Yuichiro Doki

Osaka University, Suika, Ōsaka, Japan

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Publications (818)2557.96 Total impact

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    ABSTRACT: Pancreatic cancer has a poor prognosis because of its high invasiveness and recurrence, and these properties closely link to the phenomenon of epithelial-mesenchymal transition (EMT). Recently, it has been reported that Sox4 is indispensable for EMT in vitro and in vivo and regulates various master regulators of EMT including Zeb, Twist and Snail. Moreover, Sox4 induces the transcription of Ezh2 which is the histone methyltransferase, and reprograms the cancer epigenome to promote EMT and metastasis. Therefore, the present study evaluated the importance of Sox4, Ezh2 and miR-335, which regulate Sox4 expression epigenetically, in clinical samples with pancreatic cancer. This retrospective analysis included data from 36 consecutive patients who underwent complete surgical resection for pancreatic cancer and did not undergo any preoperative therapies. We assessed the clinical significance of Sox4/Ezh2 axis and miR-335 expression, using immunohistochemistry and qRT-PCR with laser captured microdissection (LCM). The Sox4 positive patients had significantly worse prognosis as for disease-free survival (DFS) (P=0.0154) and the Ezh2-positive patients had significantly worse prognosis as for overall survival (OS) (P=0.0347). The miR-335 expression was inversely correlated with Sox4 expression in the identical clinical specimens, but it was not related to the prognosis. Sox4/Ezh2 axis was closely associated with the prognosis in pancreatic cancer patients.
    No preview · Article · Nov 2015 · International Journal of Oncology
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    ABSTRACT: Though recent studies have revealed that stem cells of many tissues are harbored in hypoxic microenvironment, little is known about the relationship between hypoxia and intestinal crypt base, where intestinal stem cells are supposed to exist. In this study, we focused on carbonic anhydrase IX (CA9), a hypoxia-inducible membrane-tethered protein, in normal intestinal crypt base, adenoma and early colorectal cancer. Using surgically resected human colorectal cancer specimen, we searched for the expression pattern and functional association of CA9 in human adult normal intestinal epithelia, adenoma and early colorectal cancer by immunofluorescent and immunohistochemical staining, flow cytometry, and quantitative real-time-polymerase chain reaction. We demonstrated that almost all crypt base slender cells in ileum and crypt base cells with eosinophilic structure in their basal cytoplasm in right and left colon were CA9+ with the ratio of 25 to 40%, and that adenoma and T1 colorectal cancer showed broad expression of CA9. Flow cytometrically sorted CA9+ population showed increased mRNA level of a Wnt signaling factor AXIN2. In conclusion, these observations indicate that CA9 expression in normal crypt base cells has association with intestinal epithelial stemness and CA9 may be involved in the carcinogenesis of colorectal cancer.
    No preview · Article · Nov 2015 · International Journal of Oncology

  • No preview · Article · Nov 2015 · General Thoracic and Cardiovascular Surgery
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    ABSTRACT: Background: In digestive cancers, it is mandatory to diagnose peritoneal metastasis prior to selecting therapy. Therefore, exploratory laparoscopy has gained wider clinical acceptance. In laparoscopy, the peritoneal metastasis is pathologically confirmed by excisional biopsy; however, there remain technical difficulties in performing precise diagnosis and adequate biopsy on small peritoneal lesions without damaging organs. We have focused on "optical biopsy" using probe-based confocal laser endomicroscopy (pCLE). The aims of this study were (1) to optimize current CLE system for real-time observation of peritoneal metastases and (2) to assess its potential usefulness as diagnostic modality in preclinical settings. Methods: To optimize condition and evaluate feasibility, we prepared peritoneal metastasis mice model with gastric cancer cell line (MKN-45). On Day 10 after seeding, the mice were laparotomized and performed pCLE observations with CellvizioLAB (LSU-F 400/488 nm, Mauna Kea Technologies, Paris, France). We evaluated two different CLE probes, three different dyes, and optimal interval time. The detected sites were excised and pathologically evaluated on its morphology. Next, the feasibility and safety were validated in porcine model for clinical usage. After injection of fluorescein, pCLE was applied for the observation of intra-abdominal organs. Result: A miniature probe-type pCLE system with 60 μm focal depth (UltraMini O) and 1 % fluorescein dye was chosen for good visualization in mice model. The irregular microarchitecture images suspected to malignancy were obtained from the metastases. In the porcine model, observation of abdominal organs was feasible without any organ injury in the laparoscopic procedures. The dosage of 1 % fluorescein (3 ml/body) was appropriate in observing intra-abdominal organs, and each intra-abdominal organ was clearly observed with the same imaging quality we obtained in mice model. Conclusion: The pCLE was feasible and safe and potentially useful for the diagnosis of the peritoneal metastasis in in vivo animal models.
