Yoshiharu Sakai

Kyoto University, Kioto, Kyōto, Japan

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Publications (167)659.58 Total impact

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    ABSTRACT: Objective: To confirm the efficacy of oral and parenteral antibiotic prophylaxis (ABX) in the elective laparoscopic colorectal surgery. Background: There is no evidence for the establishment of an optimal ABX regimen for laparoscopic colorectal surgery, which has become an important choice for the colorectal cancer patients. Methods: The colorectal cancer patients scheduled to undergo laparoscopic surgery were eligible for this multicenter, open-label, randomized trial. They were randomized to receive either oral and parenteral prophylaxis (1 g cefmetazole before and every 3 h during the surgery plus 1 g oral kanamycin and 750 mg metronidazole twice on the day before the surgery; Oral-IV group) or parenteral prophylaxis alone (the same IV regimen; IV group). The primary endpoint was the incidence of surgical site infections (SSIs). Secondary endpoints were the incidence rates of Clostridium difficile colitis, other infections, and postoperative noninfectious complications, as well as the frequency of isolating specific organisms. Results: Between November 2007 and December 2012, 579 patients (289 in the Oral-IV group and 290 in IV group) were evaluated for this study. The incidence of SSIs was 7.26% (21/289) in the Oral-IV group and 12.8% (37/290) in the IV group with an odds ratio of 0.536 (95% CI, 0.305-0.940; P = 0.028). The 2 groups had similar incidence rates of C difficile colitis (1/289 vs 3/290), other infections (6/289 vs 5/290), and postoperative noninfectious complications (11/289 vs 12/290). Conclusions: Our oral-parenteral ABX regimen significantly reduced the risk of SSIs following elective laparoscopic colorectal surgery.
    No preview · Article · Jan 2016 · Annals of surgery
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    ABSTRACT: Implications: The miR-137/DCLK1 axis as an important regulator in NCSCs and colon CSCs; further understanding of this axis may foster the development of potential gene therapeutic strategies targeting colon CSCs.
    No preview · Article · Jan 2016 · Molecular Cancer Research
  • Suguru Hasegawa · Koya Hida · Kenji Kawada · Yoshiharu Sakai

    No preview · Article · Jan 2016 · Diseases of the Colon & Rectum
  • Suguru Hasegawa · Tomoaki Okada · Koya Hida · Kenji Kawada · Yoshiharu Sakai
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    ABSTRACT: Background: Recently, the efficiency of transanal minimally invasive surgery (TAMIS) for rectal cancer has been demonstrated (Velthuis et al. in Surg Endosc 28:3494-3499, 2014; Fernandez-Hevia in Ann Surg 261:221-227, 2015; Atallah et al. in Tech Coloproctol 18:473-480, 2014). We present our procedure of TAMIS for extralevator abdominoperineal excision (ELAPE) (Holm et al. in Br J Surg 94:232-238, 2007). Methods: The patient had a rectal cancer located 4 cm from the anal verge with suspected invasion of the levator ani (cT4bN0M0). A skin incision was made around the tightly closed anus, and a GelPOINT device was placed. The fat tissue of the ischioanal fossa was divided until the levator ani muscle was widely exposed. Anterior dissection was performed just behind the transverse perineal muscle, and the arms of the puborectalis sling were identified at 1 and 11 o'clock. The levator muscle was divided from the posterior to bilateral sides, and dissection was entered into the mesorectal plane. Posterior dissection was performed until the sacral promontory was reached. Bilateral pelvic splanchnic nerves were identified at the 5 and 7 o'clock positions, and special care was taken to preserve them. At the anterior side, the arms of the puborectalis sling and perineal body were divided. Special care should be taken to avoid inadvertent injury to the anterior tissues (urethra or prostate) because the dissection tends to go toward the anterior-lateral side of the prostate in this approach. Once the dissection plane behind the prostate was established, it was easy to dissect the mesorectum circumferentially while preserving the pelvic autonomic nerves. Vascular division, mobilization of left colon and stoma creation were performed laparoscopically. Results: This approach provides better exposure of the surgical field, especially at the anterior side, compared with the conventional perineal approach of ELAPE. Since January 2014, we have performed seven cases using this procedure. There was no conversion to the conventional approach, and no major complication was encountered. Conclusion: TAMIS is a promising approach for the perineal phase of ELAPE.
