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. 2024 Nov 5;19(11):e0312385. doi: 10.1371/journal.pone.0312385

Analysis of clinicopathological factors associate with the visibility of early gastric cancer in endoscopic examination and usefulness of linked color imaging: A multicenter prospective study

Kensuke Fukuda 1, Kazuhiro Mizukami 1,*, Daisuke Yamaguch 2, Yuichiro Tanaka 2, Kazutoshi Hashiguchi 3, Takashi Akutagawa 4, Ryo Shimoda 4, Sho Suzuki 5, Tadashi Miike 5, Yorinobu Sumida 6, Hidehito Maeda 7, Fumisato Sasaki 7, Ryosuke Gushima 8, Hideaki Miyamoto 8, Keiichi Hashiguchi 9, Naoyuki Yamaguchi 9, Tetsuya Ohira 10, Tetsu Kinjo 10, Ken Ohnita 11, Tomohiko Moriyama 12, Kensei Ohtsu 13, Akira Aso 14, Ryo Ogawa 1, Tetsuya Ueo 15, Masahide Fukuda 1
Editor: Elingarami Sauli16
PMCID: PMC11537390  PMID: 39499715

Abstract

Background

This study investigated clinicopathological factors associated with the visibility of early gastric cancer and the efficacy of linked color imaging.

Methods

Patients with early gastric cancer who underwent endoscopic treatment between April 2021 and July 2022 were enrolled. All cases underwent white light imaging and linked color imaging. Three experts evaluated lesion visibility using a visual analog scale. A mean score ≥3 on white light imaging was defined as “good visibility”, and <3 as “poor visibility”. We extracted patient information and endoscopic and pathological data for the lesion and background mucosa, analyzed factors associated with the visibility of early gastric cancer, and compared visibility between white light imaging and linked color imaging.

Results

Ninety-seven lesions were analyzed, with good visibility in 49 and poor visibility in 48. Multivariate analysis revealed small lesion size (odds ratio 1.89) and presence of endoscopic intestinal metaplasia (odds ratio 0.49) as significantly associated with the poor visibility of early gastric cancer. Mean visibility score was significantly higher for linked color imaging (P<0.001). Mean score for linked color imaging was significantly higher in the poor visibility group (P<0.001), but not significantly different in the good visibility group (P = 0.292). Mean score was significantly higher with linked color imaging in cases with endoscopic intestinal metaplasia (P = 0.0496) and lesions <20 mm in diameter (<10 mm, P = 0.002; 10–20 mm, P = 0.004).

Conclusions

Lesion size and endoscopic intestinal metaplasia are associated with the visibility of early gastric cancer in white light imaging. Linked color imaging improves visibility of gastric cancer with these factors.

Introduction

Although the number of gastric cancer cases and associated deaths are decreasing with the widespread use of Helicobacter pylori (H. pylori) eradication therapy, gastric cancer remains the sixth most common cancer worldwide and the fourth leading cause of cancer-related death [1]. Early endoscopic detection of gastric cancer is essential for reducing its mortality rate of gastric cancer [2, 3]. Gastric cancers occurring among H. pylori-uninfected patients and after H. pylori eradication have increased, and it has been noted that these gastric cancers have an endoscopic appearance that is different from the conventional differentiated adenocarcinoma commonly observed in H. pylori-infected patients [4–6].

Gastric cancers after H. pylori eradication are also more difficult to visualize endoscopically than conventional gastric adenocarcinomas. In the gastric mucosa after H. pylori eradication, diffuse redness disappears due to the recovery from inflammation and atrophy, and a map-like appearance of mottled, patchy redness appears [7]. Further, gastric cancer after H. pylori eradication is characterized by endoscopic findings such as redness, flat depressed lesions, and small size [8, 9] and histological features include the presence of non-neoplastic mucosa covering the tumor surface, as a "gastritis-like appearance" [10]. For these reasons, detecting gastric cancer after H. pylori eradication may be more difficult [11].

What clinicopathological characteristics of gastric cancer make endoscopic detection difficult? Although some studies have examined the characteristics of each gastric cancer type, no study have comprehensively examined the association between endoscopic visibility of gastric cancer and patients’ background, endoscopic findings, pathological findings. The primary endpoint of this study was to identify clinicopathological factors associated with the visibility of early gastric cancer on endoscopy.

In addition, Linked color imaging (LCI) is an image-enhanced endoscopy that has been shown to improve the visibility of gastrointestinal neoplasms compared to white light imaging (WLI) [12, 13]. We therefore investigated whether LCI can improve visibility for these lesions.

Methods

Study subjects

This multicenter, prospective study was conducted from April 30, 2021 to July 31, 2022 by GI-Kyushu, a clinical research organization involving 15 high-volume facilities in the Kyushu region of Japan. All subjects provided written informed consent for inclusion before participating in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the ethics committees of Oita University (No. 1928) and registered with the University Hospital Medical Information Network (UMIN No. 000042069). Patients aged >20 years old with early flat-type gastric cancer (0-IIa, IIb, or IIc) ≤30 mm who consented to participate were consecutively enrolled in the study. Patients with gastric cancer that obviously invaded the submucosa and was not indicated for endoscopic treatment or postoperative stomach, or were deemed inappropriate by the responsible physician were excluded from this study.

Endoscopic equipment

The LASEREO/ELUXEO system (light source LL-7000/BL-7000, processor VP-7000; Fujifilm Corp., Tokyo, Japan) and a high-definition monitor were used. The LCI mode of this system acquires high-contrast blood vessel information and rich color information by irradiating short-wavelength narrow-band light and white light, enabling enhancement of slight differences in mucosal color by extending saturation and hue differences of colors close to mucosal color.

Endoscopic imaging

Endoscopy was performed by 18 endoscopy experts, each with over 12 years of experience. Endoscopic observation was performed in accordance with the recommendations in the quality assurance manual of endoscopic screening for gastric cancer in Japanese communities [14]. Endoscopic images were taken at the following 20 locations with WLI and LCI: antegrade view of upper, middle, lower, posterior wall of gastric body, posterior wall of upper gastric angle, four-quadrant views of gastric antrum, retroflexed view of lesser curvature of gastric angle, lesser curvature of lower, middle, upper gastric body, antegrade view of anterior wall and greater curvature of lower, middle, upper gastric body, retroflexed view of cardia, posterior wall of lower gastric body, antegrade view of posterior wall of gastric angle, prepylorus. Twenty images of WLI and LCI per case were taken with the same composition (S1 Fig). These images did not focus on the target lesion. At least one of the 20 images should include the lesion. All endoscopic images were collected from participating centers at a central adjudication facility, randomized by WLI and LCI, and then sent to three experts for visibility assessment.

