Tumor Resection Guided by Intraoperative Indocyanine Green Dye Fluorescence Angiography Results in Negative Surgical Margins and Decreased Local Recurrence in an Orthotopic Mouse Model of Osteosarcoma

Adel Mahjoub, Alejandro Morales-Restrepo, Mitchell S Fourman, Jonathan B Mandell, Lu Feiqi, Margaret L Hankins, Rebecca J Watters, Kurt R Weiss, Adel Mahjoub, Alejandro Morales-Restrepo, Mitchell S Fourman, Jonathan B Mandell, Lu Feiqi, Margaret L Hankins, Rebecca J Watters, Kurt R Weiss

Abstract

Background: Surgical resection with negative margins is the foundation of extremity sarcoma management. Failure to achieve negative surgical margins can result in local recurrence (LR), a potentially devastating complication. Indocyanine green (ICG) is a US FDA-approved fluorophore previously used to guide carcinoma resections. We investigated the potential of ICG as an intraoperative guide during experimental sarcoma resection.

Methods: Fifty 6-week-old immunocompetent Balb/c female mice received left proximal tibia paraphyseal injections of 5 × 105 K7M2 murine osteosarcoma cells. Animals were separated into two groups (n = 25 each): (1) ICG-assisted surgical resection; and (2) no ICG-assisted resection. Resections were performed 4 weeks after primary tumor engraftment. All animals received 7.5 ug ICG via retro-orbital injection 12 h prior to surgery. ICG fluorescence measurements and clinical evaluations were performed 4 weeks after resection to detect LR.

Results: Eleven of 25 animals from each group developed gross tumors. Four weeks after resection, group 1 had 0/11 tumor recurrences, while group 2 had recurrences in 9/11 (81.8%) experimental mice (p < 0.0002) (Fig. 2). There was a 100% NPV in group 1, and no tumor recurrence with fluorescence-free margins after the primary surgery. Group 2 had a 100% positive predictive value for the development of an LR if any fluorescent signal was present at the surgical margin after resection.

Conclusion: Intraoperative ICG guidance led to reliably negative surgical margins and a diminished LR rate. Given the benign safety profile of ICG and its prior clinical success, these results could be immediately translatable to the clinical realm.

Figures

Fig. 1
Fig. 1
Stepwise removal of positive tumor margins under indocyanine-green guidance. a Preoperative fluorescent image is seen using near infra-red. Fluorescent signal is seen in the left proximal hind limb (circled). b Positive fluorescent signal remains in the left proximal hind limb after initial resection. c No area of fluorescence left behind in the left proximal hind limb. A clear surgical margin can be seen, with no fluorescence in the resected left proximal hind limb (circled)
Fig. 2
Fig. 2
Residual tumor remains in the non-ICG-guided tumor resection at the end of surgery. a Preoperative fluorescent image shows a positive fluorescent signal in the left hind limb. b Non-ICG-guided resection shows a positive fluorescent signal in the residual left hind limb at the end of surgery. ICG indocyanine-green
Fig. 3
Fig. 3
Local recurrence assessed 4 weeks postoperatively after primary sarcoma resection of the left proximal hind limb with and without ICG guidance. a ICG-guided resection with no local recurrence and lack of fluorescent signal at the residual left proximal hind limb (circled). b Non-ICG-guided resection shows local recurrence with positive fluorescent signal at the residual left proximal hind limb (circled red). ICG indocyanine-green

