Hirohiko Kuroda

Increased PD‐1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer

Co‐signaling molecules play an important role in T cells. Programmed death‐1 (PD‐1) is an immunoinhibitory receptor and its overexpression on T cells appears to be involved in immune evasion in cancer patients. The present study was designed to investigate PD‐1 expression on T cells and its relationship with immune evasion in gastric cancer patients.

Prognostic indicators in node-negative advanced gastric cancer patients.

Despite carrying better overall prognoses, some node‐negative gastric cancer patients die from recurrent malignancies. Identifying factors associated with disease‐specific survival in adequately staged node‐negative gastric cancer is important, as these patients are presumably free of microscopic regional metastases and may derive significant benefit from existing or future adjuvant strategies.

Surgical outcomes for gastric cancer patients with intraperitoneal free cancer cell, but no macroscopic peritoneal metastasis

Gastric cancer patients with intraperitoneal cancer cells have extremely poor prognoses, because they frequently develop peritoneal metastasis. The aim of the current study is to clarify the clinicopathologic characteristics of patients with intraperitoneal free cancer cells who do not have recurrences.

Decreased number and reduced NKG2D expression of Vδ1 γδ T cells are involved in the impaired function of Vδ1 γδ T cells in the tissue of gastric cancer

BackgroundIn cancer patients, impaired function of immune cells—such as CD8+ T cells, NK cells, and dendritic cells—reportedly results in tumor progression. Although γδ T cells also play a critical role in tumor defense, their function remains unclear in cancer patients.MethodsThe frequency and function of γδ T cells in peripheral blood, normal gastric mucosa, and cancer tissue were evaluated by multicolor flow cytometry. We also determined NKG2D expression on γδ T cells in gastric cancer patients.ResultsThe frequency of Vδ1 γδ T cells in gastric cancer tissue is significantly lower than in normal gastric mucosa; however, differences in the frequencies of Vδ2 and Vγ9 γδ T cells between normal gastric mucosa and gastric cancer tissue were not statistically significant. The Vδ1 γδ T cells from gastric cancer tissue produce significantly less IFN-γ than those from normal gastric mucosa do. Expression of NKG2D on Vδ1 γδ T cells from gastric cancer tissue was significantly lower than in normal gastric mucosa. We also found a significant correlation between NKG2D expression and IFN-γ production of Vδ1 γδ T cells in gastric cancer tissue.ConclusionVδ1 γδ T cells show decreased frequency and impaired function in gastric cancer tissue, for which decreased NKG2D expression might be one of the mechanisms. Modalities specifically targeting NKG2D in Vδ1 γδ T cells may provide a breakthrough treatment for gastric cancer patients.

A new pouch reconstruction method after total gastrectomy (pouch-double tract method) improved the postoperative quality of life of patients with gastric cancer

PurposeMany reconstruction methods after total gastrectomy (TG) lead patients to dumping syndrome, reflux esophagitis, and poor postoperative quality of life (QOL). To improve patients’ postoperative QOL after TG, we introduce a new reconstruction method named “pouch-double tract” (PDT).MethodsA prospective randomized study was performed between 2005 and 2007 in 29 patients who were diagnosed as stage I or II gastric cancers preoperatively. Patients were followed until the end of 2009. Conventional Roux-en-Y reconstruction (RY) was performed in 15 patients, and PDT was used in 14 patients. Postoperative patients’ nutritional assessments and patients’ QOL were compared between the groups.ResultsPDT did not increase morbidity or mortality compared with RY. Patients in the PDT group did not complain of dumping and showed better postoperative food intake. Body weight recovered better in PDT than in RY.ConclusionPDT is safe and associated with better nutritional status compared with the RY.

Prognostic Significance of Pre- and Postoperative Lymphocyte Counts in Patients with Gastric Cancer

Background: Although preoperative lymphopenia is reportedly a prognostic factor in cancer patients, the association between postoperative lymphopenia and patient prognosis has not been widely studied. Methods: We enrolled 352 patients who underwent surgery for gastric cancer (GC) between January 2005 and April 2013 to analyze correlations among pre- and postoperative lymphocyte counts (LCs) and prognosis in GC patients. Results: Pre- and postoperative (obtained 1 day after surgery) LCs were significantly correlated (r = 0.496, p < 0.0001). Pre- and postoperative LCs of elderly patients were significantly lower than those of non-elderly patients. Postoperative lymphocyte count was significantly lower in patients with a differentiated tumor than in those with an undifferentiated tumor. Based on the results of receiver operating characteristic analysis, patients were classified into subgroups as: preoperative LC ≥1,676 (pre-LCHigh), preoperative LC <1,676 (pre-LCLow); and as postoperative LC ≥855 (post-LCHigh), and postoperative LC <855 (post-LCLow). Five-year overall survival rates significantly differed between pre-LCHigh (82.5%) and pre-LCLow (71.6%) groups (p = 0.023); and also between the post-LCHigh (81.5%) and post-LCLow (69.5%) groups (p = 0.0072). The 5-year disease specific survival rates were 91.3 and 82.4% in patients with post-LCHigh and those with post-LCLow, respectively, and differences were statistically significant (p = 0.015). Multivariate analysis indicated that postoperative lymphocyte count was an independent prognostic indicator, along with age, gender, tumor size, lymph node metastasis, and venous invasion. Conclusions: Postoperative lymphocyte count is a useful predictive factor for prognosis in GC patients.