Assessment of lesion visibility

Three endoscopic experts (22, 23, and 28 years of endoscopic experience, respectively) from the participating institutions were selected to evaluate the visibility of lesions. They were not involved in any endoscopic examinations related to this study. Evaluators were blinded to all patient and lesion information, except that the number of lesions was only informed to evaluators if a case had multiple lesions. Three endoscopists independently searched for lesions in 20 randomly arranged screening images and evaluated their visibility using the five-point visual analog scale (VAS) ranging from 1(poor: not detectable or detected wrong site) to 5(detectable at a glance). Visibility was assessed by both WLI and LCI, with the order of searching randomly determined for each case. The results of the evaluations by each endoscopists were sent to a central adjudication facility and collected. Representative images of lesions with different visibility scores on WLI are shown in Fig 1. Lesions with mean visibility score ≥3 by 3 endoscopists on WLI showed "good visibility" and lesions with mean visibility score <3 on WLI showed "poor visibility".

Fig 1. Representative images of early gastric cancer with mean visibility score of 1.0, 3.0, 5.0 on WLI.

Fig 1

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(a) Type 0-IIb early gastric cancer located on posterior wall of gastric angle (yellow triangle). Mean visibility score of this lesion was 1.0. (b) Type 0-IIc early gastric cancer located on lesser curvature of the upper gastric body (yellow triangle). Mean visibility score of this lesion was 3.0. (c) Type 0-IIc early gastric cancer located on greater curvature of gastric antrum (yellow triangle). Mean visibility score of this lesion was 5.0.

Patient and endoscopic information

The following background information was collected for patients: age, sex, underlying disease, medication, and H. pylori infection status. H. pylori infection status was defined as follows. Patients without endoscopic atrophy (C0/1) and with negative results for the rapid urease test (RUT) and urea breath test (UBT) were considered uninfected. Current infection was considered present if at least one of the RUT or UBT was positive regardless of the degree of endoscopic atrophy. Patients with history of eradication or endoscopic atrophy (≥C2) but negative RUT and UBT were considered to show past infection. The following information about the lesion and background mucosa was evaluated and registered by endoscopists at each institution as endoscopic findings. For lesions, location, size, color, and morphology were registered. For background mucosa, endoscopic atrophy, intestinal metaplasia (IM), and map-like redness were evaluated using the Kyoto classification of gastritis [15]. Endoscopic atrophy was evaluated based on the Kimura–Takemoto classification [16]: C-0, none; C-1 or C-2, mild; C-3 or O-1, moderate; and O-2 or O-3, severe. The following endoscopic findings on WLI were used as indicators of IM: whitish mucosa, rough or uneven mucosal surface, and villous appearance. A previous study found that when these endoscopic findings on WLI were defined as IM, the diagnostic accuracy of IM improved with sensitivity of 94.6%, specificity of 69.1%, and ROC/AUC of 0.818 [17]. The degree of IM was classified as none, patchy, partial, or total.

Histological evaluation

All early gastric cancers enrolled in this study were treated by ESD. Tumor size, histology, invasion depth, and proportion of epithelium with low-grade atypia (ELA) were evaluated in the resected specimen. According to previous reports [18, 19], ELA was pathologically defined as low-grade atypia or normal columnar epithelium covering the cancer surface. The degree of ELA was calculated as the number of sections showing ELA divided by the number of sections of the lesion: 0%, none; ≤33%, mild; 34–66%, moderate; and ≥67%, severe. Pathological evaluation of gastric background mucosa was performed using the normal mucosal area of the specimen removed by ESD. Histological assessment of inflammation, neutrophil activity, atrophy, and IM of surrounding mucosa were based on the updated Sydney System [20]. In three of the 12 facilities (Nagasaki University, Kumamoto University, and Inoue Hospital), only 12 lesions were evaluated by expert pathologists at each center. The remaining resection specimens were collected at Oita University and evaluated by an expert pathologist.

Statistical analysis

Continuous variables such as patient age and lesion size were expressed as median and range. Univariate and multivariate analyses using logistic regression analyses were performed to examine clinicopathological factors related to lesion visibility, factors that were significant in the univariate analysis were imputed to the multivariate analysis. Interobserver agreement for WLI and LCI was calculated using Fleiss’s kappa. The Wilcoxon signed-rank sum test was used to compare visibility scores between WLI and LCI. All statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Values of P<0.05 were considered significant.

Results

Baseline characteristics of patients, early gastric cancer, and background gastric mucosa

Between April 2021 and July 2022, 110 lesions (108 patients) were enrolled. Of these, 4 lesions >3 cm, 6 adenomas, 1 type 0-I lesion, and 2 lesions with insufficient patient/lesion information were excluded. Ninety-seven lesions in 96 patients were then analyzed, with 49 lesions in the good visibility group and 48 lesions in the poor visibility group (Fig 2). Interobserver agreement for lesion visibility by three evaluators was 0.526 for WLI and 0.504 for LCI. Baseline characteristics of patients, lesions, and background mucosa are shown in Table 1. H. pylori infection status was uninfected in 8.2%, current in 21.6%, and past infection in 70.1%. Median lesion size was 11.0 mm, 70 lesions (72.2%) were reddish in color, 66 lesions (68%) were depressed type, and 79 lesions (81.4%) were well-differentiated adenocarcinoma. The background mucosa showed moderate or severe atrophy in 83 lesions (85.6%) and endoscopic IM in 72 lesions (74.2%).

Fig 2. Study flowchart.

Fig 2

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Good visibility, lesions with mean visibility score ≥3 on WLI; poor visibility, lesions with mean visibility score <3 on WLI.

Table 1. Baseline characteristics of patients and early gastric cancer and background gastric mucosa.

n (%)
Total number of lesions 97
Age (year), median (IQR) 73.0 (43–92)
Sex
Male 77 79.4
Female 20 20.6
Comorbidities
Hypertension 45 46.4
Diabetes 20 20.6
Reflux esophagitis 7 7.2
Other organ cancer 14 14.4
Medicine
Anti-acid drugs 30 30.9
Low-dose aspirin 16 16.5
Anticoagulants 10 10.3
Prednisolone 3 3.1
NSAIDs 3 3.1
H. pylori
Uninfected 8 8.2
Current infection 21 21.6
Past infection 68 70.1
Tumor location
U 19 19.6
M 38 39.2
L 40 41.2
Color
Whitish 16 16.5
Normal tone 11 11.3
Redness 70 72.2
Macroscopic type
0-IIa 19 19.6
0-IIb 9 9.3
0-IIc 66 68.0
Others 3 3.1
Tumor size (mm), median (IQR) 11.0 (2–30)
Histological type
Undifferentiated 6 6.2
Moderately differentiated 12 12.4
Well-differentiated 79 81.4
Endoscopic atrophy
None 5 5.2
Mild (C-1, C-2) 9 9.3
Moderate (C-3, O-1) 31 32.0
Severe (O-2, O-3) 52 53.6
Endoscopic intestinal metaplasia
None 25 25.8
Patchy 18 18.6
Partial 29 29.9
Overall 25 25.8
Map-like redness
None 58 59.8
Patchy 7 7.2
Partial 26 26.8
Overall 6 6.2
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Data were presented as number (percentage) of patients unless otherwise indicated. Data for age and tumor size are presented as median. IQR, interquartile range; NSAIDs, non-steroidal anti-inflammatory drugs.

