REVIEW
Heart, Lung and Circulation (2015) 24, 780–788 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2015.03.021
ALDH1 Expression and the Prognosis of Lung Cancer: A Systematic Review and Meta-Analysis Dong Wei, MD a, Jing-Jing Peng, MD a, Hui Gao, MD a, Tao Zhang, MD a, Yong Tan, MD a, Yong-He Hu, MD b* a
Department of Oncology, Chengdu Military General Hospital, Chengdu, Sichuan, 610083, P.R. China Department of Traditional Chinese Medicine, Chengdu Military General Hospital, Chengdu, Sichuan, 610083, P.R. China
b
Received 7 February 2015; received in revised form 16 March 2015; accepted 26 March 2015; online published-ahead-of-print 3 April 2015
Purpose
Aldehyde dehydrogenase 1 (ALDH1) has been identified as a putative cancer stem cell (CSC) marker in lung cancer. However, the clinicopathological and prognostic value of this protein in lung cancer patients remains controversial. Thus, we performed a systematic review and meta-analysis of studies assessing the clinical and prognostic significance of ALDH1 expression in lung cancer.
Methods
An identification and review of publications assessing clinical or prognostic significance of ALDH1 expression in lung cancer until September 1, 2014 was undertaken. A meta-analysis was performed to clarify the association between ALDH1 expression and clinical outcomes.
Results
A total of 14 publications met the criteria and comprised 1926 cases. Analysis of these data showed that ALDH1 expression was not significantly associated with the patient age (OR = 0.82, 95% confidence interval [CI]: 0.45–1.50, P = 0.52), tumour size (OR = 0.68, 95% CI: 0.22–2.06, P = 0.49), smoking status (OR = 1.37, 95% CI: 0.85–2.22, P = 0.19), or tumour grade (OR = 1.65, 95% CI: 0.83–3.26, P = 0.15). However, in the identified studies, ALDH1 expression was highly correlated with lymph node metastasis (OR = 1.97, 95% CI: 1.16–3.34, P = 0.01), tumour TNM staging (OR = 1.68, 95% CI 1.28–2.22, P = 0.0002), decreased overall survival (relative risk [RR]: 1.97,95% CI: 1.16–3.34, P =0.01) and decreased disease free survival (RR: 1.63, 95% CI: 1.01–2.64, P=0.05).
Conclusions
This meta-analysis shows ALDH1 expression in lung cancer is connected with decreased overall and disease free survival and thus marks a worse prognosis.
Keywords
Prognosis Cancer stem cell Meta-analysis Overall survival Disease-free survival
Introduction Although lung cancer treatments have rapidly developed in recent years, the overall prognosis of patients with lung cancer remains poor. Considerable evidence has supported the proposal for a model in which tumourigenesis is driven by cancer stem cells (CSC) that are derived from mutated adult stem cells. CSCs undergo self-renewal, recapitulate the
phenotype of the tumour from which they were derived, develop into phenotypically diverse cancer cell populations, proliferate extensively, and drive both the continued expansion of malignant cells and chemotherapy resistance [1]. CSCs have recently been reported to be responsible for the poor outcomes of lung cancer [2–4]. Therefore, the identification of CSCs has become an important issue, particularly in the context of potential therapeutic targeting.
*Corresponding author. Department of Traditional Chinese Medicine, Chengdu Military General Hospital. No. 270, Rongdu Avenue, Jinniu District, Chengdu, Sichuan, 610083, Sichuan Province, China, Email: [email protected] © 2015 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
781
ALDH1 expression in lung cancer
The aldehyde dehydrogenase (ALDH) superfamily represents a diverse group of enzymes that metabolise and detoxify a wide variety of endogenous and exogenous aldehydes [5]. ALDH1 is an important member of the ALDH family that includes 17 genes that encode different substrate specificities [6]. One of these genes is ALDH1A1, which catalyses the oxidation of retinal to retinoic acid (RA) [7]. RA signalling is linked to cellular differentiation during development and has an important function in the self-protection of stem cells throughout the lifespan of an organism [7]. ALDH1 is important for normal development and homoeostasis in several organs and crucial during embryogenesis. It is an important detoxifying enzyme in the liver, also expressed in kidney, as well as haematopoeitic progenitor cells. ALDH1 is described to play a crucial role within normal differentiation of stem cells [8,9]. It has been one of the most frequently used biomarkers in CSC-related research; the use of ALDH originated from the isolation of ALDH+ CSCs from breast cancer [10]. Since then, the isolation of putative CSCs through ALDH activity has been reported from a variety of malignancies [11–13]. In vitro experiments suggest that isolated lung cancer cells with high ALDH1 activity are associated with cancer stem cell characteristics, including capacities of proliferation, self-renewal and resistance to chemotherapy [3]. ALDH1 positive cells have also shown enhanced engraftment capacity in nude mice [3]. However, the correlations between ALDH1 and the clinicopothological features of lung cancer with their corresponding prognostic values remain controversial. Some researchers have concluded that ALDH1 expression is associated with favourable outcomes [14]. Meanwhile, others have reported that ALDH1 expression decreases the survival outcome for lung cancer [3,13]. In the present study, we performed a systematic review and meta-analysis of the published literature to clarify the association of ALDH1 expression with clinicopathological features and the prognosis of lung cancer patients. The results may enable the prognostic stratification of lung cancer patients with adjuvant therapy while providing new insights into the potential cellular origin of lung cancer and its activated molecular pathways.
Materials and Methods Search Strategy The electronic databases of Pubmed, Embase, and Wanfang were searched for studies that investigated the association of clinicopathological parameters and prognosis with ALDH1 expression in lung cancer to be included in the present metaanalysis. Studies were examined, and an updated search was conducted on September 2014. The following search terms and combinations were used: ‘‘ALDH1’’ or ‘‘Aldehyde dehydrogenase 1,’’ as well as ‘‘lung neoplasms’’ or ‘‘lung cancer’’. The citation lists from all the retrieved studies were used to identify other relevant publications. Review articles were also scanned to identify additional eligible studies. The title
and abstract of each identified study were scanned to exclude any irrelevant publications. The remaining articles were reviewed to determine whether they contained information on the topic of interest.
Selection Criteria Two of the authors carefully extracted information from all eligible publications independently and according to the inclusion criteria. Disagreements were resolved through consensus. The inclusion criteria were as follows: (1) articles dealing with the expression of ALDH1 and prognostic factors, overall survival (OS), or disease-free survival (DFS) relative to lung cancer; (2) articles containing sufficient data to enable the estimation of an odds ratio (OR) or a relative risk (RR) ratio of OS or DFS; (3) articles in English or Chinese; and (4) articles published as original research. Reviews, comments, duplicated studies, and articles that were not relevant to the present analysis were excluded. Studies with less than 50 patients and those with less than two years of follow-up were also excluded.
Data Extraction The following information was extracted from the retrieved papers: author, publication year, country of the patient, time of collection, histological type, tumour pathological stage, number of patients, research technique used, the ages of the patients, and the choice of cutoff scores for the definition of positive staining or staining intensity. Two major groups were established on the basis of the objective. One group clarified the association between the expression of ALDH1 and clinicopathological parameters, including the ages of the patients, smoking status, tumour size, differentiation degree, tumour TNM stage, and lymph node status. Meanwhile, the other group investigated the association between the expression of ALDH1 and OS or DFS.
Statistical Analysis The meta-analysis was performed as previously described. ORs with 95% CI were used to evaluate the association among stem cell markers, ALDH1, and the clinicopathological features for lung cancer, which included the ages of patients, smoking status, tumour size, differentiation degree, tumour TNM stage, and lymph node status. RR combined with the retrieved studies was used to assess the association of ALDH1 and OS or DFS. For the RRs that did not come directly from the published articles, the published data and figures from original papers were used to assess the RR according to the methods described by Parmar et al. [15]. The heterogeneity across the studies was evaluated using Q test and P values. ORs and RRs were calculated with the use of a random-effect model when the P value was less than 0.05. Otherwise, a fixed-effect model was used. The influence of individual studies on the summary effect estimate was displayed using the sensitivity analysis. In addition, funnel plots and the Egger’s test were used to estimate possible publication bias [16]. Cochrane Review Manager version 5.2 (Cochrane Library, Oxford, UK) was used to calculate
782
the ORs and RRs and their variations from each investigation.
Results Description of Studies A total of 363 articles were selected for the meta-analysis by browsing the databases PubMed, Embase, and Wanfang. Out of this total, 342 were excluded after the title and abstract were reviewed, and seven articles were excluded after the full publications were reviewed (Figure 1). The reasons for exclusion were: (a) studies were not associated with the topic of interest; (b) researchers of the article used neither histopathologic analysis nor close clinical and imaging follow-up for at least six months; (c) studies associated with other diseases (d); non-original articles; (e) data could not be extracted; and (f) repeated data from the same or similar population. Eventually, 14 publications met the criteria for the present analysis [2–4,11,14,17–25]. The total number of patients was 1926, and each study had 50 to 282 patients. The
Figure 1 Literature search strategy and selection of articles.
D. Wei et al.
main characteristics of the eligible studies are summarised in Table 1. A total of 13 articles dealt with clinicopathological factors. Moreover, the assessment of OS or DFS using Kaplan–Meier method was reported in 11 of these articles.
Correlation of ALDH1 Expression with Clinicopathological Parameters The association between ALDH1 and several clinicopathological parameters is illustrated in Figure 2. ALDH1 expression had a high correlation with high tumour TNM stage (pooled OR = 1.68, 95% CI 1.28–2.22, P = 0.0002 fixed-effect) and lymph node metastasis (pooled OR = 1.97, 95% CI 1.16–3.34, P = 0.01 random-effect) (Figures 2A and 2B). However, ALDH1 expression was not associated with the patient age (pooled OR = 0.82, 95% CI 0.45–1.50, P = 0.52 fixed-effect) (Figure 2C), tumour size (pooled OR = 0.68, 95% CI 0.22–2.06, P = 0.49 random-effect) (Figure 2D), smoking status (pooled OR = 1.37, 95% CI 0.85–2.22, P = 0.19 random-effect) (Figure 2E), or tumour grade (pooled OR = 1.65, 95% CI 0.83–3.26, P = 0.15 random-effect) (Figure 2F).
ALDH1 expression in lung cancer
Table 1
Characteristics of the included studies.
Study
Patient’s
Year
country
Time of
Histological
Pathological
collection
type
stage
Method
Number of
Age in
Follow-up
Cut-off for
Blinding of
patients
years
months
ALDH1
ALDH1
positive
evaluation ND
Jiang 2009
USA
2009
ND
NSCLC
I–IV
IHC
96
ND
60
>10% staining
Sullivan 2010
USA
2010
ND
NSCLC
I–IV
IHC
282
ND
ND
ND
ND
Huang 2011
China
2011
2008-2009
NSCLC
I–III
IHC
80
ND
25
>10% staining
ND
Li X 2012
China
2012
2010-2011
LC
I–IV
IHC
50
32-76
32
>10% staining
Yes
Cortes-Dericks 2012
Italy
2012
2008-2011
AD
I–III
qRT–PCR
64
34-86
29
Median
ND
Dimou 2012
USA
2012
1993-2003
NSCLC
I–IV
Immunofluorescence
134
42-86
133
an AQUA score
ND
of 1200 Li Q 2012 Sun 2012
China China
2012 2012
2000-2010 2010-2011
NSCLC NSCLC
I–IV I–III
IHC IHC
179 67
ND 39-80
114 ND
>30% staining >10% staining
ND ND
Okudela 2012
Japan
2012
2001-2006
AD
I
IHC
177
45-85
85.1
>85% staining
Yes
Shien 2012
Japan
2012
2000-2009
NSCLC
III
IHC
150
ND
72
>10% staining
ND
Okudela 2013
Japan
2013
ND
NSCLC
I–IV
IHC
268
ND
82.5
Scores of 10
Yes
Zenke 2013
Japan
2013
1992-2009
NSCLC
I–IV
IHC
52
32-76
56
>10% staining
Yes
Alamgeer 2013
Australia
2013
1999-2010
NSCLC
I
IHC
267
34-85
140
>10% staining
ND
Hu 2014
China
2014
2009-2010
NSCLC
I–III
IHC
60
47-78
ND
>10% staining
ND
ND:not document IHC: immunohistochemistry.
783
784
D. Wei et al.
Figure 2 Forest plot depiction of ALDH1 expression and OR for clinical pathologic features. Clinicopathological parameters investigated are TMN classification (A), lymph node status (B), patient age (C), size of tumour (D), smoking status (E), tumour grade (F). OR with corresponding confidence intervals are shown.
785
ALDH1 expression in lung cancer
Figure 3 Analysis of ALDH1 expression and survival of lung cancer patients. Forest plot of RR for OS (A) and DFS (B) among included studies. Combined RR was calculated by a random mode.
ALDH1 Expression and Prognosis of Lung Cancer With the use of the methods described above, the OS and/or DFS of 1620 patients in the 11 studies were analysed. The main results of this meta-analysis are shown in Figure 3. A five-year OS rate was extracted from six studies. The meta-analysis of the six studies for the prognostic value of ALDH1 expression showed that ALDH1 expression is associated with a poor OS. This result was obtained from the DerSimonian–Laird random-effect model with a value of 1.97 (95% CI: 1.16–3.34, P =0.01) (Figure. 3A). However, heterogeneity was found among the studies (I2 = 86%, Ph
Heart, Lung and Circulation (2015) 24, 780–788 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2015.03.021
ALDH1 Expression and the Prognosis of Lung Cancer: A Systematic Review and Meta-Analysis Dong Wei, MD a, Jing-Jing Peng, MD a, Hui Gao, MD a, Tao Zhang, MD a, Yong Tan, MD a, Yong-He Hu, MD b* a
Department of Oncology, Chengdu Military General Hospital, Chengdu, Sichuan, 610083, P.R. China Department of Traditional Chinese Medicine, Chengdu Military General Hospital, Chengdu, Sichuan, 610083, P.R. China
b
Received 7 February 2015; received in revised form 16 March 2015; accepted 26 March 2015; online published-ahead-of-print 3 April 2015
Purpose
Aldehyde dehydrogenase 1 (ALDH1) has been identified as a putative cancer stem cell (CSC) marker in lung cancer. However, the clinicopathological and prognostic value of this protein in lung cancer patients remains controversial. Thus, we performed a systematic review and meta-analysis of studies assessing the clinical and prognostic significance of ALDH1 expression in lung cancer.
Methods
An identification and review of publications assessing clinical or prognostic significance of ALDH1 expression in lung cancer until September 1, 2014 was undertaken. A meta-analysis was performed to clarify the association between ALDH1 expression and clinical outcomes.
Results
A total of 14 publications met the criteria and comprised 1926 cases. Analysis of these data showed that ALDH1 expression was not significantly associated with the patient age (OR = 0.82, 95% confidence interval [CI]: 0.45–1.50, P = 0.52), tumour size (OR = 0.68, 95% CI: 0.22–2.06, P = 0.49), smoking status (OR = 1.37, 95% CI: 0.85–2.22, P = 0.19), or tumour grade (OR = 1.65, 95% CI: 0.83–3.26, P = 0.15). However, in the identified studies, ALDH1 expression was highly correlated with lymph node metastasis (OR = 1.97, 95% CI: 1.16–3.34, P = 0.01), tumour TNM staging (OR = 1.68, 95% CI 1.28–2.22, P = 0.0002), decreased overall survival (relative risk [RR]: 1.97,95% CI: 1.16–3.34, P =0.01) and decreased disease free survival (RR: 1.63, 95% CI: 1.01–2.64, P=0.05).
Conclusions
This meta-analysis shows ALDH1 expression in lung cancer is connected with decreased overall and disease free survival and thus marks a worse prognosis.
Keywords
Prognosis Cancer stem cell Meta-analysis Overall survival Disease-free survival
Introduction Although lung cancer treatments have rapidly developed in recent years, the overall prognosis of patients with lung cancer remains poor. Considerable evidence has supported the proposal for a model in which tumourigenesis is driven by cancer stem cells (CSC) that are derived from mutated adult stem cells. CSCs undergo self-renewal, recapitulate the
phenotype of the tumour from which they were derived, develop into phenotypically diverse cancer cell populations, proliferate extensively, and drive both the continued expansion of malignant cells and chemotherapy resistance [1]. CSCs have recently been reported to be responsible for the poor outcomes of lung cancer [2–4]. Therefore, the identification of CSCs has become an important issue, particularly in the context of potential therapeutic targeting.
*Corresponding author. Department of Traditional Chinese Medicine, Chengdu Military General Hospital. No. 270, Rongdu Avenue, Jinniu District, Chengdu, Sichuan, 610083, Sichuan Province, China, Email: [email protected] © 2015 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
781
ALDH1 expression in lung cancer
The aldehyde dehydrogenase (ALDH) superfamily represents a diverse group of enzymes that metabolise and detoxify a wide variety of endogenous and exogenous aldehydes [5]. ALDH1 is an important member of the ALDH family that includes 17 genes that encode different substrate specificities [6]. One of these genes is ALDH1A1, which catalyses the oxidation of retinal to retinoic acid (RA) [7]. RA signalling is linked to cellular differentiation during development and has an important function in the self-protection of stem cells throughout the lifespan of an organism [7]. ALDH1 is important for normal development and homoeostasis in several organs and crucial during embryogenesis. It is an important detoxifying enzyme in the liver, also expressed in kidney, as well as haematopoeitic progenitor cells. ALDH1 is described to play a crucial role within normal differentiation of stem cells [8,9]. It has been one of the most frequently used biomarkers in CSC-related research; the use of ALDH originated from the isolation of ALDH+ CSCs from breast cancer [10]. Since then, the isolation of putative CSCs through ALDH activity has been reported from a variety of malignancies [11–13]. In vitro experiments suggest that isolated lung cancer cells with high ALDH1 activity are associated with cancer stem cell characteristics, including capacities of proliferation, self-renewal and resistance to chemotherapy [3]. ALDH1 positive cells have also shown enhanced engraftment capacity in nude mice [3]. However, the correlations between ALDH1 and the clinicopothological features of lung cancer with their corresponding prognostic values remain controversial. Some researchers have concluded that ALDH1 expression is associated with favourable outcomes [14]. Meanwhile, others have reported that ALDH1 expression decreases the survival outcome for lung cancer [3,13]. In the present study, we performed a systematic review and meta-analysis of the published literature to clarify the association of ALDH1 expression with clinicopathological features and the prognosis of lung cancer patients. The results may enable the prognostic stratification of lung cancer patients with adjuvant therapy while providing new insights into the potential cellular origin of lung cancer and its activated molecular pathways.
Materials and Methods Search Strategy The electronic databases of Pubmed, Embase, and Wanfang were searched for studies that investigated the association of clinicopathological parameters and prognosis with ALDH1 expression in lung cancer to be included in the present metaanalysis. Studies were examined, and an updated search was conducted on September 2014. The following search terms and combinations were used: ‘‘ALDH1’’ or ‘‘Aldehyde dehydrogenase 1,’’ as well as ‘‘lung neoplasms’’ or ‘‘lung cancer’’. The citation lists from all the retrieved studies were used to identify other relevant publications. Review articles were also scanned to identify additional eligible studies. The title
and abstract of each identified study were scanned to exclude any irrelevant publications. The remaining articles were reviewed to determine whether they contained information on the topic of interest.
Selection Criteria Two of the authors carefully extracted information from all eligible publications independently and according to the inclusion criteria. Disagreements were resolved through consensus. The inclusion criteria were as follows: (1) articles dealing with the expression of ALDH1 and prognostic factors, overall survival (OS), or disease-free survival (DFS) relative to lung cancer; (2) articles containing sufficient data to enable the estimation of an odds ratio (OR) or a relative risk (RR) ratio of OS or DFS; (3) articles in English or Chinese; and (4) articles published as original research. Reviews, comments, duplicated studies, and articles that were not relevant to the present analysis were excluded. Studies with less than 50 patients and those with less than two years of follow-up were also excluded.
Data Extraction The following information was extracted from the retrieved papers: author, publication year, country of the patient, time of collection, histological type, tumour pathological stage, number of patients, research technique used, the ages of the patients, and the choice of cutoff scores for the definition of positive staining or staining intensity. Two major groups were established on the basis of the objective. One group clarified the association between the expression of ALDH1 and clinicopathological parameters, including the ages of the patients, smoking status, tumour size, differentiation degree, tumour TNM stage, and lymph node status. Meanwhile, the other group investigated the association between the expression of ALDH1 and OS or DFS.
Statistical Analysis The meta-analysis was performed as previously described. ORs with 95% CI were used to evaluate the association among stem cell markers, ALDH1, and the clinicopathological features for lung cancer, which included the ages of patients, smoking status, tumour size, differentiation degree, tumour TNM stage, and lymph node status. RR combined with the retrieved studies was used to assess the association of ALDH1 and OS or DFS. For the RRs that did not come directly from the published articles, the published data and figures from original papers were used to assess the RR according to the methods described by Parmar et al. [15]. The heterogeneity across the studies was evaluated using Q test and P values. ORs and RRs were calculated with the use of a random-effect model when the P value was less than 0.05. Otherwise, a fixed-effect model was used. The influence of individual studies on the summary effect estimate was displayed using the sensitivity analysis. In addition, funnel plots and the Egger’s test were used to estimate possible publication bias [16]. Cochrane Review Manager version 5.2 (Cochrane Library, Oxford, UK) was used to calculate
782
the ORs and RRs and their variations from each investigation.
Results Description of Studies A total of 363 articles were selected for the meta-analysis by browsing the databases PubMed, Embase, and Wanfang. Out of this total, 342 were excluded after the title and abstract were reviewed, and seven articles were excluded after the full publications were reviewed (Figure 1). The reasons for exclusion were: (a) studies were not associated with the topic of interest; (b) researchers of the article used neither histopathologic analysis nor close clinical and imaging follow-up for at least six months; (c) studies associated with other diseases (d); non-original articles; (e) data could not be extracted; and (f) repeated data from the same or similar population. Eventually, 14 publications met the criteria for the present analysis [2–4,11,14,17–25]. The total number of patients was 1926, and each study had 50 to 282 patients. The
Figure 1 Literature search strategy and selection of articles.
D. Wei et al.
main characteristics of the eligible studies are summarised in Table 1. A total of 13 articles dealt with clinicopathological factors. Moreover, the assessment of OS or DFS using Kaplan–Meier method was reported in 11 of these articles.
Correlation of ALDH1 Expression with Clinicopathological Parameters The association between ALDH1 and several clinicopathological parameters is illustrated in Figure 2. ALDH1 expression had a high correlation with high tumour TNM stage (pooled OR = 1.68, 95% CI 1.28–2.22, P = 0.0002 fixed-effect) and lymph node metastasis (pooled OR = 1.97, 95% CI 1.16–3.34, P = 0.01 random-effect) (Figures 2A and 2B). However, ALDH1 expression was not associated with the patient age (pooled OR = 0.82, 95% CI 0.45–1.50, P = 0.52 fixed-effect) (Figure 2C), tumour size (pooled OR = 0.68, 95% CI 0.22–2.06, P = 0.49 random-effect) (Figure 2D), smoking status (pooled OR = 1.37, 95% CI 0.85–2.22, P = 0.19 random-effect) (Figure 2E), or tumour grade (pooled OR = 1.65, 95% CI 0.83–3.26, P = 0.15 random-effect) (Figure 2F).
ALDH1 expression in lung cancer
Table 1
Characteristics of the included studies.
Study
Patient’s
Year
country
Time of
Histological
Pathological
collection
type
stage
Method
Number of
Age in
Follow-up
Cut-off for
Blinding of
patients
years
months
ALDH1
ALDH1
positive
evaluation ND
Jiang 2009
USA
2009
ND
NSCLC
I–IV
IHC
96
ND
60
>10% staining
Sullivan 2010
USA
2010
ND
NSCLC
I–IV
IHC
282
ND
ND
ND
ND
Huang 2011
China
2011
2008-2009
NSCLC
I–III
IHC
80
ND
25
>10% staining
ND
Li X 2012
China
2012
2010-2011
LC
I–IV
IHC
50
32-76
32
>10% staining
Yes
Cortes-Dericks 2012
Italy
2012
2008-2011
AD
I–III
qRT–PCR
64
34-86
29
Median
ND
Dimou 2012
USA
2012
1993-2003
NSCLC
I–IV
Immunofluorescence
134
42-86
133
an AQUA score
ND
of 1200 Li Q 2012 Sun 2012
China China
2012 2012
2000-2010 2010-2011
NSCLC NSCLC
I–IV I–III
IHC IHC
179 67
ND 39-80
114 ND
>30% staining >10% staining
ND ND
Okudela 2012
Japan
2012
2001-2006
AD
I
IHC
177
45-85
85.1
>85% staining
Yes
Shien 2012
Japan
2012
2000-2009
NSCLC
III
IHC
150
ND
72
>10% staining
ND
Okudela 2013
Japan
2013
ND
NSCLC
I–IV
IHC
268
ND
82.5
Scores of 10
Yes
Zenke 2013
Japan
2013
1992-2009
NSCLC
I–IV
IHC
52
32-76
56
>10% staining
Yes
Alamgeer 2013
Australia
2013
1999-2010
NSCLC
I
IHC
267
34-85
140
>10% staining
ND
Hu 2014
China
2014
2009-2010
NSCLC
I–III
IHC
60
47-78
ND
>10% staining
ND
ND:not document IHC: immunohistochemistry.
783
784
D. Wei et al.
Figure 2 Forest plot depiction of ALDH1 expression and OR for clinical pathologic features. Clinicopathological parameters investigated are TMN classification (A), lymph node status (B), patient age (C), size of tumour (D), smoking status (E), tumour grade (F). OR with corresponding confidence intervals are shown.
785
ALDH1 expression in lung cancer
Figure 3 Analysis of ALDH1 expression and survival of lung cancer patients. Forest plot of RR for OS (A) and DFS (B) among included studies. Combined RR was calculated by a random mode.
ALDH1 Expression and Prognosis of Lung Cancer With the use of the methods described above, the OS and/or DFS of 1620 patients in the 11 studies were analysed. The main results of this meta-analysis are shown in Figure 3. A five-year OS rate was extracted from six studies. The meta-analysis of the six studies for the prognostic value of ALDH1 expression showed that ALDH1 expression is associated with a poor OS. This result was obtained from the DerSimonian–Laird random-effect model with a value of 1.97 (95% CI: 1.16–3.34, P =0.01) (Figure. 3A). However, heterogeneity was found among the studies (I2 = 86%, Ph