    No preview · Article · Nov 2015 · Surgical Endoscopy
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    ABSTRACT: Aim: This study aimed at investigating the survival impact of pancreatic ductal adenocarcinoma (PDAC) recurrence as pulmonary metastasis. Methods: We performed a retrospective case-control study of 142 patients who underwent curative resection for PDAC at our institution between 2003 and 2012. Clinicopathological features were compared among patients stratified according to the recurrence pattern and pulmonary metastasis treatment strategy. Results: Patients underwent pancreaticoduodenectomy (n = 96), distal (n = 42), or total pancreatectomy (n = 4). At the last follow-up, 99 patients had developed recurrent post-resection PDAC, including 14 cases of isolated pulmonary recurrence. The median overall survival was significantly longer for patients with isolated pulmonary recurrence (40.3 months) than with other metastases (20.9 months; HR 5.85; p = 0.0156). Two patients underwent resection for isolated pulmonary recurrence, and both survived for ∼70 months after primary resection. Conclusion: Patients with first recurrence of PDAC as pulmonary metastasis had a better prognosis than patients with other types of metastases. Moreover, when isolated pulmonary metastasis is controlled for a certain period, pulmonary resection is likely to improve patient survival.
    No preview · Article · Oct 2015 · Digestive surgery
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    ABSTRACT: Background: [(18) F]fluorodeoxyglucose (FDG)-PET has been used to evaluate the response of primary tumours to neoadjuvant therapy for oesophageal cancer. The clinical significance of the number of PET-positive nodes before and after therapy has not been investigated previously. Methods: [(18) F]FDG-PET was performed before and 2-3 weeks after completion of neoadjuvant chemotherapy to identify the number of PET-positive nodes, and these numbers were assessed in relation to metabolic changes in the primary tumour. Results: Of 302 patients in total, 90 had no PET-positive nodes, 83 had one, 59 had two and 70 patients had three or more positive nodes before therapy. After treatment, the numbers were: none in 207 patients, one in 59, two in 20 and three or more in 16 patients. The number of PET-positive nodes after treatment was influenced by both the number of PET-positive nodes before therapy and the response to preoperative therapy, and correlated with the number of metastatic lymph nodes. Overall survival was longer in patients who had no PET-positive nodes after treatment than in those who had one or more. Multivariable analysis identified the numbers of PET-positive nodes before and after chemotherapy as independent prognostic factors, together with clinical response, tumour depth and lymph node involvement. Conclusion: The number of PET-positive nodes after treatment correlated with survival in patients with oesophageal cancer who underwent neoadjuvant chemotherapy.
    No preview · Article · Oct 2015 · British Journal of Surgery
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    ABSTRACT: Background The antitumor effects of antiplatelet agents in gastric cancer cells are not well known. In this study, the possibility of gastric cancer treatment with an antiplatelet agent, mainly aspirin, was examined both in vivo and in vitro. Methods For in vivo experiments, tumor-bearing mice were treated by an antiplatelet antibody or aspirin, and the tumor growth was compared. For in vitro experiments, human gastric cancer cell lines were used to confirm the cancer cell growth and inhibition by reducing the platelet count or using aspirin. We also examined several cytokines by using an ELISA assay and conducted microRNA microarray analysis of MKN-45 tumor cells to determine the influence of platelets or aspirin. Results In vivo experiments showed that tumor growth was inhibited by halving the circulating platelet count by using an antiplatelet antibody or peroral daily aspirin. In vitro experiments showed that the proliferation rates of gastric cancer cell lines were increased after coincubation with platelets and that the effect was inhibited by aspirin. Although the expression of interleukin-6, platelet-derived growth factor, transforming growth factor-β, and prostaglandin E2 did not correlate with tumor growth inhibition by aspirin, seven microRNAs showed altered expression in cancer cells in response to coincubation with platelets or addition of aspirin. Cells transfected with mir-4670-5p showed a significant increase in proliferation compared to negative control cells. Conclusions Our study showed that platelets increased the proliferation of gastric cancer cells and that this increase was inhibited by antiplatelet antibody or aspirin. Mir-4670-5p may play an important role in these responses.
