杉岡 篤

膵がんはがん遺残のない外科切除（R0切除）が唯一長期生存を得ることができる治療法であるが，その長期成績は十分とはいえない．しかし近年，術後補助化学療法の組み合わせにより徐々に成績が向上してきており，R0切除後に早期に補助療法に移行する戦略は膵がんの予後を向上させるとの方向性が示された．また近年，ロボット支援を含めた腹腔鏡下膵切除術の導入で，術後早期のQOLを向上させ，早期に補助療法を行う戦略も報告されている．一方，初診時に切除不能な膵がんに対してはadjuvant surgeryを念頭に治療を行うことが重要である．浸潤性膵管がんに対する外科治療の現状と展望について概説する．<br>

Main indications for liver transplantation in the pediatric population include biliary atresia and inherited metabolic diseases. The present study evaluated whether there are differences between pediatric patients undergoing living-related liver transplantation due to the two diseases in terms of their oxidative and immunological status Pduring their regular outpatient follow-up visits. A clinical outpatient study measuring serum oxidative stress index (calculated as serum oxidant/antioxidant ratio, in the form of serum total hydroperoxide/serum biological antioxidative potential), serum terminal complement component 5a, as an indicator of complement activity and immunological status, and transforming growth factor-β1, as a marker of liver fibrosis, in 16 patients (6 males and 10 females, 2.5-15 years old) who received living-related liver transplantation due to inherited metabolic diseases (n=6 in the form of propionic acidemia [n=1], methylmalonic acidemia [n=1], arginase deficiency [n=1], tyrosinemia [n=2], and glycogen storage disease type 1b [n=1], with an age range of 2.4-14.6 years old) and due to biliary atresia ([n=10], with an age range of 2.9-14.5 years old). Serum oxidative stress index, complement component-5a, and transforming growth factor-β1 were significantly higher in the inherited metabolic diseases group than in the biliary atresia group. In all patients, serum oxidative stress index correlated positively with complement component-5a and transforming growth factor-β1. Patients who receive living-related liver transplantation due to inherited metabolic diseases are prone to higher oxidative stress, complement activity, and serum transforming growth factor-β1.

Here we examined whether the expression of a novel immunoregulatory gene set could be used to predict outcomes in murine models of rapamycin-induced cardiac tolerance, spontaneous hepatic tolerance, and cardiac rejection. The expression of the immunoregulatory gene set was assessed with the GeXP multiplex reverse-transcription polymerase chain reaction (RT-PCR) analysis system, and it was correlated to the pathological and biochemical parameters of the allografts. In rejecting cardiac grafts, the increased expression of an inflammatory set of genes, which included CD45, CD4, CD25, suppressor of cytokine signaling 2, cytotoxic T lymphocyteassociated protein 4 (CTLA4), selectin lymphocyte, interferon-? (IFN-?), programmed cell death 1 (Pdcd1), and granzyme B (Gzmb), was seen 8 days after transplantation along with histological evidence of severe allograft rejection. In tolerant cardiac allografts, the expression of fibrinogen-like protein 2 (Fgl2), Pdcd1, killer cell lectin-like receptor G1 (Klrg1), CTLA4, and lymphocyte-activation gene 3 was associated with tolerance. In a model of liver allograft tolerance, the increased expression of lectin galactose-binding soluble 1, Fgl2, CD39, phosphodiesterase 3B, Klrg1, forkhead box P3 (Foxp3), and transforming growth factor beta as well as the inflammatory set of genes was observed 8 to 14 days after transplantation (ie, when there was severe inflammatory injury). At a later time when the liver allografts had been fully accepted and were histologically normal, the expression of the inflammatory set of genes returned to the baseline, but the expression of the tolerogenic set of genes was still increased. Genes that were expressed in tolerant cardiac and liver allografts included Fgl2, Klrg1, and Foxp3, whereas genes associated with rejection included CD25, Gzmb, and IFN-?. Our data indicate that monitoring the graft expression of a novel biomarker gene set with the GeXP multiplex RT-PCR analysis system may allow differentiation between rejection and tolerance. Liver Transpl 18:444454, 2012. (C) 2012 AASLD.

