加藤 宏之

巨大肝細胞癌は近年増加傾向にあり、外科的切除の役割について検討した。1990年1月から2013年12月までの初発肝細胞癌切除例302例を対象とし、腫瘍径10cm以上の巨大肝癌39例と非巨大肝癌263例を比較検討した。巨大肝癌では有意にnon-B non-C症例が多く、近年その傾向が強かった。多変量解析の結果、全症例の検討では腫瘍径10cm以上は独立した予後因子であったが、近年では予後因子とならず、巨大肝癌であっても積極的な治療により予後の改善が見込まれた。(著者抄録)

BACKGROUND & AIMS: Organ shortage has led to the use of steatotic livers in transplantation, despite their elevated susceptibility to ischemia/reperfusion injury (IRI). Matrix metalloproteinase-9 (MMP-9), an inducible gelatinase, is emerging as a central mediator of leukocyte traffic into inflamed tissues. However, its role in steatotic hepatic IRI has yet to be demonstrated. METHODS: We examined the function of MMP-9 in mice fed with a high-fat diet (HFD), which developed approximately 50% hepatic steatosis, predominantly macrovesicular, prior to partial hepatic IRI. RESULTS: The inability of MMP-9(-/-) deficient steatotic mice to express MMP-9 significantly protected these mice from liver IRI. Compared to fatty controls, MMP-9(-/-) steatotic livers showed significantly reduced leukocyte infiltration, proinflammatory cytokine expression, and liver necrosis. Loss of MMP-9 activity preserved platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, a modulator of vascular integrity at the endothelial cell-cell junctions in steatotic livers after IRI. Using in vitro approaches, we show that targeted inhibition of MMP-9 sheltered the extracellular portion of PECAM-1 from proteolytic processing, and disrupted leukocyte migration across this junctional molecule. Moreover, the evaluation of distinct parameters of regeneration, proliferating cell nuclear antigen (PCNA) and histone H3 phosphorylation (pH3), provided evidence that hepatocyte progression into S phase and mitosis was notably enhanced in MMP-9(-/-) steatotic livers after IRI. CONCLUSIONS: MMP-9 activity disrupts vascular integrity at least partially through a PECAM-1 dependent mechanism and interferes with regeneration of steatotic livers after IRI. Our novel findings establish MMP-9 as an important mediator of steatotic liver IRI.

Cyclooxygenase-2 (COX-2) is a mediator of hepatic ischemia and reperfusion injury (IRI). While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2-M/-M) to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2-M/-M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2-M/-M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2-M/-M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2-M/-M and WT mice. COX-2-M/-M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9) expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2-M/-M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s) other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype.

BACKGROUND: Optimal treatment types and prognosis for patients with borderline resectable pancreatic cancer (BRPC) remain unclear because of the lack of studies involving large series of patients. METHODS: We retrospectively analyzed various prognostic factors for 624 BRPC (pancreatic head/body) patients treated from June 2002 to May 2007, by distributing questionnaires to member institutions of the Japanese Society of Pancreatic Surgery in 2010. BRPC was defined according to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (2009). RESULTS: Among 624 patients, 539 (86.4 %) underwent curative-intent resection, showing an R0 resection rate of 65.9 %. The 3- and 5-year survival rates were 16.1 and 9.9 % in all patients, 22.8 and 12.5 % in the resected patients, and 4.4 and 0 % (P < 0.0001) in the unresected patients, respectively. The following factors influencing survival in all patients were selected as independent prognostic factors using multivariate analysis: major arterial involvement on imaging study; preoperative treatment; surgical resection; and postoperative chemotherapy. Among the resected cases, multivariate analysis revealed that major arterial involvement and remnant tumor status were independent prognostic factors. CONCLUSION: BRPC included two distinct categories of tumors influencing survival: those with portal vein/superior mesenteric vein invasion alone and those with major arterial invasion, which was the most exacerbating factor in the analysis.

