Abstract Background Based on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1 -hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes related to LLS remain elusive. Methods We identified dMMR tumors in 3609 tumors from 9 different solid organs, including colorectal cancer, gastric cancer, small-bowel cancer, endometrial cancer, ovarian cancer, upper urinary tract cancer, urinary bladder cancer, prostate cancer, and sebaceous tumor, and comprehensively summarized the characterization of dMMR tumors. Characterization of dMMR tumors were performed as loss of at least one of MMR proteins (MLH1, MSH2, MSH6, and PMS2), by immunohistochemistry, followed by MLH1 promotor methylation analysis and genetic testing for MMR genes where appropriate. Somatic variant analysis of MMR genes and whole exome sequencing (WES) were performed in patients with LLS. Results In total, the incidence of dMMR tumors was 5.9% (24/3609). The incidence of dMMR tumors and the proportion of the three categorized dMMR tumors varied considerably with different tumor types. One to three likely pathogenic/pathogenic somatic MMR gene variants were detected in 15 out of the 16 available LLS tumors. One patient each from 12 patients who gave consent to WES demonstrated non- MMR germline variants affect function ( POLQ or BRCA1 ). Conclusions Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.
This retrospective study evaluated immunity in elderly patients with unresectable gastric cancer receiving S-1/ Lentinan combination chemotherapy.This study included 10 patients aged≥70 years with unresectable gastric cancer who received S-1/Lentinan combination chemotherapy between October 2008 and December 2012. All patients gave written informed consent. Immune parameters for regulatory T cell(Treg)ratio, prostaglandin E2(PGE2), C3, CH50, and granulocyte/lymphocyte ratio were measured before chemotherapy initiation and at 7 weeks after it. Clinicopathological or immune parameters affecting overall survival(OS)were consequently evaluated.A high Treg ratio(p=0.02) and low PGE2(p=0.05)levels at 7 weeks after chemotherapy and a decrease in the Treg ratio(p=0.02)were found to be significant favorable factors affecting OS.The outcome of elderly patients with unresectable gastric cancer receiving S-1/Lentinan combination chemotherapy seemed to be correlated with the change in immunity.
The aim of this study was to evaluate the clinical significance of the granulocyte-to-lymphocyte(G/L)ratio as a prognostic predictor in patients with Stage IV colorectal cancer. A total of 83 patients who underwent oxaliplatin-based chemotherapy for Stage IV colorectal cancer were enrolled in the study. Univariate analysis indicated that the G/L ratio; number of involved organs(more than one organ); performance status ≥1; noncurability; and levels of hemoglobin, C-reactive protein, albumin, alkaline phosphatase, carbohydrate antigen 19-9, and lactate dehydrogenase before chemotherapy were significant prognostic factors. Noncurability was identified to be an independent, unfavorable factor for survival on multivariate analysis. When patients were divided into 2 groups according to the G/L ratio(the median was considered the cut-off value), the median survival time of patients with a high G/L ratio(≥3.0)was significantly worse than that of patients with a low G/L ratio(<3.0; 16.1 months vs 25.4 months, p=0.03). Further studies with more patients are required to examine whether the G/L ratio is a convenient biomarker affecting survival in patients with Stage IV colorectal cancer.
BRAF V600E mutation plays an important role in the serrated neoplasia pathway of colorectal tumorigenesis and is a negative predictive factor for chemotherapy response as well as a prognostic factor in patients with colorectal cancer. To evaluate BRAF V600E mutations, a conventional polymerase chain reaction(PCR)is performed but recently immunohistochemistry (IHC)with a BRAF antibody has been used. Although similarities between the PCR and IHC methods have been reported, some investigators have doubts about the usefulness of IHC for BRAF mutation analysis. The subjects were 38 colorectal cancer patients with tumors demonstrating loss of both MLH1 and PMS2, and high-level microsatellite instability. Of the original 39 patients, 1 was excluded due to Lynch syndrome, which was identified using germline mutation testing. The mutation rate of BRAF V600E was 57.9% using both methods, but the concordance rate was 68.4%, with a kappa-value of 0.33. We should consider the usefulness of the IHC method in the evaluation of BRAF mutations in colorectal cancer patients.
