Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP). However, little is known about the mechanisms of PSC activation. PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-β1-induced protein. In this study, we investigated whether Hic-5 activates PSCs, which promote pancreatic fibrosis development in CP. Hic-5 -knockout and wild type mice were subjected to caerulein injection to induce CP. Hic-5 expression was strongly upregulated in activated PSCs from human CP tissue and from mouse pancreatic fibrosis in caerulein-induced CP. Hic-5 deficiency significantly attenuated mouse pancreatic fibrosis and PSC activation in the experimental murine CP model. Mechanistically, Hic-5 knock down significantly inhibited the TGF-β/Smad2 signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. Taken together, we propose Hic-5 as a potential marker of activated PSCs and a novel therapeutic target in CP treatment.

Carcinoma-associated fibroblasts (CAFs) influence tumor initiation, progression, and metastasis within the tumor-associated stroma. This suggests that CAFs would be a potential target for tumor therapy. Here we found that Hydrogen peroxide-inducible clone-5 (Hic-5), also named transforming growth factor beta-1-induced transcript 1 protein (Tgfb1i1), was strongly induced in CAFs found in human colorectal cancer. To investigate the role of Hic-5 in CAFs, we isolated CAFs and the control counterpart normal fibroblasts (NFs) from human colorectal cancer and non-cancerous regions, respectively. Hic-5 was highly expressed in isolated human CAFs and strongly induced in NFs in culture by the supernatant from cultured colorectal cancer cells as well as cytokines such as TGF-β, IL-1β and stromal cell-derived factor 1 (SDF-1/CXCL12). Furthermore, tumor growth was inhibited in a co-culture assay with Hic-5 knockdown fibroblasts compared with control fibroblasts. To clarify the function and significance of Hic-5 in colorectal cancer in vivo, we utilized a mouse model of azoxymethane (AOM)-induced colorectal cancer using Hic-5-deficient mice. Lack of Hic-5 in CAFs completely prevented AOM-induced colorectal cancer development in the colon tissues of mice. Mechanistic investigation revealed that Hic-5 promoted the expression of lysyl oxidase and collagen I in human control counterpart fibroblasts. Taken together, these results demonstrate that Hic-5 in CAFs is responsible for orchestrating or generating a tumor-promoting stroma.

Background & Aim: Hydrogen peroxide-inducible clone-5 (Hic-5), also named as transforming growth factor beta-1-induced transcript 1 protein (Tgfb1i1), was found to be induced by TGF-beta. Previous studies have shown that TGF-beta is a principal mediator of hepatic stellate cell (HSC) activation in liver fibrosis. However, this process remains elusive. In this study, we aimed to define the role of Hic-5 in HSC activation and liver fibrosis.Methods: We examined the expression levels of Hic-5 during HSCs activation and in fibrotic liver tissues by quantitative real-time reverse transcriptase polymerase chain reaction, Western blot and immunohistochemistry. Hic-5 knockout (KO) and wild-type (WT) mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) injection to induce liver fibrosis.Results: Hic-5 expression was strongly upregulated in activated HSCs of the human fibrotic liver tissue and BDL or CCl4-induced mouse liver fibrosis. Hic-5 deficiency significantly attenuated mouse liver fibrosis and HSC activation. Furthermore, Hic-5 knockdown by siRNA in vivo repressed CCl4-induced liver fibrosis in mice. Mechanistically, the absence of Hic-5 significantly inhibited the TGF-beta/Smad2 signaling pathway, proved by increasing Smad7 expression, resulting in reduced collagen production and alpha-smooth muscle actin expression in the activated HSCs.Conclusion: Hic-5 deficiency attenuates the activation of HSCs and liver fibrosis though reducing the TGF-beta/Smad2 signaling by upregulation of Smad7. Thus, Hic-5 can be regarded as a potential therapeutic target for liver fibrosis. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