    Full-text · Article · Oct 2015 · Gastric Cancer
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    ABSTRACT: The para-aortic lymph nodes around the left renal vein (16a2lat) are now considered important to target in the treatment of advanced adenocarcinoma of the esophagogastric junction. We describe a laparoscopic approach for resecting these nodes. This new tunneling approach starts from the ligament of Treitz and then enters the retroperitoneal space. The left renal vein and left adrenal vein are dissected to identify the anatomy of the 16a2lat area. After this dissection, the 16a2lat nodes are retrieved through the suprapancreatic area. Six patients with advanced type II junctional cancer underwent laparoscopic 16a2lat lymph node dissection. The median operative time and estimated blood loss were 479 (390-750) min and 250 (130-500) ml, respectively. The median hospital stay was 22 (17-54) days and there were no deaths or serious complications. Although this series was relatively small, our technique proved effective and feasible.
    No preview · Article · Oct 2015 · Surgery Today
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    ABSTRACT: Cancer has been viewed as a heterogeneous population of cells.While the large majority of cells that constituting tumors are differentiated, and eventually stop dividing, only a minority population of cells, termed cancer stem cells, is capable of unlimited self-renewal and multi-differentiation, just like somatic stem cells in normal tissues.Cancer stem cells have been identified in a variety of cancers of the blood, brain, stomach, colon, and pancreas.In this review we present current evidence supporting the cancer stem cell model of tumor progression, and discuss the experimental and therapeutic implications.
    No preview · Article · Oct 2015 · Gan to kagaku ryoho. Cancer & chemotherapy
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    ABSTRACT: Background Few driver genes have been well established in esophageal squamous cell carcinoma (ESCC). Identification of the genomic aberrations that contribute to changes in gene expression profiles can be used to predict driver genes. Methods We searched for driver genes in ESCC by integrative analysis of gene expression microarray profiles and copy number data. To narrow down candidate genes, we performed survival analysis on expression data and tested the genetic vulnerability of each genes using public RNAi screening data. We confirmed the results by performing RNAi experiments and evaluating the clinical relevance of candidate genes in an independent ESCC cohort. Results We found 10 significantly recurrent copy number alterations accompanying gene expression changes, including loci 11q13.2, 7p11.2, 3q26.33, and 17q12, which harbored CCND1, EGFR, SOX2, and ERBB2, respectively. Analysis of survival data and RNAi screening data suggested that GRB7, located on 17q12, was a driver gene in ESCC. In ESCC cell lines harboring 17q12 amplification, knockdown of GRB7 reduced the proliferation, migration, and invasion capacities of cells. Moreover, siRNA targeting GRB7 had a synergistic inhibitory effect when combined with trastuzumab, an anti-ERBB2 antibody. Survival analysis of the independent cohort also showed that high GRB7 expression was associated with poor prognosis in ESCC. Conclusion Our integrative analysis provided important insights into ESCC pathogenesis. We identified GRB7 as a novel ESCC driver gene and potential new therapeutic target.