Background & Aims: Graft dysfunction is one of the major complications after liver transplantation, but its precise mechanism remains unclear. Since steatotic liver grafts are susceptible to post-transplant dysfunction, and peroxisome proliferator-activated receptor (PPAR) alpha plays an important role in the maintenance of hepatic lipid homeostasis, we examined the role of PPAR alpha in liver transplantation. Methods: Livers were harvested from Sv/129 wild-type (Ppara(+/+)) mice and PPAR alpha-null (Ppara(-/-)) mice and transplanted orthotopically into syngeneic Ppara(+/+) mice. Results: Hepatocellular damage was unexpectedly milder in transplanted Ppara(-/-) livers compared with Ppara(+/+) ones. This was likely due to decreased lipid peroxides in the Ppara(-/-) livers, as revealed by the lower levels of fatty acid oxidation (FAO) enzymes, which are major sources of reactive oxygen species. Hepatic PPAR alpha and its target genes, such as FAO enzymes and pyruvate dehydrogenase kinase 4, were strongly down-regulated after transplantation, which was associated with increases in hepatic tumor necrosis factor-alpha expression and nuclear factor-kappa B activity. Inhibiting post-transplant PPAR alpha down-regulation by clofibrate treatment markedly augmented oxidative stress and hepatocellular injury. Conclusions: Down-regulation of PPAR alpha seemed to be an adaptive response to metabolic alterations following liver transplantation. These results provide novel information to the understanding of the pathogenesis of early post-transplant events. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Hepatocellular carcinoma often arises in cirrhotic livers. Patients with severe liver cirrhosis who undergo hepatectomy often develop postoperative liver failure, even if the hepatectomy is limited. Here, we report six patients with severe liver cirrhosis (Child-Pugh B/C and indocyanine green retention rate at 15 min ≥ 40%) who underwent pure laparoscopic hepatectomy. Their perioperative course was favorable and comparable to that of other hepatocellular carcinoma patients with mild-moderate liver cirrhosis. In patients with severe liver cirrhosis, pure laparoscopic hepatectomy minimizes the disturbance in collateral blood and lymphatic flow caused by laparotomy and liver mobilization, as well as the mesenchymal injury caused by compression of the liver. It limits complications such as massive ascites, which can lead to severe postoperative liver failure. Good candidates for the procedure include patients with severe liver cirrhosis who have tumors on the liver surface and in whom adaptation to ablation therapy is difficult and/or who experience local recurrence after repeat treatments. © 2011 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Blackwell Publishing Asia Pty Ltd.

ABO-incompatible liver transplantation (LTx) is becoming more common in response to the paucity of liver allografts. Several studies have expressed concern about the effect of ABO compatibility on graft survival. To evaluate the differences in serum cytokine levels between ABO-incompatible (ABO-i) and ABO-compatible (ABO-c; includes ABO-compatible and identical) pediatric LTx recipients during regular outpatient follow-up. Note that, in the field of organ transplantation, transplants are categorized as incompatible, compatible or identical; accordingly, these are the terms we use in the paper. A clinical outpatient study measuring serum transforming growth factor (TGF)-beta 1, interferon (IFN)-gamma, interleukin (IL)-2 and IL-10 in 43 living related liver transplantation (LRLT) recipients, of whom 36 received ABO-c LRLT (34 were ABO-identical and 2 were non-identical) and 7 ABO-i LRLT. Serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase and bilirubin were measured as part of the patients&apos; regular follow-up visits. There were no differences between the ABO-c and ABO-i groups in terms of recipient&apos;s age [mean 12.6 vs. 11.1 years (y)], post-LTx duration (mean 7.3 vs. 7.3 y), donor&apos;s age (mean 35.5 vs. 34.6 y), body weight (28.9 +/- A 2.9 vs. 27.9 +/- A 6.9 kg), or gender (19 female and 17 male vs. 4 female and 3 male). Serum TGF-beta 1, IFN-gamma and IL-2 were significantly higher in the ABO-i group than in the ABO-c group. IL-10, however, did not differ between the two groups. There was a tendency toward higher gamma GTP levels in the ABO-i group, but this difference did not reach significance. ABO-incompatible LRLTx patients have higher serum TGF-beta 1, IFN-gamma and IL-2 levels as measured at regular outpatient visits. As a result, they face a higher risk of T-helper 1 cell polarization, which could make graft rejection more likely.

60歳男。大腸内視鏡検査で盲腸にBauhin弁を巻き込む4cm大の2型病変を認め、生検で中分化型腺癌と診断された。一方、CT検査で肝S8に10mm大の乏血性腫瘍を認め、超音波所見と合わせて肝転移巣と診断した。他に転移は認めず、腸閉塞で発症した進行盲腸癌と診断し、大腸・肝同時切除の適応と判断して、内視鏡手術支援ロボットda Vinci S Surgical Systemを用いて一期的に回盲部分切除および肝S8部分切除を行った。病理診断は大腸腫瘍はAI、moderately differentiated adenocarcinoma、pSE、int、INFβ、ly3、v3、pPM0、pDM0、N3であり、肝腫瘍は大腸癌からの転移であった。術後経過は良好で、特に合併症なく術後9日に軽快退院し、術後2ヵ月より補助化学療法を行い、術後9ヵ月の現在、無再発で生存中である。