Univariate and multivariate analysis of factors associated with visibility of early gastric cancer on WLI

Of the 97 lesions, 49 were classified as good visibility group and 48 as poor visibility group. Only small lesion size (odds ratio [OR] 1.89, 95% confidence interval [CI] 1.07–3.34) and presence of endoscopic IM (OR 0.52, 95%CI 0.29–0.93) were significantly associated with poor visibility of lesion on WLI in univariate analyses (P = 0.03, P = 0.03, respectively). Visibility was not associated with any pathological factors, including degree of ELA. Multivariate analysis identified small lesion size (OR 1.93, 95%CI 1.07–3.46; P = 0.03) and presence of endoscopic IM (OR 0.49, 95%CI 0.27–0.91; P = 0.02) as factors independently associated with poor visibility of lesion on WLI (Table 2).

Table 2. Univariate and multivariate analysis of factors associated with visibility of early gastric cancer on WLI.

Univariate analysis Multivariate analysis
OR 95%Cl P-Value OR 95%Cl P-Value
Age 1.01 0.96–1.06 0.73
Male sex 0.617 0.23–1.68 0.34
Comorbidities
Hypertension 1.05 0.47–2.32 0.91
Diabetes 0.449 0.16–1.25 0.13
Reflux esophagitis 1.33 0.28–6.30 0.72
Other organ cancer 1.89 0.58–6.13 0.29
Medicine
anti acid drugs 0.8 0.34–1.90 0.61
low dose aspirin 0.98 0.33–2.85 0.96
anticoagulant 0.38 0.09–1.57 0.18
Prednisolone 0.48 0.04–5.47 0.55
NSAIDs 0 0.04-Inf 0.99
H. pylori
uninfection 0.98 0.23–4.16 0.98
current infection 1.41 0.53–3.72 0.49
past infection 0.77 0.32–1.83 0.55
Tumor location
U 0.86 0.31–2.33 0.76
M 0.81 0.36–1.84 0.62
L 1.36 0.60–3.06 0.46
Color
Normal tone 0.52 0.14–1.91 0.33
Redness 1.4 0.57–3.42 0.46
Whitish 0.98 0.33–2.85 0.96
Macroscopic type
0-Ⅱa 1.23 0.48–3.20 0.67
0-Ⅱb 1.25 0.32–4.97 0.76
0-Ⅱc 0.84 0.35–2.03 0.70
Tumor size (0<10mm, 1<20mm, 2≦30㎜) 1.89 1.07–3.34 0.03* 1.93 1.07–3.46 0.03*
Endoscopic atrophy 0.96 0.60–1.54 0.87
none 0.64 0.10–4.00 0.63
mild (C-1, C-2) 1.25 0.32–4.97 0.75
moderate (C-3, O-1) 1.29 0.55–3.04 0.56
severe (O-2, O-3) 0.81 0.36–1.80 0.61
Endoscopic intestinal metaplasia 0.52 0.29–0.93 0.03* 0.49 0.27–0.91 0.02*
none 3.4 1.26–9.15 0.02*
patchy/partial 0.64 0.29–1.41 0.27
overall 0.56 0.22–1.42 0.23
Maplike redness 0.78 0.46–1.30 0.34
none 1.9 0.83–4.32 0.13
patchy/partial 0.51 0.22–1.19 0.12
overall 0.98 0.19–5.11 0.08
Histological type 0.78 0.38–1.61 0.50
Well differentiated 0.59 0.21–1.68 0.32
Moderately differentiated 2.15 0.60–7.67 0.24
Undifferentiated 0.98 0.19–5.11 0.98
Depth of tumor (M/SM1 vs SM2) 3.07 0.31–30.60 0.34
ELA (non/mild vs moderate/severe) 0.74 0.33–1.69 0.48
Histological atrophy 1.34 0.59–3.06 0.48
Histological IM 1.13 0.51–2.51 0.77
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Uni- and multivariate analyses using logistic regression analysis were performed to examine clinicopathological factors related to lesion visibility. WLI, White light imaging; OR, odds ratio; CI, confidence interval; NSAIDs, non-steroidal anti-inflammatory drugs; M, tumor confined to the mucosa or invasion into the muscularis mucosa; SM1, tumor invasion less than 0.5 mm into the submucosa; SM2, tumor invasion of 0.5 mm or more into the submucosa; ELA, epithelium with low-grade atypia * Statistically significant.

Comparison of lesion visibility on WLI and LCI

Lesion visibility was better with LCI (median, 3.3 [Interquartile Range (IQR), 2.3–4.0]) than with WLI (median, 3.0 [IQR, 1.7–4.0]) (P<0.001) (Fig 3). Fig 4 shows representative images of a lesion that was classified as poor visibility on WLI but was improved to good visibility on LCI. In the good visibility group, visibility did not differ significantly between WLI (median, 4.0 [IQR, 3.3–4.5]) and LCI (median, 4.0 [IQR, 3.7–4.5]) (P = 0.29). In the poor visibility group, visibility was significantly better with LCI (median, 2.3 [IQR, 1.3–3.0]) than with WLI (median, 1.6 [IQR, 1.3–2.3]) (P<0.001) (Fig 5).

Fig 3.

Fig 3

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Comparison of mean visibility score between WLI and LCI. WLI, White light imaging; LCI, Linked color imaging; *, statistically significant.

Fig 4. Representative images of early gastric cancer in which the visibility was classified as poor visibility on WLI but improved to good visibility on LCI.

Fig 4

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Type 0-Ⅱc early gastric cancer, 9 mm in size, located on posterior wall of the upper gastric body (yellow triangle). The mean visibility score on WLI was 1.7, which was classified as poor visibility (a), but the mean visibility score on LCI improved to 3.0 (b). WLI, White light imaging; LCI, Linked color imaging.

