Keiji Yoshinaga

Kyushu University, Hukuoka, Fukuoka, Japan

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Publications (16)34.42 Total impact

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    ABSTRACT: We previously reported that PSK-induced lymphocyte blastogenesis reaction (PSK-stimulation index; PSK-SI) may be a prognostic marker for immunochemotherapy using PSK in gastrointestinal cancer patients. In this study we evaluated the usefulness of PSK-SI as a prognostic marker for PSK therapy at higher and lower serum immunosuppressive acidic protein (IAP) levels. 98 gastric and 135 colorectal cancer patients were analyzed. PSK-SI and serum IAP levels were measured preoperatively. After operation, patients received UFT and PSK for two years. There were no differences between patients with higher and those with lower PSK-SI with respect to the clinicopathological factors. In patients with higher serum IAP levels (> or = 500 microg/ml), recurrence-free survival (RFS) and overall survival (OS) were apparently more favorable in the higher PSK-SI group (gastric cancer; > or = 1.75, colorectal cancer; > or = 2.1) than in lower PSK-SI group, although the differences were not significant. Serum IAP levels and PSK-SI may be useful markers for prediction of response to immunochemotherapy using PSK, although further studies are necessary.
    Fukuoka igaku zasshi = Hukuoka acta medica 12/2013; 104(12):549-58.
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    ABSTRACT: 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 three-dimensional (3D) 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. This article is protected by copyright. All rights reserved.
    Cancer Science 09/2013; · 3.48 Impact Factor
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    ABSTRACT: 5-Fluorouracil (5-FU) has long been a mainstay antimetabolite chemotherapeutic drug for the treatment of major solid tumors, particularly colorectal cancer. 5-FU is processed intracellularly to yield active metabolites that compromise RNA and DNA metabolism. However, the mechanisms responsible for its cytotoxicity are not fully understood. From the phenotypic analysis of mutant chicken B lymphoma DT40 cells, we found that homologous recombinational repair (HRR), involving Rad54 and BRCA2, and the ATR-Chk1 signaling pathway, involving Rad9 and Rad17, significantly contribute to 5-FU tolerance. 5-FU induced γH2AX nuclear foci, which were colocalized with the key HRR factor Rad51, but not with DNA double-strand breaks (DSBs), in a dose-dependent manner as cells accumulated in the S phase. Inhibition of Chk1 kinase by UCN-01 increased 5-FU-induced γH2AX and enhanced 5-FU cytotoxicity not only in wild-type cells but also in Rad54- or BRCA2-deficient cells, suggesting that HRR and Chk1 kinase have non-overlapping roles in 5-FU tolerance. 5-FU-induced Chk1 phosphorylation was significantly impaired in Rad9- or Rad17-deficient cells, and severe γH2AX nuclear foci and DSBs were formed, which was followed by apoptosis. Finally, inhibition of Chk1 kinase by UCN-01 increased 5-FU-induced γH2AX nuclear foci and enhanced 5-FU cytotoxicity in Rad9- or Rad17-deficient cells. These results suggest that Rad9- and Rad17-independent activation of the ATR-Chk1 signaling pathway also significantly contributes to 5-FU tolerance.
    DNA repair 12/2011; 11(3):247-58. · 4.20 Impact Factor
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    ABSTRACT: The mechanism of action of protein-bound polysaccharide K (PSK; KRESTIN(®)) involves the following actions: (1) recovery from immunosuppression induced by humoral factors such as transforming growth factor (TGF)-β or as a result of surgery and chemotherapy; (2) activation of antitumor immune responses including maturation of dendritic cells, correction of Th1/Th2 imbalance, and promotion of interleukin-15 production by monocytes; and (3) enhancement of the antitumor effect of chemotherapy by induction of apoptosis and inhibition of metastasis through direct actions on tumor cells. The clinical effectiveness of PSK has been demonstrated for various cancers. In patients with gastric or colorectal cancer, combined use of PSK with postoperative adjuvant chemotherapy prolongs survival, and this effect has been confirmed in multiple meta-analyses. For small-cell lung carcinoma, PSK in conjunction with chemotherapy prolongs the remission period. In addition, PSK has been shown to be effective against various other cancers, reduce the adverse effects of chemotherapy, and improve quality of life. Future studies should examine the effects of PSK under different host immune conditions and tumor properties, elucidate the mechanism of action exhibited in each situation, and identify biomarkers.
