記述言語：英語  

DOI： 10.1186/s40792-024-02033-2

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PubMed

記述言語：英語  

DOI： 10.1038/s41591-024-03254-6

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PubMed

記述言語：英語  

DOI： 10.1159/000540840

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PubMed

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記述言語：英語   出版者・発行元：Clinical Colorectal Cancer  

Background: The significance of angiogenic factors as predictors of second-line (2L) chemotherapy efficacy when combined with angiogenesis inhibitors for metastatic colorectal cancer (mCRC) remains unestablished. Patients and Methods: In this multicenter prospective observational study, 17 angiogenic factors were analyzed in plasma samples collected at pretreatment and progression stages using a Luminex multiplex assay. Patients who received chemotherapy plus bevacizumab (BEV group), FOLFIRI plus ramucirumab (RAM group), or FOLFIRI plus aflibercept (AFL group) as the 2L treatment were included. Interactions between pretreatment and treatment groups for progression-free survival (PFS), overall survival (OS), and response rate (RR) were assessed using the propensity-score weighted Cox proportional hazards model. Results: From February 2018 to September 2020, 283 patients were analyzed in the 2L cohort. A strong interaction was observed for PFS between BEV and RAM with HGF, sNeuropilin-1, sVEGFR-1, and sVEGFR-3. Interactions for RR between the BEV and RAM groups were observed for sNeuropilin-1 and sVEGFR-1. Contrarily, OS, PlGF, sVEGFR-1, and sVEGFR-3 differentiated the treatment effect between BEV and AFL. Plasma samples were evaluable for dynamic analysis in 203 patients. At progression, VEGF-A levels significantly decreased in the BEV group and increased in the RAM and AFL groups. Conclusion: The pretreatment plasma sVEGFR-1 and sVEGFR-3 levels could be predictive biomarkers for distinguishing BEV and RAM when combined with chemotherapy in 2L mCRC treatment. Based on the VEGF-A dynamics at progression, selecting RAM or AFL for patients with significantly elevated VEGF-A levels may be a 2L treatment strategy, with BEV considered for the third-line treatment. Clinical Trial Number: UMIN000028616

DOI： 10.1016/j.clcc.2024.01.003

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PubMed

記述言語：英語  

DOI： 10.1097/SLA.0000000000006290

PubMed

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

手術室と遠隔地にそれぞれ触覚フィードバック付きの術者用コンソールを設置し、遠隔手術における触覚フィードバックの有用性を検証し、さらに遠隔ロボット手術の安全性向上を目的として、動物実験を行った。術者用コンソールは福岡市と別府市の手術室に設置し、3段階の触覚フィードバックレベルをランダム順に設定した。術者(現地5名、遠隔地5名)を盲検化し、各触覚レベルでロボット鉗子によりブタの腸を把持する、持ち上げる、下げる、離すという一連の動作を10回繰り返してもらった。その結果、課題の精度や平均把持力には、術者の場所による顕著な差は見られなかった。しかし、遠隔地の場合は現地よりも平均課題完了時間が有意に長く、system usability scaleが有意に低かった。触覚フィードバックレベル間で、課題の精度や課題完了時間に顕著な差はなかったが、触覚フィードバックがある場合はない場合よりも有意に弱い力で臓器を把持することができた。さらに、触覚フィードバックがある場合、ロボット手術の経験が豊富な外科医は、経験の浅い外科医よりも弱い把持力で同等のタスクを行う傾向があった。

記述言語：英語   出版者・発行元：Surgery Today  

Purpose: To verify the usefulness of haptic feedback in telesurgery and improve the safety of telerobotic surgery. Methods: The surgeon's console was installed at two sites (Fukuoka and Beppu; 140 km apart), and the patient cart was installed in Fukuoka. During the experiment, the surgeon was blinded to the haptic feedback levels and asked to grasp the intestinal tract in an animal model. The surgeon then performed the tasks at each location. Results: No marked differences in task accuracy or average grasping force were observed between the surgeon locations. However, the average task completion time was significantly longer, and the system usability scale (SUS) was significantly lower rating for remote operations than for local ones. No marked differences in task accuracy or task completion time were observed between the haptic feedback levels. However, with haptic feedback, the organ was grasped with a significantly weaker force than that without it. Furthermore, with haptic feedback, experienced surgeons in robotic surgery tended to perform an equivalent task with weaker grasping forces than inexperienced surgeons. Conclusion: The haptic feedback function is a tool that allows the surgeon to perform surgery with an appropriate grasping force, both on site and remotely. Improved safety is necessary in telesurgery; haptic feedback will thus be an essential technology in robotic telesurgery going forward.

DOI： 10.1007/s00595-023-02732-7

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DOI： 10.1200/JCO.2024.42.3_suppl.123

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DOI： 10.1200/JCO.2024.42.3_suppl.6

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DOI： 10.1200/JCO.2024.42.3_suppl.23

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出版者・発行元：Gan to kagaku ryoho. Cancer & chemotherapy  

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

本研究の目的は、日本における、局所進行直腸癌(LARC)に対するtotal neoadjuvant therapy(TNT)の妥当性と安全性を評価することである。本研究は、5施設で施行された前向き多施設オープンラベル、シングルアーム第2相試験である。主たる適格基準は、年齢20歳以上、肛門縁から12cm以内のLARC、診断時にcT3-4N0M0またはTanyN+M0で、治癒切除可能であることとした。術前短期間放射線照射(SRCT)5Gy×5日(合計25Gy)+CAPOX(6コース)施行後に、全直腸間膜切除(TME)を施行するプロトコールとした。手術前の評価で臨床的に完全緩解(cCR)と診断された場合、非手術療法(NOM)を許容した。主要観察項目は病理学的完全緩解(pCR)率とした。30症例が登録された(男性、n=26、女性、n=4、年齢中央値、62.5(44～74)歳、cT(T2、n=1、T3、n=25、T4、n=4)、cN(N0、n=13、N1、n=13、N2、n=4))。30例全例が最終解析対象となった。SCRT完遂率は100%、CAPOX完遂率は83%であった。TME施行例が20例、NOMとなった症例が7例であった。pCRが得られた症例は6例(30%、95%CI 14.0%-50.8%)で、主要観察項目に合致した。pCR+cCRは13例(43.3%)で認められた。治療関連死はなかった。グレード3以上(CTCAE第5版)の有害事象が20%以上で認められ、下痢が23.3%、好中球減少症が23.3%であった。経過観察期間の中央値は15.6(10.5～22.8)ヵ月で、NOM症例に再発、再増殖は認められなかった。

記述言語：英語   出版者・発行元：Annals of Gastroenterological Surgery  

Aim: To evaluate the feasibility and safety of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC) in Japan. Methods: This prospective, multicenter, open-label, single-arm phase II trial was conducted at five institutions. The key eligibility criteria were age ≥ 20 years, LARC within 12 cm from the anal verge, and cT3-4N0M0 or TanyN+M0 at the time of diagnosis that enabled curative resection. Preoperative short-course radiation therapy (SCRT) 5 Gy × 5 days (total 25 Gy) + CAPOX (six courses) followed by total mesorectum excision (TME) was the treatment protocol. Non-operative management (NOM) was allowed if clinical complete response (cCR) was obtained in the preoperative evaluation. The primary endpoint was the pathological complete response (pCR) rate. Results: Thirty patients (male, n = 26; female, n = 4; median age, 62.5 [44–74] years; cT [T2, n = 1; T3, n = 25; T4, n = 4]; cN [N0, n = 13; N1, n = 13; N2, n = 4]) were enrolled. The final analysis included 30 patients in total. The completion rates were 100% for SCRT and 83% for CAPOX. TME and NOM were performed in 20 and seven patients, respectively. pCR was observed in six patients (30% [95% CI 14.0%–50.8%]). The primary endpoint was met. pCR+cCR was observed in 13 (43.3%) patients. There were no treatment-related deaths. Grade ≥3 (CTCAE ver. 5.0) adverse events (≥20%), including diarrhea (23.3%) and neutropenia (23.3%). The median follow-up period was 15.6 (10.5–22.8) months, with no recurrence or regrowth in NOM. Conclusions: ENSEMBLE-1 demonstrated satisfactory pCR and cCR, and well-tolerated safety of TNT for patients with LARC in Japan.

DOI： 10.1002/ags3.12715

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記述言語：英語   出版者・発行元：British Journal of Cancer  

Background: Although nivolumab has a high efficacy, reliable biomarkers are needed to predict the efficacy. We evaluated the nivolumab efficacy according to the TP53 mutation in advanced gastric cancer patients enrolled in the GI-SCREEN project. Methods: Sequence data of tumour specimens and clinicopathological information of 913 patients with advanced gastric cancer who were enrolled between April 2015 and March 2017 were obtained from the GI-SCREEN database. The follow-up information of 266 patients treated with nivolumab was also provided. Results: Among 266 patients treated with nivolumab, the objective response rate (ORR) of TP53 wild type (wt) patients (24.6%) was higher than that of TP53 mutant patients (14.8%). Among TP53 mutant patients, the ORR of the frameshift type tended to be higher than the transition and transversion type (23.1%, 13.6%, and 13.0%, respectively). The median progression-free survival (PFS) was statistically longer in TP53 wt patients than in mutant patients (3.3 vs 2.1 months, HR 1.4, 95% CI 1.1–1.9). Among TP53 mutant patients, PFS was statistically longer in the frameshift type than in the transversion type. Conclusion: Nivolumab showed better efficacy in TP53 wt patients than in mutant patients. Among TP53 mutant patients, the frameshift type may have efficacy from nivolumab treatment.

DOI： 10.1038/s41416-023-02378-9

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DOI： 10.1016/j.annonc.2023.09.1806

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1245/s10434-022-12974-3

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PubMed

記述言語：英語   出版者・発行元：Surgical Endoscopy  

Background: Although several studies on telesurgery have been reported globally, a clinically applicable technique has not yet been developed. As part of a telesurgical study series conducted by the Japan Surgical Society, this study describes the first application of a double-surgeon cockpit system to telesurgery. Methods: Surgeon cockpits were installed at a local site and a remote site 140 km away. Three healthy pigs weighing between 26 and 29 kg were selected for surgery. Non-specialized surgeons performed emergency hemostasis, cholecystectomy, and renal vein ligation with remote assistance using the double-surgeon cockpits and specialized surgeons performed actual telesurgery. Additionally, the impact of adding internet protocol security (IPsec) encryption to the internet protocol-virtual private network (IP-VPN) line on communication was evaluated to address clinical security concerns. Results: The average time required for remote emergency hemostasis with the double-surgeon cockpit system was 10.64 s. A non-specialized surgeon could safely perform cholecystectomy or renal vein ligation with remote assistance. Global Evaluative Assessment of Robotic Skills and System Usability Scale scores were higher for telesurgical support-assisted surgery by a non-specialized surgeon using the double-surgeon cockpits than for telesurgery performed by a specialized surgeon without the double-cockpit system. Adding IPsec encryption to the IP-VPN did not have a significant impact on communication. Conclusion: Telesurgical support through our double-surgeon cockpit system is feasible as first step toward clinical telesurgery.

DOI： 10.1007/s00464-023-10061-6

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PubMed

記述言語：日本語   出版者・発行元：金原出版(株)  

症例は60代男性で、肛門部のしこりを主訴とした。生検で直腸GISTと診断され、6ヵ月間の術前補助化学療法後の術前MRIでは、肛門管の左側～左坐骨直腸窩の脂肪織内に長径66mm大の境界明瞭な腫瘤性病変を認め、肛門管近傍の下部直腸から肛門挙筋を圧排し坐骨直腸窩へ伸展していた。手術はTaTMEの技術を応用し腹腔鏡下操作に加え、経肛門的かつ経臀部的な内視鏡操作を併用し、経臀部的な剥離に先立ち肛門管内腔側から腫瘍下縁と直腸壁との境界を認識し、腸管外側から内視鏡下にアプローチした。腫瘍部では内・外肛門括約筋と肛門挙筋を合併切除する際に腫瘍対側の切離ラインをやや口側に設定し、肛門括約筋の最大限の温存を試みた。合併症なく術後14日目に退院し、術後補助化学療法としてイマチニブ内服を開始した。術後4ヵ月半で回腸人工肛門閉鎖術を施行し、再手術後3ヵ月経過して肛門機能障害は軽微で通常通りの日常生活が可能となり、術後10ヵ月間無再発で経過している。

記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

Prof. Setsuro Fujii achieved significant results in the field of drug discovery research in Japan. He developed nine well-known drugs: FT, UFT, S-1 and FTD/TPI are anticancer drugs, while cetraxate hydrochloride, camostat mesilate, nafamostat mesilate, gabexate mesilate and pravastatin sodium are therapeutic drugs for various other diseases. He delivered hope to patients with various diseases across the world to improve their condition. Even now, drug discovery research based on Dr. Fujii’s ideas is continuing.

DOI： 10.1007/s10147-023-02326-w

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記述言語：英語   出版者・発行元：Annals of Surgical Oncology  

Background: To develop an artificial intelligence-based model to predict recurrence after curative resection for stage I–III colorectal cancer from digitized pathological slides. Patients and Methods: In this retrospective study, 471 consecutive patients who underwent curative resection for stage I–III colorectal cancer at our institution from 2004 to 2015 were enrolled, and 512 randomly selected tiles from digitally scanned images of hematoxylin and eosin-stained tumor tissue sections were used to train a convolutional neural network. Five-fold cross-validation was used to validate the model. The association between recurrence and the model’s output scores were analyzed in the test cohorts. Results: The area under the receiver operating characteristic curve of the cross-validation was 0.7245 [95% confidence interval (CI) 0.6707–0.7783; P < 0.0001]. The score successfully classified patients into those with better and worse recurrence free survival (P < 0.0001). Multivariate analysis revealed that a high score was significantly associated with worse recurrence free survival [odds ratio (OR) 1.857; 95% CI 1.248–2.805; P = 0.0021], which was independent from other predictive factors: male sex (P = 0.0238), rectal cancer (P = 0.0396), preoperative abnormal carcinoembryonic antigen (CEA) level (P = 0.0216), pathological T3/T4 stage (P = 0.0162), and pathological positive lymph node metastasis (P < 0.0001). Conclusions: The artificial intelligence-based prediction model discriminated patients with a high risk of recurrence. This approach could help decision-makers consider the benefits of adjuvant chemotherapy.

DOI： 10.1245/s10434-022-12926-x

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記述言語：英語   出版者・発行元：Journal of Cancer Research and Clinical Oncology  

Purpose: Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. Methods: Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. Results: The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39–0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. Conclusion: NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker.

DOI： 10.1007/s00432-022-04064-4

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記述言語：英語   出版者・発行元：Surgical Laparoscopy, Endoscopy and Percutaneous Techniques  

Aim: This study was performed to clarify the relationship between robotic rectal resection and postoperative ileus (POI) by comparing robotic surgery with laparoscopic surgery. Materials and Methods: We retrospectively reviewed 238 patients who underwent robotic (n=41) or laparoscopic (n=197) rectal resection for rectal cancer in our institution from January 2013 to June 2020. First, we compared the background factors and short-term surgical outcomes between robotic and laparoscopic surgery. Next, we investigated the postoperative complications of robotic and laparoscopic rectal resection. Finally, we identified the risk factors for POI following rectal cancer resection. Results: The percentages of patients with an Rb tumor location, treatment by abdominoperitoneal resection/intersphincteric resection/low anterior resection, a temporary diverting ileostomy, and a long operation time were significantly higher in robotic than laparoscopic surgery (P<0.0001, P=0.0002, P=0.0078, and P=0.0001, respectively). There was no significant difference in any individual postoperative complication between robotic and laparoscopic surgery. Risk factors for POI were male sex (P=0.0078), neoadjuvant chemoradiotherapy (P=0.0007), an Rb tumor location (P=0.0005), treatment by abdominoperitoneal resection/intersphincteric resection/low anterior resection (P=0.0044), a temporary diverting ileostomy (P<0.0001), and operation time of ≥240 minutes (P=0.0024). Notably, robotic surgery was not a risk factor for POI following rectal resection relative to laparoscopic surgery. Conclusion: Although patients who underwent robotic surgery had more risk factors for POI, the risk of POI was similar between robotic and laparoscopic rectal resection.

DOI： 10.1097/SLE.0000000000001056

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DOI： 10.1016/j.annonc.2022.05.029

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DOI： 10.1016/j.annonc.2022.04.091

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本気管食道科学会  

DOI： 10.2468/jbes.73.185

CiNii Research

記述言語：英語   出版者・発行元：Cancer Science  

According to the current international guidelines, high-risk patients diagnosed with pathological T1 (pT1) colorectal cancer (CRC) who underwent complete local resection but may have risk of developing lymph node metastasis (LNM) are recommended additional intestinal resection with lymph node dissection. However, around 90% of the patients without LNM are exposed to the risk of being overtreated due to the insufficient pathological criteria for risk stratification of LNM. Circulating tumor DNA (ctDNA) is a noninvasive biomarker for molecular residual disease and relapse detection after treatments including surgical and endoscopic resection of solid tumors. The CIRCULATE-Japan project includes a large-scale patient-screening registry of the GALAXY study to track ctDNA status of patients with stage II to IV or recurrent CRC that can be completely resected. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective study, within the GALAXY study for patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk stratification criteria for LNM. The aim of this study is to explore the ability of predicting LNM using ctDNA analysis compared with the standard pathological criteria. The ctDNA assay will build new evidence to establish a noninvasive personalized diagnosis in patients, which will facilitate tailored/optimal treatment strategies for CRC patients.

