須田 康一

Objective: The robot-assisted surgical system was developed for minimally invasive surgery and is thought to have the potential to overcome the shortcomings of laparoscopic surgery. We introduced this system for the treatment of gastric cancer in 2008. Here we report our initial experiences of robot-assisted surgery using the da Vinci system. Methods: A retrospective review of robot-assisted gastrectomy for gastric cancer patients was performed in our institute. The clinicopathological features and surgical outcomes were analyzed. Whereas the procedures of the gastrectomy were similar to those of the usual laparoscopic surgery, several aspects such as the port placement and the role of the assistant were modified from those for conventional laparoscopic surgery. Results: From January 2008 to December 2010, 61 patients with gastric cancer underwent robot-assisted surgery. Gastrectomy was distal in 46 patients, total in 14, proximal in 1 and no operation was converted to the open procedure. D2 lymph node dissection was performed on 28 patients in the distal gastrectomy group and on 11 in the total gastrectomy group. Complications occurred in 2 cases (4%): these consisted of ruptured sutures and hemorrhage from the anastomotic site. Conclusions: This study demonstrated that robot-assisted gastrectomy using the da Vinci system can be applied safely and effectively for patients with gastric cancer. Copyright (C) 2011 S. Karger AG, Basel

High-mobility group box 1 (HMGB1) is a monocyte-derived inflammatory mediator that is released in some conditions including shock, tissue injury, and endotoxin-induced lethality. In this study, we determined the plasma and hepatic tissue levels of HMGB1 in a drug-induced rat acute liver failure (ALF) model and investigated the effect of HMGB1 blockade on ALF. Adult male Sprague-Dawley rats, weighing 250 to 300 g, were used for this study. D-galactosamine was injected into the penile vein to induce ALF. To determine HMGB1 levels, plasma and hepatic tissue samples were serially collected after the D-galactosamine injection. To test the effect of HMGB1 blockade, anti-HMGB1 polyclonal antibodies or control antibodies were injected into the penile vein right after injection of D-galactosamine. Levels of HMGB1 were increased in plasma and decreased in hepatic tissue after induction of ALF. Immunohistochemical examination for HMGB1 showed that liver from animals with ALF had little staining, whereas normal liver had strong staining in the nuclei. Injection of anti-HMGB1 antibodies resulted in significant suppression of plasma HMGB1 and hepatic enzymes, marked suppression of plasma inflammatory cytokines, marked improvement of histological findings, and significant improvement of survival. The decrease of hepatic HMGB1 was also significantly suppressed in the group injected with anti-HMGB1 antibodies. The present study suggests that in ALF, the liver may release HMGB1 into the plasma, and that neutralizing the released HMGB1 has a protective effect against injury.

Major surgical procedures induce a systemic inflammatory response syndrome (SIRS) characterized by the overproduction of proinflammatory cytokines, which induces excessive stress and may trigger postoperative complications. This has prompted the hypothesis that drugs which relieve SIRS might improve the postoperative course of major surgery. One of the most promising targets for these drugs is high-mobility-group box chromosomal protein 1 (HMGB1). In 1999, HMGB1 was found to be a key late mediator of sepsis. It is now known to be associated with various kinds of acute and chronic inflammation, and is recognized as one of the most important danger signals in stress response. In this article, we present the latest information about HMGB1 and discuss its promise as a novel target for modulating stress response.

Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase, which is effective in acute lung injury associated with systemic inflammatory response syndrome. However, the effectiveness of sivelestat in sepsis has not been fully examined. In the present study, the effect of sivelestat on severe sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Adult male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: sivelestat-treated group and saline-treated controls. The serum concentrations of several inflammatory mediators were measured. Hematoxylin-eosin staining, and immunohistochemical staining for high-mobility group box chromosomal protein 1 (HMGB1), IL-8, and CD68 were performed on the lungs to assess pathological changes found 12 h after the CLP procedure. Treatment with sivelestat significantly improved the survival rate of the post-CLP septic animals (P = 0.030). Sivelestat also induced a significant reduction in serum IL-1 beta (P = 0.038) and IL-10 (P = 0.008) levels in these CLP rats. Serum HMGB1 levels had no significant difference between the sivelestat-treated and the control group. The lungs from sivelestat-treated rats exhibited less severe pathological changes and decreased the numbers of HMGB1, IL-8, and CD68-positive cells (P < 0.001). Sivelestat significantly improved survival rate of rats with clinically relevant sepsis, possibly by attenuating sepsis-induced systemic inflammatory response and lung injury. This may explain the implicated health benefits of sivelestat in reducing morbidity and mortality from sepsis.

High-mobility-group box chromosomal protein 1 (HMGB1) has recently been identified as a late mediator of various kinds of acute and chronic inflammation. A method for efficiently removing HMGB1 from systemic circulation could be a promising therapy for HMGB1-mediated inflammatory diseases. It is well known that the cationic portion of HMGB1 binds to heparin, which has abundant sulfates in its structure. In this study, we determined whether spherical sulfated cellulose (SC) efficiently adsorbed HMGB1, as well as other inflammatory mediators, in vitro. Then, we investigated the efficacy of hemoperfusion with the SC (SC group) or cellulose beads (control group) at adsorbing endogenous mediators, including HMGB1, in vivo. We have demonstrated that the SC adsorbed significantly larger amounts of HMGB1, interleukin (IL)-4, and IL-8 when compared with cellulose beads, in vitro. Hemoperfusion with the SC for 30 minute, starting 2 hour after an abdominal opening and closure operation, significantly reduced serum HMGB1 levels (p = 0.004) and consistently increased serum IL-10 levels, in vivo. These data suggest the potential benefits of hemoperfusion using the SC in treating HMGB1-mediated inflammatory diseases. ASAIO Journal 2010; 56:210-214.

Salvage esophagectomy is potentially the only treatment available that can offer a chance of long-term survival when definitive chemoradiotherapy (CRT) fails to achieve local control for patients with esophageal squamous cell carcinoma (ESCC). However, salvage esophagectomy is a highly invasive procedure with various postoperative complications compared to planned esophagectomy after neoadjuvant chemoradiotherapy (CRT). We hypothesize that severe postoperative complications may affect not only surgical mortality but also tumor recurrence and long-term survival for patients with salvage esophagectomy after definitive CRT. For the present study we reviewed the surgical procedures, postoperative complications, and the prognosis of 65 consecutive patients with thoracic ESCC who underwent the esophagectomy after neoadjuvant (neoadjuvant group: n = 40) or definitive (salvage group: n = 25) CRT. Most patients underwent right-transthoracic extended esophagectomy and reconstruction using gastric conduit by way of subcutaneous route with left cervical anastomosis. The incidence of postoperative pneumonia was found to be higher in the salvage group than in the neoadjuvant group. In both groups, the survival of patients with R0 resection was significantly better than those with R1/R2 resection. Moreover, in the salvage group, the postoperative survival rate of patients with pneumonia or bacteremia/sepsis was significantly lower than that for patients who did not suffer the same complications. In the neoadjuvant group, R0 resection was selected to be the only independent prognostic factor in univariate and multivariate analysis. In contrast, in the salvage group, R0 resection and bacteremia/sepsis remained significant and were independent of the other factors in multivariate analysis. This study reveals that postoperative morbidity affects not only the perioperative mortality but also the long-term survival of patients with ESCC who undergo salvage esophagectomy after definitive CRT.

