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The influence of anastomotic leakage on long-term survival in patients with rectal cancer is debatable. The aim of this study was to evaluate relationships between anastomotic leakage and long-term survival. In this multicenter retrospective cohort study, 395 consecutive stage I to III rectal cancer patients underwent anterior resection between 2007 and 2012. Five-year overall survival, 5-year disease-free survival, and 5-year local recurrence-free survival were compared between patients with leakage (Leakage (+)) and patients without leakage (Leakage (−)). Of 395 patients, 50 (12.7%) had anastomotic leakage. Of these 50, 34 (68.0%) required urgent surgery and 16 (32.0%) could be managed by watchful waiting or with percutaneous drainage. The median follow-up period was 62.6 months. Five-year overall survival did not differ between the two groups (Leakage (+) 93.8% vs. Leakage (−) 89.0%, P = 0.121). Five-year disease-free survival also did not differ between the two groups (81.6% vs. 80.3%, P = 0.731), and neither did 5-year local recurrence-free survival (91.9% vs. 86.1%, P = 0.206). In a multivariable Cox regression model, BMI > 25, preoperative CA19-9 > 37, pathological T stage, pathological N stage, and circumferential resection margin (CRM) positive were independent predictors of disease-free survival. Moreover, pathological T stage, pathological N stage, and CRM positive were the only independent predictors of overall survival and local recurrence-free survival. Anastomotic leakage was not a risk factor for overall survival, disease-free survival, or local recurrence-free survival. Anastomotic leakage is not associated with a significant decrease in long-term survival in rectal cancer patients.

A 71-year-old man presented with the chief complaint of fecal occult blood. Based on imaging studies, the patient was diagnosed advanced rectal cancer. He received laparoscopic low anterior resection. Three months after the rectal cancer operation, upper gastrointestinal endoscopy revealed gastric cancer. The patient had a diagnosis of synchronous cancer of the rectum and stomach, and received laparoscopic distal gastrectomy. Two years after the rectal cancer operation, liver metastasis(S4)was detected and resected. Three years after the rectal cancer operation, esophageal cancer and laryngeal cancer were detected synchronously and chemoradiotherapy was performed. Five years after the rectal cancer operation, small intestinal cancer with infiltration of descending colon and esophagus cancer were detected synchronously. Small intestinal resection and Hartmann procedure were performed for small intestinal cancer. ESD was performed for esophageal cancer. Six years after the rectal cancer operation, FDG-PET showed the peritracheal lymph node metastasis, lumbar spine metastasis and local recurrence in the pelvis. Currently, systemic chemotherapy is undergoing. We report a rare case of synchronous- metachronous cancer of the rectum, stomach, pharynx, esophagus and small intestine.

INTRODUCTION Laparoscopic surgery has become popular for colorectal cancer treatment in recent years. However, its success rate even among high-risk patients remains debatable. The present study aims to compare the short- and long-term outcomes between laparoscopic and open surgeries in the American Society of Anesthesiologists (ASA) classes 3 and 4 patients with colorectal cancer. METHODS This was a single-center, retrospective, cohort study performed at a university hospital, with 78 patients suffering from colorectal cancer who underwent surgery in ASA classes 3 and 4 as respondents. Patient and tumor characteristics, operative outcomes, and prognoses were factors compared between the open and laparoscopic groups. RESULTS Compared with the open group, laparoscopic group had longer operation time (median 287.5 vs 204.5 minutes, P = .001), less operative blood loss (median 40 vs 240 mL, P = .020), and fewer postoperative complications (24% vs 55%, P = .011). In addition, operative approach (open vs laparoscopic) served as an independent factor for the occurrence of postoperative complications [HR = 3.963 (1.344-12.269), P = .013]. In terms of overall survival and recurrence-free survival (P = .171 and .087, respectively), no significant difference was found between the two groups. CONCLUSION Laparoscopic surgery is thus associated with more favorable short-time outcomes and could be adopted as treatment even for colorectal cancer ASA class 3 and 4 patients.

The purpose of this study is to analyze doctoral students’ career plans and research productivity, as well as key factors affecting both, based on relevant findings from a 2017 national survey of doctoral students at Japanese universities. The main findings of this study are as follows. First, Japanese doctoral students tend to have diverse post-graduation career plans. They not only consider becoming academics but also expect to be hired in industry and business. This expectation is particularly strong among students from engineering, while more of those studying humanities and social sciences want to become academics. Second, the survey revealed that Japanese doctoral students’ host universities, age, gender, and their marital status, had no significant influence on their research productivity.

Background/aim The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP). Patients and methods Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8+ tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens-versus-surgical specimens after resection. We determined the prognostic significance of these factors. Results The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8+ TIL density was significantly increased after neoadjuvant treatment. However, PD-L1 expression on TCs or ICs, and CD8+ TIL density, was not significantly associated with patient survival in ESCC patients. Conclusion NAC-FP induced PD-L1 expression on ICs and CD8+ TILs in ESCC patients. This finding suggests that PD-1/PD-L1 blockade could be combined with NAC-FP to treat ESCC patients.