DOI： 10.1111/cas.15226

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

リキッドバイオプシーによる癌個別化医療の実現を目指すプロジェクト「CIRCULATE-Japan」は、観察研究(GALAXY試験)と2つの無作為化第III相試験(VEGA試験およびALTAIR試験)で構成されている。GALAXY試験では完全切除が可能なステージIIからIVまたは再発大腸癌患者の血中循環腫瘍DNA(ctDNA)状態を追跡している。著者らは、CIRCULATE-Japanのプラットフォームに基づき、GALAXY試験内で、局所完全切除を受けたpT1大腸癌患者のうち、リンパ節転移に関する標準的な病理学的リスク層別化基準に基づいてリンパ節郭清を伴う腸管追加切除が予定されている患者を対象に、新しい前向き研究であるDENEBを開始した。本研究の目的は、標準的な病理学的基準と比較して、ctDNA分析を用いたリンパ節転移の予測能力を探ることである。ctDNAアッセイは、大腸癌患者における非侵襲的な個別化診断を確立するための新たなエビデンスを構築し、大腸癌患者の個別化医療や最適な治療戦略を促進することが期待される。

記述言語：英語   出版者・発行元：Annals of Gastroenterological Surgery  

Aim: To investigate the impact of the triple-layered circular stapler compared with the double-layered circular stapler on anastomotic leakage after rectal cancer surgery. Methods: The bursting pressure was compared between porcine ileocolic anastomoses created using a double- or triple-layered stapler. We also retrospectively analyzed the incidence of severe anastomotic leakage in 194 patients who underwent colorectal anastomosis using a double- or triple-layered circular stapler during rectal cancer resection performed in two cancer centers between January 2015 and April 2021. Results: In the porcine model, the bursting pressure was higher in anastomoses created using the triple-layered stapler than the double-layered stapler (end-to-end anastomosis: 26.4 ± 6.2 mm Hg vs 14.5 ± 4.3 mm Hg, P =.0031; side-to-side anastomosis: 27.7 ± 5.0 mm Hg vs 18.0 ± 2.9 mm Hg, P =.0275). Intersectional leakage occurred in 41% and 83% of anastomoses created using the triple- or double-layered stapler, respectively (P =.0821). In the clinical cohort, the double- and triple-layered stapler was used in 153 and 41 patients, respectively. The incidence of anastomotic leakage was lower for anastomoses created using the triple-layered stapler vs the double-layered stapler (0.0% vs 5.8%, P =.0362). In multivariate analysis, the factors independently associated with a lower incidence of anastomotic leakage were female sex (odds ratio: 0.16, 95% confidence interval: 0.01-0.90, P =.0354) and triple-layered stapler usage (odds ratio: 0.00, 95% confidence interval: 0.00-0.96, P =.0465). Conclusion: Anastomoses created using a triple-layered circular stapler had high bursting pressure, which might contribute to a lower incidence of anastomotic leakage after rectal cancer surgery.

DOI： 10.1002/ags3.12516

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

直腸癌手術後に生じる吻合部漏に対する三層サーキュラーステープラーと二層サーキュラーステープラーの有効性を比較検討した。ブタ回結腸吻合部における三層サーキュラーステープラーと二層サーキュラーステープラーの破裂圧を比較した。さらに、直腸癌に対して大腸吻合術を施行された194例を対象とする多施設後ろ向きコホート研究を実施して重度吻合部漏の術後発症率を評価した。二層サーキュラーステープラー使用群(EEA群)が153例(男性84例、女性69例、中央値66歳)、三層サーキュラーステープラー使用群(tri-EEA群)が41例(男性23例、女性18例、中央値67歳)であった。ブタを用いた実験での破裂圧は三層サーキュラーステープラーが26.4±6.2mmHg、二層サーキュラーステープラーが14.5±4.3mmHgと三層の方が有意に高値を示していた。臨床研究ではtri-EEA群の方がEEA群と比較して手術時間は有意に長く、術後在院期間と術後合併症の発症率に関してtri-EEA群とEEA群との間に有意差はみられなかったが、グレード3以上の吻合部漏の発症率はtri-EEA群の方が有意に低かった(0.0% vs 5.8%)。多変量解析ではtri-EEAの施行が吻合部漏の非発症を示す独立関連因子として抽出された。

DOI： 10.1200/JCO.2022.40.4_suppl.161

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Web of Science

記述言語：英語   出版者・発行元：Annals of Gastroenterological Surgery  

Numerous clinical studies in an adjuvant setting have been conducted and the combination therapy of 5-fluorouracil and oxaliplatin has been established as the standard treatment for Stage III and as an option for high-risk Stage II patients. Biologics such as bevacizumab and antiepidermal growth factor receptor antibodies have failed to show additional survival benefits. The indication of adjuvant chemotherapy has been determined according to the pathological stage. Nevertheless, a pathological diagnosis does not necessarily result in selection of the optimal treatment. To improve treatment decisions, many trials have aimed to stratify patients into treatment groups using genomic testing. Recently, gene signature, Immunoscore, and circulating tumor DNA (ctDNA) assays have been reported and among them, ctDNA was shown to be a promising accurate predictive marker for recurrence. Treatment of ctDNA-positive patients with aggressive chemotherapy may reduce recurrence rates. The ultimate goal is to accurately predict the risk of recurrence and to prevent recurrence in colon cancer patients. In this review we focus on the clinical development of adjuvant chemotherapy and stratification of patients according to risk of recurrence and the future direction of adjuvant chemotherapy.

DOI： 10.1002/ags3.12503

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Cancer Reports  

Background: ARID1A is a component of the SWI/SNF complex, which controls the accessibility of proteins to DNA. ARID1A mutations are frequently observed in colorectal cancers (CRCs) and have been reported to be associated with high mutational burden and tumor PD-L1 expression in vitro. Aim: To clarify the role of ARID1A mutation in CRC. Method and results: We used next generation sequencing (NGS) and immunohistochemistry on clinically obtained samples. A total of 201 CRC tissues from Niigata University and Niigata Center Hospital were processed by NGS using the CANCERPLEX panel. Immunohistochemistry for ARID1A, PD-L1, MLH1, and MSH2 was performed on 66 propensity-matched (33 microsatellite instability-high [MSI-H] and 33 microsatellite-stable [MSS]) cases among 499 cases from Kyushu University. TCGA data were downloaded from cBioPortal. NGS showed significantly more mutations in ARID1A mutated CRCs (p = 0.01), and the trend was stronger for right-sided CRCs than left-sided. TCGA data confirmed these findings (p < 0.01). BRAF V600E and ATM mutations were also found at higher frequencies. Immunohistochemistry showed that 30% of MSI-H CRCs had ARID1A loss, while this was true in only 6% of MSS CRCs. In both MSI-H and MSS, PD-L1 expression by stromal cells was enhanced in the ARID1A-mutant groups (90% vs 39% in MSI-H, 100% vs 26% in MSS). Conclusion: We found a higher mutational burden in ARID1A-mutant CRCs, and IHC study showed that ARID1A loss was correlated with high PD-L1 expression in stromal cells regardless of MSI status. These data support the idea that mutant ARID1A is a potential biomarker for CRCs.

DOI： 10.1002/cnr2.1420

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/invivo.12195.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10147-020-01646-5.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Postoperative changes in skeletal muscle and their influence on outcomes after esophagectomy for patients with esophageal cancer have not been fully investigated. This study aimed to confirm that postoperative skeletal muscle decrease influences long-term patient outcomes. Methods: Data were collected from 218 patients who underwent curative esophagectomy for esophageal cancer whose data were available before and 6 months after surgery. The skeletal muscle index (SMI) was measured at the level of the L3 vertebrae, and the postoperative change in the SMI compared with preoperative values was calculated as the delta SMI. Results: The mean SMI value was − 11.64%, and the median delta SMI value was − 11.88%. The first and third quartiles were defined as cutoffs, and 218 patients were classified as the mild-loss group (54 patients), moderate-loss group (110 patients), and severe-loss group (54 patients). The patients with a more severely reduced SMI had a worse prognosis (5-year overall survival rates: mild loss, 66.6%; moderate loss, 58.8%; and severe loss, 48.5%; p = 0.0314). This correlation between reduced SMI and prognosis also was observed for the patients with preoperative sarcopenia (p < 0.0001), but not for those without preoperative sarcopenia. Conclusions: Postoperative reduced SMI and worse prognosis were significantly associated in esophageal cancer patients.

DOI： 10.1245/s10434-019-07850-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jamcollsurg.2019.10.013

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: According to the latest Japanese nationwide estimates, over a million Japanese people are newly diagnosed with cancer each year. Since gastrointestinal cancers account for more than 40% of all cancer-related deaths, it is imperative to formulate effective strategies to control them. Materials and methods, and results: Basic drug discovery research Our research has revealed that the abnormal expression of regulators of chromosomal stability is a cause of cancers and identified an effective compound against cancers with chromosomal instability. We revealed the molecular mechanism of peritoneal dissemination of cancer cells via the CXCR4/CXCL12 axis to CAR-like cells and identified an MEK inhibitor effective against these tumors. Residual tumor cells after chemotherapy in colorectal cancer are LGR5-positive cancer stem cells and their ability to eliminate reactive oxygen species is elevated. The development of surgical procedures and devices In cases of gastric tube reconstruction for esophageal cancer, we determined the anastomotic line for evaluating the blood flow using ICG angiography and measuring the tissue O2 metabolism. We established a novel gastric reconstruction method (book-binding technique) for gastric cancer and a new rectal reconstruction method focusing on the intra-intestinal pressure resistance for rectal cancer. We established a novel tissue fusion method, which allows contact-free local heating and retains tissue viability with very little damage, and developed an understanding of the collagen-related processes that underpin laser-induced tissue fusion. Strategy to prevent carcinogenesis We succeeded in cleaving hepatitis B virus DNA integrated into the nucleus of hepatocytes using genome editing tools. The development of HCC from non-alcoholic steatohepatitis (NASH) may be prevented by metabolic surgery. Conclusion: We believe that these efforts will help to significantly improve the gastrointestinal cancer treatment and survival.

DOI： 10.1007/s10147-019-01499-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: There are several methods for analyzing computed tomography (CT) images to evaluate chemotherapy efficacy in clinical studies. However, the optimal analysis method for each drug is still under debate. We conducted a pooled analysis using data from six phase II studies to evaluate four analysis methods in colorectal cancers (CRCs): morphological responses (MRs), early tumor shrinkage (ETS), depth of response (DpR), and response evaluation criteria in solid tumors (RECIST) ver.1.1. Methods: We included 249 patients in this analysis. Pretreatments and findings of subsequent CT imaging were analyzed based on the MR, ETS, DpR, and RECIST ver.1.1. Differences in overall survival (OS) between the responders and non-responders according to each method were evaluated using survival analysis. Results: The responders had significantly better hazard ratios (HRs) for OS, in terms of DpR (≥ median), ETS, objective response rate (ORR) [complete response (CR) + partial response (PR)], and disease control rate [CR + PR + stable disease (SD)]. Patients with right-sided colon cancers showed better HRs for DpR, but not for ETS and ORR. Contrastingly, patients with left-sided CRCs had better HRs for ETS, DpR, and ORR. MR was not associated with outcomes in this study, even in cases where bevacizumab was used. In patients with liver metastasis, ETS, DpR, and ORR showed better HRs, but not in those with lung metastasis. Conclusion: Early tumor shrinkage and DpR might be predictive markers only in left-sided CRCs with liver metastasis. Each imaging analysis has a different value based on the primary and metastatic sites.

DOI： 10.1007/s10147-019-01509-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: There were few studies assessed the postoperative sarcopenia in patients with cancers. The objective of present study was to assess whether postoperative development of sarcopenia could predict a poor prognosis in patients with adenocarcinoma of esophagogastric junction, (AEG) and upper gastric cancer (UGC). Methods: Patients with AEG and UGC who were judged as non-sarcopenic before surgery were reassessed the presence of postoperative development of sarcopenia 6 months after surgery. Patients were divided into the development group or non-development group, and clinicopathological factors and prognosis between these two groups were analyzed. Results: The 5-year overall survival rates were significantly poorer in the development group than non-development group (68.0% vs. 92.6%, P = 0.0118). Multivariate analyses showed that postoperative development of sarcopenia was an independent prognostic factor for poor overall survival (P = 0.0237). Conclusions: Postoperative development of sarcopenia was associated with a poor prognosis in patients with AEG and UGC.

DOI： 10.1016/j.amjsurg.2018.07.003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The relationship between postoperative changes in muscle mass and the prognosis of malignancies remains controversial. We aimed to determine whether a decrease in skeletal muscle mass after surgical resection can predict long-term outcomes in patients with adenocarcinoma of upper stomach (AUS) and esophagogastric junction (AEGJ). Methods: We reviewed 146 patients who underwent curative surgery for AUS and AEGJ. We assessed the skeletal muscle index pre- and post-surgery and 6 months postoperatively. The rate of decrease in skeletal muscle index (SMI) was calculated and its relationship with clinicopathological factors and prognosis was analyzed. Results: Among the 146 patients studied, 115 underwent re-assessment of SMI 6 months postoperatively. The mean decrease in SMI was more prominent in patients with recurrence than in those without recurrence (19.0 ± 2.3 vs. 7.4 ± 0.9%, respectively, P < 0.0001). AUS and AEGJ patients with a >19% decrease in SMI showed significantly lower 5-year overall survival and recurrence-free rates than those with a <19% decrease in SMI (recurrence-free survival: 33.4 vs. 89.2%, respectively, P < 0.0001; overall survival: 40.6 vs. 90.0%, respectively, P < 0.0001). Multivariate analyses indicated that a ≥19% decrease in SMI could predict poor overall survival independently in patients with AUS and AEGJ (P = 0.0070). Conclusions: A ≥19% postoperative decrease in SMI was substantially associated with poor survival in patients with AUS and AEGJ.

DOI： 10.1007/s00268-018-4873-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aim: Remnant gastric cancer (RGC) after distal gastrectomy occurs in 1-2% of patients, while the biological features of RGC are unknown. Patients and Methods: A total of 22 consecutive patients with RGC who underwent total gastrectomy were analyzed. Their disease history included either gastric cancer (n=16) or peptic ulcer (n=6). Overall, 18 underwent open total gastrectomy (OTG) and 4 underwent laparoscopic total gastrectomy (LTG). Results: The mean number of lymph nodes dissected and metastatic lymph nodes was larger in the Ulcer group than in the Carcinoma group (p<0.005). The mean operation time was longer in the LTG than OTG (p<0.005). The median blood loss tended to be smaller in the LTG (p=0.090). Five-year overall and recurrence-free survival rates were 94% and 81%, respectively. Conclusion: The status of lymph node metastasis after surgery for RGC should be cautiously considered in the context of disease history. Both LTG and OTG can be treatment options for RGC.

DOI： 10.21873/anticanres.13256

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Lateral lymph node dissection has been 1 of the standard treatments for mid and ow rectal cancer in Japan. The aim of this ad-hoc analysis was to evaluate the impact of lateral lymph node dissection on outcomes in the randomized clinical trial, referred to as the Adjuvant Chemotherapy for Stage II/III Rectal Cancer trial. Methods: The Adjuvant Chemotherapy for Stage II/III Rectal Cancer trial was a randomized, phase III trial of adjuvant chemotherapy of 2 different oral fluoropyrimidines; 445 patients with lower rectal cancer were studied in this ad-hoc analysis out of 959 patients in total, 215 of whom underwent lateral lymph node dissection and 230 did not. Results: There were no significant differences in background characteristics of the patients in the group, except for in age and number of dissected lymph nodes, between the lateral lymph node dissection and without lateral lymph node dissection groups. The age of the younger patients was often used to select candidates for lateral lymph node dissection (lateral lymph node dissection versus non–lateral lymph node dissection; 63.5 ± 8.9 vs 60.7 ± 9.4 [P =.0017]). Lateral lymph node dissection had no impact on relapse-free survival (hazard ratio = 0.941, 95% confidence interval: 0.696–1.271) or overall survival (hazard ratio = 0.858, 95% confidence interval: 0.601–1.224) in all patients with mid and low rectal cancer. In subset analysis, lateral lymph node dissection improved relapse-free survival in female patients and in patients with stage B/C or N3/4 disease. For cumulative recurrence across all patients, the proportion of patients with distant recurrence was slightly greater in the lateral lymph node dissection group but there was no difference in local recurrence. Conclusion: This exploratory analysis did not show that lateral lymph node dissection improves relapse-free survival and overall survival in patients with mid and low rectal cancer. Lateral lymph node dissection may, however, have a prognostic impact on patients with highly invasive rectal cancer.

DOI： 10.1016/j.surg.2018.08.027

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background and Aim: The C-reactive protein (CRP)/albumin (Alb) ratio has been reported as a novel prognostic marker in several cancers. The objective of this study was to investigate the prognostic value of the CRP/Alb ratio in patients who underwent surgery for adenocarcinoma of the esophagogastric junction (AEG) and upper gastric cancer (UGC). Methods: Data for 144 patients who underwent surgery for AEG and UGC were reviewed. The CRP/Alb ratio, neutrophil–lymphocyte ratio, platelet–lymphocyte ratio, Glasgow Prognostic Score, and controlling nutritional status score were calculated, and the relationship between these biomarkers and postoperative prognosis was analyzed. Results: The optimal cutoff value of the CRP/Alb ratio was determined to be 0.1. According to the cutoff value of CRP/Alb ratio, patients were divided into two groups (CRP/Alb < 0.1, n = 124; CRP/Alb ≥ 0.1, n = 20). The 5-year recurrence-free survival and overall survival (OS) rates were significantly lower in the patients with the CRP/Alb ratio ≥ 0.1 than in those with the CRP/Alb ratio < 0.1 (recurrence-free survival: 44.9% vs 77.9%, P = 0.0011; OS: 43.4% vs 82.0%, P < 0.0001). In the multivariate analyses, the N-stage, and CRP/Alb ratio ≥ 0.1 were identified as independent predictive factors for OS in patients with AEG and UGC (P = 0.0061 and P = 0.0439, respectively). Conclusions: The CRP/Alb ratio was strongly associated with poor prognosis in patients who underwent surgery for AEG and UGC.

DOI： 10.1111/jgh.14442

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chromosomal instability, one of the most prominent features of tumour cells, causes aneuploidy. Tetraploidy is thought to be an intermediate on the path to aneuploidy, but the mechanistic relationship between the two states is poorly understood. Here, we show that spindle polarity (e.g. bipolarity or multipolarity) in tetraploid cells depends on the level of functional phosphorylated Eg5, a mitotic kinesin, localised to the spindle. Multipolar spindles are formed in cells with high levels of phosphorylated Eg5. This process is suppressed by inhibition of Eg5 or expression of a non-phosphorylatable Eg5 mutant, as well as by changing the balance between opposing forces required for centrosome separation. Tetraploid cells with high levels of functional Eg5 give rise to a heterogeneous aneuploid population through multipolar division, whereas cells with low levels of functional Eg5 continue to undergo bipolar division and remain tetraploid. Furthermore, Eg5 protein levels correlate with ploidy status in tumour specimens. We provide a novel explanation for the tetraploid intermediate model, i.e. spindle polarity and subsequent tetraploid cell behaviour are determined by the balance of forces generated by mitotic kinesins at the spindle.

