ. Nonseminomatous germ cell tumors: enlarging masses despite chemotherapy. Radiology 1990;175:499–502.

    CAS  PubMed  Google Scholar 

  44. Stomper PC, Jochelson MS, Garnick MB, Richie JP. Residual abdominal masses after chemotherapy for nonseminomatous testicular cancer: correlation of CT and histology. AJR Am J Roentgenol 1985;145:743–6.

    CAS  PubMed  Google Scholar 

  45. Carver BS, Bianco FJ Jr., Shayegan B, Vickers A, Motzer RJ, Bosl GJ, et al. Predicting teratoma in the retroperitoneum in men undergoing post-chemotherapy retroperitoneal lymph node dissection. J Urol 2006;176:100–3. doi:10.1016/S0022-5347(06)00508-8; discussion 103–4.

    Article  PubMed  Google Scholar 

  46. Sugawara Y, Zasadny K, Grossman HB, Francis IR, Clarke MF, Wahl RL. Germ cell tumor: differentiation of viable tumor, mature teratoma, and necrotic tissue with FDG PET and kinetic modeling. Radiology 1999;211:249–55.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a grant from the French Ligue contre le cancer, comités du Calvados et de l’Orne. The Inveon small animal PET scanner was purchased with grants from the Association pour le recherche sur la cancer (ARC), the Région Basse Normandie and funds from the François Baclesse Comprehensive cancer centre. The αvβ3 microSPECT/CT studies were supported by a grant from GEFLUC - Rouen.

The authors wish to thank Prof. Joseph Wu from Stanford University, CA and Dr. Shawn Chen from the Laboratory for Molecular Imaging and Nanomedicine, Bethesda, MD for helpful advice regarding the blocking experiments in αvβ3 imaging.

Maïa and Théo Aide are thanked for their help during manuscript editing.

Dr. Aide is indebted to Prof. Rodney J Hicks from the Centre for Molecular Imaging, East Melbourne, Australia, for his fruitful comments at the initiation of this work and for his critical review of the manuscript.

Conflicts of interest

None.

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Authors and Affiliations

  1. Bioticla Team, EA1772, IFR 146 ICORE, GRECAN, François Baclesse Cancer Centre and Caen University, Caen, France

    Nicolas Aide, Mélanie Briand, Soizic Dutoit, Edwiges Deslandes & Laurent Poulain

  2. PET Unit, Caen University Hospital and François Baclesse Cancer Centre, Caen, France

    Nicolas Aide & Charline Lasnon

  3. Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital and QuantIF- LITIS (EA4108), Rouen, France

    Pierre Bohn, Jean Rouvet, Romain Modzelewski & Pierre Vera

  4. Pathology Department, François Baclesse Cancer Centre and Caen University, Caen, France

    Jacques Chasle

  5. Radiophysics Unit, François Baclesse Cancer Centre and Caen University, Caen, France

    Antony Vela

  6. ERRMECe, EA 1391, Institut des matériaux, Université de Cergy Pontoise, UFR Sciences et Techniques, Cergy-Pontoise, France

    Franck Carreiras

  7. Service de Médecine Nucléaire, Centre François Baclesse, Avenue Général Harris, 14000, Caen, France

    Nicolas Aide

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  1. Nicolas Aide
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Aide, N., Briand, M., Bohn, P. et al. αvβ3 imaging can accurately distinguish between mature teratoma and necrosis in 18F-FDG-negative residual masses after treatment of non-seminomatous testicular cancer: a preclinical study. Eur J Nucl Med Mol Imaging 38, 323–333 (2011). https://doi.org/10.1007/s00259-010-1624-9

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