    No preview · Article · Dec 2015 · Surgical Endoscopy
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    ABSTRACT: Background: Intramural metastasis (IM) is extremely rare in colorectal cancer, although it often occurred in esophageal cancer. Case presentation: We report a rare case of T1 rectal cancer with IM which was successfully resected by laparoscopic surgery. A 62-year-old man was admitted to our institution for the treatment of rectal cancer detected by medical examination. Colonoscopy revealed two tumors in the rectum: a type II rectal cancer of 2 cm in diameter located 5 cm proximal to the anal verge and a submucosal tumor of 1 cm in diameter located approximately 1.5 cm proximal to the rectal cancer. Abdominal computed tomography (CT), magnetic resonance imaging (MRI), and transrectal ultrasonography indicated the rectal cancer invaded into the submucosal layer with no metastasis to regional lymph nodes or distant organs. The patient underwent laparoscopic intersphincteric resection.Histopathological analysis revealed that the rectal cancer was moderately differentiated adenocarcinoma (stage I; pT1N0M0 according to the 7th edition of UICC) with severe lymphovascular invasion (ly1, v3) and that the submucosal tumor was composed of moderately differentiated adenocarcinoma proliferating within the muscularis propria. A number of features of the submucosal tumor indicated that this was an IM of the rectal cancer: clearly distinct location from the rectal cancer, growth predominantly within the muscularis propria, similar structural and cellular heterogeneity, and the presence of tumor emboli within vascular vessels. The patient was postoperatively followed for more than 4 years without any sign of recurrence. Conclusions: To the best of our knowledge, this is the first report of the T1 rectal cancer with IM.
    Preview · Article · Dec 2015 · World Journal of Surgical Oncology
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    ABSTRACT: Objectives: A multi-center phase II study was conducted to evaluate the safety and efficacy of neoadjuvant chemotherapy (NAC) with S-1 plus cisplatin for advanced gastric cancer. Methods: The eligibility criteria were clinical T3/T4 or N2, not Stage IV. Patients received two 35-day cycles of S-1 plus cisplatin, and then underwent D2 gastrectomy. The primary endpoint was 3-year progression free survival (PFS). Secondary endpoints were ratio of R0 resection, response rate, adverse events, and overall survival. A sample size of 49 was determined to have 80% power for detecting 15% improvement in the 3-year PFS over 55% at a one-sided alpha of 0.1. Results: Among 53 patients enrolled, 44 patients completed two cycles of NAC (83%), and 48 patients underwent R0 resection (91%). Postoperative complications occurred in 13 patients (26%). A pathological response was confirmed in 24 patients (45%), including four complete responses. The 3-year PFS was 50.7%, while the 3-year OS was 74.9%. Conclusions: Although the observed 3-year PFS rate was worse than expected, NAC with S1 plus cisplatin was safe and led to a high rate of R0 resection. A randomized controlled trial is needed to make conclusions about the effectiveness of NAC in Japanese patients undergoing D2 resection. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Nov 2015 · Journal of Surgical Oncology
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    ABSTRACT: Background: We have employed upper arm central venous ports (UACVPs) since 2006 for long-term intravenous chemotherapy (CTx) or fluid supplementation. We evaluated the long-term availability of CVPs implanted in the upper arm to determine whether UACVPs could be one of the treatment options besides chest CVPs in terms of CVP-related complications. Methods: We reviewed the medical records of all patients who underwent subcutaneous implantation of UACVPs at Kyoto University Hospital from 1 April, 2006 to 30 June, 2009. We assessed the indwelling duration of the UACVPs and the incidences of early and late UACVP-related complications. Results: A total of 433 patients underwent subcutaneous implantation of UACVPs during this time period. The cumulative follow-up period was 251,538 catheter days, and the median duration of UACVP indwelling was 439.0 days (1-2, 24). There was no UACVP-related mortality throughout the study period. A total of 83 UACVP-related complications occurred (19.2 %), including 43 cases of infection (9.9 %, 0.17/1000 catheter days), ten cases of catheter-related thrombosis (2.3 %, 0.040/1000 catheter days), ten cases of occlusion (2.3 %, 0.040/1000 catheter days), nine cases of catheter dislocation (2.0 %, 0.036/1000 catheter days), five cases of port leakage (1.2 %, 0.019/1000 catheter days), four cases of skin dehiscence (0.9 %, 0.015/1000 catheter days) and two cases of port chamber twist (0.5 %, 0.008/1000 catheter days). The removal-free one-year port availability was estimated at 87.8 %. Conclusions: UACVPs were of long-term utility, with complication rates comparable to those of chest CVPs previously reported.