DOI： 10.1242/jcs.231530

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Sarcopenia or degenerative loss of skeletal muscle mass is related to poor prognosis in patients with cancer. This study aimed to clarify the clinical significance of skeletal muscle loss (SML) during chemotherapy for metastatic colorectal cancer (mCRC). Methods: A total of 249 patients who were secondarily registered in a pooled database of mCRC patients with the first-line systemic chemotherapy and prospectively enrolled in six clinical trials of Kyushu Study Group of Clinical Cancer were included in this study. Skeletal muscle area was calculated from computed tomography images before and 3 and 6 months after treatment. Baseline sarcopenia and SML (cut-off value = 9%) were evaluated. Results: Baseline sarcopenia was observed in 135 of 219 patients who were evaluated before treatment. They tended to be male; older; and have lower body mass index, lower visceral and subcutaneous fat contents, and a lower waist circumference (P < 0.01); however, baseline sarcopenia was not associated with prognosis. SML at 3 months was associated with an incidence of adverse events (P = 0.01), poor objective response rate (ORR) (P < 0.01), and poor progression-free survival (PFS) (P = 0.03), and it was an independent predictive factor for poor ORR (P < 0.01) and PFS (P = 0.04). Conclusion: SML at 3 months after systemic chemotherapy for mCRC was associated with poor treatment response. Thus, clarifying the importance of SML prevention guarantees a more effective chemotherapy.

DOI： 10.1007/s10147-019-01460-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

KIF1Bβ, a member of the kinesin superfamily of motor proteins, is a haploinsufficient tumor suppressor mapped to chromosome 1p36.2, which is frequently deleted in neural crest–derived tumors, including neuroblastoma and pheochromocytoma. While KIF1Bβ acts downstream of the nerve growth factor (NGF) pathway to induce apoptosis, further molecular functions of this gene product have largely been unexplored. In this study, we report that KIF1Bβ destabilizes the morphological structure of mitochondria, which is critical for cell survival and apoptosis. We identified YME1L1, a mitochondrial metalloprotease responsible for the cleavage of the mitochondrial GTPase OPA1, as a physical interacting partner of KIF1Bβ. KIF1Bβ interacted with YME1L1 through its death-inducing region, as initiated the protease activity of YME1L1 to cleave the long forms of OPA1, resulting in mitochondrial fragmentation. Overexpression of YME1L1 promoted apoptosis, while knockdown of YME1L1 promoted cell growth. High YME1L1 expression was significantly associated with a better prognosis in neuroblastoma. Furthermore, in NGF-deprived PC12 cells, KIF1Bβ and YME1L1 were upregulated, accompanied by mitochondrial fragmentation and apoptotic cell death. Small interfering RNA–mediated knockdown of either protein alone, however, remarkably inhibited the NGF depletion–induced apoptosis. Our findings indicate that tumor suppressor KIF1Bβ plays an important role in intrinsic mitochondria–mediated apoptosis through the regulation of structural and functional dynamics of mitochondria in collaboration with YME1L1. Dysfunction of the KIF1Bβ/YME1L1/OPA1 mechanism may be involved in malignant biological features of neural crest–derived tumors as well as the initiation and progression of neurodegenerative diseases.

DOI： 10.1002/mc.22997

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Meticulous recurrent laryngeal nerve (RLN) lymph node dissection in thoracoscopic esophagectomy for esophageal cancer often results in RLN paralysis. Methods: We had attempted to simply cut the vessels around RLN sharply with scissors without using energy device in order to prevent RLN paralysis. However, these procedures often result in minor bleeding. Since we introduced the use of mini-clips for hemostasis before cutting the vessels with scissors, we herein compared the surgical results between before and after the introduction of use of mini-clips. Results: With regard to RLN paralysis, the incidence was 24.0% in the before group; this incidence went down to 5.1% in the after group (P = 0.0259). Moreover, length of hospital stay after surgery was significantly shortened, from 36.1 days to 22.0 days, after the introduction of energy-less techniques with mini-clips (P = 0.0075). Conclusions: Our data demonstrated that this technique contributed to prevent RLN paralysis and to shorten the patient's length of hospital stay.

DOI： 10.1016/j.amjsurg.2017.10.033

記述言語：英語   掲載種別：研究論文（学術雑誌）  

CD44 serves as a marker of cancer stem cells. Alternative splicing generates the CD44v9 isoform. Cancer stem cells are associated with the epithelial-mesenchymal transition in cancers, although little is known about their role in esophageal squamous cell carcinoma. Here, we aimed to clarify the relationship between CD44v9 expression, the epithelial-mesenchymal transition, and clinicopathological features of patients with esophageal squamous cell carcinoma. CD44v9 levels were higher at the tumor invasive front compared with the center of the tumor and higher in metastatic lymph nodes compared with primary tumors. High levels of CD44v9 at the tumor invasive front were significantly associated with deeper tumor invasion and shorter overall survival and recurrence-free survival. The expression of CD44v9 was increased by treatment with transforming growth factor-β, which induced esophageal squamous cell carcinoma cells to undergo the epithelial-mesenchymal transition. Moreover, inhibition of CD44v9 expression decreased the migration and invasiveness of esophageal squamous cell carcinoma cells. These results indicate that the expression of CD44v9 at the tumor invasive front induced by stemness was strongly associated with the epithelial-mesenchymal transition and poor prognosis of patients with esophageal squamous cell carcinoma. CD44v9 may therefore serve as a novel prognostic biomarker and a potential therapeutic target for esophageal squamous cell carcinoma.

DOI： 10.1002/cam4.1874

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: To confirm the superiority of neoadjuvant chemoradiotherapy (NACRT) over neoadjuvant chemotherapy (NAC) as preoperative therapy for locally advanced esophageal cancer. Patients and Methods: A total of 298 patients with resectable esophageal cancer were initially enrolled; 62 patients received NAC and 236 patients received NACRT. Propensity score matching was applied to create a study cohort. Results: Postoperative 30-day mortality rate, overall postoperative complication rate, and overall survival time did not differ between those groups. Complete pathological response occurred in one patient treated with NAC and 16 treated with NACRT (p<0.001). In patients with borderline-resectable T4 disease, overall survival was superior in the NACRT group compared to that in the NAC group (p=0.040). Conclusion: No survival advantage was observed between NAC and NACRT groups. Limited to patients with borderline-resectable T4, NACRT achieved a higher rate of primary tumor volume reduction and R0 resection, and a more favorable prognosis compared to NAC.

DOI： 10.21873/anticanres.13053

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Laparoscopic proximal gastrectomy (LPG) is performed as a function-preserving surgery for patients with early proximal gastric malignant tumors; however, whether LPG has advantages postoperatively compared with laparoscopic total gastrectomy (LTG) is debatable, especially with regard to nutritional outcomes. Methods: We evaluated 20 patients who underwent LTG and 10 patients who underwent LPG with double tract reconstruction (LPG-DT) who were diagnosed preoperatively with T1a or T1b N0 Stage IA gastric cancer in our department in the same time period. The statistical relevance of complications, surgical maneuvers, clinical factors and changes in weight, skeletal muscle index (SMI) and serum albumin levels after surgery was compared between the LPG-DT group and the LTG group. Results: No differences between groups were observed in patient demographics, operation time, blood loss, complications, number of dissected lymph nodes and pathological stage. The body weight reduction rate was significantly lower in the LPG-DT group compared with the LTG group at 6 months (5.7 vs. 14.9%, respectively; p = 0.0045) and 1 year after surgery (9.6 vs. 17.9%, respectively; p = 0.0042). The SMI reduction rate of the LPG-DT group in the first postoperative year was significantly lower than that of the LTG group (9.3 vs. 18.3%, respectively; p = 0.0057). Conclusions: Patients with early gastric cancer who underwent LPG-DT had acceptable morbidity and mortality, similar to those who underwent LTG. Body weight and SMI reduction rates were lower in the LPG-DT group than in the LTG group. Thus, LPG-DT is an appropriate procedure for patients with clinical Stage IA proximal gastric cancer.

DOI： 10.1007/s00268-018-4625-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Since the clinical impact of sarcopenia on multimodal therapy for patients with esophageal cancer is not well understood, this study was conducted to determine the influence of sarcopenia on the efficacy of neoadjuvant chemoradiotherapy (NACRT) for locally advanced esophageal cancer. Methods: The skeletal muscle index was quantified at the level of the third lumbar vertebra on computed tomography images, and sarcopenia was defined as a skeletal muscle index that was less than the average for each gender. We compared treatment outcomes in patients with cT3 and nearly T4 thoracic esophageal squamous cell carcinoma between the sarcopenia group (n = 85) and the non-sarcopenia group (n = 72). Results: The 5-year survival rates were 33.4% in the non-sarcopenia group and 31.5% in the sarcopenia group; these differences were not significant. The prognosis of the patients with sarcopenia was worse than that of the patients without sarcopenia in the surgery-alone group, but there was no difference between patients with and without sarcopenia in the NACRT group. Conclusions: NACRT could be a useful option for patients with locally advanced esophageal squamous cell carcinoma, even for those with sarcopenia, without increasing the incidence of morbidity and mortality.

DOI： 10.1007/s00268-018-4554-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Phosphorylation is the most extensively studied posttranslational modification of proteins. There are approximately 500 kinases known in the human genome. The kinase-activated pathways regulate almost every aspect of cell function and a deregulated kinase cascade leads to impaired cellular function. Impaired regulation of several kinase cascades, including the epidermal growth factor receptor (EGFR) pathway, leading to tumor pathogenesis, is well documented. Thus, a phosphospecific test with prognostic or predictive value was expected in oncology. However, no phosphospecific IHC test is used in oncology clinics. Human topoisomerase I (topoI) inhibitors, camptothecin and its analogues (CPT), are used extensively to treat various solid tumors. Depending on tumor type, the response rate is only 13–32%. We have demonstrated that the deregulated kinase cascade is at the core of CPT resistance. DNA-PKcs, a kinase central to the DNA–double-strand break (DSB) response pathway, phosphorylates topoI at serine 10 (topoI-pS10), and cells with higher basal levels of topoI-pS10 degrade topoI rapidly and are resistant to this class of drug. The higher basal level of topoI phosphorylation is due to continual activation of DNA-PKcs, and one potential mechanism of this pathway activation is failure of upstream effector phosphatases such as phosphatase and tensin homolog (PTEN). Based on this understanding, we have developed an IHC-based test (P-topoIDx) that can stratify the responder and non-responder patient population.

DOI： 10.1369/0022155418766503

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: Programmed death 1 (PD-1) is an immunoinhibitory receptor and has been identified as a new target for immunotherapy in cancer. Here we report the expression of PD-1 ligand 1 (PD-L1) in surgically resected gastric cancer. Materials and Methods: We examined formalin-fixed tumor samples from 144 gastric cancer patients with a primary diagnosis of gastric carcinoma. Immunohistochemistry was used to detect PD-L1. Human epidermal growth factor receptor 2 (HER2) expression and phosphatase and tensin homolog (PTEN) loss of heterozygosity were investigated in these patients. RNA interference was used to downregulate HER2 expression, and PD-L1 protein expression was assessed by flow cytometry using the gastric cancer cell line MKN45. Results: Overexpression of PD-L1 was significantly correlated with tumor invasion (p = 0.011) and associated with poor survival. The number of PD-L1-positive cases increased according to the HER2 score in clinical samples. siRNA-mediated downregulation of HER2 significantly decreased PD-L1 protein expression in MKN45 cells. Conclusions: PD-L1 expression was associated with poor survival of gastric cancer, and HER2 signaling affects the expression of PD-L1 in gastric cancer. In gastric cancer, PTEN and HER2 are potential candidate biomarkers for developing human antibodies that block PD-L1.

DOI： 10.1159/000479231

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tubulin-binding agents (TBAs) are designed to target microtubule (MT) dynamics, resulting in compromised mitotic spindles and an unsatisfied spindle assembly checkpoint. The activity of Aurora B kinase is indispensable for TBA-induced mitotic arrest, and its inhibition causes mitotic slippage and postmitotic endoreduplication. However, the precise phenomenon underlying mitotic slippage, which is caused by treatment with both Aurora B inhibitors and TBAs, and the cell fate after postmitotic slippage are not completely understood. Here, we found that HeLa and breast cancer cells treated with the different types of TBAs, such as paclitaxel and eribulin (MT-stabilizing and MT-destabilizing agents, respectively), exhibited distinct behaviors of mitotic slippage on inhibition of Aurora B. In such conditions, the cell fates after postmitotic slippage vastly differed with respect to cell morphology, cell proliferation, and cytotoxicity in short-term culture; that is, the effects of inhibition of Aurora B were beneficial for cytotoxicity enhancement in eribulin treatment but not in paclitaxel. However, in long-term culture, the cells that survived after mitotic slippage underwent endoreduplication and became giant cells in both cases, resulting in cellular senescence. We propose that MT-destabilizing agents may be more appropriate than MT-stabilizing agents for treating cancer cells with a weakened Aurora B kinase activity.

DOI： 10.1038/s41598-017-17002-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The incidence of skeletal muscle metastasis from oesophageal cancer is very low, and the treatment strategy has not been established. Case Report: A 77-year-old man underwent oesophagectomy following neoadjuvant chemotherapy for oesophageal squamous cell carcinoma (CT-pT3 N0 M0, CT-pStage II). Fourteen months after surgery, he became aware of a subcutaneous tumour in his left forearm. Computed tomography and fluorodeoxyglucose positron-emission tomography revealed a 65×75 mm intramuscular nodular lesion with a standardized uptake value of 8.5. Further examination by biopsy strongly suggested this was a solitary metastasis from oesophageal cancer. The patient received chemoradiotherapy with two cycles of 5- fluorouracil combined with cisplatin and radiation. Clinical complete response was confirmed by imaging 7 months after chemoradiation and no recurrence has occurred at 20 months since chemoradiation. Conclusion: Radiotherapy or chemoradiotherapy can be an alternative locoregional therapy to surgery for solitary skeletal muscle metastasis.

DOI： 10.21873/anticanres.12005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: This study was designed to evaluate the efficacy and toxicity of XELIRI plus bevacizumab for the treatment of Japanese patients with unresectable or recurrent colorectal cancer (CRC). Methods: This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated unresectable or recurrent CRC, presence of measurable lesions, ≥20 years of age, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients received bevacizumab (7.5 mg/kg on day 1) and XELIRI (irinotecan 200 mg/m² on day 1 plus capecitabine 800 mg/m² b.i.d. on days 1–14) every 3 weeks. The primary endpoint was the objective tumor response rate. Results: A total of 36 patients were enrolled in this study from July 2011 to September 2012. One patient did not fulfill the eligibility criteria and one patient withdrew their consent before the start of the treatment protocol. The confirmed objective response rate was 58.8% (95% CI 35.1–70.2%). The median progression-free survival was 9.6 months (95% CI 5.1–11.1 months) and the median overall survival was 23.1 months (95% CI 11.3–36.7 months). The grade ≥3 adverse events that were frequently encountered in this study were neutropenia (31.4%), leukopenia (22.9%), diarrhea (22.9%), anemia (20.0%), anorexia (20.0%) and febrile neutropenia (17.2%). The frequency of grade 3/4 adverse events, such as neutropenia and leukopenia, was much higher in patients with a UGT1A1 polymorphism. Conclusions: A first-line therapy comprising XELIRI plus bevacizumab yielded a promising response rate. However, careful attention should be given to adverse clinical events in Japanese patients receiving treatment with unresectable or recurrent CRC.

DOI： 10.1007/s10147-017-1140-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. A higher basal level of topoI-pS10 ensures rapid topoI degradation leading to CPT resistance. Importantly, PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and CPT resistance.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chromosomal instability (CIN), characterized by aneuploidy, is a major molecular subtype of gastric cancer. The deubiquitinase USP44 is an important regulator of APC activation in the spindle checkpoint and leads to proper chromosome separation to prevent aneuploidy. Aberrant expression of USP44 leads CIN in cells; however, the correlation between USP44 and DNA aneuploidy in gastric cancer is largely unknown. We analyzed USP44 expression in 207 patients with gastric cancer by immunohistochemistry and found that the proportion of USP44 expression was higher in gastric cancer tumors (mean, 39.6%) than in gastric normal mucosa (mean, 14.6%) (P < 0.0001). DNA aneuploidy was observed in 124 gastric cancer cases and high USP44 expression in cancer strongly correlated with DNA aneuploidy (P = 0.0005). The overall survival was significantly poorer in the high USP44 expression group compared with the low USP44 group (P = 0.033). Notably, USP44 expression had no prognostic impact in the diploid subgroup; however, high USP44 expression was a strong poor prognostic factor for progression-free survival (P = 0.018) and overall survival (P = 0.036) in the aneuploid subgroup. We also confirmed that stable overexpression of USP44 induced somatic copy-number aberrations in hTERT-RPE-1 cells (50.6%) in comparison with controls (6.6%) (P < 0.0001). Collectively, our data show USP44 has clinical impact on the induction of DNA aneuploidy and poor prognosis in the CIN gastric cancer subtype.

DOI： 10.1002/cam4.1090

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Colon cancer-associated transcription 2 (CCAT2) was recently identified as a novel long noncoding RNA transcript encompassing the single-nucleotide polymorphism rs6983267. CCAT2 is overexpressed in colorectal cancer (CRC) where it promotes tumor growth, metastasis, and chromosomal instability, although the clinical relevance of this enhanced expression is unknown. In this retrospective study, CCAT2 expression was evaluated using real-time polymerase chain reaction in 149 CRC patients, and its associations with clinicopathological characteristics, outcome, rs6983267 genotypes, microsatellite status, DNA ploidy, and BubR1 expression were analyzed. CCAT2 expression in cancer tissue was significantly higher than in noncancer tissue (p < 0.001), particularly in cases of metastatic cancer (p < 0.001). However, relative CCAT2 expression levels and rs6983267 genotypes were not correlated with clinicopathological features or patient prognosis. CRC cases demonstrating high CCAT2 expression were all microsatellite stable (p < 0.005). Together, this indicates that CCAT2 expression was associated with microsatellite-stable CRC.

