Laparoscopic Splenic Hilar Lymph Node Dissection is Recommended for Pathologic Stage IIIA Middle and Upper Gastric Cancer: A Comparative Study with Standard D2 Laparoscopic Distal Gastrectomy

doi:10.21203/rs.3.rs-1119017/v1

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Research Article

Laparoscopic Splenic Hilar Lymph Node Dissection is Recommended for Pathologic Stage IIIA Middle and Upper Gastric Cancer: A Comparative Study with Standard D2 Laparoscopic Distal Gastrectomy

https://doi.org/10.21203/rs.3.rs-1119017/v1

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Purpose

D2 lymphadenectomy is considered a standard procedure for distal gastrectomy (DG). However, whether splenic hilar (No. 10) lymph node (LN) should be included in the extent of D2 lymphadenectomy for total gastrectomy (TG) is still controversial. Therefore, we assessed the survival benefit of laparoscopic No.10 LN dissection based on the comparison of long-term survival of patients undergoing laparoscopic TG (LTG) with laparoscopic No.10 LN dissection and laparoscopic DG (LDG).

Methods

The clinicopathological data of 2069 patients who underwent laparoscopic radical gastrectomy were retrospectively analyzed. The survival of the LDG group, the LTG with dissection of No. 10 LN (LTG+No. 10) group and the LTG without dissection of No. 10 LN (LTG-No. 10) group was compared.

Results

After adjusting for age, pT stage, pN stage and pTNM stage by 1:1:1 propensity score matching (PSM), there were 373 patients in each group. Kaplan-Meier (K-M) survival analysis showed that only in the pIIIA stage, the 5-year survival overall survival (OS) and cancer specific survival (CSS) of the LTG+No. 10 group was significantly better than that of the LTG-No. 10 group and comparable with that of the LDG group. Multivariate Cox regression analyses showed that dissection of No. 10 LN was an independent favorable factor for OS and CSS in all patients and patients with pIIIA.

Conclusion

In patients with stage pIIIA, those undergoing LTG with No. 10 LN dissection could achieve a long-term outcome comparable to that of patients at the same pathological stage undergoing LDG.

Cancer Biology

Oncology

Gastric cancer

Splenic hilar lymph nodes

Prognosis

Survival benefit.

Gastrectomy with D2 lymphadenectomy is the recommended surgical treatment for advanced gastric cancer (GC). Splenic hilar (No. 10) lymph nodes (LNs) are important lymph nodes in the lymphatic drainage system in GC, especially in patients with advanced upper and middle gastric cancer (AUMGC). The metastasis rate of No. 10 LN in patients with AUMGC reported in the literature ranges from 8.4–27.9%, and the presence or absence of No. 10 LN metastasis is closely related to the survival of patients (Mönig et al. 2001; Sasada et al. 2009; Nashimoto et al. 2012; Zhu et al. 2012; Jeong et al. 2019). However, the survival benefit of No. 10 LN dissection remains controversial. The study of Yukio et al. showed a relatively high rate of metastasis in No. 10 LN, 13%, and No. 10 LN dissection had therapeutic value similar to that of dissection of other suprappancreatic LNs (Maezawa et al. 2018). Kosuga et al. suggested that the 5-year survival rate of patients in the group receiving No. 10 LN dissection was 51.3%, higher than that of patients in the group without No. 10 LN dissection (42.1%) (Kosuga et al. 2011). These results demonstrated the value of No.10 LNs dissection in improving the long-term prognosis of patients. In the study of Ding et al., there was no significant survival benefit from No. 10 LN dissection (Ding et al. 2019). Based on the results of JCOG 0110, No.10 LN dissection is no longer a routine requirement for D2 lymphadenectomy in the 5th edition of the Japanese gastric cancer treatment guidelines (Japanese Gastric Cancer Association 2021). However, as described by the authors, the low rate of No. 10 LN metastasis was partly attributable to the early stage of tumors in the study; for example, the proportion of pT1 GC cases included in the study was higher than expected (14.1%), and approximately 70% of patients had stage I-II disease. Therefore, the indications for No. 10 LN dissection needs to be supported by more evidence-based medical research.

