Effect of gastric background mucosal status on the invasiveness of undifferentiated early gastric cancer and the role of the glucocholesterol glycoside-a multicenter study

doi:10.21203/rs.3.rs-1612882/v1

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Effect of gastric background mucosal status on the invasiveness of undifferentiated early gastric cancer and the role of the glucocholesterol glycoside-a multicenter study

https://doi.org/10.21203/rs.3.rs-1612882/v1

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Background：Undifferentiated early gastric cancer in different patients can show a completely different type of biological behavior. The purpose of this study was to clarify the effect of a Helicobacter pylori infection in the gastric mucosa on the biological behavior of undifferentiated early gastric cancer and to provide ideas for the selection of treatment and the control of its occurrence and development.

Methods: According to the inclusion and exclusion criteria, patients suspected of undifferentiated early gastric cancer who underwent gastroscopy in several hospitals in Guangxi from 2018 to 2020 were included in succession.

Results: A total of 61 cases of undifferentiated early gastric cancer, 41 cases of H. pylori from the related gastric cancer group (including 16 cases of H. pylori infection and 25 cases of previous infection), 20 cases from the H. pylori negative group (control group). The neutrophil lymphocyte ratio, lymph node metastasis rate, and the glucocholesterol glycoside from the H. pylori related gastric cancer group were higher than those from the control group.

Conclusion: H. pylori can inhibit T cell immunity through the glucocholesterol glycoside and promote the development and metastasis of undifferentiated early gastric cancer.

undifferentiated early gastric cancer

Helicobacter pylori

glucocholesterol glycoside

lymph node metastasis

With the development of endoscopy, progress has been made in the diagnosis and treatment of early gastric cancer. In some cases of early gastric cancer with a very low risk of lymph node metastasis, an endoscopic submucosal dissection (ESD) may reduce the trauma, without changing the original structure and function of digestive tract, and may achieve the same therapeutic effect as surgery. The Japan Gastroenterological Endoscopy Society, in collaboration with the Japanese Gastric Cancer Association, included undifferentiated intramucosal cancer with a maximum diameter of less than 2 cm without an ulcer as an indication for an ESD ^[1]. However, other undifferentiated early gastric cancers have shown completely different biological behaviors with some undifferentiated early gastric cancers being inert^{[2, 3]}, while a small number of undifferentiated early gastric cancers have had high a lymph node metastasis rate. These characteristics of undifferentiated cancer make it difficult for clinicians to select ESD as a treatment method.

While many studies have found that a large proportion of undifferentiated gastric cancer is related to infections with Helicobacter pylori, which do not follow the core model of gastritis→atrophy→intestinal →metaplasia dysplasia→gastric cancer^[4–6], other studies have found that H. pylori eradication can reduce the mortality of gastric cancer (including differentiated and undifferentiated gastric cancer)^[7]. The effect of H. pylori on the development of early undifferentiated gastric cancer has not yet been reported. Therefore, the purpose of this study was to investigate the effect of H. pylori on the development of undifferentiated early gastric cancer and the mechanism of the effect.

