Supplementary Figure 2 from MicroRNA-375 Is Downregulated in Gastric Carcinomas and Regulates Cell Survival by Targeting PDK1 and 14-3-3ζ

Supplementary Tables 1-4 from MicroRNA-375 Is Downregulated in Gastric Carcinomas and Regulates Cell Survival by Targeting PDK1 and 14-3-3ζ

目的:消化器外科領域のsurgical site infection(以下,SSIと略記)発生抑制のために,SSIサーベイランスにおけるSSI発生リスク因子を明らかにする.対象と方法:当施設では2005年よりサーベイランスを実施し,SSI予防策が一定となった2009年4月から2013年3月までの消化器外科手術症例1,560例を対象とした.SSI発生のリスク因子を解析し,手術手技別に各手術アプローチのSSI発生率を調べた.結果:単変量解析にて年齢・糖尿病・悪性疾患・SSI Risk Index Score・創分類・American Society of Anesthesiologistsスコア(以下,ASAスコアと略記)・人工肛門造設術・緊急手術・合併手術・手術アプローチ(開腹/腹腔鏡手術)・手術時間におけるSSI発生率が有意に高く,性別・肥満・喫煙は有意なSSI発生率上昇を認めなかった.単変量解析で有意であった項目の多変量解析にて,ASAスコア3点以上,悪性疾患,開腹手術,合併手術,人工肛門造設術,糖尿病,80歳以上が高いオッズ比順のSSI発生の独立リスク因子であった.肝胆膵,大腸の手術においては,腹腔鏡手術で有意にSSI発生率が低下していた.結語:SSIサーベイランスにおけるSSI発生のリスク因子において,手術アプローチはSSI発生抑制に外科医が介入しうる点で重要であると考えられた.

Previously, we have reported that gain at chromosome 20q13 is the most common genomic copy number aberration in gastric cancer (GC) (29/30 cases), and that among the genes located in this region, we have identified DDX27, whose expression level shows the highest correlation with genomic copy number, as a candidate therapeutic target for GC. Here, we analyzed the clinicopathological significance of DDX27 using immunohistochemistry and studied its functions using knockdown assays. We found that DDX27 was frequently upregulated in GC tissues (98 of 140 cases, 70%), and significantly associated with venous invasion and liver metastasis. Furthermore, multivariate analysis of GC patients showed that high expression of DDX27 was independently associated with poorer prognosis. In functional assays, knockdown of DDX27 reduced the ability of GC cells to form colonies both on conventional plates and soft agar, but had little effect on their invasiveness. We also found that knockdown of DDX27 reduced the viability of GC cells through inhibition of cell cycle progression independently of apoptosis. Interestingly, DDX27 depletion induced accumulation of TP53 in a TP53 wild-type cell line, AGS, but not in a TP53-deleted cell line, 44As3, although DDX27 knockdown commonly reduced the viability of both, indicating the TP53-dependent and independent cell cycle control of DDX27. Thus, our results suggest that expression of DDX27 contributes to colony formation by GC cells through cell cycle control and may be a potential therapeutic target for GC patients with chromosome gain at 20q13.

Gastric cancer (GC) is one of the most common human cancers. Genes expressed only in cancer tissue, especially on the cell membrane, will be useful biomarkers for cancer diagnosis and therapeutics.

近年，医学生の持つ外科医へのイメージの悪化より，医学生や若い医師の外科医志望者が減少しているとされる．よって，医学生が持つ外科医に対するイメージと外科医自身のイメージの相違点を明らかにするために，大分大学医学生と大分県の外科医に，アンケート調査を行った．質問項目は，(1)外科医へのイメージ，(2)外科キャリア形成と外科教育に対するイメージ，(3)「外科医の仕事のやりがい」に関するイメージについて，49項目からなる．有効回答者数は，医学生260名（回答率:91％），外科医213名（回答率:93％）であった．結果より，医学生は外科医に比べ，外科の将来性を感じてはいるものの，外科医の労働環境の悪さや外科医自身の満足感は低いというイメージを有していた．外科医の労働環境整備に加え，学生教育を通じて外科の面白さややりがいを医学生に伝えていくことが，外科医志望者増加につながると考えられる．