転移性痔瘻癌に対して局所切除を行い，長期生存が得られた2例を経験した．症例1は58歳，男性．直腸S状部癌に対し，直腸切除術（D3郭清）を施行した．診断は，tub1＞tub2，pSE，pN1，cM0，fStage IIIaだった．8年前より痔瘻があり，術後8ヵ月目に肛門周囲に硬結が出現し，生検にて痔瘻癌と診断した．症例2は65歳，男性．下部直腸癌に対して直腸低位前方切除術（D3郭清）を施行した．診断はtub1＞tub2，pMP，pN0，cM0，fStage IIであった．術後9ヵ月目に肛門に硬結を自覚した．肛門に腫瘤を認め，生検で痔瘻癌と診断した．いずれの症例も腫瘍と瘻孔を含めた局所切除術を行った．2例とも先行する直腸癌に類似した組織像を示し，抗サイトケラチン抗体，粘液形質などの免疫染色法から直腸癌の転移性痔瘻癌と診断した．症例1は術後8年3ヵ月，症例2は術後5年10ヵ月無再発生存している．

A 77-year-old man underwent surgery for sigmoid colon cancer. He was diagnosed with Stage IIIa colon cancer; there- fore, we initiated oral administration of adjuvant chemotherapy comprising uracil/tegafur(UFT)plus Leucovorin(LV). However, chemotherapy was stopped after 21 days because of fatigue and diarrhea. He recovered after 3 weeks, and we administered the same regimen with a dose reduction. However, he again experienced fatigue and diarrhea after 20 days; therefore, chemotherapy was discontinued. Subsequently, he was hospitalized 8 times for conditions such as diarrhea, hypoalbuminemia, and fever. Computed tomography revealed thickening of the transverse colonic wall and colonoscopy revealed colitis, which we believe was induced by UFT plus LV. Twelve months after the last chemotherapy session, he was diagnosed with Clostridium difficile colitis. Therefore, we initiated the oral administration of vancomycin, which resulted in rapid recovery from colitis. However, he developed liver metastasis and died 29 months after the initiation of chemotherapy. We believe that this severe case of intractable colitis was caused by UFT plus LV. Therefore, we report this case with a review of the literature on enteritis induced by fluorouracil-based anticancer agents in Japan.

Background We report an extremely rare case of resection of localized biphasic malignant peritoneal mesothelioma of the transverse colon. Case report Computed tomography and magnetic resonance imaging in a 72-year-old man showed a tumor with enhanced borders consistent with the transverse colon. Colonoscopy showed ulcerative lesions in the transverse colon, but histological examination showed no malignancy. A gastrointestinal stromal tumor was strongly suspected, so an extended right hemicolectomy was performed. Histopathological examination showed that the tumor was a localized malignant peritoneal mesothelioma of the transverse colon. The patient did not receive postoperative chemotherapy and died 18 months after surgery. Conclusions The number of patients with malignant mesotheliomas is predicted to increase in the future both in Japan and in western countries. We report this case due to its probable usefulness in future studies pertaining to the diagnosis and treatment of malignant mesotheliomas.

大腸癌異時性卵巣転移は比較的稀で，予後は不良である．今回，当科で経験した大腸癌異時性卵巣転移の４例を報告し，最近12年間の本邦報告例を加えて，臨床病理学的特徴と診断，治療について検討した．４例とも術前の腫瘍マーカーを含めた血液生化学検査や画像所見，さらには術中迅速組織診でも原発性卵巣癌との鑑別は困難で，４例中３例で確定診断のために切除標本のCytokeratin 7，Cytokeratin 20による免疫組織学的検査が必要であった．原発巣の病理組織学的因子では全例で漿膜浸潤を認め，３例は治癒切除後の再発であった．卵巣転移の転移経路をその予後からみると，卵巣転移切除後に高頻度に腹膜転移をきたすことより，異時性卵巣転移の多くは腹膜再発の部分所見とも考えられた．予後は不良であるが，原発性卵巣癌との鑑別が困難であること，腫瘍の増大による腹部症状をきたすことから，外科的切除は容認されるものと考える．

