研究者詳細 - 北郷　実

論文 - 北郷　実

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A long (7 cm) prophylactic pancreatic stent decreases incidence of post-endoscopic papillectomy pancreatitis: a retrospective study.

Minami K, Iwasaki E, Kawasaki S, Fukuhara S, Seino T, Katayama T, Takimoto Y, Tamagawa H, Machida Y, Horibe M, Kitago M, Ogata H, Kanai T

Endoscopy international open 7 （ 12 ） E1663 - E1670 2019年12月

ISSN 2364-3722

Background and study aims Endoscopic papillectomy (EP) is a minimally invasive treatment for ampullary neoplasms and is recognized as an alternative treatment to surgical resection; however, there are few reports on a suitable pancreatic stent (PS) after EP for preventing pancreatitis. The aim of this study was to evaluate the efficacy of a long PS after EP. Patients and methods In this retrospective single-center study, 39 patients with pathologically proven ampullary neoplasms who underwent EP between March 2012 and August 2018 were enrolled. The study participants were divided into two subgroups according to the PS length: those with a PS shorter than 5 cm (short PS group, n = 17) and those with a PS of 7 cm (long PS group, n = 22). The incidence of adverse events and risk factors for pancreatitis were evaluated. Results The diameter of all PSs was 5 Fr. Post-EP pancreatitis occurred in nine patients (23.1 %), with two cases of severe pancreatitis (5.1 %). Pancreatitis occurred more frequently in the short PS group (7/17, 41.2 %) than in the long PS group (2/22, 9.1 %) ( P = 0.026). There were no significant differences between the two groups in terms of other adverse events. Univariate and multivariate analyses showed that a long PS was the only factor associated with a decreased incidence of post-EP pancreatitis ( P = 0.042; odds ratio, 0.16; 95 % confidence interval, 0.027-0.94). Conclusion A long (7 cm) PS significantly decreased incidence of pancreatitis after EP. Prospective randomized studies with a larger number of patients and wider range of PS lengths are required.

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Achievement of Durable and Complete Remission of Graft-versus-host Disease After Liver Transplantation With Ruxolitinib: A Case Report.

Endo Y, Oshima G, Hibi T, Shinoda M, Sakurai M, Koda Y, Izawa Y, Obara H, Kitago M, Yagi H, Abe Y, Matsubara K, Yamada Y, Fukushima A, Yokose T, Mori T, Kuroda T, Kitagawa Y

Transplantation （Transplantation） 103 （ 11 ） e375 - e377 2019年11月

ISSN 0041-1337

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Characterization of spatial distribution of tumor-infiltrating CD8<sup>+</sup> T cells refines their prognostic utility for pancreatic cancer survival

Masugi Y., Abe T., Ueno A., Fujii-Nishimura Y., Ojima H., Endo Y., Fujita Y., Kitago M., Shinoda M., Kitagawa Y., Sakamoto M.

Modern Pathology （Modern Pathology） 32 （ 10 ） 1495 - 1507 2019年10月

ISSN 08933952

The abundance of cytotoxic T-cell infiltrates has important implications for patient outcome and therapeutic design for pancreatic ductal adenocarcinoma. However, intratumoral heterogeneity remains a challenge to understanding the complex immune microenvironment. We hypothesized that characterizing CD8+ cell distribution within pancreatic adenocarcinoma tissues might refine the prognostic value of tumor-infiltrating CD8+ lymphocytes. Using multiplex immunohistochemistry-based image analysis on whole-tissue sections of 214 pancreatic ductal adenocarcinomas, we measured CD8+ cell densities in the tumor center, the tumor margin, and the whole tumor, along with the proximity of CD8+ cells to carcinoma cells. Multivariable Cox regression analysis was performed to assess the associations of CD8+ cell densities with pancreatic cancer-specific survival, adjusting for clinicopathologic and immune-related features, including tumor expressions of TP53, SMAD4, and the programmed cell death 1 ligand 1 (CD274, PD-L1) and the extent of tertiary lymphoid structures. There was substantial heterogeneity in CD8+ cell density, with the mean density in the tumor center less than half that in the tumor margin. Tumor CD274 expression and extensive tertiary lymphoid structures were appeared to be associated with higher CD8+ cell density in the tumor margin (P = 0.037 and P = 0.005, respectively), but not with that in the tumor center (P > 0.50). The association of higher CD8+ cell density with prolonged survival was significant for the whole tumor (Ptrend = 0.009); however, the association was stronger for the tumor center (Ptrend = 0.002) and insignificant for the tumor margin (Ptrend = 0.07). Tumor cell–CD8+ cell distance correlated strongly with CD8+ cell density, whereas the density of CD8+ cells proximate to cancer cells exhibited no prognostic association. In conclusion, spatial computational analysis on pancreatic ductal adenocarcinoma reveals the prognostic validity of CD8+ cell density in the tumor center, where CD8+ cell infiltration is ununiformly restricted, likely suggesting pro-tumorigenic roles of the immunosuppressive tumor microenvironment of pancreatic cancer.