The purpose of this chapter is to explore the changes that have occurred in Japan’s research, development, and innovation policies and among Japanese academics since the early 1990s. The chapter argues that, despite a certain continuity and coherence between these policies, they also contain dramatic changes. It is fair to say that some of these policies and strategies led to successful outcomes, while others have so far ended in failure. Further, the chapter points out that there are many daunting problems to be solved, which the national government has not paid sufficient attention to since the 1990s. For example, firstly, Japan should reconsider its modest investments in R&D and the Japanese government’s weakness in investing public funds in higher education, especially as to academic productivity in universities. Secondly, Japan needs to make more efforts to promote the R-T-S nexus, strengthening not only research universities but also teaching-oriented universities, and ensure that business makes its fair share of investments in research productivity by encouraging collaborations between industry, business, and academia.

Post-hepatectomy portal vein thrombosis (PH-PVT) is a severe complication. The risk factors of PH-PVT after laparoscopic and open hepatectomy have not been clarified yet. We aimed to retrospectively investigate the risk factors and outcome of PH-PVT in patients with primary liver cancer. We enrolled 622 consecutive patients who underwent hepatectomy in our hospital between January 2006 and August 2016. Of 21 patients (3.4%) with PH-PVT, 7 had grade I; 13, grade II; and 1, grade III. The patients with PH-PVT were significantly older than those without PH-PVT. Of the 413 patients who underwent open hepatectomy, those who underwent a major right hepatectomy (4.1%) had a slightly higher incidence of PH-PVT. Of the 209 patients who underwent laparoscopic hepatectomy, those who underwent a left lateral sectionectomy (21.2%) and major right hepatectomy (16.7%) had high incidence rates of PH-PVT. The treatment was only observation in five patients, medication with an antithrombotic drug in 15 patients, and reoperation in one patient. PH-PVT diminished in 17 patients. Cavernous transformation and/or stenosis of the portal vein developed in three patients. The patient with grade III PH-PVT after open right hemihepatectomy underwent reoperation but died of hepatic failure. This study demonstrated that patient age, left lateral sectionectomy were risk factors of PH-PVT. Laparoscopic left lateral sectionectomy and major right hepatectomy might bring about relatively higher risk of PH-PVT. Major right hepatectomy tends to lead to severe PH-PVT. Careful handling of the PV during hepatectomy and early treatment of PH-PVT are necessary.

Background/aim Perioperative intra-abdominal infection has been reported as a risk factor for metastasis. The aim of this study was to investigate the mechanism by which peritonitis induces immunosuppression in the lung, which in turn promotes lung metastasis. Materials and methods C57BL/6 mice were intravenously administered B16F10 melanoma cells to induce lung metastasis and subsequently subjected to cecal ligation and puncture (CLP) to induce peritonitis or sham surgery. The number of lung metastatic nodules was evaluated. Cell fractions in lungs and serum cytokines after CLP were investigated. Results CLP mice showed an increased number of lung metastases compared to sham-treated mice. The fraction and number of natural killer (NK) cells in lungs of CLP mice were significantly reduced in early post-CLP phase. Myeloid-derived suppressor cells (MDSCs) in lungs were significantly decreased in CLP mice. Serum IL-6 and TNF levels were significantly elevated in CLP mice. Conclusion Peritonitis promoted lung metastasis in a murine model, which may be attributable to the impact of NK cells and MDSCs in the lungs.

In tumor immunity, invariant natural killer T (iNKT) cells play a pivotal role as a link between the innate and adaptive immune systems. With a precisely regulated activation mechanism, iNKT cells have the ability to respond quickly to antigenic stimulation and rapidly produce cytokines and chemokines, and subsequently an effective antitumor immune response. The development of iNKT cell-targeted active immunotherapy enables, not only an antitumor immune response through innate and acquired immunity, but also the conversion of an immunosuppressive into an immunogenic microenvironment. This review is focused on the activation mechanism and the role of iNKT cells after therapeutic active immunization. The therapeutic strategy targeting iNKT cells is expected to be applied to clinical practice in combination with surgery and chemotherapy.

Background: Invariant natural killer T (iNKT) cells have been shown as an ideal immunotherapeutic target of which the activation via α-Galactosylceramide (α-Gal) conjugated with the MHC class 1-like CD1d molecule induces both innate and adaptive immune system. With transfection of antigen information, α-Gal loaded CD1d expressing cells can act as a vector to enhance the antigen specific immune responses. Though transfection of antigen information by using antigen coding mRNA or tumor peptide is common, the process of extracting mRNA or identifying tumor peptide is sometimes too complicated. Electroporation (EP) has been reported as a way to induce substances easily into cells. We applied EP as a simple method to deliver the antigen into the vector for iNKT cell activation.In this study, we aimed to show a feasibility of EP as a method to deliver the antigen into α-Gal loaded dendritic cells (DCs), a naturally CD1d expressing vector, in terms of inducing antigen specific antitumor responses and innate immunity. Methods: DCs were generated from bone marrow of C57BL/6 mice. Ovalbumin (OVA) was electroporated to DCs as a tumor model antigen. To load α-Gal, DCs were cultured with α-Gal for 24 hours before cultured with LPS. We compared the antitumor responses of α-Gal loaded DCs with or without electroporated OVA in C57BL/6 mice. In subcutaneous tumor model, mice were prophylactically administered each type of DCs intravenously followed by subcutaneous injection of EG7, which is OVA induced EL4, thymoma (n = 5). We evaluated the tumor size and the survival rate. We also evaluated the innate immunity which induced by α-Gal loaded DCs with or without electroporated OVA. Results: With electroporated OVA, tumors didn't grow in mice administered α-Gal loaded DCs whereas tumors in mice administered α-Gal loaded DCs without electroporated OVA aggressively progressed(P < 0.05). In mice administered α-Gal loaded DCs with electroporated OVA, no death was observed during the whole observation period. Survival rate was significantly better for mice administered α-Gal loaded DCs with electroporated OVA than those administered α-Gal loaded DCs without electroporated OVA(P < 0.05). On the other hand, α-Gal loaded DCs with or without electroporated OVA showed no difference in inducing NK cells. But, they either induced more NK cells than α-Gal unloaded DCs(P < 0.05). Conclusion: α-Gal loaded DCs with electroporated OVA showed significantly higher rate of tumor rejection and longer survival in the mice model inoculated OVA-induced tumor comparing to α-Gal loaded DCs without electroporated OVA. Also, EP didn't impair the ability of inducing innate immunity. EP was feasible as a way to deliver the antigen into the vector which induced antigen specific antitumor responses. We are trying to show the activity of antigen-specific cytotoxic T lymphocytes following the administration of α-Gal loaded DCs with electroporated antigen. Citation Format: Akihiro Watanabe, Kimihiro Yamashita, Akira Arimoto, Kouta Yamada, Kyosuke Agawa, Takashi Kamigaki, Rishu Takimioto, Yoshihiro Kakeji. Antigen electroporated DC loaded with NKT-cell ligand induces the antigen specific antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 698.

