A Reaction-Based Fluorescent Probe for Imaging of Native Hypochlorous Acid

Article abstract of DOI:10.1002/asia.201901041

Hypochlorous acid (HOCl), one of the reactive oxygen species (ROS), is highly reactive and short-lived. It is a challenge to dynamic monitor HOCl activity in living systems. Hence, we synthesized a new fluoresce nt probe RF1 based on protection of the hydroxyl group by N,N-dimethylthiocarbamate recognition group, which reached a low fluorescence background signal and highly sensitive property. On account of the electrophilic addition of Cl⁺ to the sulfide of thiocarbamate moiety, probe RF1 was converted to resorufin and triggered emitting bright. RF1 showed not only the highly sensitive and selective response to HOCl in vitro, but also can be applied in environmental water samples and detected HOCl by test strips. Besides, the ability of RF1 monitoring HOCl in HeLa cells by exogenous simulation and tracing native HOCl in macrophages cells were also explored.

Full text of DOI:10.1002/asia.201901041

Journal Pre-proof
Survival prediction and adjuvant chemotherapy based on tumor marker for stage IB
lung adenocarcinoma
Yiyang Wang, MD, Difan Zheng, MD, Tianxiang Chen, MD, Jie Zhang, MD, Feng
Yao, MD, Haiquan Chen, MD
PII:
S0003-4975(19)31584-X
DOI:
https://doi.org/10.1016/j.athoracsur.2019.09.029
ATS 33160
Reference:
To appear in: The Annals of Thoracic Surgery
Received Date: 27 December 2018
Revised Date: 20 August 2019
Accepted Date: 9 September 2019
Please cite this article as: Wang Y, Zheng D, Chen T, Zhang J, Yao F, Chen H, Survival prediction
and adjuvant chemotherapy based on tumor marker for stage IB lung adenocarcinoma, The Annals of
Thoracic Surgery (2019), doi: https://doi.org/10.1016/j.athoracsur.2019.09.029.
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© 2019 by The Society of Thoracic Surgeons

Survival prediction and adjuvant chemotherapy based on tumor marker for
stage IB lung adenocarcinoma
Short title: Tumor marker for stage IB adenocarcinoma
Yiyang Wang, MD1*, Difan Zheng, MD2*, Tianxiang Chen, MD1, Jie Zhang, MD3,
Feng Yao, MD1 and Haiquan Chen, MD2,4
1. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong
University, China;
2. Department of Thoracic Surgery, Fudan University Shanghai Cancer Center,
Shanghai, China;
3. Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University,
Shanghai, China;
4. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai,
200032, China;
* Drs Wang and Zheng contributed equally to this work.
Corresponding Authors:
Haiquan Chen, M.D.
Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, 270
Dong-An Road, Shanghai 200032, China.
E-mail: hqchen1@yahoo.com.

Abstract
Background. We aimed to find out the prognosis of stage IB invasive lung
adenocarcinoma according to perioperative tumor markers (TMs), especially
carcinoembryonic antigen (CEA), and to determine whether TMs could guide
adjuvant chemotherapy.
Methods. Stage IB adenocarcinoma patients were selected from two medical centers
in Shanghai between January 2007 and December 2013. Perioperative TMs including
preoperative and postoperative TMs were stratified into normal level, CEA normal
and CEA elevated, respectively. Propensity score matching was analyzed for
eliminating variable differences between chemotherapy and observation groups.
Univariable and multivariable cox regressions were conducted to discovery the
prognostically independent risk factors. Kaplan-Meier curves were plotted and
testified by Log-rank test. Subgroup analysis was performed to investigate
chemotherapy benefit according to postoperative TMs.
Results. Postoperative CEA elevated (HR=6.783, 95% CI 2.534-18.162, p＜0.001)
and CEA normal (HR=3.332, 95% CI 1.553-7.147, p=0.002) and older age were
independently correlated with worse recurrence. Besides, it was only the
postoperative CEA elevated (HR=11.546, 95% CI 3.854-34.588, p＜0.001) and CEA
normal (HR=4.389, 95% CI 1.566-12.300, p=0.005) that independently influenced on
survival outcome. chemotherapy showed limited recurrence and survival benefit
among primary cohort. In subgroup analysis, chemotherapy even shorten survival
outcome when normal postoperative TMs occurred (HR=8.870, 95% CI 1.134-69.381,
p=0.038).
Conclusions. Postoperative CEA normal and CEA elevated were two independent
risk indicators for poorer clinical outcome instead of preoperative ones.
Chemotherapy failed to improve clinical outcomes when postoperative TMs elevated.
Importantly, chemotherapy could not even be recommended when postoperative TMs
was in a normal level.
Key words: invasive lung adenocarcinoma; pathological stage IB; adjuvant

chemotherapy; serum tumor marker
Non-small-cell lung cancer (NSCLC) has leading the majority of lung cancer-related
morbidity and mortality in decades around the world, especially in China1,2. Large
amounts of early-stage NSCLC were testified by low-dose computed tomography
(LDCT), mainly of which were small-sized invasive lung adenocarcinoma (IADC)3,4.
However, the 5-year survival still varies, from 90% of stage IA1 to 73% of stage IB5.
Carcinoembryonic antigen (CEA), was a critical serum biomarker for gastrointestinal
cancer6,7. CEA was also recognized as a significant biomarker for NSCLC, even for
early-stage IADC8-11. Serum tumor markers (TMs) other than CEA, including
cytokeratin 19 fragment (Cyfra21-1), carbohydrate antigen 125 (CA125), squamous
cell carcinoma antigen (SCC-Ag), specific neurons enolase (NSE), were also testified
for NSCLC detection and prognostic prediction12,13
.
The significant survival improvement of adjuvant chemotherapy (ACT) has been
declared among patients with resected stage II and IIIA NSCLC14,15. However,
survival benefit still remained controversial for stage IB patients16-18. Thus, this study
aimed to find out the different prognosis of stage IB IADC according to perioperative
TMs and further determine whether TMs could indicate appropriate ACT.
Patients and Methods
Patients
Patients with resected T2aN0M0 IADC at Shanghai Chest Hospital (SCH) and Fudan
University Shanghai Cancer Center (FUSCC) from January 2007 to December 2013
were collected (Figure 1). In this flowchart, the prior cancer diagnosis was accounted
when patient suffered other cancers prior to ADC. Induction therapy included
preoperative chemotherapy, radiotherapy or concurrent chemoradiotherapy, et al.
Multiple ADCs referred to primary multiple ADCs confirmed by preoperative
examination and postoperative final pathology. The palliative treatment was declared
as patients receiving non-curative resection. Unavailable data included serum TMs
and ACT.
In this research, ACT was defined as patients receiving postoperative chemotherapy

within 120 days after surgery. Patients with single-agent chemotherapy and less than 4
cycles of ACT were also excluded. Observation group was defined as the patients not
receiving any ACT after resection.
Tumor marker examination and classification
All the candidates were received routine blood test of TMs closest to the time before
surgical operation as well as within 120 days after surgery and before ACT. Each
blood sample was analyzed for the level of CEA, Cyfra21-1, SCC-Ag, CA125 and
NSE at the Department of Laboratory Medicine, SCH or FUSCC. The level of CEA
as well as Cyfra21-1, CA125, NSE was measured using the Luminex 200 automated
analyzer. SCC-Ag assay was analyzed through the Architect I2000 automated
analyzer. As for the reference value, the cutoffs were as following: CEA<5ng/ml,
Cyfra211<5ng/ml, SCC-Ag<5ng/ml, CA125<35U/ml, NSE<25ng/ml.
The classifications of preoperative and postoperative TMs were grouped as follows:
the normal TMs, CEA normal (CEA-) and CEA elevated (CEA+). Specifically,
patients were classified into CEA+ group as long as CEA elevated. Patients were
classified into CEA- if one or more TMs elevated excepting CEA.
Follow-up strategy and study endpoints
Each patient enrolled should complete the routine preoperative examination including
chest computed tomography (CT), abdominal and cervical ultrasound, head CT or
magnetic resonance imaging (MRI), and bone scanning. Positron emission
tomography/computed tomography (PET/CT) was conducted if necessary. Our
routine follow-up interval was every 3 months with chest CT, neck and abdominal
ultrasound. It was every 6 months with head MRI and bone scanning for the first year
of surgery and then repeated every year. Telephone calls were performed if necessary.
Our primary endpoint was recurrence-free survival (RFS), defined as the interval
between the date of surgical resection and the date of recurrence or last follow-up.
The secondary endpoint was overall survival (OS), calculated from the date of surgery
to the death or last follow-up.
Statistical analysis
The continuous and categorical variables were testified through the t test and the

Pearson χ2 or Fisher’s exact test, respectively. RFS and OS were estimated by the
Kaplan-Meier curves and testified by the Log-rank test. The differences of clinical
and pathological characteristics and potential selection biases between ACT and
observation groups were adjusted through a 1:1 propensity score matching (PSM)
analysis which was established by a logistic regression model including all the
baseline variables (sex, age, smoking history, tumor location, tumor size, surgical
procedures, pathological classification, solid/micropapillary component, harvested
lymph nodes, tumor grade, pleural invasion [PI], lymphovascular invasion [LVI],
preoperative and postoperative TMs), identified by Caliper value set at 0.01. The
independent risk factors related with RFS and OS were investigated through
univariable and multivariable cox proportional hazard regressions after PSM.
Subgroup analyses were conducted to investigate the potential benefit from ACT
when facing different postoperative TMs.
Two-sided p<0.05 was set as the statistical significance for all the analyses. The
statistical softwares including SPSS (version 20.0), GraphPad (Prism 5) and R
(version 3.2.2) were all applied for related statistical analyses and pictures.
Results
The clinicopathological characteristics of primary cohort
A total of 835 patients with stage IB IADC underwent completely surgical resection
were enrolled (615 from SCH and 220 from FUSCC). Those candidates were
excluded if they had previous cancer diagnosis within 5 years (n=27), receiving
induction therapy (n=7) or palliative resection (n=1), multiple ADCs (n=25), died
within 30 days after surgery (n=1), lost to follow-up (n=11) or unavailable data
including perioperative TMs (n=56) or ACT (n=22). For the remaining 685 patients,
31 cases with single agent and 54 lacking of enough cycles were still excluded.
Therefore, totally 600 patients were identified in the final cohort, of which 451
candidates with normal postoperative TMs, 112 CEA- and 37 CEA+ (Figure 1).
The clinicopathological characteristics of postoperative TMs were summarized in
Table 1. Compared with postoperative normal TMs and CEA-, CEA+ was more male

(p=0.010), more smokers (p＜0.001), more sublobectomies (p＜0.001), worse
differentiation (p=0.001), and more preoperative CEA+ (p＜0.001). In addition,
postoperative CEA- showed more ACT treatment(p＜0.001).
A 1:1 PSM analysis
The baseline characteristics of stage IB IADC treating with ACT and observation
before PSM were listed in Table 2. Compared with observation group, ACT was much
younger (p＜0.001), contained more smokers (p=0.044), lobectomies (p=0.021), PI
(p=0.003), papillary and solid-predominant ADC (p=0.010), was larger in size
(p=0.001), contained less harvested lymph nodes (p=0.003) and more LVI (p=0.004),
as well as more elevated postoperative TMs (p＜0.001).
In order to adjust those statistical difference between two groups and eliminate the
potential influence of selection biases, a 1:1 PSM analysis was performed. After
matching, those differences were well-balanced and no statistical significance ever
presented (Table 2)
The survival analysis of primary cohort
The median follow-up time was 46.7 months (range from 1 to 84 months) during
which 108 patients (18.0%) relapsed (including local recurrence and distant
metastasis) and 75 (12.5%) died before the last follow-up (64 died from lung
cancer-specific death and 11 from other causes). The 5-year RFS and OS were 82.2%
and 88.2%, respectively.
In the aspect of postoperative TMs, CEA+ showed worst recurrence and survival
outcome against other two groups. And CEA- represented worse clinical outcome in
contrast to normal TMs before matching (Figure 2A, 2B). Similarly, the 5-year RFS
and OS of postoperative CEA+ were 18.8% and 24.7%, both of which still elucidated
worst clinical outcome against normal TMs (5-year RFS: 82.1%, 5-year OS: 92.6%)
and CEA- (5-year RFS: 45.5%, 5-year OS: 60.5%) after PSM (Figure 2C, 2D).
The univariable and multivariable cox analysis
In univariable analysis, the 5-year RFS and OS rate of ACT was 72.7% and 85.7%
before matching, manifesting no statistical difference against observation (Appendix
Figure 1A, 1B). Similar recurrence and survival outcomes even existed after PSM

