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We previously reported the feasibility and efficacy of neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer. Here, we report the results of a long-term follow-up study.This was a multi-institutional, prospective phase 2 study of patients with locally advanced rectal cancer. Patients received neoadjuvant chemotherapy with molecularly targeted agents before undergoing total mesorectal excision. Six cycles of modified FOLFOX (mFOLFOX6) with bevacizumab were administered to KRAS-mutant patients, and mFOLFOX6 with cetuximab was administered to KRAS-wild-type patients. Here, we report the secondary end points of overall survival, relapse-free survival, and local recurrence rate.Sixty patients were enrolled in this study. R0 resection was achieved in 98.3% (59/60) patients, and pathological complete response was achieved in 16.7% (10/60) patients. After a median follow-up of 5.4 years, the 5 year overall survival was 81.6%, the 5 year relapse-free survival was 71.7%, and the 5 year local recurrence rate was 12.6%. None of the patients who achieved pathological complete response developed recurrence within 5 years.The use of molecularly targeted agents in the neoadjuvant setting for locally advanced rectal cancer has an acceptable prognosis.

Lessons Learned Background The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable colorectal cancer liver metastases (CLM) is still unclear. We evaluated the feasibility of 3-month adjuvant treatment with capecitabine plus oxaliplatin in combination (CAPOX) for postcurative resection of CLM. Methods Patients received one cycle of capecitabine followed by four cycles of CAPOX as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given as 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle, and CAPOX consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3-week cycle. Primary endpoint was the completion rate of adjuvant chemotherapy. Secondary endpoints included recurrence-free survival (RFS), overall survival (OS), dose intensity, and safety. Results Twenty-eight patients were enrolled. Median age was 69.5 years, 54% of patients had synchronous metastases, and 29% were bilobar. Mean number of lesions resected was two, and mean size of the largest lesion was 31 mm. Among patients, 20 (71.4%; 95% confidence interval, 53.6%–89.3%) completed the protocol treatment and met its primary endpoint. The most common grade 3 or higher toxicity was neutropenia (29%). Five-year recurrence-free survival and overall survival were 65.2% and 87.2%, respectively. Conclusion Three-month adjuvant treatment with CAPOX is tolerable and might be a promising strategy for postcurative resection of CLM.

Patient: Male, 66-year-old Final Diagnosis: Pancreatic cancer Symptoms: Abdominal pain Medication:— Clinical Procedure: Adjuvant chemotherapy • neoadjuvant chemotherapy • radical resection Specialty: Surgery Objective: Unusual setting of medical care Background: Distal pancreatic cancers may be unresectable at the time of diagnosis because these cancers are asymptomatic and readily infiltrate neighboring organs. Radical resection of a pancreatic tail cancer with colonic perfo-ration is rare. We describe successful resection of a locally advanced pancreatic tail cancer with colonic perfo-ration using a multidisciplinary approach. Case Report: A 66-year-old man presented to our hospital with a chief concern of high fever. Abdominal computed tomography revealed a pancreatic tail tumor infiltrating the neighboring organs and causing colonic obstruction with perforation, which resulted in an intra-abdominal abscess. Colonoscopy revealed obstruction of the descending colon by extramural invasion. Laboratory tests showed high tumor marker concentrations (carcinoembryonic antigen, 11.6 ng/dL; pancreatic cancer-associated antigen-2, >1600 U/mL). We clinically diagnosed locally advanced pancreatic tail cancer with an intra-abdominal abscess caused by colonic perforation. First, we performed transverse colostomy and percutaneous drainage. We then started neoadjuvant chemotherapy with FOLFIRINOX for tumor shrinkage and prevention of distant metastases. The therapeutic effect was a partial response, and no distant metastases was found. We therefore performed radical surgery comprising distal pancreatectomy with partial resection of neighboring organs. Although pathological examination revealed a pancreatic tail tubular adenocarcinoma with direct invasion of the neighboring organs, R0 resection was achieved. The patient was discharged with no perioperative complications. Tegafur/gimeracil/oteracil potassium were administered as adjuvant chemotherapy. The patient remained recurrence-free for 19 months after surgery. Conclusions: We achieved successful en bloc resection of a locally advanced distal pancreatic cancer with colonic perforation by using a multidisciplinary approach.

