ヒト肝細胞癌においてherpesvirus entry mediatorの発現がもたらす影響

BACKGROUND: Herpes virus entry mediator (HVEM), also known as tumour necrosis factor receptor (TNFR) superfamily 14, regulates a variety of physiological and pathological responses in both innate and acquired immunity. Although HVEM is also suggested to be a critical regulator in tumours, actual roles in human cancer are largely unknown. This study aimed to clarify clinical importance of HVEM in human hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We studied HVEM expression in 150 HCC patients to explore its clinical relevance, and we examined tumour infiltrating T cells and local immune status of them. RESULTS: HVEM was expressed in HCC cells, while no or only limited expression was observed in normal tissues in the liver. Tumour HVEM expression was significantly correlated with age, serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) level, vascular invasion and tumour node metastasis (TNM) stage. Furthermore, tumour HVEM expression significantly correlated with postoperative recurrence and survival. Importantly, multivariate analysis indicated that the HVEM status had an independent prognostic value. Furthermore, HVEM status was inversely correlated with tumour-infiltrating CD4(+), CD8(+) and CD45RO(+) lymphocytes. In addition, it was also associated with reduced expression of perforin, granzyme B and interferon-γ (IFN-γ). Taken together, tumour-expressing HVEM plays a functionally important role in HCC. CONCLUSION: Tumour-expressing HVEM plays a critical role in human HCC, possibly through regulating immune evasion. Therefore, targeting HVEM may be a novel promising therapeutic strategy for HCC.博士（医学）・乙第1359号・平成27年5月28日Copyright © 2014 Elsevier Ltd

ヒト大腸癌肝転移におけるHVEM発現の重要性について

Background: Herpesvirus entry mediator (HVEM) has been suggested to play various roles in cancer biology. The authors report that HVEM expression in tumor cells is associated with a reduction in the number of tumor-infiltrating lymphocytes and a poor prognosis after surgical resection in various human gastrointestinal cancers. This study aimed to clarify the clinical significance of HVEM expression in human colorectal liver metastasis (CRLM). Methods: This study examined the cases of 104 patients with CRLM who underwent curative liver resection at Nara Medical University between 2000 and 2014. The median follow-up period was 50.2 months. Immunohistochemical staining was performed using antibodies against HVEM, CD4, CD8, and CD45RO. Results: High HVEM expression was observed in 49 patients (47.1%) with CRLM. Expression of HVEM was not associated with age, gender, administration of preoperative chemotherapy, tumor size, number of tumors, or histologic differentiation. The high-HVEM group exhibited significantly worse overall survival (OS) than the low-HVEM group (P = 0.002). Multivariate analysis showed that high HVEM expression in CRLM, age of 70 years or older, and having five or more tumors are independent poor prognostic factors for OS (hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.41-7.93; P = 0.006). The number of tumor-infiltrating CD8+ and CD45RO+ T cells was significantly lower in the high-HVEM group than in the low-HVEM group. High HVEM expression in primary colorectal cancer was significantly associated with synchronous CRLM, but not with metachronous CRLM. Conclusions: Tumor HVEM expression might play a critical role in CRLM.博士（医学）・乙第1447号・令和元年12月5日© Society of Surgical Oncology 2019This is a post-peer-review, pre-copyedit version of an article published in Annals of surgical oncology. The final authenticated version is available online at: http://dx.doi.org/10.1245/s10434-019-07625-

大腸癌肝転移におけるCD200発現の臨床的意義

Background: Approximately 30% of patients diagnosed with colorectal cancer (CRC) develop liver metastases. We evaluated the role of CD200, a potent immunosuppressive molecule, in colorectal liver metastases (CRLM). Methods: We examined 110 patients who underwent curative liver resection for CRLM at our institution between 2000 and 2016. Based on the results of immunohistochemical analysis, the patients were divided into high-CD200 (n = 47) and low-CD200 (n = 63) expression groups. The relationships between CD200 expression and various clinicopathological outcomes were investigated. Results: The overall survival (OS) of patients in the high-CD200 group was significantly worse than that in the low-CD200 group (p = 0.009). Multivariate analysis showed that the independent prognostic factors in CRLM were maximum tumor size > 30 mm (p = 0.002), preoperative carcinoembryonic antigen level > 20 ng/mL (p < 0.001), primary CRC N2-3 (p = 0.049), and high-CD200 expression (p = 0.004). Furthermore, CD4+, CD8+, and CD45RO+ tumor-infiltrating lymphocytes in CRLM were significantly higher in the low-CD200 group than in the high-CD200 group (p = 0.005, p = 0.001, and p < 0.001, respectively). In addition, patients who had received preoperative chemotherapy had higher CD200 expression than those who had not received preoperative chemotherapy, and OS was significantly worse in patients in the high-CD200 group who had received preoperative chemotherapy. Conclusions: CD200 expression was an independent prognostic factor in CRLM. CD200 may play a critical role in tumor immunity in CRLM, and can therefore be used as a potential therapeutic target in CRLM.博士（医学）・乙第1497号・令和3年3月15日© 2021. Society of Surgical Oncology.© Springer Nature Singapore Pte Ltd. 2020This is a post-peer-review, pre-copyedit version of an article published in Annals of Surgical Oncology. The final authenticated version is available online at: https://doi.org/10.1245/s10434-020-09471-w