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Prognostic significance of the postoperative level and recovery rate of serum albumin in patients with curatively resected pancreatic ductal adenocarcinoma

Nakano Y., Kitago M., Shinoda M., Yagi H., Abe Y., Takano K., Oshima G., Takeuch A., Endo Y., Kitagawa Y.

Molecular and Clinical Oncology （Molecular and Clinical Oncology） 11 （ 3 ） 270 - 278 2019年09月

ISSN 20499450

The aim of the present study was to investigate the clinicopathological features and prognostic factors associated with pre- and postoperative serum albumin levels in patients with curatively resected pancreatic ductal adenocarcinoma (PDAC). To achieve this, the data of patients who underwent pancreatectomy for PDAC between January 1995 and March 2016 were retrospectively reviewed, and the pre- and postoperative serum albumin levels at postoperative months (POMs) 3, 6, and 12 were evaluated. The serum albumin recovery rate was also investigated. A total of 196 patients were enrolled in the present study. In the multivariate Cox regression analysis, lymph node metastasis [hazard ratio (HR): 1.65; P=0.022], serum albumin level at POM 12 (≥3.9 g/dl; HR: 0.60; P=0.017), and serum albumin recovery rate at POM 12 (≥1.00; HR: 0.60; P=0.017) were independent prognostic factors for disease-free survival. Lymph node metastasis (HR: 1.79; P=0.013) and serum albumin level at POM 12 (≥3.9 g/dl) (HR: 0.60; P=0.033) were independent prognostic factors for overall survival. These results indicated that the postoperative level and recovery rate of serum albumin are potential biomarkers for predicting the prognosis of patients with curatively resected PDAC. However, further studies are required in order to investigate the survival benefit of increasing postoperative serum albumin levels in these patients.

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Efficacy and safety of preoperative 5-fluorouracil, cisplatin, and mitomycin C in combination with radiotherapy in patients with resectable and borderline resectable pancreatic cancer: A long-term follow-up study

Endo Y., Kitago M., Aiura K., Shinoda M., Yagi H., Abe Y., Oshima G., Hori S., Nakano Y., Itano O., Fukada J., Masugi Y., Kitagawa Y.

World Journal of Surgical Oncology （World Journal of Surgical Oncology） 17 （ 1 ） 145 2019年08月

ISSN 1477-7819

Background: We aimed to evaluate the efficacy and safety of 5-fluorouracil-based neoadjuvant chemoradiotherapy (NACRT) in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma (PDAC). Methods: This retrospective study investigated the clinicopathological features and > 5-year survival of patients with T3/T4 PDAC who underwent NACRT at our institute between 2003 and 2012. Results: Seventeen resectable and eight borderline resectable patients were included. The protocol treatment completion and resection rates were 92.0% and 68.0%, respectively. Two patients failed to complete chemotherapy owing to cholangitis or anorexia. Common grade 3 toxicities included anorexia (12%), neutropenia (4%), thrombocytopenia (4%), anemia (4%), and leukopenia (12%). Pathologically negative margins were achieved in 94.1% of patients who underwent pancreatectomy. Pathological response according to Evans' classification was grade IIA in 10 patients (58.8%), IIB in 5 patients (29.4%), and IV in 2 patients (11.8%). Postoperative pancreatic fistulas were observed in four patients (23.5%), delayed gastric emptying in one patient (5.9%), and other operative morbidities in four patients (23.5%). The 1-, 2-, 5-, and 10-year overall survival rates were 73.9%, 60.9%, 60.9%, and 39.1%, respectively (median follow-up period, 80.3 months). Conclusions: NACRT is tolerable and beneficial for resectable/borderline resectable PDAC, even in the long-term.