In recent years, with the enhancement of surgeons’ understanding of anatomy, spleen-preserving splenic hilar lymphadenectomy (SPSHL) has gradually become popular. Many studies have shown that there were high morbidity and mortality after splenectomy, and the long-term survival rate might not be improved (Csendes et al. 2002; Yu et al. 2006; Brar et al. 2012; Sano et al. 2017). Therefore, some researchers are inclined to adopt SPSHL for AUMGC. Moreover, laparoscopic SPSHL (LSPSHL) has been increasingly reported and has been proven to be safe and feasible with a better minimally invasive effect (Hyung et al. 2008; Sakuramoto et al. 2009; Hosogi et al. 2016; Guo et al. 2018). Thus, in this study, we further assessed the survival benefit of LSPSHL based on the comparison of long-term survival of patients undergoing laparoscopic total gastrectomy (LTG) with SPSHL and laparoscopic distal gastrectomy (LDG) with standard D2 lymphadenectomy.

Database

The clinicopathological data of patients with primary GC who underwent laparoscopic radical gastrectomy with D2 lymphadenectomy from January 2010 to December 2015 at Fujian Medical University Union Hospital (FMUUH) were retrospectively analyzed. Patients with other malignancies within 5 years, receiving neoadjuvant chemotherapy, with fewer than 15 LNs retrieved, with pathologically proven metastasis or stage T4b disease or with incomplete baseline clinicopathological data were excluded. Ultimately, a total of 2069 patients were included in the analysis. Patients were divided into the LDG group, the LTG with dissection of No. 10 LN (LTG+No. 10) group and the LTG without dissection of No. 10 LN (LTG-No. 10) group (Figure 1). The extent of resection and regional LN dissection of GC conformed to the fourth edition of the Japanese gastric cancer treatment guidelines (Japanese Gastric Cancer Association 2017). Staging was based on the eighth edition of the American Joint Committee on Cancer (AJCC) staging manual (Kakar et al. 2017).

Follow-up evaluation

The follow-up period was based on the 4th edition of the Japanese gastric cancer treatment guidelines (Japanese Gastric Cancer Association 2017). The last follow-up date was May 2019. OS was recorded from the date of surgery to the last follow-up date, date of death, or date at the end of follow-up in the database. CSS was defined as the period from the date of surgery to the date of death from recurrence or metastasis of GC or last follow-up without recurrence. Recurrence was diagnosed by imaging examination or suspicious lesion biopsy. Recurrence patterns were classified as locoregional recurrence (anastomotic or gastric stump), LN metastasis, peritoneal and hematogenous metastasis (Lee et al. 2018). Tumors involving the ovaries were considered as peritoneal metastases (Lin et al. 2019).

Statistical analysis

Statistical analyses were performed using IBM SPSS software (version 22.0, Chicago, IL, USA) and R software (version 3.5.0). Descriptive statistics were used to summarize the distribution of clinicopathological data. A logistic regression model was applied to calculate the propensity score with the following covariates: age, tumor size, pT stage, pN stage and pTNM stage. Univariate and multivariate Cox regression analyses were conducted for long-term survival to determine the independent prognostic factors. The survival rate was calculated with the Kaplan-Meier (K-M) method, and the survival curve was plotted. The survival rates were compared with the log-rank test. A P value < 0.05 was considered statistically significant.

Clinicopathological characteristics

A total of 2069 GC patients were included in this study. In supplemental table 1, the baseline clinicopathological data of the LTG+No. 10 group (724 patients), LTG-No. 10 group (422 patients) and LDG group (923 patients) were compared before PSM. There were significant differences among the three groups in age, gender, CA199, CEA, ASA, number of lesions, tumor location, tumor size, lymphovascular invasion, perineural invasion, pTNM stage and receipt of adjuvant chemotherapy (P<0.05). After PSM, there were no statistically significant differences in the distribution of important clinicopathological factors among the groups except for in gender, number of lesions, tumor location and perineural invasion (Table 1, P>0.05).