Introduction and importance Although variations from the standard anatomy of the extrahepatic bile ducts are common, duplication of the cystic duct draining a single gallbladder is an extremely rare variant. We herein describe the first report of gallbladder cancer spreading into the aberrant cystic duct. Case presentation A 60-year-old female presented with upper abdominal pain, and she was diagnosed with gallbladder cancer. Intraoperatively, she was found to have a duplicated cystic duct draining a single gallbladder, and her cancer had spread into the aberrant cystic duct entering the anterior right hepatic duct. Right hepatectomy with extrahepatic bile duct resection was performed to achieve R0 resection. Clinical discussion In the English literature, 28 cases of duplicated cystic duct draining a single gallbladder have been reported. However, no cases of gallbladder cancer have been described in these previous reports. Conclusion We report the first case of gallbladder cancer spreading into the aberrant cystic duct. To perform an oncologically adequate operation, exact assessment of the biliary tree is essential not only preoperatively but also intraoperatively., Highlights • Duplication of the cystic duct draining a single gallbladder is rare in the anatomical variations of the biliary tract. • A 60-year-old female with gallbladder cancer was found to have a duplicated cystic duct draining a single gallbladder. • Her cancer had spread into the aberrant cystic duct entering the anterior right hepatic duct. • We report the first case of gallbladder cancer spreading into the aberrant cystic duct.

399 Background: Prognosis for locally advanced gastric cancer (LAGC), such as clinical T4 disease, bulky nodal metastases, type 4 and large type 3 gastric cancer, was not satisfactory even by D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach, therefore, we have conducted a phase II study to evaluate the efficacy and safety of the neoadjuvant chemotherapy of S-1 and oxaliplatin (G-SOX) followed by gastrectomy with D2/3 lymph node dissection for LAGC, and the primary endpoint of curative resection rate was met [Miki A, ESMO 2019]. We show longer follow-up data from this study. Methods: Patients with adenocarcinoma of the stomach; clinical T4; clinically resectable gastric cancer of type 4 or large type 3; bulky nodal involvement around major branched arteries to the stomach were enrolled. Patients receive two cycles of neoadjuvant chemotherapy with S-1 (80 mg/m2, p.o., days 1-14 followed by 1 week rest) and oxaliplatin (130 mg/m2 at day 1), followed by D2 or higher surgery with no residual disease. Patients with pathological R0/1 resection received S-1 (80 mg/m2, p.o., days 1-28 followed by 2 week rest) for 1 year as adjuvant chemotherapy. Primary endpoint was curative resection rate. Results: Between August 2015 and March 2017, forty-one patients were in enrolled. Of the patients, 39 patients (95%) completed the two courses of neoadjuvant chemotherapy of G-SOX, 37 (90%) received gastrectomy, and 36 (87.8%) received curative resection (R0/1). Grade 3 or higher toxicities during neoadjuvant chemotherapy of G-SOX were neutropenia (7%), fatigue (7%), diarrhea (5%) and thrombocytopenia (2%). No treatment related deaths were observed. Surgical complications including postoperative complications were observed in 13 patients (35%). Pathological response rate after neoadjuvant G-SOX was 40%. With a median follow-up period of 33.8 months, 3year-relapse free survival and 3year-ovearll survival was 54.3% and 73.1%, respectively. Conclusions: An update analysis confirmed that neoadjuvant chemotherapy of G-SOX is a feasible and might be one of the promising strategies for patients with LAGC. Clinical trial information: UMIN000018661.