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Efficacy of New Polylactic Acid Nonwoven Fabric as a Hemostatic Agent in a Rat Liver Resection Model

Wakabayashi T., Yagi H., Tajima K., Kuroda K., Shinoda M., Kitago M., Abe Y., Oshima G., Hirukawa K., Itano O., Kitagawa Y.

Surgical Innovation （Surgical Innovation） 26 （ 3 ） 312 - 320 2019年06月

ISSN 15533506

Background. During minimally invasive surgery, efficient and nontoxic hemostats are important for difficult to access bleeding areas. Polylactic acid is an ecofriendly hemostatic agent and we aimed to evaluate the efficacy of a polylactic acid nonwoven fabric (PLAF) developed by Toray Industries, Inc, on liver hemostasis in a preclinical study. Materials and Methods. PLAF consists of both 1-µm diameter fibers and 100-µm diameter beaded fibers. Four rats were used, and 2 trough-shaped resections of the liver parenchyma were performed (n = 8 lobes). Immediately after the resection, PLAF (PLAF group: n = 4 lobes) or rayon gauze (Rayon group: n = 4 lobes) were applied on the resected plane and compressed manually. We compared the mean time to hemostasis and blood loss per lobe, as well as histological findings between the groups. Results. The PLAF group had a significantly shorter bleeding time (P =.006), and showed lower blood loss compared with the Rayon group (P =.076). Histopathological evaluation showed a large amount of beads on the liver surface in the PLAF group. Aggregated red blood cells evident by electron microscopy and von Willebrand factor immunofluorescence were seen surrounding the beads. The PLAF group showed significantly greater von Willebrand factor expression than the Rayon group (P =.004). Discussion. This new PLAF showed superior outcomes thanks to its unique characteristic of forming beaded nanofibers, and it has the potential to be an efficient hemostat in minimally invasive surgery in the human body.

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Comparison of olanexidine versus povidone-iodine for preventing surgical site infection in gastrointestinal surgery: Study protocol for a multicentre, single-blind, randomised controlled clinical trial

Takeuchi M., Obara H., Kawakubo H., Shinoda M., Okabayashi K., Mayanagi S., Irino T., Fukuda K., Nakamura R., Wada N., Kitago M., Yagi H., Abe Y., Oshima G., Hori S., Tsuruta M., Ishida T., Yokose T., Hirukawa K., Isobe Y., Sekimoto Y., Harada H., Maeda Y., Shito M., Kondo T., Sato Y., Kitagawa Y.

BMJ Open （BMJ Open） 9 （ 5 ） e028269 2019年05月

ISSN 2044-6055

Introduction: The prevalence of surgical site infection (SSI) remains higher in gastrointestinal surgery than in other surgeries. Although several guidelines have indicated the efficacy of chlorhexidine and povidone-iodine in reducing the SSI rate, the optimal recommendation has still not been established. Therefore, it is necessary to determine the more effective antiseptic for surgical site preparation. Olanexidine (1.5% olanedine, Otsuka Pharmaceutical Factory, Tokushima, Japan), which is a new antiseptic in Japan, has antimicrobial activity against a wide range of bacteria, including Gram-positive and Gram-negative bacteria. Our study will contribute to determining a new antiseptic for use in gastrointestinal and other surgeries. Methods and analysis: We propose a multicentre, randomised controlled clinical trial for comparing two treatments, that is, 1.5% olanexidine or 10% povidone-iodine, for surgical skin preparation to prevent SSI in clean-contaminated gastrointestinal surgeries with surgical wounds. Patients aged ≥20 years at the time of consent will be included. The primary outcome measure is the 30-day postoperative SSI rate. For the primary analysis, which is aimed at comparing the treatment effects, the adjusted risk ratio and its 95% CI will be estimated using the Mantel-Haenszel method. Ethics and dissemination: The protocol was first approved by the Institutional Review Board of Keio University School of Medicine, followed by the institutional review board of each participating site. Participant recruitment began in June 2018. The final results will be published in international peer-reviewed medical journals.

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Successful resection of pancreatic metastasis from oesophageal squamous cell carcinoma: a case report and review of the literature

Koizumi W., Kitago M., Shinoda M., Yagi H., Abe Y., Oshima G., Hori S., Inomata K., Kawakubo H., Kawaida M., Kitagawa Y.