    No preview · Article · Oct 2015 · International Journal of Clinical Oncology
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    ABSTRACT: Prostaglandin E2 plays important roles in the maintenance of colonic homeostasis. The recently identified prostaglandin E receptor (EP) 4–associated protein (EPRAP) is essential for an anti-inflammatory function of EP4 signaling in macrophages in vitro. To investigate the in vivo roles of EPRAP, we examined the effects of EPRAP on colitis and colitis-associated tumorigenesis. In mice, EPRAP deficiency exacerbated colitis induced by dextran sodium sulfate (DSS) treatment. Wild-type (WT) or EPRAP-deficient recipients transplanted with EPRAP-deficient bone marrow developed more severe DSS-induced colitis than WT or EPRAP-deficient recipients of WT bone marrow. In the context of colitis-associated tumorigenesis, both systemic EPRAP null mutation and EPRAP-deficiency in the bone marrow enhanced intestinal polyp formation induced by azoxymethane (AOM)/DSS treatment. Administration of an EP4-selective agonist, ONO-AE1-329, ameliorated DSS-induced colitis in WT, but not in EPRAP-deficient mice. EPRAP deficiency increased the levels of the phosphorylated forms of p105, MEK, and ERK, resulting in activation of stromal macrophages in DSS-induced colitis. Macrophages of DSS-treated EPRAP-deficient mice exhibited a marked increase in the expression of pro-inflammatory genes, relative to WT mice. By contrast, forced expression of EPRAP in macrophages ameliorated DSS-induced colitis and AOM/DSS-induced intestinal polyp formation. These data suggest that EPRAP in macrophages functions crucially in suppressing colonic inflammation. Consistently, EPRAP-positive macrophages were also accumulated in the colonic stroma of ulcerative colitis patients. Thus, EPRAP may be a potential therapeutic target for inflammatory bowel disease and associated intestinal tumorigenesis.
    Full-text · Article · Oct 2015 · PLoS Genetics

  • No preview · Article · Oct 2015 · Journal of the American College of Surgeons
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    ABSTRACT: Purpose: This study aimed to assess the effect of intraoperative blood loss (IBL) on short- and long-term outcomes of colorectal cancer surgery for very elderly patients. Methods: We acquired the data of consecutive patients aged 80 years or older who underwent elective radical surgery for stage I to III colorectal cancer between January 2003 and December 2007 in 41 institutions. The patients were divided into high and low IBL groups, and the differences in postoperative morbidity and survival between the two groups were primarily assessed. Eleven factors were treated as potential confounders in multivariate analyses. Results: A total of 1554 patients were eligible for this study, with an age range of 80-103 years. Median IBL was 71 ml (interquartile range, 25 to 200 ml), and 412 patients had IBL ≥200 ml. Morbidity was 46 % among patients with IBL ≥200 ml, compared with 30 % among those with IBL <200 ml (p < 0.001). Patients with IBL ≥200 ml had worse overall survival rates and recurrence-free survival rates at 1, 3, and 5 years than those with IBL <200 ml. In multivariate analyses, IBL ≥200 ml was identified as an independent risk factor for postoperative adverse events (odds ratio (OR) 1.41, 95 % confidence interval (CI) 1.08 to 1.86), overall survival (hazard ratio (HR) 1.34, 95 % CI 1.04 to 1.72), and recurrence-free survival (HR 1.29, 95 % CI 1.03 to 1.62). Conclusion: The degree of IBL is significantly associated with postoperative morbidity and survival in very elderly colorectal cancer patients.
