Yoshimasa Oku

Re‐expression of CEACAM1 long cytoplasmic domain isoform is associated with invasion and migration of colorectal cancer

Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is known to be downregulated at the transcriptional level in adenoma and carcinoma. Recent reports have shown that CEACAM1 is overexpressed at protein level in colorectal cancer and correlated with clinical stage. The reason why colorectal cancer cells re‐expressed CEACAM1 remains unclear. The aim of our study was to clarify the implication of CEACAM1 re‐expression in colorectal cancer. Immunohistochemical analyses were conducted with CEACAM1 long (CEACAM1‐L) or short (CEACAM1‐S) cytoplasmic domain‐specific antibodies on clinical samples from 164 patients with colorectal cancer. The risk factors for metastasis and survival were calculated for clinical implication of CEACAM1 re‐expression. Invasion chamber and wound healing assays were performed for the effect of CEACAM1 expression on invasion and migration of colorectal cancer cells. CEACAM1‐L and CEACAM1‐S stained with greater intensity at the invasion front than at the luminal surface of tumors. Differences between the long and short cytoplasmic isoform expression levels were observed at the invasion front. Multivariate analysis showed that CEACAM1‐L dominance was an independent risk factor for lymph node metastasis, hematogenous metastasis and short survival. The Kaplan–Meier evaluation demonstrated that CEACAM1‐L dominance was associated with shorter survival time (p < 0.0001). In the invasion chamber and wound healing assays, CEACAM1‐L promoted invasion and migration. Re‐expression of CEACAM1 is observed at the invasion front of colorectal cancer. CEACAM1‐L dominance is associated with metastasis and shorter survival of the patients with colorectal cancer. CEACAM1‐L dominance is important for colorectal cancer cells invasion and migration.

Randomized clinical trial of defaecatory function after anterior resection for rectal cancer with high versus low ligation of the inferior mesenteric artery

Defaecatory function is often poor after anterior resection. Denervation of the neorectum following high ligation of the inferior mesenteric artery (IMA) is a possible cause of impaired defaecatory function. The purpose of this randomized clinical trial was to clarify whether the level of ligation of the IMA in patients with rectal cancer affects defaecatory function.

Identification of the Molecular Mechanisms for Dedifferentiation at the Invasion Front of Colorectal Cancer by a Gene Expression Analysis

Purpose: The aim of this study is to identify gene expression signatures that accompany dedifferentiation at the cancer invasion front in colorectal cancer. Experimental Design: Two types of colorectal cancer were selected. Both types were well-differentiated adenocarcinomas at the superficial lesion. One type showed a dedifferentiated phenotype at the invasion front (type A, 13 samples); the other showed almost no dedifferentiated cancer cells at the invasion front (type B, 12 samples). Laser microdissection was combined with a cDNA microarray analysis to investigate the superficial lesions and the invasion front in colorectal cancers. Results: Eighty-three genes were differentially expressed between types A and B in the superficial lesions, and the samples of superficial lesions were divided correctly into two clusters by these genes. Interestingly, the samples of the invasion front were also divided into the two same clusters by these genes. The text mining method selected 10 genes involved in potential mechanisms causing dedifferentiation of cancer cells at the invasion front. The potential mechanisms include the networks of transforming growth factor-β, Wnt, and Hedgehog signals. The expression levels of 10 genes were calculated by quantitative reverse transcription-PCR and 8 genes were confirmed to be significantly differentially expressed between two types (P < 0.05). The gene expression profiles of 8 genes divided 12 test cases into two clusters with one misclassification. Conclusions: The molecular mechanisms constructed with 8 genes from three networks of transforming growth factor-β, Wnt, and Hedgehog signals were found to correlate with dedifferentiation at the invasion front of colorectal cancer.

Combination of p53 codon 72 polymorphism and inactive p53 mutation predicts chemosensitivity to 5-fluorouracil in colorectal cancer

There are increasing reports showing the clinical significance of the p53 polymorphism status in terms of the response to chemotherapy. We investigated whether p53 polymorphism and mutation were associated with in vitro sensitivity to 5‐fluorouracil (5‐FU) in patients with colorectal cancer. Chemosensitivity to 5‐FU was evaluated by the collagen gel droplet embedded culture drug sensitivity test. 5‐FU sensitivity of tumor cells without inactive p53 mutation in the arginine/arginine (Arg/Arg) variant was significantly higher than that of tumor cells with or without inactive p53 mutation in other variants (p = 0.022), whereas the 5‐FU sensitivity of tumor cells with inactive p53 mutation in the Arg/Arg variant was significantly lower than that of tumor cells with or without inactive p53 mutation in other variants (p = 0.002). In the Arg/Arg variant, apoptotic cells induced by 5‐FU treatment in patients without inactive p53 mutation were more markedly increased than those in patients with inactive p53 mutation (p = 0.037). Bax and Bcl‐2 protein expressions in tumor tissue treated with 5‐FU were associated with both 5‐FU sensitivity and the apoptotic cell count. Our data show that the Arg/Arg genotype without inactive p53 mutation could be predictive of a more favorable response and the Arg/Arg genotype with inactive p53 mutation a less favorable response to chemotherapy using 5‐FU in CRC. The combination of the p53 codon 72 polymorphism and p53 mutation status is a potential predictive marker of sensitivity to 5‐FU in CRC.