Patients

The complete biochemical and pathological data of patients suspected of early undifferentiated gastric cancer (including early poorly differentiated cancer, signet ring cell cancer and mixed component cancer with both components, as defined by the JCGC standard) who underwent gastroscopy in several hospitals in Guangxi from 2017 to 2020 and underwent ESD or surgical treatment, were obtained. The patients who underwent ESD required a CT or MRI examination to exclude the presence of a lymph node metastasis before the operation. These patients could only be included only after a CT or MRI follow-up for more than one year. The exclusion criteria were: the accompaniment of other primary or secondary gastric malignancies, with or without lymph node metastasis; no ESD or surgical pathology data were obtained (according to JCGC standard, multiple pathological biopsies do not support the diagnosis of undifferentiated gastric cancer); patients with advanced undifferentiated gastric cancer, confirmed by postoperative pathology; patients who were unable to tolerate biopsies due to being treated with anticoagulants or the presence of other factors(coagulation disorders, Active bleeding et al); and patients who underwent a gastrectomy. All the patients provided written informed consent to undergo a gastroduodenoscopy. The study was approved by the University Ethical Review Committee. According to the status of an infection with H. pylori, the patients were divided into a H. pylori negative group (control group) and H. pylori current infection or previous infection group (H. pylori related undifferentiated early gastric cancer group). H. pylori was considered as negative if any of the following conditions were met: the gastroscope showed a normal gastric mucosa, a negative serological antibody or fecal antigen test, or the gastroscope showed the presence of normal gastric mucosa while the 13C/14C breath test was negative. A H. pylori infection was defined using the following criteria: when the patient did not use PPIs or antibiotics within two weeks and the breath test, rapid urease test, or fecal antigen test were positive; if H. pylori was determined to be positive in a pathological examination. If one of these two items was met, it was considered as a current infection of H. pylori. Any one of the following was considered to be a previous infection of H. pylori: when the patient did not use PPIs or antibiotics within two weeks, the breath test, rapid urease test, or fecal antigen test were negative, but the serological antibody test was positive; atrophy above the Kimura-Takemoto classification C2 where the gastroscopic or histopathological examination showed atrophy dominated by non-gastric bodies with no evidence of autoimmune gastritis; the presence of a clear history of H. pylori positive sterilization and there no evidence of any present H. pylori infection.

Endoscopy

The stomach was scanned according to Professor Yao's gastric system scanning (SSS) system to clarify the background mucosal status (H. pylori negative, H. pylori infecting and sterilized mucosa), and then the suspected lesion was enlarged and observed, and an accurate biopsy performed. If early gastric cancer was suspected from the endoscopy and not confirmed by the pathological findings from the biopsy, a re-biopsy or diagnostic ESD should be performed according to the patient's wishes and microscopic manifestations.

Postoperative specimen treatment and pathological diagnosis

Surgical patients underwent a D2 lymph node dissection and complete mesogastrectomy (D2 + CME). The lesion was marked under endoscopy before or after operation. Surgical specimens were sectioned with a thickness of ≤ 5 mm in the lesion area, the ESD specimens were sectioned with a thickness of 2–3 mm. The number of lymph nodes in surgical specimens was more than or equal to 15. A pathological diagnosis was carried out according to the JCGC standard, and the lesion size, lymph node metastasis and vascular infiltration were evaluated. The expressions of Shh and Gli were detected using immunohistochemistry.

Glucocholesterol glycoside detection

We selected 10 patients for the H. pylori related gastric cancer group and collected their cancer tissues as well as adjacent tissues. We also selected 10 patients for the H. pylori negative control group and examined the content of glucocholesterol glycoside in the above three kinds of tissues.

Testing process: The cholesterol glucosides were extracted from 50 mg of the tissues using isopropanol and the clean supernatant was collected into a fresh tube. The extraction was repeated once and the extracts were pooled and dried in the SpeedVac (Genevac miVac，Tegent Scientific Ltd., UK). The dried extract was resuspended in chloroform: methanol: 0.1 M ammonium acetate 100:100:4 (v/v/v) containing d6-CE18:0. LCMS analyses were conducted using an Agilent 1260 LC system coupled to Sciex TripleQuad 5500. The separation of the cholesterol glucoside was achieved using a Phenomenex Kinetex-C18 2.6 µm column (i.d. 4.6 × 100 mm) with an isocratic mobile phase containing chloroform: methanol: 0.1 M ammonium acetate 100:100:4 (v/v/v) at a flow rate of 0.7 mL/min for 10 min. The Sciex TripleQuad 5500 operated in heated electrospray positive ionization mode and multiple reaction monitoring was conducted. The mass transitions used for the cholesterol glucoside were m/z 566.4 with the fragment being m/z 369.3, for the d6-CE18:0, m/z 676.8 with the fragment being m/z 375.3. The ion spray voltage was set at 5500 V, curtain gas at 10, temperature at 350 °C, ion source gas 1 at 35, ion source gas 2 at 35. The cholesterol glucoside was quantitated with reference to the intensities of their corresponding deuterated internal standards.