(Appendix Figure 1C, 1D), all of which indicated the limited survival benefit of ACT
among stage IB IADCs. Older age, sublobectomy, poor differentiation, and elevated
TMs were also potentially associated with shorted RFS and OS after PSM. Smoking
even showed its impact on poor survival outcomes (Table 3).
Multivariable analysis revealed that it was postoperative CEA+ (HR=6.783, 95% CI
2.534-18.162, p＜0.001) and CEA-(HR=3.332, 95% CI 1.553-7.147, p=0.002), that
independently correlated with worse RFS. Older age was another independent risk
factor for cancer recurrence (Table 3). Most importantly, only the postoperative CEA+
(HR=11.546, 95% CI 3.854-34.588, p＜0.001) and CEA- (HR=4.389, 95% CI
1.566-12.300, p=0.005) independently demonstrated a critical relationship with worse
OS (Table 3).
The subgroup analysis
Previous multivariable analysis has pointed out that postoperative TMs, especially
CEA showed important survival influence among stage IB IADCs. We conducted the
subgroup analysis of ACT according to different postoperative TMs situations. In the
aspect of cancer recurrence, ACT showed no statistically survival benefit from either
postoperative normal TMs, CEA- or CEA+ groups (Figure 3).
In addition, similar results found that neither postoperative CEA- nor CEA+ could
benefit from ACT on OS (Figure 4). Remarkably, the most reduced OS was obtained
when postoperative TMs were in the normal level after ACT (HR=8.870, 95% CI
1.134-69.381, p=0.038) (Figure 4).
Comment
It was well-known that ACT was recommended for patients with stage IB IADCs
larger than 4cm19. However, the necessity and importance of ACT for those equal to
or less than 4cm still remained controversial20-23. Serum TMs have been widely
testified for perioperative NSCLC treatment. Fewer studies showed the potential
relationship between perioperative TMs and ACT treatment of stage IB patients.
CEA has been recognized as the most diagnostic and prognostic TM in NSCLC24,25
.
In early-stage IADC, high level of perioperative CEA was also correlated with more

aggressive tumor invasiveness and poorer clinical outcomes26,27. In this study, we
confirmed that it was the postoperative elevated TMs instead of preoperative ones that
independently influenced stage IB IADCs. Compared with postoperative CEA normal,
elevated CEA was a more significant factor correlated with reduced clinical outcomes
for those patients, which was in line with previous studies28,29
.
Dr. Noonan has stated that almost 81% NSCLC presented more than one TM, and
only 50% of early-stage one was associated with elevated CEA10. In addition, the
combination of two or more TMs could improve the diagnostic sensitivity and
prognostic accuracy, mainly of which included CEA30,31. However, in this study, what
we focused was CEA level and we divided the elevated TMs into CEA- and CEA+.
As expected, the perioperative CEA- persisted relatively better recurrence rate and
survival outcome when against corresponding CEA elevated.
The reason for this phenomenon could be largely explained as CEA other than other
TMs was the early-releasing TM and represented heavy tumor burden and severe
cancer invasiveness32. More importantly, it was the postoperative TMs instead of
preoperative ones that can independently predict the recurrence and survival
prognosis. Necessary interventions should be considered for those patients with
postoperative TMs elevation, especially CEA elevation. Undoubtably, ACT was one
of the few options for our clinicians to pursue a better clinical outcome. Nevertheless,
ACT elucidated no statistically improved recurrence rate and survival outcomes in the
stratified analysis. In addition, it showed an obvious decrease of OS with
postoperative TM normal. Hence, we could conclude that neither postoperative CEA-
nor CEA+ should be considered as an indication for ACT to stage IB IADCs. Stage IB
IADCs with normal postoperative TMs could not even be recommended for ACT
procedures. Therefore, clinicians should be much more discreet when considering
ACT as a routine treatment to stage IB IADC patients. Whether ACT was necessary
for those patients should be studied in further investigations.
There were several limitations in this research. First, it was a retrospective analysis
from two medical centers in Shanghai, thus the selection biases were unavoidable.
Secondary, we focused on the difference between CEA normal and CEA elevated.