It is widely postulated that systemic inflammation related to lung infections is largely caused by cytokine translocation from the lungs into the systemic circulation but there is a paucity of animal models to evaluate this hypothesis. In this proof-of-concept study, we developed a murine model to determine whether interleukin (IL)-6, a primary inflammatory cytokine, translocates following airway exposure to endotoxin. We collected central venous blood from the right atrium and arterial blood from the aorta simultaneously at 4 h and 24 h following intratracheal exposure to endotoxin (25 mg) and measured IL-6 in the serum and broncho-alveolar lavage (BAL) fluid (n = 33 mice). We repeated the experiment following 3d of treatment with dexamethasone (n = 31 mice). Without stimulation, there was no significant arteriovenous gradient (3 pg/ml with interquartile range [IQR] of 3-5 pg/ml in arterial versus 18 pg/ml with IQR of 8-24 pg/ml in venous serum; P = 0.86). A significant arteriovenous difference was observed by 4 h post-exposure to endotoxin (2813 pg/ml with IQR of 1578-4316 pg/ml in arterial versus 1282 pg/ml with IQR of 778-2699 pg/ml in venous serum; P < 0.0001). The rise in the BAL IL-6 levels correlated with the increases in the arterial serum levels (P < 0.0001). Administration of intraperitoneal dexamethasone for 3d attenuated the increased arteriovenous gradient. This murine model facilitates the estimation of cytokine translocation across the lungs and evaluation of compounds to modulate this gradient.

Background: Radio-guided detection of sentinel lymph nodes (SLN) has been used to predict regional lymph node metastasis in patients with melanoma and breast cancer. However, the validity of the SLN hypothesis is still controversial for esophageal cancer. The aim of this study is to evaluate the feasibility and accuracy of radio-guided SLN mapping for esophageal cancer. Methods: Seventy-five consecutive patients who were diagnosed preoperatively with T1NOMO or T2NOMO primary esophageal cancer were enrolled. Endoscopic injection of technetium-99m tin colloid was performed before surgery and radioactive SLNs were identified with preoperative lymphoscintigraphy and gamma probe. Standard radical esophagectomy with lymphadenectomy was performed in all patients and all resected nodes were evaluated by routine pathologic examination. Results: SLNs were identified successfully in 71 (95%) of 75 patients. The mean number of identified SLNs per case was 4.7. Twenty-nine (88%) of 33 cases with lymph node metastasis showed positive SLNs. The diagnostic accuracy based on SLN status was 94% (67/71). Distribution of identified SLNs was widely spread from the cervical to abdominal areas. Conclusions: This study reveals that radio-guided SLN mapping is an accurate diagnostic procedure for detecting lymph node metastasis in patients with early-stage esophageal cancer.

近年、高齢者に対する外科手術の増加の一途を辿っている。周術期管理の進歩により高齢者の消化器外科手術は以前より安全に施行できるようになったものの、一般的に主要臓器機能の予備能が低下しており、併存する基礎疾患の有無により手術リスクはきわめて高いものとなる。ひとたび術後合併症を併発すれば、臓器不全から致命的となる場合もある。高齢者においては個々の症例において各主要臓器の予備能やリスクの評価を十分に行い、より安全性を重視した治療法の選択と緻密な周術期管理が必要である。(著者抄録)

Background: Circulating tumor cells (CTCs) measured by the CellSearch system in metastatic breast cancer have been reported to correlate with shorter overall survival. The purpose of this study was to clarify the clinicopathologic characteristics of CTCs in gastrointestinal cancers. Methods: Pre- and postoperative CTCs from 130 gastrointestinal cancer patients and 41 healthy volunteers were measured by this system. Correlation between CTC counts and clinicopathologic variables was examined. Results: The number of CTCs in metastatic patients (n = 79) was larger than in nonmetastatic patients (n = 35) and in healthy donors (n = 41) (P < 0.001). CTC counts were larger in metastatic gastric cancer (n = 27) than in nonmetastatic gastric cancer (n = 14) (P = 0.016). Two or more CTCs was significantly correlated with advanced tumor stage in all gastrointestinal cancers (P < 0.001) and in gastric cancer (P = 0.032). Two or more CTCs had significant correlation with peritoneal dissemination of gastric or colorectal cancer (P = 0.007) and pleural dissemination of esophageal cancer (P = 0.033). The survival of patients with >= 2 CTCs was shorter than that of patients with < 2 CTCs (P = 0.005). The change in CTCs tended to correlate with disease progression and chemotherapeutic effect. Conclusion: This study suggests that measurement of CTCs in gastrointestinal cancer patients could be useful as a tool for judging tumor stage, predicting the presence of peritoneal or pleural dissemination and patients' survival, and monitoring response to cancer therapy.

