Toshinaga Suto

MicroRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation

MicroRNA-7 (miR-7) has been reported to be a tumor suppressor in all malignancies including colorectal cancer (CRC). However, its significance for CRC clinical outcomes has not yet been explored. The potential for miR-7 to act as a tumor suppressor by coordinately regulating the epidermal growth factor receptor (EGFR) signaling pathway at several levels was examined. We investigated the tumor inhibitory effect of miR-7 in CRC, with particular focus on the relationship between miR-7 and the EGFR pathway. Quantitative reverse transcription-PCR was used to evaluate miR-7 expression in 105 CRC cases to determine the clinicopathologic significance of this miRNA. The regulation of EGFR by miR-7 was examined with miR-7 precursor-transfected cells. Furthermore, we investigated whether miR-7 suppresses proliferation of CRC cells in combination with cetuximab, a monoclonal antibody against EGFR. Multivariate analysis indicated that low miR-7 expression was an independent prognostic factor for poor survival (P = 0.0430). In vitro assays showed that EGFR and RAF-1 are direct targets of miR-7, which potently suppressed the proliferation of CRC cells, and, interestingly, that the growth inhibitory effect of each of these was enhanced by cetuximab. miR-7 is a meaningful prognostic marker. Furthermore, these data indicate that miR-7 precursor, alone or in combination with cetuximab, may be useful in therapy against CRC.

The efficacy of fondaparinux for the prophylaxis of venous thromboembolism after resection for colorectal cancer.

BACKGROUND/AIMS The advantages of combined pharmacological and physical methods for venous thromboembolism (VTE) prophylaxis after colorectal surgery have not been clearly determined. The aim of this study is to compare the efficacy and safety of fondaparinux combined with intermittent pneumatic compression (IPC) with IPC alone for VTE prophylaxis after resection for colorectal cancer. METHODOLOGY Between June 2008 and March 2010, 137 consecutive patients with colorectal cancer (CRC) who underwent colorectal resection in our surgical unit were enrolled in the study. Patients were divided into 2 groups. The IPC group was treated with IPC alone as controls. The fondaparinux group was treated with IPC and received subcutaneous injections of fondaparinux once daily. The aim of this study was to compare the efficacy and safety of fondaparinux combined with IPC with IPC alone for VTE prophylaxis. RESULTS The demographic variables and risk factors, operating time, blood loss and length of the postoperative hospital stay were similar in the two groups. No clinically evident VTE, critical bleeding, and postoperative death occurred during the study period. No adverse reactions due to fondaparinux were observed. CONCLUSIONS In patients undergoing resection of colorectal cancer, receiving fondaparinux and IPC thromboprophylaxis was highly effective, well tolerated and safe. The use of combined modalities for VTE prophylaxis is justified in patients at high risk of VTE.

The progression potential of peritoneal dissemination nodules from gastrointestinal tumors.

It is necessary to examine the characteristics of the dissemination nodules to establish a therapeutic strategy for peritoneal dissemination from digestive malignancy. Ki-67 expression as a proliferation marker in peritoneal dissemination nodules was investigated. The subjects were 15 patients with gastrointestinal cancers who underwent resection of the primary tumor and disseminated nodules. The expression of Ki-67 in both primary tumor and peritoneal dissemination nodule from each patient was evaluated by immunohistochemistry. Ki-67 labeling index in the original tumor was higher than that in the disseminated nodule in 13 of 15 patients (P < 0.0001). The mean value of Ki-67 labeling index was 42.2% in the 15 original tumors and 18.7% in the 15 disseminated nodules. Proliferative activity in the disseminated nodules was lower than that in the primary tumors. Further examination about characteristics of cancer dissemination is needed to treat patients with peritoneal metastasis.

KPNA2 over-expression is a potential marker of prognosis and therapeutic sensitivity in colorectal cancer patients.

Karyopherin α 2 (KPNA2) is a member of the Karyopherin α family and has recently been reported to play an important role in tumor progression. The aim of the current study was to elucidate the clinicopathological significance of KPNA2 over‐expression in colorectal cancer (CRC).

Control of primary lesions using resection or radiotherapy can improve the prognosis of metastatic colorectal cancer patients.

Control of the primary lesions in metastatic colorectal cancer (mCRC) is still controversial. For rectal cancer patients, not only resection but also irradiation is expected to provide palliative effects. We investigated the effects of resection and irradiation of primary lesions (local control) on the prognosis of mCRC patients.

Establishment of a novel method to evaluate peritoneal microdissemination and therapeutic effect using luciferase assay

Peritoneal dissemination is a major cause of recurrence in patients with malignant tumors in the peritoneal cavity. Effective anticancer agents and treatment protocols are necessary to improve outcomes in these patients. However, previous studies using mouse models of peritoneal dissemination have not detected any drug effect against peritoneal micrometastasis. Here we used the luciferase assay to evaluate peritoneal micrometastasis in living animals and established an accurate mouse model of early peritoneal microdissemination to evaluate tumorigenesis and drug efficacy. There was a positive correlation between luminescence intensity in in vivo luciferase assay and the extent of tumor dissemination evaluated by ex vivo luciferase assay and mesenteric weight. This model has advantages over previous models because optimal luciferin concentration without cell damage was validated and peritoneal microdissemination could be quantitatively evaluated. Therefore, it is a useful model to validate peritoneal micrometastasis formation and to evaluate drug efficacy without killing mice.

Prophylactic and Informational Abdominal Drainage Is Not Necessary After Colectomy and Suprapromontory Anastomosis

Several randomized prospective studies in western countries regarding the usefulness of prophylactic drainage have concluded that prophylactic abdominal drainage tubes are unnecessary. In Japan, however, longitudinal and vascular margins are rather different from in western countries. Furthermore, body mass index and volume of mesentery differed. Thus, although it is a retrospective study, it is worth investigating the usefulness of prophylactic drainage in the Japanese context. Two hundred sixty patients underwent colectomy and suprapromontory anastomosis. Prophylactic drainage tubes were inserted in 124 cases (47%) and not inserted in 136 cases (53%). In terms of postoperative complications, no statistically significant difference was found between the with-drainage and the without-drainage groups. The incidence of the abscess formation was not statistically different in the with-drainage group (4.0%) or the without-drainage group (0.7%). We concluded that the prophylactic and informational drainage tubes are not necessary even in Japanese cases of suprapromontory anastomosis, which typically have a wide resection and regional lymphadenectomy containing the roots of regional vessels.