BMC Cancer （BMC Cancer） 19 （ 1 ） 320 2019年04月

ISSN 1471-2407

Background: Oesophageal cancer has a high metastatic potential and poor prognosis, with a significant risk of recurrence after radical resection. However, resected pancreatic metastasis from oesophageal cancer is rare. Case presentation: Eleven years prior, a seventy-year-old woman had been treated with transthoracic radical oesophagectomy for oesophageal squamous cell carcinoma. Four years prior, she had undergone chemotherapy for lymph node recurrence at the splenic hilum and achieved a partial response. She had also received chemoradiotherapy for lymph node recurrence at the splenic hilum 3 years prior; a complete response was achieved. However, routine follow-up with abdominal computed tomography recently revealed a tumour at the pancreatic tail and swollen lymph nodes. The patient underwent distal pancreatectomy on the basis of a pre-operative diagnosis of primary pancreatic cancer, although a histological examination of the surgical specimen revealed metastatic squamous cell carcinoma that was compatible with metachronous pancreatic metastasis from oesophageal squamous cell carcinoma. The patient has been undergoing clinical follow-up without adjuvant therapy and has been disease-free for 24 months after resection of the pancreatic metastasis. Conclusions: Resection of pancreatic metastasis may improve prognosis and should be considered when treating patients with solitary metastasis from oesophageal squamous cell carcinoma.

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Myelopathy due to human T-cell leukemia virus type-1 from the donor after ABO-incompatible liver transplantation

Wakabayashi T., Obara H., Seki M., Shinoda M., Kitago M., Yagi H., Abe Y., Matsubara K., Yamada Y., Oshima G., Oki K., Nagoshi N., Watanabe K., Hibi T., Itano O., Hoshino K., Suzuki N., Kuroda T., Kitagawa Y.

Annals of Hepatology （Annals of Hepatology） 18 （ 2 ） 397 - 401 2019年03月

ISSN 16652681

We report the case of a 53-year-old-man who developed human T-cell leukemia virus type-1-associated myelopathy (HAM) after ABO-incompatible liver transplantation for alcoholic liver cirrhosis. The living donor was seropositive for human T-cell leukemia virus type-1 (HTLV-1) and the recipient was seronegative for HTLV-1 before transplantation. After transplantation, the recipient developed steroid-resistant acute cellular rejection, which was successfully treated using anti-thymocyte globulin, and he was eventually discharged. He underwent spinal surgery twice after the transplantation for the treatment of cervical spondylosis that had been present for a period of 9 months before the transplantation. The surgery improved his gait impairment temporarily. However, his gait impairment progressed, and magnetic resonance imaging revealed multiple sites of myelopathy. He was diagnosed with HAM 16 months after the transplantation. Pulse steroid therapy (1000 mg) was administered over a period of 3 days, and his limb paresis improved. Presently, steroid therapy is being continued, with a plan to eventually taper the dose, and he is being carefully followed up at our institution. Our case suggests that liver transplantation involving an HTLV-1-positive living donor carries the risk of virus transmission and short-term development of HAM after transplantation.

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Diffuse and canalicular patterns of glypican-3 expression reflect malignancy of hepatocellular carcinoma

Kawaida M., Yamazaki K., Tsujikawa H., Fukuma M., Abe Y., Kitago M., Shinoda M., Kitagawa Y., Sakamoto M.

Pathology International （Pathology International） 69 （ 3 ） 125 - 134 2019年03月

ISSN 13205463

Glypican-3 (GPC3) is expressed in most hepatocellular carcinomas (HCCs). To investigate the significance of various GPC3 staining patterns in HCC, we classified 134 HCC patients into three groups: those with diffuse GPC3 staining, canalicular GPC3 staining, and others (including negative staining). HCCs with diffuse staining were correlated with poor differentiation, high Ki-67 indices, high serum α-fetoprotein (AFP) levels, and early recurrence. In contrast, HCCs with canalicular staining were well differentiated with lower AFP levels. Overall survival in this group was better than that of the other two groups. Comparative analysis of GPC3 staining patterns with markers for HCC subclassification showed that diffuse staining was correlated with the expression of biliary/stem cell markers, whereas canalicular staining was correlated with expression of the markers of WNT-activated HCCs. Induction of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), known as a target of the WNT signaling pathway, in HCC cells resulted in reduced GPC3 expression in vitro. The LGR5-induced cells formed tumors with canaliculus-like structures in mice and showed canalicular GPC3 staining. The current findings showed the significance of recognizing distinct GPC3 staining patterns, i.e., diffuse and canalicular, which may reflect different carcinogenetic mechanisms and indicate the level of malignancy of HCC.