References

    1. Jeys LM, Thorne CJ, Parry M, Gaston CLL, Sumathi VP, Grimer JR. A novel system for the surgical staging of primary high-grade osteosarcoma: the Birmingham classification. Clin Orthop Relat Res. 2017;475(3):842–850. doi: 10.1007/s11999-016-4851-y.
    1. O’Donnell PW, Griffin AM, Eward WC, Sternheim A, Catton CN, Chung PW, et al. The effect of the setting of a positive surgical margin in soft tissue sarcoma. Cancer. 2014;120(18):2866–2875. doi: 10.1002/cncr.28793.
    1. Bertrand TE, Cruz A, Binitie O, Cheong D, Letson GD. Do Surgical Margins Affect Local Recurrence and Survival in Extremity, Nonmetastatic, High-grade Osteosarcoma? Clin Orthop Relat Res. 2016;474(3):677–683. doi: 10.1007/s11999-015-4359-x.
    1. Gronchi A, Casali PG, Mariani L, Miceli R, Fiore M, Lo Vullo S, et al. Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: a series of patients treated at a single institution. J Clin Oncol. 2005;23(1):96–104. doi: 10.1200/JCO.2005.04.160.
    1. Hasley I, Gao Y, Blevins AE, Miller BJ. The significance of a “close” margin in extremity sarcoma: a systematic review. Iowa Orthop J. 2018;38:123–130.
    1. Lemeur M, Mattei JC, Souteyrand P, Chagnaud C, Curvale G, Rochwerger A. Prognostic factors for the recurrence of myxoid liposarcoma: 20 cases with up to 8 years follow-up. Orthop Traumatol Surg Res. 2015;101(1):103–107. doi: 10.1016/j.otsr.2014.09.024.
    1. Maretty-Nielsen K, Aggerholm-Pedersen N, Safwat A, Jørgensen PH, Hansen BH, Baerentzen S, et al. Prognostic factors for local recurrence and mortality in adult soft tissue sarcoma of the extremities and trunk wall: a cohort study of 922 consecutive patients. Acta Orthop. 2014;85(3):323–332. doi: 10.3109/17453674.2014.908341.
    1. Salipas A, Dowsey MM, May D, Choong PFM. ‘Beware the lump in the foot!’: predictors of recurrence and survival in bone and soft-tissue sarcomas of the foot and ankle. ANZ J Surg. 2014;84(7–8):533–538. doi: 10.1111/ans.12593.
    1. Talleur AC, Navid F, Spunt SL, McCarville MB, Wu J, Mao S, et al. Limited margin radiation therapy for children and young adults with ewing sarcoma achieves high rates of local tumor control. Int J Radiat Oncol Biol Phys. 2016;96(1):119–126. doi: 10.1016/j.ijrobp.2016.04.001.
    1. Daigeler A, Zmarsly I, Hirsch T, Goertz O, Steinau HU, Lehnhardt M, et al. Long-term outcome after local recurrence of soft tissue sarcoma: a retrospective analysis of factors predictive of survival in 135 patients with locally recurrent soft tissue sarcoma. Br J Cancer. 2014;110(6):1456–1464. doi: 10.1038/bjc.2014.21.
    1. Charoenlap C, Imanishi J, Tanaka T, Slavin J, Ngan SY, Chander S, et al. Outcomes of unplanned sarcoma excision: impact of residual disease. Cancer Med. 2016;5(6):980–988. doi: 10.1002/cam4.615.
    1. Takeuchi A, Lewis VO, Satcher RL, Moon BS, Lin PP. What are the factors that affect survival and relapse after local recurrence of osteosarcoma? Clin Orthop Relat Res. 2014;472(10):3188–3195. doi: 10.1007/s11999-014-3759-7.
    1. Loh AHP, Navid F, Wang C, Bahrami A, Wu J, Neel MD, et al. Management of local recurrence of pediatric osteosarcoma following limb-sparing surgery. Ann Surg Oncol. 2014;21(6):1948–1955. doi: 10.1245/s10434-014-3550-8.
    1. Nystrom LM, Reimer NB, Reith JD, Scarborough MT, Gibbs CP. The treatment and outcomes of extraskeletal osteosarcoma: institutional experience and review of the literature. Iowa Orthop J. 2016;36:98–103.