The interleukin (IL)-6 concentration in plasma or serum has been considered to represent the degree of stress resulting from surgery. However, IL-6 in peritoneal fluid has rarely been considered. The aim of this study was to assess the concentration and amount of IL-6 in peritoneal fluid as indicators of surgical stress. To obtain basic data on peritoneal release of IL-6 during gastric cancer surgery, we measured IL-6 in peritoneal drainage samples, stored for up to 72 hours postoperatively, from patients who had undergone conventional open (ODG group, n = 20) and laparoscopic-assisted (LADG group, n = 19) distal gastrectomy. Within 24 hours, 61 and 77% of the IL-6 was released into the peritoneal cavity in the LADG and ODG groups, respectively. In both groups, the concentration and amount of peritoneal fluid IL-6 were significantly correlated with each other (LADG group: Spearman's rank correlation test [rS] = 0.48, P = 0.04; ODG group: rS = 0.58, P = 0.01). The concentration and amount of IL-6 in peritoneal fluid was 2.8- and 3.6-fold higher in the ODG than in the LADG group, respectively (P < 0.01). With regard to the relationship between the serum C-reactive protein (CRP) peak and the concentration or amount of peritoneal fluid IL-6 released within 24 hours, only the concentration of peritoneal fluid IL-6 in the LADG group was significantly correlated (rS = 0.60, P = 0.01) with the serum CRP peak. Our findings suggest that the amount and concentration of IL-6 released into the peritoneal cavity for up to 24 hours after surgery can each be a reliable parameter for assessment of surgical stress.
Surgical treatments for curatively unresectable gastric cancer include reduction surgery and palliative surgery(palliative gastrectomy and bypass operation). Both palliative gastrectomy and reduction surgery reduce the tumor volume. In this study, the clinical significance of these treatment methods was investigated. The subjects were 58 patients with unresectable gastric cancer for which surgery was performed as the primary treatment. Of these patients, 38 patients underwent reduction surgery and 20 patients underwent palliative surgery. On univariate analysis, age and gender were not significant. Pre-operative performance status(PS) in patients treated with reduction surgery was favorable compared to that in patients receiving palliative surgery(PS 0: 65.8 vs 40.0%, p=0.06). The administration rate of post-operative chemotherapy in patients treated with reduction surgery was higher than that in patients with palliative surgery (92.1 vs 65.0%, p<0.01). The median survival time in patients treated with reduction surgery was 18.2 months, while that in patients with palliative surgery was 11.0 months (p<0.01). These results indicated that reduction surgery was clinically different compared to palliative surgery in terms of the administration rate of post-operative chemotherapy and prognosis.
Immune checkpoint inhibitors(ICIs)are widely used for the treatment of unresectable gastric cancer. We treated approximately 70 patients with ICIs. ICI treatment with pembrolizumab was administered for MSI-high cases and nivolumab for MSS cases in the second- or third-line chemotherapy. We observed 5 cases of complete response. Among these, 2 patients presented with liver metastases, 2 with peritoneal disseminations, and 1 with pulmonary metastasis. In 1 patient, the primary tumor invaded the diaphragm and descending aorta; whereas, in another patient the primary tumor invaded the pancreas and liver. All patients had progressive disease after first-line chemotherapy.
A 47-year-old woman diagnosed with transverse colon cancer with liver, peritoneal, and lymph node metastases was admitted. Modified FOLFOX6(mFOLFOX6)regimen was given as a first line chemotherapy and was followed by pembrolizumab after 1 cycle of the mFOLFOX6, because microsatellite instability(MSI)test of the tumor showed high-frequency MSI. Because of the transverse colon obstruction after 2 cycles of pembrolizumab, she underwent right hemicolectomy. Histological examination of the resected specimen revealed no residual tumor cells in the primary tumor and reginal lymph nodes. Immunohistochemistry for mismatch repair proteins(IHC-MMR)showed loss of MSH2 and MSH6 expression. Genetic test identified a MSH2 pathogenic variant leading to the diagnosis of Lynch syndrome. The present case shows the importance of MSI test or IHC-MMR before the treatment of metastatic colorectal cancer.
