Modified Frailty Index is Useful in Predicting Non-home Discharge in Elderly Patients with Gastric Cancer Who Undergo Gastrectomy.

BACKGROUND: Development of laparoscopic gastrectomy and the Enhanced Recovery After Surgery (ERAS) protocol enable early discharge to home of patients with gastric cancer (GC). However, a significant proportion of patients are still discharged to inpatient facilities after surgery. We aimed to identify predictive factors of non-home discharge in patients with GC who undergo gastrectomy. METHODS: We enrolled 517 patients with histopathologically confirmed diagnosis of GC who underwent gastrectomy. RESULTS: The number of patients with non-home discharge was 23 (4.4%), and non-home discharge was only observed in patients with GC aged ≥65 years. Patients were divided into the mFIHigh (≥0.272) and mFILow (<0.272) groups according to the cut-off value determined by ROC analysis. The mFIHigh classification was significantly more frequent in patients aged ≥75 years, who underwent either total or proximal partial gastrectomy, who underwent limited lymph node dissection, and with non-home discharge than in patients aged <75 years (p = 0.0002), those who underwent distal partial gastrectomy (p = 0.032), those who underwent standard lymph node dissection (p = 0.036), and those without non-home discharge (p = 0.0071). Multivariate analysis revealed mFI as an independent predictive indicator of non-home discharge, along with postoperative complications and surgical approach, in patients with GC aged ≥65 years. The frequency of patients with non-home discharge was significantly associated with the number of these three predictive factors in GC patients aged ≥65 years (p < 0.0001). CONCLUSIONS: The combination of mFI, postoperative complications, and surgical approach is useful for predicting non-home discharge in patients aged ≥65 years who underwent gastrectomy for GC.

The attenuation value of preoperative computed tomography as a novel predictor for pancreatic fistula after pancreaticoduodenectomy.

PURPOSE: Pancreatic fistula (PF) is the most serious complication following pancreaticoduodenectomy (PD). This study was performed to identify new clinical factors that may predict the development of PF after PD to improve perioperative management. METHODS: Seventy-five consecutive patients who underwent PD from 2012 to 2015 were evaluated. The patients' perioperative data including the computed tomography (CT) parameters were collected. The minimum, maximum, and mean CT attenuation values (HUmin, HUmax, and HUmean, respectively) were extracted from the pancreatic parenchyma (≥ 100 pixels), and the standard deviation of these values (HUSD) was determined from the slice in which the superior mesenteric and splenic veins were merged. PF was defined as grade B or C according to the International Study Group for Pancreatic Fistula criteria. RESULTS: The PF occurrence rate (grade B or C) was 25.3% in 75 patients. A multivariate analysis identified a larger HUSD (odds ratio 3.092; 95% CI 1.018-9.394) and higher amylase concentration in drainage fluid on postoperative day 1 (odds ratio 1.0001; 95% CI 1.00001-1.00022) as significant risk factors for PF. CONCLUSIONS: The HUSD of preoperative CT attenuation values in the pancreatic parenchyma was found to be an independent predictor for PF after PD and it might therefore positively contribute to the perioperative management of PD.

Nicotine enhances the malignant potential of human pancreatic cancer cells via activation of atypical protein kinase C.

