Haploinsufficiency by minute MutL homolog 1 promoter DNA methylation may represent unique phenotypes of microsatellite instability-gastric carcinogenesis

Promoter DNA methylation of MutL homolog 1 (MLH1) is considered to play a causative role in microsatellite instability (MSI) carcinogenesis in primary gastric cancer, and a high MSI status is associated with treatment sensitivity to human cancers. Nevertheless, clinicopathological analysis is defective for MLH1 methylation status in a quantitative manner. We newly developed quantitative methylation specific PCR using a TaqMan probe and applied it to 138 patients with primary gastric cancer who underwent gastrectomy in addition to basic molecular features such as MSI, Epstein Barr virus, and other DNA methylation status. (1) In primary gastric cancer, median methylation value was 0.055, ranging from 0 to 124.3. First, MLH1 hypermethylation was strongly correlated with MSI-High/MSI-Low status and suppressed immunostaining (P < 0.0001). (2) The MLH1 hypermethylation was associated with advanced age (P = 0.0048), antral location (P = 0.0486), synchronous multiple gastric cancer (P = 0.0001), and differentiated histology (P = 0.028). (3) Log-rank plot analysis identified the most relevant cut-off value (0.23) to reflect gentle phenotypes in MLH1 hypermethylation cases (P = 0.0019), especially in advanced gastric cancer (P = 0.0132), which are designated as haploinsufficiency of MSI (MSI-haplo) phenotype in this study. (4) In synchronous multiple gastric cancer, MLH1 hypermethylation was not necessarily confirmed as field cancerization. (5) MSI-haplo defined by MLH1 methylation status represented distinct prognostic phenotype even after molecular classifications. MLH1 hypermethylation designated as MSI-haplo may represent unique prognostic phenotype during gastric carcinogenesis.

Time Interval After Various Types of Gastrectomy Until Metachronous Multiple Gastric Cancer: Analysis of Data From A Nationwide Japanese Survey

Background The time interval between initial partial gastrectomy and diagnosis of cancer in the remnant stomach reportedly differs according to the reconstruction procedure used in the initial gastrectomy. However, factors correlated with the time interval from the initial surgery for gastric cancer to the detection of metachronous multiple gastric cancer (MMGC) remain unclear. This study was performed to evaluate the association between the type of initial gastrectomy or reconstruction procedure and the time interval from initial gastrectomy to detection of MMGC as well as the association between the type of initial gastrectomy and the procedure performed for MMGC. Methods A questionnaire survey on remnant stomach cancer was conducted by the Japanese Society for Gastro-Surgical Pathophysiology in 2018. Participating facilities were asked to indicate the number of patients who underwent surgery for MMGC between 2003 and 2017, in accordance with the time interval from the initial gastrectomy until treatment for MMGC by type of initial gastrectomy or reconstruction procedure. The number of patients who underwent each treatment procedure (completion total gastrectomy or partial gastrectomy) was also collected. Results Analyses were performed using data from 45 facilities. Gastrectomy for MMGC was performed in 1,234 patients during the period. Billroth-II and Roux-en Y accounted for 22.3% (103/462) and 1.3% (6/462), respectively, of patients who underwent surgery for MMGC ≥ 10 years from initial DG, while these patients accounted for 8.0% (23/286) and 21.7% (65/286), respectively, of patients who underwent surgery for MMGC within 5 years after initial DG. Likewise, the proportion of each reconstruction procedure differed by the time interval from initial proximal gastrectomy to treatment for MMGC. In terms of the treatments performed for MMGC, the proportion of patients who underwent partial gastrectomy increased in accordance with the size of the remnant stomach after the initial gastrectomy. Conclusions The types of gastrectomy or reconstruction procedures for initial gastrectomy differed significantly by time interval between the initial gastrectomy and treatment for MMGC, and their time trends were assumed to be a major cause of the differences. The proportion of patients who underwent completion total gastrectomy deceased as the size of the remnant stomach increased.