DOI： 10.1159/000452143

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: In colorectal cancer (CRC), the BRAF V600E mutation is an important biomarker for poor prognosis, while high microsatellite instability (MSI-H) indicates good prognosis. Using a commercial BRAF V600E-specific antibody, we investigated the BRAF V600E mutation according to immunohistochemistry (IHC) and the MSI status in Japanese patients with CRC. Methods: In this retrospective study, tissue samples from 472 Japanese patients with CRC, stratified for MSI, were analyzed to determine the prognostic value of BRAF V600E, as assessed using IHC. Mutations in 254 patients were evaluated using the direct sequencing method to check for concordance. Results: The frequency of MSI-H was 9.3 % (44/472), and BRAF V600E mutation was detected immunohistochemically in 8.7 % patients (41/472). The sensitivity and specificity for detection of BRAF V600E mutations by IHC were 100 % (17/17) and 98.7 % (234/237), respectively. BRAF V600E mutations were significantly correlated with the anatomical tumor site (P = 0.0035), histological type (P < 0.0001), and MSI status (P < 0.0001). Consistent with other published series, patients with BRAF V600E mutation exhibited a significantly shorter overall survival (hazard ratio = 1.500, P = 0.0432). In particular, the microsatellite stable/BRAF mutation group had inferior prognosis compared with the MSI-H/BRAF wild-type group (hazard ratio = 2.621, P = 0.0004). Conclusions: IHC using a BRAF V600E-specific antibody was useful for diagnosis and concurred with direct sequencing results. CRC cases could be stratified by combining BRAF V600E mutation and MSI status as a prognostic factor in Japanese patients.

DOI： 10.1007/s00432-016-2275-4

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Programmed cell death 1 ligand 1 (PD-L1) and human leukocyte antigen (HLA) class I molecules on malignant cell surfaces are pivotal for tumor immunity. The clinical significance of their expression in patients with esophageal squamous cell carcinoma (ESCC) remains to be determined. Methods: PD-L1 and HLA class I protein expression was investigated by immunohistochemical staining of resected specimens from 90 ESCC patients who underwent radical surgery without preoperative therapy. The relationships between the expression of PD-L1 and HLA class I and clinicopathologic factors and patient prognosis were assessed. Results: High expression of PD-L1 and HLA class I were observed in 17 (18.9 %) and 35 (38.9 %) of 90 cases, respectively. High PD-L1 expression was correlated with the depth of tumor invasion (P = 0.0379), lymph node metastasis (P = 0.0031), recurrence (P = 0.0085), and poor overall survival (OS) (5-year survival rate; low/high: 60.9/28.4 %, P = 0.0110). Among those patients with high expression of HLA class I, high PD-L1 expression was correlated with significantly poorer recurrence-free survival (median survival time, low/high: 102.5/3.1 months, P = 0.0016) and poorer OS (median survival time, low/high: 102.5/13.1 months, P = 0.0027). Multivariate analysis showed that combined high PD-L1/high HLA class I expression was an independent prognostic factor for recurrence-free survival (hazard ratio 2.88, 95 % confidence interval 1.02–7.04, P = 0.0455) and OS (hazard ratio 2.95, 95 % confidence interval 1.03–7.50, P = 0.0447). Conclusions: High PD-L1 expression was a significant independent prognostic factor in ESCC patients with high HLA class I expression.

DOI： 10.1245/s10434-016-5376-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gastric cancer is the fourth most common cancer worldwide. Although it is important to identify patients at high risk for a poor outcome, factors correlating with prognosis in gastric cancer are largely unknown. Here, we focus on the correlations among expression of Polo-like kinase 1 (PLK1), DNA ploidy, and clinical outcome in gastric cancer patients. Gastric cancer specimens were analyzed from 207 consecutive patients. Patients were classified into two groups according to tumor PLK1 expression and DNA content, and an analysis of their clinical outcomes was carried out. Prognoses of patients with PLK1-high tumors were worse than those of patients with PLK1-low tumors, but the differences were not statistically significant. In cell lines, overexpression of PLK1 induced centrosome amplification and multipolar spindles, potentially leading to DNA aneuploidy. Indeed, high expression of PLK1 was also associated with DNA aneuploidy in clinical gastric cancer specimens. Patients with both high PLK1 expression and DNA aneuploidy had poor recurrencefree survival, whereas PLK1 expression and DNA ploidy status alone were not significantly associated with outcome. Here, we provide clinical evidence that high expression of PLK1 could have detrimental effects in tumors with DNA aneuploidy, which may increase the risk of recurrence in gastric cancer patients.

DOI： 10.1159/000445952

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Molecular profiling in gastric cancer (GC) is important for diagnosis and treatment. In this study, we investigated signal transduction pathways that might induce chromosomal instability in GC. Methods: Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and p-AKT expression were analyzed using immunohistochemistry, and chromosomal instability was assessed by DNA aneuploidy using laser scanning cytometry, in a total of 202 GC cases. Results: The rate of EGFR expression and p-AKT expression was 70.3 and 34.2 %, respectively, in GC patients. In total, 57.5 % of GC patients exhibited DNA aneuploidy, and p-AKT positively correlated with EGFR and HER2 (p = 0.0127 and p = 0.00031, respectively). Patients with EGFR overexpressing GC showed shorter disease-specific survival than the other cases (hazard ratio 2.00, 95 % confidence interval 1.19–3.53; p = 0.0104). Moreover, EGFR and p-AKT expression was significantly correlated with DNA aneuploidy (p = 0.0002 and p = 0.0302, respectively). Conclusions: Our data showed that both EGFR and p-AKT overexpression were clearly associated with DNA aneuploidy. Aneuploidy could be a useful marker for therapies that target EGFR.

DOI： 10.1245/s10434-016-5097-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The significance of neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) remains controversial with regard to the pathological response and long-term survival. We herein review the current status of and future perspectives regarding NACRT followed by esophagectomy for locally advanced ESCC. Some studies have suggested that a pathological complete response with NACRT is more common in patients with ESCC than in those with adenocarcinoma and that NACRT provided a survival benefit limited to patients with ESCC. However, NACRT may increase the risk of postoperative complications after esophagectomy. It is obvious that a favorable pathological response is the most important factor for obtaining a survival benefit, although no established parameters have been implemented clinically to predict the response to NACRT. Prospective clinical studies and basic research studies to identify predictive biomarkers for the response to NACRT are needed to aid in the development of NACRT treatment strategies for patients with ESCC.

DOI： 10.1007/s00595-015-1144-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jamcollsurg.2015.11.001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The occurrence of venous thromboembolism (VTE), manifesting as deep vein thrombosis or pulmonary embolism, after gastric and colorectal cancer surgery remains poorly characterized. The purpose of this study was to investigate the incidence of VTE following laparoscopic surgery in Japanese patients with gastric and colorectal cancer and identify the associated risk factors. Methods: We prospectively analyzed VTE events after laparoscopic surgery for gastric and colorectal cancer from April 2012 to March 2013 in our institute. Deep vein thrombosis was diagnosed with Doppler ultrasound sonography of the lower limb. Thromboprophylaxis, graduated compression stockings, and intermittent pneumatic compression were used in all patients. Fondaparinux sodium was used in several patients. We examined all patients' plasma D-dimer levels throughout the perioperative period. Results: In total, 101 patients were enrolled in this study; 71 who underwent laparoscopic surgery for gastrointestinal cancer were finally analyzed. Thirteen patients (18.3 %) developed asymptomatic VTE. There were no relationships between the development of VTE and perioperative factors such as cardiovascular disease, operation time, blood loss, postoperative complications, and fondaparinux administration. Neoadjuvant treatment (chemotherapy or chemoradiotherapy) was significantly associated with VTE (p < 0.05). Plasma D-dimer levels were higher 7 days after surgery in patients with than without VTE, although the levels remained high after surgery in all patients. Conclusions: The incidence of VTE among Japanese patients who underwent laparoscopic surgery for gastrointestinal cancer was not low. In particular, clinicians should consider the higher risk of VTE in patients undergoing neoadjuvant therapy.

DOI： 10.1007/s00268-015-3234-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Adjuvant chemotherapy (ACT) may prevent recurrence in patients with stage III colorectal cancer (CRC). However, only 10% of patients benefit from ACT and no effective indicators exist to predict which patients are likely to benefit. The present study validated metastatic lymph node (MLN) number as a new indicator for ACT. Patients and Methods: We retrospectively reviewed 173 patients with stage III CRC, who were classified by Union for International Cancer Control (UICC) stage or N category, and analyzed their overall survival (OS) and disease-free survival (DFS) according to stage, number of MLNs and ACT use. Results: Among 173 patients, we found 65 with only one MLN (N1a). For N1a patients treated with ACT, the 5-year OS rate was 100%; the 3-year DFS rate was 92.7% for those treated with oral ACT. Conclusion: The number of MLNs is a simple indicator for ACT in patients with stage III CRC. For patients with only one MLN, oral chemotherapy is a good option.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We herein present the case of a 44-year-old male who was successfully treated with pharyngo-laryngo-esophagectomy for severe corrosive esophagitis associated with pharyngitis. He accidentally ingested an unidentified liquid and subsequently developed esophagitis and progressive pharyngolaryngitis. Since he also developed dyspnea, he initially underwent a tracheotomy at an emergency hospital. Afterward, dysphagia due to hypopharingoesophageal stricture gradually developed, and the patient was referred to our hospital. Therefore, under laparotomy, a feeding tube was inserted into the jejunostomy, and the gastroendoscope inserted via the anterior gastric wall revealed that the gastric mucosa along the greater curvature was intact. Based on this information, it was concluded that the patient could undergo reconstruction with a gastric tube following pharyngo-laryngo-esophagectomy, and this was successfully accomplished 3 months later.

DOI： 10.1007/s10388-014-0466-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: The aim of this study was to clarify the usefulness of two-stage operation for the patients with esophageal cancer who have liver dysfunction. Methods: Eight patients with esophageal cancer concomitant with liver dysfunction who underwent two-stage operation were analyzed. The patients initially underwent an esophagectomy, a cervical esophagostomy and a tube jejunostomy, and reconstruction with gastric tube was performed after the recovery of patients' condition. Results: The average time of the 1^st and 2^nd stage operation was 410.0 min and 438.9 min, respectively. The average amount of blood loss in the 1^st and 2^nd stage operation was 433.5 ml and 1556.8 ml, respectively. The average duration between the operations was 29.8 days. The antesternal route was selected for 5 patients (62.5%) and the retrosternal route was for 3 patients (37.5%). In the 1^st stage operation, no postoperative complications were observed, while, complications developed in 5 (62.5%) patients, including 4 anastomotic leakages, after the 2^nd stage operation. Pneumonia was not observed through two-stage operation. No in-hospital death was experienced. Conclusion: A two-stage operation might prevent the occurrence of critical postoperative complications for the patients with esophageal cancer concomitant with liver dysfunction.

DOI： 10.2152/jmi.62.149

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Surgery is a major treatment option for rectal cancer, and total mesorectal excision has been demonstrated to be advantageous in terms of oncological outcome and thus has been the standard surgical approach. Radiotherapy before or after radical surgery is the optimal treatment to control local recurrence of advanced rectal cancer. To date, in many countries, the combination of neoadjuvant concurrent chemotherapy and radiotherapy is considered the standard therapy. A more recent interest in neoadjuvant therapy has been the use of oxaliplatin or targeted agents for neoadjuvant chemoradiotherapy. However, despite many trials of oxaliplatin and targeted agents, 5-FU-based concurrent chemoradiotherapy has remained the only standard treatment option. Postoperative adjuvant chemotherapy with neoadjuvant chemoradiotherapy or induction chemotherapy with neoadjuvant chemoradiotherapy may further improve patient survival, as some clinical studies recently indicated. In Japan, neoadjuvant therapy is not the standard treatment method, because surgery with lateral lymph node dissection is usually performed and this type of surgery may reduce recurrence rate as does radiation therapy. The phase III study to evaluate the oncological effect of the Japanese standard operation (mesorectal excision, ME) with lateral lymph node dissection in comparison with ME alone for clinical stage II and III lower rectal cancer is currently ongoing.

DOI： 10.1007/s10147-015-0858-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

With the development of new chemotherapy agents and methods, metastatic colorectal cancer patients can now achieve a survival time of >30 months. Higher line therapies have had a significant influence on the survival of these patients. However, it remains uncertain as to which therapy is the most effective and best tolerated. Herein, we describe the case of a patient with metastatic KRAS wild-type colorectal cancer who received panitumumab monotherapy as a third-line therapy after failure of 5-fluorouracil, irinotecan, oxaliplatin and bevacizumab. This patient had both lymph node and lung recurrence. The patient achieved a partial response time of 15 months. The lymph node and recurrent lung tumor had shrunk by 74 and 100 %, respectively, and the treatment was well tolerated with limited cutaneous toxicity. Panitumumab monotherapy may be an effective and well-tolerated treatment of KRAS wild-type metastatic colorectal cancer patients who have undergone many prior therapies. The present case showed a response to panitumumab monotherapy extending over a period of >1 year.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aim: Regorafenib has been approved for treatment of patients with unresectable or recurrent gastrointestinal stromal tumors resistant to imatinib or sunitinib. However, regorafenib has severe side-effects, including acute liver failure. We describe the case of a patient with multiple liver metastases of a small intestinal stromal tumor who experienced acute liver failure while being treated with regorafenib. Case Report: A 50-year-old patient with an unresectable small intestinal stromal tumor resistant to prior treatment with imatinib and sunitinib was started on regorafenib, but experienced acute liver failure 10 days later. Plasma exchange and steroid pulse treatment improved her liver function. During liver failure, abdominal ultrasonography showed to-and-fro flow in the portal vein. Lactate dehydrogenase concentration was markedly elevated to 1633 U/l. These findings indicate that liver failure in this patient was due to impaired liver blood flow. Conclusion: Regorafenib may impair liver blood flow, inducing acute liver failure.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The double-stapling technique using a circular stapler (CS) to create an end-to-end anastomosis is currently used widely in laparoscopic-assisted rectal surgery. However, a high rate of anastomotic failure has been reported. We report new side-to-side anastomosis creation using a CS, the so-called circular side stapling technique (CST). After excising the rectum at the oral and anal sides of the tumor with a linear stapler, a side-to-side colorectal anastomosis was made on the anterior wall of the rectosigmoid colon and the anterior or posterior wall of the rectum with a CS. Between 2012 and 2013, we recorded 30 serial cases of rectal-sigmoid or rectal cancer that were treated with laparoscopic-assisted surgeries using this method. In the 30 cases, the mean age was 68 ± 12 years, operating time was 288 ± 80 minutes, and blood loss was 66 ± 67 mL. None of the patients suffered from anastomosis leakage or postoperative anastomotic bleeding, and none complained of their stool habits. Three months after the last surgery in this cohort, no anastomosis strictures were reported. Based on these results, we propose an alternative method of side-to-side anastomosis for low anterior resection by using a CS to prevent staple overlap. Our experience indicates that the CST is easy and safe. Therefore, this method is a useful alternative to the current method used in laparoscopic surgery.

DOI： 10.9738/INTSURG-D-14-00202.1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aim: Definitive chemoradiotherapy (dCRT) is frequently administered in oesophageal cancer. We carried out hyperthermochemotherapy (HCT) for residual or recurrent cases after dCRT for oesophageal cancer. The aim of this study was to elucidate the usefulness of salvage HCT for these patients. Patients and Methods: Salvage HCT after dCRT was performed in 11 patients with residual or recurrent oesophageal cancer. We used an 8-MHz radiofrequency capacitive heating system for hyperthermia. The combined chemotherapy comprised of cisplatin/5-fluorouracil, an oral fluoropyrimidine and irinotecan. Results: There were no severe adverse events caused by hyperthermia. Complete response and stable disease was achieved in three and five patients, respectively; symptoms were improved in the remaining three patients. The median survival time after HCT was 12 (range=3-88) months. Conclusion: HCT is a feasible and potent salvage therapy for patients with residual or recurrent oesophageal cancer after dCRT, unless salvage surgery is indicated.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102, which consists of FTD and a thymidine phosphorylase inhibitor. Like 5-fluoro-2′-deoxyuridine (FdUrd), a deoxynucleoside form of 5-fluorouracil metabolite, FTD is sequentially phosphorylated and not only inhibits thymidylate synthase activity, but is also incorporated into DNA. Although TAS-102 was effective for the treatment of refractory metastatic colorectal cancer in clinical trials, the mechanism of FTDinduced cytotoxicity is not completely understood. Here, we show that FTD as well as FdUrd induce transient phosphorylation of Chk1 at Ser345, and that this is followed by accumulation of p53 and p21 proteins in p53-proficient human cancer cell lines. In particular, FTD induced p53-dependent sustained arrest at G₂ phase, which was associated with a proteasome-dependent decrease in the Cyclin B1 protein level and the suppression of CCNB1 and CDK1 gene expression. In addition, a p53-dependent increase in p21 protein was associated with an FTD-induced decrease in Cyclin B1 protein. Although numerous ssDNA and dsDNA breaks were induced by FdUrd, few DNA strand breaks were detected in FTD-treated HCT-116 cells despite massive FTD misincorporation into genomic DNA, suggesting that the antiproliferative effect of FTD is not due to the induction of DNA strand breaks. These distinctive effects of FTD provide insights into the cellular mechanism underlying its antitumor effect and may explain the clinical efficacy of TAS-102.