BACKGROUND: Pancreatic cancer (PC) is the most lethal malignancy among solid tumors, and the most common risk factor for its development is cigarette smoking. Atypical protein kinase C (aPKC) isozymes function in cell polarity, proliferation, and survival, and have also been implicated in carcinogenesis. However, the involvement of aPKC in PC progression and the effect of nicotine, a major component of cigarette smoke, on the biological activities of aPKC remain to be fully elucidated. METHODS: We investigated the effects of nicotine on the proliferation, migration and invasion of the human PC cell lines Panc1 and BxPC3. We analyzed aPKC localization and activity by immunohistochemistry and in vitro kinase assays, respectively, to assess their involvement in the regulation of PC progression. Moreover, we examined the effect of nicotine on implanted peritoneal tumors of PC cells in mice. RESULTS: Nicotine enhanced cell proliferation, migration and invasion in Panc1 and BxPC3 cells. In nicotine-treated PC cells, the aPKC was significantly activated. We also found that nicotine induced phosphatidylinositol 3-kinase (PI3K) signal activation, and a specific inhibitor of the nicotine acetylcholine receptor (nAChR) as well as knockdown of nAChR prevented nicotine-mediated Akt phosphorylation and aPKC activation. In a peritoneal dissemination model of PC, nicotine-treated mice had larger tumors and increased numbers of nodules. Immunohistochemistry showed enhanced expression levels of aPKC and phosphorylated Akt in nodules from nicotine-treated mice. CONCLUSIONS AND GENERAL SIGNIFICANCE: Nicotine induces aberrant activation of aPKC via nAChR/PI3K signaling in PC cells, resulting in enhancement of cellular proliferation, migration and invasion.

Glasgow prognostic score and neutrophil-lymphocyte ratio are good prognostic indicators after radical neck dissection for advanced squamous cell carcinoma in the hypopharynx.

PURPOSE: Locally advanced carcinomas arising in the hypopharynx have been traditionally treated by resection of the hypopharynx, larynx, and cervical esophagus. However, the prognosis of these patients is still low. In the present study, we retrospectively analyzed the long-term survival of patients with locally advanced hypopharyngeal squamous cell carcinoma (HSCC) reconstructed by jejunal graft. METHODS: Between 2004 and 2014, 68 patients with HSCC were treated at Tottori University Hospital. Nine patients with synchronous esophageal cancer were excluded. We analyzed the overall survival of 59 patients with clinical stage III and IV HSCC who underwent pharyngo-laryngo-cervical esophagectomy with definitive tracheostomy followed by free jejunal graft reconstruction. Additionally, prognostic significances of preoperative patients' Glasgow prognostic score (GPS), neutrophil-lymphocyte ratio (NLR), and prognostic nutritional index were analyzed. RESULTS: Postoperative complications occurred in 18.6 % of 59 patients. There were no cases of graft loss, and no patient died from complications. Preoperative poor performance status of patients was a risk factor for postoperative complications. The 5-year overall survival rate of the 59 patients was 46.1 %, and the median survival time was 28 months. In univariate and multivariate survival analyses, high GPS (1 or 2), and high NLR (≥5) were recognized as independent poor prognostic markers for patients with HSCCs. CONCLUSIONS: Pharyngo-laryngo-cervical esophagectomy followed by free jejunal reconstruction was performed safely. Additional treatment, such as chemoradiotherapy, should be introduced for patients with high preoperative GPS or NLR after curative operation.

Predictive factors for recurrence in T2N0 and T3N0 gastric cancer patients.

PURPOSE: Adjuvant chemotherapy is an indispensable component of treatment for preventing recurrence in advanced gastric cancer patients after macroscopically complete tumor resection (R0). However, the efficacy of this treatment for patients with T2N0 and T3N0 gastric cancer is not well characterized. METHODS: This study examined 1019 T1, 126 T2N0, and 67 T3N0 gastric adenocarcinoma patients who underwent gastrectomies at our institution between 1975 and 2005 to determine the predictive factors for recurrence in T2N0 and T3N0 gastric cancer patients. RESULTS: Among 193 T2N0 and T3N0 patients, 14 patients (7.3 %) have recurred. The prevalence of ly2/3 and v2/3 was significantly higher in patients with recurrence compared with those without recurrence. The prognosis for either T2N0 or T3N0 gastric cancer patients was significantly worse than that for T1 gastric cancer patients. Multivariate analysis indicated that lymphatic and blood vessel invasion were independent prognostic indicators in T2N0 and T3N0 gastric cancer patients. Ten-year survival rates for T2N0 and T3N0 gastric cancer patients with both ly2/3 and v2/3, with either ly2/3 or v2/3, and without ly2/3 and v2/3 were 42.9, 86.1, and 96.7 %, respectively. T2N0 and T3N0 gastric cancer patients with both ly2/3 and v2/3 had a significantly worse prognosis than that of patients with either ly2/3 or v2/3 and those without ly2/3 and v2/3. CONCLUSIONS: Our data indicate that T2N0 and T3N0 patients with both ly2/3 and v2/3 have a high risk of recurrence. Therefore, adjuvant chemotherapy should be administered to these patients.