An outbreak of cholangiocarcinoma in a printing company was reported in Japan, and these cases were regarded as an occupational disease (occupational cholangiocarcinoma). This study examined the expression status of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in occupational cholangiocarcinoma. Immunostaining of PD-1, PD-L1, CD3, CD8, and CD163 was performed using tissue sections of occupational cholangiocarcinoma (n = 10), and the results were compared with those of control cases consisting of intrahepatic (n = 23) and extrahepatic (n = 45) cholangiocarcinoma. Carcinoma cells expressed PD-L1 in all cases of occupational cholangiocarcinoma, whereas the detection of PD-L1 expression in cholangiocarcinoma cells was limited to a low number of cases (less than 10%) in the control subjects. In cases of occupational cholangiocarcinoma, occasional PD-L1 expression was also noted in precancerous/preinvasive lesions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. Additionally, tumor-associated macrophages and tumor-infiltrating T cells expressed PD-L1 and PD-1, respectively. The number of PD-L1-positive mononuclear cells, PD-1-positive lymphocytes, and CD8-positive lymphocytes infiltrating within the tumor was significantly higher in occupational cholangiocarcinoma compared with that in control cases. These results indicate that immune escape via the PD-1/PD-L1 axis may be occurring in occupational cholangiocarcinoma.

The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP).Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8NAC-FP induced PD-L1 expression on ICs and CD8

In 2012, the Central Council for Education (cce) issued a report concerning the introduction of active learning (al) and educational management into higher education. Its main object was to foster students’ ability of active learning (or active study [as]) to enable them not only to fulfill the outcome required by the dp (Diploma Policy) but also to respond to an unpredictable future in a knowledge-based society. In order to enhance students’ al, it is necessary to innovate educational methods, such as High Impact Practice (hip) and Institutional Research (ir), to establish educational management, including dp, cp (curriculum policy), and ap (admission policy), and to promote the Research-Teaching-Service (r-t-s) nexus. Based on the cce’s report, the Ministry of Education, Culture, Sports, Science and Technology (mext) started a nationwide program in 2013 to pursue active learning. As a result, the Japan Society for the Promotion of Science (jsps) selected a project of a four-university collaboration as one of the projects related to the programs in which the author of this paper conducted a national survey with a focus on the institutionalization of academic learning in academia.

Introduction Laparoscopic liver resection (LLR) has been widely performed throughout the world. Although prospective registry studies to clarify the safety of LLR have been feasible, no prior multicenter prospective study has addressed this issue. We have conducted a multicenter prospective cohort study to reveal the current status of LLR in Japan. Methods From April 2015 to March 2016, candidates for LLR were preoperatively enrolled at 12 institutions. The primary end-point was surgical safety, which was evaluated based on surgical factors and on short-term and midterm outcomes. Results A total of 102 patients were enrolled. Planned laparoscopic procedures included 96 pure laparoscopies, 1 hand-assisted laparoscopy, and 5 hybrid techniques. Non-anatomical partial resection or left lateral sectionectomy were performed in almost all cases. The median duration of surgery was 221 min. The median blood loss was 80.5 mL. Conversion was required for four patients (3.9%). The 90-day postoperative morbidities with grades more severe than II in the Clavien-Dindo classification were observed in six patients (5.9%). The median postoperative hospital stay was 9.5 days. No cases involved reoperation or mortality. Conclusion Minor resection of LLR has been performed safely. To ensure the safe dissemination of LLR, including for major resection, a larger multicenter prospective study is required.

Background Cholangiocarcinoma caused by exposure to 1,2-dichloropropane and/or dichloromethane is recognized as occupational cholangiocarcinoma. The aim of this study was to investigate the outcomes after resection of occupational cholangiocarcinoma to establish a treatment strategy for this disease. Methods Clinicopathological findings and outcomes after surgical intervention in 20 patients with occupational cholangiocarcinoma were investigated. Results Of 20 the patients, curative resection was performed in 16 patients. Three patients underwent radiation at the stump of the bile ducts. Adjuvant chemotherapy was performed in 12 patients. Biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, and/or chronic bile duct injury was detected in most subjects. Intraabdominal infection developed after surgery in nine patients. Cholangiocarcinoma recurred in 12 of the 20 patients. The recurrent tumors in five patients developed at a different part of the bile duct from the primary tumor and a second resection was performed in four of these five patients. Conclusions The incidence of postoperative complications including intraabdominal infection was high in patients with occupational cholangiocarcinoma. Multicentric recurrence occurred not infrequently after surgery because the bile ducts had a high potential for the development of carcinoma. The aggressive treatment including second resection for the multicentric recurrence appeared to be effective.