PURPOSE: We propose a morphological classification of intraductal papillary neoplasm of the bile duct (IPN-B). METHODS: A retrospective analysis of 16 patients with IPN-B who had undergone surgical resection was conducted. These 16 cases were classified into three types based on the primary lesion's anatomical location: branch duct type (6 cases), main duct type (5 cases) and mixed type (5 cases). In this paper we have analyzed the characteristics of IPN-B according to our new classification. RESULTS: All branch duct type IPN-B was located in the left lobe and 5 of them were resected by left hepatectomy without extrahepatic bile duct resection (EBDR). On the other hand, all patients with main duct and mixed type IPN-B underwent EBDR in addition to hepatectomy or pancreatoduodenectomy. Microscopically, 2 of 6 patients with branch duct type IPN-B had no malignant component and, in the remaining 4 patients, cancer invasion was restricted to within the ductal wall. There were no cases of branch duct type IPN-B with lymph node metastasis and superficial intraductal tumor spread. In contrast, all patients with main duct and mixed duct type IPN-B had the malignant component. In all cases, lymph node metastasis was not observed, but superficial intraductal tumor spread was frequently found in extrahepatic bile duct lesions: 3 of main duct type and 3 of mixed type. Four patients with superficial intraductal spread had non-curative resection due to a cancer-positive ductal margin. Most patients with IPN-B obtained a good prognosis, but two patients with a cancer-positive ductal margin developed local recurrence. CONCLUSIONS: Our classification vividly reflects clinical and pathological characteristics of IPN-B and is useful to determine appropriate surgical strategy.

BACKGROUND/PURPOSE: Wound infection; that is, incisional surgical site infection (ISSI), is a common complication after biliary tract surgery. The aim of the present study was to identify the various risk factors for wound infection and to establish a formula to predict the development and severity of wound infections. METHODS: We analyzed the clinical data on 207 consecutive patients who underwent biliary surgery for benign diseases at our hospital. We identified the factors with the greatest influence on wound infection after biliary tract surgery, based on a statistical procedure. An original scoring system (ISSI predictive score) was proposed based on these risk factors. RESULTS: The incidence of postoperative wound infection was 9.7% (20/207). The patient's performance status; bile culture; perioperative fasting period (days); and intraoperative bile spillage were the most influential risk factors for wound infection. The incidences of wound infection in patients with ISSI predictive scores of >2.7 points and those with scores of 0-2.7 points were 75.0% (12/16) and 4.2% (8/191), respectively. Our score also correlated significantly with the severity of wound infection (r = 0.488, P < 0.001) and the length of the postoperative hospital stay (R = 0.508, P < 0.001). CONCLUSION: Our original scoring system makes it possible to predict not only the development of a wound infection and its severity after biliary tract surgery, but also the length of the postoperative hospital stay.

患者は78歳の女性で,発熱と下血を主訴に受診した.入院時現症は,体温38.5℃,腹部は平坦軟で腫瘤を触知せず,体表リンパ節に腫脹を認めなかった.直腸診にて肛門より4cmの直腸壁に不整な隆起性病変を触知し,著明な血便を認めた.検査所見では可溶性Interleukin2(IL-2)レセプターが1,910U/mlと上昇していた.CTにて直腸壁の肥厚を認め,下部消化管内視鏡で,肛門より約4cmの部位に3/4周性の2型隆起性病変を認めた.術前組織生検では悪性腫瘍と診断したが確定診断には至らなかった.腹会陰式直腸切断術を行った.免疫染色にてCD3陽性,CD56陰性,EBER陽性,TIA-1陽性であり,他領域に病変を認めないことから,直腸原発節外性NK/T細胞リンパ腫,鼻型と診断した.術後に他院に転院して化学療法を施行したが,術後約11ヵ月目にDICを発症し死亡した.(著者抄録)