An increased number of PD-1+ and Tim-3+ CD8+ T cells is involved in immune evasion in gastric cancer.

PURPOSE: Co-signaling molecules play an important role in T cells. This study was designed to investigate PD-1 and Tim-3 expression on T cells and the relationships between PD-1 and Tim-3 expression and immune evasion in patients with gastric cancer. METHODS: Using multicolor flow cytometry, we analyzed PD-1 and Tim-3 expression on CD8+ T cells obtained from peripheral blood mononuclear cells (PBMCs) and gastric cancer tissue. RESULTS: Significantly more PD-1+ and Tim-3+ CD8+ T cells in peripheral blood were found in gastric cancer patients than in healthy controls. PD-1+ CD8+ T cells were significantly correlated with Tim-3+ CD8+ T cells in peripheral blood from the gastric cancer patients (r = 0.29, p = 0.036). Furthermore, significantly greater numbers of PD-1+ and Tim-3+ CD8+ T cells were seen in the gastric cancer tissue samples than in the PBMCs. CD8+ T cells positive for both PD-1 and Tim-3 produced significantly less IFN-gamma than cells negative for both and cells positive for PD-1 and negative for Tim-3. CONCLUSION: An increased number of PD-1+ and Tim-3+ CD8+ T cells is closely related to impaired function of CD8+ T cells in gastric cancer patients.

Prognostic indicators based on inflammatory and nutritional factors after pancreaticoduodenectomy for pancreatic cancer.

PURPOSE: We evaluated prognostic indicators based on inflammatory and nutritional factors, namely, the modified Glasgow Prognostic Score (mGPS), the Prognostic Nutritional Index (PNI), the neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR), to determine their efficiency and significance after pancreaticoduodenectomy for pancreatic cancer. METHODS: The subjects of this study were 46 patients who underwent pancreaticoduodenectomy for pancreatic cancer between October 2007 and December 2014. Patients were divided into preoperative mGPS (0/1 and 2), PNI (<40 and ≥40), NLR (<2.5 and ≥2.5), and PLR (<200 and ≥200) groups, to evaluate various perioperative outcomes. RESULTS: Hemoglobin concentrations were significantly lower (P = 0.019), whereas intra-abdominal bleeding was significantly higher (P = 0.040) in the PNI (<40) group than in the PNI (≥40) group. The incidence of postoperative pneumonia was significantly higher in the mGPS (2) group (P = 0.009), and surgical complications greater than grade 3 (Clavien-Dindo classification) were significantly increased in the NLR (≥2.5) group (P = 0.041). Overall survival rates in the PNI (<40) (P = 0.019), NLR (≥2.5) (P = 0.001), and PLR (≥200) (P < 0.001) groups were significantly lower than those in the other groups. The PLR was the only independent prognostic indicator (P = 0.002) according to multivariate analysis. CONCLUSIONS: The mGPS, PNI, and NLR were effective predictive indicators of postoperative complications. The PLR was the most useful prognostic indicator for pancreatic cancer patients after pancreaticoduodenectomy.

Prognostic Benefits of Thoracoscopic Esophagectomy for Thoracic Esophageal Squamous Cell Carcinomas.