DOI： 10.1158/1535-7163.MCT-14-0236

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: A gastrectomy for gastric cancer is sometimes required in patients older than 80 years due to the continuously increasing age of society. However, if a gastrectomy worsens the postoperative quality of life and daily activity in elderly patients because of poor nutrition, the procedure may not always be a useful treatment strategy.
Patients and Methods: Clinicopathological data of patients with gastric cancer who underwent a gastrectomy at our Department between 1998 and 2008 (N=471) were collected and analyzed. The results of treatment for patients older than 80 years (N=41) were analyzed and compared against those of patients younger than 80 years (N=430).
Results: Patients older than 80 years had a higher frequency of preoperative co-morbidities than patients younger than 80 years. However, there was no statistical difference in postoperative complications regarding nutrition between the two groups.
Conclusion: Older age is not a determinant of poor nutrition following gastrectomy. Gastrectomy for gastric cancer is, therefore, a useful treatment strategy, regardless of ageing.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Cardiac tamponade, due to bleeding in the pericardial space after esophagectomy for esophageal cancer, is an extremely rare complication and may be associated with sudden hemodynamic instability that can lead to death unless there is prompt diagnosis and appropriate treatment.
Case Report: A 76-year-old man underwent subtotal esophagectomy via a cervico-right thoracoabdominal approach and reconstruction with a gastric tube through the retrosternal route. On postoperative day 4, the patient developed hypotension due to cardiac tamponade caused by bleeding into the pericardial space and he had a decreased level of consciousness. Pericardial resection and open drainage via a minimal left anterior thoracotomy was performed that resulted in hemodynamic improvement followed by an uneventful recovery.
Conclusion: Cardiac tamponade due to postoperative bleeding, which is a rare but life-threatening complication, should be considered as a cause of hemodynamic instability in the early postoperative period after esophagectomy.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: This study aimed to clarify the clinical significance of surgical resection for recurrent lesions after esophagectomy for esophageal cancer.
Methods: Recurrence was detected in 113 of 365 consecutive patients who underwent surgical resection for esophageal cancer, and some treatment was performed for recurrence in 100 of the 113 patients. The treatments were classified into two groups: chemotherapy and/or radiation with surgery (surgery group, n = 14) and chemotherapy and/or radiation without surgery (no surgery group, n = 86). The outcomes were retrospectively analyzed.
Results: Of the 14 patients in the surgery group, 3 underwent repeated resection. Thus, a total of 22 resections were performed for these patients. The resected organs were the lymph nodes in nine patients, the lungs in six patients, local recurrence in two patients, subcutaneous recurrence in two patients, the liver in one patient, the brain in one patient, and the parotid gland in one patient. Among the 22 recurrent cases, 20 involved solitary lesions or multiple lesions located in a small resectable region. When the two groups were compared, the surgery group showed a more favorable prognosis in terms of both survival after esophagectomy (median survival time, 103.3 vs 23.1 months; p = 0.0060) and survival after initial recurrence (92.1 vs 12.2 months; p = 0.0057).
Conclusions: Multimodal treatment provides a significant benefit for patients with recurrence after esophagectomy for esophageal cancer. Surgical intervention should be aggressively included in the treatment strategy when the recurrent lesion is solitary or localized.

DOI： 10.1245/s10434-014-3970-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: More effective treatment is necessary to improve the poor prognosis for patients with unresectable gastric cancer. We investigated the efficacy and feasibility of adjuvant surgery following chemotherapy.
Patients and Methods: Records of 70 patients with unresectable stage IV gastric cancer who underwent induction chemotherapy were reviewed retrospectively. Patients who developed an absence of non-curative clinical factors during chemotherapy underwent gastrectomy [adjuvant surgery (AS) group]; the others continued chemotherapy [non-AS group].
Results: Non-AS and AS groups contained 56 (80%) and 14 (20%) patients, respectively. In the AS group, 92.9% of patients had one noncurative clinical factor, while 48.2% of patients in the non-AS group had two or more non-curative clinical factors (p=0.0386). In the AS group, operative outcomes, including the postoperative complication rate (21.4%), were acceptable. The 3-year overall survival rate in the AS group was 65.6% versus 7.7% in the non-AS group (p<0.0001). In patients with one noncurative clinical factor of peritoneal dissemination, the median survival of the AS group was 29.5 months versus 11.4 months in the non-AS group (p=0.0230).
Conclusion: Adjuvant surgery for initially unresectable stage IV gastric cancer was safe and feasible, and may improve the prognosis for patients with one non-curative clinical factor, such as peritoneal dissemination.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: This study clarifies age differences in clinicopathologic characteristics and risk factor exposure of patients who have undergone esophagectomy for esophageal cancer (EC).
Methods: Clinical results of esophagectomy were compared between 22 patients younger than 50years of age (Group I) and 327 patients older than 50 years of age (Group II) with esophageal squamous cell carcinoma.
Results: The two groups did not significantly differ in clinicopathological characteristics, including prognosis. Postoperative pulmonary complication incidence rates were 4.2% (Group I) and 14.4% (Group II). In Group I, the incidence of multiple ECs was 36.4%, and association with head and neck cancer was 31.8%, which were significantly higher than in Group II (13.4%, p=0.021; and 9.2%, p=0.015, respectively). Furthermore, the patients in Group I with multiple cancers were almost all heavy smokers and/or users of alcohol.
Conclusions: These results suggest that multiple upper aerodigestive tract cancers are associated with heavy exposure to risk factors in patients younger than 50years of age.

DOI： 10.1245/s10434-014-3856-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Results from the Trastuzumab for Gastric Cancer (ToGA) trial highlighted the clinical significance of trastuzumab in the treatment of HER2 (Human Epidermal Growth Factor Receptor type 2)-positive gastric cancer. However, whether expression of HER2 is related to prognosis of gastric cancer is still controversial. A total of 360 consecutive patients with gastric cancer who underwent surgical resection in our Department from 1994 to 2007 were analyzed. We performed immunohistochemical analysis of HER2 expression. HER2 expression level was classified into four scores (0, 1+, 2+ and 3+). There were 37 (10%) patients with a score of 3+. A score of 3+ was defined as being HER2-positive. Recurrence-free survival was worse in HER2-positive cases (p=0.045). When the analysis was conducted with intestinal types of cancer, RFS was considerably worse in the HER2-positive group (p=0.011). HER2 expression may have potential as a prognostic factor for intestinal cancer types. Further research is warranted.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Immunohistochemistry staining of p53 is a cheap and simple method to detect aberrant function of p53. However, there are some discrepancies between the result of immunohistochemistry staining and mutation analysis. This study attempted to find a new definition of p53 staining by its staining pattern. Immunohistochemistry staining of p53 and TP53 gene mutation analysis were performed in 148 gastric cancer patients. Also SNP-CGH array analysis was conducted to four cases. Positive staining of p53 was observed in 88 (59.5%) tumors. Tumors with positive p53 staining showed malignant features compared to negative tumors. Mutation of TP53 gene was observed in 29 (19.6%) tumors with higher age and differentiated type. In positive p53 tumors, two types could be distinguished; aberrant type and scattered type. With comparison to TP53 gene mutation analysis, all the scattered type had wild-type TP53 gene (P = 0.0003). SNP-CGH array showed that scattered-type tumors had no change in the structure of chromosome 17. P53-scattered-type staining tumors may reflect a functionally active nonmutated TP53 gene. In interpretation of p53 immunohistochemistry staining, distinguishing p53-positive tumors by their staining pattern may be important in gastric cancer.

DOI： 10.1002/cam4.346

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Anastomotic leakage (AL) is a major complication after anterior resection. However, its therapeutic strategies and technical risk factors have not been well established. Therefore, we endoscopically evaluated anastomotic regions after laparoscopic colorectal anastomosis using a double-stapling technique (DST) for determination of treatment and investigation of technical factors. Methods: In total, 191 consecutive patients underwent laparoscopic anterior resection with a DST from September 2008-January 2013. Anastomotic regions were endoscopically evaluated in patients suspected to have AL after surgery. Results: Anastomotic dehiscence was observed in 19 patients, and AL was diagnosed in 18 (9.3%). Of the 19 patients, 12 were treated by creation of an intestinal stoma and 7 were treated conservatively based on their clinical status and endoscopic findings. Twentythree dehiscences were observed among 19 anastomotic regions; all 23 were observed on the circular stapler anastomosis lines. Of these 23 dehiscences, 13 (56.5%) were located at the point at which the anastomosis lines of the circular and linear staplers overlapped, and 10 (43.5%) were located on the circumferential aspect between the overlapping points. Conclusions: Endoscopic evaluation of anastomotic regions is safe and useful for the determination of therapeutic strategies. The DST anastomotic technique itself may be closely related to the development of AL.

DOI： 10.1016/j.jss.2014.07.009

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chylothorax is an uncommon but potentially life-threatening complication of esophagectomy. A 72-year-old man underwent thoracoscopy-assisted subtotal esophagectomy and reconstruction with a gastric tube, through a retrosternal route, after preoperative chemoradiotherapy. Chylothorax was detected after starting enteral feeding on postoperative day (POD) 7. Despite conservative therapy such as fasting, total parenteral nutrition, and octreotide administration, massive fluid drainage continued. On POD 19, lymphoscintigraphy with ^99mTc-diethylenetriamine pentaacetic acid-human serum albumin (HSA-D) was performed and the site of leakage was detected at the level of the fourth thoracic vertebra. On POD 23, the thoracic duct was ligated, following which the volume of chylothorax decreased. Lymphoscintigraphy 12 days after the reoperation showed no leakage from the thoracic duct. We recommend lymphoscintigraphy with ^99mTc-HSA-D for locating the chyle leakage site and helping decide about the operative indication.

DOI： 10.1007/s00595-014-0968-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background Anastomotic leakage is a major complication after anterior resection for rectal cancer. The double-stapling technique (DST) is the main method for creating a colorectal anastomosis. However, the rate of anastomotic leakage after DST remains high, and the technical risk factors have not been well established. Materials and methods Five methods of colorectal anastomosis were performed on the porcine rectum and colon: single-stapled double-purse-string (SSDP), DST, side-to-side with a linear stapler (SS-L), side-to-side with a circular stapler (SS-C), and SS-C with hand-sewn reinforcement (n = 6 for each method). In each group, burst pressures were tested, paying special attention to the locations of the first disruptions. The anastomosis line, including staples, was embedded in polyester resin, and polished sections were examined histologically. Results Burst pressures were significantly higher in the SS-L and SS-C than those in the SSDP and DST groups (P < 0.001) and were higher in the SS-C with hand-sewn reinforcement than those in the SS-L and SS-C groups (P < 0.001). Remarkably, in the SSDP, DST, and SS-C groups, the first disruptions occurred on the staple line created by the circular stapler. Conclusions The experimentally strongest colorectal anastomosis created with instruments currently in use was a SS-C. This anastomosis does not overlap staple lines and does not require a purse-string suture. Hand-sewn reinforcement was effective in increasing the anastomotic strength.

DOI： 10.1016/j.jss.2014.11.045

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jamcollsurg.2015.04.022

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Surgery for RGC can generally be difficult because of the severity of intra-abdominal adhesion due to past gastrectomy. Laparoscopic gastrectomy for RGC has been reported in some cases, but the adequacy of this procedure is still unclear. Herein we report four cases of RGC that underwent laparoscopic gastrectomy at our Hospital and discuss the benefit of the laparoscopic approach for RGC.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: PTEN (the encoding phosphate and tensin homolog) is a well-known cancer suppressor gene and its mutation and loss of heterozygosity (LOH) occurs in various types of carcinomas. This study aimed to examine the association between LOH of PTEN and prognosis in HER2-expressing and nonexpressing gastric cancer patients. Methods: Fresh-frozen tumor samples of 221 gastric cancer patients with a primary diagnosis of gastric carcinoma were examined for LOH of PTEN. The results were compared with pathological parameters and the HER2 status. To elucidate the role of LOH of PTEN, the activation of the PI3K/AKT pathway was examined immunohistochemically using a phosphorylation-specific antibody. Results: LOH of PTEN was observed in 20% of the patients (39 of 195 cases). LOH of PTEN was associated with vascular involvement (25 of 39 cases; p = 0.0083), equivocal to positive staining for HER2 (p = 0.0080), and phospho-Akt expression (p = 0.0067). Patients with HER2-expressing gastric cancer with LOH of PTEN had a significantly worse prognosis (p = 0.0050). Conclusions: Although HER2 expression itself was not a prognostic factor, the combination of HER2 expression and LOH of PTEN exacerbates the malignant potential of gastric cancer through its proliferative function.

DOI： 10.1159/000368984

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1245/s10434-013-3332-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: To date, no large-scale study has been undertaken to understand the clinical features of non-occlusive mesenteric ischemia (NOMI) after surgery. We thus performed a multicenter investigation to clarify the clinical outcomes and prognostic factors of NOMI. Patients and Methods: Clinical databases from 22 Japanese facilities were reviewed for evaluation of patients who received surgery for NOMI between 2004 and 2012. NOMI patients (n = 51) were divided into two groups: group I (n = 28) consisted of patients who survived, and group II (n = 23) consisted of patients who did not survived. Prognostic factors were compared between the two groups. Results: NOMI surgery represented 0.04 % of the total number of operations performed in this time period. The overall mortality rate for NOMI surgery was 45 %. Hemodialysis was a significant negative prognostic factor (p = 0.027). Preoperative elevation of transaminases, potassium, and white blood cell count, as well as metabolic acidosis and colon ischemia was poor prognostic factors. The mean Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (POSSUM) score of group I versus group II was 54.5 ± 3.6 and 85.2 ± 4.1, respectively (p < 0.001). Conclusions: Currently, NOMI surgery has a 45 % mortality rate. POSSUM scores can be used to predict the clinical outcome of patients who receive NOMI surgery.

DOI： 10.1007/s11605-014-2579-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease characterized by chronic fibrosing inflammation with abundant IgG4-positive plasma cells, and responds well to steroids. Previous reports of IgG4-RD have focused on pancreatic and extrapancreatic including the gastrointestinal tract, however, the colonic IgG4-RD is rare.
Presentation OF CASE: We herein report the case of a 74-year-old female with edematous wall thickening of the terminal ileum to the lower ascending colon confirmed by several preoperative imaging studies, who underwent right hemi-colectomy for suspected malignant lymphoma. The resected specimen showed an irregular wall thickness with subserosal sclerosis, and the lesion was 10 cm in length from the terminal ileum to the ascending colon. The patient was diagnosed with IgG4-RD by pathological examinations, which demonstrated an increased number of IgG4-positive plasma cells (150/HPF), and an elevated IgG4/IgG ratio (50%).
Discussion: Gastrointestinal IgG4-RD appears to be difficult to diagnose prior to surgical resection because of its rarity, and the similarity of its features to malignancy. The measurement of the serum IgG4 levels, immunohistochemical examination of biopsy specimens and use of several imaging modalities might help us to diagnose the disease without surgical resection, and this disease can generally be treated with steroid therapy. However, surgical resection for IgG4-RD may still be also necessary for patients with concerns regarding malignancy or with intractable gastrointestinal obstruction caused by this disease.
Conclusion: Gastrointestinal IgG4-RD often mimics malignancy, and we should therefore consider this disease in the differential diagnosis of colonic lesions in order to optimize the treatment.

DOI： 10.1016/j.ijscr.2014.08.003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Simultaneous resection for colorectal cancer and synchronous colorectal liver metastases (SCRLM) has been found to be safe and effective. However, pure laparoscopic simultaneous resection (PULSAR) for primary colorectal cancer and SCRLM is usually difficult, especially in the right lobe of the liver. The purpose of this study was to assess the feasibility of PULSAR for patients with primary colorectal cancer and SCRLM.
METHODS: From January 2008 to December 2012, a total of 10 patients (9 men and 1woman; mean age, 64 years) underwent PULSAR for a primary tumor and SCRLM.
RESULTS: Seven patients (70%) with lesions in the right lobe (segments 6, 7, and 8) successfully underwent resection with a pure laparoscopic procedure while in the left semi-prone position. No patient was converted to conventional open surgery. The mean operative duration, volume of bleeding, and postoperative hospital stay were 606 ± 46 min, 585 ± 145 mL, and 18 ± 3.5 days, respectively. Although a liver abscess developed in one patient, no colonic complications or perioperative death occurred.
CONCLUSION: PULSAR for primary colorectal cancer and SCRLM is a feasible multidisciplinary treatment. Moreover, PULSAR can be safely and effectively performed with the patient in the semi-prone position, even when SCRLM exists in the right lobe of the liver.

DOI： 10.1111/ases.12098

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: The purpose of this study was to clarify the gender differences in the prognosis, as well as mortality and morbidity, of patients who have undergone esophagectomy for esophageal cancer. Methods: The clinical results of esophagectomy were compared between 975 male and 156 female patients with esophageal cancer. Results: The male to female ratios of cervical and thoracic esophageal cancer were 1.87 and 7.38, respectively (P < 0.01). The incidence of preoperative comorbidities was 32.4 and 17.4 %, respectively, and the rates of both tobacco and alcohol abuse were significantly lower in the females than in the males. The mortality rate was lower in the females (3.8 %) than in the males (5.7 %), although the differences were not significant. The overall survival was significantly better in the female than in the male patients (P = 0.039). The 5- and 10-year overall survival rates were 32.6 and 20.5 % in the males and 39.5 and 32.5 % in the females, respectively. A multivariate analysis revealed gender to be an independent prognostic factor. However, no significant differences were recognized in disease-specific survival. Conclusions: These results suggest that the prognosis of females with esophageal cancer is better than that of males after esophagectomy, most likely due to multiple clinical factors, such as a more favorable lifestyle and general status.

DOI： 10.1007/s00595-013-0573-x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: DNA aneuploidy, which is characterized by cells containing an abnormal number of chromosomes, is closely associated with carcinogenesis and malignant progression. Aneuploidy occurs during cell division when the chromosomes do not separate properly. Aurora kinases (Aurora-A, -B, and -C) contribute to accurate cell division, and are candidate molecular targets for mitosis-specific anticancer drugs. Methods: We determined the expression of Aurora-A and -B in 110 gastric cancer specimens by performing an immunohistochemical analysis. We also determined the DNA content, TP53 gene mutations, and microsatellite instability in the same samples. Results: We found the nuclear expression of Aurora-A and -B to increase in tumor tissue in comparison to that in normal epithelial tissue. A high Aurora-B expression significantly correlated with aneuploidy and TP53 mutations, but not with microsatellite instability. In contrast, the Aurora-A expression did not correlate with either aneuploidy or microsatellite instability. In addition, the expression of Aurora-A or -B was not significantly associated with the clinical outcomes or prognosis. Conclusions: Our results suggest that an overexpression of Aurora-B, but not of Aurora-A, might contribute to DNA aneuploidy in gastric cancers by promoting chromosomal instability.