Fig 5. Comparison of mean visibility score of WLI and LCI in good visibility lesions and poor visibility lesions.

Fig 5

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WLI, White light imaging; LCI, Linked color imaging; good visibility, lesions with mean visibility score ≥3 on WLI; poor visibility, lesions with mean visibility score <3 on WLI; *, statistically significant.

In lesions without IM (n = 25), no significant difference in mean visibility score was seen between WLI (median, 3.7 [IQR, 2.7–4.3]) and LCI (median, 3.7 [IQR, 3.0–4.3]) (P = 0.29). In lesions with IM (n = 72), visibility was clearly better with LCI (median, 3.2 [IQR, 1.9–4.0]) than with WLI (median, 2.7 [IQR, 1.7–3.7])) (P = 0.0496). Regarding lesion size, another factor associated with visibility, visibility scores did not differ significantly between groups for lesions 21–30 mm (WLI median, 3.7 [IQR, 3.0–4.3]) vs. LCI median, 3.7 [IQR, 3.3–4.5]); P = 0.40), but were significantly better with LCI (median, 3.0 [IQR, 1.7–3.7])) than with WLI (median, 2.3 [IQR, 1.7–3.1]) (P = 0.002) for lesions <10 mm and with LCI (median, 3.3 [IQR, 2.4–4.3]) than with WLI (median, 3.0 [IQR, 1.7–4.3]) (P = 0.004) for lesions 11–20 mm (Fig 6).

Fig 6. Comparison of visibility score of WLI and LCI by presence or absence of intestinal metaplasia and lesion size.

Fig 6

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(a), (b) Comparison of visibility score of WLI and LCI by presence or absence of intestinal metaplasia, (c), (d), (e) Comparison of visibility score of WLI and LCI by lesion size. WLI, White light imaging; LCI, Linked color imaging; IM-, lesions without endoscopic intestinal metaplasia; IM+, lesions with mild or sever endoscopic intestinal metaplasia; *, statistically significant.

Discussion

This is the first study that comprehensively examined factors affecting endoscopic visibility for early gastric cancer, including not only endoscopic and pathological findings of gastric cancer and background mucosa but also, patient background and H. pylori infection status. We also investigated the effectiveness of LCI on the visibility of early gastric cancer. The results showed that lesion size and endoscopic IM are associated with the visibility of early gastric cancer in WLI and LCI improves visibility of gastric cancer with negative visibility factors.

The characteristics of gastric cancer have changed, with the recent increases in gastric cancer after H. pylori eradication, the recognition of H. pylori-uninfected gastric cancer, and the establishment of new concepts. Gastric endoscopic screening is currently becoming more and more difficult to perform.

In the present study, the incidence rate of gastric cancer after eradication was overwhelmingly high. Previous studies have shown that H. pylori eradication suppresses the incidence of gastric cancer, but a certain percentage of gastric cancers still occur after eradication [21, 22]. Since the incidence rate of gastric cancer after H. pylori eradication is expected to increase with the spread of H. pylori eradication therapy, gastric endoscopic screening that contributes to gastric cancer detection after eradication will be required.

In the present study, endoscopic IM was an independent factor in making gastric cancer difficult to visualize. There are no studies that investigated the relationship between endoscopic findings of the gastric mucosa and the visibility of gastric cancer. IM is found in the course of chronic gastritis and atrophic gastritis caused by H. pylori infection and has been considered a risk factor for gastric cancer [23–25]. IM is characterized by morphological features such as villous appearance, whitish mucosa, and rough mucosal surface on WLI [17]. In addition, after H. pylori eradication, IM is characterized by the appearance of patchy, map-like redness, representing depressed erythema of various sizes [7]. In this study, type 0-I lesions were excluded as clearly identifiable, mostly type 0-II lesions with slight elevations or depressions, and frequently an erythematous tone. In general, early gastric cancer after H. pylori eradication is often differentiated adenocarcinoma, which endoscopically presents as small, erythematous, depressed lesions [26]. Early gastric cancer with subtle morphology and coloration may be intermingled in the gastric background mucosa with IM, reducing lesion visibility.

In this study, multivariate analysis showed the visibility of early gastric cancer worsened with decreasing size. Few papers have examined lesion size and visibility on WLI. A previous study revealed that small gastric tumors less than one cm in size were a risk factor of missed lesion during 12 months follow up after endoscopic resection of gastric tumors [27]. This result supports the results of the present study but included not only gastric cancer but also adenoma. The other study reported no significant difference in visibility comparing early gastric cancers ≥21 mm and ≤20 mm (OR 1.1, 95%CI 0.96–1.26; P = 0.161) [28]. Unlike previous studies, this study evaluated lesion visibility by identifying lesions in 20 images. This method assumes a situation consistent with actual clinical gastric screening endoscopy, and the results suggested that lesion size affects visibility during routine endoscopy.

Conversely, the degree of ELA was not associated with lesion visibility in this study. ELA represents a coating of tumor cells by epithelial cells with low or no cellular atypia [11, 18, 19]. It has been thought that gastric cancer after eradication, which is characterized by ELA, is more difficult to detect endoscopically than H. pylori current infection or uninfected gastric cancer. However, there are no study that clarify this. This study suggested that the degree of ELA and H. pylori infection status are not related to the visibility of gastric cancer.

The current study showed that endoscopic gastric screening with LCI improves gastric cancer visibility. LCI is an image-enhanced endoscopy that uses two types of narrow-band laser light to rearrange the color information obtained with narrow-band light and white light to enhance the tonal difference between reddish and whitish tones. In the diagnosis of early gastric cancer, LCI has also been shown to improve lesion visibility by significantly increasing the color difference between the lesion and surrounding mucosa [13, 29], and LCI has been shown to improve lesion visibility compared to WLI in endoscopic gastric screening [12, 30, 31]. The present results, as in previous studies, showed significantly improved lesion visibility scores for LCI compared to WLI. In particularly, the present study found no significant difference between LCI and WLI in lesions with good visibility on WLI. LCI significantly improved visibility in lesions with poor visibility on WLI. This suggests that LCI may facilitate detection for lesions that are difficult for endoscopists to find. Observations of LCI also showed improved visibility scores in lesions with IM. Previous studies have reported that IM exhibits purple called “lavender color” when observed using LCI [32]. It has also been shown that LCI increases the color difference between the lesion and the surrounding mucosa even in lesions surrounded by intestinal metaplasia [29]. The color difference between the lesion and purple-colored IM is enhanced, presumably increasing lesion visibility. As a factor that reduced gastric cancer visibility in this study, IM is expected to prove advantageous in LCI due to its characteristics.

