Yoshiharu Sakai

Kyoto University, Kioto, Kyōto, Japan

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Publications (155)605.27 Total impact

  • PLoS Genetics 10/2015; 11(10):e1005542. DOI:10.1371/journal.pgen.1005542 · 7.53 Impact Factor
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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.
    International Journal of Colorectal Disease 09/2015; DOI:10.1007/s00384-015-2405-5 · 2.45 Impact Factor
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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.
    Clinical Cancer Research 09/2015; DOI:10.1158/1078-0432.CCR-15-0726 · 8.72 Impact Factor
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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.
    Surgery Today 08/2015; DOI:10.1007/s00595-015-1242-z · 1.53 Impact Factor
  • Asian Journal of Endoscopic Surgery 08/2015; 8(3):246-262. DOI:10.1111/ases.12222
  • Cancer Research 08/2015; 75(15 Supplement):3229-3229. DOI:10.1158/1538-7445.AM2015-3229 · 9.33 Impact Factor
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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.
    Digestive surgery 07/2015; 32(5):353-360. DOI:10.1159/000437216 · 2.16 Impact Factor
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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.
    Journal of Biochemistry 07/2015; DOI:10.1093/jb/mvv077 · 2.58 Impact Factor
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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.
    Journal of Nuclear Medicine 07/2015; 56(9). DOI:10.2967/jnumed.115.160614 · 6.16 Impact Factor
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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.
    Digestive surgery 06/2015; 32(4):275-283. DOI:10.1159/000430469 · 2.16 Impact Factor
  • 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.
    Surgery Today 06/2015; DOI:10.1007/s00595-015-1195-2 · 1.53 Impact Factor
  • 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.
    Surgery Today 05/2015; DOI:10.1007/s00595-015-1190-7 · 1.53 Impact Factor
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    ABSTRACT: Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in the homeostasis of mucosal immunity; however, their role in inflammatory bowel disease (IBD) is unclear. Flow cytometry was used to enumerate peripheral blood MAIT cells in 88 patients with ulcerative colitis (UC), 68 with Crohn's disease (CD), and in 57 healthy controls. Immunohistochemistry identified MAIT cells in intestinal tissue samples from patients with UC (n = 5) and CD (n = 10), and in control colon (n = 5) and small intestine (n = 9) samples. In addition, expression of activated caspases by MAIT cells in the peripheral blood of 14 patients with UC and 15 patients with CD, and 16 healthy controls was examined. Peripheral blood analysis revealed that patients with IBD had significantly fewer MAIT cells than healthy controls (P < 0.0001). The number of MAIT cells in the inflamed intestinal mucosae of patients with UC and CD was also lower than that in control mucosae (P = 0.0079 and 0.041, respectively). The number of activated caspase-expressing MAIT cells in the peripheral blood of patients with UC and CD was higher than that in healthy controls (P = 0.0061 and 0.0075, respectively), suggesting that the reduced MAIT cell numbers in IBD are associated with an increased level of apoptosis among these cells. The number of MAIT cells in the peripheral blood and inflamed mucosae of patients with UC and CD was lower than that in non-IBD controls. Also, MAIT cells from patients with IBD exhibited proapoptotic features. These data suggest the pathological involvement and the potential for therapeutic manipulation of these cells in patients with IBD.
    Inflammatory Bowel Diseases 05/2015; 21(7). DOI:10.1097/MIB.0000000000000397 · 4.46 Impact Factor
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    ABSTRACT: A 79-year-old woman who had undergone laparoscopic radical cystectomy and ileal conduit construction for bladder cancer 4 years earlier presented to our hospital with anemia. We diagnosed advanced ascending colon cancer (cT4bN2M1) and documented tumor regression after six courses of folinic acid, 5-fluorouracil, and oxaliplatin therapy. We then performed laparoscopic right hemicolectomy. Intraoperatively, we found that the right colic artery was the feeding artery of the tumor, whereas the ileocolic artery, which was the main feeder of the conduit, was not. We performed lymph node dissection along the surgical trunk with central vascular ligation of the right colic artery and the right branch of the middle colic artery while preserving the ileal conduit and its blood supply (ileocolic artery and ileal branches). The postoperative course was uneventful, and the patient remains well and cancer-free 2 years after colonic surgery. We believe that this is the first report of laparoscopic right colectomy in a patient with an ileal conduit. © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
    Asian Journal of Endoscopic Surgery 05/2015; 8(2). DOI:10.1111/ases.12173
  • Yoshiharu Sakai · Seigo Kitano
    Asian Journal of Endoscopic Surgery 05/2015; 8(2). DOI:10.1111/ases.12166
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    ABSTRACT: Patients with colorectal liver metastasis (CRLM) might be down-staged by chemotherapy from an initially unresectable stage to a resectable stage. Because the tumor response to preoperative chemotherapy has been correlated with resection rate, the improved efficacy from the concept that only the patients without K-ras mutations receive an anti-EGFR antibody might be expected to increase the conversion rate. The purpose of this study is to evaluate the conversion rate from unresectable CRLM to complete resection. We conducted a multi-institutional phase II trial for unresectable CRLM. Patients received mFOLFOX6 with either bevacizumab (bev) or cetuximab (cet) based on K-ras status (UMIN000004310). Planned treatment was for six cycles during which tumors were assessed for resectability every three cycles. Patients whose disease was unresectable after six cycles switched their chemotherapy regimen from mFOLFOX6 to FOLFIRI. The primary endpoint was R0 resection rate. Thirty-five patients with unresectable CRLM were enrolled. A total of 22/12 patients with K-ras wild-type/mutant (wt/mt) were treated with mFOLFOX6 plus cet/bev, respectively. The overall response rate was 64.7% (wt/mt; 77.3%/41.7%, P = 0.04). In 20 patients (58.8%), hepatectomy was performed according to protocol treatment, and the conversion rate was 72.7%/33.3% in wt/mt patients, respectively (P = 0.03). Finally, 23 patients (67.6%) underwent hepatectomy, and the conversion rate was 77.2%/50.0% in wt/mt patients (P = 0.09). The overall R0 resection rate was 47.1% (wt/mt; 50.0%/41.7%, P = 0.36). This prospective study showed that combined chemotherapy based on K-ras status can facilitate conversion to resection in patients with unresectable CRLM. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
