Koya Hida

Hepatic stellate cells promote liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis.

BackgroundIt has been determined that the chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1) regulate several key processes in a wide variety of cancers. However, the function and mechanism of the SDF-1/CXCR4 system in the metastasis of colorectal cancer remain controversial.MethodsImmunohistochemistry was performed to examine quantitatively the expression of CXCR4 in 40 human samples of colorectal cancer and liver metastasis. The functions of SDF-1 on HCT116 colon cancer cells were investigated in vitro. We subcutaneously inoculated HCT116 cells with hepatic stellate cells (HSCs) expressing SDF-1. The CXCR4 inhibitor AMD3100 was tested in vitro and in vivo.ResultsBy quantitatively counting the number of cells, it was shown that there are more CXCR4-positive cells at the metastatic site in the liver compared with the primary sites. We demonstrated the effect of SDF-1 on the invasion and antiapoptosis of HCT116 cells in vitro. In mouse experiment of liver metastasis, intraperitoneal administration of AMD3100 blocked the metastatic potential of HCT116 cells. Furthermore, we found that α-smooth muscle actin (α-SMA)-positive myofibroblasts derived from HSCs, surrounding the liver metastasis foci, secreted SDF-1. The subcutaneous inoculation of HCT116 cells with HSCs promoted the tumor initiation in nude mice, indicating the importance of the direct interaction between these cells in vivo.ConclusionThese results suggest that HSCs play important role in liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis and provide preclinical evidence that blockade of the axis is a target for antimetastasis therapy.

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

Chemokines and their receptors play key roles in leukocyte trafficking and are also implicated in cancer metastasis. We previously demonstrated that forced expression of CXCR3 promotes colon cancer metastasis preferentially to the draining lymph nodes (LNs), with poor prognosis. Using clinical colorectal cancer (CRC) samples, here, we show that expressions of CXCR3 and CXCR4 are significantly higher in metastatic foci within LNs and liver compared to primary tumors, whereas ligands for CXCR3 and CXCR4 are not. We also have demonstrated that some human CRC cell lines constitutively express both CXCR3 and CXCR4, and that activation of CXCR3 strengthens the CXCR4‐mediated cell migration in vitro in a synergistic manner. By constructing SW620 cell lines with reduced expression of CXCR3 and/or CXCR4 using microRNA, we investigated in vivo metastatic activities in a mouse rectal transplantation model. Six weeks after inoculation, CXCR3‐, CXCR4‐, and CXCR3/CXCR4 double‐knockdowns significantly reduced metastasis to LNs, liver and lungs, compared to the control (p < 0.05). Importantly, its suppressive effect on LN metastasis was significantly stronger in CXCR3‐ and CXCR3/CXCR4 double‐knockdowns. In addition, CXCR3‐ and CXCR3/CXCR4 double‐knockdowns significantly decreased the dissemination of cancer cells to liver and lungs, even after 2 weeks. These results indicate that targeting CXCR3 and CXCR4 can be a promising therapy against CRC metastasis.

Relationship between 18F-Fluorodeoxyglucose Accumulation and KRAS/BRAF Mutations in Colorectal Cancer

Purpose: Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has been widely used in the management of colorectal cancer (CRC). However, the relationship between FDG accumulation and KRAS/BRAF mutations has not yet been investigated. The purpose of this study was to investigate whether KRAS/BRAF mutations affect FDG accumulation in CRC. Experimental Design: Retrospective analysis was conducted in 51 patients with CRC who underwent FDG-PET/computed tomographic (CT) scans for staging before primary tumor resection. The maximum standardized uptake value (SUVmax) for the primary tumor and the tumor-to-liver ratio (TLR) were calculated from FDG accumulation and compared between KRAS/BRAF mutated and wild-type groups. Expression levels of glucose transporter-1 (GLUT1) and hexokinase type-II (HXK-II) were assessed by immunohistochemical analysis. Results: Both SUVmax and TLR were significantly higher in the KRAS/BRAF-mutated group compared with the wild-type group (P = 0.006 and 0.001, respectively). Multivariate analysis indicated that SUVmax and TLR remained significantly associated with KRAS/BRAF mutations (P = 0.016 and 0.01, respectively). KRAS/BRAF status could be predicted with an accuracy of 75% when a SUVmax cutoff value of 13 or 14 was used. GLUT1 expression in cancer cells was positively correlated with FDG accumulation and KRAS/BRAF status whereas HXK-II expression was not. Conclusion: FDG accumulation was higher in CRC with KRAS/BRAF mutations. FDG-PET/CT scans may be useful for predicting the KRAS/BRAF status of patients with CRC and thus aid in determination of therapeutic strategies for patients with CRC. Clin Cancer Res; 18(6); 1696–703. ©2012 AACR.

Open versus laparoscopic resection of primary tumor for incurable stage IV colorectal cancer: a large multicenter consecutive patients cohort study.

