Hidehiko Iizuka

Clinicopathologic features of gastric cancers producing alpha-fetoprotein.

Background: Patients with gastric cancers producing alpha-fetoprotein (AFP) were reported to have a poor prognosis with high rates of liver metastasis. The purpose of the present study was to clarify the clinicopathological features of AFP-producing gastric cancers, in particular characteristics of liver metastasis, and to evaluate treatment of these cancers. Methods: In 27 of the 29 cases with elevated preoperative serum AFP levels among a total of 974 primary gastric cancers, AFP production was confirmed in gastric cancer cells by immunohistochemistry. These cases were included in the AFP-positive gastric cancer group (AFP(+), 2.7%). The remaining 945 cases with normal serum AFP levels were designated the AFP-negative gastric cancer group (AFP(–)). Results: There was a higher incidence of lymph node metastasis, a deeper invasion of the gastric wall, a higher frequency of advanced stage, a more marked lymphatic invasion and a higher rate of liver metastasis in the AFP(+) group than in the AFP(–) group. The patients received curative resection in AFP(+) group had a significantly worse survival rates in comparison to that in AFP(–) group. With respect to liver metastasis (n = 17) in AFP(+) group, of 3 cases who received curative hepatic resection, 1 patient survived more than 3 years, while the remaining 2 died in less than 3 years due to multiple liver recurrence. The patients (n = 5) who received palliative resection for liver metastasis followed by transarterial continuous infusion chemotherapy all died in less than 1 year. Conclusion: AFP-producing gastric cancers had aggressive behavior and their clinical or biological features were quite different from the common AFP-negative gastric cancers. Surgical resection of liver metastasis from AFP-producing gastric cancers was unsatisfactory. The development of a novel multimodal therapy against AFP-producing gastric cancers is needed.

c-Met Expression in Gastric Cancer with Liver Metastasis

Liver metastasis is one of the poor prognostic factors for gastric cancer. Hepatocyte growth factor (HGF) and its receptor, c-Met, have been reported to be related to the proliferation of carcinoma cells. We examined c-Met and HGF expression in stage IV gastric cancers (n = 121) and compared the results in groups with liver metastasis (n = 47, LM group) and without liver metastasis (n = 74, no-LM group). The survival rate for the LM group was significantly poorer than for the no-LM group (p < 0.01). We found a high frequency of c-Met expression in the LM group compared with the no-LM group at protein level detected by immunohistochemistry (p = 0.0005) and at mRNA level detected by semiquantitative reverse transcriptase-polymerase chain reaction (p = 0.0386) in primary gastric tumors. Furthermore, we evaluated HGF expression in both carcinoma cells and stromal cells in gastric cancers. There was no significant difference in the HGF expression between the LM and no-LM groups. The labeling index of proliferating cell nuclear antigen for the carcinomas in the LM group was higher than that in the no-LM group (47.1 ± 24.5 vs. 26.2 ± 24.5%, p < 0.0001). Thus, the high frequency of c-Met overexpression in carcinoma cells may be involved in the mechanism of liver metastasis in gastric cancers. Moreover, the evaluation of c-Met expression might be a useful indicator of liver metastasis in patients with gastric cancer.

Improved quality of life with jejunal pouch reconstruction after total gastrectomy

BACKGROUND There is increasing evidence that the effect of jejunal pouch reconstruction is satisfactory for reservoir function in several randomized control studies. However, these studies were performed in patients with advanced gastric cancer, where significant numbers of the patients died of disease recurrence. In order to exclude the influence of disease recurrence, we performed jejunal pouch reconstruction after total gastrectomy in patients with early gastric cancer in a randomized controlled study and investigated whether or not an improved quality of life (QOL) was observed with jejunal pouch reconstruction. METHODS Fifty consecutive patients receiving total gastrectomy for early gastric cancer were prospectively divided into the Roux-en-Y reconstruction group without pouch (RY group) or the jejunal pouch reconstruction group (pouch group). Body weight, eating capacity, QOL assessment by gastrointestinal symptom rating scale (GSRS), nutritional parameters, endoscopical examination, 24-hour pH monitoring and Bilitec monitoring were evaluated at 3, 12, and 48 months after surgery. RESULTS Jejunal pouch reconstruction provided the better QOL than Roux-en-Y reconstruction without pouch both at short-term and long-term periods in a randomized control study. Moreover, as a new finding, pouch reconstruction provided less bile reflux into the esophagus compared with Roux-en-Y reconstruction. CONCLUSIONS Jejunal pouch reconstruction provided improvement of QOL in patients receiving total gastrectomy.

