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

無症候性腎機能障害が結腸癌術後の臨床経過に及ぼす影響

Purpose: To evaluate the effect of mild renal dysfunction on the clinical course after colectomy in patients with colon cancer. Methods: The subjects of this retrospective study were 263 patients who underwent surgical resection for colon cancer at our hospital between 2011 and 2015. Renal function was assessed based on preoperative estimated glomerular filtration rate (eGFR) values. Patients were divided into groups based on their eGFR value of 55 ml/min/1.73 m2. The Mann-Whitney U test, chi-square or Fisher exact test, and log-rank test were used in the data analysis. Results: There were 59 patients (22.4%) in the low eGFR group and 204 patients in the normal eGFR group. There were differences between the groups in age, comorbidities, and the levels of hemoglobin, albumin, and serum creatinine. The overall postoperative complication rate, frequency of severe complications, and length of stay were significantly higher in the low eGFR group than in the normal eGFR group. Multivariate analysis revealed that low eGFR was the only independent risk factor for severe complications (Clavien-Dindo classification III/IV). There were no differences in survival between the groups. Conclusion: Preoperative asymptomatic renal dysfunction may be correlated with the development of postoperative complications and a possible significant risk factor for severe complications after colon cancer surgery.博士（医学）・甲第804号・令和3年12月21日© 2021. Springer Nature Singapore Pte Ltd.The version of record of this article, first published in Surgery Today, is available online at Publisher’s website: http://dx.doi.org/10.1007/s00595-021-02363-w.発行元が定める登録猶予期間終了の後、本文を登録予定（2021.01

下部直腸癌における側方リンパ節転移に関して、造影MRI で描出される中直腸動脈の転移予測因子に関する検討

Purpose: Lateral lymph node (LLN) metastasis is one of the leading causes of local recurrence in patients with lower rectal cancer. Unfortunately, no diagnostic biomarkers are currently available that can predict LLN metastasis preoperatively. Accordingly, we investigated the relationship between the middle rectal artery (MRA) identified by contrast-enhanced magnetic resonance imaging (ceMRI) and LLN metastases. Methods: Data from 102 patients with lower rectal cancer who underwent surgery, and were evaluated by preoperative ceMRI, between 2008 and 2016 were reviewed retrospectively. Two expert radiologists evaluated the MRA findings. The diagnostic performance of MRA for LLN metastasis was evaluated by a multivariate analysis with conventional clinicopathological factors. Results: The MRA was detected in 67 patients (65.7%), including 32 (31.4%) with bilateral MRA and 35 (34.3%) with unilateral MRA. The tumor size, presence of the MRA, and clinical LLN status were significantly correlated with LLN metastasis. A multivariate analysis demonstrated that the presence of MRA (P = 0.045) and clinical LLN status (P = 0.001) were independent predictive factors for LLN metastasis. Furthermore, the sensitivity and negative predictive value of MRA for LLN metastasis were 95% and 97.1%, respectively. Conclusion: We successfully demonstrated that MRAs could be clearly detected by ceMRI, and the presence of MRA robustly predicted LLN metastasis in patients with lower rectal cancer, highlighting its clinical significance in the selection of more appropriate treatment strategies. Trial registration: Trial registration number: retrospectively registered 2126 Trial registration date of registration: August 23, 2019.博士（医学）・乙第1512号・令和3年12月21日© 2021. The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/

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

Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis

Sphingosine 1-phosphate (S1P), an inflammatory mediator, is abundantly contained in red blood cells and platelets. We hypothesized that the S1P concentration in the peritoneal cavity would increase especially during the menstrual phase due to the reflux of menstrual blood, and investigated the S1P concentration in the human peritoneal fluid (PF) from 14 non-endometriosis and 19 endometriosis patients. Although the relatively small number of samples requires caution in interpreting the results, S1P concentration in the PF during the menstrual phase was predominantly increased compared to the non-menstrual phase, regardless of the presence or absence of endometriosis. During the non-menstrual phase, patients with endometriosis showed a significant increase in S1P concentration compared to controls. In vitro experiments using human intra-peritoneal macrophages (MΦ) showed that S1P stimulation biased them toward an M2MΦ-dominant condition and increased the expression of IL-6 and COX-2. An in vivo study showed that administration of S1P increased the size of the endometriotic-like lesion in a mouse model of endometriosis