Primary adenocarcinoma of the esophagus is rare in Japan and, in most cases, arises from Barrett's esophagus epithelium. A 72-year-old man reporting heartburn and dysphagia and preoperatively diagnosed with adenosquamous carcinoma arising from Barrett's esophagus underwent thoracic esophagectomy and lymph node dissection in curative resection. Pathological diagnosis of the resected specimen showed adenosquamous carcinoma (coexistent adenocarcinoma and squamous cell carcinoma) invasive to the submucosal layer; metastasis was found in regional lymph nodes. Pathological staging was pT1bN1M0, stage II. Unfortunately, the man died of liver and lung metastasis 17 months postoperatively. To our knowledge, this rare case is only the fifth reported in the English literature on adenosquamous carcinoma arising from Barrett's esophagus.

Purpose: Platinum-based chemotherapy is widely recognized to cause severe gastrointestinal disorders. The aim of this study was to assess the plasma gastrointesitinal peptide levels and their association with appetite during chemotherapy in patients with esophageal cancer.

135 Background: Chemotherapy-induced nausea and vomiting (CINV) is still one of the major problems in cancer treatment. However detailed profile of CINV in patients with esophageal cancer is not known. Prospective multi-center observational study was conducted to assess the current status of CINV in Japan. Methods: Between May 2011 and December 2012, 193 patients with esophageal cancer who underwent systemic chemotherapy with high (HEC) or moderate emetogenic agents (MEC) were registered. Antiemetic drugs (5-HT3 receptor antagonists, dexamethasone and NK1receptor antagonist) were used to suppress CINV. Occurrence and severity of CINV were assessed with a diary provided to the patients prior to chemotherapy. Acute phase (within 24 hours from the start of chemotherapy) and late phase CINV (24 hours or later) were assessed separately. Multivariate logistic regression analysis was conducted to identify the predictive factors for acute and late phase CINV. Results: Of 193 patients 165 were male and 28 were female. Median age was 66 (range 40-84). HEC and MEC were administered in 180 and 13 patients, respectively. Acute phase nausea and vomiting were observed in 9 (4.7%) and 7 (3.6%) of 193 patients, respectively. Late-phase nausea and vomiting were observed in 75 (38.9%) and 18 (9.3%) of 193 patients, respectively. Risk factors for acute phase nausea, acute phase vomiting, late phase nausea and late-phase vomiting were assessed separately. By multivariate analysis for late-phase vomiting, younger age (Odds ratio 0.523 [every 10 years]; 95%CI 0.278-0.986; p=0.045) and male gender (Odds ratio 5.796; 95%CI 1.806-18.603; p=0.003) were independent predictive factors. By multivariate analyses for acute phase nausea, acute phase vomiting and late-phase nausea, no independent predictive factor was identified. Conclusions: Acute phase CINV was effectively suppressed by antiemetic drugs, while late phase CINV was not sufficiently suppressed. Further intervention to suppress late phase CINV should be considered, especially in high-risk patients. Clinical trial information: UMIN000005971.

In advanced esophageal carcinoma, aortic complications can be fatal. Here, we report our experience with a patient undergoing salvage lymphadenectomy after preoperative aortic stent grafting for paraaortic lymph node recurrence for esophageal carcinoma. The patient was a 54-year-old man, who underwent subtotal esophagectomy for thoracic esophageal carcinoma. Computed tomography performed 12 months after the initial surgery revealed lymphadenopathy on the left side of the thoracic aorta and radiotherapy was performed for lymph node recurrence. FDG-PET performed after radiotherapy revealed slight growth of the lymph node involvement and an accumulation of FDG. We decided to insert a stent graft into the aorta at the site of tumor invasion before surgery to ensure safety. The tumor was sharply dissected and excised with Cooper’s scissors after the aorta had been taped at the levels upstream and downstream from the tumor. After surgery, chylothorax was observed, but resolved with conservative treatment. The patient was discharged 30 days after surgery.

Cancer ScienceVolume 105, Issue 1 p. January cover-January cover Cover ImageOpen Access Nardilysin protein promotes invasion of esophageal cell carcinoma (ESCC) cells through induction of MMP2 and MMP3. Immunohistochemical analysis of nardilysin in ESCC tissue Naohiro Uraoka, Naohiro UraokaSearch for more papers by this authorNaohide Oue, Naohide OueSearch for more papers by this authorNaoya Sakamoto, Naoya SakamotoSearch for more papers by this authorKazuhiro Sentani, Kazuhiro SentaniSearch for more papers by this authorHtoo Zarni Oo, Htoo Zarni OoSearch for more papers by this authorYutaka Naito, Yutaka NaitoSearch for more papers by this authorTsuyoshi Noguchi, Tsuyoshi NoguchiSearch for more papers by this authorWataru Yasui, Wataru YasuiSearch for more papers by this author Naohiro Uraoka, Naohiro UraokaSearch for more papers by this authorNaohide Oue, Naohide OueSearch for more papers by this authorNaoya Sakamoto, Naoya SakamotoSearch for more papers by this authorKazuhiro Sentani, Kazuhiro SentaniSearch for more papers by this authorHtoo Zarni Oo, Htoo Zarni OoSearch for more papers by this authorYutaka Naito, Yutaka NaitoSearch for more papers by this authorTsuyoshi Noguchi, Tsuyoshi NoguchiSearch for more papers by this authorWataru Yasui, Wataru YasuiSearch for more papers by this author First published: 24 January 2014 https://doi.org/10.1111/cas.12325AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume105, Issue1January 2014Pages January cover-January cover RelatedInformation

INTRODUCTION:We recently observed an increased incidence of severe enterocolitis following laparoscopic low anterior resection (LAR) in some patients with stage II/III rectal cancer. This study aimed to examine the influence of laparoscopic LAR on postoperative enterocolitis compared with open LAR for Stage II/III rectal cancer.METHODS:From April 2002 to March 2012, we evaluated 65 patients with stage II/III cancer of the upper or lower rectum who underwent LAR. Among these, 27 patients underwent open LAR and 38 underwent laparoscopic LAR. First, we compared short-term outcomes between the two groups. Next, we evaluated the incidence of postoperative enterocolitis in the laparoscopic LAR group. The clinicopathological factors were examined by univariate and odds ratio (OR) analysis.RESULTS:Univariate analysis revealed significant differences in the occupancy rate, tumor location, depth of tumor invasion, operative time, amount of intraoperative blood loss, and postoperative enterocolitis between the laparoscopic and open groups. Postoperative enterocolitis developed in 6 of 38 patients (15.8%) in the laparoscopic group and in no patient in the open group. The occurrence of postoperative enterocolitis was significantly associated with BMI (≥28 kg/m(2) ), operative time, and wound infection in the laparoscopic LAR group (OR: 0.11, 95% confidence interval: 0.044-0.280, P < 0.05; OR: 1.40, 95% confidence interval: 1.068-1.835, P < 0.05; and OR: 15.0, 95% confidence interval, 1.752-128.310, P < 0.05, respectively).CONCLUSION:Postoperative enterocolitis occurred more frequently after laparoscopic LAR than after open LAR in patients with stage II/III rectal cancer. Clinical management in the perioperative period of laparoscopic LAR is necessary to prevent postoperative enterocolitis in obese patients and those with a prolonged operative time.

Endocrine cell carcinoma (ECC) of the esophagogastric region is a rare malignancy with varied etiologies. In this report, we describe a 64-year-old patient in whom a superficial carcinoma at the esophagogastric junction was detected via endoscopy. No metastasis was noted, and the patient underwent total gastrectomy. During a 1-year follow-up, there was no evidence of recurrence or metastasis. Upon histological analysis, the lesion was found to comprise squamous cell carcinoma (SCC) with an in situ component and a component that had invaded the submucosal layer, in addition to an ECC component. There was no indication of a collision carcinoma, and Nanog negativity excluded the possibility that a cancer stem cell etiology could explain the different cell types. The evidence suggested differentiation from SCC to ECC during the progression to invasive SCC. We describe the possibility of SCC differentiation into ECC and discuss the associated controversial issues.

