Shinsuke Kazama

Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma

BackgroundThe stromal cell-derived factor-1/CXC chemokine receptor-4 (SDF-1/CXCR4) signal has been shown to be important in various immunological reactions. Recent studies have suggested that CXCR4 is expressed in certain cancer cells and that they use this chemokine receptor efficiently for metastasis formation.MethodThe expression of CXCR4 was evaluated by immunohistochemical study in 79 surgically resected invasive ductal carcinomas, and the relation between the staining pattern and clinicopathological features was examined.ResultsCXCR4 was diffusely and homogeneously expressed in 59 cancers, which were further divided into 28 high-expression and 31 low-expression cancers by their staining intensity. The other 20 cancers showed heterogeneous immunoreactivity in tumor tissue, which was defined as focal type. In comparison with the diffuse type, focal type tumors showed significantly more extensive lymph node metastasis, because the number and extent of metastatic nodes were larger in the focal than the diffuse type. In the diffuse type, the rate of node-positive cases did not show a difference in staining intensity. However, high-CXCR4 tumors showed more extensive nodal metastasis in comparison with low-expression tumors. In contrast, the expression pattern of CXCR4 did not have a significant correlation with hematogeneous metastasis. The overall survival of these patients tended to be better in the diffuse type than in the focal type, although the difference was not statistically significant.ConclusionThe expression pattern of CXCR4 was significantly correlated with the degree of lymph node metastasis in breast cancers. Our data suggest that CXCR4 might be particularly important in facilitating metastasis through the lymphatic system.

Earlier surveillance colonoscopy programme improves survival in patients with ulcerative colitis associated colorectal cancer: results of a 23-year surveillance programme in the Japanese population

Patients with long-standing ulcerative colitis (UC) are known to have an increased risk for the development of colorectal cancer (CRC). The aim of this study was to clarify the cumulative risk for the development of dysplasia or invasive cancer and the effectiveness of surveillance colonoscopy in the Japanese population. A total of 217 patients received a total of 1027 surveillance colonoscopies between January 1979 and December 2001 at the University of Tokyo hospital. Patients with invasive cancer found in the surveillance group were compared to those referred to our hospital from the other hospitals without surveillance colonoscopy. Surveillance colonoscopy confirmed 15 patients with definite dysplasia. Of these, five were proved to have invasive cancer in the resected specimens. The cumulative risk for the development of invasive cancer at 10, 20, and 30 years was 0.5, 4.1, and 6.1%, respectively, while that for the development of definite dysplasia at 10, 20, and 30 years was 3.1, 10.0, and 15.6%, respectively. All the patients with invasive cancer in the surveillance group remained alive, while three out of four patients in the nonsurveillance group died. Our surveillance programme is useful for detecting UC-associated CRC, and survival may be improved by surveillance colonoscopy.

Tumour budding at the deepest invasive margin correlates with lymph node metastasis in submucosal colorectal cancer detected by anticytokeratin antibody CAM5.2

In the past few years, tumour budding at the invasive margin has been reported as a new risk factor for lymph node metastasis in advanced colorectal cancers, but it is sometimes difficult to detect tumour budding in submucosal colorectal cancer by haematoxylin and eosin staining. We immunohistochemically examined tumour budding at the deepest invasive margin of 56 surgically resected submucosal colorectal carcinomas using anticytokeratin antibody CAM5.2, furthermore checked by AE1/AE3, and determined the relation between tumour budding and clinicopathological factors. Moreover, we used the monoclonal antibody D2-40 for immunohistochemistry to detect lymphatic involvement. Tumour budding was detected in 42 cases (75.0%), and the budding-positive group showed a significantly higher rate of lymph node metastasis (including isolated tumour cells) (16/42 vs 0/14; P=0.004) than the budding-negative group. The sensitivity and negative predictive value of tumour budding alone for lymph node metastasis were superior to those of lymphatic invasion alone. Furthermore, the specificity and positive predictive value of the combination of either lymphatic invasion or tumour budding were superior to those of lymphatic invasion alone. Tumour budding detected immunohistochemically by using CAM5.2 is a newly found risk factor for lymph node metastasis and may help to avoid oversurgery in the future.

Poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum show higher rates of loss of heterozygosity and loss of E-cadherin expression due to methylation of promoter region.