Objective:To investigate the hypothesis that laparoscopic primary tumor resection is safe and effective when compared with the open approach for colorectal cancer patients with incurable metastases. Background:There are only a few reports with small numbers of patients on laparoscopic tumor resection for stage IV colorectal cancer. Methods:Data from consecutive patients who underwent palliative primary tumor resection for stage IV colorectal cancer between January 2006 and December 2007 were collected retrospectively from 41 institutions. Short- and long-term outcomes were compared between patients who underwent laparoscopic or open resection. Results:A total of 904 patients (laparoscopic group: 226, open group: 678) with a median age of 64 years (range: 22–95) were included in the analysis. Conversion was required in 28 patients (12.4%) and the most common reasons for conversion (23/28: 82%) were bulky or invasive tumors. There was no 30-day postoperative mortality in either group. The complication rate (NCI-CTCAE grade 2–4) after laparoscopic surgery (17%) was significantly lower than that after open surgery (24%) (P = 0.02), and the difference was greater (4% vs 12%; P < 0.001) when we limited the analysis to severe (≥grade 3) complications. The median length of postoperative hospital stay in the laparoscopic group was significantly shorter than that in the open group (14 vs 17 days; P = 0.002). In univariate analysis, overall survival for the laparoscopic group was significantly better than that for open surgery (median survival time: 25.9 vs 22.3 months, P = 0.04), although no difference was apparent in multivariate analysis. Conclusions:Compared with open surgery, laparoscopic primary tumor resection has advantages in the short term and no disadvantages in the long term. It is a reasonable treatment option for certain stage IV colorectal cancer patients with incurable disease.

Molecular mechanisms of liver metastasis

Colorectal cancer is the second most common cancer, and is the third leading cause of cancer-related death in Japan. The majority of these deaths is attributable to liver metastasis. Recent studies have provided increasing evidence that the chemokine–chemokine receptor system is a potential mechanism of tumor metastasis via multiple complementary actions: (a) by promoting cancer cell migration, invasion, survival and angiogenesis; and (b) by recruiting distal stromal cells (i.e., myeloid bone marrow-derived cells) to indirectly facilitate tumor invasion and metastasis. Here, we discuss recent preclinical and clinical data supporting the view that chemokine pathways are potential therapeutic targets for liver metastasis of colorectal cancer.

Oral and Parenteral Versus Parenteral Antibiotic Prophylaxis in Elective Laparoscopic Colorectal Surgery (JMTO PREV 07-01): A Phase 3, Multicenter, Open-label, Randomized Trial.

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.

Male sexual function after laparoscopic total mesorectal excision

Aim  The aim of this prospective study was to clarify the frequency of male sexual dysfunction after laparoscopic total mesorectal excision (LTME) and to examine the relationship between pelvic autonomic nerve (PAN) preservation status and functional outcomes.

Obtaining secure stapling of a double stapling anastomosis.

BACKGROUND Anastomotic leakage is a serious complication after rectal surgery. The aim of this study was to assess the effect of waiting time during firing of stapling devices on optimal staple formation. METHODS An endoscopic linear stapler (Echelon Flex 60 Endopath) with either a 60 mm blue or gold cartridge was applied to the cardiac and pyloric portions of 27 fresh porcine stomachs. Three different waiting times were used for the precompression and interstroke periods (0/0, 2/0, and 2/2 min). The staple line was divided into four portions (oral, anal and top, base), and the shape of each staple was evaluated. Optimal staple formation was also assessed using the circular stapler (CDH 29). RESULTS Mean thickness of the cardiac and pyloric portions was 2.4 ± 0.35 mm and 4.0 ± 0.4 mm, respectively. The waiting time improved optimal staple formation for the blue cartridge, especially when it was used for the pyloric portion. Staple malformation was observed more commonly in the top portion than in the base portion; however, the former was improved by an interstroke waiting time. Staple formation using the circular stapler was satisfactory and not influenced by the prefiring waiting time or tissue thickness. CONCLUSIONS Employment of a waiting time improves optimal staple formation when the endoscopic linear stapler is used for challenging tissue.

ICG fluorescence imaging for quantitative evaluation of colonic perfusion in laparoscopic colorectal surgery

BackgroundFluorescence technology with indocyanine green (ICG) provides a real-time assessment of intestinal perfusion. However, a subjective evaluation of fluorescence intensity based on the surgeon’s visual judgement is a major limitation. This study evaluated the quantitative assessment of ICG fluorescence imaging in determining the transection line of the proximal colon during laparoscopic colorectal surgery.MethodsThis is a retrospective analysis of a prospectively maintained database of 112 patients who underwent laparoscopic surgery for left-sided colorectal cancers. After distal transection of the bowel, the specimen was extracted extracorporeally and then the proximal colon was divided within the well-perfused area based on the ICG fluorescence imaging. We evaluated whether quantitative assessment of intestinal perfusion by measuring ICG intensity could predict postoperative outcomes: Fmax, Tmax, T1/2, and Slope were calculated.ResultsAnastomotic leakage (AL) occurred in 5 cases (4.5%). Based on the fluorescence imaging, the surgical team opted for further proximal change of the transection line up to an “adequate” fluorescent portion in 18 cases (16.1%). Among the 18 patients, AL occurred in 4 patients (4/18: 22.2%), whereas it occurred in only 1 case (1/94: 1.0%) in the good perfusion patients who did not need proximal change of the transection line. The Fmax of the AL group was less than 52.0 in all 5 cases (5/5), whereas that of the non-AL group was in only 8 cases (8/107): with an Fmax cutoff value of 52.0, the sensitivity and specificity for the prediction of AL were 100 and 92.5%, respectively. Regarding postoperative bowel movement recovery, the Tmax of the early flatus group or early defecation group was significantly lower than that of the late flatus group or late defecation group, respectively.ConclusionsICG fluorescence imaging is useful for assessing anastomotic perfusion in colorectal surgery, which can result in more precise operative decisions tailored for an individual patient.

Transanal total mesorectal excision for rectal cancer

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.