食道切除後の臨床経過に対する無症候性腎機能障害の影響

Purpose: Recent large-scale clinical studies have shown that preoperative renal insufficiency is associated with an increased risk of postoperative complications after esophagectomy; however, it remains unclear whether asymptomatic renal dysfunction affects the postoperative course after esophagectomy. Methods: The subjects of this retrospective study were 177 patients who underwent esophagectomy between May, 2009 and December, 2018. Renal function was evaluated based on the pretreatment estimated glomerular filtration rate (eGFR). Patients were divided into two groups according to the eGFR cut-off value of 55 ml/min per 1.73 m2. Results: There were 17 patients in the low eGFR group and 160 patients in the normal group eGFR group. The rate of severe complications was significantly higher in the low eGFR than in the normal eGFR group. A low eGFR was the only significant complication risk factor identified; however, there were no marked differences in mortality or survival between the low and normal eGFR groups. Conclusion: Our findings demonstrate that pretreatment asymptomatic renal dysfunction may be a significant risk factor for severe morbidity after esophagectomy.博士（医学）・乙第1494号・令和3年3月15日© Springer Nature Singapore Pte Ltd. 2020This is a post-peer-review, pre-copyedit version of an article published in Surgery today. The final authenticated version is available online at: https://doi.org/10.1007/s00595-020-02118-z

ヒト胃癌患者におけるtripartite motif 32の過剰発現は予後不良に関連する

Tripartite motif protein (TRIM) 32 belongs to the TRIM family, which is composed of RING finger, B-box and coiled-coil domains. TRIM32 has been reported to function as an enzyme 3 ubiquitin ligase and is overexpressed in numerous types of cancer. The present study evaluated the clinical significance of TRIM32 expression levels in gastric cancer. The current study also investigated the TRIM32 expression levels in 142 patients with gastric cancer using immunohistochemistry and examined its clinical importance and potential as a prognostic marker. Furthermore, the function of TRIM32 was examined in vitro. High TRIM32 expression levels were detected in gastric cancer tissues. The postoperative overall and relapse-free survival rates were significantly reduced in patients with tumors with high levels of TRIM32 expression compared with those with tumors expressing low levels of TRIM32. Tumors expressing high levels of TRIM32 were associated with an increased risk of postoperative recurrence, particularly hematogenous recurrence. Multivariate analysis identified TRIM32 status as an independent prognostic factor. Furthermore, TRIM32 gene silencing induced apoptosis and inhibited the proliferation of gastric cancer cells in vitro. Therefore, TRIM32 expression levels may be of potential prognostic value in gastric cancer.博士（医学）・乙第1402号・平成29年6月28日Copyright © Spandidos Publications 2017. All rights reserved.The Spandidos Publications link is available at " http://dx.doi.org/10.3892/ol.2017.5806

食道扁平上皮癌における予後因子および腫瘍進展メカニズムとCullin4A高発現との関連性について

Background: Cullin4A (CUL4A), which is a component of E3 ubiquitin ligase, is implicated in many cellular events. Although the altered expression of CUL4A has been reported in several human cancers, the role of CUL4A in esophageal cancer remains unknown. Methods: We investigated the CUL4A expression in primary esophageal squamous cell carcinoma (ESCC) tissue specimens from 120 patients by immunohistochemistry and explored its clinical relevance and prognostic value. Furthermore, the effect of the expression of CUL4A on cancer cell proliferation was analyzed in vitro using an siRNA silencing technique. Results: The higher expression of CUL4A was significantly associated with a deeper depth of tumor invasion (P < 0.001) and the presence of venous invasion (P = 0.014). The disease-specific survival (DSS) rate in patients with tumors that showed high CUL4A expression levels was significantly lower than that in patients whose tumors showed low CUL4A expression levels (P = 0.001). Importantly, the CUL4A status was identified as an independent prognostic factor for DSS (P = 0.045). Our results suggested that the CUL4A expression has significant prognostic value in ESCC. Furthermore, CUL4A gene silencing significantly inhibited the proliferation of ESCC cells in vitro. In addition, the knockdown of the CUL4A expression induced G1 phase arrest and increased the p21 and p27 protein levels. Conclusions: CUL4A might play an important role in regulating the proliferation of ESCC cells and promoting the development of postoperative recurrence.博士（医学）・乙第1449号・令和2年3月16日© Japan Society of Clinical Oncology 2019This is a post-peer-review, pre-copyedit version of an article published in International journal of clinical oncology. The final authenticated version is available online at: http://dx.doi.org/10.1007/s10147-019-01547-2