Influence of prognostic nutritional index and tumor markers on survival in gastric cancer surgery patients

PurposeBlood analytes are easily used in routine clinical practice. Tumor markers (TMs) are useful in diagnosing, treating, and predicting prognosis of gastric cancer (GC). The prognostic nutritional index (PNI) was also recently found to be useful in predicting GC prognosis.MethodsThe PNI and serum levels of CEA and CA19-9 of 453 patients with GC were measured to examine correlations between those levels and patients’ prognoses.ResultsOf the 453 patients, 84 (18.5%) were positive for CEA and/or CA19-9 and therefore considered positive for TMs. Prognosis of patients who were TM+ was significantly worse than for those who were TM−. Mean PNI was 48.2 (range 27.7–63.6). ROC analysis indicated that 46.7 was the optimal PNI cutoff value. Prognosis of patients in the PNILow group (<46.7) was significantly worse than in the PNIHigh group (≥46.7). Prognosis of patients who were both TM+ and PNILow was significantly worse than that of patients who were either TM+ or PNILow and those who were both TM− and PNIHigh. Multivariate analysis indicated that combination of TM and PNI was an independent prognostic indicator.ConclusionsThe combination of TM and PNI offers accurate information about a patient’s prognosis.

A high number of IgG4-positive cells in gastric cancer tissue is associated with tumor progression and poor prognosis

IgG4-related disease is a newly defined disease characterized by elevated serum IgG4 levels and infiltration of affected organs by IgG4-positive plasma cells. Recently, increased IgG4 levels were reported to be closely related with malignancy. To assess the relationship between IgG4 and the progression of gastric cancer, we immunohistochemically stained in this study gastric cancer tissue samples for IgG4-positive cells using an anti-IgG4 antibody. In addition, pre- and postoperative serum concentrations of IgG4 were measured, using an enzyme-linked immunosorbent assay. In gastric cancer samples, the number of CD138-positive plasma cells was significantly lower and the number of IgG4-positive cells significantly higher than in non-cancerous gastric mucosa. The number of IgG4-positive cells was significantly correlated with gross tumor appearance, tumor depth, lymph node metastasis, venous invasion, and lymphatic invasion. Prognosis was significantly poorer in patients with a high number of IgG4-positive cells than in those with a low number. Multivariate analysis indicated that both the number of IgG4-positive cells and the depth of tumor invasion were independently prognostic of survival. In conclusion, in gastric cancer, the number of IgG4-positive cells is increased and this is closely associated with gastric cancer progression.

Combined analysis of the pre- and postoperative neutrophil–lymphocyte ratio predicts the outcomes of patients with gastric cancer

PurposeThe neutrophil–lymphocyte ratio (NLR) is a biochemical marker of the systemic inflammatory response and has been associated with prognosis for various types of cancer. This retrospective study investigates the relationship between the pre- and postoperative NLR and the prognosis of gastric cancer patients.MethodsThe subjects were 280 patients who underwent curative surgery for histopathologically diagnosed gastric adenocarcinoma.ResultsThe preoperative NLR was significantly correlated with tumor size, tumor depth, lymphatic invasion, venous invasion, and disease stage. In contrast, there was no correlation between the postoperative NLR and the various clinicopathological variables. Prognosis was significantly worse for patients with a high preoperative NLR than for those with a low preoperative NLR. Prognosis was also significantly worse for patients with a high postoperative NLR than for those with a low postoperative NLR. Furthermore, the prognosis was worse for gastric cancer patients whose pre- and postoperative NLRs were both high. Multivariate analysis indicated that a high pre- and postoperative NLR was an independent prognostic indicator.ConclusionsThe combination of pre- and postoperative NLRs appears to be useful for predicting the prognosis of gastric cancer patients.

Tumor infiltration pattern into the surrounding tissue has prognostic significance in advanced gastric cancer

Gastric cancer can be classified into three subgroups according to pattern of tumor infiltration into the surrounding tissue: INFa (expanding growth and a distinct border with the surrounding tissue), INFc (infiltrating growth and an indistinct border with the surrounding tissue), and INFb (in-between a and c). How the tumor infiltration pattern (INF) relates to prognosis and type of recurrence in advanced gastric cancer has not been sufficiently explored. We examined 805 consecutive advanced gastric adenocarcinoma patients who underwent curative gastrectomy at our institution between 1980 and 2005. Poor differentiation, serosal invasion, and lymph node metastasis were significantly more frequent in patients with INFc tumors than in those with INFa/b tumors. For patients with a T2 or T3 tumor, there was no significant difference in prognosis between those with INFa/b and with INFc. However, for patients with a T4a or T4b tumor, the prognosis of those with INFc was significantly worse than that of those with INFa/b. In multivariate analysis, INF was an independent prognostic indicator in T4a but not T2, T3, and T4b. Furthermore, the prognosis of T4 patients with INFc tumors was significantly worse than that of those with INFa/b, especially in node-negative but not in node-positive cases. In patients with a T4a or T4b tumor, peritoneal recurrence was significantly more frequent for those with INFc than for those with INFa/b. Our data indicate that INF is useful to predict the prognosis and recurrence pattern in T4a node-negative gastric cancer.