Background Anastomotic leak (AL) is a serious complication of low anterior resection (LAR). This study aimed to evaluate the effect of transanal tube placement for prevention of AL. Methods This multicenter retrospective cohort study enrolled 328 consecutive patients who underwent LAR for rectal cancer at participating hospitals from 2009 to 2014. Multivariate logistic regression was used to adjust for confounding factors. Results A transanal tube was placed in 205 patients (TA group) and not placed in 123 patients (non-TA group). Symptomatic AL occurred in 36 cases (11%), with significantly higher incidence of symptomatic AL in the non-TA group than in the TA group (15% vs 8.3%, odds ratio [OR] 2.02, 95% confidence interval [CI] 1.01-4.06). After adjusting for confounding factors, multivariate analysis revealed that placement of a transanal tube could decrease the incidence of symptomatic AL (adjusted OR 0.37, 95%CI 0.15-0.91). There was no significant difference in postoperative morbidity, mortality, length of hospital stay, or local recurrence rate between the two groups. Local recurrence rate tended to be higher in patients with symptomatic AL (3/36) than in those without it (10/292). Conclusions Transanal tube placement is effective for decreasing the incidence of symptomatic AL after LAR.

This prospective multicenter phase 2 study aimed to evaluate the feasibility and efficacy of neoadjuvant chemotherapy (NAC) without radiotherapy for locally advanced rectal cancer (LARC). Patients with LARC (cStage II and III) were included in the study. Those with cT4b tumor were excluded. Six cycles of modified FOLFOX6 (mFOLFOX6) plus either bevacizumab or cetuximab, depending on KRAS status, were administered before surgery. The primary end point of the study was the R0 resection rate. The secondary end points were adverse effect, rate of NAC completion, postoperative complications, and pathologic complete response (pCR) rate. The study enrolled 60 patients from eight institutions. For the study, mFOLFOX6 was administered with cetuximab to 40 patients who had wild-type KRAS and with bevacizumab to 20 patients who had KRAS mutations. The completion rate for NAC was 88.4%. Sphincter-preserving surgery was performed for 43 patients and abdominoperineal resection for 17 patients. The median operation time was 335 min, and the median blood loss was 40 g. The R0 resection rate was 98.3%, and the pCR rate was 16.7%. The overall postoperative complication rate (≥grade 2) was 21.7%. The complications included anastomotic leakage (11.6%), surgical-site infection (6.7%), and urinary dysfunction (3.3%). The patients with wild-type KRAS did not differ significantly from those with KRAS mutations in terms of response rate, postoperative complication rate, and pCR rate. The findings show that NAC is a feasible and promising treatment option for LARC (This study is registered with UMIN-CTR, UMIN000005654).

Masahito Kotaka,1 Fusao Ikeda,2 Masaki Tsujie,3 Shinichi Yoshioka,4 Yoshihiko Nakamoto,5 Takaaki Ishii,6 Takahisa Kyogoku,7 Takeshi Kato,8 Akihito Tsuji,9 Michiya Kobayashi101Gastrointestinal Cancer Center, Sano Hospital, Kobe, Hyogo, 2Department of Surgery, Kohka Public Hospital, Koka, Shiga, 3Department of Colorectal Surgery, Sakai City Medical Center, Sakai, Osaka, 4Department of Surgery, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Hyogo, 5Department of Surgery, Seikei-kai Chiba Medical Center, Chiba, Chiba, 6Department of Surgery, Kobe-Ekisaikai Hospital, Kobe, Hyogo, 7Department of Surgery, Nishikobe Medical Center, Kobe, Hyogo, 8Department of Colorectal Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo, 9Kagawa University Hospital Cancer Center, Kita-gun, Kagawa, 10Department of Human Health and Medical Sciences, Kochi Medical School, Kochi University, Nangoku, Kochi, JapanBackground: There has been remarkable progress in systemic chemotherapy for metastatic colorectal cancer due to the widespread use of irinotecan, oxaliplatin, anti-vascular endothelial growth factor antibody, and anti-epidermal growth factor receptor antibody. It is important to continue treatment with the optimal combination of these drugs and prolong progression-free survival (PFS) to improve overall survival (OS). We conducted a prospective observational cohort study of 40 patients treated with XELOX plus bevacizumab for previously untreated metastatic colorectal cancer to investigate treatment continuity.Patients and methods: Eligibility criteria were as follows: 1) histologically confirmed metastatic colorectal cancer; 2) lesions evaluable by imaging; 3) previously untreated; 4) suitable condition to receive XELOX plus bevacizumab; and 5) written informed consent. Outcomes were treatment continuity, overall response rate, resection rate, liver resection rate, time to treatment failure, PFS, and OS. Forty patients were enrolled and followed up for 2 years.Results: Between July 2010 and June 2012, 40 patients were enrolled. The median number of treatment cycles was 7.5, and the reasons for discontinuation of treatment were as follows: complete response (five patients), resection (ten patients), progression (15 patients), adverse events (seven patients), and patient refusal (three patients). The overall response rate was 57.5%, resection rate was 25%, and liver resection rate was 15%. After a median follow-up of 31.4 months, the median time to treatment failure, PFS, and OS were 5.3, 13.3, and 38.9 months, respectively.Conclusion: Although the median time to treatment failure was 5.3 months, the median PFS and OS were prolonged to 13.3 and 38.9 months, respectively. This may have resulted from the chemotherapy-free interval due to complete response in five patients and resection in ten patients. Keywords: observational cohort study, metastatic colorectal cancer, XELOX plus bevacizumab, treatment continuity

866 Background: Hepatic resection is one of the treatment strategies for resectable colorectal cancer liver metastases (CLM). The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable CLM is still unclear. Adjuvant chemotherapy consisting of capecitabine plus oxaliplatin (CapeOx) appears to be equivalent to FOLFOX in patients with stage III colon cancer. Furthermore, the IDEA collaboration reported that adjuvant chemotherapy with the three months of CapeOx after curative resection for stage III colon cancer has equivalent efficacy to adjuvant chemotherapy for 6 months. We conducted a multi-institutional, single-arm, phase II trial to confirm the feasibility of the three months of adjuvant CapeOx for post curative resection of CLM. Methods: Patients received one course of capecitabine followed by four courses of CapeOx for a total five courses (15 weeks) as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given with 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle, and CapeOx consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3-week cycle. The primary endpoint was completion rate of adjuvant chemotherapy. We set a threshold completion rate of protocol treatment of 45% and an expected completion rate of 70%. Given a one-sided α of 0.1 and statistical power of 80%, a minimum of 25 patients was required. Results: From May 2013 to November 2015, Twenty-eight patients were enrolled from six institutions: median age 69.5y, 54% male, 78.5% left-sided primary. Of the patients, 15 were synchronous metastases and 13 were metachronous. The locations of the metastases were unilobar in 20 patients and bilobar in 8. The mean number of lesions resected was two (range, 1 to 4). Among the 28 patients, 20 (71.4%: 95% CI, 53.6 to 89.3%) completed the protocol treatment. The most common grade 3/4 toxicities were neutropenia (29%). No treatment related death was observed. With a median follow-up period of 36 months (range 15-53months), 3 year-relapse free survival was 75.3%. Conclusions: The three months of adjuvant CapeOx is tolerable for post curative resection of CLM. Clinical trial information: 000011164.

症例は76歳，女性．急性胆嚢炎の疑いで他院より紹介受診した．当院腹部CTにて後腹膜気腫像を認め，十二指腸穿孔・後腹膜膿瘍の診断で緊急手術を施行した．十二指腸下行脚内側に直径2cm大の壊死に陥っている嚢胞性病変を認め，嚢胞壁切開とドレナージ術を施行し，手術を終了した．十二指腸憩室穿孔の可能性を考えたが，画像で証明できず確定診断には至らなかった．術後のドレーンからの造影で，術中には証明できなかった十二指腸憩室と十二指腸が描出され，十二指腸憩室穿孔であることが判明した．診断に苦慮したものの，ドレナージ術で治癒した十二指腸傍乳頭憩室穿孔の1例を経験したので報告する．

乳癌術後13×8cmの皮膚欠損創に対し, ラップ療法で治癒した1例を経験したので報告する. 症例は55歳, 女性. 左乳房に15×25×5cm大のカリフラワー様の腫瘍を認め, 乳癌の診断で左乳房切除術を施行した. 第5肋骨の露出を伴う13×8cm大の皮膚欠損創となったが, 創感染のリスクが高いと判断し, 一期的遊離皮膚移植は行わず, 水道水による洗浄後, ポリ塩化ビニリデン製食品包装用ラップフィルムを用いた開放ドレッシング (ラップ療法) を続けた. 術後8日目に肉芽増生が開始し, 17日目には平坦化した. 上皮化は14日目に縦方向, 37日目に横方向が開始したが, 次第に停滞したため, 57日目よりステロイド外用剤を使用したところ, 翌週には, 潰瘍の辺縁に上皮化を認め, 以後1週間に1cmのスピードで上皮化が進み, 約2カ月でほぼ治癒となった. 以上より, ラップ療法は10cm以上の大きな皮膚欠損創でさえも治癒することができる優れた治療法であると考える.

症例は62歳の男性で, 結核性胸膜炎の治療歴と胃癌, 胆石の手術歴がある. 黄疸の精査目的に紹介受診した. 腹部超音波検査で膵頭部に5.2cmの不整形の低エコー腫瘤を認め, 腹部CTでは辺縁がリング状に造影された. 黄疸はまもなく軽快し, その他全く無症状であったが, 胸部X線上の肺浸潤影, ツベルクリン反応陽性などから結核性リンパ節炎による胆管狭窄と診断, 確定診断目的に開腹した. リンパ節摘出, 総胆管十二指腸吻合を行った. 組織学的に中心乾酪壊死を伴う類上皮細胞肉芽腫を認め, 結核性リンパ節炎と診断した. 術後の喀痰培養で抗酸菌を検出した. 術後抗結核剤投与を行い, 経過良好である. 肺外結核のなかでも胆管狭窄を来す腹部リンパ節結核はまれであり, 本邦報告例は8例のみである. また, 腹部, 消化管疾患においても, 結核は常に念頭に置くべきことを再認識させられた.

胃固有筋層に固定される進行胃癌が十二指腸内に嵌入をきたした稀な症例を報告した.症例は77歳,男性,食欲不振と嘔気を主訴に来院.内視鏡検査では胃下部の隆起局面が幽門輪内に入り込み幽門が狭窄されていた. CTおよび超音波検査では,十二指腸内腔に胃内より連続した9 cm大の充実性腫瘤を認め,胃腫瘍の嵌入と診断した.開腹にて胃壁は幽門直前で重積様に陥凹し,十二指腸は腫瘍により拡張し壁は肥厚していた.胃内へ腫瘍は還納されず,胃幽門側および腫瘍を含む十二指腸を切除した.腫瘍は胃下部小彎の90×70×30mm大のBorrmann 1型,深達度MPの高分化型腺癌であった.

経肛門的イレウス管挿入後に発症したイレウス管による結腸穿孔の1例を経験した.症例は54歳,女性.横行結腸人工肛門閉鎖術施行後に吻合部の狭窄による腸閉塞がみられた.経肛門的に内視鏡にて狭窄部の拡張を行うとともに減圧目的にイレウス管を狭窄部を越えて挿入した.イレウス管挿入後2日目に腹痛と発熱が出現したためイレウス管造影を行ったところ減圧された結腸壁を管の先端が圧迫していた.イレウス管を抜去するも腹痛は改善せず,腸管穿孔と判断し緊急手術を行った. 近年大腸の狭窄による腸閉塞に経肛門的イレウス管が有用とされているが,拡張腸管の減圧にともない管の先端による腸管壁穿孔がみられることがあり合併症としての留意が必要である.

幽門側胃切除術後に留置された胃管による残胃穿孔症例を報告した.症例は68歳,男性.胃体部癌に対して幽門側胃切除, D2郭清を行い,ビルロートI法で再建し残胃内に経鼻胃管を留置した. 術後2日目,一過性の強い腹痛が出現し不穏行動がみられたが3日目には軽快し,胃管も抜去した.しかし,腹部所見は乏しいものの,術後5日目まで39度台の発熱が続き,白血球数増多, CRP値の上昇がみられた. 術後6日目, free airと上腹部膿瘍像を画像検査にて認め,胃透視にて残胃の大弯側より造影剤の胃外への流出を認めた. 胃穿孔と診断し再開腹したところ,胃体部大弯線上に,初回手術時の胃管の先端位置と一致して穿孔を認めた.穿孔部は縫合閉鎖した.

730 Background: The aim of this prospective multi-center phase II study was to evaluate the feasibility and efficacy of neoadjuvant chemotherapy (NAC) for locally advanced rectal cancer (LARC). Methods: Patients with LARC (cStage II–III) were included; those with cT4b tumor were excluded. Six cycles of mFOLFOX6 plus either bevacizumab (bev) or cetuximab (cet), depending on KRAS status, were administered before surgery. Primary endpoint was R0 resection rate. Secondary endpoints included completion rate of NAC, response rate, postoperative complications, pathological complete response (CR) rate, overall and disease-free survival, and quality of life. Results: Sixty patients from 7 institutes were enrolled. mFOLFOX6 was administered with bev to 40 patients who had wild-type KRAS and with cet to 20 patients who had K-RAS mutations. Completion rate of NAC was 88.4% and overall response rate was 81.7%. Sphincter-preserving surgery and abdominoperineal resection were performed in 43 and 17 patients, respectively. Median operation time was 335 min and median blood loss was 40 g. R0 resection rate was 98.3% and pathological CR rate was 16.7%. Overall postoperative complication rate ( ≥ grade 2) was 21.7%, including anastomotic leakage (11.6%), surgical site infection (6.7%), and urinary dysfunction (3.3%). There were no significant differences between patients with wild-type KRAS and those with KRAS mutations in response rate, postoperative complication rate, and pathological CR rate. Conclusions: NAC was a feasible and promising treatment option for LARC. Clinical trial information: UMIN000005654.

数年にわたり下血を繰り返し,診断に苦慮した膵管出血の1例を報告した.症例は65歳,男性,慢性膵炎にて通院中. CTでは膵管の拡張なく,膵尾部に1.5cm大の仮性嚢胞を認めていた.平成8年より間欠的に突然下血を繰り返すようになる.下血時は腹痛や膵酵素の上昇は認めなかった.頻回に内視鏡検査を行うも出血源は同定できなかった.平成9年に上行結腸および下行結腸の憩室よりの出血を疑い右側結腸切除さらに下行結腸切除術を行うも下血を繰り返した.平成11年内視鏡にて十二指腸乳頭からの出血を認め,膵管出血と診断した.経過中膵炎の増悪はみられず,膵尾部の嚢胞にも変化がみられなかったが,嚢胞が出血の原因と考え膵体尾部脾切除術を行った.組織学的に嚢胞と膵周囲血管および膵管との交通を認め,消化管出血は以降みられなくなった.

To study the role of pancreatic blood flow and vasoactive substances in the development of acute pancreatitis, we measured portal vein blood levels of bradykinin, prostaglandin E2 (PGE2), histamine, serotonin, and pancreatic enzymes, and with an electromagnetic blood flowmeter we recorded gastroduodenal arterial flow (GDAF), superior mesenteric arterial flow (SMAF), and mean arterial blood pressure for 6 hr in dogs with acute hemorrhagic necrotizing pancreatitis induced by the retrograde injection of autologous bile (0.5 ml/kg) into the pancreatic duct. GDAF and SMAF decreased immediately in the early phase of acute pancreatitis (-17.8 +/- 6.1%** at 10 min and -15.8 +/- 7.1%* at 20 min; *P < 0.05, **P < 0.01); portal bradykinin concentration increased quickly (3.2 +/- 1.2 pM at 0 time, 16.2 +/- 5.2 pM* at 5 min, 30.4 +/- 4.8** pM** at 10 min, and 39.6 +/- 15.1 pM* at 20 min). Portal PGE2 concentration increased gradually after the induction of acute pancreatitis, and differences from the control group were significant at 20, 30, and 180 min (1426 +/- 175 pM at 0 time, 1956 +/- 273 pM* at 20 min, 2148 +/- 265 pM** at 30 min, and 3369 +/- 686 pM* at 180 min). Portal histamine and serotonin concentrations increased somewhat, but not significantly. These findings suggest that the injection of bile into the pancreatic duct causes the pancreas to quickly release a large amount of bradykinin into the portal vein, which immediately reduces the pancreatic blood flow in the early phase, thus accelerating the progress of acute pancreatitis.

To define the role of free radicals and of lipid peroxide involvement during the progress of cerulein-induced acute pancreatitis in mice, we evaluated the effect of a novel free radical scavenger, 2-octadecylascorbic acid (CV-3611), on pancreatic edema formation, and the levels of serum enzymes (amylase, lipase) and of lipid peroxide in pancreatic tissue. Mice were divided into three groups: control group, intraperitoneal injection of saline only; pancreatitis group, cerulein 50 micrograms/kg injected intraperitoneally six times at 1-hr intervals; treatment groups, CV-3611 10 mg/kg subcutaneously just after intraperitoneal cerulein injection. After the cerulein injection, the degree of pancreatic edema formation, serum amylase and lipase levels, and the amount of lipid peroxide in pancreatic tissue increased significantly during the observation period of 12 hr. Treatment with CV-3611 resulted in significant reduction in pancreatic edema formation at 3.5 hr (P less than 0.05) and 9 hr (P less than 0.05), serum amylase and lipase levels at 3.5 hr (P less than 0.05) and 12 hr (P less than 0.05), and lipid peroxide levels at 3.5 hr (P less than 0.05), 6 hr (P less than 0.05) and 12 hr (P less than 0.05). These results indicate that a novel free radical scavenger, CV-3611, has a strong therapeutic effect during the development of acute pancreatitis and suggest that oxygen-derived free radicals play an important role in the pathogenesis of acute pancreatitis.

The role of free radicals in the development of cerulein-induced pancreatitis was evaluated by measuring the activity of the endogenous scavengers, superoxide dismutase (SOD), catalase (CAT) and gluta

Metallothioneins are a family of intracellular metalloproteins that have been thought to be involved in anticancer drug resistance. However, the role of metallothioneins in pancreatic cancer has not been investigated in detail. The immunohistochemical localization of metallothionein was examined in normal human adult pancreas tissue and in 75 pancreatic duct cell carcinomas, using monoclonal anti-metallothionein antibody. Furthermore, in vitro studies on the sensitivity of pancreatic cancer to cisplatin were performed in 10 cases of pancreatic carcinoma. Metallothionein staining was weakly positive in the acinar and islet cells and intralobular ducts but was negative in the large pancreatic ducts. In pancreatic carcinomas, metallothionein staining was diffusely positive in 6 (8%), focally positive in 25 (33%) and negative in 44 (59%) of the 75 pancreatic carcinomas. The expression of metallothioneins in pancreatic tumors was related to metastasis, poor prognosis and poor histological grading (poorer glandular differentiation and nuclear anaplasia). The in vitro study of tumor sensitivity to cisplatin showed no significant correlation between metallothionein expression and resistance to cisplatin. Metallothionein-positive pancreatic carcinoma will be potentially highly malignant or acquire an enhanced ability to produce metallothioneins as the malignant potential increases. The expression of metallothionein could be a prognostic indicator in pancreatic carcinomas.

The prognosis for carcinoma of the pancreas is extremely poor. One of the characteristics of this tumor is its invasion of the surrounding tissues. Reduction of glycoprotein is considered to be conducive to invasion of the basement membrane by carcinoma cells. Heparan sulfate proteoglycan (HSPG), a kind of glycoprotein, is an important component of basement membrane. In this study, the relation between HSPG and carcinoma of the pancreas was examined by using the immunohistochemical method, and the survival rate of pancreatic adenocarcinoma was evaluated. We found that some carcinomas contained little or no HSPG. The poorer the differentiation of an adenocarcinoma of the pancreas, the lower was its content of HSPG. The level of HSPG was significantly different in carcinomatous and in noncarcinomatous cells. There was a close correlation among the content of HSPG, the degree of differentiation of carcinomas of the pancreas, and the survival time. HSPG seems to be useful in prognosis of adenocarcinoma of the pancreas.

Platelet activating factor (PAF) was administered to anesthetized rabbits with cerulein-induced acute pancreatitis to investigate the role of PAF in the development of acute pancreatitis. In acute edematous pancreatitis, induced with cerulein 20 micrograms/kg/h i.v. for 5 h, blood flow in the gastroduodenal and superior mesenteric arteries (GDAF and SMAF) had decreased significantly by 30 min and the serum amylase and lipase levels were significantly increased in the early phase. In the cerulein+PAF group, in which PAF was injected 100 ng/kg/min i.v. for 20 min simultaneously with cerulein, GDAF and SMAF declined significantly to 52 +/- 4 and 47 +/- 3% (p0.05), serum amylase and lipase levels rose significantly to 1,110 +/- 150 and 1,370 +/- 190% (p0.01) at 300 min, much higher than in the cerulein group. Furthermore, scattered hemorrhages and more marked inflammatory cell infiltration were observed histologically. These findings suggest that PAF has an additive role in the aggravation of acute pancreatitis.

Ischemia has been considered to play a role in the development of acute pancreatitis. The aim of this study was to investigate the effect of ischemia, caused by hemorrhagic shock, on cerulein-induced acute pancreatitis in rats. Acute pancreatitis was induced by the intravenous infusion of a supramaximally stimulating dose of cerulein (10 micrograms/kg/hr) for 6 hr. Hemorrhagic shock was induced by the removal of blood until the mean arterial blood pressure reached 35 mm Hg. This level was maintained for 30 min, after which time all the blood was reinfused. Hemorrhagic shock alone induced no morphological change in the pancreas. However, after the induction of hemorrhagic shock in animals treated with cerulein, hemorrhage and parenchymal necrosis were frequently observed in the pancreas. Seven of 20 rats (35%) receiving cerulein plus hemorrhagic shock had died by 48 hr after the start of cerulein infusion, whereas none of the rats in the cerulein or shock group died during this experiment. Cathepsin B activity in the pancreas of the cerulein plus shock group was significantly higher than in the other groups at 48 hr. These results suggest that ischemia may be a contributing factor in the pathogenesis of acute pancreatitis.

Functional changes of the exocrine pancreas in cerulein-induced pancreatitis were evaluated with the isolated perfused rat pancreas. In control specimens (n = 7), baseline pancreatic juice volume was 0.23 +/- 0.06 microliter/min and after stimulation with CCK-8 (10(-10) M) and secretin (10(-10) M), it was 2.26 +/- 0.45 microliter/min, and in cerulein-induced pancreatitis specimens (n = 8), the corresponding values were 0.11 +/- 0.03 and 0.23 +/- 0.08 microliter/min. The amylase content in the pancreatic juice (IU/min) was 0.73 +/- 0.15 (baseline) and 7.03 +/- 1.66 (stimulated) in the control specimens, and 0.012 +/- 0.002 (baseline) 0.018 +/- 0.004 (stimulated), in the cerulein-induced pancreatitis specimens. Amylase and lipase concentrations in the portal effluents were significantly higher in the cerulein-induced pancreatitis (481.3 +/- 79.4 IU/ml, 283.7 +/- 47.2 BALB U/ml) than in the control specimens (10.7 +/- 1.8 IU/ml, 8.9 +/- 2.9 BALB U/ml). Using the electron microscope fusion of large vacuoles with lateral plasma membrane was observed in cerulein-induced pancreatitis. In cerulein-induced pancreatitis, normal secretion was markedly decreased, and the lateral secretion was suggested to result in the elevation of pancreatic enzyme levels in portal effluents.

In this experiment, free radicals in the pancreas of endotoxemia and ethionine induced acute pancreatitis in mice were attempted to be detected directly by ESR spectroscopy, using 77 K freeze-trapping and 25 degrees C DMPO spin trapping techniques. In the 77 K freeze-trapping method, Mn (II) ion and R-00. radical were detected in endotoxemia and ethionine induced pancreatic lesions. The heme-NO radical was observed at 6 and 24 h after isolation of the normal pancreas, and signal intensity was increased with time. This finding supports that ESR spectroscopy is a useful method for detecting the tissue degeneration process from ischemia to necrosis. Using the DMPO spin trapping technique (25 degrees C), 6-line was detected at 6 h after intraperitoneal administration of E. coli in the model of endotoxemia, and 3- and 6-lines and a signal suggestive of DMPO-OH adduct were noted at 12 and 24 h in ethionine pancreatitis. These findings suggest that impaired pancreatic tissues exist in a considerably oxidative environment and oxygen derived free radicals may be considered to play an important role in the development of pancreatic lesions.