    No preview · Article · Sep 2015 · International Journal of Colorectal Disease
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    ABSTRACT: We previously reported loss of SMAD4 promotes chemokine CCL15 expression to recruit CCR1+ myeloid cells via the CCL15-CCR1 axis, which facilitates metastasis of colorectal cancer (CRC) to the liver. The purposes of this study are to investigate whether essentially the same mechanism works in tumor invasion of the primary CRC and to evaluate the clinical importance of CCL15 expression and CCR1+ cell accumulation. Using human CRC cell lines with reduced expression of SMAD4 or CCL15, we investigated tumor growth activities in vivo. We used immunohistochemistry (IHC) to investigate expression of SMAD4, CCL15 and CCR1 with 333 clinical specimens of primary CRC. We next characterized the CCR1+ cells using double immunofluorescence staining with several specific cell-type markers. Finally, we determined the serum CCL15 levels in 132 CRC patients. In an orthotopic xenograft model, CCL15 secreted from SMAD4-deficient CRC cells recruited CCR1+ cells, resulting in aggressive tumor growth. IHC indicated loss of SMAD4 was significantly associated with CCL15 expression, and that CCL15-positive primary CRCs recruited ~2.2 times more numbers of CCR1+ cells at their invasion front than CCL15-negative CRCs. Importantly, these CCR1+ cells were of the myeloid derived suppressor cell (MDSC) phenotype (CD11b+, CD33+, and HLA-DR-). Most CCR1+ cells showed the granulocytic-MDSC phenotype (CD15+), although some did the monocytic-MDSC phenotype (CD14+). Serum CCL15 levels in CRC patients were significantly higher than in controls. Blocking the recruitment of CCR1+ MDSCs may represent a novel molecular targeted therapy, and serum CCL15 concentration can be a novel biomarker for CRC. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Sep 2015 · Clinical Cancer Research
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    ABSTRACT: To investigate the outcomes of patients with colorectal cancer and initially unresectable or not optimally resectable liver metastases, who were treated using the liver-first approach in the era of modern chemotherapy in Japan. We analyzed and compared data retrospectively on patients with asymptomatic resectable colorectal cancer and initially unresectable or not optimally resectable liver metastases, who were treated either using the liver-first approach (n = 12, LF group) or the primary-first approach (n = 13, PF group). Both groups of patients completed their therapeutic plan and there was no mortality. Postoperative morbidity rates after primary resection and hepatectomy, and post-hepatectomy liver failure rate were comparable between the groups (p = 1.00, p = 0.91, and p = 0.55, respectively). Recurrence rates, median recurrence-free survival since the last operation, and 3-year overall survival rates from diagnosis were also comparable between the LF and PF groups (58.3 vs. 61.5 %, p = 0.87; 10.5 vs. 18.6 months, p = 0.57; and 87.5 vs. 82.5 %, p = 0.46, respectively). The liver-first approach may be an appropriate treatment sequence without adversely affecting perioperative or survival outcomes for selected patients.