A 65-year-old man reported nausea and anorexia after falling down a flight of stairs. Computed tomography (CT) showed a ruptured descending thoracic aortic aneurysm, and emergency thoracic endovascular aortic repair (TEVAR) was performed. However, after resuming food intake, the patient developed a fever. CT scan showed severe pneumomediastinum and a mediastinal abscess, and the patient was diagnosed with esophageal perforation. Emergency esophagectomy was performed, with an esophageal fistula made at the cervix. Jejunostomy was then performed to enable enteral nutrition. Histological examination showed substantial necrosis at the middle intrathoracic esophagus, and the patient was diagnosed with esophageal necrosis leading to perforation. Five months after the esophagectomy, gastric conduit reconstruction through the retrosternal route was performed. The patient was able to resume food intake, and survived more than 1 year after this surgery. Here, we describe the successful management of this rare case of esophageal necrosis after TEVAR for ruptured traumatic aortic aneurysm.

Background: The enhancement of antitumor immune response with radiotherapy was reported recently, but there are few reports on the mechanism of the effect in rectal cancer. In neoadjuvant chemoradiotherapy (NACRT) for rectal cancer, we reported that CD8+T cells in tumor tissues were highly induced and the density of CD8+T cells were a favorable prognostic factor. The aim of the present study was to elucidate the dynamics of CD8+T cells in the tumor after irradiation. Methods: For this purpose, we established a therapeutic model of irradiation for BALB/c mice inoculated with CT26 colon cancer cell line. They are irradiated with a single dose of 10Gy after 14 days. We analyzed CD8+ T cells infiltration of both irradiated (mice) and no treated (control) mice by flow cytometry. Intratumor CD8+ T cells were fractionated into three populations according to the expression of PD-1 and Tim-3. The numbers and ratios were measured and their dynamics were analyzed. Next, purified CD8+T cells from the tumor with or without irradiation and intracellular cytokines such as IFNγ, TNF-α, and IL-2 were measured. Finally, we analyzed mice treated with FTY720 to test newly infiltrating T cell infiltration after irradiation delivered locally into tumors. Results: In our model, elevated numbers of tumor-infiltrating CD8+ T cells between day11 and day18 after irradiation were observed in tumors of mice compared to control. We observed that the number of PD-1+Tim-3+ CD8+ T cells, that comprised the major population among intratumoral CD8+ T cells, were markedly increasing in irradiated mice. Functionally, intratumoral CD8+ T cells in irradiated mice produced more INF-γ compared to control. Especially, PD-1+Tim-3+ CD8+ T cells enhanced INF-γ production. Among the three populations, PD-1+Tim-3+ CD8+ T cells contained the largest fraction of effector memory (CD44hiCD62Llow) cells, but the lowest fraction of central memory (CD44hiCD62Lhi) cells. Finally, after administration of FTY-720, the decrease rate of intratumoral CD8+ T cells in irradiated mice was much higher than in control. This results suggest that newly infiltrating CD8+ T cell number in irradiated mice was higher than in control. Conclusions: In mouse model of irradiation, there were newly infiltrating CD8+ T cells which was markedly increased compared to the control. This population may be involved in the increase of intratumor CD8+ T cells and may contribute to antitumor effects. This change is expected to trigger further therapeutic intervention. Citation Format: Kimihiro Yamashita, EIJI Fukuoka, Yutaka Sugita, Akira Arimoto, Akihiro Watanabe, Gousuke Takiguchi, Naoki Urakawa, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji. Radiotherapy enhances newly infiltrating CD8+T cells into tumor tissue to increase intratumor CD8+T cells and exert an anti-tumor effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2260.

Background: Invariant natural killer T (iNKT) cells have been shown as an ideal immunotherapeutic target of which the activation via α-galactosylceramide (α-Gal) conjugated with the MHC class I- like CD1d molecule induces both innate and adaptive immune system. With transfection of antigen information, α-Gal loaded CD1d expressing cells can act as a vector to enhance the antigen specific immune responses. Though transfection of antigen information coded as mRNA is popular, the process of extracting mRNA or identifying tumor peptide is sometimes too complicated. Electroporation (EP) has been reported as a way to induce substances easily into cells. We applied EP to deliver the antigen into the vector for iNKT cell activation just as a simple procedure. In this study, we aimed to show a feasibility of EP as a method to deliver the antigen into α-Gal loaded dendritic cells (DCs), a naturally CD1d expressing vector, in terms of inducing antigen specific antitumor responses. Methods: DCs were generated from bone marrow of C57BL/6 mice. Ovalbumin (OVA) was electroporated to DCs as a tumor model antigen. To load α-Gal, DCs were cultured with α-Gal for 48 hours. We compared the antitumor responses of α-Gal loaded DCs with or without electroporated OVA in C57BL/6 mice. In subcutaneous tumor model, mice were prophylactically administered each type of DCs intravenously followed by subcutaneous injection of EG7, which is OVA induced EL4, thymoma (n = 5, respectively). We evaluated the tumor size and the survival rate. We also evaluated the antitumor responses of which EP density of OVA can induce efficient antitumor response. Results: With electroporated OVA, tumors didn't grow in mice administered α-Gal loaded DCs whereas tumors in mice administered α-Gal loaded DCs without electroporated OVA aggressively progressed (P < 0.05). In mice administered α-Gal loaded DCs with electroporated OVA, no death was observed during the whole observation period. Survival rate was significantly better for mice administered α-Gal loaded DCs with electroporated OVA than those administered α-Gal loaded DCs without electroporated OVA (P < 0.05). The α-Gal loaded DCs also induce more memory progenitor cells than control group (P < 0.01). Conclusion: α-Gal loaded DCs with electroporated OVA showed significantly higher rate of tumor rejection and longer survival in the mice model inoculated OVA-induced tumor comparing to α-Gal loaded DCs without electroporated OVA. EP was feasible as a way to deliver the antigen into the vector which induced antigen specific antitumor responses. We are trying to show the activity of antigen-specific cytotoxic T lymphocytes following the administration of α-Gal loaded DCs with electroporated antigen. Citation Format: Akihiro Watanabe, Kimihiro Yamashita, Akira Arimoto, Yutaka Sugita, Eiji Fukuoka, Takashi Kamigaki, Rishu Takimoto, Yoshihiro Kakeji. Antigen specific antitumor effect induced by antigen-electroporated, natural killer T cell ligand-loaded dendritic cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6534.