Statistical analysis

The correlation between lymph node metastasis and Ki67, lesion size, pathological components of undifferentiated cancer, depth of invasion, presence or absence of ulcer and background mucosal status, was analyzed. The influencing factors related to lymph node metastasis were analyzed using a logistic regression. The measurement data were compared between the groups using the t-test. The Chi square test and exact probability method were used to compare the rates. A ROC curve was used to calculate the cut-off value of the lesion size with the highest sensitivity and specificity in the diagnosis of a lymph node metastasis. The IBM SPSS 22 0, (IBM, Beijing, China) statistical software was used.

A total of 61 cases of undifferentiated early gastric cancer were included. The location is shown in Table 1. Seven cases underwent ESD and 54 cases surgery. The average number of lymph nodes found was 25 ± 9. Among these, there were 38 cases of pure poorly differentiated or pure signet ring cell cancer, 23 cases were poorly differentiated cancer with signet ring cell cancer, 44 cases were limited to the mucosa and 17 cases were confined to the superficial submucosa. The lymph node metastasis rates were 4.5% and 29.4%, respectively (P < 0.05).The average size of the lesions in single component cancer group and mixed component cancer group were 1.91 ± 1.25 cm and 2.41 ± 1.56 cm respectively. The incidence of ulcer was 44.7% and 47.8%, respectively, and the rate of lymph node metastasis was 0.5% and 26.1% respectively, P < 0.05. There were 38 cases of H. pylori related gastric cancer (including 16 cases of H. pylori positive and 22 cases of previous infection), and the lymph node metastasis rate was 15.8%. There were 23 cases of H. pylori negative gastric cancer, and the lymph node metastasis rate was 4.3%. Twenty one patients met the absolute indication for undergoing an ESD (Intramucosal cancer without ulcer with maximum diameter less than 2 cm) according to the Japan Early Cancer Society, including 17 patients with pure poorly differentiated cancer or pure signet ring cell cancer and FOUR cases with mixed component cancer. The rate of lymph node metastasis or vascular invasion was 0 in the former; one case had vascular infiltration in the latter, and the incidence of vascular infiltration was higher in the latter compared to the former. Among the patients who met the absolute indications for undergoing an ESD, there was one case of vascular infiltration and zero case of lymph node metastasis in the H. pylori related gastric cancer group, and there was no vascular infiltration and lymph node metastasis in H. pylori negative group. The logistic regression analysis of risk factors related to lymph node metastasis showed that the lesion size, pathological composition of cancer and preoperative neutrophil lymphocyte ratio (NLR) were included in the regression curve. The cut-off value of tumor size calculated using the ROC curve to predict the risk of lymph node metastasis was three. Therefore, we analyzed the intramucosal cancer with the size of 2cm ≤ 3cm according to the mucosal background state, including six cases from the H. pylori negative gastric cancer group and 16 cases from the H. pylori related gastric cancer group. The lesion size of each group was compared using the t-test for independent samples. The lesion size of the two groups were 2.74 ± 0.37 and 2.85 ± 0.25 respectively, and the difference was not statistically significant, P > 0.05. The exact probability method shows that the proportion of mixed component cancer was the same in the H. pylori related gastric cancer group and H. pylori negative gastric cancer group, and the difference was not statistically significant. The lymph node metastasis rate was 0% in H. pylori negative group, while the lymph node metastasis rate in H. pylori related gastric cancer group was 25%, which was higher than that in H. pylori negative gastric cancer group (Table 2), suggesting that the background mucosal state was related to the risk of lymph node metastasis in the subgroup. The correlation analysis showed that the pathological components of cancer were correlated with the state of the H. pylori infection, P = 0.028. At the same time, the NLR in peripheral blood of H. pylori negative gastric cancer group and H. pylori related gastric cancer group were 55.3 ± 18.3 and 41.9 ± 5.2, respectively. The former was higher than that of H. pylori related gastric cancer group (P = 0.029). There were no significant differences in the NLR between the different mucosal background groups in patients with intramucosal carcinoma with the maximum diameter of lesion < 2cm. The content of the glucocholesterol glycoside in the H. pylori related gastric cancer group was significantly higher than that in the H. pylori negative control group, P = 0.047. At the same time, the content of the glucocholesterol glycoside in the cancer tissue was also significantly higher than that in the adjacent tissues, P = 0.032. There were no significant differences in the content of the glucocholesterol glycoside between the adjacent tissues and the control group. The pathological sections of 33 cases of H. pylori related gastric cancer cases and the ten cases from the H. pylori negative control group were detected using immunohistochemistry. The expression of Shh and Gli in the former was higher than the latter.