Lymph node metastasis

Table 2 shows the lymph node metastasis at each station. The rate of No. 10 LN metastasis in the LTG+No. 10 group was 10.5% (39/373 patients), which was higher than that of No. 5 LN and No. 12a LN metastasis. The rate of No. 12a LN metastasis in the LTG+No. 10 group was significantly lower than that in the LTG-No. 10 group. The rates of LN metastasis at other LN stations were similar between the two groups. Compared with those in the LDG group, the rates of No. 1 LN and No. 11 LN metastasis were significantly higher in the LTG+No. 10 group and the LTG-No. 10 group, while the rates of No. 4-6 LN metastasis were significantly lower in the LTG+No. 10 group and the LTG-No. 10 group (P<0.05).

Association of No. 10 LN dissection with survival

The median follow-up time of all patients was 60 months (IQR 34-85 months). The 1-year, 3-year and 5-year OS rates were 91.7%, 73.8% and 66.4% respectively. The 1-year, 3-year and 5-year CSS rates were 93.8%, 78.6% and 73.5%, respectively. Before PSM, there were significant differences in OS and CSS between the LDG group, LTG+No. 10 group and LTG-No. 10 group (P<0.05, supplemental figure 1). After PSM, the 5-year OS (63.1% vs 62.0%, P=0.954) and 5-year CSS (64.5% vs 64.7%, P=0.990) in the LTG+No. 10 group were comparable to those in the LDG group, and both were obviously better than those in the LTG-No. 10 group (P<0.05, figure 2). Univariate and multivariate Cox analyses showed that No. 10 LN dissection, age, CEA, Bormann type, perineural invasion and pTNM stage were independent prognostic factors for OS in patients receiving LTG (Table 3, supplemental table 2). No. 10 LN dissection was also an independent favorable factor for CSS in patients receiving LTG (Table 4, supplemental table 3).

Stratificationanalysis of survival based on pTNM stage

K-M survival analyses stratified by pTNM stage were shown in figure 3 and figure 4. In the pIII stage, the 5-year OS (45.1% vs 44.4%, P=0.949, figure 3C) and 5-year CSS (46.3% vs 47.9%, P=0.816, figure 4C) of the LTG+No. 10 group were comparable to those of the LDG group and significantly better than those of the LTG-No. 10 group (for the LTG-No. 10 group, 5-year OS: 29.7%, 5-year CSS: 31.7%). In the pI stage and pII stage, the 5-year OS and CSS of the LTG+No. 10 group were comparable to those of the LDG group and the LTG-No. 10 group (Figure 3-4 A，B). Further stratified survival analysis was performed for patients with stage III disease. Only in pIIIA stage，the LTG+No. 10 group had comparable 5-year OS and CSS to patients with the LDG group, and both were significantly better than those of the LTG-No. 10 group. There was no significant difference in OS and CSS of patients with pIIIB stage disease or pIIIC stage disease among the three groups (P>0.05, supplemental figure 2).

Supplemental table 4 shows the clinicopathological data of patients with stage IIIA disease. There were significantly more patients with multiple lesions in the LTG-No. 10 group than in the other two groups. The number of patients with perineural invasion in the LTG+No. 10 group was higher than that of the other two groups. Univariate and multivariate Cox analyses of OS showed that No. 10 LN dissection was an independent favorable factor for OS in patients with pIIIA stage disease who underwent LTG (supplemental table 5). In the univariate and multivariate Cox analyses of CSS, No. 10 LN dissection remained an independent favorable factor (supplemental table 6).

Comparison of recurrence patterns

Table 5 shows the recurrence patterns of patients in the three groups. The recurrence rate of both the LTG+No. 10 group and LDG group was 34.6%, which was significantly lower than that of the LTG-No. 10 group (40.2%). The locoregional recurrence rate, lymph node metastasis rate and peritoneal metastasis rate were similar among the three groups. The local lymph node metastasis rates of the LTG+No. 10 group (1.1%) and LDG group (2.1%) were significantly lower than that of the LTG-No. 10 group (3.5%). Moreover, patients in the LTG-No. 10 group were more likely to develop hematogenic metastasis than those in the LDG group and the LTG+No.10 group (17.2% vs 11.8% vs 11.8%, P<0.05).