Previous studies have reported that poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum (Por & Muc) show a low incidence and poor prognosis. However, genetic alterations and tumourigenesis of Por & Muc remain unclear. In our study, we analyzed the genetic and epigenetic alterations of Por & Muc to clarify the difference from those of well‐differentiated adenocarcinoma (WD). First, we evaluated the loss of heterozygosity (LOH) on 4 chromosomes (2p, 5q, 17p, 18q) frequently observed in colorectal cancer. Second, to determine large‐scale allelic losses, we performed wide‐ranging allelotyping study. Using 27 microsatellite markers spanning every 10 cM on chromosome 17 and 18, we defined the LOH ratio as the proportion of markers that exhibit LOH out of 27 markers. Third, we evaluated the methylation of E‐cadherin. With respect to LOH of 4 loci, higher rates of LOH were observed in Por & Muc and a statistical significance was found on the markers adjacent to MSH2 and SMAD4/DCC. Moreover, as the evidence of large‐scale allelic imbalance, the average LOH ratio was higher in Por & Muc (0.70) than in WD (0.24) (p = 0.01). Methylation analysis showed that 54.5% of Por & Muc demonstrated hypermethylation of E‐cadherin. In immunohistochemistry, 77.8% of Por & Muc exhibited abnormal expression of E‐cadherin. Hypermethylation of E‐cadherin correlated significantly with abnormal expression (p = 0.047). These results suggest that the higher rates of LOH contribute to Por & Muc tumourigenesis and most of Por & Muc lose normal E‐cadherin expression, partly because of the methylation of promoter region.

Endovascular stent graft repair of aortopulmonary fistula

Two patients who had aortopulmonary fistula of postoperative origin with hemoptysis underwent successful repair by means of an endovascular stent graft procedure. One patient had undergone repeated thoracotomies two times, and the other one time to repair anastomotic aneurysms of the descending aorta after surgery for Takayasus arteritis. A self-expanding stainless steel stent covered with a Dacron graft was inserted into the lesion through the external iliac or femoral artery. The patients recovered well, with no signs of infection or recurrent hemoptysis 8 months after the procedure. Endovascular stent grafting may be a therapeutic option for treating patients with aortopulmonary fistula.

Expression of platelet-derived endothelial cell growth factor in inflammatory bowel disease

Background: Platelet-derived endothelial cell growth factor (PD-ECGF) is reported to be highly expressed in tumors and inflammatory tissues, but its expression and role in inflammatory bowel disease (IBD) are still unclear. In this study we examined the location and tissue density of cells immunoreactive for PD-ECGF in the colonic mucosa of IBD. Methods: Paraffin-embedded sections of colonic tissue from patients with ulcerative colitis (UC) or Crohns disease (CD) were immunostained for PD-ECGF. As controls, noninflamed mucosa of IBD, as well as normal colonic mucosa from patients with colorectal cancer, were used. Also, cancer tissues were evaluated. In addition, changes in the expression of PD-ECGF in human umbilical vein endothelial cells (HUVEC) after treatment with inflammatory cytokines and angiogenic factors, as well as after coculture with colon cancer cell lines, were evaluated by flow cytometry. Results: In normal colonic mucosa and noninflamed mucosa of IBD, PD-ECGF expression was negligible. In inflamed colonic mucosa, strong expression was observed, predominantly in macrophages and fibroblasts. Vascular endothelial cells of the inflamed colonic mucosa, but not of normal colonic mucosa or of neoplastic tissues, stained for PD-ECGF, and the microvessel density was significantly increased in the severely inflamed mucosa. Flow cytometry demonstrated that PD-ECGF was constitutively expressed in HUVEC. Inflammatory cytokines and vascular endothelial growth factor (VEGF) increased its expression, whereas basic fibroblast growth factor (bFGF) decreased it. Coculture with colon cancer cell lines in direct contact, but not in those without contact, also resulted in an important decrease in the expression of PD-ECGF in HUVEC. Conclusions: Autocrine production of PD-ECGF by endothelial cells may be a mechanism of inflammatory angiogenesis, but not tumor angiogenesis, and may be particularly important for the maintenance of damaged vasculature in IBD.

