Table 4 Patient characteristics and outcome summary of clinical studies.

From: The strategy and clinical relevance of in vitro models of MAP resistance in osteosarcoma: a systematic review

Reference	Year	Study location	Age	Gender (F:M)	Sample characteristics	Patient characteristics	Treatment	Sample number	Sample type	Expression analysed	Method	Outcome measure	P<0.05
[75]	1995	Italy	47% ≤14, 53% 15-39	1.04: 1	Stage IIA-IIB, High grade	ND, NM, Op, EOS	hdMAP	92	PRE	↑PGP, ATP-dependent efflux protein	IHC	Necrosis	No
[83]	1999	Italy	54% ≤14, 46% >14	1: 1.18	Grade III-IV, Mixed subtype	ND, NM, Op, EOS	Post-op DOX	37	PRE	↑PGP, ATP-dependent efflux protein	IHC	Relapse	Yes
[84]	2020	China	53% <18, 47% ≥18	1: 1.4	Stage IIA-IIB, Mixed subtype	ND, NM, Op, EOS	hdMAP	72	PRE	↓Circ-LARP4, gene regulation, miR-424 sponge	qPCR	Necrosis	Yes
[76]	2003	Israel	15-67	Mixed	Matched	EOS	hdMAP	6	PRE vs R	↑MRP1, ATP-dependent efflux protein	WB	Relapse	No
			15-67	Mixed	Matched			6		↑RFC, MTX entry			No
			11-81	1: 2.1	Mixed subtype			20		↑MRP1, ATP-dependent efflux protein			No
				1: 2.1				20		↑RFC, MTX entry			Yes
				1: 2				9	PRE	↓RFC1, MTX entry		Necrosis	Yes
[74]	2021	Japan	<21	1: 2.83	High grade, Mixed subtype	EOS	MAPi	24	PRE	↑CDK4, Cell cycle regulator	qRT-PCR	Necrosis	Yes
[85]	2016	Japan	Mean 15, 10-25	1: 1	Osteoblastic	EOS	MAP	8	PRE	↑miR-100, Post-transcriptional gene regulation	qRT-PCR	Necrosis	Yes
										↑miR-125b, Post-transcriptional gene regulation			Yes
										↑miR-483-3p, Post-transcriptional gene regulation			No
										↑miR-124, Post-transcriptional gene regulation			No
										↑miR-127-3p, Post-transcriptional gene regulation			No
										↓miR-887, Post-transcriptional gene regulation			No
			Mean 14, 9-22	1: 1.22	Mixed subtype			20		↑miR-125b, Post-transcriptional gene regulation			Yes
			Mean 14, 9-22	1: 1.22	Mixed subtype			20		↑miR-100, Post-transcriptional gene regulation			Yes
[28]	2001	China	Mean 18, 4-16	–	Stage II-B	–	hdMAP	45	PRE	↑PGP, ATP-dependent efflux protein	IHC	Necrosis	No
[28]	2001	China	Mean 18, 4-16	–	Stage II-B	–	hdMAP	45	POST	↑PGP, ATP-dependent efflux protein	IHC	Necrosis	Yes
[86]	2018	China	Matched	1: 1	Stage matched	–	MAP	42	POST	↓miR-377, Post-transcriptional gene regulation, Targets apoptosis regulator XIAP	RT-PCR	Necrosis	Yes
[77]	2009	Iran	20% ≤12, 80% 13-39	1: 2.33	Stage IIB, High grade, Mixed subtype	ND, NM, Op, EOS	hdMAPi	30	PRE	↑PGP, ATP-dependent efflux protein	IHC	Relapse	Yes
[77]	2009	Iran	20% ≤12, 80% 13-39	1: 2.33	Stage IIB, High grade, Mixed subtype	ND, NM, Op, EOS	hdMAPi	15	PRE	↑PGP, ATP-dependent efflux protein	IHC	Necrosis	No
[36]	2008	Italy	<40	–	High grade	ND, NM, EOS, COS	hdMAPi	61	PRE	↑DHFR, Folate metabolism	IHC	Relapse	No
										↑DHFR, Folate metabolism			Yes
										↑c-MYC, Transcription factor			Yes
										↑c-MYC, Transcription factor		Necrosis	No
										↑PGP, ATP-dependent efflux protein			No
										↑PGP, ATP-dependent efflux protein			No
[78]	1995	Italy	–	–	Grade III-IV, Mixed subtype	NM, Op, EOS	hdMAPi	36	–	↑PGP, ATP-dependent efflux protein	SQ-IF	Necrosis	No