他臓器浸潤大腸癌における治療方針決定の一助とすることを目的とし，大腸癌手術症例2,090例のうち肉眼的他臓器浸潤陽性168例を検討した．組織学的他臓器浸潤陽性は68例であり，肉眼的他臓器浸潤症例の40.8％（68/168）であった．占居部位別にはS状結腸30.0％，上行結腸26.8％，盲腸10.1％の順で多く．浸潤臓器は腹壁，小腸，膀胱の順で多かった．高分化型腺癌と中分化型腺癌を合わせた分化型腺癌と，低分化型腺癌と粘液癌などのそれ以外組織型の２群間で肉眼的ならびに組織学的他臓器浸潤率を比較したが有意差はなかった．根治手術を施行した組織学的他臓器浸潤例と他臓器浸潤のない壁深達度pSS・SE・Aの症例との間に予後の差はなかったが，Stage別ではpStageⅢで他臓器浸潤例の予後は不良であり，根治度Aが得られた組織学的他臓器浸潤症例の再発様式は半数以上が血行性再発であった．さらには鏡視下に切除した症例は開腹手術を行った症例と比べて予後不良であった．

INTRODUCTION:Laparoscopic-assisted colorectal surgery requires a mini-laparotomy to extract the specimen and insert the anvil head of the circular stapler into the proximal colon. However, such a mini-laparotomy occasionally causes local pain and surgical-site infection. To avoid mini-laparotomy, we invented a new laparoscopic technique, complete laparoscopic surgery for colorectal cancer.MATERIALS AND SURGICAL TECHNIQUE:Sigmoid colon or rectal cancer patients who had undergone colonoscopic excision for T1 cancer and subsequently required bowel resection due to unfavorable histology were recruited. This new procedure used both the double stapling technique and the rectal-prolapsing technique, where the anvil was transanally inserted into the proximal colon and bowel resection was extracorporeally performed after pulling out the colon-rectum via the anus.DISCUSSION:This procedure was attempted in 17 patients and successfully achieved in 13 patients. Total laparoscopic colorectal surgery has some problems such as bacterial contamination or infection, as well as dissemination caused by intraluminal exfoliated cancer cells. This procedure is limited to post-endoscopic resection patients who are suited for reconstruction by double stapling technique, and it may be impossible in patients with thick mesentery or anal stenosis. Moreover, this method resolves issues of peritoneal contamination and dissemination. However, a new protection method for implantation of exfoliated cancer cells needs to be established, so that complete laparoscopic surgery can be employed in patients with small cancers.

症例は48歳男性で,便潜血反応陽性の精査にて下部消化管内視鏡検査を施行され,横 行結腸癌が認められた.CT colonographyにて横行結腸に高度の壁変形像を認め,さら に,non-rotation typeの腸回転異常症を伴っていた.CT angiographyにて,腫瘍の支 配血管は中結腸動脈(MCA)で,上腸間膜動脈(SMA)の左側から分岐し,上腸間膜 静脈(SMV)背側を走行していた.以上より,腸回転異常症に併存した横行結腸癌と 診断した.癒着が高度であり,開腹にて横行結腸部分切除術を施行した.郭清は, MCAがSMVの背側を走行していたためMCAの右枝で処理しD2 とした.診断はtub2, pSS,pN0,ly0,v0,fStage IIだった.腸回転異常症に併存した右側結腸癌は,SMA とSMVの分枝の走行異常が多く,術前にCT angiographyにて血管走行を把握してお くことが重要である.