Previous studies have shown that No. 10 LN metastasis is closely related to the long-term prognosis of GC patients [1-5]. The 5th edition of the Japanese gastric cancer treatment guidelines excludes No. 10 LNs from the extent of D2 lymph node dissection for AUMGC not invading the greater curvature (non-Gre) based on data from JCOG 0110 researchers. And most studies have shown that the rate of No. 10 LN metastasis for non-Gre AUMGC is significantly lower than that for AUMGC with greater curvature invasion (Chen et al. 2014; Huang et al. 2014; Watanabe et al. 2016; Watanabe et al. 2019; Yura et al. 2019). However, the results from our center showed that among the 256 patients with pT4a stage GC, who had invasion of the lesser curvature and No. 7 LN or No. 11 LN metastasis, the rate of No. 10 LN metastasis was up to 11.3% (Huang et al. 2014). In addition, a pooled analysis of 4 prospective trials from our center found that No. 10 LN metastasis rate of patients with non-Gre locally advanced proximal GC (tumor size > 5 cm and positive preoperative locoregional LNs) was 19.4%, far higher than 10%, and the authors strongly recommended for No. 10 LN dissection (Zhong et al. 2021).

Recent studies have shown that No. 10 LN dissection can improve the long-term prognosis of GC patients. Chikara et al reported that the 5-year survival rates were significantly lower in No. 10 LN metastasis patients than in patients without metastasis (23.8 vs 41.1%) (Chikara et al. 2001). Shin et al also showed similar results (Shin et al. 2009). In the study of Ding et al., patients with high-risk No. 10 LN metastasis did not benefit from No. 10 LN dissection (Ding et al. 2019). Therefore, whether patients benefit from No. 10 LN dissection is still controversial. There is consensus on the extent of D2 lymph nodes for DG. Thus, in the present study, a large number of patients with long-term follow-up were included, and the survival benefit of No. 10 LN dissection was analyzed by comparing the survival of the LTG+No.10 group and the LDG group. PSM was used to reduce the influence of confounding factors. The K-M survival analysis showed that the 5-year OS of the LTG+No. 10 group was comparable to that of the LDG group (63.1% vs 62.0%, P>0.05) and significantly better than that of the LTG-No. 10 group (47.5%). Similar results were shown in the analysis of CSS.

According to the K-M survival stratification analysis based on pTNM stage, a survival benefit of No. 10 LN dissection was observed on in patients with pIIIA stage disease in LTG+No. 10 LN group, and they achieved a long-term prognosis similar to that of the LDG group. This is similar to the results of our earlier study based on 3-year survival rates (Huang et al. 2017). GC patients with pI stage and pII stage disease failed to benefit from No. 10 LN dissection, possibly because of the low rate of No. 10 LN metastasis in these patients. For pIIIB stage and pIIIC stage patients, despite the high rate of No. 10 LN metastasis, No. 10 LN dissection brought little additional survival benefit due to the advanced stage of these patients. For these patients, neoadjuvant therapy with the goal of reducing the tumor stage is recommended to increase the chance of radical resection and improve the prognosis of patients. However, a well-designed prospective randomized controlled trial is still needed to confirm that.

In addition, this study compared the recurrence patterns among the three groups, and the recurrence rates in both the LTG+No. 10 group and the LDG group were significantly lower than that in the LTG-No. 10 group. Further analysis showed that the local lymph node metastasis rates of the LTG+No. 10 group and the LDG group were significantly lower than that of the LTG-No. 10 group. And the patients in the LTG-No. 10 group were more likely to develop hematogenic metastasis than the patients in the other two groups. These results suggest that metastatic No. 10 LNs that have not been thoroughly dissected may develop local lymph node metastasis postoperatively and increase the probability of hematogenic metastasis, resulting in poor prognosis. Special attention should be paid to monitoring for local lymph node and hematogenic metastasis during the follow-up of AUMGC patients without No. 10 LN dissection.

There were still several limitations in this study. The retrospective design of this study led to inevitable selection bias. There are differences in tumor biological behavior and clinical manifestations for GC at different locations. However, this study minimized the bias by PSM. In this study, to more accurately evaluate the survival difference between the LTG+No. 10 group, LTG-No. 10 group and LDG group, pathological stage was used, which required more accurate clinical staging to guide the treatment.