    No preview · Article · Aug 2015 · Surgery Today

  • No preview · Article · Aug 2015 · Asian Journal of Endoscopic Surgery

  • No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: To evaluate the effect of Tri-staple™ technology and slow firing using the Endo-GIA™ endoscopic linear stapler. The cardiac and pyloric portions of porcine stomachs were divided using the endoscopic linear stapler with different reload types. A total of 8 min of waiting time was employed during firing in the slow-firing group and no waiting time was employed in the normal-firing group. The shape of the staples was then evaluated. The length of the staple line and serosal laceration was also determined. There was a moderate negative correlation between tissue thickness and secure staple formation. Tri-staple™ reloads (purple, black) offered more secure staple formation compared with Universal green reload. Although slow firing enhanced secure staple formation, its effect was greater when using green reload, compared with Tri-staple™ reloads. Significantly shorter staple line length and longer serosal laceration was observed in the thick tissue. Although the cartridge type did not influence lengths of the staple line or serosal laceration, both were better in the slow-firing group. Tri-staple™ reloads offered more secure staple formation compared with the Universal reload. Although slow firing improved staple line shortening and serosal laceration, its effect on secure stapling was relatively small when using Tri-staple™ reloads. © 2015 S. Karger AG, Basel.
    No preview · Article · Jul 2015 · Digestive surgery
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    ABSTRACT: Amino-terminal enhancer of split (Aes) is a member of Groucho/Transducin-like enhancer (TLE) family. Aes is a recently found metastasis suppressor of colorectal cancer (CRC) that inhibits Notch signaling, and forms nuclear foci together with TLE1. While some Notch-associated proteins are known to form subnuclear bodies, little is known regarding the dynamics or functions of these structures. Here we show that Aes nuclear foci in CRC observed under an electron microscope are in a rather amorphous structure, lacking surrounding membrane. Investigation of their behavior during the cell cycle by time-lapse cinematography showed that Aes nuclear foci dissolve during mitosis and reassemble after completion of cytokinesis. We have also found that heat shock cognate 70 (HSC70) is an essential component of Aes foci. Pharmacological inhibition of the HSC70 ATPase activity with VER155008 reduces Aes focus formation. These results provide insight into the understanding of Aes-mediated inhibition of Notch signaling. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.
    No preview · Article · Jul 2015 · Journal of Biochemistry
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    ABSTRACT: A number of studies have shown that KRAS mutations in colorectal cancer (CRC) result in the lack of response to anti-epidermal growth factor receptor (EGFR)-based therapy; thus, KRAS mutational testing has been incorporated into routine clinical practice. However, one limitation of this test is the heterogeneity of KRAS status, which can either be intratumoral heterogeneity within an individual primary CRC, or discordant KRAS status between a primary CRC and its corresponding metastases. We previously reported that fluorodeoxyglucose (FDG) accumulation was significantly higher in primary CRCs with mutated KRAS than in those with wild-type KRAS. However, the clinical utility of the previous report has been limited because endoscopic biopsy for testing KRAS status is safe and feasible only in primary CRC. The purpose of this study was to investigate whether KRAS status is associated with FDG accumulation in metastatic CRC, and whether FDG-Positron emission tomography/computed tomography (PET/CT) scans can be used to predict the KRAS status of metastatic CRC. A retrospective analysis was performed on 55 metastatic CRC tumors that were identified by FDG-PET/CT before surgical resection. Maximum standardized uptake value (SUVmax) of the respective metastatic tumor was calculated from FDG accumulation. From the analysis with the 55 tumors, no significant correlation was found between SUVmax and KRAS status. We next analyzed only tumors larger than 10mm to minimize the bias of partial volume effect, and found that SUVmax was significantly higher in the KRAS mutated group than in the wild-type group (8.3 ± 4.1 vs. 5.7 ± 2.4, respectively; P = 0.03). Multivariate analysis indicated that SUVmax remained significantly associated with KRAS mutations (P = 0.04). KRAS status could be predicted with an accuracy of 71.4% when SUVmax cutoff value of 6.0 was used. FDG accumulation into metastatic CRC was associated with KRAS status. FDG-PET/CT scans may be useful for predicting the KRAS status of metastatic CRC, and help in determining the therapeutic strategies against metastatic CRC. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    No preview · Article · Jul 2015 · Journal of Nuclear Medicine