However, not enough attention was paid to the different chemotherapy benefit when
different single or combined perioperative TMs expect CEA and this required further
investigation. Third, we did not run blood assays in duplication and this needed to be
improved in further investigation.
In conclusion, postoperative elevated CEA and normal CEA were two independent
risk indicators for poorer recurrence rates and survival outcomes among stage IB
IADC patients. Current ACT failed to improve clinical outcomes despite
postoperative CEA being elevated or normal. In addition, ACT could not be
recommended as a proper postoperative treatment when postoperative TMs presented
in a normal level. These finding revealed that other adjuvant interventions might be
considered among stage IB IADC patients.
Acknowledgement
This work was supported by the National Natural Science Foundation of China
(81372525 and 81572693).
Ethical approval
All the procedures involving human participants were in line with the ethical
standards of institutions and national research committees and the 1964 Helsinki
Declaration and its subsequent amendments and/or similar ethical standards. And for
this research, formal consent was not needed.

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Figure Legends
Figure 1. Study cohort flowchart.
Figure 2. Kaplan-Meier curves for stage IB IADC of postoperative tumor
markers PSM and after PSM. A) RFS curve before PSM. B) OS curve before PSM.
C) RFS curve after PSM. D) OS curve after PSM.
Figure 3. Subgroup analysis among stage IB IADC of RFS between ACT and
observation after PSM. A) Postoperative TM normal. B) Postoperative CEA-. C)
Postoperative CEA+.
Figure 4. Subgroup analysis among stage IB IADC of OS between ACT and
observation after PSM. A) Postoperative TM normal. B) Postoperative CEA-. C)
Postoperative CEA+.

Abbreviations
Invasive lung adenocarcinoma, IADC
Tumor marker, TM
Carcinoembryonic antigen, CEA
Adjuvant chemotherapy, ACT
Non-small-cell lung cancer, NSCLC
Low-dose computed tomography, LDCT
Cytokeratin 19 fragment, Cyfra21-1
Carbohydrate antigen 125, CA125
Squamous cell carcinoma antigen, SCC-Ag
Specific neurons enolase, NSE
Shanghai Chest Hospital, SCH
Fudan University Shanghai Cancer Center, FUSCC
CEA normal, CEA-
CEA elevated, CEA+
Computed tomography, CT
Magnetic resonance imaging, MRI
Positron emission tomography/computed tomography, PET/CT
Recurrence-free survival, RFS
Overall survival, OS
Propensity score matching, PSM
Pleural invasion, PI
Lymphovascular invasion, LVI