Objective: The present study aimed to identify the clinical significance of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in patients with occupational cholangiocarcinoma. Methods: This study included 10 men with occupational cholangiocarcinoma who were former or current workers at a printing company in Osaka, Japan. Of the 10 patients, 2 had 2 main tumors and 1 had 3 main tumors. Twelve FDG-PET imaging findings in the 10 patients could be analyzed. We evaluated the relationships between FDG-PET imaging parameters and clinicopathological findings of occupational cholangiocarcinoma. Results: Abnormal FDG uptake was observed in 8 of the 14 main tumors, with maximum standardized uptake values ranging from 2.9 to 11.0, and the sensitivity was 57.1%. Four patients had lymph node metastases, and abnormal marrow uptake was detected in all these patients. Although precancerous lesions, such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB) without any invasion, were not detected, abnormal FDG uptake was demonstrated in 2 of 4 patients with IPNB having an associated invasive carcinoma.Conclusions: Although FDG-PET may be useful for assessing tumor progression factors, such as lymph node metastasis, it cannot accurately detect precancerous lesions, such as BilIN and IPNB without invasive carcinoma.

Introduction Anatomical evaluation of the splenic flexure vein is essential for complete mesocolic excision with central vascular ligation when treating patients with splenic flexure cancer. Although there have been several studies relating to the arterial branches of the splenic flexure, very limited data are available regarding the variation in venous anatomy in this region. Methods Sixty-six patients with colorectal cancer who underwent preoperative 3-D CT between April 2016 and April 2017 were included in this retrospective study. The pattern of the venous drainage of the splenic flexure and its association with the inferior border of the pancreas were evaluated. Results The inferior mesenteric vein flowed into the splenic vein in 32 patients (48.5%), into the superior mesenteric vein in 27 patients (40.9%), and into the confluence of splenic vein and superior mesenteric vein in 7 patients (10.6%). The splenic flexure vein joined the inferior mesenteric vein in 62 patients (93.9%), the splenic vein in 2 patients (3.0%), and the middle colic vein in 2 patients (3.0%). The splenic flexure vein flowed into the inferior mesenteric vein below the level of the inferior border of the pancreas in 58 patients (90.6%) and above it in 4 patients (6.3%). Conclusion Preoperative evaluation of the venous pattern of the splenic flexure on 3-D CT is useful before complete mesocolic excision with central vascular ligation to avoid intraoperative bleeding during splenic flexure cancer surgery.

This chapter discusses the change of governance caused by the revision of School Education Act (SEA) in 2014. The revision of SEA proposed to empower the University President and disempower the Faculty Meeting which had formerly been the major mechanism for protecting collegiality in Japanese universities. Faculty members are being regarded like other organizational members employed in other public sectors or as school teachers. In addition, the declining collegiality and academic freedom may harm the quality of teaching and research because of decreased academic compatibility. Managerial reforms place too much emphasis on the close relationship between university and industry, and while this lead to a useful partnership between the university and industry, in the long run it may lead to decreased academic competitiveness.

Doctoral education was institutionalized in Japan at Teikoku Daigaku in 1886 by importing the model directly from the USA, although the German model had a great impact both in the prewar and postwar period. The US model, imported as part of a formal higher education system during the postwar period, has only recently been successfully established at the doctoral level, especially in the humanities and social sciences. In this paper, the author highlights some important issues related to doctoral education in Japan. First, doctoral educatin as well as graduate school was incorporated into a Japanese university in the nineteenth century, which is relatively early compared to other countries. Nevertheless, there was little development during the prewar period due to the Japanese higher education climate. Second, the number of doctoral students and doctoral degree grantees has been declining in recent years because of economic stagnation. This is likely to affect the future social and scientific development of Japan as academic productivity declines in relation to that of other countries.