BACKGROUND: Thoracoscopic esophagectomy has been introduced to reduce postsurgical pulmonary complications in patients with esophageal squamous cell carcinomas (ESCCs). However, the survival benefit of this procedure has not been well examined. In the present study, we retrospectively investigated the clinical outcomes of thoracoscopic esophagectomy in patients with operable thoracic ESCCs. METHODS: Eighty-four patients were enrolled in this study. They were diagnosed with resectable clinical stage I-III thoracic ESCCs and underwent thoracic esophageal resection with three-field lymph node dissection at Tottori University Hospital between January 2007 and December 2013. Occurrence of postoperative complications, disease-free survival (DFS) and overall survival (OS) were compared between the open thoracotomy group and the thoracoscopic esophagectomy group. RESULTS: Fifty-one patients underwent the thoracoscopic method, while 38 underwent the open method. Morbidity was 42.9% and mortality was 2.4%. The thoracoscopic method showed a lower occurrence of postoperative pulmonary complications. The 5-year DFSs of the two groups were not different. However, the 5-year OS of patients in the thoracoscopic method group was superior to that of those in the open method. CONCLUSIONS: Thoracoscopic esophagectomy for thoracic ESCCs is technically feasible and the low rate of postoperative pulmonary complications may prolong the OS of patients.

New Prognostic Indicator is Useful for Predicting the Survival of Patients with Unresectable Advanced Colorectal Cancer.

BACKGROUND/AIMS: Complete resection of tumors is possible after heavy chemotherapy in a few patients with unresectable colorectal cancer (UCRC). This study evaluated the ability of new prognostic score to identify such patients. METHODOLOGY: Four peripheral blood markers were evaluated in 50 patients diagnosed with UCRC at the time of patients' first visit to the hospital: C-reactive protein (CRP), albumin (ALB), neutrophil/lymphocyte ratio (NLR), and carcinoembryonic antigen (CEA). Each was scored +1 or 0 for that marker. For example, when patient shows CRP ≥ 1.0 mg/dL, ALB 3.5 g/dL, NLR ≥ 5, and CEA ≥ 10 ng/mL, his score is +4. Thus, patients' scores could range from 0 to +4. RESULTS: The median survival time (MST) of the 15 patients with scores 0 and +1 was longer than that of the 35 with scores +2, +3, and +4 (35 vs. 6 months, P < 0.001). R0 operation after treatment was performed in 2 patients (4%) with score 0 and +1. CONCLUSION: Our prognostic score is useful in selecting patients with UCRC who will survive.

Perioperative Outcomes after Pancreaticoduodenectomy in Elderly Patients.

BACKGROUND/AIMS: Pancreaticoduodenectomy (PD) is highly invasive and may be associated with critical to fatal complications. The purpose of this study is to demonstrate, using multivariate analysis of preoperative and intraoperative patient characteristics to determine risk factors for negative outcomes, that PD can be performed safely in the elderly. METHODOLOGY: We enrolled 108 patients who underwent PD between October 2007 and December 2014. We compared perioperative outcomes such as the incidence of post-operative complications, duration of hospital stay, and mortality between elderly (group A; age ≥ 75 years, n = 44) and younger (group B; age < 75 years, n = 64) groups. RESULTS: Death occurred in one patient (2.3%) in group A. There were no significant differences between the groups in rates of major complications, including pancreatic fistula (PF), delayed gastric emptying, intra-abdominal bleeding, pneumonia, or duration of hospital stay. Multivariate analysis revealed complications in elderly to be associated with hemoglobin concentration (P = 0.016), and PF to be associated with body mass index (P = 0.013) and soft pancreas (P = 0.005). CONCLUSIONS: PD can be performed safely in elderly patients aged ≥ 75 years. However, PD indication for elderly having low hemoglobin concentration patients should be carefully selected.

Clinical relevance of the number of interleukin-17-producing CD 8+ T cells in patients with gastric cancer.

