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Published in: Annals of Surgical Oncology 3/2019

Open Access 01-03-2019 | Translational Research and Biomarkers

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

Authors: Adel Mahjoub, BA, Alejandro Morales-Restrepo, MD, Mitchell S. Fourman, MD, M.Phil, Jonathan B. Mandell, BA, Lu Feiqi, BA, Margaret L. Hankins, MD, Rebecca J. Watters, PhD, Kurt R. Weiss, MD

Published in: Annals of Surgical Oncology | Issue 3/2019

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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.
Literature
1.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
2.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
4.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
5.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
6.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
7.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
8.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
9.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
10.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
11.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
12.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
13.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
14.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
15.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
16.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
18.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
go back to reference Rochwerger A, Mattei JC. Management of soft tissue tumors of the musculoskeletal system. Orthop Traumatol Surg Res. 2018;104(1S):S9–S17.CrossRefPubMed Rochwerger A, Mattei JC. Management of soft tissue tumors of the musculoskeletal system. Orthop Traumatol Surg Res. 2018;104(1S):S9–S17.CrossRefPubMed
21.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
22.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
23.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
24.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
25.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
26.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
27.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
28.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
Metadata
Title
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
Authors
Adel Mahjoub, BA
Alejandro Morales-Restrepo, MD
Mitchell S. Fourman, MD, M.Phil
Jonathan B. Mandell, BA
Lu Feiqi, BA
Margaret L. Hankins, MD
Rebecca J. Watters, PhD
Kurt R. Weiss, MD
Publication date
01-03-2019
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 3/2019
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-018-07114-9

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