深達度EP(m1),LPM(m2)の食道癌はほとんどリンパ節転移を認めないことから、EMRの絶対適応と考えられる。しかし、過去に深達度M2の症例で他臓器やリンパ節転移を認めた症例の報告は少ないながらも存在する。また、食道癌は多発する傾向を有し、他臓器との重複癌にも注意が必要である。今回我々は深達度M2と診断され、経過観察中に壁内およびリンパ節転移をきたしたと考えられる症例を経験したので報告する。(著者抄録)

cT3N1胸部食道癌に対する手術および化学放射線療法(CRT)の治療成績を検討した。対象は1993〜2005年までに治療したUICC cT3N1M0臨床病期III胸部食道癌99例で、初回治療が手術の75例(S群:男性68例、女性7例、平均年齢62歳)と根治的CRTの24例(CRT群:男性22例、女性2例、平均年齢65歳)に分けて比較した。その結果、1)S群では術後合併症を肺炎15例(20%)、縫合不全7例(9%)に認められ、手術死亡1例を含む在院死亡3例(4%)であった。2)CRT群の治療効果はCR:2例、PR:13例、奏効率63%であった。一方、非CR中の5例にはSalvage食道切除術が行われ、術後合併症は肺炎2例(40%)、縫合不全4例(80%)とS群に比し高頻度であったものの、手術死亡や在院死亡は認められなかった。3)5年生存率はS群30%、CRT群15%とS群で有意に良好であったが、CRT群でCRの症例やSalvage手術を行った症例の計7例ではS群と差はなかった。

長期ステロイド投与患者は、視床下部-下垂体-副腎皮質系の抑制により、侵襲下において急性副腎不全による重篤な低血圧発症の高リスク状態にある。また、過量の糖質コルチコイドは創傷治癒を障害するため、縫合不全やsurgical site infection(SSI)の高リスク状態にある。適切なステロイドカバーや術式の選択、SSI対策等により、安全・確実な周術期管理を行う必要がある。(著者抄録)

食道アカラシアは,下部食道括約帯の弛緩不全による食物の通過障害や食道の異常拡張などがみられる機能的食道疾患である.良性疾患であり,かつ機能性疾患である食道アカラシアに対する手術適応は,原則的には薬物療法や内視鏡下バルーン拡張術に対する抵抗例と考えることができる.これまでの欧米の報告では概ねバルーン拡張術よりも手術(Heller myotomy)のほうが良好な症状改善効果を示している.近年,鏡視下手術手技の発達により,低侵襲で美容上にも優れた腹腔鏡下食道アカラシア手術が普及しつつあり,手技に熟練した施設を中心に,治療第一選択としての腹腔鏡下手術の適応拡大が予想される.(著者抄録)

現在,早期胃癌では腫瘍径や肉眼型,組織型などから深達度診断やリンパ節転移頻度予測が可能となっている.しかし,CT,US,EUS,MRIなどの術前画像によるリンパ節転移診断はいまだ不完全と言わざるを得ず,実際に郭清範囲を決めるのは術中のリンパ節の視触診や迅速病理診断に委ねられることが多いのが現状である.センチネルリンパ節(SN)生検は,SNに集中した病理学的あるいは分子生物学的転移診断を行うことによって,時間的,経済的に効率よいリンパ節微小転移診断を行うことができる.またSN転移陰性早期胃癌に対する胃局所切除術や分節切除術は新しい機能温存・個別化縮小手術として注目されている.(著者抄録)

化学放射線療法後に施行した食道切除術の成績を検討し、その問題点を明らかにした。化学放射線療法を施行した胸部食道扁平上皮癌158例中、化学放射線療法後に食道切除術を行った56例を対象とした。照射量50Gy未満の35例(A群)と50Gy以上の根治的照射を受けた21例(B群)に分けた。縫合不全、循環不全の頻度はA、B群間に差を認めなかったが、呼吸器合併症(肺炎)の頻度は、B群で有意に高かった。また、気管切開を要した重症肺炎例もB群では高頻度であった。術後30日以内の手術死亡例はA群で1例認めた。手術死亡例を含む在院死亡は両群ともに2例ずつ認めた。A、B群間では生存率に差を認めなかった。術後合併症の有無による生存率の比較検討では、とくにB群のsalvage例において呼吸器合併症、縫合不全、循環不全ともに有意な予後不良因子となった。

急性呼吸促迫症候群(ARDS)患者における気管支肺胞洗浄(BAL)液中サイトカインの網羅的解析を行うことで、その病態解析を試みた。健常ボランティア8例および診断確定を目的としてBALが施行されたARDS症例4例を対象とした。炎症性サイトカインについては、TNF-α、IL-1β、IL-6、IL-8のいずれもARDS群において著明な高値を示した。Th-1細胞関連サイトカインについて見ると、IL-2、IL-12、IFN-γいずれもARDS群において高値を示した。Th-2細胞関連サイトカインについても、IL-4、IL-5、IL-10、IL-13のいずれも、ARDS群において有意に高値を示した。GM-CSFのみ他のサイトカインとは異なる挙動を示し、ARDS群の全てにおいて測定感度以下であった。他のG-CSF、MCP-1、MIP-1βは、ARDS群において有意に高値を示した。IL-7、IL-17は、ARDS群において有意に高値を示した。

本邦の食道がん年間罹患者数、年間死亡者数はともに約1万人である。男性、高齢者に多い。発見時にすでに進行がんであることが多く、依然として予後不良である。現状では検診で発見される頻度は低い。食道扁平上皮がん罹患危険因子:飲酒、喫煙、多発がん・重複がん、アルデヒド脱水素酵素2型ヘテロ欠損、高齢者、男性 食道腺がん罹患危険因子:胃食道逆流症、Barrett食道、肥満 より早期に、より多くの罹患者を発見し、治療成績を向上するためには、問診(former flusher)や既往歴(頭頸部がん、食道がん)、生活歴(飲酒、喫煙)からハイリスク群を設定し、ヨード染色、narrow band imaging、拡大内視鏡、高解像度内視鏡を用いた積極的上部消化管スクリーニングが必要である。(著者抄録)

早期食道癌発見率の上昇によって内視鏡的粘膜切除術の適応症例は増加している.リンパ節転移のないT1aでは深達度m2までが適応となるが,耐術能不良例などを中心にm3〜sm1まで適応を拡大する試みもなされている.従来,cT1bN0例では根治手術が選択されてきたが,化学放射線療法による高いCR率が明らかとなり,今後,手術療法との比較試験の結果が注目される.T4ないしM1 Lym症例を対象に始められた化学放射線療法は,従来は外科治療が中心であったT2,T3食道癌にも適応が拡大しており,その是非に関しても臨床試験による検証が必要となろう.また今後,化学放射線療法後の腫瘍遺残,再発例に対するsalvage治療の適応決定とその臨床的意義の評価,根治性と安全性を重視したsalvage手術手技の確立などが求められる.無作為化比較試験の結果,術前化学療群の術後生存率は術後化学療群よりも有意に良好であることが明らかとなった.この結果から,今後わが国では手術療法に際し,術前化学療法が標準治療として組み込まれることが予想される.(著者抄録)