Background We aimed to identify the pathological characteristics of occupational cholangiocarcinoma. Methods We examined the location and distribution of the carcinomas: atypical epithelium including biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB); and chronic bile duct injuries in operative or autopsy liver specimens from 16 patients. We examined the detailed pathological findings and diagnostic imaging of three patients. Immunohistochemical analysis using primary antibodies against γH2AX and S100P was performed. Results BilIN and chronic bile duct injury were observed in 16 patients, and IPNB or invasive IPNB was observed in 11 patients. BilIN, IPNB, and/or chronic bile duct injury were observed in almost all the large bile ducts. Regional dilatation of the bile ducts without tumor-induced obstruction revealed such pathological changes. Highly positive results for the γH2AX and S100P markers were noted in invasive carcinoma, BilIN, and IPNB, whereas positive results for γH2AX and negative results for S100P were noted in non-neoplastic biliary epithelium. Conclusions The carcinogenic process of occupational cholangiocarcinoma comprised chronic bile duct injury and DNA damage in almost all the large bile ducts, along with induction of precancerous lesions and development of invasive carcinoma. Such pathological findings reflected radiological changes on diagnostic imaging.

Backgrounds The prognostic value of biomarkers in metastatic colorectal cancer (mCRC) patients with liver metastases remains unclear. We assessed the difference of expression of biomarkers between primary tumors and liver metastases treated with chemotherapy in mCRC patients, as well as the prognostic value of these markers. Methods Forty-three mCRC patients with liver-limited disease from January 2007–November 2011 were analyzed. They all received resection of primary tumors followed by oxaliplatin-based chemotherapy. After chemotherapy, they all received hepatic resection. Forty-three paired primary and metastatic tumor specimens were collected to measure the messenger RNA expression of six biomarkers by the Danenberg tumor profile method (thymidylate synthase, dihydropyrimidine dehydrogenase [DPD], excision repair cross-complementing gene1, thymidine phosphorylase [TP], folylpolyglutamate synthase, and regenerating islet-derived family, member 4). Results Thirty-six patients' messenger RNA was used for analysis. All markers showed similar expression between primary and metastatic sites. The low-expression group of Danenberg tumor profile and TP in the primary tumor showed significantly higher overall survival than the high-expression group ( P P = 0.033), but for DPD and TP in liver metastases, there were no significant differences of overall survival between the two groups. The ratios of marker expression in liver metastatic site to that in primary site of DPD and TP were significantly higher in chemo-responders than in non-chemo-responders ( P = 0.034 and P = 0.022). Conclusions Biomarkers' expressions in liver metastases were similar to those in the primary tumor. DPD and TP in the primary lesion may be a prognostic factor in chemotherapy-naive mCRC patients with liver-limited disease, but those in liver tumor were not. Further validated analysis to our results would be warranted.

From a framework of this study, modern society may be explained by a paradigm transformation from ascription to achievement and also from particularism to universalism. According to this hypothesis, Japanese university society has not developed successfully for more than the closed society to the opened society. This paper intends to deal with the Japanese differentiated university stratification, which has been formed among these value orientations by connection of particularism and ascription, with a focus on its effects on the academic productivity including both research and teaching productivity. For example, a closed academic structure with an inbreeding mechanism in tate-shakai (vertical society) has brought about a great deal of effect either positively or negatively on academic system throughout the country. We intend to discuss the reasons behind the declining symptom of academic productivity of the university on the basis of the given framework.

We evaluate surgical outcomes of intracorporeal esophagojejunostomy in laparoscopic total gastrectomy using 2 linear stapler methods.The functional end-to-end anastomosis (FEEA) method was chosen as a first choice. The overlap method was chosen in cases with esophageal invasion. We retrospectively analyzed the early and late surgical outcomes of consecutive 168 laparoscopic total gastrectomy cases from April 2011 to December 2016.The FEEA method was selected in 120 cases, and the overlap method was selected in 48 cases. The mean time of esophagojejunostomy for the FEEA and overlap method was 13.2 and 36.5 minutes, respectively. Two cases with FEEA method and 3 cases with overlap method experienced complications due to esophagojejunostomy leakage. These cases were treated without performing a reoperation. One case with FEEA method was complicated due to esophagojejunostomy stenosis. This case was endoscopically treated. Our procedures are safe and feasible.

BACKGROUND Malignant tumors inhibit antitumor immune responses, which are driven by T-regulatory cells or myeloid-derived suppressor cells (MDSCs). Since MDSCs are involved in invasion, migration, and metastasis of tumor cells, we hypothesized that MDSCs are also involved in tumor recurrence after surgical resection. MATERIALS AND METHODS C57BL/6 mice were subcutaneously inoculated with B16F10 melanoma cells in the right flank. In some experiments, established tumors were surgically resected. Peripheral blood was drawn over time, and immune cells and cytokines were evaluated using flow cytometry. RESULTS MDSCs and relevant pro-inflammatory cytokines increased in the peripheral blood of tumor-bearing mice. Moreover, the frequency of MDSCs rapidly increased in mice with tumor recurrence. CONCLUSION The frequency of MDSCs in the peripheral blood of tumor-bearing mice reflects the status of tumor progression as well as tumor recurrence. Continuous monitoring of MDSCs in the peripheral blood might be a useful indicator of tumor recurrence.