The results suggest that No. 10 LN dissection is not required for all patients with AUMGC. Patients with pIIIA stage AUMGC undergoing LTG with No. 10 LN dissection could achieve a long-term outcome comparable to that of patients receiving LDG at the same pathological stage and significantly better than that of patients not receiving No. 10 LN dissection.

Author Disclosures

Jian-Xian Lin, Ying-Qi Huang, Yi-hui Tang, Jian-Wei Xie, Jia-Bin Wang, Jun Lu, Qi-Yue Chen, Long-Long Cao, Mi Lin, Ru-Hong Tu, Ze-Ning Huang, Ju-Li Lin, Ping Li1, Chang-Ming Huang and Chao-Hui Zheng have no conflict of interest or financial ties to disclose.

Author contributions

Lin JX, Huang YQ, Zheng CH, Huang CM and Li P conceived of the study, analyzed the data, and drafted the manuscript, Tu RH, Tang YH, Xie JW, Wang JB, and Huang ZN helped revise the manuscript critically for important intellectual content, Wang ZK, Lu J, Lin JL, Chen QY, Cao LL, and Lin M helped collect data and design the study.

Funding

This study was supported by Minimally invasive medical center of Fujian Province (No. [2017]171) and Scientific and Technological Innovation Joint Capital Projects of Fujian Province (2017Y9011).

Acknowledgements

The authors thank all the medical staff who contributed to the maintenance of the medical record database.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Informed consent from all individual participants was waved because of the retrospective nature of this study.

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Table 1. Clinicopathologic characteristics after PSM. (N=1119)

Characteristics	LDG(n=373)		P*	LTG+No.10(n=373)		P^#	LTG-No.10(n=373)		P^$
Characteristics	No. of case	%	P*	No. of case	%	P^#	No. of case	%	P^$
Age(y)			0.941			1.000			0.941
<65	201	53.9		200	53.6		200	53.6
≥65	172	46.1		173	46.4		173	46.4
Gender			0.005			0.196			<0.001
Male	259	69.4		293	78.6		307	82.3
Female	114	30.6		80	21.4		66	17.7
BMI			0.560			0.773			0.769
≥25	61	16.4		67	18.0		64	17.2
<25	312	83.6		306	82.0		309	82.8
CA-199			0.672			0.258			0.478
<37.0	319	85.5		323	86.6		312	83.9
≥37.0	54	14.5		50	13.4		61	16.4
CEA			0.342			0.558			0.125
<5.0	291	78.0		280	75.1		273	73.2
≥5.0	82	22.0		93	24.9		100	26.8
Abdominal surgery history			0.369			0.369			1.000
No	324	86.9		332	89.0		324	86.9
Yes	49	13.1		41	11.0		49	13.1
ASA			0.291			0.231			0.384
I	215	57.6		228	61.1		205	55.0
II	142	38.1		136	36.5		157	42.1
III	16	4.3		9	2.4		11	2.9
Number of lesions			<0.001			0.318			0.003
Single	370	99.2		351	94.1		357	95.7
Multiple	3	0.8		22	5.9		16	4.3
Tumor Location			<0.001			0.484			<0.001
Upper	0	0.0		154	41.3		156	41.8
Middle	7	1.9		126	33.8		137	36.7
Lower	356	95.4		0	0.0		0	0.0
Mixed	10	2.7		93	24.9		80	21.4
Characteristics	LDG(n=373)		P*	LTG+No.10(n=373)		P^#	LTG-No.10(n=373)		P^$
Characteristics	No. of case	%	P*	No. of case	%	P^#	No. of case	%	P^$
Tumor Location*			0.053			0.028			0.794
Lesser	289	77.5		310	83.1		286	76.7
Non-lesser	84	22.5		63	16.9		87	23.3
Borrmann type			0.119			0.670			0.256
Non-type 4	334	89.5		320	85.8		324	86.9
Type 4	39	10.5		53	14.2		49	13.1
Tumor Size(mm)			0.934			0.396			0.351
<40	98	26.3		97	26.0		87	23.3
≥40	275	73.7		276	74.0		286	76.7
Histologic type			0.542			0.536			0.219
Differentiated	235	63.0		243	65.1		251	67.3
Undifferentiated	138	37.0		130	34.9		122	32.7
Lymphovascular invasion			0.518			1.000			0.518
Negative	269	72.1		261	70.0		261	70.0
Positive	104	27.9		112	30.0		112	30.0
Perineural invasion			0.002			0.001			0.928
Negative	295	79.1		257	68.9		296	79.4
Positive	78	20.9		116	31.1		77	20.6
pT			0.997			0.941			0.904
1	50	13.4		52	13.9		52	13.9
2	39	10.5		38	10.2		33	8.8
3	129	34.6		129	34.6		131	35.1
4a	155	41.6		154	41.3		157	42.1
pN			0.989			0.873			0.911
0	105	28.2		107	28.7		107	28.7
1	54	14.5		54	14.5		45	12.1
2	69	18.5		68	18.2		73	19.6
3	145	38.9		144	38.6		148	39.7
pTNM Stage			0.973			0.710			0.965
I	68	18.2		70	18.8		70	18.8
II	84	22.5		85	22.8		76	20.4
III	221	59.2		218	58.4		227	60.9