Clinicopathological features and risk factors analysis of lymph node metastasis and long-term prognosis in patients with synchronous multiple gastric cancer

Background As a common malignancy, gastric cancer (GC) remains an important threat to human’s health. The incidence of synchronous multiple gastric cancer (SMGC) has increased obviously with technical advances of endoscopic and pathological examinations. Several studies have investigated the relationship between SMGC and solitary gastric cancer (SGC). However, little is known about the relationship between early and advanced SMGCs, and the independent risk factors of lymph node metastasis and prognosis in SMGC patients remain unclear. Methods We retrospectively collected 57 patients diagnosed as SMGC and underwent radical gastrectomies from December 2011 to September 2019. Epidemiological data and clinicopathological characteristics of all patients were recorded. Postoperative follow-up was performed by telephone or outpatient service. Chi-squared test or Fisher’s exact test was adopted in analysis of categorical data. Continuous data were analyzed by using unpaired t test. Univariate and multivariate analyses were performed to investigate the independent risk factors of lymph node metastasis and tumor recurrence of SMGC. Results There were 45 males and 12 females. The average age was 62.1 years old. There were 20 patients with early SMGC and 37 patients with advanced SMGC. Most of patients (91.2%) had two malignant lesions. Tumor recurrence occurred in 8 patients, among which 7 patients died from recurrence. The rates of total gastrectomy, tumor size ≥ 2 cm, poorly differentiated type, lymph node metastasis, ulcer and nerve invasion, and preoperative CEA level were significantly higher in advanced SMGC patients compared to those with early SMGC. Lymphovascular cancer plug and preoperative CA125 were the independent risk factors of lymph node metastasis in patients with SMGC. Lymph node metastasis, nerve invasion, and preoperative AFP might be the risk factors of tumor recurrence of SMGC, but need further validation. Conclusions In patients with SMGC, the presence of tumor size ≥ 2 cm, poorly differentiated type, lymph node metastasis, ulcer, nerve invasion, and relatively high preoperative CEA level might indicate the advanced SMGC. More attention should be paid to lymph node metastasis in SMGC patients with lymphovascular cancer plug and high preoperative CA125. Lymph node metastasis, nerve invasion, and preoperative AFP might be associated with recurrence of SMGC, needing further validation.

Clinicopathological features and risk factors analysis of lymph node metastasis and long-term prognosis in patients with synchronous multiple gastric cancer

Background As a common malignancy, gastric cancer (GC) remains an important threat to human’s health. The incidence of synchronous multiple gastric cancer (SMGC) has increased obviously with technical advances of endoscopic and pathological examinations. Several studies have investigated the relationship between SMGC and solitary gastric cancer (SGC). However, little is known about the relationship between early and advanced SMGCs, and the independent risk factors of lymph node metastasis and prognosis in SMGC patients remain unclear.Methods We retrospectively collected 57 patients diagnosed as SMGC and underwent radical gastrectomies from December 2011 to September 2019. Epidemiological data and clinicopathological characteristics of all patients were recorded. Postoperative follow-up was performed by telephone or outpatient service. Chi-square test or Fisher’s exact test was adopted in analysis of categorical data. Continuous data were analyzed by using unpaired t-test. Univariate and multivariate analyses were performed to investigate the independent risk factors of lymph node metastasis and tumor recurrence of SMGC.Results There were 45 males and 12 females. The average age was 62.1-year-old. There were 20 patients with early SMGC and 37 patients with advanced SMGC. Most of patients (91.2%) had two malignant lesions. Tumor recurrence occurred in 8 patients, among which 7 patients died from recurrence. The rates of total gastrectomy, tumor size ≥2 cm, poorly-differentiated type, lymph node metastasis, ulcer and nerve invasion and preoperative CEA level were significantly higher in advanced SMGC patients compared to those with early SMGC. Lymphovascular cancer plug and preoperative CA125 were the independent risk factors of lymph node metastasis in patients with SMGC. Lymph node metastasis, nerve invasion and preoperative AFP might be the risk factors of tumor recurrence of SMGC, but need further validation.Conclusions In patients with SMGC, the presence of tumor size ≥2 cm, poorly-differentiated type, lymph node metastasis, ulcer, nerve invasion and relatively high preoperative CEA level might indicate the advanced SMGC. More attention should be paid to lymph node metastasis in SMGC patients with lymphovascular cancer plug and high preoperative CA125. Lymph node metastasis, nerve invasion and preoperative AFP might be associated with recurrence of SMGC, needing further validation.