Furthermore, no difference in visibility was seen between WLI and LCI for relatively large lesions >20 mm, but visibility was significantly improved for LCI compared to WLI for small lesions <10 mm and 11–20 mm. From these results, LCI can be inferred to provide significant benefits not only for normal lesions, but also even for difficult-to-see lesions (lesions with IM, lesions <20 mm, etc.) that might have been overlooked by WLI. In this study, there were 58 cases of lesions <20mm with IM, and in 35 (60%) of these, visibility was improved with LCI compared to WLI. These results suggest that early gastric cancer with severe IM in the background gastric mucosa and small size, which are difficult to detect on WLI, can be easier to detect using LCI.

This study showed several limitations. First, pathological evaluation of background gastric mucosa was not performed according to the Updated Sydney system. In this study, endoscopic IM was related to lesion visibility, but histological IM was uninvolved. This discrepancy in IM between endoscopy and histology remains problematic. The Updated Sydney system recommends biopsy of the antrum and corpus to accurately assess histological atrophy and IM [20]. However, in this study, we did not perform additional biopsy to avoid invasiveness to the patient, and instead used a non-tumor area of resected specimens to evaluate the histology of the background gastric mucosa. This suggests that the severity of histological IM may not be accurately evaluated and may be the cause of the discrepancy between endoscopic IM and histological IM. Second, this study used still images to evaluate lesion visibility. Since lesions were identified from 20 screening images that were not focused on the lesion, the distance from the endoscope varies for each lesion. Lesions far from the endoscope may appear dark, and lesions close to the scope may be affected by halation, which may affect visibility. Furthermore, the visibility evaluation using still images did not consider the time required to detect lesions. In actual clinical practice, the time required for endoscopic examination is limited, and lesions that require time to be detected have low visibility and are more likely to be overlooked. Therefore, the time required to detect a lesion is an important factor in evaluating the visibility of a lesion. If visibility is to be evaluated in a situation that assume actual clinical setting, visibility should have been evaluated in real time while performing an endoscopic examination, or it should have been evaluated using endoscopic video rather than endoscopic images. Third, the sample size was small for the number of items considered. Finally, visibility determinations were performed by endoscopic specialists, but may be performed by unskilled endoscopists in routine practice, thus contributing to bias. Because of the present study was a pilot study, further large-scale clinical studies involving young endoscopists should be conducted assuming various endoscopic gastrointestinal screening conditions, and this will hopefully lead to the development of screening strategies for new gastric lesions. In conclusion, with WLI, smaller lesion size and more severe endoscopic IM were associated with lower visibility of early gastric cancer, and with LCI, inclusion of these lesions improved the visibility of early gastric cancer.

Supporting information

S1 Fig. Twenty endoscopic images recommended in quality assurance manual of endoscopic screening for gastric cancer in Japanese community.

Endoscopic images was obtained for each WLI and LCI in upper, middle, lower, posterior wall of gastric body (a-c), posterior wall of upper gastric angle (d), four-quadrant views of gastric antrum (e-h), lesser curvature of gastric angle (i), lesser curvature of lower, middle, upper gastric body (j-l), anterior wall and greater curvature of lower, middle, upper gastric body(m-p), retroflexed view of cardia, posterior wall of lower gastric body (q,r), antegrade view of posterior wall of gastric angle, prepylorus (s,t). These images were not focused on the target lesion and at least one of the 20 images should include the lesion.

(TIF)

pone.0312385.s001.tif (6.9MB, tif)
S1 File

(XLSX)

pone.0312385.s002.xlsx (21.6KB, xlsx)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Elingarami Sauli

9 Aug 2024

PONE-D-24-24128Analysis of clinicopathological factors associate with the visibility of early gastric cancer in endoscopic examination and usefulness of Linked color imagingPLOS ONE

Dear Dr. Mizukami,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

When responding to reviewers comments, please make sure to detail the following aspects of your work; 

  • More clarity on the visibility scores of early gastric cancer using endoscopic images

  • More clarity regarding assessment of lesion visibility by Endoscopists and their selection criteria

  • Details on the gastric screening endoscopic examination.

==============================

==============================

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

Reviewer #5: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In the method section, “Patients with gastric cancer > 30mm, morphological type 0-I gastric cancer”, and “who did not consent to participate” are antonyms of the inclusion criteria already stated and therefor unnecessary as exclusion criteria and should be removed.

How many sites participated in this study should be described in the method section.

Were the endoscopic images collected from the participating sites to the central adjudication site?

The visibility score that authors described in this paper is not a Visual Analogue Scale which is a quantifiable numerical rating using a linear scale, but a kind of ordinal qualitative scale.

How were three experts who evaluated the visibility score chosen? Whether were they blinded from the enrolled patients and corresponding images of WLI and LCI ?

Who evaluated the endoscopic findings other than visibility score, endoscopists at each site?

How were the values for imputing to the logistic regression model chosen?

The comparison of visibility score between WLI and LCI was analyzed using Wilcoxon signed rank test, so to avoid misinterpretation, median with IQR should be stated and presented as a box plot with p-value. As an alternative test method, it may be appropriate to use McNemar test to compare the proportion of at least a score of 3 between WLI and LCI.

Comparing visibility scores between WLI and LCI in subgroups of good visibility or poor visibility is inappropriate because good or poor visibility were outcomes, not background characteristics of lesions. Figure 4 and lines 264 to 267 should be removed.

For patients with two lesions, how was each lesion assessed? Was it possible to analyze the lesions separately to assess the visibility score? Was the number of lesions informed to the assessor?

Figures 1 and 2 are similar, therefore Figure 1 should be removed.

Table 2 is an analysis of the lesions on WLI. The authors should make that clear in the table title and manuscript.

Lines 215 to 216 appeared to be factually incorrect.

Lines 220 to 221 are hard to understand why there is a contradiction between the process of eligible patients enrollment and the high rate of eradication of H. pylori.

The improved detection of early gastric cancer with LCI described in lines 279 to 281 should be suggested by the cases with improved visibility scores. How many cases have had improved visibility scores with LCI when the lesions were small and involved IM?

Reviewer #2: Overall:

The authors examined the association between endoscopic visibility of gastric cancer and patients’ background, endoscopic findings, pathological findings. Moreover, they investigated whether LCI can improve visibility for these lesions. They showed that lesion size and endoscopic IM are associated with the visibility of early gastric cancer in WLI and LCI improves visibility of gastric cancer with negative visibility factors.