    Full-text · Article · Oct 2015 · PLoS ONE
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    ABSTRACT: Background and objectives: The impact of postoperative complications on long-term outcome has been reported in several types of malignancies. However, it is unclear why postoperative complications affect long-term outcome. The aim of this study is evaluating whether postoperative complication occurrence or C-reactive protein (CRP) elevation better reflects long-term outcome in gastric cancer patients. Methods: This study included 305 patients who underwent curative surgery for pT2-T4b gastric cancer. Patients were divided into two groups based on the peak CRP value (CRPmax ): low (<12 mg/dl) and high CRPmax (≥12 mg/dl). A multivariate analysis was conducted to identify independent prognostic factors for recurrence-free survival (RFS). Results: Postoperative complications (≥Grade II) occurred in 86 of 305 patients (28.2%). Although CRP elevation (P = 0.001) and postoperative complication occurrence (P = 0.045) was each significantly associated with RFS in the univariate analysis, multivariate analysis identified CRP elevation (P = 0.017) but not complication occurrence (P = 0.682) as an independent prognostic factor. Among patients without complications, those in the high CRPmax group had significantly worse RFS than those in the low CRPmax group (P = 0.004). Conclusions: CRP elevation is a more reliable indicator of survival after gastric cancer surgery than postoperative complication occurrence. Surgeons should minimize the postoperative inflammatory response to improve prognosis. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Oct 2015 · Journal of Surgical Oncology
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    ABSTRACT: Background There is a lack of critical evidence to justify the methods of follow-up after a curative esophagectomy or a complete response to definitive chemoradiotherapy (dCRT). Consequently, a wide variety of practices are in place throughout the world. Methods A questionnaire concerning follow-up protocols was sent via electronic email for a nation-wide survey of the 117 Japanese hospitals that are recognized by the Japan Esophageal Society as training facilities for certified esophageal surgeons. Seventy-seven hospitals responded to the questionnaire. Results Most hospitals follow their patients for at least 5 years after esophagectomy or dCRT, usually at a frequency of more than 4 times per year with clinical visits and physical examinations in the 1st and 2nd year after treatment. About 65–75 and 40 % of the hospitals continue the follow-up until the 7th and 10th year after treatment, respectively. Most hospitals measure CEA and SCC-Ag and almost all hospitals utilize CT scans of the cervix, chest and abdomen for the follow-up. Most of the hospitals reported performing an upper gastrointestinal endoscopy at least once per year until the 5th year after treatment, more frequently for post-dCRT patients than for post-esophagectomy patients. Other imaging modalities such as FDG-PET/CT, cervical and abdominal USs, and chest and abdominal X-rays were incorporated at much lower rates. Conclusions Follow-up protocols for patients who have been treated for esophageal cancer with curative intent vary among the hospitals in Japan. Based on these data, the most popular follow-up protocols in Japan are shown.
    Full-text · Article · Oct 2015 · Esophagus

  • No preview · Article · Oct 2015 · Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology
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    ABSTRACT: Background: The incidence of postoperative biliary leakage and hemorrhage is low, but these factors remain important in liver surgery, and this study's objective was to explore the efficacy of fibrin sealant (FS) with polyglycolic acid (PGA) vs fibrinogen-based collagen fleece (CF) at the liver cut surface. Fibrinogen-based collagen fleece is generally used for hemostasis; PGA-FS has reduced biliary leakage in several retrospective studies. Study design: We designed a multicenter, randomized, controlled trial. The primary outcome was the rate of biliary leakage and hemorrhage. Secondary outcomes included morbidities and effusion at the liver cut surface at 3 months post-surgery. Biliary leakage was diagnosed when the drain/serum bilirubin ratio was >5. Hemorrhage was diagnosed when relaparotomy or transfusion was needed. Results: Of 786 patients from 11 institutions enrolled from 2009 to 2014, a total of 391 were randomly assigned to PGA-FS and 395 to CF. Regarding primary outcomes, rates of biliary leakage were 4.1% with PGA-FS and 5.1% with CF, and rates of hemorrhage were 1.0% in each group; groups did not differ significantly. For secondary outcomes, morbidity rates were 18.7% in the PGA-FS group and 24.6% in the CF group (p = 0.0450). Effusion at the cut liver surface was less with PGA-FS (22.2%) than with CF (32.9%) (p = 0.0142). Regarding morbidity, infection around the liver, jaundice, and abdominal paracentesis were less in the PGA-FS group. Conclusions: Compared with CF, PGA-FS did not reduce biliary leakage and hemorrhage. Surgical site infection around the liver, effusion at the liver cut surface, and abdominal paracentesis were less in the PGA-FS group.