The search for effective antibodies (Ab) for curable cancer immunotherapy has been a quest of many research groups in order to find an effective target that exists on the cancer cell surface. So far there have been no conclusive answers to shed light on the search. This study therefore aimed to bridge the gap of cancer therapy. Screening against 49 kinds of cell lines belonging to 11 kinds of solids cancers was performed. Isolation and characterization for approximately 4200 monoclonal antibodies (mAb) was also performed thereafter. Of those mAb 488 clones that turned out to bind to 29 tumor-associated antigens (TAA) were subjected to immunohistochemical (IHC) analyses. Selection of target antigens (Ag) and a potential antibody for cancer therapy was conducted prior to clinical examinations. In order to find predictably effective targets for therapeutic Ab against solid cancers, expression of the Ag on the surface of cancer and normal cells was extensively examined by IHC analyses using fresh cancer specimens resected from patients. In this study, the tendencies of all staining patterns and distribution of the Ab are reported. While all of the TAA appeared to be involved in tumorigenesis, their expression was not restricted to some specific tumor types but rather randomly distributed among various cancers. Some kinds of Ab including anti-epidermal growth factor receptor (EGFR) and anti-human epidermal growth factor receptor 2 (HER2) indicated the frequency of expression in normal cells was generally low. We concluded that identification of 488 mAb and the accumulated results of IHC analyses in this study could be the key for further therapeutic Ab against cancers. The targets that showed cancer-specific expression are expected to be better for therapeutic Ab than the other Ab. Moreover, further investigation into the growth of cancer cell lines using full human IgG form of Ab shows available efficacy in specific cases. (Cancer Sci 2011; 102: 175-181).

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology. Hepatic involvement was reported in about 11% of patients with sarcoidosis. However, cases of sarcoidosis in which the granuloma is solitary and limited in the liver are very rare. A 51-year-old woman with tumors in the liver underwent extended left lobectomy with caudate lobectomy and bile duct resection. The tumor was located between segment 4 and the hilar region. Some daughter nodules were found in the left lobe, which were regarded as intrahepatic metastasis. Our case displayed clinical and radiologically distinct findings, which are very similar to those of hilar cholangiocarcinoma restricted to the liver. This report demonstrates that sarcoidosis can show solitary hepatic involvement in the absence of thoracic lymphadenopathy. In such a case, it is difficult to distinguish the diagnosis from other malignant neoplasms. In conclusion, the diagnosis of hepatic sarcoidosis has to be made through prudent and comprehensive investigations that include a full clinical history of sarcoidosis in other organs. Despite utilizing several detailed diagnostic modalities, the definitive diagnosis of cases of solitary sarcoidosis may remain difficult. In these cases, surgical treatment including liver resection should be considered in order to avoid missing a suitable opportunity for treatment. © 2011 S. Karger AG, Basel.

Cholangiocarcinoma, arising from bile duct epithelium, is categorized into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC), including hilarcholangiocarcinoma. Recently, there has been a worldwide increase in the incidence and mortality from ICC. Complete surgical resection is the only approach to cure the patients with ICC. However, locoregional extension of these tumors is usually advanced with intrahepatic and lymph-node metastases at the time of diagnosis. Resectability rates are quite low and variable (18%-70%). The five-year survival rate after surgical resection was reported to be 20%-40%. Median survival time after ICC resection was 12-37.4 mo. Only a small number of ICC cases, accompanied with ECC, gall bladder carcinoma, and ampullary carcinoma, have been reported in the studies of chemotherapy due to the rarity of the disease. However, in some reports, significant anti-cancer effects were achieved with a response rate of up to 40% and a median survival of one year. Although recurrence rate after hepatectomy is high for the patients with ICC, the residual liver and the lung are the main sites of recurrence after tentative curative surgical resection. Several patients in our study had a long-term survival with repeated surgery and chemotherapy. Repeated surgery, combined with new effective regimens of chemotherapy, could benefit the survival of ICC patients. © 2010 Baishideng.

In order to isolate monoclonal antibodies (mAbs) that bind to tumor-associated antigens (Ags) we developed the following strategy. Using the phage-display Ab library we isolated a large number of mAbs that bind to the surface of human tumor cells. The mAbs were individually screened by immunostaining, and clones that preferentially and strongly stained the malignant cells were chosen. Thereafter, the Ags recognized by the mAbs were identified. For identification of the Ags by MS candidate molecules had to be purified either by immunoprecipitation or by affinity chromatography. We isolated several hundred mAbs that showed cancer-specific staining patterns. In order to identify the Ags that were recognized by the numerous mAbs within a short time we developed two methods. Using the GFC [grouping of clones by flow cytometry (FCM)] method many Abs could be grouped by comparing the staining patterns of FCM. Members in each group turned out to bind to the same molecule in many cases. After a candidate Ag was revealed, the polypeptide corresponding to its extracellular portion was prepared and used for identification of clones that bound to the Ag among all the mAbs by SITE (simultaneous identification of clones through three dimensional ELISA) method. Both methods can be generally applicable to various kinds of membrane proteins and the mAbs against them. (C) 2009 Elsevier B.V. All rights reserved.

Peliosis hepatis is a rare lesion histologically characterized by multiple cavities representing dilated sinusoids filled with blood in the liver. Although it has been observed in the liver parenchyma in association with several diseases and medications, there are few reports of nodules of hepatocellular carcinoma (HCC) showing extensive peliotic change. We describe a case of HCC showing extensive peliotic change in the cancer nodule. A 73-year-old man with a liver tumor was referred to our hospital for further investigation. Abdominal ultrasonography revealed an 8-cm hyperechoic lesion with a halo and mosaic pattern in segment 8 (S8) of the liver. Dynamic magnetic resonance imaging of the liver showed early irregular enhancement of the peripheral part of the lesion, and the effect persisted into the late phase, spreading into the central part of the nodule. Hepatic arteriography showed the "cotton-wool" sign, usually observed in cavernous hemangiomas. Fine-needle aspiration biopsy revealed the diagnosis of HCC. Anterior sectionectomy of the liver was conducted. Histological examination of the resected specimen showed that the tumor was a well-differentiated HCC with extensive dilated sinusoid-like structures in the main portion of the nodule, suggestive of peliotic change.

Background: The results of 12 consecutive patients with unresectable advanced biliary tract carcinoma treated with first line chemotherapy of S1/cisplatin, combined surgical resection and second line chemotherapy of gemcitabine are evaluated. Patients and Methods: Eight patients with intrahepatic cholangiocarcinoma, 1 with extrahepatic cholangiocarcinoma and 3 with gallbladder carcinoma were included in the study. All patients were treated with S1/cisplatin. Two of the patients underwent combined surgical resection before and 2 after therapy. Second line chemotherapy of gemcitabine was administerd in 6 patients. Results: MST of the patients was 14.9 months. With S1/cisplatin therapy, 6 patients had PR and 4 had SD. Two patients with surgical resection after the therapy survived more than 3 years. Second line chemotherapy of gemcitabine with moderate effects and mild adverse effects was well tolerable. Conclusion: S1/cisplatin showed considerable anti-cancerous effects. Employing surgical resection for patients with good response may lead to the chance of long-term survival.

Acute allograft rejection remains a major complication after liver transplantation. We report a semiquantitative imaging method of detecting acute allograft rejection with F-18-FDG PET. Methods: Syngeneic and allogeneic transplanted rats, with or without immunosuppressive treatment, were subjected to serial PET. Autoradiography of the liver was conducted in both the syngeneic and the allogeneic rats. Results: A significant increment of F-18-FDG accumulation in liver allografts was observed by PET on day 2. The F-18-FDG signal was concentrated in the area where inflammatory cells around the vessels were detected by autoradiography. Allotransplanted rats treated with an immunosuppressive agent displayed a marked decrease in hepatic F-18-FDG uptake, compared with allotransplanted rats that were not treated. Conclusion: F-18-FDG PET may be a valid method for facilitating the development of protocols to diagnose graft rejection and to monitor the efficacy of immunosuppressive therapy.

We developed a method termed ICOS (isolation of antigen-antibody complexes through organic solvent) for comprehensive isolation of monoclonal antibodies (mAbs) bound to molecules on the cell surface. By mixing a large number of phage particles of an antibody (Ab) library with living cells, antigen (Ag)-Ab complexes were formed on the cell surface. The mixture was overlaid on organic Solution in a tube and subjected to centrifugation. Phages bound to cells were recovered from the precipitate. The phage fraction isolated turned out to contain mAbs that bind to very heterogeneous epitopes and show strong binding activity to Ags. The ICOS method was applied to isolation of human mAbs that may be therapeutic against cancers. Sixty percent of clones isolated by the screening of a phage Ab library against cancer cells turned out to bind to various kinds of tumor-associated Ags. The precise protocol of ICOS method and the rationale of efficient screening were described. (C) 2008 Elsevier Inc. All rights reserved.