Clinical application of scaffolds for cartilage tissue engineering

The purpose of this paper is to review the basic science and clinical literature on scaffolds clinically available for the treatment of articular cartilage injuries. The use of tissue-engineered grafts based on scaffolds seems to be as effective as conventional ACI clinically. However, there is limited evidence that scaffold techniques result in homogeneous distribution of cells. Similarly, few studies exist on the maintenance of the chondrocyte phenotype in scaffolds. Both of which would be potential advantages over the first generation ACI. The mean clinical score in all of the clinical literature on scaffold techniques significantly improved compared with preoperative values. More than 80% of patients had an excellent or good outcome. None of the short- or mid-term clinical and histological results of these tissue-engineering techniques with scaffolds were reported to be better than conventional ACI. However, some studies suggest that these methods may reduce surgical time, morbidity, and risks of periosteal hypertrophy and post-operative adhesions. Based on the available literature, we were not able to rank the scaffolds available for clinical use. Firm recommendations on which cartilage repair procedure is to be preferred is currently not known on the basis of these studies. Randomized clinical trials and longer follow-up periods are needed for more widespread information regarding the clinical effectiveness of scaffold-based, tissue-engineered cartilage repair

結腸直腸内視鏡的粘膜下層剥離術後腸管内洗浄液中遊離腫瘍細胞に対する in vitro 解析

Purpose: Colorectal endoscopic submucosal dissection (ESD) produces exfoliated tumor cells that occasionally cause local recurrence. However, the biological characteristics of these tumor cells have not been clarified. The aim of this study was to clarify the genetic background and viability of exfoliated tumor cells in colorectal ESDs, as well as possible method for their elimination. Methods: Post-ESD intraluminal lavage samples from 19 patients who underwent colorectal ESDs were collected. In four patients with adenocarcinoma, gene mutations in the primary tumors and exfoliated cells in lavage samples were analyzed using a next-generation sequencer (NGS). In 15 patients with adenoma or adenocarcinoma, the viability of exfoliated cells and the cell-killing effect of povidone-iodine on exfoliated cells were evaluated. Results: The analysis using a NGS demonstrated that tumors targeted for ESD had already acquired mutations in many genes involved in cell proliferation, angiogenesis, and invasions. Furthermore, gene mutations between the exfoliated tumor cells and tumors resected by ESDs showed a 92 to 100% concordance. The median viable cell counts and the median viability of exfoliated cells in intraluminal lavage samples after ESDs were 4.9 × 105 cells/mL and 24%, respectively. The viability of the exfoliated cells did not decrease even 12 h after ESD. However, contact with 2.0% povidone-iodine solution reduced both viable cell counts and viability, significantly. Conclusion: A large number of tumor cells exfoliated during colorectal ESDs had acquired survival-favorable gene mutations and could survive for some time. Therefore, a lavage using a solution of 2.0% povidone-iodine may be effective against such cells. Trial registration: The prospective study registered 1317, and the retrospective study registered 2729. The prospective study approved on June 20, 2016, and the retrospective study approved on October 6, 2020.博士（医学）・乙第1520号・令和4年3月15日© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1007/s00384-021-04037-y.発行元が定める登録猶予期間終了の後、本文を登録予定（2023.01

3-(4-Hydroxy-3-methoxyphenyl) propionic acid contributes to improved hepatic lipid metabolism via GPR41

Abstract 3-(4-hydroxy-3-methoxyphenyl) propionic acid (HMPA) is a metabolite produced by the gut microbiota through the conversion of 4-hydroxy-3-methoxycinnamic acid (HMCA), which is a widely distributed hydroxycinnamic acid-derived metabolite found abundantly in plants. Several beneficial effects of HMPA have been suggested, such as antidiabetic properties, anticancer activities, and cognitive function improvement, in animal models and human studies. However, the intricate molecular mechanisms underlying the bioaccessibility and bioavailability profile following HMPA intake and the substantial modulation of metabolic homeostasis by HMPA require further elucidation. In this study, we effectively identified and characterized HMPA-specific GPR41 receptor, with greater affinity than HMCA. The activation of this receptor plays a crucial role in the anti-obesity effects and improvement of hepatic steatosis by stimulating the lipid catabolism pathway. For the improvement of metabolic disorders, our results provide insights into the development of functional foods, including HMPA, and preventive pharmaceuticals targeting GPR41

A Case of Early-Stage Gallbladder Cancer, Positive for ALDH1A1, Which Arose from Adenomyomatosis of the Gallbladder

Adenomyomatosis (ADM) of the gallbladder is a condition characterized by the proliferation of Rokitansky–Aschoff sinus (RAS), in which the epithelium of the gallbladder extends into the muscular layer, causing a thickening of the gallbladder wall. Although ADM is generally considered not to be a precancerous lesion of gallbladder cancer, there are some reports of cases of gallbladder cancer from ADM. Therefore, the relationship between ADM and gallbladder cancer remains controversial. We herein report a case of early-stage gallbladder cancer, BilIN3 (high grade), arising from ADM that was positive for ALDH1A1, an important marker of stem cells and cancer stem cells