BACKGROUND/AIM The aim of this study was to evaluate the safety and effectiveness of laparoscopic surgery in elderly patients with colorectal cancer. PATIENTS AND METHODS In total, 223 patients aged

We aimed to examine the relationship between the preoperative GSA index [uptake ratio of the liver to the liver plus heart at 15 min (LHL15) to uptake ratio of the heart at 15 min to that at 3 min (HH15) ratio] calculated from 99mTc‑labeled diethylene triamine pentaacetate-galactosyl human serum albumin (99mTc-GSA) scintigraphy and background liver fibrosis and to investigate whether the GSA index can be a useful predictor in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) patients treated with surgical resection (SR). A total of 213 HCV-related HCC patients were analyzed. Receiver operating characteristic (ROC) curve analysis was performed for calculating the area under the ROC (AUROC) for nine noninvasive parameters including GSA index, indocyanine green retention at 15 min, aspartate aminotransferase (AST) to platelet ratio index, FIB-4 index, AST to alanine aminotransferase ratio, serum albumin, total bilirubin, platelet count and prothrombin time for cirrhosis. We also examined predictive factors associated with overall survival (OS) and recurrence-free survival (RFS) after SR in univariate and multivariate analyses. There were 153 males and 60 females with the mean age of 69.9 years. The median observation periods were 2.8 years. The mean maximum tumor size was 4.1 cm. HH15 ranged from 0.452 to 0.897. LHL15 ranged from 0.669 to 0.982. The mean value of the GSA index was 1.41. Among the nine parameters, the GSA index yielded the highest AUROC for cirrhosis with a level of 0.786 at an optimal cut-off value of 1.37 (sensitivity, 65.9%; specificity, 79.0%). In multivariate analyses, the GSA index was an independent predictor (P

The aims of the present study were to examine the relationship between the preoperative FIB-4 index and background liver fibrosis in non-tumor parts obtained from surgical specimens and to investigate whether the FIB-4 index can be a useful predictor for non-B non-C hepatocellular carcinoma (NBNC-HCC) patients treated with surgical resection (SR). A total of 118 patients with NBNC-HCC treated with SR with curative intent were analyzed. Receiver operating characteristic (ROC) curve analysis was performed for calculating the area under the ROC (AUROC) for the FIB-4 index, aspartate aminotransferase (AST) to platelet ratio index, AST to alanine aminotransferase ratio, serum albumin, total bilirubin and platelet count for cirrhosis. We also examined predictors linked to overall survival (OS) and recurrence-free survival (RFS) after SR. The mean patient age was 68.9±9.0 years (93 males and 25 females) with a median observation period of 3.2 years. In extracted surgical specimens, background liver cirrhosis (F4) was observed in 39 patients (33.1%). The mean maximum tumor size was 5.7±3.2 cm. The mean body mass index was 24.3±3.9 kg/m2. The FIB-4 index yielded the highest AUROC for cirrhosis with a level of 0.887 at an optimal cut-off value of 2.97 (sensitivity, 92.3; specificity, 69.6%). In the multivariate analysis, serum α-fetoprotein >40 ng/ml (P=0.026) was the only significant independent predictor linked to OS, while tumor number (P=0.002) and FIB-4 index >2.97 (P=0.044) were significant factors linked to RFS. In conclusion, preoperative FIB-4 index can be a useful predictor for NBNC-HCC patients who undergo SR.

Objectives: We previously reported a cluster of cholangiocarcinoma patients among proof-printing workers who were exposed to 1,2-DCP for a long term. The present study was conducted to evaluate blood parameters in these proof-printing workers during and after exposure. Methods: Health examination records during employment and after retirement were obtained for ten cholangiocarcinoma patients to analyze their blood parameters. The patients and/or their relatives were also interviewed about lifestyle and occupational history. Results: All study patients were exposed to 1,2-DCP for 6–17 years. Red blood cells, hemoglobin, hematocrit, total cholesterol, triglycerides, and fasting plasma glucose were within the standard ranges for almost all patients, but the γ-glutamyl transpeptidase (γ-GTP) levels exceeded the standard range during 1,2-DCP exposure for six patients. Two of the six patients were diagnosed with cholangiocarcinoma during 1,2-DCP exposure, and the other four patients were diagnosed 1–9 years after termination of exposure. The remaining four patients had γ-GTP levels within the standard range during 1,2-DCP exposure, but had increased γ-GTP levels thereafter, and were diagnosed with cholangiocarcinoma 4–10 years after termination of exposure. Aspartate aminotransferase and alanine aminotransferase levels started to increase following the increase in γ-GTP levels. Conclusions: Workers exposed to 1,2-DCP should be provided with periodic health examinations during and after exposure. In the examination, even small increases in γ-GTP levels should be considered a signal of early development of cholangiocarcinoma.(J Occup Health 2014; 56: 279-284)

Background An outbreak of cholangiocarcinoma occurred among workers in the offset color proof-printing department at a printing company in Japan. The aim of this study was to clarify the characteristics of the patients with cholangiocarcinoma. Methods This was a retrospective study conducted in 13 Japanese hospitals between 1996 to 2013. The clinicopathological findings of cholangiocarcinoma developed in 17 of 111 former or current workers in the department were investigated. Most workers were relatively young. Results The cholangiocarcinoma was diagnosed at 25–45 years old. They were exposed to chemicals, including dichloromethane and 1,2-dichloropropane. The serum γ-glutamyl transpeptidase activity was elevated in all patients. Dilated intrahepatic bile ducts without tumor-induced obstruction were observed in five patients. The cholangiocarcinomas arose from the large bile ducts. The precancerous or early cancerous lesions, such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile ducts, as well as non-specific bile duct injuries, such as fibrosis, were observed in various sites of the bile ducts in all eight patients for whom operative specimens were available. Conclusions The present results showed that cholangiocarcinomas occurred at a high incidence in relatively young workers of a printing company, who were exposed to chemicals including chlorinated organic solvents.