DOI： 10.1007/s00595-013-0581-x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) is beneficial in the setting of a complete pathological response. Rad51 expression affects both chemo- and radiosensitivity in many cancers; however, its role in ESCC is unclear. Methods: Rad51 expression was investigated by immunohistochemical staining with resected specimens in 89 ESCC patients who underwent surgery without preoperative therapy. The association with Rad51 and clinicopathological factors was assessed. The expression of Rad51 was also investigated in pretreatment biopsy specimens in 39 ESCC patients who underwent surgery after NACRT and compared with the pathological response to NACRT. Results: Lymph node metastasis was more frequently observed in Rad51-positive cases than negative cases (58.5 vs. 30.6 %, P = 0.0168) in patients treated with surgery alone. Disease-specific survival was decreased in Rad51-positive cases compared to Rad51-negative cases (5 year survival: 79.6 vs. 59.3 %, P = 0.0324). In NACRT patients, completed pathological responses were more frequently observed in Rad51-negative cases than in Rad51-positive cases (68.8 vs. 46.5 %, P = 0.0171). Conclusions: Rad51 expression in ESCC was associated with lymph node metastasis and poor survival. Additionally, Rad51 expression in pretreatment biopsy specimens was a predictive factor for the response to NACRT.

DOI： 10.1245/s10434-013-3220-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: Total pharyngo-laryngo-esophagectomy (PLE) is highly invasive, and the subsequent reconstruction is difficult. The purpose of this study was to clarify the techniques that can decrease the surgical stress and allow for safe reconstruction after this operation. Methods: The surgical method and clinical outcomes of total PLE were reviewed in 12 patients with either cervicothoracic esophageal cancer or double cancer of the esophagus and pharynx. Microscopic venous anastomosis was principally performed, and arterial anastomosis was added, if needed. Results: A narrow gastric tube was used in ten patients, including two patients who underwent free jejunal interposition, while the colon was used as the main reconstructed organ in two other patients. Staged operations were performed in three high-risk patients. All six patients treated after 2010 were able to undergo thoracoscopic and/or laparoscopic surgery. No critical postoperative complications developed, although minor anastomotic leakage developed in two patients who were successfully treated conservatively. Conclusion: When performing PLE, it is important to decrease the surgical stress and ensure a reliable reconstruction by adopting techniques that are appropriate for each case, such as thoracoscopic and laparoscopic surgery, staged operations, microvascular anastomosis, and muscular flaps.

DOI： 10.1245/s10434-013-3453-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aim: Defects in mitotic checkpoint and p53-dependent pathways associate with chromosomal instability. In the present study, we investigated the interplay between BUBR1 and p53 and their association with genetic instability in colorectal cancer. Patients and Methods: 139 colorectal cases were examined for BUBR1, p53 and genetic instability indicators. BUBR1 expression was evaluated by immunohistochemistry and TP53 gene was directly sequenced. DNA ploidy was studied by laser scanning cytometry; MSI and TP53 loss of heterozygosity was also examined. Results: 64% of cases had high BUBR1 expression and were associated with the TP53 mutation. High BUBR1 expression and TP53 mutation associated with DNA aneuploidy and showed an inverse association with MSI. Cases with high BUBR1 expression and TP53 mutation had profound aneuploidy phenotypes and less frequent MSI compared to cases with one or neither aberration. Conclusion: Our findings indicated an interplay between BUBR1 and p53 in colorectal cancer. Altered expression of both molecules was associated with chromosomal instability.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jamcollsurg.2014.09.001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Global DNA hypomethylation is associated with increased chromosomal instability and plays an important role in tumorigenesis. The methylation status of the long interspersed nuclear element-1 (LINE-1) element is a useful surrogate marker for global DNA methylation. Although LINE-1 hypomethylation is recognized as a poor prognostic marker, the correlation of LINE-1 methylation level with tumor suppressor gene mutation, chromosomal instability, and clinical significance in esophageal squamous cell carcinoma (ESCC) remains unclear.
Methods: Using resected tumor tissues and the corresponding normal esophageal mucosa from 105 patients with ESCC, bisulfite pyrosequencing analysis was performed to quantify the LINE-1 methylation levels. p53 mutations in exons two to ten were detected by polymerase chain reaction direct sequencing. Chromosomal instability was assessed by single nucleotide polymorphism array comparative genomic hybridization analysis.
Results: The LINE-1 methylation level of ESCC was significantly lower than matched normal mucosa. LINE-1 methylation levels of normal mucosa from the esophagus had a significant inverse correlation with both cigarette smoking and alcohol consumption of the study subjects. LINE-1 hypomethylation of ESCC was significantly associated with lymph node metastasis, lymphovascular invasion, the frequency of p53 mutation and poor survivability. The LINE-1 methylation levels in ESCC had a significant inverse association with the percentage of copy number alterations in the whole genome, mirroring chromosomal instability.
Conclusions: Our results suggested that whole genome hypomethylation caused by chronic inflammation could initiate carcinogenesis of esophageal squamous cells through chromosomal instability. In addition, chromosomal instability associated with the global hypomethylation might correlate highly with the progression of ESCC.

DOI： 10.1245/s10434-014-3818-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purposes: This retrospective study evaluated the treatment outcomes and clinical relevance of the KRAS mutation status in Japanese metastatic colorectal cancer patients treated with second-line and later cetuximab-containing therapy. Methods: The subjects comprised 65 patients with metastatic colorectal cancer who received cetuximab-containing therapy. At the start of cetuximab-containing therapy, the KRAS mutation status had been proven to be wild type in 12 patients. Tumors were retrospectively screened for KRAS mutations using direct sequencing. Results: A detailed analysis revealed the presence of 24 wild-type (57.1 %) and 18 mutant tumors (42.9 %). Grade 3-4 neutropenia and anemia were observed in 21 (32.3 %) and nine (13.8 %) patients, respectively. An acne-like rash was observed in 50 patients (76.9 %), and among them three patients (4.6 %) experienced a Grade 3 rash. A KRAS mutation was associated with resistance to cetuximab-containing treatment (11.1 vs. 41.7 % responders among 18 mutant and 36 wild-type patients, respectively; P = 0.03). A KRAS mutation was also associated with poorer survival (MST: 6.9 vs. 14.1 months in 18 mutant and 36 wild-type patients, respectively; P = 0.018). Conclusions: The present results indicated the clinical relevance of KRAS mutations in predicting the efficacy of cetuximab-containing therapy for metastatic colorectal patients in the Japanese population.

DOI： 10.1007/s00595-013-0716-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: Vascular endothelial growth factor C (VEGFC) is thought to promote lymphangiogenesis in various human cancer tissues. Materials and Methods: The present study analyzed data from 72 patients with gastric cancer. The lymphatic vessel density (LVD) was determined by immunohistochemical staining using a monoclonal antibody (mAb) against D2-40, and the expression of VEGFC was investigated using a mAb against VEGFC. Results: The intratumoral LVD was higher in cases with nodal metastasis. The VEGFC-positive cases had a higher intratumoral LVD and were more invasive to the lymphatic vessels or lymph nodes than negative cases. Patients with VEGFC-positive cancer had significantly lower survival than those with negative cancer (p<0.05). Conclusion: The expression of VEGFC was related to intratumoral lymph angiogenesis and serves as a pertinent predictive factor for lymphatic invasion or metastasis, while also providing prognostic value.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: With the recent popularization of living donor liver transplantation (LDLT), providing treatment for comorbidities in LDLT recipients has become important. We report the first case of a patient who was successfully treated with LDLT followed by total gastrectomy for early gastric cancer concomitant with decompensated liver cirrhosis. Case Report: A 64-year-old female was admitted for the treatment of severe liver cirrhosis. The patient's preoperative liver function was evaluated as Child-Pugh classification grade C. Upper gastrointestinal endoscopy revealed early gastric cancer. We first performed LDLT to improve her liver function and coagulopathy. Nineteen days after the LDLT, we performed total gastrectomy. Results: The patient's postoperative course was uneventful and she left our hospital on the 18th day after gastrectomy. The final pathological diagnosis of gastric cancer was Stage IA. Conclusion: Aggressive and adequate surgical strategy including LDLT is effective as curative treatment in patients with controllable malignancy concomitant with severe liver dysfunction.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Mortalin is a heat-non-inducible member of the heat shock protein 70 family. Mortalin binds to p53 and prevents p53 from entering the nucleus. To understand the significance of mortalin in gastric cancer, we investigated the expression of mortalin and p53. Methods: Expression of mortalin and p53 was examined by immunohistochemical staining of 182 clinical samples of gastric cancer. Results: Mortalin-positive and aberrant p53-positive tumors were found in 75.2 and 49.5 % of cases, respectively. Mortalin-positive tumors were deeper in invasion and had more lymph node and liver metastases compared with mortalin-negative tumors (P < 0.01, P < 0.05, respectively). Mortalin-positive tumors had worse prognosis compared with mortalin-negative tumors (P = 0.035). Moreover, in tumors with normal p53 function, mortalin-positive tumors had worse prognosis compared with mortalin-negative tumors (P = 0.017). Conclusions: Mortalin has a great impact on gastric cancer with normal p53. Therefore, mortalin is a target molecule for treatment of gastric cancer, as well as a promising prognostic factor, especially in tumors with normal p53.

DOI： 10.1007/s10120-013-0279-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a case of portal-systemic encephalopathy occurring secondary to a splenorenal shunt, 2 years after a pancreaticoduodenectomy for locally advanced duodenal carcinoma. A 55-year-old woman was brought to our hospital with a decreased level of consciousness. Laboratory testing revealed an elevated serum ammonia level (221 μg/dl) and normal liver function. Retrospective review of a series of contrast-enhanced computed tomography scans of the abdomen identified a splenorenal shunt, which had gradually enlarged over the past 2 years (Fig. 1). The decreased level of consciousness was thought to be due to portal-systemic encephalopathy secondary to the splenorenal shunt. We performed balloon-occluded retrograde transvenous obliteration to occlude the splenorenal shunt, following which her serum ammonia level returned to normal (28 μg/dl) and an alert level of consciousness was maintained.

DOI： 10.1007/s00595-013-0679-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The CXCL12/CXCR4 axis plays a pivotal role in cancer progression and metastases in various epithelial cancer cells. The aim of the present study was to evaluate the localization and correlation between CXCL12/CXCR4 expression and clinicopathological features in gastric cancers. Materials and Methods: This study included 111 Japanese patients with primary gastric cancers, which invade submucosa or more, all of whom underwent gastrectomy between 1992 and 1996. Immunohistochemical analysis was performed. Results: A significant correlation was found in the immunoreactivity of nuclear CXCR4 and poor differentiation (p=0.0026), infiltrated pattern (p<0.0001), larger size (p<0.0001), advanced stage (p=0.0342) and reduced 5-year survival rate (30% vs. 61%, p=0.0012). Multivariate analysis revealed that high nuclear CXCR4 immunoreactivity (RR: 3.077, p=0.0329) retained its strength as an independent prognostic factor for overall survival. Conclusion: High immunoreactivity of nuclear CXCR4 in gastric cancer suggests that CXCL12 binds to its unique receptor CXCR4 at the membrane, translocates to the nucleus and then becomes more invasive, and thus can be considered a prognostic factor.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: The present study aimed to clarify the safety and feasibility of esophagojejunostomy during totally laparoscopic total gastrectomy (TLTG). Patients and Methods: In 45 consecutive patients who underwent TLTG for gastric cancer, esophagojejunostomy was performed with a functional end-to-end anastomosis (FEEA) using a linear stapler in 24 patients or with a double stapling technique (DST) using a trans-orally inserted anvil (OrVil) in 21 patients. Results: The DST was more likely to be chosen in patients with tumors located in the upper stomach. In the FEEA group, both the mean length of the operation and the mean postoperative hospital stay were significantly shorter compared to those in the DST group. Two patients in the FEEA group and four patients in the DST group developed postoperative complications but there were no postoperative deaths in either group. Conclusion: Both FEEA and DST in esophagojejunostomy during TLTG are safe and feasible.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: HER2 testing in gastric cancer differs from testing in breast cancer because of inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity and incomplete membrane staining. The aim of the present study was to evaluate the frequency and accuracy of detection of HER2 expression by application of standard criteria in Japanese patients with gastric cancer. Material and Methods: A total of 198 tumor specimens were assessed for HER2 expression by immunohistochemistry (IHC) using the antibodies HercepTest™ and 4B5. Both hand-operated and automated IHC were performed. Results: HER2 expression differed according to the IHC method and antibodies used. HER2 IHC3+ tumors were identified in 21 (10%) and 7 (3.5%) cases by hand-operated and automated IHC, respectively. Conclusion: Among patients with gastric cancer, FISH may be performed in cases of IHC1+ by automated IHC. Further research is required to clarify the relevance of HER2 staining and scoring for the clinical response to HER2-targeted therapy.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

It is now common to resect colorectal cancer by laparoscopic surgery. Hepatectomy has become a standard treatment for patients with colorectal cancer with resectable liver metastases. The resection of liver tumors can now be done partly by laparoscopic surgery. However, metastatic tumors in the right lobe are often difficult to resect laparoscopically. Furthermore, simultaneous resection of the colorectum and liver may also be difficult. In this study, we evaluated a new method to resect both colorectal cancer and liver metastases in the right lobe by laparoscopic surgery. Two cases are presented that underwent total laparoscopic resection of a right lobe tumor, associated with laparoscopic colorectal resection. The metastatic tumor in the right lobe was first resected in the left hemi-prone position. Then, the colorectal cancer was resected in the lithotomy position. The method for resecting the right lobe liver tumor and colorectal cancer was safe and feasible. The mean duration of surgery was 443.5 min, and the mean blood loss was 158 mL. The postoperative course was uneventful. In selected patients, laparoscopic hepatectomy for right lobe synchronous metastatic tumors can be safely performed simultaneously with colorectal surgery.

DOI： 10.1007/s00595-013-0801-4

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background. Cancer of the hypopharynx and cervical esophagus (PhCe cancer) frequently develops synchronously or metachronously with esophageal cancer. The surgical approach is usually difficult, especially in metachronous PhCe cancer after esophagectomy. The purpose of this study was to clarify the treatment outcomes of patients with metachronous PhCe cancer with a history of esophagectomy. Methods. The subjects evaluated in this study were 14 patients with metachronous PhCe cancer who underwent pharyngo-laryngo-esophagectomy after subtotal esophagectomy and gastric tube pull-up for primary esophageal cancer. Results. Definitive chemoradiotherapy (CRT; radiation dose >50 Gy) was performed for primary laryngeal (n = 1), pharyngeal (n = 2), esophageal (n = 1), and recurrent esophageal cancer (n = 2). For seven patients with metachronous PhCe cancer, induction CRT (radiation dose <40 Gy) was performed. In all 14 patients, pharyngo-laryngo-esophagectomy was followed by free jejunal graft interposition with reconstruction of the jejunal vessels. Although postoperative complications developed in four patients, no perioperative death or necrosis of the reconstructed free jejunum occurred. The 2- and 5-year overall survival rates were 84 and 50 %, respectively. Conclusions. Pharyngo-laryngo- esophagectomy with free jejunal transfer is considered to be safe for metachronous PhCe cancer, even in patients with a history of CRT and esophagectomy.

DOI： 10.1245/s10434-013-3454-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Esophageal cancer is frequently associated with squamous cell carcinoma in the head and neck. Both cigarette smoking and alcohol consumption are risk factors for multiple cancers of the head and neck, as well as the esophagus. Routine screening and close follow-up for second cancers are important in patients with esophageal cancer or head and neck cancer. For this purpose, endoscopy with Lugol's staining, as well as narrow-band imaging combined with magnifying endoscopy, is a powerful tool for the early detection of esophageal cancer. Multimodal therapy is essential for patients with double cancers. When considering surgical treatment, the curability of both cancers must be carefully evaluated. If both tumors are potentially curable, each lesion should be treated individually. In patients with metachronous double cancers, the prior treatment of the first primary carcinoma often affects the treatment of the second cancer. Close cooperation among medical staff members is essential for complicated surgeries for double cancers. Techniques that are appropriate for each case must be adopted, such as careful dissection, staged operations, muscular flaps and microvascular anastomosis.

DOI： 10.1007/s00595-013-0713-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Mutations of the KRAS or BRAF genes are now recognized as prognostic markers for colorectal cancer (CRC). They are also important predictive markers for resistance to the monoclonal antibodies that target the epidermal growth factor receptor. Methods: In this retrospective study, KRAS and BRAF mutations were analyzed using a direct sequence method in 254 Japanese CRC patients, and the associations between KRAS or BRAF mutations and clinicopathological characteristics or outcome were evaluated. Results: KRAS and BRAF mutations were detected in 33.5 and 6.7 % of all patients, respectively. Consistent with previous reports, BRAF mutations were significantly correlated with the anatomical site of the tumor (P < 0.001), tumor grade (P = 0.001) and high frequency of microsatellite instability (P < 0.001). BRAF mutations were correlated with poor overall survival in the full patient cohort (P = 0.009). KRAS mutations were significantly correlated with poor recurrence-free survival (P = 0.03), particularly in patients with stage II CRC (P = 0.007). Cox regression analysis showed that KRAS mutations were a negative predictor of recurrence-free survival in patients with stage II CRC. Conclusion: KRAS mutation status could be a novel biomarker for predicting disease recurrence in Japanese patients with stage II CRC.

