The prognostic role of NK cells and their ligands in squamous cell carcinoma of the head and neck: a systematic review and meta-analysis

Figures & data

Figure 1. Flow chart of the 3520 articles initially selected, 49 were included after full-text screening. (Moher et al. 2009. prisma flow chart).^98.

Table 1. Quality assessment of the classical marker studies. Total bias score excluded study attrition

Study	Study participation	Study attrition	Prognostic factor measurement	Outcome measurement	Study confounding	Statistical analysis and reporting	Total Bias score
Lazaris 2009	2	2	1	0	0	2	5
Zancope 2010	0	2	1	0	2	1	4
Fraga 2011	0	2	0	2	0	0	2
Sakakura 2014	0	2	0	0	2	2	4
Wagner 2015	0	2	0	0	0	0	0
Stangl 2016	0	2	0	0	0	0	0
Taghavi 2016	1	2	0	0	2	0	3
Fang 2017	1	2	0	0	1	0	2
Kartpathiou 2017	0	2	0	0	0	2	2
Maciel 2017	1	2	0	0	2	0	3
Stasikowska 2017	2	2	2	2	1	0	7
Schoenfeld 2018	0	2	0	0	2	0	2
Santos 2019	0	2	0	2	0	0	2

Figure 2. Forest plot of prognostic value of CD56+/CD57+ NK cells on overall survival; high CD56/CD57 cell count correlated with better overall survival (HR 0.19, CI 0.11–0.35). (RevMan 2014).^99.

Table 2. The outcomes of activating and inhibiting marker studies are summarized based on high expression of the markers in question. Oral Cavity (OC), Oropharynx (OP), Hypopharynx (HP), Larynx (L), Lip (Lip), Tongue (T). Overall survival (OS), Disease-free survival (DFS), Progression-free survival (PFS), Distant metastasis-free survival (DMFS), Disease-specific survival (DSS), Local recurrence (LR), Local-regional control (LRC)

Marker (High expression)	Study	Sample Size	Subsite	Outcome
NKP46	Ikeda 2017	41	OC	No correlation with survival or characteristics
	Ladanyi 2018	50	OP, HP, L, OC	Low grade tumors
CD70	De Meulenaere 2016	95	OP, HP, L, OC	Poorly differentiated carcinomas, Lower density TIL’s
CEACAM1	Shinozuka 2009	78	OC	High expression in T1 and T2 groups, Early stage disease, Better OS and DFS
	Wang 2013	74	T	High clinical stage, Lymph node metastasis
	Lucarini 2018	54	L	High tumor grade, LR, Lymph node- and distant metastasis
	Simonetti 2018	40	OC	Worse OS, Worse DSS, High tumor grade
RCAS1	Dutsch Wicherek 2009	102	OP, HP, L	High tumor grade, Lymph node metastasis

Table 3. The outcomes of death receptor studies are summarized based on high expression of the markers in question. Oral Cavity (OC), Oropharynx (OP), Hypopharynx (HP), Larynx (L), Lip (Lip), Tongue (T). Overall survival (OS), Disease-free survival (DFS), Progression-free survival (PFS), Distant metastasis-free survival (DMFS), Disease-specific survival (DSS), Local recurrence (LR), Local-regional control (LRC)

Marker (High expression)	Study	Sample Size	Subsite	Outcome
Fas and Fas-L	Fuijeda 2000	58	OC, OP	No correlation with T stage, N stage, clinical stage, LR, OS, DFS
	Guler 2005	26	OC, OP	High clinical stage
	Tsuzuki 2005	58	OP	No correlation with OS
	De Carvalho-Neto 2013	60	OC	Fas: Negative lymph nodes, better DSS Fas- L: Worse DFS
Fas	Bayazit 2000	30	L	No correlation with T stage, N stage, Tumor grade, Tumor site
	Muraki 2000	46	OC	Better OS, Absence of LR, lower clinical stage.
	Jackel 2001	88	L	No correlation with OS, DSS or clinicopathologic parameters
	Asensio 2007	45	L	Better survival
Fas-L	Reichert 2002	28	OC	No correlation with T -or N stage
	Das 2011	41	OC	High clinical stage, higher T and N stage (not statistically significant)
	Fang 2013	38	OC	Lymph node metastasis
	Peterle 2015	64	OC	Fas-L expression in lymphoid cells correlated with lymph node metastasis, low DFS and low DSS
FADD	Prapinjumrune 2009	60	T	Cervical lymph node metastasis, Worse DSS
	Schrijvers 2011	92	L	Trend toward better LRC, No correlation with OS or clinicopathologic parameters
	Rasamny 2012	222	OP, OC, HP, NP	Worse OS, DSS and DFS
	Pattje 2012	177	OP, HP, L, OC	Lymph node metastasis, Shorter DMFS
	Fan 2013	200	OP, OC, L	Worse OS and DFS
	Chien 2016	339	OP, HP, OC	Lymph node metastasis, Younger age, Higher tumor grade, Worse DFS and OS
	Wachters 2017	60	L	No correlation with survival or clinicopathologic parameters
	Noorlag 2017	158	OC	Lymph node metastasis
TRAIL	Vigneswaran 2007	45	OC	High TRAIL-R DR5:  higher T stage
	Carcini 2010	134	OC	Worse OS
	Erkul 2016	20	L	High TRAIL-R DR5: higher clinical stage
GrB	Costa 2010	55	OC	Better survival, Lower T stages
FAP-1	Nariai 2011	50	OC	Worse OS

Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C. Assessing bias in studies of prognostic factors. Ann Intern Med. 2013 Feb 19;158(4):280–286. doi:10.7326/0003-4819-158-4-201302190-00009.

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Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.

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