    No preview · Article · Oct 2015 · Journal of the American College of Surgeons
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    ABSTRACT: Around the lower esophagus, the diaphragm obstructs the laparoscopic dissection of mediastinal lymph nodes in surgery for Siewert type II cancer. To address this problem, we developed the open left diaphragm approach. After dissecting the esophageal hiatus along the diaphragm, the anterior mediastinum is dissected along the pericardium. The left side of the mediastinal pleura is then opened and the left diaphragm is incised with a 60-mm linear stapler to create sufficient working space in the lower mediastinum for the lower mediastinal lymph nodes to be resected with a good view. Six patients who received neoadjuvant chemotherapy underwent mediastinal dissection using this technique. The median operative time and estimated blood loss were 479 (390-750) min and 250 (130-500) ml, respectively, and there were no deaths or severe complications. The open left diaphragm approach provides clear surgical space and a good view for performing mediastinal lymph node dissection and is useful for laparoscopic mediastinal dissection and reconstruction.
    No preview · Article · Sep 2015 · Surgery Today
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    ABSTRACT: Introduction: Single-site laparoscopic colectomy (SLC) is a promising minimally invasive and safe treatment for colorectal cancer. Improvements of the working instruments and procedures for SLC have helped to overcome challenges regarding the difficulty of operation, supporting the gradual acceptance of this technique. In contrast, narrow working space of the abdominal cavity sometimes prevents securing an adequate surgical view. To obtain precise anatomical information and enable complete mesocolic excision (CME), we routinely perform three-dimensional computed tomography prior to SLC. Case presentation: A 69-year-old Japanese woman was clinically diagnosed with rectosigmoid cancer. Unexpectedly, preoperative examination revealed asymptomatic stenosis of the great artery, which was diagnosed as middle aortic syndrome. Because radical colectomy requires dissection of vessels that supply blood flow to the legs, a vascular stent was inserted prior to operation. We chose SLC due to the reduced risk of damaging epigastric arteries, which may eventually become collaterals in the event of stent re-stenosis. We accomplished SLC with CME, and the patient was discharged on the tenth day after operation without complications. Conclusion: The present case is the first to proceed by SLC for colorectal cancer complicated by vascular obstructive disease. Preoperative imaging enabled us to identify an unexpected rare disease and to still accomplish SLC with CME, thus reinforcing the importance of preoperative imaging to optimize the use of SLC. In addition, SLC may become one of the most adequate procedures for patients complicated by vascular obstructive disease.
    Full-text · Article · Sep 2015
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    ABSTRACT: Background: There is no consensus about the extent of lymphadenectomy for patients with esophageal squamous cell carcinoma at the cervicothoracic junction (CT-ESCC). The purpose of this study was to examine the pattern of lymph node spread in patients with CT-ESCC and the extent of lymphadenectomy that is necessary. Methods: We included 64 consecutive patients with CT-ESCC who underwent surgery. All patients were divided into two groups based on the location of the epicenter or anal edge of the primary tumor. Using the height of the epicenter, 27 and 37 patients were classified as having cervical-centered and thoracic-centered tumors, respectively; while, using the height of the anal edge, 38 and 26 patients had tumors that were cervical-localized and thoracic-invading, respectively. Results: In the patients with cervical-centered tumors, the incidences of metastasis and/or recurrences in the cervical paraesophageal, supraclavicular, and upper mediastinal nodes were 21.4-28.5 %. No patient had metastasis or recurrence in the middle and lower mediastinal and perigastric nodes. In patients with thoracic-centered tumors, the lymph node metastasis and/or recurrence spread to the cervical paraesophageal (41.7 %), supraclavicular (25 %), and upper mediastinal (55.6 %) nodes, as well as the middle (22.2 %) and lower mediastinal (8.3 %) and perigastric (19.4 %) nodes. There was no difference in the distribution and incidence of lymphatic spread between patients with the cervical-localized and thoracic-invading classifications. Conclusions: Our results indicate a cervical and upper mediastinal lymphadenectomy is better indicated for patients with cervical-centered CT-ESCC, whereas patients with thoracic-centered CT-ESCC should be treated with a three-field lymphadenectomy.
    No preview · Article · Sep 2015 · Annals of Surgical Oncology
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    ABSTRACT: Cancer metabolism characterizes the malignant behavior of tumors. Pyruvate kinase M2 (PKM2), a key player in maintaining aerobic glycolysis, stimulates tumor growth by controlling the Warburg effect. It has been shown that PKM2 translocates into the nucleus to regulate the transcriptions of numerous down-stream genes, including PDK1 and LDHA. To investigate the significance of PKM2 in epithelial-mesenchymal transition (EMT), a biological process which promotes the metastasis of cancer cells, we induced EMT in gastrointestinal cancer cells using TGFβ and EGF in vitro. After EMT induction, E-cadherin was down-regulated, whereas Vimentin was up-regulated. PKM2 expression was increased at both the transcriptional and the translational level, and PKM2 translocated into the nucleus. Immunohistochemical staining of PKM2 revealed that PKM2 positivity correlated significantly with lymph node metastasis and distant organ metastasis of gastrointestinal cancer. The present results indicate that nuclear PKM2 plays a crucial role in controlling invasion and metastasis.