    Journal of Hepato-Biliary-Pancreatic Sciences 04/2015; 22(8). DOI:10.1002/jhbp.254 · 2.99 Impact Factor
  • Tatsuto Nishigori · Koji Kawakami · Rei Goto · Koya Hida · Yoshiharu Sakai
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    ABSTRACT: Health Technology Assessment (HTA) is the systematic evaluation to measure the value of new health technologies. It improves the quality of choices on hand for cost-effective health technologies that are considered valuable. Japan has built a society of longevity consisted of the institution of the universal health care system, which is financially unsustainable. In Japan, no independent HTA organization has been publicly established but the government is contemplating implementation of such system. To advance the usage of HTA into surgery, we need to establish methods for evaluating new surgical technologies with steep learning curves. The promotion of clinical researches is also essential, especially by taking advantage of observational studies from medical big data such as the Japanese nationwide database which has more than four million surgical cases registered. In addition, we need more clinical information regarding each surgical patient's quality of life and socioeconomic status. The countries already introduced HTA into their health care system have measures to solve the problems that arose and have developed necessary evaluating methods. To introduce and promote HTA in Japan without taking away the benefit of our current healthcare, it is required that surgeons collaborate with other specialists such as methodologists and health economists.
    Nippon Geka Gakkai zasshi 04/2015; 116(1):64-9.
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    ABSTRACT: Several studies of minimally invasive esophagectomy (MIE) for esophagogastric junction (EGJ) tumors have been reported from Western countries with high incidences of lower esophageal cancer. Less invasiveness and a better quality of life after MIE compared with open esophagectomy were found in a randomized controlled trial in Europe. On the other hand, as laparoscopic total gastrectomy for upper gastric cancer has gradually become more common, laparoscopic transhiatal resection and reconstruction to treat EGJ tumors have been reported in Japan. Some potential benefits of laparoscopic total gastrectomy for upper gastric cancer, such as less blood loss and fewer complications, were indicated in comparative studies. Therefore, similar benefits are also expected for EGJ tumors, although there is no current evidence for this. It is difficult to determine which minimally invasive approach is better because the appropriate approach and extent of resection may differ depending on the location and size of each tumor. For the minimally invasive approach to the treatment of EGJ tumors to be accepted as an option, a safe reconstruction method with good long-term quality of life needs to be established.
    Nippon Geka Gakkai zasshi 04/2015; 116(1):45-9.
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    ABSTRACT: In the seventh TNM classification, stage IIIA includes tumors with early stage of bowel wall invasion and regional lymph node metastasis. We investigated the validity of the current TNM classification of patients with stage IIIA colorectal cancer and identified prognostic factors of them for ameliorating treatment strategies for them. This study included the participation of four tertiary hospitals. A total of 4,236 patients with Stages I-IIIB colorectal cancer were analyzed. The primary end point was the 5-year relapse-free survival. The 5-year relapse-free survival of patients with stage IIIA disease was similar to that of patients with stage IIA. The 5-year relapse-free survival was 88.9% in the chemotherapy group (n = 152) and 82.3% in the no-chemotherapy group (n = 36, P = 0.111). Tumor differentiation (moderate or poor) and venous invasion were independent prognostic factors of relapse-free survival. The relapse-free survival of patients with stage IIIA tumors was similar to that of patients with stage IIA tumors, and the prognosis of stage IIIA tumors varied significantly by the tumor factors identified. These factors can be used to predict the risk of disease recurrence and to optimize the use of adjuvant chemotherapy. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 04/2015; 111(7). DOI:10.1002/jso.23892 · 3.24 Impact Factor
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    ABSTRACT: Background Remnant gastric cancer is increasing with the earlier detection of gastric cancer and improved medical care. Laparoscopic gastrectomy for remnant gastric cancer has been reported sporadically in association with the increased use of minimally invasive techniques. However, because of the rarity of remnant gastric cancer, the number of cases reported per study has been small. We therefore reviewed all published English-language reports, including our experience, to better characterize the technical aspects of currently used procedures. Methods Ten patients who underwent laparoscopic gastrectomy for remnant cancer between August 2005 and March 2014 were retrospectively studied. A comprehensive literature search was performed using the PubMed database to identify English-language studies on laparoscopic gastrectomy for remnant gastric cancer that were published before May 2014. Results There was no conversion to open surgery. The mean operating time was 325 min, and mean intraoperative blood loss was 55 g. The mean number of retrieved lymph nodes was 22, and mean postoperative hospital stay was 13 days. There was only one minor wound infection (overall morbidity rate, 10 %). From the literature review, all comparative studies revealed that laparoscopic gastrectomy for remnant gastric cancer required a longer operating time, and most studies reported less intraoperative blood loss, an equivalent number of harvested lymph nodes, and a shorter postoperative stay as compared with open surgery. Conclusion Proficiency in advanced laparoscopic surgical techniques, such as proper adhesiolysis and stable laparoscopic anastomosis, will allow laparoscopic gastrectomy for remnant gastric cancer to be performed with satisfactory short-term results. This minimally invasive approach can be one treatment option for remnant gastric cancer.
    Gastric Cancer 12/2014; DOI:10.1007/s10120-014-0451-2 · 3.72 Impact Factor