The prognosis for brain metastasis from primary esophageal or gastric cancer is often poor because of late detection and a lack of effective treatments. We encountered two cases of long-term survival after resection of brain metastasis that was detected >1 year after primary esophagogastric junction adenocarcinoma resection. Both patients underwent total gastrectomy, middle to lower esophagectomy, and Roux-en-Y reconstruction using the jejunum, and intrathoracic anastomosis was performed via right thoracotomy and laparotomy for primary tumor resection as well as brain metastasis resection followed by CyberKnife irradiation. They remained recurrence free-one remains alive after 6.5 years, while the other died of myocardial infarction 4 years after surgery. The present cases emphasize that long-term survival in patients with brain metastasis from gastric cancer can be expected after resection and stereotactic radiosurgery of brain metastasis detected >1 year after the resection of primary gastric adenocarcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. In the present study, to identify novel prognostic markers or therapeutic targets for ESCC, we reviewed a list of genes with upregulated expression in ESCC compared with normal esophagus, as identified by our serial analysis of gene expression (SAGE) analysis. We focused on the NRD1 gene, which encodes the nardilysin protein. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in 34 ESCC tissue samples revealed that mRNA expression of NRD1 was upregulated in 56% of ESCC tissue samples. Immunohistochemical analysis of nardilysin in 109 ESCC tissue samples demonstrated that 43 (39%) ESCC cases were positive for nardilysin. Nardilysin-positive ESCC cases were more advanced in terms of T classification (P = 0.0007), N classification (P = 0.0164), and tumor stage (P < 0.0001) than nardilysin-negative ESCC cases. Furthermore, nardilysin expression was significantly associated with poorer prognosis (P = 0.0258). Univariate and multivariate analyses revealed that nardilysin expression is an independent prognostic classifier of patients with ESCC. The invasiveness of NRD1-knockdown TE1 and TE5 esophageal cancer cell lines was less than that of the negative control siRNA-transfected cell lines. Expression of MMP2 and MMP3 mRNA was significantly lower in NRD1-knockdown TE5 cells than in negative control siRNA-transfected cells. These results suggest that nardilysin is involved in tumor progression, and is an independent prognostic classifier in patients with ESCC.

近年の外科医不足は社会問題化しており，早急な状況の改善が期待されている．臨床現場での問題点を明らかにするために，大分県内の病院に勤務する外科医に郵送によるアンケート調査を行い，「更なる外科医を必要と感じる」要因について検討を行った．質問項目は，(1)勤務施設環境，(2)診療状況，(3)福利・厚生に関する31項目からなる．211名（回答率91％）の回答のうち，大学以外の勤務外科医179名の回答を対象とした．結果は，1）40歳以上，2）病床100床以上の病院，3）週間手術数5件以上（執刀が3件以上）4）担当入院患者数が11人以上，の外科医が更なる外科医を必要と感じていた．医師派遣を調整している大学や病院経営者にとってこれらの結果は有用な情報となるであろう．

Abstract Gastric cancer remains one of the most common malignant diseases, despite its steady declining trend worldwide. Overall, gastric cancer mortality is estimated to be 700000 cases annually (10.4% of all cancer related death), ranking second only after lung cancer. 14-3-3zeta, a member of 14-3-3 proteins, have important roles in a wide range of biological processes through the interactions with >100 key proteins, such as FOXO3a, Bad and CCND1. Recent studies have revealed that up-regulation of 14-3-3zeta contribute to the transformation phenotype of breast and lung cancer. However, the relevance of 14-3-3zeta expression in gastric carcinogenesis remained poorly understood. In this study, we aimed to clarify the clinicopathological significance of 14-3-3zeta expression in patients with gastric cancer. A total of 192 gastric cancer specimens were obtained from patients undergoing curative surgery at Oita University Hospital. The expression levels of 14-3-3zeta were investigated by immunohistochemistry. The relationship between the 14-3-3zeta expression pattern and the clinicopathological variables of the gastric cancer patients were analyzed. 14-3-3zeta was strongly expressed in 102of the 192 cases. Strong expression of 14-3-3zeta was correlated with Lymph node metastasis, Histological subtype and Tumor stage (Fisher's exact test, p<0.05). These results suggest that up-regulation of 14-3-3zeta is associated with the clinically malignant features of gastric cancer. Citation Format: Tetsuya Aizawa, Yoshiyuki Tsukamoto, Masatsugu Moriyama, Tsuyoshi Noguchi. The relationship between the 14-3-3zeta expression pattern and the clinicopathological variables of the 192 gastric cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1161. doi:10.1158/1538-7445.AM2013-1161

BACKGROUND:Previously, using miRNA microarray, we have found that miR-29c is significantly downregulated in advanced gastric carcinoma. In the present study, we investigated whether miR-29c functions as a tumor-suppressor miRNA in gastric carcinoma cells. For this purpose, we verified the downregulation of miR-29c in gastric carcinoma tissues, and assessed the biological effect of miR-29c on gastric carcinoma cells.RESULTS:In miR-29c-transfected cells, both proliferation and colony formation ability on soft agar were significantly decreased. Although apoptosis was not induced, BrdU incorporation and the proportion of cells positive for phospho-histone H3 (S10) were significantly decreased in miR-29c-transfected cells, indicating that miR-29c may be involved in the regulation of cell proliferation. To explain the mechanism of growth suppression by miR-29c, we explored differentially expressed genes (>2-fold) in miR-29c-transfected cells in comparison with negative control transfected cells using microarray. RCC2, PPIC and CDK6 were commonly downregulated in miR-29c-transfected MKN45, MKN7 and MKN74 cells, and all of the genes harbored miR-29c target sequences in the 3'-UTR of their mRNA. RCC2 and PPIC were actually upregulated in gastric carcinoma tissues, and therefore both were identified as possible targets of miR-29c in gastric carcinoma. To ascertain whether downregulation of RCC2 and/or PPIC is involved in the growth suppression by miR-29c, we transfected siRNAs against RCC2 and PPIC into MKN45 and determined cell viability, the rate of BrdU incorporation, and caspase activity. We found that RCC2-knockdown decreased both cell viability and BrdU incorporation without any increase of caspase activity, while PPIC-knockdown did not, indicating that downregulation of RCC2 may be at least partly responsible for the growth suppression by miR-29c.CONCLUSIONS:Our findings indicate that miR-29c may have tumor-suppressive functions in gastric carcinoma cells, and that its decreased expression may confer a growth advantage on tumor cells via aberrant expression of RCC2.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a serious neurologic disease characterized by visual disturbance, seizures, headache, and altered mental status associated with white matter changes, particularly in the occipital lobes. RPLS has been attributed to chemotherapy, including modified FOLFOX6 regimens consisting of 5-fluorouracil, oxaliplatin, and leucovorin. Although the mechanism of development of RPLS remains unclear, impaired cerebral blood flow autoregulation and endothelial dysfunction seem to be involved. In particular, endothelial dysfunction has been implicated in the pathophysiology of RPLS associated with platinum agents. Platinum-based chemotherapy is thought to have a direct toxic effect on the vascular endothelium, leading to capillary leakage, disruption of the blood–brain barrier, and axonal swelling, triggering vasogenic edema. Much progress has been made in chemotherapy for colorectal cancer, and the increasing use of molecular-targeted agents is expected to further improve the outcome of therapy. RPLS has recently been associated with such molecular-targeted therapy, particularly in patients concurrently receiving platinum agents. This finding is consistent with previous reports suggesting that RPLS occurs more often in patients receiving platinum-based therapy than in those receiving molecular-targeted agents. Because platinum agents are the most widely used in cancer chemotherapy, clinicians should strongly suspect RPLS in patients receiving treatment with this class of drug.

BACKGROUND/AIMS:It remains unclear whether synchronous, multiple, early gastric cancers can be radically resected with endoscopic resection.METHODOLOGY:Patients who underwent gastrectomy for early gastric cancer were included in this study and divided into two groups: a solitary gastric cancer group and a multiple gastric cancer group. The clinicopathological features of patients in each group were compared and the criteria for endoscopic resection were subsequently investigated.RESULTS:A total of 244 patients were included in the present study. The solitary and multiple gastric cancer groups included 228 patients (93.4%) and 16 patients (6.6%), respectively. The multiple gastric cancer group included 35 lesions, including a greater number of larger tumors and protruded- type tumors, as well as increased incidence of submucosal and lymphatic invasion. Only 2 of 16 cases (12.5%) in the multiple gastric cancer group met the criteria for endoscopic resection. Eleven cases were excluded due to submucosal invasion and three cases were excluded due to undifferentiated histopathological type tumors.CONCLUSIONS:To be suitable for radical endoscopic resection, prompt detection of early gastric cancer is essential, before they become multiple gastric cancers and invade the submucosa.