Table 1

Location of the lesions
Location	Number of cases
Gastric fundus	1
Junction of fundus and body of stomach	1
Gastric body	19
Gastric horn	19
Junction of antrum and body of stomach	8
Gastric antrum	13

Table 2

Grouping and number of the lesions
Grouping	Number of cases	Lymph node metastasis rate (%)
Pure poorly differentiated cancer or pure signet ring cell cancer	38	0.5
Poorly differentiated cancer with signet ring cell cancer	23	26.1
Intramucosal cancer	44	0.5
Submucosal superficial cancer (Sm1)	17	29.4
H. pylori negative undifferentiated gastric cancer	20	5
H. pylori associated undifferentiated gastric cancer	41	13.5
Intramucosal cancer (r<2 cm)	21	0
Intramucosal H. pylori associated undifferentiated gastric cancer (r ≤ 3 cm)	27	7.4
H. pylori negative undifferentiated gastric cancer (2 ≤ r ≤ 3)	6	0
H. pylori associated undifferentiated gastric cancer (2 ≤ r ≤ 3)	16	25
^{note: R refers to the maximum diameter of the tumor}

With the deeper understanding of undifferentiated early gastric cancer, the indications for the endoscopic treatment of undifferentiated gastric cancer was found to have changed in recent years. The undifferentiated gastric cancer without ulcer with maximum diameter < 2cm had changed from the expanded indication of endoscopic treatment to the absolute indication [6]。It has been reported that the overall survival rate of patients with undifferentiated early gastric cancer after undergoing an ESD was higher than that of surgical patients, although there were no significant differences after propensity score matching^[8]; however, there were also reports that some undifferentiated gastric early cancers had distant metastasis at a very early stage [11–14]. Therefore, the choice of ESD for undifferentiated gastric cancer should be made appropriately. In addition, because of the specific characteristics of the biological behavior of undifferentiated early gastric cancer, it has been difficult to assess the accurate boundaries using endoscopy^[9]. Therefore, clinicians were still conservative in their choice of endoscopic treatment for undifferentiated early gastric cancer. In many medical centers, surgical treatment was the only option as long as it was pathologically proved to be undifferentiated gastric cancer, regardless of its stage. However, esophageal reflux and residual gastric bile reflux caused by surgical treatment being common led to several secondary problems. Therefore, it was important to explore the risk factors that can promote the development of undifferentiated early gastric cancer and lymph node metastasis.