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Colon perforation due to antigenemia-negative cytomegalovirus gastroenteritis after liver transplantation: A case report and review of literature

Yokose T., Obara H., Shinoda M., Nakano Y., Kitago M., Yagi H., Abe Y., Yamada Y., Matsubara K., Oshima G., Hori S., Ibuki S., Higashi H., Masuda Y., Hayashi M., Mori T., Kawaida M., Fujimura T., Hoshino K., Kameyama K., Kuroda T., Kitagawa Y.

World Journal of Gastroenterology （World Journal of Gastroenterology） 25 （ 15 ） 1899 - 1906 2019年

ISSN 10079327

BACKGROUND Cytomegalovirus (CMV) remains a critical complication after solid-organ transplantation. The CMV antigenemia (AG) test is useful for monitoring CMV infection. Although the AG-positivity rate in CMV gastroenteritis is known to be low at onset, almost all cases become positive during the disease course. We treated a patient with transverse colon perforation due to AG-negative CMV gastroenteritis, following a living donor liver transplantation (LDLT). CASE SUMMARY The patient was a 52-year-old woman with decompensated liver cirrhosis as a result of autoimmune hepatitis who underwent a blood-type compatible LDLT with her second son as the donor. On day 20 after surgery, upper and lower gastrointestinal endoscopy (GE) revealed multiple gastric ulcers and transverse colon ulcers. The biopsy tissue immunostaining confirmed a diagnosis of CMV gastroenteritis. On day 28 after surgery, an abdominal computed tomography revealed transverse colon perforation, and simple lavage and drainage were performed along with an urgent ileostomy. Although the repeated remission and aggravation of CMV gastroenteritis and acute cellular rejection made the control of immunosuppression difficult, the upper GE eventually revealed an improvement in the gastric ulcers, and the biopsy samples were negative for CMV. The CMV-AG test remained negative, therefore, we had to evaluate the status of the CMV infection on the basis of the clinical symptoms and GE. CONCLUSION This case report suggests a monitoring method that could be useful for AG-negative CMV gastroenteritis after a solid-organ transplantation.

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A Pre-Clinical Large Animal Model of Sustained Liver Injury and Regeneration Stimulus

Inomata K., Tajima K., Yagi H., Higashi H., Shimoda H., Matsubara K., Hibi T., Abe Y., Tsujikawa H., Kitago M., Shinoda M., Obara H., Itano O., Soto-Gutierrez A., Kitagawa Y.

Scientific Reports （Scientific Reports） 8 （ 1 ） 14987 2018年12月

ISSN 2045-2322

A feasible large animal model to evaluate regenerative medicine techniques is vital for developing clinical applications. One such appropriate model could be to use retrorsine (RS) together with partial hepatectomy (PH). Here, we have developed the first porcine model using RS and PH. RS or saline control was administered intraperitoneally to Göttingen miniature pigs twice, two weeks apart. Four weeks after the second dose, animals underwent PH. Initially, we tested different doses of RS and resection of different amounts of liver, and selected 50 mg/kg RS with 60% hepatectomy as our model for further testing. Treated animals were sacrificed 3, 10, 17 or 28 days after PH. Blood samples and resected liver were collected. Serum and liver RS content was determined by Liquid Chromatograph-tandem Mass Spectrometer. Blood analyses demonstrated liver dysfunction after PH. Liver regeneration was significantly inhibited 10 and 17 days after PH in RS-treated animals, to the extent of 20%. Histological examination indicated hepatic injury and regenerative responses after PH. Immunohistochemical staining demonstrated accumulation of Cyclin D1 and suppression of Ki-67 and PCNA in RS-treated animals. We report the development of the first large animal model of sustained liver injury with suppression of hepatic regeneration.

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Decreased Incidence of Acute Cellular Rejection in Low-Muscle-Mass Recipients After Living-donor Liver Transplantation

Wakabayashi T., Shinoda M., Obara H., Kitago M., Yagi H., Abe Y., Matsubara K., Yamada Y., Oshima G., Hirukawa K., Mizota T., Hibi T., Itano O., Hoshino K., Kuroda T., Kitagawa Y.