Table 1. Baseline Characteristics of Primary Cohort
NO. of patients (%)
Variables
Male
p
Postoperative TM normal
Postoperative CEA normal
Postoperative CEA elevated
n=451
192
259
61.12
346
105
157
42
%
n=112
54
58
59.41
73
39
36
13
15
32
16
2.45
2
%
n=37
25
12
62.51
19
18
12
2
%
67.6
32.4
11.36
51.4
48.6
32.4
5.4
Sex
42.6
57.4
9.72
76.7
23.3
34.8
9.3
48.2
51.8
8.56
65.2
34.8
32.1
11.6
13.4
28.6
14.3
0.69
1.8
0.010
Female
Mean (SD)
No
Age
Smoking
0.138
＜0.001
Yes
Location
RUL
RML
RLL
LUL
LLL
Mean (SD)
Sublob
Lob
0.682
85
107
60
2.39
25
18.8
23.7
13.4
0.73
5.5
5
13
5
2.57
9
28
0
13.5
35.2
13.5
0.80
24.3
75.7
0
Size
Surgery
0.300
＜0.001
426
21
94.5
4.7
110
2
98.2
1.8
Pathology
LEP
0.107
ACN
PAP
SOL
239
134
33
53.0
29.7
7.3
53
41
11
0
47.3
36.6
9.8
20
8
7
54.1
21.6
18.9
0
MIP
9
2.0
0
0
Others
No
15
322
3.3
71.4
5
75
4.5
67.0
2
22
5.4
59.5
SOL/MIP
0.240
Component
Yes
129
16.81
319
28.6
7.21
70.7
37
16.31
63
33.0
7.24
56.3
15
14.33
18
40.5
3.58
48.6
harvested LN Mean (SD)
Grade Well/
0.483
0.001

Moderate
Poor
No
Yes
No
132
41
410
420
31
29.3
9.1
90.9
93.1
6.9
49
9
103
99
13
67
43.7
8.0
92.0
88.4
11.6
59.8
19
6
31
32
5
51.4
16.2
83.8
86.5
3.5
PI
0.313
0.123
LVI
Yes
Preoperative Normal
335
74.3
8
21.6
＜0.001
TM
CEA-
CEA+
No
65
51
339
14.4
11.3
75.2
24.8
32
13
28
84
28.6
11.6
25.0
75.0
3
8.1
26
27
10
70.3
73.0
27.0
ACT
＜0.001
Yes
112
Abbreviations: TM, tumor marker; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower
lobe; Sublob, sublobectomy; Lob, lobectomy; LEP, lepidic-predominant adenocarcinoma; ACN, acinar-predominant adenocarcinoma; PAP,
papillary-predominant adenocarcinoma; SOL, solid-predominant adenocarcinoma MIP, micropapillary-predominant adenocarcinoma; harvested
LN, harvested lymph node; PI, pleural invasion; LVI, lymphovascular invasion; ACT, adjuvant chemotherapy.

Table 2. Baseline Characteristics of Stage IB IADC Patients before and after PSM
No. of patients
Observation
Variables
Before PSM
ACT
After PSM
ACT
Observation
n=394 (%)
172 (43.7)
222 (56.3)
62.26 (10.20)
298 (75.6)
96 (24.4)
126 (32.0)
38 (9.6)
p
p
n=206 (%)
99 (48.1)
107 (51.9)
58.26 (7.84)
140 (68.0)
66 (32.0)
79 (38.3)
19 (9.2)
28 (13.6)
47 (22.8)
33 (16.1)
2.48 (0.65)
6 (2.9)
n=106 (%)
48 (45.3)
58 (54.7)
59.13 (11.22)
79 (74.5)
27 (25.5)
36 (34.0)
12 (11.3)
17 (16.0)
31 (29.2)
10 (9.5)
n=106 (%)
48 (45.3)
58 (54.7)
59.05 (7.90)
74 (69.8)
32 (30.2)
42 (39.6)
7 (6.6)
17 (16.0)
23 (21.8)
17 (16.0)
2.48 (0.72)
3 (2.8)
Sex
Male
0.303
1.000
Female
Mean (SD)
No
Age
Smoking
0.948
0.444
＜0.001
0.044
Yes
Location
RUL
RML
RLL
LUL
LLL
Mean (SD)
Sublob
Lob
0.157
0.311
77 (19.5)
105 (26.6)
48 (12.3)
2.38 (0.76)
30 (7.6)
Size
Surgery
0.001
0.021
2.48 (0.67)
3 (2.8)
103 (97.2)
3 (2.8)
0.724
1.000
364 (92.4)
19 (4.8)
200 (97.1)
4 (1.9)
103 (97.2)
1 (0.9)
Pathology
LEP
0.010
0.228
ACN
PAP
SOL
216 (54.8)
107 (27.2)
30 (7.6)
96 (46.6)
76 (36.9)
21 (10.2)
0 (0)
60 (56.6)
29 (27.5)
10 (9.4)
53 (50.0)
39 (36.9)
10 (9.4)
MIP
9 (2.3)
3 (2.8)
0 (0)
Others
No
13 (3.3)
277 (70.3)
9 (4.4)
142 (68.9)
1 (0.9)
75 (70.8)
3 (2.8)
73 (68.9)
SOL/MIP
Component
0.728
0.003
0.765
0.261
Yes
Mean (SD)
117 (29.7)
17.61 (7.15)
64 (31.1)
13.63 (5.99)
31 (29.2)
9.44 (5.65)
33 (31.1)
8.90 (6.16)
harvested LN