In order to explore the risk factors of lymph node metastasis, all the patients who underwent surgery, underwent D2 + CME. Previous studies have shown that the surgical dissection of 15 or more lymph nodes per patient can provide an accurate diagnosis lymph node metastasis^[10]. Therefore, the patients we included were diagnosed accurately with a lymph node metastasis. It had been reported that the risk of lymph node metastasis of undifferentiated early gastric cancer containing both signet ring cell cancer and poorly differentiated cancer was higher than that of pure signet ring cell cancer or poorly differentiated cancer^{[11, 12]}. In this study, the lymph node metastasis rate of undifferentiated early gastric cancer with mixed components was significantly higher than that of undifferentiated early gastric cancer with pure components, which was consistent with the findings of previous studies. In this study, although the lymph node metastasis rate of undifferentiated early gastric cancer that met the absolute indication of ESD was 0%, there was one case of vascular invasion in the H. pylori related gastric cancer group, while the lymph node metastasis rate and vascular invasion rate of H. pylori negative intramucosal gastric cancer with the maximum diameter ≥ 2, but ≤ 3 which exceeded the absolute indication, were still 0%. Therefore, the infection status of H. pylori may be used to predict the feasibility of ESD treatment for undifferentiated early gastric cancer. For H. pylori negative intramucosal undifferentiated gastric carcinoma, when the lesion was less than or equal to 3 cm, its biological behavior was still inert, and endoscopic treatment was still safe. For H. pylori related undifferentiated intramucosal gastric cancer, even if the lesion was less than 2 cm, the lymph node metastasis should be carefully evaluated before ESD, because H. pylori may disturb the inertia and increase its invasiveness. Regardless of lesion size and depth of invasion, the rate of lymph node metastasis in H. pylori associated early gastric cancer was higher than that in H. pylori negative gastric cancer.

We further analyzed the related factors of lymph node metastasis. The correlation analysis showed that lesion size, depth of lesion invasion, pathological cancer cell composition were related to the risk of lymph node metastasis, and previous studies confirmed the impact of the above factors on the risk of lymph node metastasis^[13]. Therefore, in the subgroup analysis, we compared the lesion size, invasion depth and pathological components between the H. pylori related gastric cancer group and H. pylori negative gastric cancer group using the Chi square test and exact probability method. The results showed that there were no significant differences between the two groups for the above factors. Excluding the above effects, we further compared the lymph node metastasis rate and NLR value between the two groups. The Chi square test results showed that the lymph node metastasis rate of the H. pylori related gastric cancer group was significantly higher than that of the H. pylori negative group. When the size of intramucosal cancer was between 2–3cm, the preoperative NLR value of the observation group was higher than that of the control group. The NLR shows the inflammatory response and immune status of the body, which was of great significance in the prognosis of the tumors. Previous studies have also found that the NLR in early gastric cancer group was higher than that in the H. pylori negative control group, and could predict the risk of lymph node metastasis^{[14, 15]}. This suggested that H. pylori may affect the immune status of the body, and increase the risk of a lymph node metastasis. It was found that the cholesterol- α- glucosyltransferase of H. pylori may transform the cholesterol of the cell membrane to glucocholesterol glycoside. The presence of excessive cholesterol promotes the phagocytosis of H. pylori through antigen-presenting cells and enhances the antigen-specific T cell response. Intrinsic cholesterol α- glycosylation can eliminate the phagocytosis of antigen-presenting cells on H. pylori and the subsequent T cell activation^[16–18]. In this study, the content of glucocholesterol glycoside in H. pylori related gastric cancer was significantly higher than that in the H. pylori negative control group, and the vascular invasion rate and lymph node metastasis rate of H. pylori related gastric cancer were also higher than those in the control group, suggesting that glucocholesterol glycoside on the one hand inhibited the phagocytosis of H. pylori by cholesterol related antigen-presenting cells, so that the pathogenic factors of H. pylori could continue to play a role and affect the development of gastric cancer. However, the development of the tumor was influenced not only by the biological behavior of tumor itself, but also by the body's antitumor immunity. Studies had shown that the low level of CD8 mRNA was a potential predictive biomarker of poor prognosis in patients with gastric cancer undergoing surgery. In addition, some studies have shown that the decreased expression of NKG2D in CD8 + T cells may be one of the key mechanisms for gastric cancer to escape immunity^{[19, 20]}. Therefore, the glucosylation of cholesterol may also enhance the invasiveness of undifferentiated early gastric cancer by inhibiting the antitumor immunity of T cells, which enabled the H. pylori related undifferentiated early gastric cancer to develop faster with a higher risk of a lymph node metastasis. However, when the maximum diameter of the lesion was less than 2 cm, there were no significant differences in the NLR between the H. pylori related gastric cancer group and the H. pylori negative control group; however, the inflammatory response of H. pylori infecting adjacent tissues was significantly higher than the latter, which may have been due to the difference in the inflammatory response which was limited mainly to the gastric mucosa. This did not affect the NLR in the peripheral blood. There were no significant differences in the inflammatory response of adjacent tissues infected with H. pylori and the H. pylori negative control group, suggesting that in addition to immune factors, other factors played a role in enhancing the invasiveness of gastric cancer after sterilization.