Transplantation Proceedings （Transplantation Proceedings） 50 （ 10 ） 3626 - 3634 2018年12月

ISSN 00411345

Background: Sarcopenia has recently been studied as a potential risk factor for mortality and complications after liver transplantation. We investigated the impact of low muscle mass on postoperative outcomes after living-donor liver transplantation. Methods: Our study population consisted of 100 adult recipients who underwent living-donor liver transplantation in our department between 2005 and 2017. Recipients were divided into a low-muscle-mass group (L group) and a normal-muscle-mass group (N group) based on skeletal muscle index (SMI) values, and postoperative outcomes were compared between the groups. Regarding factors that were significantly different between the groups, multivariate analyses were performed to identify predictive factors. Results: Based on the SMI definition, 47 and 53 of the recipients were categorized as having low muscle mass (L group) and normal muscle mass (N group), respectively. Comparison between the groups revealed a significantly reduced incidence of rejection (10.6% in L group vs 30.2% in N group, P =.017) and increased incidences of bacterial infection (61.7% in L group vs 37.7% in N group, P =.017) in the L group compared with the N group. The survival rate did not differ significantly between the groups. Multivariate analyses indicated that muscle mass was a significant predictive factor for both rejection and bacterial infection. Conclusion: It is important to recognize that muscle mass has an impact not only on bacterial infection but also on rejection in recipients with low muscle mass in the postoperative course of living-donor liver transplantation.

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Evaluation of pancreatic fibrosis with acoustic radiation force impulse imaging and automated quantification of pancreatic tissue components

Fujita Y., Kitago M., Abe T., Itano O., Shinoda M., Abe Y., Yagi H., Hibi T., Ishii M., Nakano Y., Okuma K., Hashimoto M., Takeuchi A., Masugi Y., Jinzaki M., Sakamoto M., Kitagawa Y.

Pancreas （Pancreas） 47 （ 10 ） 1277 - 1282 2018年11月

ISSN 08853177

Objectives The aim of this study was to determine whether computer-assisted digital analysis and acoustic radiation force impulse (ARFI) imaging were useful for assessing pancreatic fibrosis, and if ARFI imaging predicted postoperative pancreatic fistula (POPF). Methods Seventy-eight patients scheduled to undergo pancreatic resection were enrolled. Shear wave velocity (SWV) at the pancreatic neck was measured preoperatively using ARFI imaging. Pancreatic tissue components on a whole slide image were quantified using an automatic image processing software. The relationship between SWV, fibrotic tissue content, and POPF incidence and clinical severity was analyzed. Results The median collagen fiber, fatty tissue, and acinar cell contents were 11.6%, 8.5%, and 61.3%, respectively. Unlike fatty tissue, collagen fiber content and acinar cells were correlated with SWV (ρ = 0.440, P < 0.001 and ρ =-0.428, P < 0.001, respectively). Although collagen fiber content and SWV were associated with the overall incidence of POPF (P = 0.004 and 0.001, respectively), collagen fiber content and SWV had no statistical correlation with clinically relevant POPF (P = 0.268 and 0.052, respectively). Conclusions We objectively quantified the pancreatic tissue components using an automatic image processing software. Shear wave velocity was significantly related to collagen fiber content and suggests that ARFI imaging can be useful for evaluating pancreatic fibrosis.

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Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification

Kurebayashi Y., Ojima H., Tsujikawa H., Kubota N., Maehara J., Abe Y., Kitago M., Shinoda M., Kitagawa Y., Sakamoto M.

Hepatology （Hepatology） 68 （ 3 ） 1025 - 1041 2018年09月

ISSN 02709139

Immune cells constitute an important element of tumor tissue. Accumulating evidence indicates their clinicopathological significance in predicting prognosis and therapeutic efficacy. Nonetheless, the combinations of immune cells forming the immune microenvironment and their association with histological findings remain largely unknown. Moreover, it is unclear which immune cells or immune microenvironments are the most prognostically significant. Here, we comprehensively analyzed the immune microenvironment and its intratumor heterogeneity in 919 regions of 158 hepatocellular carcinomas (HCCs), and the results were compared with the corresponding histological and prognostic data. Consequently, we classified the immune microenvironment of HCC into three distinct immunosubtypes: Immune-high, Immune-mid, and Immune-low. The Immune-high subtype was characterized by increased B-/plasma-cell and T cell infiltration, and the Immune-high subtype and B-cell infiltration were identified as independent positive prognostic factors. Varying degrees of intratumor heterogeneity of the immune microenvironment were observed, some of which reflected the multistep nature of HCC carcinogenesis. However, the predominant pattern of immunosubtype and immune cell infiltration of each tumor was prognostically important. Of note, the Immune-high subtype was associated with poorly differentiated HCC, cytokeratin 19 (CK19)+, and/or Sal-like protein 4 (SALL4)+ high-grade HCC, and Hoshida's S1/Boyault's G2 subclasses. Furthermore, patients with high-grade HCC of the predominant Immune-high subtype had significantly better prognosis. These results provide a rationale for evaluating the immune microenvironment in addition to the usual histological/molecular classification of HCC. Conclusion: The immune microenvironment of HCC can be classified into three immunosubtypes (Immune-high, Immune-mid, and Immune-low) with additional prognostic impact on histological and molecular classification of HCC. (Hepatology 2018).