Correlation of Vascular Endothelial Growth Factor-C Expression with Tumor-Infiltrating Dendritic Cells in Gastric Cancer

It has been reported that dendritic cells (DCs) play a crucial role in the host’s immune defense against tumors, and there is an inverse correlation between the density of DCs and the expression of vascular endothelial growth factor (VEGF). However, the relationship between the expression of VEGF-C and DC infiltration remained unclear. In the present study, we investigated whether the expression of VEGF-C correlated with the number of DCs in vivo. We immunohistochemically analyzed gastric carcinoma tissue in this study. The survival curves show that the prognosis for patients with a low density of DCs was significantly poorer than that for patients with high DC density (p < 0.01). Further, the survival curves according to the VEGF-C status showed that the survival rate in patients with low VEGF-C expression was higher than that in patients with higher expression (p < 0.01). There was a significant negative correlation between the density of DCs and the expression of VEGF-C (r = –0.26, p < 0.05). We suggest that VEGF-C produced by cancer causes DCs to become dysfunctional. This may be one of the ways that cancers evade immunosurveillance.

High frequency of c-Met expression in gastric cancers producing alpha- fetoprotein.

Gastric cancers producing α-fetoprotein (AFP) have a poor prognosis and a high incidence of liver metastasis. Hepatocyte growth factor (HGF) and its receptor, c-Met, are known to induce mitosis and cell movement and to promote tumor progression. In the present study, c-Met and HGF expression in AFP-producing gastric cancer was compared with those gastric cancers that do not produce AFP. Twenty-six patients with AFP-producing gastric cancers [AFP(+)] and 26 patients stage-matched gastric cancers without AFP production [AFP(–)] were evaluated for c-Met and HGF expression and proliferating cell nuclear antigen-labelling index using immunohistochemical analysis. A higher frequency of c-Met expression was observed in the AFP(+) group than in the AFP(–) group (p < 0.01). A higher expression of c-Met might be one explanation for the poorer prognosis of AFP-producing gastric cancers.

Expression of signal transducing T‐cell receptor ζ molecules after adoptive immunotherapy in patients with gastric and colon cancer

We and others have shown decreased expression of T‐cell receptor‐CD3‐associated signal transducing ζ molecules (TCRζ) in tumor infiltrating and peripheral T cells of patients with advanced cancer. In the present study, we performed adoptive immunotherapy (AIT) with tumor‐associated lymphocytes (TAL) in patients with gastric (n = 11) and colon (n = 3) cancer with stage IV and investigated whether the alteration of signal transducing molecules was observed with AIT, compared to an untreated control group (n = 13). Autologous TALs isolated from malignant ascites or pleural effusion were cultured with stimulation of autologous tumor in the presence of interleukin‐2 (IL‐2) and were transferred to the patients. TCR ζ expression in peripheral T cells was measured by flow cytometric analysis of permeabilized cells with anti‐ζ monoclonal antibody (MAb) (TIA‐2) before and after AIT. We confirmed the down‐regulation of TCR ζ expression in peripheral blood lymphocytes (PBL) of patients with gastric and colon cancer with stage IV compared to healthy donors (n = 15). AIT induced up‐regulation of TCR ζ expression in 2 of 14 treated patients, caused no significant change of TCR ζ expression in 7 patients and induced further down‐regulation in 5 patients. The patients who achieved clinical responses (n = 3) with AIT showed no significant change of TCR ζ expression. On the other hand, in the control group without adoptive transfer, further down‐regulation of TCR ζ expression was observed during the corresponding periods, paralleling disease progression. Taken together, TCR ζ expression in the patients was further down‐regulated, corresponding to disease progression in individual cancer patients. In some patients, AIT could induce increased or stable TCR ζ expression. The quantitative analysis of TCR ζ expression might provide vital information that can be used to optimize therapy by preserving immune functions within cancer patients. Int. J. Cancer 78:301–305, 1998.© 1998 Wiley‐Liss, Inc.

Serum Level of HER-2/neu in Patients with Gastric Cancer: Correlation with HER-2/neu Overexpression in Gastric Carcinoma Tissue

Serum HER-2/neu (c-erbB-2) levels in patients with gastric cancer were evaluated by an enzyme-linked immunosorbent assay and tissue levels of HER-2/neu in the same cohort were determined by immunohistochemistry. Nine (16%) of 57 gastric carcinomas had an overexpression of HER-2/neu detected immunohistochemically. Of these 9 patients, 6 had elevated serum HER-2/neu levels, while 45 of 48 tissue samples with negative staining exhibited normal serum HER-2/neu levels. These results indicated that overall accuracy, positive predictive value, and negative predictive values of their serum measurements were 89, 67 and 94%, respectively. Serum levels of HER-2/neu were correlated with tissue overexpression of HER-2/neu in patients with gastric cancer.

