齋藤 心

The growth, invasiveness and metastasis of human cancers are determined not only by cancer cells, but also by their microenvironment. Activated stromal fibroblasts promote tumor progression by secreting growth factors. In the present study, we focused on interrelations between cancer and fibroblasts, the main component of tumor stroma. We retrospectively analyzed the relations of mortality to clinical, pathological, and α-smooth muscle actin (α-SMA) characteristics in 97 consecutive patients with esophageal squamous cell carcinoma (ESCC). In vitro, we used TE-11, KYSE150 and KYSE220 ESCC cell lines and isolated esophageal stromal fibroblasts, some of which were immortalized. Migration assays were conducted to assess the effects of fibroblasts on cancer-cell migration and 3-dimensional organotypic cultures. In vivo, TE-11 and KYSE220 cells plus immortalized fibroblasts were co-transplanted subcutaneously in Nod/Scid mice to assess the effects of fibroblasts on tumorigenicity. Clinicopathologically, the α-SMA expression of cancer stroma was correlated with venous invasion (p<0.01), nodal involvement (p=0.02), recurrence (p=0.01), and was a predictor of survival in patients with stage I and II ESCC (p=0.04). In vitro, the presence of fibroblasts strongly promoted the migration of TE-11, KYSE150 and KYSE220 cells. On organotypic culture, stromal invasion was observed only in the presence of immortalized fibroblasts. In vivo, tumors developed or grew in a fibroblast‑dependent manner after implantation. Our findings provide evidence that stromal fibroblasts and tumor cells interact to promote tumor progression in ESCC. In patients with earlier stage ESCC, α-SMA may be a predictor of mortality. Inhibition of paracrine systems associated with tumor fibroblasts may slow or reverse tumor progression, potentially leading to the development of new targeted therapies.

Although cisplatin (CDDP) is a key drug in the treatment of esophageal squamous cell carcinoma (ESCC), acquired chemoresistance remains a major problem. Combination therapy may represent one strategy to overcome this resistance. Heat shock protein 90 (HSP90) is known to be overexpressed in several types of cancer cells, and its inhibition by small molecules, either alone or in combination, has shown promise in the treatment of solid malignancies. In the present study, we evaluated the synergistic effects of combining CDDP with the HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) on two CDDP-resistant human esophageal squamous cancer cell lines, KYSE30 and KYSE150. The results obtained demonstrated the synergistic inhibitory effects of CDDP and 17-AAG on the growth of KYSE30 and KYSE150 cells. Cell growth and cell number were more effectively reduced by the combined treatment with CDDP and 17-AAG than by the treatment with either CDDP or 17-AAG alone. Western blotting revealed that the combined action of CDDP and 17-AAG cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3, which demonstrated that the reduction in both cell growth and cell number was mediated by apoptosis. Time-course experiments showed that reduction in X-linked inhibitor of apoptosis protein (XIAP) and phosphorylated Akt were concomitant with apoptosis. The results of the present study demonstrate that 17-AAG synergizes with CDDP and induces apoptosis in CDDP-resistant ESCC cell lines, and also that modulation of the Akt/XIAP pathway may underlie this synergistic effect. Combination therapy with CDDP and an HSP90 inhibitor may represent a promising strategy to overcome CDDP resistance in ESCC.

BACKGROUND: The double-stapling technique (DST) for esophagojejunostomy using the transorally inserted anvil (OrVil; Covidien Japan, Tokyo, Japan) is one of the reconstruction methods used after laparoscopy-assisted total gastrectomy (LATG). This technique has potential advantages in terms of less invasive surgery without the need to create a complicated intraabdominal anastomosis. METHODS: From 2008 to 2011, 262 patients with gastric cancer underwent total gastrectomy and reconstruction with a Roux-en-Y anastomosis, and 52 patients underwent LATG with DST. A retrospective analysis then was performed comparing the patients who experienced postoperative stenosis after LATG-DST (positive group) and the patients who did not (negative group). A comparative analysis was performed among patients comparing conventional open total gastrectomy and LATG, and multivariate analysis was performed to evaluate risk factors for the development of anastomotic stenosis. RESULTS: A minor leak was found in 1 patient (1.9 %), and 11 patients experienced anastomotic stenosis (21 %) after LATG with DST. Among the patients with anastomotic stenosis, three (3/4, 75 %) anastomoses were performed with the 21-mm end-to-end anastomosis (EEA) stapler, and eight anastomoses were performed (8/47, 17 %) with the 25-mm EEA stapler. The median interval to the diagnosis of anastomotic stenosis was 43 days after surgery. The patients with stenosis needed endoscopic balloon dilation an average of four times, and the rate of perforation after dilation was 13 %. The clinical and operative characteristics did not differ between the two groups. Anastomotic stenosis after open total gastrectomy occurred in two cases (0.98 %). Multivariate analysis showed that the size of the EEA stapler and the use of DST were risk factors for anastomotic stenosis. CONCLUSION: Esophagojejunostomy using DST with OrVil is useful in performing a minimally invasive procedure but carries a high risk of anastomotic stenosis.