* Significance level of comparison of characteristics between the LDG group and LTG+No.10 group.

# Significance level of comparison of characteristics between the LTG+No.10 group and the LTG-No.10 group.

$ Significance level of comparison of characteristics between the LDG group and the LTG-No.10 group.

Table 2. Lymph node metastasis of each station.

Lymph node station	LDG		P*	LTG+No.10		P^#	LTG-No.10		P^$
Lymph node station	No. of case	%	P*	No. of case	%	P^#	No. of case	%	P^$
No.1	30	8.0	<0.001	69	18.5	0.925	68	18.2	<0.001
No.2	/	/	/	84	22.5	0.724	80	21.4	/
No.3	201	53.9	0.032	230	61.7	0.411	219	58.7	0.184
No.4	154	41.3	<0.001	93	24.9	0.162	110	29.5	0.001
No.5	108	29.0	<0.001	35	9.4	0.624	39	10.5	<0.001
No.6	183	49.1	<0.001	52	13.9	0.358	61	16.4	<0.001
No.7	94	25.2	0.051	118	31.6	0.215	134	35.9	0.001
No.8	75	20.1	0.068	56	15.0	0.171	70	18.8	0.644
No.9	69	18.5	0.148	85	22.8	0.347	96	25.7	0.017
No.10	/	/	/	39	10.5	/	/	/	/
No.11	53	14.2	0.033	75	20.1	0.856	77	20.6	0.021
No.12a	65	17.4	<0.001	31	8.3	0.014	47	12.6	0.133

* Significance level of comparison of lymph node metastasis rates between the LDG group and LTG+No.10 group.

# Significance level of comparison of lymph node metastasis rates between the LTG+No.10 group and the LTG-No.10 group.

$ Significance level of comparison of lymph node metastasis rates between the LDG group and the LTG-No.10 group.

Table 3. Mutivariate analysis of clinicopathologic variables in relation to OS in patients undergoing potentially curative resection for gastric cancer.

Variables	LDG(n=373)		P	LTG(n=746)		P
Variables	HR	95% CI	P	HR	95% CI	P
Age(y)
<65	Ref			Ref
≥65	1.585	1.159-2.168	0.004	1.320	1.072-1.626	0.009
CA-199
<37.0	Ref			/	/	/
≥37.0	2.042	1.407-2.964	<0.001	/	/	/
CEA
<5.0	/	/	/	Ref
≥5.0	/	/	/	1.462	1.173-1.821	0.001
Tumor Size(mm)
<40	Ref			/	/	/
≥40	3.188	1.657-6.136	0.001	/	/	/
Borrmann type
Non-type 4	/	/	/	Ref
Type 4	/	/	/	1.808	1.400-2.334	<0.001
Histologic type
Differentiated	Ref			/	/	/
Undifferentiated	1.486	1.080-2.044	0.015	/	/	/
Lymphovascular invasion
Negative	/	/	/	/	/	/
Positive	/	/	/	/	/	/
Perineural invasion
Negative	/	/	/	Ref
Positive	/	/	/	1.444	1.150-1.813	0.002
pTNM Stage			<0.001			<0.001
I	Ref			Ref
II	1.143	0.483-2.703	0.761	1.674	1.010-2.776	0.046
III	3.203	1.447-7.090	0.004	4.757	3.065-7.384	<0.001
No.10 lymphadenectomy
No	/	/	/	Ref
Yes	/	/	/	0.650	0.524-0.805	<0.001

Table 4. Mutivariate analysis of clinicopathologic variables in relation to CSS in patients undergoing potentially curative resection for gastric cancer.

Variables	LDG(n=373)		P	LTG(n=746)		P
Variables	HR	95% CI	P	HR	95% CI	P
Age(y)
<65	/	/	/	/	/	/
≥65	/	/	/	/	/	/
CA-199
<37.0	Ref			Ref
≥37.0	2.324	1.576-3.426	<0.001	1.335	1.018-1.752	0.037
CEA
<5.0	/	/	/	Ref
≥5.0	/	/	/	1.414	1.121-1.784	0.003
Tumor Size(mm)
<40	Ref			/	/	/
≥40	3.457	1.690-7.072	0.001	/	/	/
Borrmann type
Non-type 4	/	/	/	Ref
Type 4	/	/	/	1.604	1.227-2.098	0.001
Histologic type
Differentiated	Ref			/	/	/
Undifferentiated	1.560	1.112-2.189	0.010	/	/	/
Lymphovascular invasion
Negative	/	/	/	/	/	/
Positive	/	/	/	/	/	/
Perineural invasion
Negative	/	/	/	Ref
Positive	/	/	/	1.427	1.127-2.098	0.003
pTNM Stage			<0.001			<0.001
I	Ref			Ref
II	0.895	0.350-2.286	0.817	2.758	1.436-5.297	0.002
III	2.952	1.262-6.909	0.013	9.608	5.347-17.265	<0.001
No.10 lymphadenectomy
No	/	/	/	Ref
Yes	/	/	/	0.658	0.548-0.858	0.001
Adjuvant therapy
No	/	/	/	Ref
Yes	/	/	/	0.661	0.514-0.850	0.001

Table 5. Patterns of recurrence between different groups.

Patterns of recurrence	LDG(n=373)		P*	LTG+No.10(n=373)		P^#	LTG(n=373)		P^$
Patterns of recurrence	No. of case	%	P*	No. of case	%	P^#	No. of case	%	P^$
Recurrence			0,812			0.001			0.005
No	240	59.2		238	60.3		218	48.8
Yes	129	34.6		129	34.6		150	40.2
Unclear	4	6.2		6	5.1		5	11.0
Local			0.777			1.000			0.777
No	345	92.5		347	93.0		347	93.0
Yes	28	7.5		26	7.0		26	7.0
Lymphonodus			0.892			0.109			0.083
No	344	92.2		343	92.0		330	88.5
Yes	29	7.8		30	8.0		43	11.5
Local	8	2.1	0.244	4	1.1	0.027	13	3.5	0.268
Distant	23	6.2	0.657	26	7.0	0.148	37	9.9	0.059
Hematogenous			1.000			0.037			0.037
No	329	88.2		329	88.2		309	82.8
Yes	44	11.8		44	11.8		64	17.2
Peritoneum			0.797			0.074			0.126
No	339	90.9		341	91.4		326	87.4
Yes	34	9.1		32	8.6		47	12.6

* Significance level of comparison of recurrence patterns between the LDG group and LTG+No.10 group.

# Significance level of comparison of recurrence patterns between the LTG+No.10 group and the LTG-No.10 group.

$ Significance level of comparison of recurrence patterns between the LDG group and the LTG-No.10 group.

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Laparoscopic Splenic Hilar Lymph Node Dissection is Recommended for Pathologic Stage IIIA Middle and Upper Gastric Cancer: A Comparative Study with Standard D2 Laparoscopic Distal Gastrectomy

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