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Concurrent presentation of an intraductal tubulopapillary neoplasm and intraductal papillary mucinous neoplasm in the branch duct of the pancreas, with a superior mesenteric artery aneurysm: A case report

Inomata K., Kitago M., Obara H., Fujii-Nishimura Y., Shinoda M., Yagi H., Abe Y., Hibi T., Matsubara K., Oshima G., Sekimoto Y., Inoue M., Itano O., Sakamoto M., Kitagawa Y.

World Journal of Surgical Oncology （World Journal of Surgical Oncology） 16 （ 1 ） 83 2018年04月

Background: Since the concept of intraductal tubulopapillary neoplasm (ITPN) was introduced in the current World Health Organization classification of tumors, the number of reports of ITPN occurrence has increased gradually. However, ITPN is usually located in the main pancreatic duct, with few reports of a branch duct ITPN. As a result, imaging protocols for the diagnosis of a branch duct ITPN have not been established. Case presentation: We report a case of a concurrent presentation of a branch duct ITPN and intraductal papillary mucinous neoplasm (IPMN) in the head of the pancreas, with a superior mesenteric artery (SMA) aneurysm. Initially, the cystic masses in the pancreatic head were diagnosed as branch duct IPMNs, with treatment consisting of a pylorus-preserving pancreaticoduodenectomy, in combination with an aneurysmectomy performed for treatment of the SMA aneurysm. Pathological examination confirmed these cysts were a combination of branch-type ITPN and IPMN. The patient recovered from the treatment without complication, with no evidence of recurrence over a period of 34 months post-surgery. Conclusion: This case report of a synchronous presentation of an ITPN and IPMN indicates the difficulty in differentiating these two types of neoplasms in the branch duct of the pancreatic head.

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Mesenchymal–epithelial transition of pancreatic cancer cells at perineural invasion sites is induced by Schwann cells

Fujii-Nishimura Y., Yamazaki K., Masugi Y., Douguchi J., Kurebayashi Y., Kubota N., Ojima H., Kitago M., Shinoda M., Hashiguchi A., Sakamoto M.

Pathology International （Pathology International） 68 （ 4 ） 214 - 223 2018年04月

ISSN 13205463

Epithelial–mesenchymal transition (EMT) promotes invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the importance of its reverse process, mesenchymal–epithelial transition (MET), for PDAC remains unclear. We aimed to characterize the histological finding “focal differentiation” in PDAC at perineural invasion sites in the context of MET and to investigate the role of Schwann cells in inducing tumor MET. Tumor differentiation and immunohistochemical expressions of E-cadherin, SMAD3, and vimentin at perineural invasion sites were examined in 168 PDAC tissues. Four PDAC cell lines were co-cultured with Schwann cells to investigate cell morphology, motility, or EMT-related markers using immunocytochemistry and quantitative PCR. Of 168 tumors, 124 (74%) showed focal differentiation with enhanced E-cadherin membrane expression (P < 0.001) and decreased nuclear accumulation of SMAD3 (P < 0.001). Among 115 PDACs harboring grade 1/2 tumor, tumors with focal differentiation showed worse survival compared to those without focal differentiation (P = 0.019). PDAC cells co-cultured with Schwann cells demonstrated a sheet-like appearance, increased E-cadherin expression, decreased expressions of SMAD3 and vimentin, and reduced cell motility. In conclusion, MET-like change is induced by Schwann cells, suggesting that Schwann cells contribute to PDAC colonization in pancreatic nerves through activating the MET machinery inside tumor cells in the pancreatic tumor microenvironment.

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KRAS mutations in cell-free DNA from preoperative and postoperative sera as a pancreatic cancer marker: A retrospective study

Nakano Y., Kitago M., Matsuda S., Nakamura Y., Fujita Y., Imai S., Shinoda M., Yagi H., Abe Y., Hibi T., Fujii-Nishimura Y., Takeuchi A., Endo Y., Itano O., Kitagawa Y.