根治切除後の結腸癌StageⅡ、StageⅢ、及び大腸癌肝転移における原発部位が与える影響

Purpose: Primary tumor location of colon cancer has been reported to affect the prognosis after curative resection. However, some reports suggested the impact was varied by tumor stage. This study analyzed the prognostic impact of the sidedness of colon cancer in stages II, III, and liver metastasis after curative resection using propensity-matched analysis. Methods: Right-sided colon cancer was defined as a tumor located from cecum to splenic flexure, while any more distal colon cancer was defined as left-sided colon cancer. Patients who underwent curative resection at Nara Medical University hospital between 2000 and 2016 were analyzed. Results: There were 110 patients with stage II, 100 patients with stage III, and 106 patients with liver metastasis. After propensity matching, 28 pairs with stage II and 32 pairs with stage III were identified. In the patients with stage II, overall survival (OS) and recurrence-free survival (RFS) were not significantly different for right- and left-sided colon cancers. In the patients with stage III, OS and RFS were significantly worse in right-sided colon cancer. In those with liver metastasis, OS of right-sided colon cancer was significantly worse than left-sided disease, while RFS was similar. Regarding metachronous liver metastasis, the difference was observed only in the patients whose primary colon cancer was stage III. In each stage, significantly higher rate of peritoneal recurrence was found in those with right-sided colon cancer. Conclusion: Sidedness of colon cancer had a significant and varied prognostic impact in patients with stage II, III, and liver metastasis after curative resection.博士（医学）・乙第1495号・令和3年3月15日Copyright © 2021 The Korean Society of Coloproctology.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

Risk factors for incisional hernia according to different wound sites after open hepatectomy using combinations of vertical and horizontal incisions: A multicenter cohort study.

Background:Although several risk factors for incisional hernia after hepatectomy have been reported, their relationship to different wound sites has not been investigated. Therefore, this study aimed to examine the risk factors for incisional hernia according to various wound sites after hepatectomy.Methods:Patients from the Osaka Liver Surgery Study Group who underwent open hepatectomy using combinations of vertical and horizontal incisions (J-shaped incision, reversed L-shaped incision, reversed T-shaped incision, Mercedes incision) between January 2012 and December 2015 were included. Incisional hernia was defined as a hernia occurring within 3 y after surgery. Abdominal incisional hernia was classified into midline incisional hernia and transverse incisional hernia. The risk factors for each posthepatectomy incisional hernia type were identified.Results:A total of 1057 patients met the inclusion criteria. The overall posthepatectomy incisional hernia incidence rate was 5.9% (62 patients). In the multivariate analysis, the presence of diabetes mellitus and albumin levels <3.5 g/dL were identified as independent risk factors. Moreover, incidence rates of midline and transverse incisional hernias were 2.4% (25 patients), and 2.3% (24 patients), respectively. In multivariate analysis, the independent risk factor for transverse incisional hernia was the occurrence of superficial or deep incisional surgical site infection, and interrupted suturing for midline incisional hernia.Conclusions:Risk factors for incisional hernia after hepatectomy depend on the wound site. To prevent incisional hernia, running suture use might be better for midline wound closure. The prevention of postoperative wound infection is important for transverse wounds, under the presumption of preoperative nutrition and normoglycemia

New Hepatic Resection Criteria for Intermediate-Stage Hepatocellular Carcinoma Can Improve Long-Term Survival: A Retrospective, Multicenter Collaborative Study.

Background:Hepatic resection (HR) is not recommended for intermediate-stage hepatocellular carcinoma (HCC) by the Barcelona Clinic Liver Cancer criteria. We examined the prognostic factors of HR for intermediate-stage HCC and developed new HR criteria for intermediate-stage HCC.Methods:A total of 110 patients who underwent HR without any prior treatment for intermediate-stage HCC between January 2007 and December 2012 were enrolled at eight university hospitals. The outcomes and prognostic factors of HR were evaluated to develop new HR criteria.Results:In terms of tumor size and number, the most significant prognostic factors were within the up-to-seven criteria. Furthermore, serum albumin level ≥35 g/L and serum alpha-fetoprotein (AFP) level

Preventative effects of ramelteon against postoperative delirium after elective liver resection.

BackgroundPostoperative delirium was reported to be associated with increased postoperative mortality after liver resection. Therefore, it is crucial to prevent postoperative delirium in such cases. Ramelteon, an agonist of melatonin receptor has been suggested to be useful for preventing delirium. The aim of this study was to examine whether ramelteon is effective at preventing delirium after elective liver resection.MethodsThe cases of patients who underwent liver resection at Nara Medical University (Nara, Japan) between January 2014 and August 2018 were analyzed. During the period from January 2017 to August 2018, ramelteon was prospectively administered to patients who underwent liver resection [8 mg/day on the day before surgery and on postoperative days 1 to 3] (ramelteon group), whereas ramelteon was not administered during the period from January 2014 to December 2016 (control group). The perioperative outcomes of the two groups were compared.ResultsThere were 120 patients in the ramelteon group and 186 patients in the control group. No significant intergroup differences in background factors, including age, gender, and preoperative serological laboratory data, were detected. The incidence of postoperative delirium was significantly lower in the ramelteon group (5.8% vs. 15.1%, P = 0.035). Multivariate analysis revealed that being aged ≥75 (P = 0.002), being male (P = 0.020), cardiovascular disease (P = 0.023), blood loss ≥1000ml (P = 0.001) and the absence of ramelteon treatment (P = 0.046) were independent risk factors for postoperative delirium.ConclusionThe administration of ramelteon might reduce the risk of postoperative delirium after elective liver resection