Comments:

1. Please describe and explain interobserver agreement of expert endoscopists.

2. If the authors have cases in which WLI had better visibility than LCI, please describe and explain.

Reviewer #3: Thank you for the opportunity to review this article. There are a few points we need to clarify before accepting the article, so here is a list of those points.

Major

1．In the Introduction and Discussion sections, the authors emphasize that the visibility of gastric cancer after H. pylori （HP） eradication is poor and the detection rate is low. However, why did the current study include cases of both current infection and uninfected HP? If the authors want to resolve a clinical question, it may be better to limit the study to cases after HP eradication.

2. Please clarify the number of years of experience in endoscopic practice of the three endoscopists who evaluated the endoscopic images.

3. VAS-based evaluation is a subjective evaluation and lacks objectivity. Is there a correlation between "VAS-based evaluation" and "the actual color difference obtained from WLI and LCI images"? I think it is important to confirm that there is a correlation between the subjective evaluation and the color difference.

4. How long did it take to detect the lesion after viewing the endoscopic images of the 20 pairs? If you are assuming a situation consistent with actual clinical gastric screening endoscopic examinations, please clarify this because it is an important point.

Minor

1. The resolution of the image is poor, so the text cannot be seen in detail.

Reviewer #4: The authors conducted a multicenter prospective study to investigate the clinicopathological findings that are useful in identifying gastric cancers. Moreover, the authors investigate the usefulness of Linked Color imaging. The manuscript is written comprehensively, however, there are some concerns that should be addressed.

Major

1. Title. Please clearly indicate in the title that the present study was conducted prospectively in multicenter institutions.

2. Abstract. Although the authors describe the odds ratio to show the results, I think it is better to describe the direction of the results clearly. For example, lesion size is associated with “good” visibility, while intestinal metaplasia is associated with “bad” visibility.

3. Introduction. The authors described that “Early endoscopic detection of gastric cancer is essential for reducing its mortality rate of gastric cancer”, please add the reference for this sentence.

4. Introduction and Methods. The authors emphasize the difficulty of identifying gastric cancers after H.pylori eradication in the introduction section. Moreover, the authors described the characteristic findings of gastric cancers after H. Pylori eradication. Moreover, the authors also described in the 1st paragraph of the introduction section that the findings of gastric cancers after H. pylori eradication are different from those of H. pylori-infected gastric cancers. However, the authors included three types of gastric cancers in the analysis. I think it is better to focus on gastric cancers after H.pylori eradication. The situation where endoscopists do not know or cannot judge H. pylori's status is highly unlikely. Information about H.pylori infection status is critically important when conducting upper screening endoscopy.

5. Methods. Regarding the assessment of lesion visibility, did three endoscopists evaluate the lesion separately? Moreover, how did they evaluate the images? Did they use a cloud-type database? How much time did they have to evaluate the lesion? Was the final decision made by a majority vote of those three endoscopists?

6. Statistical analysis. Were there any measurements for sample size calculation?

7. Results. Regarding the paragraph on page 12 which showed the results of univariate analysis, please describe the direction of the results as I pointed out in the abstract.

8. Results. Please describe the number of good or poor visibility patients in the manuscript. (Although, the authors showed it in the figure). This information is important for logistic regression analysis.

9. Discussion. The “rate” in the following sentence could be revised as“incidence rate”. “The present study enrolled as many early gastric cancers £30 mm that met the eligibility criteria as possible, but the rate of gastric cancer after eradication was overwhelmingly high.” “Since the rate of gastric cancer after H. pylori eradication is expected to increase with the spread of H. pylori eradication therapy, gastric endoscopic screening that contributes to gastric cancer detection after eradication will be required.”

Reviewer #5: This manuscript describes the clinicopathological factors associated with the visibility of early gastric cancer and the efficacy of linked color imaging.

I read this manuscript with great interest. I have a few comments as shown below.

1. Please provide a representative images evaluated "poor visibility" by white light but "good visibility" by LCI.

2. p 18, line 256

In the discussion, the authors state "The current study showed that endoscopic gastric screening with image-enhanced endoscopy improves gastric cancer visibility". This sentence can be interpreted to mean that all IEEs can improve the visibility of cancer. The results of screening endoscopy with other IEEs are not discussed in the manuscript. Is there any evidence that other image-enhanced endoscopy also improves gastric cancer visibility? If so, please describe it, and if there is no clear evidence, just describe the LCI results used in this study.

3. This study evaluates visibility by looking at recorded endoscopic images. Please include in the appropriate part of the discussion that a clinical study to evaluate the real-time detection rate of gastric cancer during endoscopic examination is desired.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

**********

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PLoS One. 2024 Nov 5;19(11):e0312385. doi: 10.1371/journal.pone.0312385.r002

Author response to Decision Letter 0

25 Sep 2024

Dear Editor and reviewers

Thank you very much for reviewing our manuscript and offering valuable advice. We have carefully reviewed the comments and revised the manuscript accordingly. Our responses are given in a point-by-point manner below. Changes to the manuscript are shown in underline/ red bold.

We hope the revised version is now suitable for publication and look forward to hearing from you in due course.

Sincerely,

Kazuhiro Mizukami

Response to Reviewer #1

We thank the reviewer for positive comments and their valuable feedback which have helped us significantly improve the paper. We have answered each of your points below.

1) In the method section, “Patients with gastric cancer > 30mm, morphological type 0-I gastric cancer”, and “who did not consent to participate” are antonyms of the inclusion criteria already stated and therefor unnecessary as exclusion criteria and should be removed.

R: We thank the reviewer for these comments. We completely agree that three exclusion criteria reviewer mentioned are antonyms of the inclusion criteria and are unnecessary. We have removed the relevant sections in lines 61 to 64.

Lines 61-64; Patients with gastric cancer >30 mm, morphological type 0-I gastric cancer, gastric cancer that obviously invaded the submucosa and was not indicated for endoscopic treatment or postoperative stomach, or who did not consent to participate or were deemed inappropriate by the responsible physician were excluded from this study.

2) How many sites participated in this study should be described in the method section.

R: We appreciate reviewer’s comment. We have added the number of participating facilities to lines 55 as follows.

Lines 55; a clinical research organization involving 15 high-volume facilities

3) Were the endoscopic images collected from the participating sites to the central adjudication site?

R: We appreciate reviewer’s comment. As reviewer pointed out, endoscopic images collected from the participating sites to the central adjudication site. The endoscopic images were then sent to three endoscopic experts. We have added the sentence to lines 84-86 as below.

Lines 84-86 All endoscopic images were collected from participating centers at a central adjudication facility, randomized by WLI and LCI, and then sent to three experts for visibility assessment.

4) The visibility score that authors described in this paper is not a Visual Analogue Scale which is a quantifiable numerical rating using a linear scale, but a kind of ordinal qualitative scale.

