Respond to the reviewer(s)' comments (MS: 1202955429351138- A novel insight of sentinel
lymph node concept based on 1-3 positive nodes in patients with pT1-2 gastric cancer.)
We appreciate the reviewers’ positive comments and elaborative revision concerning our
manuscript. The reviewers were very helpful, and we have revised the manuscript in accordance
with their suggestions as indicated below:
Reviewer 1 (Elena Orsenigo)
1. The authors classify the design of the study as case-control (case group = SLM and control
group =1-3 positive nodes). Such denomination is reserved for studies that begin with the absence
or presence of an outcome and then look backward in time to try to detect possible causes or risk
factors. Departing from the “case control” design and taking into account the study groups, one
would expect analysis of correlation in order to identify difference in the distribution of
clinicopathological factors between the groups. Which risk factors were associated to the fact that
the patient presented just a single metastatic node or 1-3 positive nodes? The distribution of
positive nodes throughout the lymph node stations is not a risk factor for the study groups being
studied. I would give the denomination “retrospective study conducted on a prospectively
collected database”.
Reply:
Many thanks for your suggestion. It is not appropriate indeed that we classify the design of the
study as case-control. We accept the denomination “retrospective study conducted on a
prospectively collected database” and it has been added in the revised manuscript. ( page 1 as
highlighted in red color). In order to find which risk factors were associated to the fact that the
patient presented just a single metastatic node or more than one positive node, we analyzed the
clinicopathological factors between two groups. However, there was no significant difference
between them except for the lymphatic/venous invasion (detailed in the followed table). In this
study, the main content is to compare the distribution difference between SLM and 1-3 positive
nodes. So we think it might not be suitable to add it in the manuscript if you agree.
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Tab.1 the association between clinicopathological factors and number of positive nodes
number of positive nodes
factors
1.382
0.24
58.2 ± 10.4
0.936
0.334*
3.9 ± 1.1
0.004
0.952*
1.124
0.289
2.714
0.257
0.286
0.867
0.184
0.668
2.167
0.141
5.559
0.062
4.597
0.032
94 (42.0)
female
43 (66.2)
22 (33.8)
mean ± sd
59.4 ± 10.4
mean ± sd
3.9 ± 1.2
D2
123 (58.0)
89 (42.0)
more than D2
50 (64.9)
27 (35.1)
age (year)
tumor size(cm)
tumor site
L
129 (62.3)
78 (37.7)
M
17 (60.7)
11 (39.3)
U
27 (50.0)
27 (50.0)
T1
17（60.7）
11（39.3）
T2a
53（57.6）
39（42.4）
T2b
103 (60.9)
66 (39.1)
well/moderately
79 (61.2)
50 (38.8)
poorly
94 (58.8)
66 (41.2)
depth of tumor
invasion
differentiation
P value
more than one node (%)
130 (58.0)
sex
lymphadenectomy
ｘ2
SLM (%)
male
macroscopic type
lauren type
lymphatic/venous
invasion
Borr. 1/2
Borr. 3/4
intestenal
diffused
mixed
37 (68.5)
17 (31.5)
119 (57.5)
88 (42.5)
66 (59.5)
45 (40.5)
99 (58.2)
71 (41.8)
8 (100.0)
0 (0.0)
-
152（62.6）
91（37.4）
+
21（45.7）
25（54.3）
note: * the difference was tested by unpaired t test
2. The inclusion criteria of the present study is patients with pT1/2 with SLM or 1-3 metastatic
nodes. One of the limitations of this paper is the applicability of the results in the context of
clinical routine practice, as patients usually considered eligible for sentinel node trial is those
clinically staged as cT1/2cN0. Were all the patients enrolled in the study staged as clinically node
negative by the preoperative imaging workup? A clinically node positive patients should not be
offered the sentinel node technique.
Reply:
Thank you for your good question. The patients in this study were staged as node negative and no
macroscopic serosal invasion during operation by surgeons, and proved as pT1/2 with 1-3
metastatic nodes pathologically after surgery, according to the records. As this was a retrospective
study, only in recent ten to fifteen years endoscopic ultrasonography (EUS) and spiral computed
tomography (CT) scan were used to diagnose in most patients, and who were all staged as
clinically node negative (cN0) by the preoperative imaging workup. This was added in the
manuscript in page 5.
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3. One of the most important finding of the study is the analysis of transversal and 2 stations
lymph node metastasis. The possibility to identify such pattern of lymph node invasion would
guide the surgeon to extend the lymphatic dissection in order to avoid the occurrence of false
negative SLN, in the context of SLN biopsy. In cases of tumor located in the lesser (or great)
curvature with negative SLN, when would the authors propose the dissection of transverse lymph
node station or the dissection of more than one station?
Reply:
Thanks for the constructive suggestion. The correlation between clinicopathological features and
transversal and 2 stations lymph node metastasis was analyzed in order to find some associated
factors. However, there was no significant association between them (detailed in tab.4). The most
possible reason for the high frequency of transversal and 2 stations lymph node metastasis might
be the multidirectional and complicated lymphatic flow from stomach. These were supplied in the
revised manuscript. In our study, among patients with 2 stations involved in N2 compartment, 4
patients located in the upper third of stomach were all proved as ss (pT2b), 1 patient in the middle
third was proved as ss (pT2b), and 2 patients in the lower third were proved as sm (pT1) and as
mp (pT2a), respectively. With an increase of T parameter, a progressively augmented nodal
involvement was showed in 2 stations. Therefore, although we don’t propose exactly when should
perform the dissection of transverse lymph node station or the dissection of more than one station,
all these data suggest that D2 lymphadenectomy should be essential in patients with pT2 stage,
and the en-bloc dissection of lymphatic basins from the cancer should be performed to avoid the
occurrence of false negative SLN, in the context of SLN biopsy, as the existence of high frequency
of transversal and 2 stations lymph node metastasis.
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Tab.4 The correlation between clinicopathological factors and transversal and 2 stations
lymph node metastasis
transversal metastasis
factors
2 station positive nodes
ｘ2
- (%)
+ (%)
male
88 (58.3)
63 (41.7)
female
20 (46.5)
23 (53.5)
age (year)
tumor
size(cm)
mean ± sd
58.4 ± 9.8
58.3 ± 11.5
0.005
mean ± sd
3.6 ± 1.1
3.5 ± 1.3
lymphadenectomy
D2
81 (54.4)
68 (45.6)
more than D2
27 (60.0)
18 (40.0)
L
75 (52.4)
68 (47.6)
M
12 (75.0)
4 (25.0)
21 (60.0)
14 (40.0)
sex
tumor site
U
depth of tumor
invasion
differentiation
macroscopic
type
lauren type
lymphatic/venous invasion
T1
14（58.3） 10（41.7）
T2a
31（49.2） 32（50.8）
ｘ2
P value
0.003
0.958
59.5 ± 11.2
0.204
0.652*
3.9 ± 1.2
4.0 ± 1.0
0.581
0.446*
168 (79.2)
44 (20.8)
2.243
0.134
67 (87.0)
10 (13.0)
173 (83.6)
34 (16.4)
21 (75.0)
7 (25.0)
2.463
0.292
3.318
0.19
0.773
0.379
2.068
0.15
4.027
0.134
0.433
0.511
- (%)
+ (%)
182 (81.3)
42 (18.7)
53 (81.5)
12 (18.5)
0.942*
58.6 ± 10.2
0.195
0.659*
0.445
0.505
1.878
3.29
1.582
P value
0.171
0.193
0.453
41 (75.9)
13 (24.1)
26（92.9）
2（7.1）
76（82.6）
16（17.4）
T2b
63 (58.9)
44 (41.1)
133 (78.7)
36 (21.3)
well/moderately
47 (54.0)
40 (46.0)
102 (79.1)
27 (20.9)
poorly
61 (57.0)
46 (43.0)
133 (83.1)
27 (16.9)
Borr. 1/2
Borr. 3/4
intestenal
diffused
mixed
22 (64.7)
12 (35.3)
72 (52.9)
64 (47.1)
41 (55.4)
64 (56.1)
3 (50.0)
3 (50.0)
0.173
0.677
47 (87.0)
7 (13.0)
162 (78.3)
45 (21.7)
33 (44.6)
85 (76.6)
26 (23.4)
50 (43.9)
142 (83.5)
28 (16.5)
8 (100.0)
0 (0.0)
196（80.7）
47（19.3）
39（84.8）
7（15.2）
-
89（55.3） 72（44.7）
+
19（57.6） 14（42.4）
1.523
0.217
0.09
0.956
0.059
0.809
note: * the difference was tested by unpaired t test
4. The authors at the end concluded that D2 lymph node dissection is essential in pT2 tumors. The
data derived from the study that guided the authors to draw such conclusion was the fact that the
higher occurrence of skip metastasis and higher frequency of some stations involved in N2
compartment in these patients. However the formal indication of D2 lymph node dissection in
cases of pT2 tumors resides in a more simple fact that the chances of lymph node metastasis in
this subset is pretty much high (more than 50%) and the performance of SLN technique would
benefit only a small proportion of node negative patients.
Reply:
Many thanks for your constructive suggestion. We totally agree that the formal indication of D2
lymphadenectomy in pT2 tumors resides in the higher frequency of lymph node metastasis. In this
study, we draw such conclusion only from another fact that the higher occurrence of skip
metastasis and higher frequency of some stations involved in N2 compartment in these patients.
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After thoughtful consideration, this conclusion is not closely correlated with the topic of the study.
We deleted this sentence and added “Transversal and 2 stations lymph node metastasis are
common” in conclusion (page 2 and 13).
Reviewer 2 (ShigehroYanagita)
In pathological analysis, it is not sentinel node strictly as they described. How much is the size of
metastasis? It should be described. Macrometastasis? micrometastasis? Isolated tumor cells? If the
metastasis occupay the lymph node, the other metastasis may be from this metastasis. From this
point of view, this study design should be rearranged.
Reply:
Many thanks for your constructive questions. Because this was a retrospective study, some
drawbacks existed inevitably. The results from this study didn’t present the distribution of SN in
gastric cancer directly, as the routine methods in SLN biopsy were not used. However, it could
provide some valuable information for the use of SN concept in the practice. In our study, lymph
node metastasis referred to macrometastasis, as it was defined as direct extension of the primary
tumor into a lymph node(s) by routine hematoxylin and eosin staining. This was added in the
revised manuscript in page 4. Micrometastasis and isolated tumor cells were not included because
the methods, such as immunohistochemistry and so on, were not used in these patients. Some
pathological slices were reviewed by our pathologists again, and we found that most metastasis
occurred in the marginal sinus of lymph nodes, and not occupied the whole nodes.
The reviewers’ comments have helped us to strengthen our study. The revised parts are highlighted
in red color. We are not sure whether you will be satisfactory about our response or not. Anyway,
thank you very much for your comments.
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Hui-mian Xu, MD
Bao-jun HUANG, MD
Department of Surgical Oncology,
First Hospital of China Medical University
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