PURPOSE: There is accumulating evidence that inflammation is linked to cancer development and progression. Interleukin-17 (IL-17), an inflammatory cytokine, is produced by CD 8+ T cells (Tc17 cells); however, the specific role of Tc17 cells in tumor immunity against gastric cancer remains unclear. METHODS: The prevalence of Tc17 cells in both peripheral blood mononuclear cells and gastric tissue was evaluated by multicolor flow cytometry and the concentration of IL-17 in sera was quantitated by an enzyme-linked immunosorbent assay. RESULTS: Circulating Tc17 cells were significantly more numerous in gastric cancer patients than in controls, and significantly more numerous before surgery than after surgery. IL-17 concentrations in gastric cancer patients and healthy controls were 0.51 ± 0.54 and 0.084 ± 0.084 pg/mL, respectively, with this difference being significant. The percentage of Tc17 cells was significantly related to serum IL-17 concentration. Tc17 cells were significantly more numerous than peripheral blood mononuclear cells in gastric cancer tissue. Furthermore, Tc17 cells were more numerous in cancerous gastric tissue than in normal gastric tissue. CONCLUSIONS: Tc17 cells may be the main source of IL-17 in gastric cancer patients and thus involved in the progression of gastric cancer.

Feasibility study of alternate-day S-1 as adjuvant chemotherapy for gastric cancer: a randomized controlled trial.

BACKGROUND: The Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer established oral S-1 administration for 1 year as the standard postoperative adjuvant chemotherapy for gastric cancer in Japan. We conducted a multicenter cooperative prospective study comparing daily and alternate-day S-1 administration as postoperative adjuvant therapy for gastric cancer. METHODS: Patients with Stage II or III gastric cancer who underwent curative surgery were randomly assigned to receive standard daily S-1 administration [group A: 80-120 mg/day S-1 depending on body surface area (BSA); days 1-28 every 6 weeks for 1 year] or alternate-day administration (group B: 80-120 mg/day S-1 depending on BSA; alternate days for 15 months). Treatment completion rate was the primary endpoint, and relative dose intensity and safety, overall survival, and relapse-free survival (RFS) were secondary endpoints. RESULTS: Seventy-three patients were enrolled. The treatment completion rate was 72.2 % in group A and 91.8 % in group B; the relative dose intensity was 67.5 % in group A and 81.2 % in group B; and compliance was better in group B. Digestive system adverse effects were less frequent in group B than in group A. Median follow-up time was 2.8 years; 3-year survival rate was 69.6 % in group A and 87.3 % in group B; and 3-year RFS rate was 76.4 % in group A and 73.1 % in group B. CONCLUSIONS: Our data show improved compliance and fewer adverse effects with alternate-day S-1 administration, which appears to be a more sustainable option for adjuvant chemotherapy for Stage II or III gastric cancer.

Maintaining a surgery service for local hospitals under the situation of a decreasing number of surgeons in a region of Japan.

BACKGROUND: The number of surgeons is decreasing in Japan, leading to the problem of how to maintain a surgery service in local hospitals. We introduce our strategy for supporting ongoing surgical services in regional hospitals by dispatching surgeons temporarily to assist in operations. METHODS: We conducted a questionnaire-based survey at three local hospitals in Tottori and a neighboring prefecture to which surgeons from our department were temporarily dispatched over 5 years from January 2008 to March 2013. RESULTS: We supported 686 operations at three hospitals over 5 years. The average age of the patients was 72.4 years. Of the diseases treated, 45.1 % were malignant, and 54.9 % were benign. The emergency operation rate was 17.3 %. CONCLUSIONS: Our strategy has produced a continuous surgical service at local hospitals in the face of diminishing numbers of surgeons. We recommend that such a strategy be adopted in other regions in which there are a decreasing number of surgeons and where it is not easy to move patients elsewhere for care.

Inflammation-based prognostic scores and nutritional prognostic index in patients with locally-advanced unresectable colorectal cancer.