In this study, the glucocholesterol glycoside in gastric cancer tissue after sterilization was still significantly higher than that in the control group, which suggested that with the successful sterilization, the originally formed glucocholesterol glycoside may still be deposited partially in cells, resulting in immune inhibition, which may be one of the reasons why the open atrophic gastric mucosa after sterilization was still at a high risk of gastric cancer. However, there were no significant differences in the inflammatory response of the adjacent tissues and the NLR of peripheral blood between the H. pylori negative group and the post sterilization group with the maximum diameter less than 2 cm. This suggested that the invasiveness of undifferentiated early gastric cancer was also affected by other factors other than immunity. It is unclear whether glucocholesterol glycoside also affects the invasiveness of undifferentiated early gastric cancer through other mechanisms. In addition, in this study, the expression of Shh and Gli in H. pylori related gastric cancer with a high expression of glucocholesterol glycoside was significantly higher than that in the H. pylori negative control group (Fig. 1). Studies have shown that Shh plays an important role in the occurrence and development of gastric cancer. ^[21–24]. Therefore, whether glucocholesterol glycoside also affects the development of gastric cancer through Shh signaling pathway, needs further research.

In conclusion, H. pylori negative undifferentiated intramucosal early gastric cancer was inert, and patients who meet the absolute indications for ESD had a high safety profile after undergoing ESD. However, an H. pylori infection could destroy this inertia and increase the invasiveness of gastric cancer. The glucocholesterol glycoside may be the key to breaking this inertia. Therefore, inhibiting the production or effect of the glucocholesterol glycoside may reduce the invasiveness of undifferentiated early gastric cancer and delay the progression of the tumor.

Funding

Guangxi Clinical Medical Research Center for Digestive Diseases (no. AD17129027) provided equipment support for this study. Youth fund of People's Hospital of Guangxi Zhuang Autonomous Region (no. QN2021-13)

Author contributions: All the authors have contributed to the preparation of the manuscript and collection of pictures.