Background; The relationship between tumor immunological microenvironment and irradiation has been studied so far. Based on these findings, we examined a tumor microenvironment of rectal cancer performed by neoadjuvant chemoradiotherapy (NACRT) with immunohistochemical analysis of surgical specimens. But, for introduction to clinical settings, the analysis is not yet sufficient. So, in more detail, we investigate tumor infiltrating CD8+ T cells by irradiation in mouse CT26 colon tumor model. Methods; Locally advanced rectal cancer were enrolled and 68 were eligible for this study. Immunohistochemical staining of programmed cell death- lignad1(PD-L1), CD8, and CD163 was performed on specimens of all cases. In a mouse model, CT26 tumor cells were inoculated in mouse, tumors are irradiated with a single dose of 10Gy after 14 days. We analyzed CD8+ T cells infiltration of both irradiated mouse and no treated mouse by flow cytometry. Results; There were 44 cases in which NACRT was performed (NA group) and 24 cases in which surgery alone was performed (SA group). In the SA group, there was no significant change in the infiltration of PD-L1+immune cells (PD-L1+IC) nor CD8 +cells before and after treatment, but in the NA group, the infiltrations of them were significantly increased. In multivariate analysis, low infiltration of CD8 +cells were identified as poor prognostic factors in disease-free survival. Moreover, in our mouse model, elevated numbers of tumor-infiltrating CD8+ T cells between day11 and day18 after irradiation were observed in tumors of irradiated mice compared to no treated mouse. We observed that among CD8+ T cells, cells that coexpress PD-1 and Tim-3 comprise the major population in irradiated mouse. PD-1+Tim-3+ CD8+ T cells produced more INF-γ compared to that by PD-1+Tim-3-CD8+ T cells and PD-1-Tim-3- CD8+ T cells in irradiated mouse and no treated mouse. Among the three populations PD-1+Tim-3+ population contained the largest fraction of central memory (CD44hiCD62Llow) cells, but the lowest fraction of central memory (CD44hiCD62Lhi) cells. Conclusion; The infiltration of PD-L1+IC and CD8 +cells was induced by NACRT. In the mouse model, we confirmed the kinetical and phenotypical changes of tumor-infiltrating CD8+ T cells. Citation Format: Eiji Fukuoka, Kimihiro Yamashita, Yutaka Sugita, Akira Arimoto, Tetsu Nakamura, Yoshihiro Kakeji. The induction of CD8+ T lymphocytes and PD-L1+ immune cells by neoadjuvant chemoradiotherapy for rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2809.

Background: Myeroid-derived suppressor cells (MDSCs) are heterogeneous cell populations derived from bone marrow, and two subsets of M-MDSC and PMN-MDSC are known in mice. They accumulate in the tumor-bearing host, and suppresse cell-mediated immunity mainly on T cells, and inhibit anti-tumor immune responses. We have previously reported that (1) the increase of MDSCs in lung, peripheral blood, and spleen reflects the cancer progression, (2) MDSCs in peripheral blood would be useful as a marker of recurrence as it increases in recurrent cases after surgical resection. On the other hand, no detailed report on the dynamics of intraperitoneal MDSCs has been made. In this study, we made peritoneal dissemination mouse models and monitored intraperitoneal MDSCs, and investigated whether MDSCs are involved in the progression of peritoneal dissemination. Methods: MC38 colon cancer cell line was intraperitoneally injected to C57BL / 6J mice and the change in the number and ratio of immune cells (MDSC, Macrophage, T-cell, B-cell) in the spleen, peripheral blood and peritoneal cavity was monitored over time. We examined the correlation between transition of immune cells and cancer progression. Results: MDSCs increased with cancer progression in all spleen, peripheral blood, and intraperitoneal cavity. The proportion of PMN-MDSCs in MDSCs increased in peripheral blood. In contrast, the proportion of M-MDSCs increased initially, then the PMN-MDSCs increased in the abdominal cavity. Conclusion: Intraperitoneal MDSCs were thought to reflect the progression of peritoneal dissemination as well as spleen and peripheral blood. The proportion of M-MDSCs reflects the disease state in the microperitoneal dissemination with serous ascitic fluid, and ascites became bloody and the proportion of PMN-MDSCs increased with the progression of seeding. We are examining treatment for peritoneal dissemination with this feature in mind. Citation Format: Yutaka Sugita, Kimihiro Yamashita, Rishu Takimoto, Tomoko Tanaka, Akira Arimoto, Eiji Fukuoka, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji. Intraperitoneal myeloid-derived suppressor cells in peritoneal dissemination mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1527.

In the present era of entecavir (ETV) use for chronic hepatitis B (CHB), the prognostic factors in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unclear. The aims of the present study were to investigate the prognostic factors in patients with HBV-related HCC treated with ETV who underwent curative therapy. A total of 74 HBV-related HCC patients treated with ETV who underwent curative therapy were analyzed. Predictive factors associated with overall survival (OS) and recurrence-free survival (RFS) were examined using univariate and multivariate analysis. Our study population included 49 males and 25 females with a median age of 62 years. The median observation period was 3.4 years (range, 0.2–11.5 years). The 1-, 3- and 5-year cumulative OS rates were 100, 89.8 and 89.8%, respectively. The corresponding RFS rates were 82.8, 52.1 and 25.6%, respectively. In this study, 73 patients (98.6%) achieved an HBV DNA level of