R: We appreciate reviewer’s comment. As the reviewer pointed out, the Visual Analog Scale described in the paper looks like an ordinal qualitative scale. This is probably because the scale was defined to make it easier for the readers to understand. In the actual evaluation, the evaluators were asked to score the item at their own discretion between 1 (poor: not detectable, detected wrong site) and 5 (detectable at a glance). In response to the reviewer's suggestion, we have changed lines 96 to 98 as follows:

Lines 95-97: the five-point visual analog scale (VAS) ranging from 1(poor: not detectable or detected wrong site) to 5(detectable at a glance).

5) How were three experts who evaluated the visibility score chosen? Whether were they blinded from the enrolled patients and corresponding images of WLI and LCI?

R: We appreciate reviewer’s comment. Three experienced endoscopists from the participating institutions were randomly selected to evaluate the visibility. They were not involved in any endoscopic examinations related to this study. Evaluators were blinded to all patient and lesion information, except that the number of lesions was only informed to evaluators if a case had multiple lesions. We have added following sentence to lines 90 to 94.

Lines 90-94: Three endoscopic experts (22, 23, and 28 years of endoscopic experience, respectively) from the participating institutions were selected to evaluate the visibility. They were not involved in any endoscopic examinations related to this study. Evaluators were blinded to all patient and lesion information, except that the number of lesions was only informed to evaluators if a case had multiple lesions.

6) Who evaluated the endoscopic findings other than visibility score, endoscopists at each site?

R: We appreciate reviewer’s comment. That is true. Endoscopic findings other than lesion visibility were evaluated by endoscopists at each site. We have changed Lines 119 to120 as below.

Lines 118-119: The following information about the lesion and background mucosa was evaluated and registered by endoscopists at each institution as endoscopic findings.

7) How were the values for imputing to the logistic regression model chosen?

R: We appreciate reviewer’s comment. Factors that were significant in the univariate analysis were imputed to the multivariate analysis. We have added the same sentence to lines 148 to 149.

Lines 147-148: factors that were significant in the univariate analysis were imputed to the multivariate analysis.

8) The comparison of visibility score between WLI and LCI was analyzed using Wilcoxon signed rank test, so to avoid misinterpretation, median with IQR should be stated and presented as a box plot with p-value. As an alternative test method, it may be appropriate to use McNemar test to compare the proportion of at least a score of 3 between WLI and LCI.

R: We appreciate reviewer’s comment. As pointed out by the reviewer, we made mistakes in the description of the data and figures. Since we used the Wilcoxon singed rank test to compare of visibility score between WLI and LCI, we should have stated the median and IQR. In response to the comment, we changed the (mean score) to (median [IQR]) in lines 198-213 in the manuscript and changed the figure 3,5 and 6. Thank you very much for your accurate comment.

9) Comparing visibility scores between WLI and LCI in subgroups of good visibility or poor visibility is inappropriate because good or poor visibility were outcomes, not background characteristics of lesions. Figure 4 and lines 264 to 267 should be removed.

R: We appreciate reviewer’s comment. We agree with the reviewer's comment. However, We believe that the results of this study, that visibility was equivalent between WLI and LCI in lesions with good visibility on WLI, and that visibility was improved with LCI in lesions with poor visibility on WLI, are meaningful. This result also supports the statement in the discussion (lines 293) that "This suggests that LCI may facilitate detection for lesions that are difficult for endoscopists to find." If the reviewer could allow us to include this analysis result in the text, we would be very grateful.

10) For patients with two lesions, how was each lesion assessed? Was it possible to analyze the lesions separately to assess the visibility score? Was the number of lesions informed to the assessor?

R: We appreciate reviewer’s comment. As we answered in the fifth question, when there were multiple lesions, we informed only the number of lesions to avoid confusion for the evaluator. The evaluators assessed visibility of each lesion separately. In fact, there was only one case in this study with two lesions.

11) Figures 1 and 2 are similar, therefore Figure 1 should be removed.

R: We appreciate reviewer’s comment. We completely agree. We have changed Lines 55-56 as follow and removed Figure 1 and Figure legend of manuscript.

Lines 55-56; a clinical research organization involving 15 high-volume facilities in the Kyushu region of Japan, using the method shown in Fig 1.

12) Table 2 is an analysis of the lesions on WLI. The authors should make that clear in the table title and manuscript.

R: We appreciate reviewer’s comment. We completely agree. We have emphasized in lines 179 to 180 and 187to 188 and table title (lines 189).

Lines 179-180: Univariate and multivariate analysis of factors associated with visibility of early gastric cancer on WLI

Lines 187-188: independently associated with poor visibility of lesion on WLI (Table 2).

Lines 189-190: Table 2: Univariate and multivariate analysis of factors associated with visibility of early gastric cancer on WLI.

13) Lines 215 to 216 appeared to be factually incorrect.

R: We appreciate reviewer’s comment. We completely agree. I think it's an insufficient expression and incorrect. We have removed that section.

Lines 244-245; Previously, gastrointestinal endoscopic screening only had to look for differentiated gastric cancer associated with H. pylori.

14) Lines 220 to 221 are hard to understand why there is a contradiction between the process of eligible patients enrollment and the high rate of eradication of H. pylori.

R: We appreciate reviewer’s comment. We completely agree. There is no reason why the expression in the text is a contradiction, and it seems difficult to understand. Therefore, part of the text has been chaged as follows

Lines 248-249; In the present study, enrolled as many early gastric cancers �30 mm that met the eligibility criteria as possible, but the incidence rate of gastric cancer after eradication was overwhelmingly high.

15) The improved detection of early gastric cancer with LCI described in lines 279 to 281 should be suggested by the cases with improved visibility scores. How many cases have had improved visibility scores with LCI when the lesions were small and involved IM?

R: We appreciate reviewer’s comment. As the reviewer says, the effectiveness of LCI would be clearer if the number of cases in which visibility was improved with LCI was listed. In this study, there were 58 cases of lesions less than 2 cm in size with IM, and in 35 (60%) of these, visibility was improved with LCI compared to WLI. We have added the same sentence to lines 305 to 307.

Lines 305-307; In this study, there were 58 cases of lesions <20mm with IM, and in 35 (60%) of these, visibility was improved with LCI compared to WLI.

Response to Reviewer #2

Overall

The authors examined the association between endoscopic visibility of gastric cancer and patients’ background, endoscopic findings, pathological findings. Moreover, they investigated whether LCI can improve visibility for these lesions. They showed that lesion size and endoscopic IM are associated with the visibility of early gastric cancer in WLI and LCI improves visibility of gastric cancer with negative visibility factors.