    1. Fourman MS, Mahjoub A, Mandell JB, Yu S, Tebbets JC, Crasto JA, et al. Quantitative primary tumor indocyanine green measurements predict osteosarcoma metastatic lung burden in a mouse model. Clin Orthop Relat Res. 2018;476(3):479–487. doi: 10.1007/s11999.0000000000000003.
    1. Fourman MS, McKenna P, Phillips BT, Crawford L, Romanelli F, Lin F, et al. ICG angiography predicts burn scarring within 48 h of injury in a porcine vertical progression burn model. Burns. 2015;41(5):1043–1048. doi: 10.1016/j.burns.2014.11.001.
    1. Lieto E, Galizia G, Cardella F, Mabilia A, Basile N, Castellano P, et al. Indocyanine Green Fluorescence Imaging-Guided Surgery in Primary and Metastatic Liver Tumors. Surg Innov. 2018;25(1):62–68. doi: 10.1177/1553350617751451.
    1. Crasto JA, Fourman MS, Morales-Restrepo A, Mahjoub A, Mandell JB, Ramnath K, et al. Disulfiram reduces metastatic osteosarcoma tumor burden in an immunocompetent Balb/c or-thotopic mouse model. Oncotarget. 2018;9(53):30163–30172. doi: 10.18632/oncotarget.25733.
    1. Cartiaux O, Docquier P-L, Paul L, Francq BG, Cornu OH, Delloye C, et al. Surgical inaccuracy of tumor resection and reconstruction within the pelvis: an experimental study. Acta Orthop. 2008;79(5):695–702. doi: 10.1080/17453670810016731.
    1. Rochwerger A, Mattei JC. Management of soft tissue tumors of the musculoskeletal system. Orthop Traumatol Surg Res. 2018;104(1S):S9–S17. doi: 10.1016/j.otsr.2017.05.031.
    1. Saeed H, King DM, Johnstone CA, Charlson JA, Hackbarth DA, Neilson JC, et al. Preoperative Radiation Therapy Followed by Reexcision May Improve Local Control and Progression-Free Survival in Unplanned Excisions of Soft Tissue Sarcomas of the Extremity and Chest-Wall. Int J Surg Oncol. 2016;2016:5963167.
    1. Tan MCB, Brennan MF, Kuk D, Agaram NP, Antonescu CR, Qin L-X, et al. Histology-based Classification Predicts Pattern of Recurrence and Improves Risk Stratification in Primary Retroperitoneal Sarcoma. Ann Surg. 2016;263(3):593–600. doi: 10.1097/SLA.0000000000001149.
    1. Willeumier JJ, Rueten-Budde AJ, Jeys LM, Laitinen M, Pollock R, Aston W, et al. Individualised risk assessment for local recurrence and distant metastases in a retrospective transatlantic cohort of 687 patients with high-grade soft tissue sarcomas of the extremities: a multistate model. BMJ Open. 2017;7(2):e012930. doi: 10.1136/bmjopen-2016-012930.
    1. Xu J, Li D, Xie L, Tang S, Guo W. Mesenchymal chondrosarcoma of bone and soft tissue: a systematic review of 107 patients in the past 20 years. PLoS One. 2015;10(4):e0122216. doi: 10.1371/journal.pone.0122216.
    1. Zhao R-P, Yu X-L, Zhang Z, Jia L-J, Feng Y, Yang Z-Z, et al. The efficacy of postoperative radiotherapy in localized primary soft tissue sarcoma treated with conservative surgery. Radiat Oncol. 2016;11:25. doi: 10.1186/s13014-016-0605-y.
    1. Gronchi A, Stacchiotti S, Verderio P, Ferrari S, Martin Broto J, Lopez-Pousa A, et al. Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. Ann Oncol. 2016;27(12):2283–2288. doi: 10.1093/annonc/mdw430.
    1. Dürr HR, Rauh J, Baur-Melnyk A, Knösel T, Lindner L, Roeder F, et al. Myxoid liposarcoma: local relapse and metastatic pattern in 43 patients. BMC Cancer. 2018;18(1):304. doi: 10.1186/s12885-018-4226-8.
    1. Ducimetière F, Lurkin A, Ranchère-Vince D, Decouvelaere A-V, Péoc’h M, Istier L, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294. doi: 10.1371/journal.pone.0020294.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera