Objectives: Clinically relevant postoperative pancreatic fistula (POPF) after pancreatoduodenectomy is often accompanied by bacterial infection. To elucidate the mechanism of bacterial infection associated with POPF, we investigated the relationship between POPF and bacteria isolated from ascitic fluid and removed drains.Methods: Subjects were 101 patients who had undergone pancreatoduodenectomy. Microbial culture was performed using ascitic fluid obtained from drains. We also compared the isolated bacteria from removed drains on postoperative day (POD) 4 and after POD 7.Results: In 23 patients (22.8%), microbial cultures were already positive on POD 1, although purulent discharge was not observed. Among patients with grade B/C POPF, bacteria were detected on POD 1 in 53.8%; these isolated bacteria were the same as those isolated after POPF formation. In contrast, only 7.7% of patients with grade A POPF were positive on POD 1. The number of bacteria isolated from drains removed after POD 7 significantly increased compared with those isolated from drains removed on POD 4.Conclusions: Bacterial contamination in ascitic fluid may be an initiating event that leads to the development of clinically relevant POPF. Therefore, it is important to perform both the administration of the appropriate antibiotics and early drain removal.

BACKGROUND/AIMS Since there is a difference in the slice thickness between preoperative images of liver metastases (1-3mm slices) and surgical liver pathology specimens (5mm slices), micrometastases may not be detected in these specimens. In addition, the accuracy of preoperative imaging for the detection of metastases degenerated by chemotherapy is unclear. METHODOLOGY Five patients with liver metastases from colorectal cancer who had received adjuvant chemotherapy and undergone hepatectomy were included. The whole resected liver was sliced at approximately 1mm intervals and the slices were examined carefully for gross lesions. The preoperative CT and EOB-MRI findings of each lesion were compared with gross and histopathological findings. RESULTS The accuracy of EOB-MRI was higher than that of CT for the detection of liver metastases. The number of lesions detected on EOB-MRI was in agreement with that of histopathologically proven liver metastases in 4 of the 5 patients. All lesions that were grossly identified but turned out to be non-neoplastic were regenerative nodules associated with drug-induced liver injury or lobular nodules associated with marked fatty change, measuring about 1mm in diameter. CONCLUSIONS EOB-MRI was the most accurate method for the preoperative detection of liver metastases, enabling the visualization of almost all liver metastases.

In addition to the use of chemotherapeutic agents for the prevention of multiple liver metastases from colorectal cancer, the anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, is often used, and its effectiveness has been established. By contrast, it has been reported that the use of bevacizumab prior to or following surgery delays wound healing or liver regeneration. In this study, we investigated whether the administration of bevacizumab following hepatectomy inhibits remnant liver regeneration or the growth of remnant metastases. Mice were partially hepatectomized (31% of the liver was removed), transplanted with the murine colorectal cancer cell line, CT26, in the remnant lobe, and intraperitoneally injected with bevacizumab (4 mg/kg) for a total of 6 times. Serum VEGF levels were measured on day 1 following surgery, and each lobe of the liver was weighed on day 14. Serum VEGF levels in non-hepatectomized, tumor-bearing mice exceeded those in their non-tumor-bearing counterparts; however, the administration of bevacizumab did not reduce the serum VEGF levels. The volume of the liver lobe of the hepatectomized, CT26-transplanted and non-CT26-transplanted mice was 1,349.6 and 735.5 mg, respectively, indicating rapid growth of the CT26 transplant (p=0.023). The volume of the CT26-transplanted lobe of the bevacizumab-administered mice was 1,379.0 mg, which was not significantly different from that (1,349.6 mg) of the non-bevacizumab-administered mice. The volume of the remnant lobe of the bevacizumab-administered mice was 1,051.0 mg, which did not significantly differ from that (957.3 mg) of the non-bevacizumab-administered mice. The administration of bevacizumab following hepatectomy did not delay remnant liver regeneration, and did not suppress the growth of metastases in the remnant lobes or remnant liver regeneration.

We previously reported that the administration of bevacizumab for pancreatic neuroendocrine tumors inhibited angiogenesis in the host, resulting in tumor growth inhibition. In light of these results, we compared the effect of bevacizumab/gemcitabine/S-1 combination therapy vs. bevacizumab monotherapy. The QGP-1 pancreatic neuroendocrine carcinoma cell line and the BxPC-3 ductal cell carcinoma cell line were transplanted into the subcutaneous tissue of mice, and the mice were treated for 3 weeks with bevacizumab [50 mg/kg intraperitoneally (i.p.) twice weekly], gemcitabine (240 mg/kg i.p. once weekly) and S-1 (10 mg/kg orally five times weekly). The antitumor effect and side effects were evaluated by measuring the tumor volume and weight and by changes in body weight, respectively. The tumor volume became smaller (from the maximum volume) in the group treated with bevacizumab, gemcitabine and S-1 (BGS) and the group treated with bevacizumab and gemcitabine (BG). A significant difference was noted in the tumor weight between the BG group and the group treated with bevacizumab alone. A relatively significant decrease in the body weight was observed in the BGS and BG groups. We conclude that gemcitabine is appropriate as a drug used in combination with bevacizumab for pancreatic neuroendocrine tumors.

Type IV-A choledochal cysts (CCs) are a congenital biliary anomaly which involve dilatation of the extrahepatic and intrahepatic bile ducts. We present the case of a 30-year-old woman with type IV-A CC, on whom three-dimensional computed tomography (3D CT) and virtual endoscopy were performed. 3D CT revealed partial dilatation in the posterior branch of the intrahepatic bile duct and a relative stricture between it and the extrahepatic bile duct. Virtual endoscopy showed that this stricture was membrane-like and separated from the surrounding blood vessels. Based on these image findings, complete cyst resection, bile duct plasty for the stricture, and hepaticojejunostomy were safely performed. To the best of our knowledge, there are no reports of imaging by virtual endoscopy of the biliary tract which show the surrounding blood vessels running along the bile duct.

In addition to the use of chemotherapeutic agents for the prevention of multiple liver metastases from colorectal cancer, the anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, is often used, and its effectiveness has been established. By contrast, it has been reported that the use of bevacizumab prior to or following surgery delays wound healing or liver regeneration. In this study, we investigated whether the administration of bevacizumab following hepatectomy inhibits remnant liver regeneration or the growth of remnant metastases. Mice were partially hepatectomized (31% of the liver was removed), transplanted with the murine colorectal cancer cell line, CT26, in the remnant lobe, and intraperitoneally injected with bevacizumab (4 mg/kg) for a total of 6 times. Serum VEGF levels were measured on day 1 following surgery, and each lobe of the liver was weighed on day 14. Serum VEGF levels in nonhepatectomized, tumor-bearing mice exceeded those in their non-tumor-bearing counterparts; however, the administration of bevacizumab did not reduce the serum VEGF levels. The volume of the liver lobe of the hepatectomized, CT26-transplanted and non-CT26-transplanted mice was 1,349.6 and 735.5 mg, respectively, indicating rapid growth of the CT26 transplant (p=0.023). The volume of the CT26-transplanted lobe of the bevacizumab-administered mice was 1,379.0 mg, which was not significantly different from that (1,349.6 mg) of the nonbevacizumab-administered mice. The volume of the remnant lobe of the bevacizumab-administered mice was 1,051.0 mg, which did not significantly differ from that (957.3 mg) of the non-bevacizumab-administered mice. The administration of bevacizumab following hepatectomy did not delay remnant liver regeneration, and did not suppress the growth of metastases in the remnant lobes or remnant liver regeneration. Introduction Over the years, advances in surgical resection procedures, chemotherapeutic agents and molecular-targeted drugs have led to an increase in the number of patients undergoing hepatectomy following neoadjuvant chemotherapy (NAC) for multiple liver metastases from colorectal cancer. No recurrence is generally observed in the remnant liver following complete surgical tumor resection. However, recurrence occurs in the remnant liver in a number of patients, indicating incomplete cancer resection or the persistence of micrometastases not visualized by imaging studies (1). Furthermore, if the future remnant liver volume and hepatic functional reserve are insufficient for the resection of multiple liver metastases, two-stage hepatectomy for initially unresectable multiple colorectal hepatic metastases is occasionally performed, in which case the cancer is knowingly left behind (2). Such patients at high risk of remnant liver recurrence need to undergo chemotherapeutic therapy as adjuvant chemotherapy (AC) and molecular-targeted therapy in the early post-operative period, as the levels of tumor growth factors, such as the vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF), are higher in the liver tissue of patients with colorectal liver metastases than in that of healthy controls, and become even higher following hepatectomy, due to liver regeneration (3,4). It is well-known that when chemotherapy or molecular-targeted therapy is withheld following hepatectomy, the residual tumor enlarges (5). VEGF plays a central role in angiogenesis, and the VEGF-neutralizing antibody, bevacizumab, is one of the most useful drugs in suppressing tumor growth. However, VEGF has also been shown to increase the production of growth factors, such as HGF, and induce bone marrow cells, including vascular endothelial precursor cells, at sites of injury. This means that VEGF is involved not only in angiogenesis but also in liver cell regeneration following hepatectomy (6). In other words, there is concern that the administration of bevacizumab in the early period following hepatectomy may negatively affect the hypertrophy of the remnant liver and recovery of the liver function. The purpose of this study was to evaluate the effect of bevacizumab on the regeneration of the remnant liver following hepatectomy and to investigate whether bevacizumab exhibits an antitumor effect Administration of anti-vascular endothelial growth factor antibody following hepatectomy does not inhibit remnant liver regeneration or growth of remnant metastases KAZUHIKO KASUYA1, MINAKO SUZUKI1, YUICHI NAGAKAWA1, YOSHIAKI SUZUKI1, SATORU KIKUCHI1, BUNSO KYO1, TAKAAKI MATSUDO1, TAKAO ITOI2, AKIHIKO TSUCHIDA1 and TATSUYA AOKI1 Departments of 1Digestive Surgery and 2Internal Medicine, Tokyo Medical University, Tokyo, Japan Received September 28, 2011; Accepted December 2, 2011 DOI: 10.3892/etm.2011.409 Correspondence to: Dr Kazuhiko Kasuya, Department of Digestive Surgery, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjukuku, Tokyo 167-0023, Japan E-mail: kasuya-k@jcom.home.ne.jp

BACKGROUND/AIMS:Single nucleotide polymorphism (SNP) of the genes for ATP-binding cassette transporters is related to the side effects of anticancer drugs and that of drug metabolism-related enzyme genes is involved in the activation of gemcitabine (GEM).METHODOLOGY:Forty eight patients treated with adjuvant GEM chemotherapy after pancreatic cancer resection was examined for the SNP of multidrug-resistance 1 (MDR1) 2677, MDR1 3435, breast cancer resistance protein (BCRP) 421, ribonucleotide reductase M1 (RRM1)(-)524, RRM1(-)37 and deoxycytidine deaminase (CDA) 208. We divided the patients according to normal group: patients homozygous for a wild-type allele or heterozygous for a mutant allele and mutant group: those homozygous for a mutant allele. Both groups were compared regarding the outcome and the occurrence and severity of side effects.RESULTS:MDR1 2677, MDR1 3435, BCRP421, RRM1(-) 524, RRM1(-) 37 and CDA mutant groups comprised 37.5, 31.3, 0, 12.5, 4.2 and 4.2%, respectively. The occurrence of >G3 side effects was the most frequent in the MDR1 2677 mutant group at 39%. The disease-free survival and overall survival tended to be longer in the MDR1 2677 mutant group.CONCLUSIONS:A correlation between the SNP of MDR1 2677 and drug response in patients receiving GEM chemotherapy.

BACKGROUND/AIMS:Pancreaticobiliary maljunction (PBM) is a high risk factor in biliary tract cancer. The relation of CD44s and CD44v6 expression in biliary epithelium with PBM and the carcinogenetic process was immunohistochemically examined.METHODOLOGY:One hundred and seven lesions were randomly selected from gallbladders and bile ducts, which were resected from 25 patients with PBM, and immunostaining for CD44s, CD44v6 and MIB-1 was carried out.RESULTS:Among gallbladder lesions, cancerous lesions (dysplasia, cancer) had a higher immunoreactivity with statistical significance for CD44s and CD44v6 compared to non-cancerous lesions (normal, hyperplasia). In bile ducts as well, cancerous lesions had a higher immunoreactivity for CD44s and CD44v6. In both gallbladders and bile ducts, positive cases of CD44s and CD44v6 had a higher statistical significance of Ki-67 labeling index in comparison with negative cases.CONCLUSIONS:In biliary epithelium with PBM, CD44 was indicated to be strongly related to cancer progression via an increase of cellular proliferative potential.

We describe the surgical method of cases showing a distended gallbladder. Because the most important thing does not cause biliary tract injury, it is to find orientation carefully. The frequency of incidental gallbladder cancer was in 7 (0.7%) of the 983. Only cholecystectomy is necessary to be performed for Tis or T1 cancer, and surgery has to be changed to radical surgery for T2 cancer or deeper invasion. Laparoscopic cholecystectomy is already an established standard operation. In the presence of acute or severe chronic inflammation, special attention should be paid to these points.

The mitochondrial permeability transition (mPT) is considered to be a major cause of cell death under a variety of pathophysiological conditions of the central nervous system (CNS) and other organs. Pharmacological inhibition or genetic knockout of the matrix protein cyclophilin D (CypD) prevents mPT and cell degeneration in several models of brain injury. If these findings in animal models are translatable to human disease, pharmacological inhibition of mPT offers a promising therapeutic target. The objective of this study was to validate the presence of a CypD-sensitive mPT in adult human brain and liver mitochondria. In order to perform functional characterization of human mitochondria, fresh tissue samples were obtained during hemorrhage or tumor surgery and mitochondria were rapidly isolated. Mitochondrial calcium retention capacity, a quantitative assay for mPT, was significantly increased by the CypD inhibitor cyclosporin A in both human brain and liver mitochondria, whereas thiol-reactive compounds and oxidants sensitized mitochondria to calcium-induced mPT. Brain mitochondria underwent swelling upon calcium overload, which was reversible upon calcium removal. To further explore mPT of human mitochondria, liver mitochondria were demonstrated to exhibit several classical features of the mPT phenomenon, such as calcium-induced loss of membrane potential and respiratory coupling, as well as release of the pro-apoptotic protein cytochrome c. We concluded that adult viable human brain and liver mitochondria possess an active CypD-sensitive mPT. Our findings support the rationale of CypD and mPT inhibition as pharmacological targets in acute and chronic neurodegeneration.

BACKGROUND/AIMS:Pancreaticobiliary maljunction (PBM) is a high risk factor of biliary tract cancer. The chemopreventive effects of Vitamin K2 (menaquinone-4: MK4) in a hamster PBM model were investigated.METHODOLOGY:The extrahepatic bile duct at the distal end of the common duct was ligated and cholecystoduodenostomy was performed (Group I). The same surgery was performed and from 4 weeks after surgery, 10 mg/kg of N-nitrosobis (2-oxopropyl) amine was subcutaneously injected once a week with a one-week interval (Group II). In addition of Group II, MK4 was orally administered once a day, five times with every week (Group III). The hamsters were sacrificed 20 weeks after surgery and histopathological findings of gallbladder were investigated.RESULTS:Group I showed predominantly proper epithelium without cancer. In Group II, atypical epithelium (AE) was observed in 75% of animals and early cancer was observed in 25%. Group III showed less AE and no cancer. The PCNA labeling index in Group III was statistically significantly lower than in Group II. In addition, no statistically significant differences were noted among the groups in terms of the apoptosis labeling index.CONCLUSIONS:MK4 suppressed biliary carcinogenesis by the induction of cell cycle arrest in a hamster biliary carcinogenetic model.

MicroRNAs (miRNAs) belong to a class of the endogenously expressed non‐coding small RNAs which primarily function as gene regulators. Growing evidence suggests that miRNAs have a significant role in tumor development and may constitute robust biomarkers for cancer diagnosis and prognosis. The miR‐17‐92 cluster especially is markedly overexpressed in several cancers, and is associated with the cancer development and progression. In this study, we have demonstrated that miR‐92a is highly expressed in hepatocellular carcinoma (HCC). In addition, the proliferation of HCC‐derived cell lines was enhanced by miR‐92a and inhibited by the anti‐miR‐92a antagomir. On the other hand, we have found that the relative amount of miR‐92a in the plasmas from HCC patients is decreased compared with that from the healthy donors. Interestingly, the amount of miR‐92a was elevated after surgical treatment. Thus, although the physiological significance of the decrease of miR‐92a in plasma is still unknown, deregulation of miR‐92 expression in cells and plasma should be implicated in the development of HCC.

S-1 is a key drug for advanced, recurrent gastric cancer. It is difficult to administer S-1 for inoperable gastric cancer with stenosis. We report that a simple suspension method allows administration of S-1 for improved quality of life. The patient was a 65-year-old woman. She consulted a doctor regarding her poor food intake, and had a medical examination with chest-abdominal CT and gastrofiberscopy. She was diagnosed as type 4 gastric cancer with esophageal invasion. It was difficult for her to drink a cup of water due to the stenosis, but we could insert a 6 Fr-Elemental Diet (ED) tube into her stomach. S-1 was dissolved by the simple suspension method. She received combination chemotherapy of S-1 100mg/body (day 1-21) and CDDP 80 mg/body (day 8). After two courses, her intake was much improved; she was able to eat rice porridge and was discharged with improved quality of life. S-1 suspension with ED tube was effective for advanced gastric cancer with stenosis.

症例は72歳の女性で, 心窩部不快感のため近医にて上部消化管内視鏡検査を施行した. 十二指腸第4部に隆起性病変を認めたため当院を紹介された. 画像検査所見で遠隔転移やリンパ節腫大などは認めなかった. 腫瘍マーカーは正常だった. 生検結果はadenoma with moderate tosevere atypiaであったが, 長径40mmと大きく腺腫内癌を否定しえず, 手術を施行した. 術中リンパ節を迅速病理組織学的診断に提出して転移のないことを確認し十二指腸部分切除術を施行した. 病理組織学的診断は40×30mm, very well differentiated adenocarcinoma, T1 N0 M0stage Iであった. 原発性十二指腸第4部早期癌の報告は極めてまれであり, 文献的考察を加え報告した.

Introduction: Transnasal endoscopy, which allows upper gastrointestinal examination has been used since 1993. Currently, an ultrathin endoscope with a tip diameter of 4.9 mm is available in Japan. To date, 1700 people have been examined using it in our hospital, with a successful insertion rate of 98.8%. Percutaneous endoscopic gastrostomy (PEG) plays an important role in the management of long-term eating difficulties, but it was conventionally difficult to perform PEG in patients with trismus or gastrointestinal stenosis. This report describes our transnasal PEG (TN-PEG) procedure in such patients. Aims and Methods: The aim of this study is clarify the safety of TN-PEG using the above technique. 30 patients with and 45 patients without trismus or gastrointestinal stenosis (associated with hypopharyngeal, esophagel, gastric cardiac cancer) undergone this procedure were evaluated, and the two groups were compared for intraoperative oxygen saturation, blood pressure, heart rate, surgery time, and abdominal wall infection and aspiration pneumonia. Before insertion of the transnasal endoscope, patients were given a mixture of lidocaine hydrochloride and epinephrine as a nasal spray and naphazoline nitrate as a nasal drop to constrict the nasal turbinate mucosa and dilate the nasal cavity. In all patients, the stomach was fixed to the abdominal wall using a fixation device, followed by abdominal wall puncture and the placement of a 15 Fr gastrostomy tube by introducer method. Results: 1) TN- PEG was feasible in all patients of the two groups. 2) After surgery, all patients were able to receive tube feeding and no patient experienced intra- or post-operative bleeding. 3) Both groups included some patients who had respiratory tract infection with MRSA before surgery (19 patients in total), but none of them developed postoperative abdominal wall infection or aspiration pneumonia.4) Oxygen saturation: ore-ope 98.4 ± 1.1 vs 98.3 ± 1.5%, intra-ope 96.9 ± 1.0 vs 96.8 ± 2.1%.5) Blood pressure: ore-ope 94.7 ± 17.7 vs 108.6 ± 26.6 mm Hg, intra-ope 96.6 ± 17.4 vs 110.9 ± 21.4 mm Hg.6) Heart rate: ore-ope 79.6 ± 17.4 vs 75.1 ± 11.5 /min, intra-ope 83.7 ± 19.2 vs 79.9 ± 14.7 /min.7) Surgery time was 14.3 ± 2.3 vs 13 ± 2.1 minutes (N.S.). Conclusion: The use of an ultrathin transnasal endoscope enabled PEG, which used to be difficult in patients with trismus or gastrointestinal stenosis. Even patients with preexisting MRSA infection of the respiratory tract were free of postoperative wound infection. In addition, intraoperative vital signs did not change compaired with preoperative status in both group, thus these results suggest that TN-PEG is extremely safe procedure.

症例は33歳の男性で, 平成17年10月下旬に下腹部痛, 嘔吐が出現した. 翌日, 症状が増悪したため, 当院受診し緊急入院となった. 腹部単純X線検査で骨盤腔内に石灰化像を認めた. 腹部CTでは骨盤腔内に小腸の腸間膜対側に接する嚢胞様の腫瘤があり, 内部に石灰化を伴っていた. 石灰化を伴ったメッケル憩室炎を疑い, 99mTcシンチグラフィーを行うも99mTcの集積は認めなかった. 入院翌日に反跳痛を認めたため, 緊急手術を行った. 腸石を伴ったメッケル憩室炎であったため, 憩室切除術を行った. 結石分析ではシュウ酸カルシウム結石であった. 腸石は真性腸石と仮性腸石に分類されるが, 臨床で経験されるのはほとんどが仮性腸石である. 今回, 極めてまれな真性腸石を伴ったメッケル憩室炎の症例を経験したので文献的考察を加え報告する.