Risk Factors for Aspiration Pneumonia after Percutaneous Endoscopic Gastrostomy

Background: Percutaneous endoscopic gastrostomy (PEG) is generally used for long-term enteral nutrition. Patients who require PEG placement are often very sick, and postoperative complications, especially aspiration pneumonia, can be fatal. Objective: In this study we investigated the risk factors for aspiration pneumonia after PEG using a simple two-step swallowing provocation test (S-SPT), as reported in 1999 by Teramoto et al. Methods: The study included 29 patients (10 men, 19 women; mean age 84.6 years) who underwent S-SPT before PEG. We evaluated the presence of reflux esophagitis (RE) and esophageal hiatal hernia (EHH) with PEG. According to the S-SPT results, a normal response to the 1st step S-SPT was given a score of 0, a normal response to the 2nd step S-SPT was given a score of 1, and an abnormal response to the 2nd step S-SPT was given a score of 3. In addition to S-SPT, the presence of RE was given a score of 3, the absence of RE was given a score of 0, the presence of EHH was given a score of 2, and the absence of EHH was given a score of 0. We evaluated the association between the presence of aspiration pneumonia, as an early and critical complication, up to 1 month after PEG and determined the total risk score (score of S-SPT+ score of RE+ score of EHH). Results: The group with an abnormal response to the 2nd step S-SPT and the group with RE both exhibited aspiration pneumonia. The patients with aspiration pneumonia all achieved total scores ≧3, and 8 of 13 patients without aspiration pneumonia achieved scores ≤2. Conclusions: S-SPT is particularly useful in PEG patients. The scores provided by S-SPT and endoscopic examination can be very useful for aspiration pneumonia after PEG. The patients with scores ≤2 appear to be at very low risk for aspiration pneumonia, and patients with the scores ≧3 should be carefully followed up.

Macrophages in tumor‐draining lymph node with different characteristics induce T‐cell apoptosis in patients with advanced stage‐gastric cancer

A hosts immune‐defense system is suppressive by many factors in patients with cancer. We have previously shown one possible mechanism behind the T‐cell dysfunction, whereby H2O2 secreted from macrophages in tumor‐draining lymph node (MTDL) induced T‐cell dysfunction with down‐regulation of TCR ζ molecules. In the present study, we analyzed how MTDL affect T cells, with a particular focus on T‐cell apoptosis, by co‐culturing MTDL with autologous peripheral blood T cells in gastric cancer. Moreover, we characterized the MTDL according to surface marker, oxygen‐burst capacity and intracellular cytokine status. T‐cell apoptosis was significantly induced in comparison to T‐cell alone control in patients with advanced disease, concomitant to the elevated caspase activity and following impaired T‐cell function. In patients with early disease, no significant difference was seen in the proportions of T cells that underwent apoptosis between T cells plus MTDL and T cells alone. Moreover, the addition of a selective scavenger of H2O2, catalase inhibited the apoptosis of T cells co‐cultured with MTDL in patients with advanced disease. In the characterization of MTDL, the production of H2O2 in MTDL from advanced disease was significantly higher than that in early disease. The amounts of intracellular IL‐10 and IL‐12 in MTDL in advanced disease were significantly higher than those in early disease. These results indicated that MTDL induced apoptosis of autologous T cells and this T‐cell dysfunction was mediated by H2O2 derived from MTDL. Furthermore, the characteristics of MTDL including the capacity of oxygen‐burst and intracellular cytokine production were different depending on the disease progression.

Interposed Colon between Remnants of the Small Intestine Exhibits Small Bowel Features in a Patient with Short Bowel Syndrome

We describe herein the case of a 48-year-old man who underwent emergency massive resection of the small intestine due to a strangulated ileus, which led to short bowel syndrome (SBS), as he was left with only 7 cm of jejunum and 8 cm of ileum with ileocecal valve. He then received interposition of a colon segment between the jejunum and ileum remnants isoperistaltically. For 24 months after the operation, he has been able to tolerate oral intake, but still requires partial home parenteral nutritional support during the night on a bimonthly basis. Biochemical and nutritional parameters, including the analysis of minerals and trace elements, indicated that the patient was in relatively good health. Histological examination revealed that the mucosa of the interposed colon showed hypertrophy and hyperplasia of the crypt glands, and cells resembling Paneth cells which are usually seen in the small intestine, suggesting that the colon segment exhibits adaptive changes to the small intestine. Colon interposition may be a useful technique in patients with SBS when the small bowel is too short for the other surgical considerations.