DOI： 10.1007/s10147-012-0501-x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The expression of podoplanin is reportedly involved in collective cell invasion, which is independent from the epithelial-mesenchymal transition (EMT). We focused on the expression of podoplanin in esophageal squamous cell carcinomas (ESCC) and investigated the correlation of podoplanin and EMT-related markers, and evaluated its prognostic significance. Five ESCC cell lines were subjected to western blot analysis for podoplanin and EMT markers. The effects of podoplanin on EMT and carcinoma invasion were evaluated with wound healing assays, invasion assays and 3-D culture. Transfection of ectopic podoplanin into a podoplanin-negative ESCC cell line (TE-15) induced cell migration and invasive activity (P < 0.001 and P < 0.05, respectively) without downregulation of E-cadherin. In contrast, transfection of si-podoplanin RNA into a podoplanin-positive ESCC cell line (TE-13) reduced cell migration and invasive activity (P < 0.05). We reviewed 101 patients who had undergone esophagectomy for ESCC. Podoplanin expression was observed in 58 patients (57.4%), and positive expression was positively correlated with expression of E-cadherin (P < 0.01), deeper wall invasion (P < 0.01), venous invasion (P < 0.05) and poorer prognosis (P < 0.01). Multivariate Cox analysis revealed that expression of podoplanin was a significant and independent unfavorable predictor of survival (P < 0.05). These data suggest that podoplanin is significantly associated with and likely contributes to ESCC invasion in the absence of EMT.

DOI： 10.1111/cas.12286

記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study evaluated the feasibility of totally laparoscopic distal gastrectomy (TLDG) in elderly patients with gastric cancer. We retrospectively analyzed the data from 138 patients who underwent TLDG from April 2005 to March 2009. Of these 138 patients, 20 were older than 75 years of age, and 118 were 75 years of age or younger. The preoperative respiratory function and American Society of Anesthesiologists (ASA) -physical status were significantly worse in the elderly patients than in the younger patients (P = 0.013). Hypertension and respiratory disease were more common in the elderly patients than in the younger patients (P = 0.032 / P = 0.005). The findings for the following parameters were similar in the two groups: intraoperative blood loss, operation time, severe postoperative complication rate, time required to start a solid diet, and duration of postoperative hospital stay. The rate of major complications was not different between the two groups, although minor complications were more commonly observed in the elderly patients. TLDG was found to be a safe procedure for elderly patients. This method can be used as one of the standard treatments for gastric cancer in elderly patients.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose. Our goal was to create a multimodal treatment strategy for patients with locally advanced esophageal cancer (EC). Methods. A retrospective review identified a total of 193 patients with clinical T3 thoracic EC were categorized into 3 groups: 81 who had surgery only (group I); 102 who had planned neoadjuvant chemoradiotherapy (NACRT; group II); and 10 who had salvage esophagectomy after definitive chemoradiotherapy (dCRT; group III). Results. Postoperative complications developed in 27, 45, and 80 % of patients in group I, group II, and group III, respectively. NACRT and dCRT were independent risk factors associated with postoperative complications; the odds ratios for group II and group III, compared with group I, were 2.1 and 8.8, respectively. The respective mortality rates were 4, 2, and 20 % (group I vs. group III, p\0.05; group II vs. group III, p\0.01). The 5-year survival rate was 25.2 % in group I and 41.6 % in group II. The 5-year survival rate in group II patients with markedly effective NACRT (89.2 %) was significantly better than in patients with ineffective/slightly effective (11.8 %; p\0.0001) and moderately effective treatment (51 %; p\0.05). Four patients who had noncurative surgery died within 4 months after salvage esophagectomy, whereas four of six patients were still alive after curative surgery. Conclusions. A pathological complete response to NACRT is critical for improving survival in patients with clinical T3 thoracic EC. Salvage surgery should be considered only in carefully selected patients with locally advanced EC.

DOI： 10.1245/s10434-013-3192-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 68-year-old man was introduced to our hospital with right lower abdominal pain. Endoscopic examination and abdominal CT revealed gastric cancer with liver metastasis. We started chemotherapy using S-1 (120 mg/body/day), orally administered for 2 weeks followed by a 2-week rest period, and docetaxel (35 mg/m²), administered intravenously on day 1 and 15 as 1 course. After 4 courses of chemotherapy, the liver tumor reduced markedly and no new cancerous region was found by examination; therefore total gastrectomy and partial hepatectomy were performed. Histological examination showed an undifferentiated adenocarcinoma remaining as Grade 1b in the resected stomach. A resected specimen of the liver showed necrotic tissue without any cancer cells. This case suggests that S-1/docetaxel chemotherapy may reduce the stage of unresectable liver metastasis from gastric cancer and make a curative operation possible.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Esophageal cancer is frequently associated with head and neck cancer, and esophagectomy is usually difficult in such a case. The purpose of this study was to clarify the clinical significance of esophagectomy for patients with esophageal cancer associated either synchronously or metachronously with head and neck cancer. Methods: The clinical outcomes of surgical resections for esophageal cancer were compared between 26 patients with head and neck cancer (double cancer group) and 176 without head and neck cancer (control group). Results: Staged operations were performed in 5 patients in the double cancer group, while microvascular anastomosis as well as a muscle flap was added for 3 and 4 patients, respectively. The mortality and morbidity of the double cancer group were 0 and 35 %, respectively, which were not significantly different from those of the control group (3 and 31 %, respectively). There were no significant differences in overall survival in the double cancer and control groups, which had 5-year survival rates of 59 and 49 %, respectively. Conclusions: Esophagectomy can be an effective treatment when techniques are adopted that are appropriate for each case, such as staged operations, muscular flaps, and microvascular anastomosis, even in patients with double cancers of the esophagus and the head and neck.

DOI： 10.1245/s10434-013-2875-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jamcollsurg.2013.02.005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 64-year-old man was initially diagnosed with rectal cancer and liver metastasis. He underwent rectal amputation and partial hepatectomy. mFOLFOX6 was begun as first-line chemotherapy, but multiple pulmonary and right femoral lymph node metastases were found 1 year postoperatively. FOLFIRI plus bevacizumab was then started, but the tumors recurred after 2 years and 11 months. The regimen was changed to cetuximab with CPT-11. The lesions partially responded after 3 months, and the patient was free from progression for 1.5 years. Four years and 7 months after the adjuvant chemotherapy was started, the metastatic lesions gradually increased again, and the regimen was changed to panitumumab. After 2 months, the lesions had markedly decreased again and showed a partial response for 6 months. Although the pulmonary lesions became progressive again, the patient has been alive for 5 years and 8 months since the first operation.

DOI： 10.1159/000353781

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: To justify esophagectomy for elderly patients. Patients and Methods: A total of 1,002 patients with thoracic esophageal cancer who underwent esophagectomy were divided into three groups: I (≤74 years old, n=898); II (75-79 years, n=81); and III (≥80 years, n=23). Historical changes were compared between the first surgical period (1964-1989) and the second period (1990-2011). Results: The morbidity rates were 40%, 41% and 26% in the respective groups. Pulmonary complications decreased historically in groups II and III (36% to 15% and 43% to 0%, respectively). The mortality was higher in the older groups (4.8%, 8.6% and 13.0%, respectively); however, there was a marked historical decrease in groups II (18.2% to 5.1%) and III (28.6% to 6.3%). The 5-year survival improved from 5% to 35% in group II and from 0% to 17% in group III. Conclusion: The outcomes of esophagectomy for elderly patients have markedly improved, with acceptable mortality even in octogenarians.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: A prospective feasibility study was planned to clarify the proportion of compliance and adverse events in the administration of capecitabine as adjuvant chemotherapy for colon cancer in Japanese patients. Methods: We aimed initially to register 92 cases of R0 stage III colon cancer. Capecitabine (2,500 mg/m²/day) was given orally on days 1-14 every 3 weeks for 8 cycles. The proportion of treatments completed as planned was selected as the primary endpoint. Results: Ninety-seven cases were registered and treated between September 2008 and August 2009. The proportion of treatments completed in the full analysis set was 64/97 [66.0%; 95% confidence interval (CI), 55.7-75.3%] and in the per protocol set was 64/91 (70.3%; 95% CI, 59.8-79.5%). Adverse events which led to treatment discontinuation included hand-foot syndrome (HFS) (7), haematotoxicity (5) and increased hepatic damage (4). The proportions of patients with major grade 3/4 adverse events were HFS 22.7%, neutropenia 7.2%, diarrhoea 2.1%, and increased bilirubin 0.0%. Conclusions: This collaborative multi-facility study, the first of its kind in Japan, presented results of a safety confirmation experiment on capecitabine as adjuvant chemotherapy for stage III colon cancer. The results suggest that capecitabine may be administered safely to Japanese patients.

DOI： 10.1007/s10147-011-0371-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A case was a 77 years old male. Exertional breathlessness was a chief complaint, and anemia was pointed out. A duodenum GIST was detected by gastroscopy. The CT scan showed infiltration in an inferior vena cava, the right kidney, and an ascending colon, so we judged that radical cure resection was difficult. We started Imatinib medication. Six months after the medication start, because the border with surroundings also became clear, we became a plan of the operation. The tumor existed in the descending limb of duodenum and the distance with papilla Vater was maintained, so the complete excision by duodenal portion resection was possible for it. Although meaning of primary systemic therapy for GIST was not established, it was shown that medicating Imatinib to the high-level partial advance GIST before an operation may become an effective cure which avoids an extended operation and makes complete resection of a tumor possible.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The purpose of this study was to clarify the outcomes of preoperative CDDP/5-FU chemotherapy (FP therapy) followed by surgery for patients with clinical Stage II/III thoracic esophageal cancer. Seventeen patients with clinical Stage II/III thoracic esophageal cancer who underwent FP therapy followed by esophagectomy were investigated with regard to the perioperative clinical results and postoperative outcomes. Grade 3 or 4 adverse effects associated with FP therapy were recognized in 2 of the 17 (11.8%) cases, and 16 patients completed 2 cycles of FP therapy (94.1%). Complications after surgery occurred in 7 cases (41.2%). There were 7 patients with postoperative recurrences (41.2%), 6 of whom had clinical Stage III disease. Similarly, 4 out of the 5 patients who died of cancer had clinical Stage III disease. All recurrences and cancer-related deaths were recognized in histological effectiveness of Grade 0/1 cases. Preoperative FP therapy was found to be safe for patients with clinical Stage II/III thoracic esophageal cancer. However, the treatment seemed to be less beneficial for Stage III patients than for Stage II patients, thus suggesting that a more powerful preoperative treatment may be necessary for clinical Stage III patients.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DNA aneuploidy is observed in various human tumors and is associated with the abnormal expression of spindle assembly checkpoint (SAC) proteins. Oxidative stress (OS) causes DNA damage and chromosome instability that may lead to carcinogenesis. OS is also suggested to contribute to an increase in aneuploid cells. However, it is not clear how OS is involved in the regulation of SAC and contributes to carcinogenesis associated with aneuploidy. Here we show that an oxidant (KBrO₃) activated the p53 signaling pathway and suppressed the expression of SAC factors, BubR1, and Mad2, in human diploid fibroblast MRC5 cells. This suppression was dependent on functional p53 and reactive oxygen species. In p53 knockdown cells, KBrO₃ did not suppress BubR1 and Mad2 expression and increased both binucleated cells and cells with >4N DNA content. BubR1 and not Mad2 downregulation suppressed KBrO₃-induced binucleated cells and cells with >4N DNA content in p53 knockdown cells, suggesting that BubR1 contributes to enhanced polyploidization by a mechanism other than its SAC function. In analysis of 182 gastric cancer specimens, we found that BubR1 expression was significantly high when p53 was positively stained, which indicates loss of p53 function (P = 0.0019). Moreover, positive staining of p53 and high expression of BubR1 in tumors were significantly correlated with DNA aneuploidy (P = 0.0065). These observations suggest that p53 deficiency may lead to the failure of BubR1 downregulation by OS and that p53 deficiency and BubR1 accumulation could contribute to gastric carcinogenesis associated with aneuploidy. We found that OS could contribute to the emergence of polyploid cells when p53 was deficient in normal human fibroblast cells. Importantly, this polyploidization could be suppressed by downregulating the expression of one spindle assembly checkpoint factor, BubR1. We also found that p53 dysfunction and BubR1 accumulation strongly correlate with the extent of aneuploidy in gastric cancer specimen and our data suggest that p53 deficiency and BubR1 accumulation could contribute to gastric carcinogenesis associated with aneuploidy.

DOI： 10.1002/cam4.101

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gastric cancer with peritoneal dissemination may be diagnosed as unresectable. More recently, as a result of progress in chemotherapy, some patients with peritoneal dissemination have exhibited extended survival. We report on our experience with three patients in whom induction chemotherapy allowed for totally laparoscopic total gastrectomy (TLTG). All three patients were diagnosed as having advanced gastric cancer with peritoneal dissemination using staging laparoscopy. As induction chemotherapy, S-1 combined with cisplatin was administered to two patients and trastuzumab plus capecitabine combined with cisplatin to one patient. TLTG was performed in all patients and there were no postoperative complications. Adjuvant chemotherapy was initiated within 3 weeks after surgery in all three patients. Laparoscopic gastrectomy undertaken after induction chemotherapy was found to be effective and safe; this treatment has the potential to achieve good treatment outcomes in patients with stage IV gastric cancer.

DOI： 10.1159/000357591

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Total pharyngo-laryngo-esophagectomy (TPLE) is indicated for either cervical esophageal cancer or synchronous double cancer of the thoracic esophagus and head and neck and this operation is extremely invasive. We adopted minimally invasive surgery for three patients who underwent this operation: VATS (video-assisted thoracoscopic surgery) esophagectomy was undergone in left semi-prone position and laparoscopic approach was also applied to reconstruction with gastric tube. After pharyngo-laryngectomy and gastric tube pull-up through post-mediastinal route, cervical anastomosis was performed. Free jejunal interposition was added in a case, while microvascular venous anastomosis between short gastric vein and cervical vein in another two cases. All patients recovered well without any postoperative complications. This is the first report, which describes minimally invasive TPLE using both VATS and laparoscopic technique in addition with plastic surgery.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Billroth I (B-I) gastroduodenostomy is an anastomotic procedure that is widely performed after gastric resection for distal gastric cancer. A circular stapler often is used for B-I gastroduodenostomy in open and laparoscopic-assisted distal gastrectomy. Recently, totally laparoscopic distal gastrectomy (TLDG) has been considered less invasive than laparoscopic-assisted gastrectomy, and many institutions performing laparoscopic-assisted distal gastrectomy are trying to progress to TLDG without markedly changing the anastomosis method. The purpose of this report is to introduce the technical details of new methods of intracorporeal gastroduodenostomy using either a circular or linear stapler and to evaluate their technical feasibility and safety. Methods: Seventeen patients who underwent TLDG with the intracorporeal double-stapling technique using a circular stapler (n = 7) or the book-binding technique (BBT) using a linear stapler (n = 10) between February 2010 and April 2011 were enrolled in the study. Clinicopathological data, surgical data, and postoperative outcomes were analyzed. Results: There were no intraoperative complications or conversions to open surgery in any of the 17 patients. The usual postoperative complications following gastroduodenostomy, such as anastomotic leakage and stenosis, were not observed. Anastomosis took significantly longer to complete with DST (64 ± 24 min) than with BBT (34 ± 7 min), but more stapler cartridges were needed with BBT than with DST. Conclusions: TLDG using a circular or linear stapler is feasible and safe to perform. DST will enable institutions performing laparoscopic-assisted distal gastrectomy with circular staplers to progress to TLDG without problems, and this progression may be more economical because fewer stapler cartridges are used during surgery. However, if an institution has already been performing δ anastomosis in TLDG but has been experiencing certain issues with δ anastomosis, converting from δ anastomosis to BBT should be beneficial.

DOI： 10.1007/s00464-012-2433-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although the use of laparoscopic gastrectomy for gastric cancer has been widespread, it has remained controversial whether it can be applied for the patients with advanced gastric cancer. The aim of this study was to clarify the safety and usefulness of totally laparoscopic gastrectomy for patients with advanced gastric cancer. Totally laparoscopic gastrectomy was applied for a total of 38 patients with pStage IB-III advanced gastric cancer at our institute. The surgical and long-term results were analyzed in those patients. Twenty-seven patents underwent distal gastrectomy and 11 patients underwent total gastrectomy. The mean number of dissected lymph nodes was 41 (range, 16-87). The mean length of the operation and amount of blood loss was 324 min and 123 ml, respectively. Two cases of postoperative bleeding were noted, while neither anastomosis-related complications nor in-hospital death was observed. The follow-up period after surgery was 8-72 months. Postoperative recurrence was observed in 6 patients (peritoneal dissemination: 3 patients, pleural dissemination: 1 patient, liver metastasis: 1 patient, ovarian metastasis: 1 patient). The overall survival rates at 1, 3 and 5 years were 94.7%, 76.3% and 76.3%, respectively. Totally laparoscopic gastrectomy is safe and can lead to satisfactory long-term outcomes in cases of advanced gastric cancer. Prospective controlled studies are warranted to confirm our findings.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: It is important for patients to complete the planned hormone therapy to reduce both the recurrence and mortality rates of hormone receptor-positive breast cancer. We investigated the rates and factors related to the early discontinuation of adjuvant hormone therapy at our institution.
Methods: We identified 145 females prescribed adjuvant hormone therapy who were followed up for longer than 5 years. The rate of completing the planned hormone therapy and factors related to early discontinuation were examined. The relapse-free survival rate was examined between the completion group and the discontinuation group.
Results: The completion rate was 90.6 %. The primary reason for discontinuing hormone therapy within 5 years was side effects, such as arthritic pain. The primary factor related to early discontinuation was a significantly younger age. The relapse-free survival rate was significantly lower in the discontinuation group (p = 0.025).
Conclusions: More than 90 % of the patients completed the planned adjuvant hormone therapy, and early discontinuation was related to a shorter RFS. To improve the rate of the successful completion of adjuvant hormone therapy, it is important to provide supportive care to reduce the occurrence of side effects and to care for young females with a desire to become pregnant.

DOI： 10.1007/s00595-013-0762-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose The results and outcomes of surgical resection for esophageal carcinoma have improved remarkably in recent years; however, recurrence still frequently develops, even after complete resection. The purpose of this study is to clarify the characteristics of recurrence in this patient population. Methods Among 208 patients, who underwent R0 resection for esophageal carcinoma, recurrence developed in 61. Clinical data were available for 56 of these patients, who were the subjects of this study. We evaluated the time, patterns, and treatment of recurrence in these patients. Results Recurrence developed within 1 and 2 years after esophagectomy in 71 and 84% of the patients, respectively, and was classified as loco-regional (54%), hematogenous (36%), or mixed type (10%). The prognosis of patients with loco-regional recurrence tended to be better than that of those with distant metastasis, although the difference was not significant (P = 0.088). Patients with recurrence treated by chemotherapy alone or multimodal therapy, such as radiation or surgery combined with systemic chemotherapy, survived significantly longer than those with untreatable recurrence (P = 0.016). Conclusion These findings reinforce the importance of careful follow-up for both loco-regional and hematogenous recurrence after esophagectomy, particularly during the first 2 years.

