目的：探讨胃神经内分泌瘤（gastric neuroendocrine tumors,g-NETs）个体化治疗方案的缓解率、复发率、治疗后复发的相关因素以及生长抑素类似物（somatostatin analogue, SSA）抑制肿瘤生长的潜在分子机制。

方法：收集2015年11月至2023年9月于北京协和医院确诊为g-NETs 的51例病例资料，分析所有病例的内镜下肿瘤的部位、数量、直径、形态特征、临床分型、病理分级、生物标志物表达情况，并对内镜治疗、SSA治疗及外科手术治疗的疗效进行分析评价, 确定其个体化治疗方案的缓解率、复发率以及复发的相关因素。采用免疫组化方法检测g-NETs组织标本中SSTR2、β-catenin、c-Myc等表达水平，探讨SSA抑制肿瘤生长的潜在分子机制。

结果：51例g-NETs患者，内镜治疗（EMR、ESD）25例，SSA治疗19例（均为胃内病变大于6个的1型g-NETs），外科手术治疗7例。中位随访49个月，治疗总缓解率为78.4%（40/51），其中内镜治疗组缓解率为76.0%（19/25），SSA治疗组缓解率为78.9%（15/19），外科手术组缓解率为85.7%（6/7），三组缓解率差异无显著性（P＞0.05）；总复发率为15.7%（8/51），内镜治疗组复发率为24.0%（6/25），其中EMR复发率为80.0%（4/5），ESD复发率为10.0%（2/20），SSA治疗组复发率为5.3%（1/19），外科手术组复发率为14.3%（1/7），四种不同治疗方法复发率差异有显著性（P＜0.05）。复发组8例患者治疗前血清胃泌素水平均大于1000pg/ml，未复发组43例患者中治疗前血清胃泌素水平大于1000pg/ml者有22例，占51.2%（22/43），复发组治疗前血清胃泌素水平大于1000pg/ml的患者比例明显高于未复发组（P＜0.05）。多因素logistic回归分析显示，治疗前血清胃泌素水平和治疗方法与g-NETs治疗后复发有显著相关性（P＜0.05）。此外，在32例g-NETs组织中，SSTR2阳性表达24例，SSTR2阴性表达8例，阳性率为75.0%（24/32）。在SSTR2表达阳性的g-NETs中β-catenin的阳性表达率为75.0%（18/24），在SSTR2表达阴性的g-NETs中β-catenin的阳性表达率为12.5%（1/8），SSTR2与β-catenin在g-NETs中的表达呈正相关，差异有显著性（P＜0.05）。在SSTR2表达阳性的g-NETs中c-Myc的阳性表达率为79.2%（19/24），在SSTR2表达阴性的g-NETs中c-Myc的阳性表达率为25.0%（2/8）。SSTR2与c-Myc在g-NETs中的表达呈正相关，差异有显著性（P＜0.05）。

结论：综合考虑肿瘤的分型、分级、数量、直径以及有无转移等因素而制定的g-NETs个体化治疗方案，三组治疗缓解率无显著差异，而四种不同治疗方法复发率差异有显著性。g-NETs治疗后复发与治疗前血清胃泌素水平大于1000pg/ml及治疗方法有显著相关性。SSA治疗复发率较低，且SSA治疗无创伤，病人依从性较好，长期SSA治疗胃内病变大于6个的1型g-NETs安全有效。SSA可能通过结合SSTR2影响Wnt信号传导通路，调控β-catenin蛋白，影响下游c-Myc等靶基因的表达，从而调控g-NETs生长。

Background: To investigate the remission and recurrence rates of individualized treatment for gastric neuroendocrine tumors (g-NETs), factors associated with recurrence after treatment, and the potential molecular mechanisms of somatostatin analogue (SSA) in inhibiting tumor growth.

Methods: The clinical data of 51 patients with g-NETs were collected in Peking Union Medical College Hospital from November 2015 to September 2023. The endoscopic tumor location, number, diameter and morphological characteristics, clinical classification, pathological grading, and biomarker expression were analyzed. The efficacy of endoscopic treatment, SSA treatment, and surgical treatment was evaluated to determine the remission and recurrence rates for individualized treatment options, and the related factors of recurrence. The expression levels of SSTR2, β-catenin, and c-Myc in g-NETs samples were detected by immunohistochemistry to explore the potential molecular mechanisms of SSA in inhibiting tumor growth through SSTR2.

Results: Among 51 patients with g-NETs, 25 cases underwent endoscopic treatment (EMR or ESD), 19 cases underwent SSA treatment (all patients were type 1 g-NETs with more than 6 lesions in the stomach), and 7 cases underwent surgical treatment. After a median follow-up of 49 months, the overall remission rate was 78.4% (40/51).Among them, the remission rate of endoscopic treatment was 76.0% (19/25), the remission rate of SSA treatment was 78.9% (15/19), and the remission rate of surgery was 85.7% (6/7). The difference of the remission rate among three groups was not statistically significant (P＞0.05). The overall recurrence rate was 15.7% (8/51). Among them, the recurrence rate of endoscopic treatment was 24.0% (6/25),the recurrence rate of EMR was 80.0% (4/5),the recurrence rate of ESD was 10.0% (2/20),the recurrence rate of SSA treatment was 5.3% (1/19), and the recurrence rate of surgery was 14.3% (1/7)，the difference of the recurrence rate among four different treatment methods was statistically significant(P＜0.05). Eight patients in the recurrence group had serum gastrin levels greater than 1000pg/ml before treatment. Among the 43 patients in the non-recurrence group, 19 had serum gastrin levels greater than 1000pg/ml before treatment, accounting for 51.2% (22/43). The proportion of patients with gastrin levels greater than 1000pg/ml before treatment in the recurrence group was significantly higher than that in the non-recurrence group (P＜0.05). Multivariate logistic regression analysis showed that the recurrence after g-NETs treatment was significantly correlated with the gastrin levels before treatment and treatment methods (P<0.05).In addition, in the 32 cases of g-NETs, SSTR2 was positive in 24 cases and negative in 8 cases.The positive rate of SSTR2 was 75.0% (24/32). The positive expression rate of β-catenin in SSTR2 positive g-NETs was 75.0% (18/24), and that in SSTR2 negative g-NETs was 12.5% (1/8). The expression of SSTR2 was positively correlated with β-catenin in g-NETs, and the difference was statistically significant (P＜0.05). The positive expression rate of c-Myc in SSTR2 positive g-NETs was 79.2% (19/24), and that in SSTR2 negative g-NETs was 25.0% (2/8). The expression of SSTR2 was positively correlated with c-Myc in g-NETs, and the difference was statistically significant (P＜0.05).

Conclusions: The individualized treatment plan of g-NETs was formulated by comprehensively considering the type, grade, number, diameter and metastasis of tumors. There was no significant difference in remission rate among the three groups, but there is a significant difference in the recurrence rate among the four different treatment methods. The recurrence after g-NETs treatment was significantly correlated with the gastrin levels greater than 1000pg/ml before treatment and treatment methods. SSA treatment has a lower recurrence rate, and better patient compliance because of non-invasive treatment, long-term SSA treatment was safe and effective for type 1 g-NETs with more than 6 lesions in the stomach. SSA may affect the Wnt signaling pathway by binding to SSTR2, regulate β-catenin protein, and affect the expression of downstream target genes such as c-Myc, thereby regulating the growth of g-NETs.