Ring box protein-1 は食道癌の予後不良因子であり、腫瘍の進行と関連している

Ring box protein-1 (RBX1) is an essential component of the S-phase kinase-associated protein, Cullin and F-box containing ubiquitin ligases. Overexpression of RBX1 has been reported in several cancer types; however, little is known regarding the prognostic value and role of RBX1 in esophageal cancer. The present study examined 120 patients with esophageal cancer (EC) who underwent curative esophagectomy and 61 patients with EC who underwent neoadjuvant combination chemotherapy with docetaxel, cisplatin and 5-fluorouracil (5-FU; DCF) using immunohistochemistry. All specimens were classified into two groups according to the percentage of RBX1-positive tumor cells. In addition, the impact of RBX1 expression on cancer cell proliferation was analyzed in vitro using a small interfering RNA silencing technique. RBX1 expression levels showed significant differences according to tumor size (P<0.001), tumor depth (P=0.002), lymph node metastasis (P=0.004), pathological stage (P=0.001), lymphatic invasion (P=0.001) and venous invasion (P=0.001). The overall survival (OS) rate in the RBX1 high expression group was significantly lower compared with that in the low group (P=0.004). Multivariate analysis demonstrated that RBX1 status was an independent prognostic factor. RBX1 gene silencing inhibited the proliferation of human EC cells and enhanced the antitumor effect of 5-FU. Among patients who underwent neoadjuvant DCF therapy, the RBX1 high expression group had a significantly lower OS rate compared with that of the RBX1-low group (P<0.001). In conclusion, RBX1 has notable prognostic value, and RBX1 may serve an important function in the tumor progression of EC.博士（医学）・乙第1480号・令和2年12月24日Copyright: © Kunishigeet al. This is an open access article distributed under theterms of CreativeCommons Attribution License(https://creativecommons.org/licenses/by-nc-nd/4.0/)

A neuroendocrine carcinoma with a well-differentiated adenocarcinoma component arising in Barrett’s esophagus: a case report and literature review

Abstract Background An esophageal neuroendocrine carcinoma arising in Barrett’s esophagus is extremely rare. Here, we report a case of an esophageal neuroendocrine carcinoma with a well-differentiated adenocarcinoma component arising in Barrett’s esophagus and review the literature. Case presentation A 71-year-old man with no symptoms was admitted to our hospital because of the detection of an esophagogastric junction tumor on regular upper endoscopy screening. Endoscopy revealed a sliding hiatal hernia and an approximately 10 mm elevated mass at the esophagogastric junction. Biopsy showed a moderately differentiated tubular adenocarcinoma. Computed tomography did not indicate lymph node metastasis or distant metastasis. Proximal gastrectomy with D1 lymph node dissection was performed along with jejunal interposition. On immunohistochemical staining, the tumor was positive for chromogranin A and synaptophysin. Ki-67 was positive in 40% of the tumor cells. The histological diagnosis was a neuroendocrine carcinoma with a well-differentiated adenocarcinoma component arising in Barrett’s esophagus. The postoperative course was good, and the patient was discharged on the twentieth postoperative day. He has remained free of the disease at 36 months postoperatively. Conclusions Barrett’s esophagus may be related to the development of a neuroendocrine carcinoma

Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis

DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S-adenosyl-l-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affects Ccnd2 expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit S-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits S-nitrosylation of DNMT3B at low concentrations (IC50 <= 100nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrant S-nitrosylation of DNMT3B