Predicting lymph node metastasis in early colorectal cancer using the CITED1 expression.

BACKGROUND The identification of molecular markers that are useful for predicting lymph node metastasis is urgently needed to determine treatment strategies for T1 colorectal cancer (CRC). We previously showed that 10 candidate genes are correlated with de-differentiation at the invasion front of CRC using a gene expression analysis. These 10 genes are potential markers that may predict lymph node metastasis by CRC. MATERIALS AND METHODS Samples were obtained from 161 patients with CRC. Quantitative real-time reverse transcription-polymerase chain reaction assays were performed using 66 T3 samples in order to extract genes correlated with lymph node metastasis. Immunohistochemical studies of the extracted genes were performed on 66 T3 and 95 T1 samples. A univariate analysis followed by a multivariate logistic regression model was used to examine independent risk factors for lymph node metastasis. RESULTS The CITED1 messenger RNA expression was found to be an independent risk factor for lymph node metastasis in T3 CRC patients (P = 0.040). A high CITED1 protein expression, as detected with immunohistochemistry, was also an independent risk factor in T3 CRC patients (P = 0.035). In T1 colorectal cancer patients, a high CITED1 protein expression was found to be an independent risk factor for lymph node metastasis (P = 0.010). The positive predictive and negative predictive values in the T1 colorectal cancer patients were 27.5% and 95.5%, respectively. CONCLUSIONS The CITED1 expression is correlated with lymph node metastasis in patients with CRC. In T1 colorectal cancer patients, CITED1 has the potential ability to predict the presence of lymph node metastasis.

Literature review of the energy sources for performing laparoscopic colorectal surgery.

Laparoscopic surgery for colorectal disease has become widespread as a minimally invasive treatment. This is important because the increasing availability of new devices allows us to perform procedures with a reduced length of surgery and decreased blood loss. We herein report the results of a literature review of energy sources for laparoscopic colorectal surgery, focused especially on 6 studies comparing ultrasonic coagulating shears (UCS) and other instruments. We also describe our laparoscopic dissection techniques using UCS for colorectal cancer. The short-term outcomes of surgeries using UCS and Ligasure for laparoscopic colorectal surgery were superior to conventional electrosurgery. Some authors have reported that the length of surgery or blood loss when Ligasure was used for laparoscopic colorectal surgery is less than when UCS was used. On the other hand, a recent study demonstrated that there were no significant differences between the short-term outcomes of UCS and Ligasure for laparoscopic colorectal surgery. It is therefore suggested that the choice of technique used should be made according to the surgeons preference. We also describe our laparoscopic dissection techniques using UCS (Harmonic ACE) for colorectal cancer with regard to the retroperitoneum dissection, dissection technique, dissection technique around the feeding artery, and various other dissection techniques. We therefore review the outcomes of using various energy sources for laparoscopic colorectal surgery and describe our laparoscopic dissection techniques with UCS (Harmonic ACE) for colorectal cancer.

Hollow spheroids beyond the invasive margin indicate the malignant potential of colorectal cancer

Objective Tumour budding formed by histologically undifferentiated cancer cells beyond the border of the tumour margin is associated with lymph node metastasis. However, hollow tumour nests, a possible histologically advanced phenotype of tumour budding, have not been discussed. We examined whether hollow spheroids exist beyond the border of the invasive margin and are associated with metastasis and prognosis. Moreover, we suggest that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) isoform balance is associated with hollow spheroid formation. Methods Immunohistochemical analyses with CEACAM1 and M30 as an apoptosis marker were performed to examine the importance of hollow spheroid CEACAM1 expression and central cell apoptosis in hollow spheroid formation. The correlations between the presence of hollow spheroids beyond the invasive margin and the clinicopathological characteristics of 314 patients with colorectal cancer were retrospectively evaluated. A 3D culture with colorectal cancer cells transfected with CEACAM1 cDNA or shRNA was used to determine whether CEACAM1 isoform balance controls colorectal hollow spheroid formation. Results Hollow spheroid formation accompanying central cell apoptosis was confirmed by M30 staining and serial section with CEACAM1 staining. Of the 314 patients, 96 (30.4%) were classified as having hollow spheroids. The presence of hollow spheroids is an independent risk factor for metastases and shorter survival. In 3D culture, CEACAM1 isoform balance modulated hollow spheroid formation of colorectal cancer cells. Conclusions Hollow spheroid formation beyond the border of the tumour margin in colorectal cancer is more important than tumour budding for the prediction of malignant potential.