Previous clinical study has demonstrated that 30-40% of patients undergoing pancreaticoduodenectomy (PD) developed hepatic steatosis. However, nonalcoholic steatohepatitis (NASH) is a little-known complication after PD. Recently we encountered two patients with PD who later developed NASH diagnosed by liver biopsy. Case 1 was a 79-year-old woman who underwent PD for intraductal papillary mucinous neoplasm (IPMN). She had postoperative severe diarrhea due to pseudomembranous enterocolitis. Severe liver dysfunction was observed on the 31st postoperative day. Abdominal computed tomography (CT) on the 32nd day showed remarkably decreased hepatic CT value of 6 HU. Immediate liver biopsy revealed NASH (Brunt criteria: grade 2, stage 2). Case 2 was a 71-year-old woman who underwent PD for IPMN. Liver biopsy on 70th postoperative day, which was performed for assessment of moderate liver dysfunction and decreased hepatic CT value of 44 HU, demonstrated simple steatosis. In the 21st postoperative month, she developed severe urinary tract infection together with marked liver dysfunction. Immediate liver biopsy revealed NASH (Brunt criteria: grade 1, stage 1). For each patient, treatment of infection and high-dose pancreatic enzyme supplements improved liver dysfunction and liver steatosis. Clinical features of our cases seem to support the current leading hypothesis of the pathogenesis of NASH, i.e., the two-hit theory.

IPMNに対する膵頭十二指腸切除術(PD)後に非アルコール性脂肪肝炎(NASH)を発症した2例について検討した。症例1は79歳女性で、術後5日目より発熱、重度の下痢を認め、MRSAを検出した。偽膜性腸炎と診断し、バンコマイシンを投与した。術後31日目に肝機能異常、肝CT値の低下を認めたため、肝生検を行いNASHと診断した。症例2は71歳女性で、術後67日目に肝機能異常を認め、肝生検よりsimple steatosisと診断した。術後21ヵ月に尿路感染症を発症し、肝機能異常、肝CT値の低下を認めたため、肝生検を行いNASHと診断した。2例とも膵酵素大量補充療法が奏効し、CT所見にて寛解を得た。2例はPD後の膵外分泌機能低下に伴うNonalcoholic fatty liver disease(NAFLD)からNASHへ移行したと考察した。なお、膵機能低下に伴うNASH、NAFLDの報告は極めて稀である。

PURPOSE: Dysfunction of the remnant liver after a hepatectomy is caused by microthrombus formation due to endothelial cell (EC) damage. This study evaluated the effect of prostaglandin I(2) (PGI(2)) on the expression of thrombomodulin (TM), a marker for the anticoagulant properties of ECs, using cultured human umbilical vein endothelial cells (HUVECs), and using a canine extensive hepatectomy model. METHODS: The presence of PGI(2) receptors was confirmed on HUVECs by reverse transcription-polymerase chain reaction, and the effect of the PGI(2) analog on TM expression on HUVECs was determined by an enzyme-linked immunosorbent assay. Twenty mongrel dogs were divided into four groups comprising a sham operation, 70% hepatectomy, 84% hepatectomy, and 84% hepatectomy, with the administration of the PGI(2) analog, respectively, and TM expression in the liver, spleen, pancreas, kidney, lung, portal vein, and intestine was determined immunohistochemically. RESULTS: The TM expression on HUVECs was upregulated by the PGI(2) analog. The TM expression on ECs in the hepatic sinusoids and splenic sinus were markedly decreased after the 84% hepatectomy, but such damage was markedly mitigated following an 84% hepatectomy with administration of the PGI(2) analog. CONCLUSIONS: An extensive hepatectomy induced severe EC damage not only in the hepatic sinusoids but in the splenic sinuses as well. Prostaglandin I(2) prevented damage to these ECs, suggesting that PGI(2) improves the microcirculation in the remnant liver.

AIM: To prevent pancreatic leakage after pancreaticojejunostomy, we designed a new standardized technique that we term the "Pair-Watch suturing technique". METHODS: Before anastomosis, we imagine the faces of a pair of watches on the jejunal hole and pancreatic duct. The first stitch was put between 9 o'clock of the pancreatic side and 3 o'clock of the jejunal side, and a total of 7 stitches were put on the posterior wall, followed by the 5 stitches on the anterior wall. Using this technique, twelve stitches can be sutured on the first layer anastomosis regardless of the caliber of the pancreatic duct. In all cases the amylase activity of the drain were measured. A postoperative pancreatic fistula was diagnosed using postoperative pancreatic fistula grading. RESULTS: From March 2007 to July 2008, 29 consecutive cases underwent pancreaticojejunostomy using this technique. Pathologic examination results showed pancreatic carcinoma (n = 14), intraductal papillary-mucinous neoplasm (n = 10), intraductal papillary-mucinous carcinoma (n = 1), carcinoma of ampulla of Vater (n=1), carcinoma of extrahepatic bile duct (n = 1), metastasis of renal cell carcinoma (n = 1), and duodenal carcinoma (n = 1). Pancreaticojejunal anastomoses using this technique were all watertight during the surgical procedure. The mean diameter of main pancreatic duct was 3.4 mm (range 2-7 mm). Three patients were recognized as having an amylase level greater than 3 times the serum amylase level, but all of them were diagnosed as grade A postoperative pancreatic fistula grading and required no treatment. None of the cases developed complications such as hemorrhage, abdominal abscess, and pulmonary infection. There was no postoperative mortality. CONCLUSION: Our technique is less complicated than other methods and very secure, providing reliable anastomosis for any size of pancreatic duct.

BACKGROUND: The main etiology of NAFLD and NASH after pancreatic resection is still unclear, and the therapeutic strategy has yet to be established. The focus of this review is how predict and prevent NAFLD/NASH after pancreaticoduodenectomy. METHODS: From April 2005 to October 2008, 54 patients who underwent pancreaticoduodenectomy in our institution were enrolled in this study. From the pre-, intra- and postoperative risk factors, we identified the most influential risk factors of postoperative NAFLD by uni- and multivariate analyses. Moreover, a postoperative NAFLD scoring system was proposed based on these risk factors. RESULTS: The incidence of postoperative NAFLD was 37.0% (20/54). Of these, 10% (2/20) of patients were diagnosed as having NASH by percutaneous liver biopsy. By multivariate analysis, pancreatic adenocarcinoma (p < 0.05), pancreatic resection line (p < 0.01) and postoperative diarrhea (p < 0.01) were identified as the most influential factors concerning postoperative NAFLD. Based on these results, we proposed a postoperative NAFLD scoring system (0-10) and evaluated the correlation between the score and decreasing rates of CT values, revealing a significant correlation (r = 0.829 p < 0.001). The prevalence of postoperative NAFLD in the patients with our scores of 0-3, 4-6 and 7-10 points was 0 (0/22), 35 (6/17) and 93% (14/15), respectively. CONCLUSIONS: In conclusion, NAFLD develops frequently in patients who undergo PD, and some patients even progress to NASH. A postoperative NAFLD scoring system makes it possible to predict the occurrence of NAFLD after PD, and aggressive nutrition support is needed for patients with high scores.

For the resection of advanced liver tumors in which the tumor thrombus extends into the intrathoracic inferior vena cava (IVC) above the diaphragm, surgeons need very skillful techniques and much experience. However, after detachment of the line of fusion of the pericardium to the diaphragm (LFPD), the intrathoracic IVC can be exposed easily. We herein present this novel surgical method, an approach to the intrathoracic IVC through the abdominal cavity. A 66 year-old man was referred to our hospital because of high-grade fever. Computed tomography revealed a large tumor of the left hepatic lobe with tumor thrombus extending into the intrathoracic IVC through the left hepatic vein. Laboratory data showed elevated levels of alpha-fetoprotein (AFP) (726 ng/ml) and protein induced by vitamin K absence (114 AU/ml). The patient was diagnosed with hepatocellular carcinoma (HCC) of the left hepatic lobe with tumor thrombus extending into the IVC. He underwent left hepatectomy with partial resection of the IVC and intravascular tumor thrombectomy under total hepatic vascular exclusion (THVE) without the use of cardiopulmonary bypass (CPB). Before THVE, we approached the IVC through the abdominal cavity with vertical dissection of the diaphragm after detachment of the LFPD without cutting the pericardium or performing median sternotomy. This procedure could be very beneficial and helpful for many liver surgeons.

The poor prognosis of patients with intrahepatic cholangiocarcinoma (ICC) or hilar cholangiocarcinoma is well known. Herein, we described the first reported case of severe locally advanced ICC in which radical surgery was successfully achieved based on the marked effect of neoadjuvant chemoradiation therapy (NCRT) using gemcitabine. A 54-year-old man was admitted to our institution with obstructive jaundice. Abdominal computed tomography (CT) showed a large low-density mass in the caudate lobe, extensively involving the inferior vena cava and main portal vein. Moreover, nodal involvements of the hepatoduodenal ligament were detected concurrently. We therefore regarded this tumor as a severe locally advanced ICC and attempted to initiate combined treatment with gemcitabine (800 mg/m(2) biweekly) and three-dimensional conformation radiation (45 Gy/25 days). After completion of NCRT, this patient underwent a left trisegmentectomy with combined resection of the portal vein and inferior vena cava. Postoperative microscopic findings surprisingly revealed that more than 90% of tumor cells had disappeared with extensive fibrosis, achieving tumor downstaging and tumor volume reduction which were related to the radical resection. In conclusion, ICC showed a favorable histological response to chemoradiation therapy using gemcitabine. Further studies are needed to conclusively assess the effect of NCRT on locally advanced ICC.

Although interferon (IFN) based therapy for recurrent hepatitis C virus (HCV) infection after liver transplantation has been widely accepted, it induces various adverse effects such as thrombocytopenia, resulting in its interruption. Recently, concomitant splenectomy at the time of living donor liver transplantation (LDLT) has been tried to overcome this problem, but this procedure leads to several complications such as excessive intraoperative bleeding and serious infection. A 60-year-old female received LDLT using a left lobe graft from her second son for liver failure caused by hepatitis C-related cirrhosis. Six months after LDLT, she was diagnosed as recurrent HCV infection by liver biopsy. IFN monotherapy was started from 7 mo after LDLT and her platelet count decreased to less than 50,000/microL, which thus made it necessary to discontinue the treatment. We decided to attempt laparoscopic splenectomy (LS) under general anesthesia. Since intra-abdominal findings did not show any adhesion formations around the spleen, LS could be successfully performed. After LS, since her platelet count immediately increased to 225,000/microL 14 d after operation, IFN therapy was restarted and we could convert the combination therapy of IFN and ribavirin, resulting in no detectable viral marker. In conclusion, LS can be performed safely even after LDLT, and LS after LDLT is a feasible and less invasive modality for thrombocytopenia caused by antiviral therapy.

症例は78歳の男性で,黄疸,白色便を主訴として当院受診.精査にて中下部胆管癌もしくは膵頭部癌と診断され亜全胃温存膵頭十二指腸切除+リンパ節郭清を施行.摘出標本では中下部胆管と膵頭部に2種の腫瘍を認め,病理組織学的検査では中下部胆管に印環細胞癌を認め膵臓に高度浸潤を認めた.また,膵頭部には高分化型管状腺癌を認め両腫瘍間に細胞移行像は認められないことから多発腫瘍による衝突癌と考えられた.患者はgemcitabineを用いた化学療法を施行中であり術後14ヵ月現在,無再発生存中である.膵衝突癌は術前画像診断で中下部胆管癌と膵頭部癌の両者の特徴を併せ持っており術中所見においてもその診断は困難であった.(著者抄録)