    Surgery Today 12/2011; 42(1):8-28. · 0.96 Impact Factor
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    ABSTRACT: We report three cases of successful surgical removal of a denture with sharp clasps impacted in the cervical esophagus. Patient 1 was a 57-year-old woman institutionalized for over 30 years for schizophrenia, patient 2 was a 62-year-old man hospitalized for brain paralysis, and patient 3 was a 64-year-old man suffering cerebral hemorrhage sequelae. All three patients swallowed a denture accidentally. Chest X-rays showed the denture with sharp clasps in the cervicothoracic region of the esophagus, and endoscopy revealed that it was lodged in the esophageal mucosa. The denture was subsequently removed by cervical esophagotomy. All three patients had a good clinical postoperative course without any complications. Thus, we recommend surgery via a cervical approach to remove a denture with sharp clasps impacted in the cervicothoracic esophagus, with intraoperative endoscopic examination for esophageal injury.
    Surgery Today 09/2011; 41(9):1275-9. · 0.96 Impact Factor
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    ABSTRACT: We herein present the case of a 66-year-old man with both gastric cancer and an infrarenal abdominal aneurysm. The patient's medical history included bladder cancer, chronic renal failure, and ischemic heart disease. We performed a simultaneous endovascular aneurysm repair (EVAR) and total gastrectomy. Following the procedure, the patient remained in the intensive care unit for 3 days. Oral feeding was resumed on postoperative day 7, and the patient was discharged from the hospital on postoperative day 13 with no complications. Despite the patient's medical problems and higher operative risk, he tolerated simultaneous EVAR and total gastrectomy, and had a good outcome after undergoing these simultaneous procedures.
    Surgery Today 05/2011; 41(5):721-5. · 0.96 Impact Factor
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    ABSTRACT: LOH at the p53 locus has been reported to be associated with esophageal squamous cell carcinogenesis. The aim of this study is to identify potential mechanisms resulting in LOH around the p53 locus in its carcinogenesis. We investigated 10 esophageal cancer cell lines and 91 surgically resected specimens, examining them for LOH at the p53 locus on chromosome 17. We examined the p53 gene by using microsatellite analysis, comparative genomic hybridization (CGH), FISH, and single-nucleotide polymorphism-CGH (SNP-CGH). In an analysis of specimens by microsatellite markers, a close positive correlation was found between p53 mutations and LOH at the p53 locus (P < 0.01). Although four cell lines were found to be homozygous for p53 mutations, LOH at the p53 locus was not detected by CGH. Among two p53 mutant cancer cell lines and five p53 mutant/LOH cancer specimens analyzed by FISH, both the cell lines and four of the specimens exhibited no obvious copy number loss at the p53 locus. SNP-CGH analysis, which allows both determination of DNA copy number and detection of copy-neutral LOH, showed that LOHs without copy number change were caused by whole or large chromosomal alteration. LOH without copy number change at the p53 locus was observed in p53 mutant esophageal squamous cell carcinomas. Our data suggest that copy-neutral LOH occurring as a result of chromosomal instability might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with p53 mutation.
    Clinical Cancer Research 02/2011; 17(7):1731-40. · 7.84 Impact Factor
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    ABSTRACT: Resections for esophageal cancer are invasive, with high mortality and morbidity rates. The object of this study was to clarify the factors associated with in-hospital death while also evaluating any associated historical changes in the characteristics of such deaths. The factors associated with mortality were examined by logistic regression analysis in 1106 patients who underwent an esophagectomy for esophageal cancer. The historical changes in the characteristics of in-hospital deaths were also evaluated. A multivariate analysis revealed that not only undergoing an esophagectomy before 1979, but also a patient's age (odds ratio 1.070 for every increase in age by year) and an incomplete resection (odds ratio 2.265) were independent factors associated with in-hospital death. The in-hospital mortality rates were 16.1%, 5.8%, 2.5%, and 3.1%, while the 30-day mortality rates were 9.2%, 2.2%, 0.8%, and 0.3% during 1964-1979, the 1980s, the 1990s, and the 2000s, respectively. Eight patients had preoperative comorbidities among 11 patients who died in the hospital after 1997. The mortality rate was 5.5% in patients with any comorbidities, while it was 1.3% in patients without any comorbidities (P = 0.026). The most common direct cause of in-hospital death was previous pulmonary complications; however, cancer progression has recently become the most common cause. To prevent in-hospital mortality after an esophagectomy, strict indications for surgery and careful perioperative management are important, especially in high-risk patients with advanced esophageal cancer.