    No preview · Article · Sep 2015 · [Rinshō ketsueki] The Japanese journal of clinical hematology
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    ABSTRACT: Adipose-derived stem cell (ADSC) transplantation is expected to be a minimally invasive, but effective, treatment for postoperative enterocutaneous fistulas associated with poor blood flow and chronic inflammation. The aim of this study was to assess the safety and efficacy of a novel ADSC therapy for this condition. We conducted an open-label, single-arm exploratory phase I study to assess the safety and efficacy of a novel ADSC therapy. Using the Celution system, we isolated adipose-derived regenerative cells (ADRCs) containing abundant ADSCs from liposuction-obtained gluteal adipose tissue. A mixture of ADRCs and fibrin glue was subsequently transplanted into the fistula, and ADRCs were percutaneously and endoscopically injected around the fistula. We evaluated the safety and feasibility of ADRC transplantation and fistula closure in six patients (UMIN000007316). ADRC transplantation was completed in all patients. The fistula closure rates were 83.3 % at 4 and 12 weeks and 100 % at 24 weeks. All patients had grade 1 pain and subcutaneous hemorrhage at the liposuction sites, but no serious adverse events related to this procedure were observed. Transplantation of autologous ADRCs is safe, feasible and advantageous, as it can secure a sufficient cell count without culture or multiple passages, and will likely be effective for a postoperative enterocutaneous fistula.
    No preview · Article · Sep 2015 · Surgery Today
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    ABSTRACT: Unlike other cyclins that positively regulate the cell cycle, cyclin G2 (CCNG2) regulates cell proliferation as a tumor suppressor gene. A decreased CCNG2 expression serves as a marker for poor prognosis in several types of cancer. The aim of the present study was to clarify the correlation of CCNG2 expression with overall survival and histopathological factors in pancreatic cancer patients. This retrospective analysis included data from 36 consecutive patients who underwent complete surgical resection for pancreatic cancer and did not undergo any preoperative therapies. The association between prognoses and the expression of CCNG2 was assessed using immunohistochemical staining. Multivariate analysis identified that the expression of CCNG2 is an independent prognostic factor. In addition, the Kaplan-Meier curve for overall survival revealed that decreased expression of CCNG2 was a consistent indicator of poor prognosis in pancreatic cancer patients (P=0.0198). A decreased CCNG2 expression significantly correlated with venous invasion in tumor specimens and the tumor invasion depth. In conclusion, CCNG2 expression inversely reflected cancer progression and may be a novel, independent prognostic marker in pancreatic cancer.
    Preview · Article · Sep 2015 · Oncology letters

Publication Stats

11k Citations
2,557.96 Total Impact Points

Institutions

  • 1998-2016
    • Osaka University
      • • Department of Surgery
      • • Graduate School of Medicine
      • • Division of Gastroenterological Surgery
      Suika, Ōsaka, Japan
  • 2015
    • Osaka National Hospital
      Ōsaka, Ōsaka, Japan
  • 2002-2015
    • Osaka City University
      • • Department of Gastroenterological Surgery
      • • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan
    • Keio University
      • Department of Applied Chemistry
      Edo, Tokyo, Japan
  • 2011
    • Oita University
      • Faculty of Medicine
      Ōita, Ōita, Japan
  • 2000-2008
    • Osaka Medical Center for Cancer and Cardiovascular Diseases
      Ōsaka, Ōsaka, Japan
    • COMPREHENSIVE BÖOOD AND CANCER CENTER
      Bakersfield, California, United States
  • 1995-1997
    • Columbia University
      • College of Physicians and Surgeons
      New York, New York, United States
  • 1993-1995
    • Kyoto University
      • Department of Biophysics
      Kioto, Kyōto, Japan