Ono H, Yao K, Fujishiro M, Oda I, Uedo N, Nimura S, Yahagi N, Iishi H, Oka M, Ajioka Y, Fujimoto K. Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer (second edition). Dig Endosc 2021; 33: 4–20 [PMID: 33107115 DOI: 10.1111/den.13883]
Murai K, Takizawa K, Shimoda T, Fujii S, Sugino T, Yoshida M, Kawata N, Tanaka M, Kakushima N, Terashima M, Ono H. Effect of double-layer structure in intramucosal gastric signet-ring cell carcinoma on lymph node metastasis: a retrospective, single-center study. Gastric Cancer 2019; 22: 751–758 [PMID: 30523555 DOI: 10.1007/s10120-018-00905-9]
Imamura T, Komatsu S, Ichikawa D, Kawaguchi T, Kosuga T, Okamoto K, Konishi H, Shiozaki A, Fujiwara H, Otsuji E. Early signet ring cell carcinoma of the stomach is related to favorable prognosis and low incidence of lymph node metastasis. J Surg Oncol 2016; 114: 607–612 [PMID: 27562147 DOI: 10.1002/jso.24377]
Ono Y, Hirabayashi K, Ishida M, Sakuma K, Tomita S, Sano Y, Ichikawa K, Terano A, Ueda Y, Fujimori T. Helicobacter pylori infection in early gastric adenocarcinoma: relationship between histologic subtypes and ulcer-formation. J Physiol Pharmacol 1997; 48 Suppl 4: 123–31 [PMID: 9440063
Sarker K K, Kabir M J, Bhuyian A, Alam M S, Chowdhury F R, Ahad M A, Rahman M A, Rahman M M. H. pylori infection and gastric cancer in Bangladesh: a case-control study. Int J Surg Oncol (N Y) 2017; 2: e44 [PMID: 29177209 DOI: 10.1097/IJ9.0000000000000044]
Tatemichi M, Sasazuki S, Inoue M, Tsugane S. Different etiological role of Helicobacter pylori (Hp) infection in carcinogenesis between differentiated and undifferentiated gastric cancers: a nested case-control study using IgG titer against Hp surface antigen. Acta Oncol 2008; 47: 360–5 [PMID: 18347999 DOI: 10.1080/02841860701843035]
Ford A C, Yuan Y, Forman D, Hunt R, Moayyedi P. Helicobacter pylori eradication for the prevention of gastric neoplasia. Cochrane Database Syst Rev 2020; 7: CD005583 [PMID: 32628791 DOI: 10.1002/14651858.CD005583.pub3]
Ahn J Y, Kim Y I, Shin W G, Yang H J, Nam S Y, Min B H, Jang J Y, Lim J H, Kim J, Lee W S, Lee B E, Joo M K, Park J M, Lee H L, Gweon T G, Park M I, Choi J, Tae C H, Kim Y W, Park B, Choi I. Comparison between endoscopic submucosal resection and surgery for the curative resection of undifferentiated-type early gastric cancer within expanded indications: a nationwide multi-center study. Gastric Cancer 2021; 24: 731–743 [PMID: 33211219 DOI: 10.1007/s10120-020-01140-x]
Ishioka M, Yoshio T, Miyamoto Y, Namikawa K, Tokai Y, Yoshimizu S, Horiuchi Y, Ishiyama A, Hirasawa T, Tsuchida T, Fujisaki J. Incidence of metachronous cancer after endoscopic submucosal dissection: a comparison between undifferentiated-type and differentiated-type early gastric cancer. Gastrointest Endosc 2021; 93: 557–564.e1 [PMID: 32621817 DOI: 10.1016/j.gie.2020.06.067]
Xie D, Yu C, Liu L, Osaiweran H, Gao C, Hu J, Gong J. Short-term outcomes of laparoscopic D2 lymphadenectomy with complete mesogastrium excision for advanced gastric cancer. Surg Endosc 2016; 30: 5138–5139 [PMID: 27005289 DOI: 10.1007/s00464-016-4847-4]
Lee I S, Lee S, Park Y S, Gong C S, Yook J H, Kim B S. Applicability of endoscopic submucosal dissection for undifferentiated early gastric cancer: Mixed histology of poorly differentiated adenocarcinoma and signet ring cell carcinoma is a worse predictive factor of nodal metastasis. Surg Oncol 2017; 26: 8–12 [PMID: 28317588 DOI: 10.1016/j.suronc.2016.12.001]
Horiuchi Y, Fujisaki J, Yamamoto N, Ishizuka N, Omae M, Ishiyama A, Yoshio T, Hirasawa T, Yamamoto Y, Nagahama M, Takahashi H, Tsuchida T. Mixed poorly differentiated adenocarcinoma in undifferentiated-type early gastric cancer predicts endoscopic noncurative resection. Gastric Cancer 2018; 21: 689–695 [PMID: 29236187 DOI: 10.1007/s10120-017-0788-4]
Zhu Z L, Shi H P, Beeharry M K, Feng T N, Yan M, Yuan F, Zheng-Gang Z, Zhang B Y, Wu W. Expanding the indication of endoscopic submucosal dissection for undifferentiated early gastric cancer is safe or not? Asian J Surg 2020; 43: 526–531 [PMID: 31706922 DOI: 10.1016/j.asjsur.2019.08.006]
Fang T, Wang Y, Yin X, Zhai Z, Zhang Y, Yang Y, You Q, Li Z, Ma Y, Li C, Song H, Shi H, Zhang Y, Yu X, Gao H, Sun Y, Xie R, Xue Y. Diagnostic Sensitivity of NLR and PLR in Early Diagnosis of Gastric Cancer. J Immunol Res 2020; 2020: 9146042 [PMID: 32211444 DOI: 10.1155/2020/9146042]
Wang Y, Zhai J, Zhang T, Han S, Zhang Y, Yao X, Shen L. Tumor-Associated Neutrophils Can Predict Lymph Node Metastasis in Early Gastric Cancer. Front Oncol 2020; 10: 570113 [PMID: 33072602 DOI: 10.3389/fonc.2020.570113]
Qaria M A, Qumar S, Sepe L P, Ahmed N. Cholesterol glucosylation-based survival strategy in Helicobacter pylori. Helicobacter 2021; 26: e12777 [PMID: 33368895 DOI: 10.1111/hel.12777]
Wunder C, Churin Y, Winau F, Warnecke D, Vieth M, Lindner B, Zahringer U, Mollenkopf H J, Heinz E, Meyer T F. Cholesterol glucosylation promotes immune evasion by Helicobacter pylori. Nat Med 2006; 12: 1030–8 [PMID: 16951684 DOI: 10.1038/nm1480]
Rubin E J, Trent M S. Colonize, evade, flourish: how glyco-conjugates promote virulence of Helicobacter pylori. Gut Microbes 2013; 4: 439–53 [PMID: 23859890 DOI: 10.4161/gmic.25721]
Osaki T, Saito H, Yoshikawa T, Matsumoto S, Tatebe S, Tsujitani S, Ikeguchi M. Decreased NKG2D expression on CD8 + T cell is involved in immune evasion in patients with gastric cancer. Clin Cancer Res 2007; 13: 382-7 [PMID: 17255258 DOI: 10.1158/1078-0432.CCR-06-1454]
Ito S, Masuda T, Noda M, Hu Q, Shimizu D, Kuroda Y, Eguchi H, Tobo T, Utsunomiya T, Mimori K. Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer. Oncology 2020; 98: 501–511 [PMID: 32380498 DOI: 10.1159/000506075]
Doheny D, Manore S G, Wong G L, Lo H W. Hedgehog Signaling and Truncated GLI1 in Cancer. Cells-Basel 2020; 9 [PMID: 32957513 DOI: 10.3390/cells9092114]
Samadani A A, Nikbakhsh N, Taheri H, Shafaee S, Fattahi S, Pilehchian L M, Hajian K, Akhavan-Niaki H. CDX1/2 and KLF5 Expression and Epigenetic Modulation of Sonic Hedgehog Signaling in Gastric Adenocarcinoma. Pathol Oncol Res 2019; 25: 1215–1222 [PMID: 30685841 DOI: 10.1007/s12253-019-00594-4]
Merchant J L, Ding L. Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions. Cell Mol Gastroenterol Hepatol 2017; 3: 201–210 [PMID: 28275687 DOI: 10.1016/j.jcmgh.2017.01.004]
Martin J, Donnelly J M, Houghton J, Zavros Y. The role of sonic hedgehog reemergence during gastric cancer. Dig Dis Sci 2010; 55: 1516–24 [PMID: 20437100 DOI: 10.1007/s10620-010-1252-z]

No competing interests reported.

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Effect of gastric background mucosal status on the invasiveness of undifferentiated early gastric cancer and the role of the glucocholesterol glycoside-a multicenter study

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