Background. This study addresses clinicopathological differences between patients with gastric cardia and subcardial cancer with and without esophagogastric junctional invasion. Methods. We performed a single-center, retrospective cohort study. We studied patients who underwent curative surgery for gastric cardia and subcardial cancers. Tumors centered in the proximal 5 cm of the stomach were classed into two types, according to whether they did (Ge) or did not (G) invade the esophagogastric junction. Results. A total of 80 patients were studied; 19 (73.1%) of 26 Ge tumors and 16 (29.6%) of 54 G tumors had lymph nodes metastases. Incidence of nodal metastasis in pT1 tumors was significantly higher in the Ge tumor group. No nodal metastasis in cervical lymph nodes was recognized. Only two patients with Ge tumors had mediastinal lymph node metastases. Incidence of perigastric lymph node metastasis was significantly higher in those with Ge tumors. Ge tumors tended to be staged as progressive disease using the esophageal cancer staging manual rather than the gastric cancer staging manual. Conclusion. Because there are some differences in clinicopathological characteristics, it is thought to be adequate to distinguish type Ge from type G tumor.

大腸領域の腹腔鏡手術は大腸癌を治療対象として研究され発達してきた歴史がある．一方で大腸癌に対して開発され，実証された術式，手術器具を駆使することが大腸良性疾患に対しても応用されてきている．腹腔鏡下虫垂切除術（急性虫垂炎），腸管部分切除術（憩室炎，憩室出血，腸管穿孔など），大腸全摘出術（炎症性腸疾患），直腸固定術（直腸脱）などが代表的なものである．このうち虫垂切除術と直腸固定術は大腸良性疾患に限られる代表的な術式であり，本稿ではこれら二つの術式について概説する．

AIM:The aim of this study was to investigate the effect of splenectomy on survival outcomes and recurrence in patients who underwent curative surgery for gastric cancer.PATIENTS AND METHODS:This is a retrospective study of 129 patients who underwent upper-third gastric cancer curative resection with lymphadenectomy. Forty-two patients (32%) also underwent splenectomy.RESULTS:The median follow-up period was 33 months. Approximately 40% of the patients had lymph node metastases; four of them had nodal involvement along the splenic artery and 5 had nodal involvement at the splenic hilum. No patients in the pT1-2 group with nodal metastases had involvement of the splenic hilar lymph nodes. There was no significant association between splenectomy and either overall or disease-free survival in the patients.CONCLUSION:Splenectomy should not be performed in patients with pT1-2 tumors for prophylactic lymphadenectomy.

A 63-year-old woman was admitted to our hospital for a palpable mass and abdominal pain. Abdominal CT showed an abscess in the abdominal wall and a contiguous mass in the intraperitoneal cavity. After drainage of the abscess was performed, we conducted a colonoscopy to investigate the cause of the mass. It revealed a type 2 tumor and a whole-circumferential stenosis in the cecum. It required preoperative chemotherapy with CPT-11 and S-1 to achieve radical cure characteristics with the operation. Because there was tumor reduction, right hemicolectomy and resection of the abdominal wall were performed. The patient was discharged 15 days after the operation with an eventful clinical course. Although 5 years have passed since the operation, she is alive and has had no recurrence. This patient accepted tumor reduction by chemotherapy , and the abdominal wall deficit that resulted from excision did not have it was it with a small range, and to rebuild the abdominal wall. The utility of preoperative chemotherapy is recommended in colon cancer which invades other organs.

症例は50歳，男性．左側腹部痛を主訴に前医を受診し，同部に腫瘤を指摘され紹介となった．初診時に左下腹部に圧痛を伴う可動性不良な腫瘤を触知した．血液生化学検査では炎症反応の上昇と軽度貧血を認めた．CTでは下行結腸背側に手拳大の腫瘍を認め，内部は均一で一部に石灰化を伴っていた．MRIではT1強調・T2強調像で腫瘍は不均一な高信号を示した．後腹膜腫瘍と診断し，下行結腸と一塊に腫瘍を切除した．腫瘍は10.5×7.0×7.0cm，割面は充実性で白色調の部位と黄色調の部位が混在していた．病理組織学検査では紡錘形細胞が車軸状に増殖する像を認め，悪性線維組織球腫に類似した所見であった．CDK4およびMDM2が陽性で，腫瘍内には骨肉腫と平滑筋肉種の成分も認め，骨肉腫と平滑筋肉腫への分化を示す脱分極型脂肪肉腫と診断した．