BACKGROUND: Unresectable colorectal cancer has a poor prognosis. However, some patients survive intensive chemotherapy, and complete resection of primary and metastatic tumors may even be possible. In the present study, we examined the prognostic factors associated with survival after intensive chemotherapy in patients with unresectable colorectal cancer. METHODS: This retrospective study enrolled 61 patients diagnosed with unresectable locally advanced colorectal cancer between January 2004 and December 2013. Among the prognostic parameters, we found that the prognoses of patients with abnormal performance status (PS) of 2 or 3, high Glasgow Prognostic Score (GPS) of 1 or 2, high neutrophil/lymphocyte ratio (NLR) >5, and low prognostic nutritional index (PNI) <40 were poor. Thus, we scored each patient according to our scoring system (abnormal PS, 2 or 3 = +1; high GPS, 1 or 2 = +1; high NLR, >5 = +1; and low PNI, <40 = +1). If the patient showed abnormalities in every parameter, the score would be +4. RESULTS: Sixteen patients had a score of 0, 17 scored +1, 10 scored +2, 17 scored +3, and one scored +4. The median survival time (MST) of the 61 patients was 9 months. Patients were divided into two groups, a low-score group (0 and +1) and a high-score group (+2, +3, and +4). The MST of the 33 patients in the low-score group was significantly longer than that of the 28 patients in the high-score group (15 months versus 4 months, P < 0.001). Also, conversion chemotherapy was performed in 4.9% (3/61) of patients. And these 3 patients were in a low-score group. CONCLUSIONS: This new prognostic scoring system may help to select patients with unresectable advanced colorectal cancer who are able to survive through intensive chemotherapy.

[Long-term disease-free survival by S-1 therapy in a case of gastric cancer with peritoneal dissemination].

The patient was a 77-year-old woman who underwent gastrectomy for gastric cancer. Since the patient had positive peritoneal washing cytology and positive peritoneal dissemination, she was started on oral S-1 therapy post-surgery for 4 weeks, followed by a 2-week rest period. During the first course of therapy, her white blood cell count decreased; therefore, the regimen was changed to a 1-week administration, followed by a 1-week rest period. No subsequent adverse events were noted. The patient has experienced no relapse in the four years she has been followed up after surgery in our outpatient clinic. We report our experience with an elderly patient for whom S-1 monotherapy was effective in the treatment of gastric cancer with peritoneal dissemination.

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

BACKGROUND: 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. METHODS: PD-1 expression on CD4+ and CD8+ T cells obtained from peripheral blood mononuclear cells (PBMC), normal gastric mucosa, and gastric cancer tissue was evaluated by multicolor flow cytometry. RESULTS: PD-1 expression on CD4+ and CD8+ T cells from gastric cancer patients was significantly higher than that from normal controls. PD-1 expression on CD4+ and CD8+ T cells was related to disease progression. Furthermore, PD-1 expression on CD4+ and CD8+ T cells from gastric cancer tissue was significantly higher than that from normal gastric mucosa and PBMC. PD-1 positive CD4+ and CD8+ T cells produced significantly less IFN-gamma than PD-1 negative CD4+ and CD8+ T cells. CONCLUSIONS: Upregulation of PD-1 on both CD4+ and CD8+ T cells may be, in part, responsible for immune evasion in gastric cancer patients.

Increased apoptosis and elevated Fas expression in circulating natural killer cells in gastric cancer patients.

BACKGROUND: Immune cells undergo extensive apoptosis in patients with cancer, which may be related to immune evasion by cancerous cells. The present study was designed to investigate the relationship between natural killer (NK) cell apoptosis and Fas expression in gastric cancer patients. METHODS: NK cell apoptosis and Fas expression were evaluated by multicolor flow cytometry. Soluble Fas ligand (sFasL) was quantitated by enzyme-linked immunosorbent assay. RESULTS: The frequency of apoptotic NK cells in gastric cancer patients was significantly higher than in normal controls (p = 0.0016). Moreover, their frequency was related to the progression of gastric cancer. Fas-positive NK cells were significantly more common in gastric cancer patients compared with normal controls (p = 0.034). Furthermore, Fas expression was closely related to the frequency of NK cell apoptosis (r = 0.6, p < 0.0001). The frequency of tumor-infiltrating NK cell apoptosis was significantly higher than that of circulating NK cell apoptosis (p = 0.035). Furthermore, Fas-positive NK cells in gastric cancer tissues occurred significantly more often than in peripheral blood (p = 0.029). FasL concentration in gastric cancer patients was lower than that in normal controls, and the difference tended to be significant (p = 0.057). Apoptotic circulating NK cells significantly decreased after surgery compared to before surgery (p = 0.023). Furthermore, Fas expression on circulating NK cells also significantly decreased after surgery compared with before surgery (p = 0.021). CONCLUSIONS: Upregulation of Fas expression on NK cells is related to increased apoptosis of circulating NK cells in gastric cancer patients.