Rectal transection by the Nelaton catheter pulling method during a laparoscopic low anterior resection.

BACKGROUND: A laparoscopic low anterior resection with double-stapling technique for lower rectal cancer is considered to be technically challenging because it is difficult to perform rectal transection and anastomosis in the narrow pelvic cavity. METHODS: We developed a new method for transecting the rectum with stapling a small number of cartridges. In laparoscopic low anterior resection, a 70-mm endovascular clip clamps the rectal wall at the anal side of the tumor. An endolinear stapler is applied at the rectal wall parallel and caudal to the 70-mm endovascular clip. A Nelaton catheter of 3.5 to 4.5 mm in outer diameter is inserted, and the loop of the Nelaton catheter is made behind the rectum. The Nelaton catheter loop is applied at the rectal wall parallel and caudal to the endolinear stapler and is pulled parallel the endolinear stapler toward the anterior side of the rectum. The endolinear stapler with opened jaws can be pushed deeper into the space, then the jaws can be closed in a position that can transect the rectum with one firing using only one cartridge. RESULTS: Curative low anterior resection with rectal transection using the Nelaton catheter pulling method was performed in 13 patients with rectal cancer. The median value and range of tumor distance from the anal verge were 6.0 and 4.5 to 10.0 cm. The median duration of the operation was 284 minutes, and median blood loss was 10 mL. The number of stapling cartridges used for rectal transection was 1 in all cases, and there were no major complications. CONCLUSIONS: We have demonstrated a safe, easy, and effective new transection method for rectal cancer resection using one firing with a Nelaton catheter.

Hemangiopericytoma in the sacrococcygeal space: a case report

IntroductionA hemangiopericytoma is a rare, soft-tissue tumor of vascular origin derived from a pericyte of Zimmerman, which is a modified smooth muscle cell that surrounds the small blood vessels. Hemangiopericytomas can occur wherever there are vascular capillaries. However, there are no previous reports of a hemangiopericytoma in the sacrococcygeal space.Case presentationWe describe the first reported case of a hemangiopericytoma found in the sacrococcygeal space. A 47-year-old Japanese woman presented with a palpable tumor on the left side of her anus. Preoperative imaging indicated that the tumor was in the sacrococcygeal space without invasion of other organs. A complete resection was performed via a parasacral incision. The histological and immunohistochemical staining patterns supported the diagnosis of a hemangiopericytoma.ConclusionA complete resection without piecemeal excision is the best way to treat a hemangiopericytoma. Recognizing the presence of a hemangiopericytoma in the sacrococcygeal space requires appropriate surgery.

Clinical Impact of Matrix Metalloproteinase-7 mRNA Expression in the Invasive Front and Inner Surface of Tumor Tissues in Patients with Colorectal Cancer

PurposeMatrix metalloproteinase-7, reversion-inducing cysteine-rich protein with Kazal motifs, chemokine receptor 7, and vascular endothelial growth factor-C have been correlated with tumor invasion and lymph node metastasis in patients with gastrointestinal cancer. Our study of patients with colorectal cancer quantified the messenger ribonucleic acid (RNA) expressions at the deepest site of tumor invasion (the invasive front) and the tumor’s inner surface. We investigated whether messenger RNA expressions can predict lymph node metastasis in colorectal cancer tumors and then evaluated the clinical implications of these results on the endoscopic treatment of early colorectal cancer.MethodsSixty patients with colorectal cancer participated in the study. Levels of matrix metalloproteinase-7, reversion-inducing cysteine-rich protein with Kazal motifs, chemokine receptor 7, and vascular endothelial growth factor-C messenger RNA in both the invasive front and inner surface of colorectal cancer tumors were measured by using real-time quantitative reverse transcriptase-polymerase chain reaction.ResultsThe matrix metalloproteinase-7 values in the invasive front and inner surface were significantly higher in tumors with lymph node metastasis than in tumors without lymph node metastasis. The matrix metalloproteinase-7 expression levels in the invasive front correlated with inner surface expression levels. Both a univariate and multiple logistic regression analysis showed the matrix metalloproteinase-7 expression levels in both the invasive front and inner surface of tumors to be significantly associated with lymph node metastasis.ConclusionsMatrix metalloproteinase-7 messenger RNA in both the invasive front and inner surface of the tumor is a predictive factor associated with lymph node metastasis for patients with colorectal cancer. The results of this study might indicate further clinical applications of an endoscopic excision for cancer with submucosal invasion.