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    ABSTRACT: The efficacy of neoadjuvant chemotherapy without radiation (NAC) in the treatment of rectal cancer remains unclear. This retrospective study was aimed at determining the pathological complete response rate and short-term outcomes of NAC in patients with locally advanced rectal cancer. We collected data on 159 consecutive patients treated for rectal cancer (cT3/cT4a, cN+, and cM0 status) at five tertiary referral hospitals between 2005 and 2010. Pathological complete response (pCR) and safety were assessed as the main outcomes in 124 eligible patients comprising 15 who received NAC (NAC group) and 109 who received no neoadjuvant chemotherapy (non-NAC group). In the NAC group, 2 patients (13.3%) achieved a pCR (95% confidence interval: 1.7-40.5%) and 3 patients (20%) experienced grade 3/4 adverse events. No significant differences were found between the NAC and non-NAC groups in terms of short-term outcomes, including R0 proportion (100 vs. 96.3%, p = 0.45) and postoperative grade 3/4 complications (13.3 vs. 18.4%, p = 0.63). Neoadjuvant systemic chemotherapy without radiation appears to be safe, without worsening short-term outcomes, in patients with locally advanced rectal cancer. A further study is needed to verify these findings in larger samples. © 2015 S. Karger AG, Basel.
    No preview · Article · Jun 2015 · Digestive surgery
  • Suguru Hasegawa · Ryo Takahashi · Koya Hida · Kenji Kawada · Yoshiharu Sakai
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    ABSTRACT: Although laparoscopic surgery for rectal cancer has been gaining acceptance with the gradual accumulation of evidence, it remains a technically demanding procedure in patients with a narrow pelvis, bulky tumors, or obesity. To overcome the technical difficulties associated with laparoscopic rectal dissection and transection, transanal endoscopic rectal dissection, which is also referred to as transanal (reverse, bottom-up) total mesorectal excision (TME), has recently been introduced. Its potential advantages include the facilitation of the dissection of the anorectum, regardless of the patient body habitus, and a clearly defined safe distal margin and transanal extraction of the specimen. This literature review shows that this approach seems to be feasible with regard to the operative and short-term postoperative outcomes. In experienced hands, transanal TME is a promising method for the resection of mid- and low-rectal cancers. Further investigations are required to clarify the long-term oncological and functional outcomes.
    No preview · Article · Jun 2015 · Surgery Today
  • Kazutaka Obama · Yoshiharu Sakai
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    ABSTRACT: Although over 3000 da Vinci Surgical System (DVSS) devices have been installed worldwide, robotic surgery for gastric cancer has not yet become widely spread and is only available in several advanced institutions. This is because, at least in part, the advantages of robotic surgery for gastric cancer remain unclear. The safety and feasibility of robotic gastrectomy have been demonstrated in several retrospective studies. However, no sound evidence has been reported to support the superiority of a robotic approach for gastric cancer treatment. In addition, the long-term clinical outcomes following robotic gastrectomy have yet to be clarified. Nevertheless, a robotic approach can potentially overcome the disadvantages of conventional laparoscopic surgery if the advantageous functions of this technique are optimized, such as the use of wristed instruments, tremor filtering and high-resolution 3-D images. The potential advantages of robotic gastrectomy have been discussed in several retrospective studies, including the ability to achieve sufficient lymphadenectomy in the area of the splenic hilum, reductions in local complication rates and a shorter learning curve for the robotic approach compared to conventional laparoscopic gastrectomy. In this review, we present the current status and discuss issues regarding robotic gastrectomy for gastric cancer.
    No preview · Article · May 2015 · Surgery Today