Chromosome 18q deletion and Smad4 protein inactivation correlate with liver metastasis: a study matched for T- and N- classification

Smad4 protein, whose gene is coded at chromosome 18q21.1, is an important tumour suppressor that mediates transforming growth factor-beta. It has been reported that inactivation of the Smad4 gene and allelic loss of chromosome 18q correlate with liver metastasis and poorer prognosis in colorectal cancers. Utilising a recently developed method of immunohistochemical staining for Smad4 protein, we focused on the specific impact of Smad4 protein expression on liver metastasis in colorectal cancer. We also evaluated the association between chromosome18q deletion and liver metastasis. We selected 20 colorectal cancers with liver metastasis for the experimental group, and 20 cases without liver metastasis for the control. In order to exclude the influence of lymph node metastasis, all cases were lymph node negative. In addition, the two groups were matched for tumour depth, tumour differentiation and tumour location. We compared the expression level of Smad4 protein immunohistochemically in these 20 matched pairs. We also compared the loss of heterozygosity status at chromosome 18q in these 20 matched pairs. Immunohistochemical staining revealed a significant difference (P=0.024) in the level of Smad4 protein between the two groups. We also observed a significantly different (P=0.0054) ratio of allelic deletion at chromosome 18q21. Smad4 protein expression level and allelic loss at 18q21 are associated with the process of liver metastasis in colorectal cancers evaluated when excluding clinical and pathological features except for liver metastasis.

Impact of a lymphocyte to monocyte ratio in stage IV colorectal cancer

BACKGROUND Recent studies have proposed that the use of the lymphocyte-to-monocyte ratio (LMR) is a good prognostic indicator for patients with nonmetastatic colorectal cancer (CRC). In the present study, we aimed to evaluate the prognostic impact of the LMR in stage IV CRC patients who have undergone curative resection. METHODS We performed a retrospective review of 117 stage IV CRC patients who underwent curative resection at our institute between 1997 and 2012. Patients were divided into a low-LMR group and a high-LMR group according to their LMR. The cutoff value of the LMR was determined based on receiver operating characteristics curve analysis. The relationships between the LMR and disease-free survival (DFS) and cancer-specific survival (CSS) rates were assessed. RESULTS The cutoff value for LMR was 3.00. DFS was not significantly different between the high- and low-LMR groups (P = 0.277). By contrast, CSS was significantly better in the high-LMR group than in the low-LMR group (P = 0.001). Multivariate analysis indicated that the LMR was an independent prognostic factor for CSS in patients with stage IV CRC who had undergone curative resection (hazard ratio: 2.75; 95% confidence interval: 1.40-5.44; P = 0.004), but not for DFS. CONCLUSIONS The preoperative LMR is a simple and useful prognostic indicator in patients with stage IV CRC who have undergone curative resection.

Laparoscopic surgery for ulcerative colitis: a review of the literature

Despite the development of new therapies, including anti-TNF alpha antibodies and immunosuppressants, a substantial proportion of patients with ulcerative colitis (UC) still require surgery. Restorative proctocolectomy with ileal-pouch anal anastomosis is the standard surgical treatment of choice for UC. With the advent of laparoscopic techniques for colorectal surgery, ileal-pouch anal anastomosis has also been performed laparoscopically. This paper reviews the history and current trends in laparoscopic surgery for UC. The accumulation of experience and improvement of laparoscopic devices have shifted the paradigm of UC surgery towards laparoscopic surgery over the past decade. Although laparoscopic surgery requires a longer operation, it provides significantly better short and long-term outcomes. The short-term benefits of laparoscopic surgery over open surgery include shorter hospital stays and fasting times, as well as better cosmesis. The long-term benefits of laparoscopy include better fecundity in young females. Some surgeons favor laparoscopic surgery even for severe acute colitis. More efforts are being made to develop newer laparoscopic methods, such as reduced port surgery, including single incision laparoscopic surgery and robotic surgery.

Signet Ring Cell Carcinoma of the Appendix Manifesting as Colonic Obstruction and Ovarian Tumors : Report of a Case

Appendiceal cancer is rare and associated with a poor prognosis because it is usually found at an advanced stage. We report a case of appendiceal adenocarcinoma manifesting as a colonic obstruction with a lower abdominal mass. Laparotomy revealed bilateral ovarian tumors and a small appendiceal tumor with peritoneal metastases. We performed ileocecal resection, colectomy, and oophorectomy, following which a histological diagnosis of signet ring cell carcinoma was made. Immunohistochemical analysis revealed positive expression of cytokeratin 7 and 20, and mucin core protein 2 (MUC2), compatible with appendiceal cancer and Kruckenberg metastases. When a patient is found to have disseminated pelvic signet ring cell carcinoma of unknown origin, the appendix should be considered as a possible primary site.