Prevalence and clinical relevance of Th17 cells in patients with gastric cancer.

BACKGROUND: Th17 cells have recently been identified as a distinct T helper (Th) lineage in a cancer animal model and in human cancers. Their specific role in tumor immunity is unclear. We, therefore, sought to evaluate the role of Th17 cells in gastric cancer. METHODS: The prevalence of Th1, Th2, Treg, and Th17 cells in both peripheral blood mononuclear cells (PBMC) and gastric tissue was evaluated by multicolor flow cytometry. The concentration of interleukin (IL)-17 in sera was quantitated by enzyme-linked immunosorbent assay. RESULTS: We observed a clear difference in the prevalence of Th17 cells in PBMC (0.34 ± 0.24%) versus gastric cancer tissues (19.4 ± 12.1) (P = 0.0002). Subset-specific phenotypic analysis of CD4+ T cells in both PBMC and gastric cancer tissue showed that Th1 and Treg cells predominate in PBMC, whereas Th17 cells are the most abundant CD4+ T cell subset in cancerous tissue. The concentrations of IL-17, a hallmark of Th17, in gastric cancer patients and normal controls were 0.6 ± 0.67 and 0.16 ± 0.19 pg/mL (P = 0.0032). Five-year survival rates of patients with high IL-17 and low IL-17 concentration were 47.1% and 83.9% (P = 0.0075). Multivariate analysis indicated that IL-17 concentration was an independent prognostic indicator, as well as lymph node metastasis. CONCLUSIONS: There was a significant skewing toward a Th17 phenotype in gastric cancer tissue. IL-17 seems to play an important role in the progression of gastric cancer.

Decreased NKG2D expression on NK cells correlates with impaired NK cell function in patients with gastric cancer.

BACKGROUND: Although malignant diseases are known to be associated with immune suppression, the detailed mechanisms involved are still unknown. NKG2D is an activating cell surface receptor expressed by natural killer (NK) cells and CD8+ T cells, and the engagement of NKG2D is extremely important for NK cell activation. Although decreased NKG2D expression on NK cells is closely related to immune evasion by some cancers, the immunopathological importance of this phenomenon in gastric cancer patients remains unclear. METHODS: NKG2D expression on NK cells was determined, using multicolor flow cytometry, to investigate the mechanisms responsible for immune evasion in gastric cancer patients. RESULTS: NKG2D expression on NK cells from gastric cancer patients was significantly lower than that in healthy controls. Also, NKG2D expression in advanced gastric cancer was significantly lower than that in early gastric cancer. NK cells from patients with lymph node metastasis expressed significantly lower levels of NKG2D than the NK cells from those without lymph node metastasis, and NKG2D expression on NK cells in gastric cancer tissue was significantly lower than that of circulating NK cells. NKG2D expression on NK cells obtained from cancer patients was restored after 48 h in culture with RPMI containing 10% AB serum. Furthermore, NKG2D expression on NK cells obtained after surgery was significantly higher than that before surgery. CONCLUSIONS: Decreased NKG2D expression on NK cells may be one of the key mechanisms responsible for NK cell dysfunction in gastric cancer.

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.

BACKGROUND: In 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. METHODS: The 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. RESULTS: The 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. CONCLUSION: Vδ1 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.