    Annals of Surgical Oncology 01/2011; 18(6):1757-65. · 4.12 Impact Factor
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    ABSTRACT: Hepatic artery injury is one complication associated with surgery for gastric cancer. This complication does not occur frequently, but it can cause serious problems. Anatomical variations of the hepatic arteries are thought to be a factor in such injuries. Recognizing vascular variations before the operation is thus very important. This report presents a case with a rare variation of the hepatic arteries identified on three-dimensional computed tomography (3D-CT) angiography before gastric cancer surgery. Hepatic artery injury was avoided as a result of the recognition of this extremely rare variation. Preoperative 3D-CT angiography is useful for preventing the complications associated with hepatic artery injury during surgery for gastric cancer.
    Surgery Today 10/2010; 40(10):967-71. · 0.96 Impact Factor
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    ABSTRACT: Prediction of the postoperative course of esophagectomy is an important part of the strict perioperative management of patients undergoing surgery for esophageal cancer. 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. 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. 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.
    Surgery Today 07/2010; 40(7):626-31. · 0.96 Impact Factor
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    ABSTRACT: 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.
    Cancer Science 03/2010; 101(3):639-45. · 3.48 Impact Factor
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    ABSTRACT: Both cigarette smoking and alcohol drinking are well-established risk factors for esophageal squamous cell carcinoma (ESCC), and the relationship of dose to cancer risk has already been described. Furthermore, the synergistic effect of these two factors has been reported. Our case-control study revealed the odds ratio of ESCC to be 50.1 for those who were both heavy smokers and heavy drinkers in comparison to people who neither drank nor smoked. In patients with ESCC, head and neck cancers as well as dysplastic lesions are frequently observed. Heavy smoking and heavy drinking are closely related to such multicentric carcinogenesis events in the upper aerodigestive tract (UADT), including the esophagus and head andneck region. Polymorphisms in acetaldehyde dehydrogenase 2 (ALDH2) are reported to be a key event in deciding individual susceptibility to UADT cancer. Patients with inactive ALDH2, in whom facial flushing is usually observed after the drinking of alcohol, are at high risk for ESCC as well as multiple UADT cancers. For the early detection of the disease, effective follow up using endoscopy with Lugol staining or narrow band imaging endoscopy is strongly recommended for high-risk populations, such as smokers, heavy drinkers, people with experience of flushing after the drinking of alcohol, and patients with UADT cancer.
    International Journal of Clinical Oncology 03/2010; 15(2):126-34. · 1.41 Impact Factor
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    ABSTRACT: Anastomotic leakage with an intractable cutaneous fistula frequently develops after an esophagectomy and reconstruction via the subcutaneous route. A pectoralis major muscle (PMM) flap was used for the treatment of 6 patients with esophageal cancer who developed anastomotic leakage with fistula after reconstruction via the subcutaneous route. A gastric tube and colon had been used for reconstruction in 2 and 4 patients, respectively. A trimming and repair of the leakage site was initially performed and the anastomotic site was then covered with a muscle flap. Recurrent anastomotic leakage did not develop in 5 patients. Among these patients, oral intake was initiated from 11-15 days after the repair operation in 4 patients. A patient having recurrent anastomotic leakage after a repair operation recovered well with conservative therapy. The coverage with a PMM flap over the repair site is a simple method for preventing the development of recurrent leakage after a repair operation. Even when recurrent anastomotic leakage has occurred after this operation, healing is normally expected by means of conservative treatment. We, therefore, recommend this method for the repair of intractable anastomotic leakage after reconstruction via the subcutaneous route for esophageal cancer.
    Surgery 10/2009; 147(2):212-8. · 3.37 Impact Factor
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    ABSTRACT: The factors associated with the clinical results of preoperative chemoradiotherapy (CRT) for esophageal cancer and its effect on postoperative complications are still unclear. The 686 patients with esophageal cancer were classified into 376 who received preoperative CRT (group I) and 310 who received surgery alone (group II). A multivariate analysis for group I patients revealed pathologically complete response to be a favorable prognostic factor. Preoperative use of cisplatin was significantly associated with pathological effect and patients' prognosis. Both pulmonary complications and anastomotic leakage more frequently developed in group I (16.0 and 27.9%) than in group II (10.0%, p<0.05 and 16.5%, p<0.01, respectively). A multivariate analysis revealed preoperative CRT to be an independent factor of postoperative complications. Although preoperative CRT for esophageal cancer may be associated with postoperative complications, a pathologically complete response, which is associated with a cisplatin-based regimen, is critical for improving patient prognosis.
    Anticancer research 07/2009; 29(7):2555-62. · 1.71 Impact Factor
  • Fukuoka igaku zasshi = Hukuoka acta medica 07/2008; 99(6):115-22.
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