R: We wish to express our appreciation to the Reviewer for insightful comments, which have helped us significantly improve the paper. We have answered each of your points below.

1) Please describe and explain interobserver agreement of expert endoscopists.

R: We appreciate reviewer’s comment. Following the reviewer's suggestion, we calculated the interobserver agreement using the Fleiss’ Kappa. The results were as follow:

κ=0.526 (WLI), κ=0.504 (LCI)

Based on the above results, the following sentence was added to the manuscript:

Lines 148-149; Interobserver agreement for WLI and LCI was calculated using Fleiss's kappa.

Lines 161-162; Interobserver agreement for lesion visibility by three evaluators was 0.526 for WLI and 0.504 for LCI.

2) If the authors have cases in which WLI had better visibility than LCI, please describe and explain.

R: We appreciate reviewer’s comment. Of the 97 lesions, 16 lesion (16%) showed better visibility with WLI compared to LCI. The clinicopathological characteristics of these 16 lesions were not identified. However, among the 16 lesions, some were imaged at close range, and halation appeared to affect the visibility of the lesions. We thought that the effect of halation was greater in LCI, which may have led to a negative evaluation of visibility in LCI. In this study, the 20 screening images were not focused on the lesions, so the distance from the endoscope varies for each lesion. Lesions far from the endoscope may appear darker, and lesions close to the endoscope may be affected by halation. In response to the reviewer's comments, we thought that evaluating visibility with still images was one of the limitations of this study, so we added the following sentence to the lines 319 to 329 of the Discussion. Thank you very much for very important comments.

Lines 319-329; Second, this study used still images to evaluate lesion visibility. Since lesions were identified from 20 screening images that were not focused on the lesion, the distance from the endoscope varies for each lesion. Lesions far from the endoscope may appear dark, and lesions close to the scope may be affected by halation, which may affect visibility. Furthermore, the visibility evaluation using still images did not consider the time required to detect lesions. In actual clinical practice, the time required for endoscopic examination is limited, and lesions that require time to be detected have low visibility and are more likely to be overlooked. Therefore, the time required to detect a lesion is an important factor in evaluating the visibility of a lesion. If visibility is to be evaluated in a situation that assume actual clinical setting, visibility should have been evaluated in real time while performing an endoscopic examination, or it should have been evaluated using endoscopic video rather than endoscopic images.

Response to Reviewer #3

Thank you for the opportunity to review this article. There are a few points we need to clarify before accepting the article, so here is a list of those points.

R: We wish to express our appreciation to the Reviewer for insightful comments, which have helped us significantly improve the paper. We have answered each of your points below.

Major

1) In the Introduction and Discussion sections, the authors emphasize that the visibility of gastric cancer after H. pylori （HP） eradication is poor and the detection rate is low. However, why did the current study include cases of both current infection and uninfected HP? If the authors want to resolve a clinical question, it may be better to limit the study to cases after HP eradication.

R: We appreciate reviewer’s comment. As the reviewer pointed out, gastric cancer that occurs after H. pylori eradication has been considered to be more difficult to detect by endoscopy than gastric cancer with current H. pylori infection because of changes in the background gastric mucosa, such as map-like redness, and the surface of the lesion being covered by normal mucosa, but there have been no papers that objectively prove this. Therefore, as described in lines 41 to 46, our aim in this study was to comprehensively examine all clinical pathological factors, including the infection status of H. pylori, that affect the visibility of gastric cancer. Therefore, this study included not only patients after H. pylori eradication, but also uninfected and current infection.

2) Please clarify the number of years of experience in endoscopic practice of the three endoscopists who evaluated the endoscopic images.

R: We appreciate reviewer’s comment. The three endoscopists had 22, 23, and 28 years of endoscopic experience, respectively. We have added following sentence to lines 91 to 92.

Lines 90-91; Three endoscopic experts (22, 23, and 28 years of endoscopic experience, respectively) from the participating institutions were selected to evaluate the visibility of lesions.

3) VAS-based evaluation is a subjective evaluation and lacks objectivity. Is there a correlation between "VAS-based evaluation" and "the actual color difference obtained from WLI and LCI images"? I think it is important to confirm that there is a correlation between the subjective evaluation and the color difference.

R: We appreciate reviewer’s comment. As the reviewer pointed out, the color difference between the lesion and the surrounding mucosa is one of the important factors related to the visibility of the lesion. Therefore, as the reviewer suggested, the validity of the subjective visibility assessment may be proven by examining the relationship between the VAS-based evaluation and the actual color difference, but the actual visibility evaluation may be affected not only by the color difference but also by morphological changes such as the unevenness of the surrounding mucosa due to atrophy and intestinal metaplasia

Attachment

Submitted filename: Respons to the reviewers.docx

pone.0312385.s003.docx (41.8KB, docx)

Decision Letter 1

Elingarami Sauli

7 Oct 2024

Analysis of clinicopathological factors associate with the visibility of early gastric cancer in endoscopic examination and usefulness of Linked color imaging: a multicenter prospective study

PONE-D-24-24128R1

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Reviewers' comments:

Reviewer's Responses to Questions

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Reviewer #2: (No Response)

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Reviewer #6: All comments have been addressed

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #6: Yes

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Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #6: Yes

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Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #2: The authors examined the association between endoscopic visibility of gastric cancer and patients’ background, endoscopic findings, pathological findings.

The authors have appropriately revised the paper.

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I think this manuscript will be acceptable.

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Acceptance letter

Elingarami Sauli

25 Oct 2024

PONE-D-24-24128R1

PLOS ONE

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Twenty endoscopic images recommended in quality assurance manual of endoscopic screening for gastric cancer in Japanese community.

    Endoscopic images was obtained for each WLI and LCI in upper, middle, lower, posterior wall of gastric body (a-c), posterior wall of upper gastric angle (d), four-quadrant views of gastric antrum (e-h), lesser curvature of gastric angle (i), lesser curvature of lower, middle, upper gastric body (j-l), anterior wall and greater curvature of lower, middle, upper gastric body(m-p), retroflexed view of cardia, posterior wall of lower gastric body (q,r), antegrade view of posterior wall of gastric angle, prepylorus (s,t). These images were not focused on the target lesion and at least one of the 20 images should include the lesion.

    (TIF)

    pone.0312385.s001.tif (6.9MB, tif)
    S1 File

    (XLSX)

    pone.0312385.s002.xlsx (21.6KB, xlsx)
    Attachment

    Submitted filename: Respons to the reviewers.docx

    pone.0312385.s003.docx (41.8KB, docx)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

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