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.

胃切除術後6年目に発症したビタミンB1欠乏による脚気ニューロパチー、衝心脚気の1例を経験したので報告する。患者は58歳男性。胃癌に対して噴門側胃切除術、近位側空腸嚢間置法による再建術を受けた。術後極端な偏食はなく、通常量の食事を摂取していたが、術後の腹部CT検査や内視鏡検査では、毎回間置空腸嚢内に食物残渣が多量に貯留していた。術後6年目に四肢遠位筋優位の筋力低下、異常知覚、両下腿浮腫、易疲労感が出現した。症状は進行し、乳酸アシドーシスと急性心不全を発症した。血中ビタミンB1値は10(正常値20-50)ng/mlと低値であり、ビタミンB1の静脈内投与により症状は劇的に改善した。胃切除術後長期経過症例であっても、近位側空腸嚢間置法による再建術を受け、間置空腸嚢内に残渣が貯留している症例では、潜在的にビタミンB1吸収障害を来しやすい可能性があり、脚気を含めた栄養吸収障害発症のリスクを考慮する必要がある。(著者抄録)

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.

19歳男。生後1日目のGross C型先天性食道閉鎖症に対し食道気管瘻結紮切離・胃瘻造設術、生後6ヵ月目にLivaditis法による食道延長術を付加した食道-食道吻合術が施行された。術後早期より高度の吻合部狭窄をきたし。狭窄部に対して内視鏡的バルーン拡張術を繰り返し施行されたが再狭窄を繰り返していた。15歳時より当科で頻回の内視鏡的バルーン拡張術や硬性ブジーあるいはAPCを用いた狭窄部切開を行ってきたが、狭窄は改善しなかった。気管軟化症による著しい呼吸機能低下のため食道再建は不可能で、少量の経口摂取に胃瘻栄養を併用していた。経口内視鏡と経胃瘻孔的内視鏡を併用した磁石圧迫吻合による狭窄解除術を行ったところ、術後第3病日に磁石同士は接着し、第15病日に磁石の長軸が変化し、第18病日に自然落下し便とともに排泄され、第19病日より基本食を開始し、第21病日に退院となった。合併症はなく約2ヵ月後の軽度の狭窄に対しバルーン拡張術を2回行ったが、その後、再狭窄はなく拡張を維持しQOLは著明に改善した。

自治医科大学附属病院における食道癌手術成績について報告する。1999年から2009年を対象期間として生存率と術後合併症を評価した。進行癌では集学的治療として、2000-2006年:術前化学放射線療法(低用量FP[5-FU:300mg/m2 Day1-5、CDDP:3mg/m2 Day1-5]と加速多分割40Gy)、2006-07年:術後標準FP[5-FU:800mg/m2 Day1-5、CDDP:80mg/m2 Day1]2コース、2008年以降:術前標準FP2コースを施行した。術式は原則3群リンパ節郭清とした。全体で317例、進行度別の3年生存率はStage0=86%(n=25)、StageI=91%(n=54)、StageII=79%(n=94)、StageIII=56%(n=106)、StageIV=11%(n=38)であった。術後に呼吸器合併症6%、縫合不全4%、在院死亡0.6%を認めた。食道癌手術は3領域リンパ節郭清まで施行可能であるが、切除範囲は限界に達している。StageIまでは内視鏡切除や鏡視下手術などのより侵襲の少ない治療が望まれる。StaegII以上ではさらなる集学的治療の開発が重要と考えられる。(著者抄録)

画像強調内視鏡の1つであるFICE(flexible spectral imaging color enhancement)は,大腸腫瘍の拾い上げ診断・質的診断における有用性が既に報告されている.FICEは,遠景像が明るく,通常画像からFICE画像への切り替えが速い特長があり,拾い上げ診断における有用性が特に期待される.腫瘍と非腫瘍の鑑別は,病変表層の微小血管模様に注目することにより可能であり,その正診率はpit pattern診断に匹敵する.SM高度以深浸潤癌の診断では,腫瘍表面のpit様模様・無血管野の存在に着目することにより,筆者らの検討では高い正診が得られた.(著者抄録)

背景:胃切除後にはビタミンB1の吸収が障害され、脚気、アシドーシスなどの発症例も散見される。ビタミンB1が配合されたビーフリード輸液は、2,000ml/日投与した際には静脈栄養時のビタミンB1投与推奨量3.0mg/日が補給できるとされるが、実際には胃切除後にビーフリード2,000ml/日投与していない症例も多い。対象と方法:胃癌にて胃切除術(胃全摘群15例、幽門側胃切除群15例)を受けた患者を対象に、ビーフリード輸液を周術期に1,000mL/日投与し、術前・術後のビタミンB1濃度の測定を行った。結果:血中ビタミンB1値は、両群ともに術前に比較し経口開始前日にわずかに上昇したものの、退院前には胃全摘群4例、幽門側胃切除群5例で基準値28ng/mL以下であった。手術操作や進行度、合併症によるビタミンB1値への影響は認められなかった。結語:胃周術期にはビタミンB1値が低下していることが判り、ビーフリード輸液1,000mL/日以上の投与が推奨されると考えられた。(著者抄録)

Background/Aims: Laparoscopic-assisted distal gastrectomy (LADG) is a minimally invasive procedure for patients with gastric carcinoma. We have previously reported gasless LADG with a Billroth-I reconstruction using a 5-7cm mini-laparotomy. We modified the technique for gasless LADG to include a Roux-en Y reconstruction and to expand the indications for its use. Methodology: A total of 40 patients with early stage gastric tumors (T1 n=38, T2 n=2) underwent this procedure. Following gasless laparoscopic distal gastrectomy with lymph node dissection, a jejunum to greater curvature of the gastric remnant anastomosis was performed using an intracorporeal laparoscopic stapled method. The jejuno-jejunal anastomosis was performed using a hand-sewn technique under direct vision through a mini-laparotomy. Results: The mean surgical time (n=40) was 222min, estimated blood loss 101ml, and the mean number of lymph nodes harvested was 21. There were no postoperative complications such as bleeding, leak, or cardio-pulmonary dysfunction. Mean body weight loss was 3.9 kg, and there is no evidence of recurrence during a mean follow-up of 14 months. Conclusions: Gasless LADG with Roux-en-Y reconstruction is a feasible, novel procedure for a minimally invasive approach to gastric cancer.