Clinicopathological features and risk factors analysis of lymph node metastasis and long-term prognosis in patients with synchronous multiple gastric cancer

Background As a common malignancy, gastric cancer (GC) remains an important threat to human’s health. The incidence of synchronous multiple gastric cancer (SMGC) has increased obviously with technical advances of endoscopic and pathological examinations. Several studies have investigated the relationship between SMGC and solitary gastric cancer (SGC). However, little is known about the relationship between early and advanced SMGCs, and the independent risk factors of lymph node metastasis and prognosis in SMGC patients remain unclear. Methods We retrospectively collected 57 patients diagnosed as SMGC and underwent radical gastrectomies from December 2011 to September 2019. Epidemiological data and clinicopathological characteristics of all patients were recorded. Postoperative follow-up was performed by telephone or outpatient service. Chi-square test or Fisher’s exact test was adopted in analysis of categorical data. Continuous data were analyzed by using unpaired t-test. Univariate and multivariate analyses were performed to investigate the independent risk factors of lymph node metastasis and tumor recurrence of SMGC. Results There were 45 males and 12 females. The average age was 62.1-year-old. There were 20 patients with early SMGC and 37 patients with advanced SMGC. Most of patients (91.2%) had two malignant lesions. Tumor recurrence occurred in 8 patients, among which 7 patients died from recurrence. The rates of total gastrectomy, tumor size ≥ 2 cm, poorly-differentiated type, lymph node metastasis, ulcer and nerve invasion and preoperative CEA level were significantly higher in advanced SMGC patients compared to those with early SMGC. Lymphovascular cancer plug and preoperative CA125 were the independent risk factors of lymph node metastasis in patients with SMGC. Lymph node metastasis, nerve invasion and preoperative AFP might be the risk factors of tumor recurrence of SMGC, but need further validation. Conclusions In patients with SMGC, the presence of tumor size ≥ 2 cm, poorly-differentiated type, lymph node metastasis, ulcer, nerve invasion and relatively high preoperative CEA level might make them more likely to be advanced SMGC. More attention should be paid to lymph node metastasis in SMGC patients with lymphovascular cancer plug and high preoperative CA125. Lymph node metastasis, nerve invasion and preoperative AFP might be associated with recurrence of SMGC.

The incidences of metachronous multiple gastric cancer after various types of gastrectomy: analysis of data from a nationwide Japanese survey

Background The incidence of metachronous multiple gastric cancer (MMGC) after gastrectomy remains unclear. This study evaluated the incidences of MMGC according to specific gastrectomy types, including pylorus-preserving gastrectomy (PPG), proximal gastrectomy (PG), and function-preserving gastrectomy (FPG), which was categorized as segmental gastrectomy and local resection. Methods We conducted a questionnaire survey of the Japanese Society for Gastro-Surgical Pathophysiology members, who were asked to report their institutional numbers of radical gastrectomy cases for cancer between 2003 and 2012. The cases were categorized according to whether the remnant stomach’s status was followed for > 5 years, confirmation of MMGC, time to diagnosis, and treatment for MMGC. We calculated the “precise incidence” of MMGC by dividing the number of MMGC cases by the number of cases in which the status of remnant stomach was followed up for > 5 years. Results The responses identified 33,731 cases of gastrectomy. The precise incidences of MMGC were 2.35% after distal gastrectomy (DG), 3.01% after PPG, 6.28% after PG (p < 0.001), and 8.21% after FPG (p < 0.001). A substantial proportion of MMGCs (36.4%) was found at 5 years after the initial surgery. The rates of MMGC treatment using endoscopic submucosal dissection were 31% after DG, 28.6% after PPG, 50.8% after PG (p < 0.001), and 67.9% after FPG (p < 0.001). Conclusions The incidence of MMGC was 2.4% after DG, and higher incidences were observed for larger stomach remnants. However, the proportion of cases in which MMGC could be treated using endoscopic submucosal dissection was significantly higher after PG and FPG than after DG.