[79]	2003	Italy	24% ≤12, 76% 13-39	1: 1	High grade, Mixed subtype	ND, NM, Op, EOS	hdMAP	149	PRE	↑PGP, ATP-dependent efflux protein	IHC	Relapse	Yes
[79]	2003	Italy	24% ≤12, 76% 13-39	1: 1	High grade, Mixed subtype	ND, NM, Op, EOS	hdMAP	149	PRE	↑PGP, ATP-dependent efflux protein	IHC	Necrosis	No
[80]	2006	Italy	19% ≤12, 81% 13-39	1 : 1.56	High grade, Mixed subtype	ND, NM, Op, EOS, COS	hdMAPi	94	PRE	↑PGP, ATP-dependent efflux protein	IHC	Necrosis	No
[80]	2006	Italy	19% ≤12, 81% 13-39	1 : 1.56	High grade, Mixed subtype	ND, NM, Op, EOS, COS	hdMAPi	94	PRE	↑PGP, ATP-dependent efflux protein	IHC	Relapse	Yes
[48]	2021	China	50% ≤20, 50% >20	1.13: 1	Grade I-III, Mixed subtype	–	MAP	68	POST	↑ABCG2, ATP-dependent efflux protein	IHC	Necrosis	Yes
[26]	1997	Japan	Mean 16.2, 5-30	1: 1.5	Stage IIA-III, Grade III-IV, Mixed subtype	EOS	hdMAPi	54	PRE	↑MT, Zinc binding protein	IHC	Necrosis	No
										↑GST, Glutathione transferase			No
										↑HSP27, Chaperone protein			No
										↑LRP, Co-receptor for Wnt pathway			No
								60	POST	↑MT, Zinc binding protein			Yes
										↑GST, Glutathione transferase			Yes
										↑HSP27, Chaperone protein			Yes
										↑LRP, Co-receptor for Wnt pathway			Yes
[81]	2017	China	66% ≤20, 44% >20	1: 1.71	Stage I-IV	Op, EOS	hdMAPi	133	–	↑PTN, Growth factor, Regulates PGP expression via ALK/GSK3β/β-catenin pathway	IHC	Local relapse	Yes
												Necrosis	Yes
												Lung metastasis	No
[82]	2014	China	Mean 9.6, 7-14, Matched	1: 1	Stage IIA-III, Matched	Op, EOS	hdMAP	12	POST	↓TWIST-1, Transcription factor	WB	Necrosis	Yes
			6-16	1: 1.7	Stage IIA-III			70		↑miR-33a, Post-transcriptional gene regulation, Downregulates TWIST1	qRT-PCR		Yes
			6-16	1: 1.7	Stage IIA-III			70		↓TWIST-1, Transcription factor	WB		Yes
[87]	2018	China	70% <25, 30% ≥ 25	1: 1.43	Stage I-III	Op	MAPi	80	–	↑circPVT1, Gene regulation, Regulator of PGP expression	qRT-PCR	Necrosis	Yes
[87]	2018	China	70% <25, 30% ≥ 25	1: 1.43	Stage I-III	Op	MAPi	80	–	↑circPVT1, Gene regulation, Regulator of PGP expression	qRT-PCR	Lung metastasis	Yes

Data was extracted from clinical studies included in this review. Treatment is shown for neoadjuvant regimen unless otherwise stated. Doses of each drug and number of cycles may vary and were not recorded. Due to variability in reporting patient age is recorded as mean with range, % in each age group, matched or < or >. The common function of each resistance factor is indicated in italics with any proposed functions as listed in each study recorded after. (Pro) Prospective, (Ret) Retrospective, (ND) Newly diagnosed, (NM) Non-metastatic, (Op) Operable, (EOS) extremity OS, (COS) central OS, (PRE) Pre-treatment, (R) Relapsed, (POST) Post-treatment, (IHC) Immunohistochemistry, (SQ-IF) Semi-quantitative immunofluorescence, (WB) Western blot, (–) Not clearly stated.

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Table 4 Patient characteristics and outcome summary of clinical studies.

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