Grade
PI
Well/Moderate
Poor
No
Yes
No
273 (69.3)
121 (30.7)
47 (11.9)
347 (88.1)
371 (94.2)
23 (5.8)
127 (61.7)
79 (38.3)
9 (4.4)
197 (95.6)
180 (87.4)
26 (12.6)
146 (70.9)
0.059
0.003
0.004
0.235
70 (66.0)
36 (34.0)
7 (6.6)
99 (93.4)
95 (89.6)
11 (10.4)
80 (75.4)
78 (73.6)
38 (26.4)
8 (7.5)
98 (92.5)
94 (88.7)
12 (11.3)
74 (69.8)
0.773
0.789
0.825
0.634
LVI
Yes
Normal
Preoperative
TM
264 (67.0)
CEA-
CEA+
Normal
73 (18.5)
57 (14.5)
339 (86.0)
27 (13.1)
33 (16.0)
112 (54.4)
13 (12.3)
13 (12.3)
84 (79.3)
15 (14.2)
17 (16.0)
90 (84.9)
Postoperative
TM
0.332
＜0.001
CEA-
CEA+
28 (7.1)
27 (6.9)
84 (40.8)
10 (4.8)
10 (9.4)
12 (11.3)
10 (9.4)
6 (5.7)
Abbreviations: PSM, propensity score matching.

Table 3. Univariable and Multivariable Cox Regressions for Stage IB IADC Patients after PSM
Recurrence-free survival
Overall survival
Multivariable
Variables
Male
Univariable
Multivariable
95%CI
Univariable
p
HR
p
p
HR
95%CI
p
Sex
0.316
0.085
Female
Mean (SD)
No
Age
Smoking
1.057
1.025-1.090
0.025
0.015
1.029
1.772
0.992-1.068
0.804-3.908
0.121
0.156
＜0.001
0.512
＜0.001
Yes
Location
RUL
RML
RLL
0.592
0.807
LUL
LLL
Size
Surgery
Mean (SD)
Sublob
Lob
0.803
0.023
0.642
0.002
(Ref=1)
0.906
0.774
(Ref=1)
0.634
0.186
0.463-1.774
0.323-1.246
Pathology
LEP
0.694
0.674
ACN
PAP
SOL
MIP
Others
No
SOL/MIP
0.099
0.421
Component
Yes
harvested LN Mean (SD)
Grade Well/
0.607
0.003
0.896
0.246
(Ref=1)
0.111

Moderate
Poor
No
Yes
No
1.274
0.946-1.714
0.881
0.143
PI
0.426
0.385
0.025
0.539
0.483
0.005
LVI
Yes
Preoperative Normal
(Ref=1)
(Ref=1)
0.952
TM
CEA-
CEA+
1.951
0.702
0.898-4.237
0.254-1.937
0.091
0.494
1.067
0.879
0.345-3.295
0.289-2.677
0.911
0.821
Postoperative Normal
TM
(Ref=1)
(Ref=1)
＜0.001
＜0.001
＜0.001
＜0.001
CEA-
CEA+
3.332
6.783
1.553-7.147
2.534-18.162
0.002
＜0.001
4.389
11.546
1.566-12.300
3.854-34.588
0.005
＜0.001
ACT
No
0.582
0.459
Yes
Abbreviations: HR, hazard ratio; CI, confidence interval.