We report on a 53-year-old male with esophageal cancer. He had no evidence of distant metastasis, and received a subtotal esophagectomy. Histopathologically, the tumors were contiguous with Barrett's epithelium. Undifferentiated carcinoma components existed independently of differentiated adenocarcinoma components. Undifferentiated carcinoma was present proximal to the esophagogastric junction. Both tumors had invaded the submucosa and were associated with a prominent lymphoid stroma. Metastasis from undifferentiated carcinoma was found in the paraesophageal lymph nodes. Immunohistochemically, both components were negative for 34bE12 and positive for CAM5.2 and showed nearly identical staining patterns for p53, indicating that the tumors were derived from Barrett's epithelium. Because the undifferentiated carcinoma did not express CK20 or carcinoembryonic antigen, the properties of adenocarcinoma had apparently been lost during the process of tumor cell progression. This is the first report of undifferentiated carcinoma associated with Barrett's esophagus with adenocarcinoma.

OBJECTIVE: Adenosquamous carcinoma originating in the stomach is an unusual neoplasm with few existing histological studies. This study was aimed to gain insight into the histogenetic and clinicopathological characteristics of gastric cancer with squamous cell carcinoma (SCC) components. METHODS: From January 2001 to June 2010 a total of 1735 patients underwent a resection of gastric cancer. Histopathologically, eight patients had adenocarcinoma containing SCC components, in which the proportion of SCC components was above 25% of the total tumor mass in four patients. The immunohistochemical and clinicopathological characteristics of these eight patients were analyzed. RESULTS: The median survival duration was 22 months. Adenocarcinoma was present at the superficial layer of all tumors and SCC was primarily present at sites with deep invasion. Immunohistochemically, adenocarcinoma components were positive for cytokeratin (CK) 8/18/19 and CK7 in all cases. SCC components were positive for carcinoembryonic antigen and CK7 in more than 60% of patients. Expression patterns of p53 product were identical in both components. SCC components were positive for 34βE12 and adenocarcinoma components were negative for 34βE12 in all patients. CONCLUSIONS: SCC components are derived from squamous metaplasia in a pre-existing adenocarcinoma. A gastric adenocarcinoma with SCC components is associated with various patterns of metastasis and both SCC and adenocarcinoma components have the potential for metastasis. Gastric cancer with SCC components is a clinically aggressive tumor.

BACKGROUND: To decrease the incidence of internal hernia after laparoscopic gastric bypass, current recommendations include closure of mesenteric defects. Laparoscopic gastric resection is used increasingly for the treatment of gastric cancer, but the incidence of internal hernia in the treated patients has not been studied. METHODS: This study retrospectively reviewed 173 patients who underwent laparoscopic resection for gastric cancer at one institution, including distal and total gastric resections with antecolic Roux-en-Y reconstruction. RESULTS: An internal hernia occurred in 4 (7%) of 58 patients whose jejunojejunal mesenteric defect was not closed a mean of 326 days after surgery. All the patients underwent reoperation with reduction and repair of the hernia. In 115 subsequent cases, with closure of the mesenteric defect, internal hernias did not occur (0/115 cases; p < 0.05). CONCLUSION: Based on the current recommendations for patients undergoing bariatric surgery, closure of this potential hernia defect is mandatory after laparoscopic gastrectomy with a Roux-en-Y reconstruction for gastric cancer.