British Journal of Cancer （British Journal of Cancer） 118 （ 5 ） 662 - 669 2018年03月

ISSN 00070920

Background:Pancreatic ductal adenocarcinoma (PDAC) has very poor prognosis despite existing multimodal therapies. This study aimed to investigate whether KRAS mutations at codons 12/13 in cell-free DNA (cfDNA) from preoperative and postoperative sera from patients with PDAC can serve as a predictive biomarker for treatment response and outcomes after surgery.Methods:Preoperative and postoperative serum samples obtained from 45 patients with PDAC whom underwent curative pancreatectomy at our institution between January 2013 and July 2016 were retrospectively analysed. Peptide nucleic acid-directed PCR clamping was used to identify KRAS mutations in cfDNA.Results:Among the 45 patients enrolled, 11 (24.4%) and 20 (44.4%) had KRAS mutations in cfDNA from preoperative and postoperative sera, respectively. Multivariate analysis revealed that KRAS mutations in postoperative serum (hazard ratio (HR)=2.919; 95% confidence interval (CI)=1.109-5.621; P=0.027) are an independent prognostic factor for disease-free survival. Furthermore, the shift from wild-type KRAS in preoperative to mutant KRAS in postoperative cfDNA (HR=9.419; 95% Cl=2.015-44.036; P=0.004) was an independent prognostic factor for overall survival.Conclusions:Changes in KRAS mutation status between preoperative and postoperative cfDNA may be a useful predictive biomarker for survival and treatment response.

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Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression

Seino T., Kawasaki S., Shimokawa M., Tamagawa H., Toshimitsu K., Fujii M., Ohta Y., Matano M., Nanki K., Kawasaki K., Takahashi S., Sugimoto S., Iwasaki E., Takagi J., Itoi T., Kitago M., Kitagawa Y., Kanai T., Sato T.

Cell Stem Cell （Cell Stem Cell） 22 （ 3 ） 454 - 467.e6 2018年03月

ISSN 19345909

Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression. Sato and colleagues established a library of patient-derived pancreas cancer organoids and identified heterogeneous patterns of dependency on Wnt ligands among pancreas cancers. Biological and genetic analyses highlighted GATA6 as a mediator of the Wnt niche requirement, which links pancreatic tumor progression to independence from the stem cell niche.

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Hemoadsorption of high-mobilitygroup box 1 using a porous polymethylmethacrylate fiber in a swine acute liver failure model

Amemiya R., Shinoda M., Yamada M., Ueno Y., Shimada K., Fujieda H., Yagi H., Mizota T., Nishiyama R., Oshima G., Yamada S., Matsubara K., Abe Y., Hibi T., Kitago M., Obara H., Itano O., Kitagawa Y.

International Journal of Artificial Organs （International Journal of Artificial Organs） 41 （ 4 ） 190 - 200 2018年02月

ISSN 03913988

Background: High-mobility-group box chromosomal protein 1 has been identified as an important mediator of various kinds of acute and chronic inflammation. In this study, we aimed to develop a column that effectively adsorbs highmobility- group box chromosomal protein 1 by altering the pore size of the fiber. Materials and methods: First, we produced three types of porous polymethylmethacrylate fiber by altering the concentration of polymethylmethacrylate dissolved in dimethylsulfoxide. We then selected a fiber based on the results of an in vitro incubation test of high-mobility-group box chromosomal protein 1 adsorption. Using the selected fiber, we constructed a new column and tested its high-mobility-group box chromosomal protein 1 adsorption capacity during 4-h extracorporeal hemoperfusion in a swine acute liver failure model. Results: Electron microscope observation showed that the three types of fibers had different pore sizes on the surface and in cross section, which were dependent on the concentration of polymethylmethacrylate. In the in vitro incubation test, fiber with moderate-sized pores demonstrated the highest adsorption capacity. In the in vivo hemoperfusion study, the ratio of the high-mobility-group box chromosomal protein 1 concentration at the outlet versus the inlet of the column was significantly lower with the new column than with the control column during 4-h extracorporeal hemoperfusion. The normalized plasma level of high-mobility-group box chromosomal protein 1 at 12 h after the completion of hemoperfusion was significantly lower with the new column than with the control column. Conclusion: The newly developed polymethylmethacrylate column adsorbs high-mobility-group box chromosomal protein 1 during hemoperfusion in swine ALF model.

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