DOI： 10.1007/s00595-012-0133-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The biological characteristics of cancers depend mostly on genetic alterations in the cancer cells of individuals. Gastric cancers show a high frequency of DNA aneuploidy, a phenotype of chromosomal instability. Compared to diploid tumors, gastric carcinomas with aneuploidy have been shown to have high proliferative activity and high metastatic or invasive potential; these characteristics lead to a poor prognosis. It has been suggested that an abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. This review, in order to determine whether gastric carcinomas that display aneuploidy are associated with a poorer prognosis than diploid tumors, and to discuss the biological mechanisms that induce aneuploidy, summarizes the results of studies on DNA ploidy in gastric cancer published in the English literature. Analysis of DNA ploidy in gastric cancer may provide clinically useful information from diagnostic, therapeutic, and prognostic standpoints. Further investigations may be needed to clarify the relationship between chromosome instability and DNA ploidy.

DOI： 10.1007/s00535-012-0565-4

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Extra-gastrointestinal stromal tumors (EGISTs) that do not originate in the digestive tract are rare. We report a case of multiple EGISTs, which was monitored closely by KIT gene mutation analysis and other investigations. The patient was a 52-year-old man in whom multiple tumors in the abdominal cavity were diagnosed as EGISTs. Immunohistochemical analysis revealed positive staining for c-kit; however, no mutations were found in the KIT gene. The tumors decreased in size remarkably following treatment with imatinib mesylate, but after 2 years of this treatment, multiple liver metastases and some regrowth of the abdominal masses were found simultaneously. The liver metastasis and the abdominal masses were excised, and further analysis of the KIT gene revealed the same mutation in exon 11 in the KIT gene in the metastatic tumors. We speculate that the treatment might have triggered development of the imatinib mesylate-resistant clone, which may have existed in the primary lesion as a KIT gene mutant. This report provides valuable insight into the mechanisms of recurrent GISTs after treatment with imatinib mesylate.

DOI： 10.1007/s00595-010-4477-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: Prediction of the postoperative course of esophagectomy is an important part of the strict perioperative management of patients undergoing surgery for esophageal cancer. Methods: To evaluate their clinical importance, peripheral blood values, including white blood cell count (WBC), lymphocyte count, and the levels of total protein, transferrin, factor XIII, D-dimer, fibrin, and fibrinogen degradation products (FDP) were measured before and after esophagectomy for esophageal cancer in 24 patients. Results: The preoperative WBC and the pre- and postoperative lymphocyte count were decreased remarkably in patients who received preoperative chemoradiotherapy. The values of perioperative serum transferrin were significantly lower in patients with postoperative pneumonia than in those without. The activity of plasma factor XIII was suppressed on postoperative day (POD) 7 in patients with pneumonia and on POD 14 in patients with leakage. Conclusions: These results suggest that patients who receive preoperative chemoradiotherapy are potentially immunosuppressed, the preoperative serum transferrin level is a possible predictive marker of postoperative pneumonia, and suppression of factor XIII activity is related to anastomotic insufficiency.

DOI： 10.1007/s00595-009-4135-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gastric cancers show high frequency of DNA aneuploidy, a phenotype of chromosomal instability. It is suggested that the abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. We studied the mechanism by assessing the expression of BUBR1 in gastric cancer. The DNA ploidy patterns of 116 gastric cancer samples obtained from the Department of Surgery and Science at Kyushu University Hospital were analyzed. Of those, DNA aneuploidy was seen in 70 (60.3%) cases of gastric cancer. The expression of BUBR1 was studied by immunohistochemistry in 181 gastric cancer samples and by real-time RT-PCR in several gastric cancer cell lines. Ninety-one (50.3%) cases had high expression of BUBR1 and those cases correlated significantly with DNA aneuploidy (P < 0.05). Also high expression of BUBR1 cases had significant correlation with deep invasion, lymph node metastasis, liver metastasis, and poor prognosis. In gastric cancer cell lines, high expression of BUBR1 had a significant relationship with DNA aneuploidy (P < 0.05). Then, gastric cancer cell lines MKN-28 and SNU-1 were transfected with full-length BUBR1 to observe the significance of the change in BUBR1 expression. Enforced expression of BUBR1 resulted in changes to the ploidy pattern and high Ki-67 expression. Collectively, our clinical and in vitro data indicate that high expression of BUBR1 may be one of causative factors for the induction of DNA aneuploidy and progression of gastric cancer.

DOI： 10.1111/j.1349-7006.2009.01457.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The purpose of this study was to evaluate the genetic background of colorectal cancer according to the tumor site, and to investigate the impact of the genetic features regarding the lesion location of colorectal cancer. Microsatellite instability (MSI), DNA index, and the mutation and loss of heterozygosity of the TP53 gene were systemically examined in 180 Japanese colorectal cancer cases. The correlation between these genetic features and clinicopathologic factors was analyzed. A logistic regression was undertaken to analyze the association between genetic features and tumor locations. The data demonstrated location-related genetic differences in colorectal cancer. The proximal subset was distinct in patterns of genomic instability and TP53 gene defects. The genetic features of distal colon cancers paralleled those of rectal cancers. Intriguingly, a multivariate analysis implicated MSI as the only factor significantly associated with tumor location. When MSI tumors were excluded, the statistical association between tumor location and alternations in the DNA index and TP53 vanished. The location-related differences of colorectal cancer were derived from the unequal distribution of the MSI tumors. On the other hand, the microsatellite stable colorectal cancers were genetically homogeneous regardless of the tumor location. Therefore, instead of tumor location, microsatellite status should be a major focus for the study of colorectal cancers in the future.

DOI： 10.1016/j.cancergencyto.2009.09.009

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Head-and-neck cancer is frequently associated with esophageal cancer. Because the operative procedures for these synchronous double cancers are too invasive, definitive chemoradiotherapy tends to be applied as an initial treatment. A salvage esophagectomy for either recurrent or residual disease after definitive chemoradiotherapy in patients with such double cancer has never been reported. We reviewed 21 patients with esophageal cancer who underwent a salvage esophagectomy after definitive chemoradiotherapy. Among them, the treatment course of five patients who underwent a salvage esophagectomy for patients with synchronous double cancers of the esophagus and head-and-neck region was analyzed. Because head-and-neck cancer was well controlled after chemoradiotherapy in all five patients, a salvage esophagectomy was indicated for either recurrent or residual esophageal cancer after definitive chemoradiotherapy. Anastomotic leakage developed in four patients; however, no other complications including pulmonary complications were recognized. All of them were discharged to home and three of them are still alive without any recurrence for 20-43 months. A salvage esophagectomy should be considered as a treatment option for either recurrent or residual esophageal cancer with well-controlled head-and neck cancer after definitive chemoradiotherapy when complete resection of the esophagus is expected.

DOI： 10.1111/j.1442-2050.2009.00973.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: Primary esophageal small cell carcinoma is a comparatively rare disease. It is thought to have a poor prognosis, and no standard treatment strategy has yet been established. Surgical cases of small cell carcinoma of the thoracic esophagus were reviewed with regard to clinical characteristics and treatment strategy. Patients and methods: Among the 993 patients who underwent an esophagectomy for thoracic esophageal cancer from 1965 to 2007, 12 cases (1.2%) demonstrated a diagnosis of small cell carcinoma based on the histopathology findings. Results: There were 3 cases of Stage I, 1 case of Stage II, 4 cases of Stage III, and 4 cases of Stage IVa. Five cases (42%) were treated preoperatively (chemoradiotherapy, 4 cases; radiotherapy, 1 case), and the pathological criteria for the effects of preoperative therapy were 3 cases of Grade 3. Eleven patients died of cancer; only 1 patient achieved long-term survival and complete response for treatment with chemoradiation after recurrence. The median survival time was 7.6 months, the 1-year survival rate was 33%, and the 3-year survival rate was 8.3%. Conclusions: The prognosis of surgically resected cases of esophageal small cell carcinoma is poor; therefore, either chemotherapy or chemoradiotherapy should be administered to such cases. Furthermore, improved understanding of the biological characteristics of this type of tumor will result in the development of new therapeutic strategies, which are expected to improve patient outcome.

DOI： 10.1007/s10388-009-0197-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Conflicting data exist regarding the relevance of high-frequency microsatellite instability (MSI-H) for predicting the prognosis and benefits of 5-fluorouracil (5-FU)-based chemotherapy. This study investigated the usefulness of MSI as either a prognostic indicator or predictor of distinct clinical attributes regarding the use of adjuvant chemotherapy with 5-FU and its analogues in gastric cancer. Materials and methods: Data and tumor specimens were collected from 240 gastric cancer patients from 1993 to 2002. Five microsatellite loci were analyzed using a high-intensity microsatellite analysis reported previously. A Cox proportional hazard model was used to compare the clinical data and survival as well as any associations between MSI and 5-FU treatment status of patients with MSI or microsatellite stability (MSS) gastric cancers. A 3-(4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was conducted in 168 cases to investigate chemosensitivity to 5-FU. Results: This analysis identified 22 MSI-H (9.4%), 25 MSI-L (10.7%), and 193 MSS (79.9%) tumors. Gastric cancer with MSI-H tended to have increased likelihood to show higher age, antral location of the tumor, and lymph vessel involvement (P < 0.05). Univariate analyses failed to show any difference between the MSI-H and MSS/MSI-L groups with respect to overall survival. Furthermore, survival after the administration of 5-FU did not correlate with MSI status, and MSI was not associated with 5-FU sensitivity by MTT assay. Conclusion: The results of this study indicate that MSI status has no clear influence on overall survival or response to 5-FU in gastric cancer.

DOI： 10.1245/s10434-009-0580-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: To examine the methylation status of the promoter region of the checkpoint with forkhead-associated and ring finger (CHFR) and microsatellite mutator status in 59 primary gastric cancers. Methods: We investigated the promoter methylation of CHFR in 59 cases of gastric cancer using methylation-specific PCR. Five microsatellite loci were analyzed using high-intensity microsatellite analysis reported previously, and p53 gene mutations were investigated by direct sequencing. Results: Twenty cases (33.9%) showed promoter methylation and no relation was observed with the clinicopathological factors. We found that the promoter methylation of CHFR was frequently accompanied with microsatellite instability (MIN). Seven of 20 (35.0%) cases showed MIN in hypermethylation of the CHFR tumor, while three of 39 (7.7%) cases showed MIN in the non-methylated CHFR tumor (P < 0.01). However, we failed to find any relationship between CHFR methylation and p53 mutation status. Conclusion: The coordinated loss of both the mitotic check point function and mismatch repair system suggests the potential to overcome the cell cycle check point, which may lead to an accumulation of mutations. However, the p53 mutation was not related to hypermethylation of the CHFR promoter and MIN, which indicates that an abnormality in p53 occurs as an independent process from the mismatch repair deficiency in carcinogenesis.

DOI： 10.3748/wjg.15.2520

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nowadays, the advancements of systemic chemotherapy for colorectal carcinoma improve a clinical response rate, and expand the possibility of resection which couldn't operable at the initial visit. In addition, the prognoses of the patients, who had a radical operation for metastasis, are clearly longer than the non-operable patients. Bevacizumab, anti-human VEGF monoclonal antibody, is significantly effective when used in combination with one of the systemic multi-agent chemotherapy such as FOLFOX regimen or FOLFIRI regimen. We report here two cases with colon carcinoma, which had initially unresectable liver metastases, were respond to the treatment of systemic multi-agent chemotherapy with bevacizumab. Then, both cases were able to undergo radical resections of primary tumor and liver metastases safely.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, standard therapies for either gastric cancer or colorectal cancer have been established through the development of multidrug systemic chemotherapy and the appearance of molecular targeting drugs. For example, either FOLFIRI or FOLFOX therapy is normally chosen for the treatment of unresectable liver metastasis from colorectal cancer. On the other hand, hepatic artery infusion (HAI) chemotherapy is generally used as only a second-line therapy. There are, however, some cases in which systemic chemotherapy is not indicated due to age and/or the risk of side effects. We herein report three cases that were treated by HAI after initially performing systemic chemotherapy in order to treat liver metastasis from either gastric cancer or colorectal cancer.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gastric cancers show high frequency of DNA aneuploidy, a phenotype of chromosomal instability. It is suggested that the abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. We studied the mechanism by assessing the expression of BUBR1 in gastric cancer. The DNA ploidy patterns of 116 gastric cancer samples obtained from the Department of Surgery and Science at Kyushu University Hospital were analyzed. Of those, DNA aneuploidy was seen in 70 (60.3%) cases of gastric cancer. The expression of BUBR1 was studied by immunohistochemistry in 181 gastric cancer samples and by real-time RT-PCR in several gastric cancer cell lines. Ninety-one (50.3%) cases had high expression of BUBR1 and those cases correlated significantly with DNA aneuploidy (P < 0.05). Also high expression of BUBR1 cases had significant correlation with deep invasion, lymph node metastasis, liver metastasis, and poor prognosis. In gastric cancer cell lines, high expression of BUBR1 had a significant relationship with DNA aneuploidy (P < 0.05). Then, gastric cancer cell lines MKN-28 and SNU-1 were transfected with full-length BUBR1 to observe the significance of the change in BUBR1 expression. Enforced expression of BUBR1 resulted in changes to the ploidy pattern and high Ki-67 expression. Collectively, our clinical and in vitro data indicate that high expression of BUBR1 may be one of causative factors for the induction of DNA aneuploidy and progression of gastric cancer.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

It is now common to resect colorectal cancer by laparoscopic surgery. Hepatectomy has become a standard treatment for patients with colorectal cancer with resectable liver metastases. The resection of liver tumors can now be done partly by laparoscopic surgery. However, metastatic tumors in the right lobe are often difficult to resect laparoscopically. Furthermore, simultaneous resection of the colorectum and liver may also be difficult. In this study, we evaluated a new method to resect both colorectal cancer and liver metastases in the right lobe by laparoscopic surgery. Two cases are presented that underwent total laparoscopic resection of a right lobe tumor, associated with laparoscopic colorectal resection. The metastatic tumor in the right lobe was first resected in the left hemi-prone position. Then, the colorectal cancer was resected in the lithotomy position. The method for resecting the right lobe liver tumor and colorectal cancer was safe and feasible. The mean duration of surgery was 443.5 min, and the mean blood loss was 158 mL. The postoperative course was uneventful. In selected patients, laparoscopic hepatectomy for right lobe synchronous metastatic tumors can be safely performed simultaneously with colorectal surgery.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Mortalin is a heat-non-inducible member of the heat shock protein 70 family. Mortalin binds to p53 and prevents p53 from entering the nucleus. To understand the significance of mortalin in gastric cancer, we investigated the expression of mortalin and p53.
METHODS: Expression of mortalin and p53 was examined by immunohistochemical staining of 182 clinical samples of gastric cancer.
RESULTS: Mortalin-positive and aberrant p53-positive tumors were found in 75.2 and 49.5 % of cases, respectively. Mortalin-positive tumors were deeper in invasion and had more lymph node and liver metastases compared with mortalin-negative tumors (P < 0.01, P < 0.05, respectively). Mortalin-positive tumors had worse prognosis compared with mortalin-negative tumors (P = 0.035). Moreover, in tumors with normal p53 function, mortalin-positive tumors had worse prognosis compared with mortalin-negative tumors (P = 0.017).
CONCLUSIONS: Mortalin has a great impact on gastric cancer with normal p53. Therefore, mortalin is a target molecule for treatment of gastric cancer, as well as a promising prognostic factor, especially in tumors with normal p53.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Extra-gastrointestinal stromal tumors (EGISTs) that do not originate in the digestive tract are rare. We report a case of multiple EGISTs, which was monitored closely by KIT gene mutation analysis and other investigations. The patient was a 52-year-old man in whom multiple tumors in the abdominal cavity were diagnosed as EGISTs. Immunohistochemical analysis revealed positive staining for c-kit; however, no mutations were found in the KIT gene. The tumors decreased in size remarkably following treatment with imatinib mesylate, but after 2 years of this treatment, multiple liver metastases and some regrowth of the abdominal masses were found simultaneously. The liver metastasis and the abdominal masses were excised, and further analysis of the KIT gene revealed the same mutation in exon 11 in the KIT gene in the metastatic tumors. We speculate that the treatment might have triggered development of the imatinib mesylate-resistant clone, which may have existed in the primary lesion as a KIT gene mutant. This report provides valuable insight into the mechanisms of recurrent GISTs after treatment with imatinib mesylate.

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

大腸癌に対する薬物療法の進歩はめざましい.現在ではさまざまな分子標的薬や支持療法によって,切除不能大腸癌であってもQOL(quality of life)を保ちながら約30ヵ月以上の生存期間中央値を得るまでになっている.薬剤の適切な治療法の選択のためには,RAS/BRAF,MSI,HER2などの遺伝子ステータスの他,原発巣の部位など多くのバイオマーカーが重要となっている.一方で,根治切除後の術後補助化学療法は,病理学的分類のみでその適応が決定されている.術後補助療法の効果を層別化する遺伝子学的バイオマーカーとして,今後Circulating DNA(ctDNA:血中微量遊離がん由来DNA)をはじめとした新しい手法が注目される.(著者抄録)

記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞ポイント　◆TaTMEにおけるランドマークは,後壁:endopelvic fascia,側壁:S4骨盤内臓神経,前壁:前立腺(腟後壁).◆直腸仙骨筋膜より尾側の後壁では,腫瘍の深達度に応じてendopelvic fasciaのabove/belowの剥離層を選択.◆側壁のMRF involved症例では,骨盤筋膜腱弓を切開し,臓側骨盤筋膜外側の剥離層を選択してCRMを確保.

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：日本語   出版者・発行元：(株)へるす出版  

記述言語：日本語   出版者・発行元：(株)へるす出版  

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd