Tomohide Mukogawa

The Membrane-Anchored Matrix Metalloproteinase (MMP) Regulator RECK in Combination with MMP-9 Serves as an Informative Prognostic Indicator for Colorectal Cancer

Purpose: RECK, a membrane-anchored regulator of matrix metalloproteinases (MMPs), is widely expressed in healthy tissue, whereas it is expressed at lower levels in many tumor-derived cell lines. Studies in mice and cultured cells have shown that restoration of RECK expression inhibits tumor invasion, metastasis, and angiogenesis. However, the clinical relevance of these findings remains to be fully documented. Here we examined the expression of RECK and one of its targets, MMP-9, in colorectal cancer tissue. Experimental Design: The RECK and MMP-9 expression levels in colorectal cancer samples from 53 patients were determined by immunohistochemical techniques. The expression level of each protein was scored, and the patients were divided into two groups based on these scores. In 33 cases, we performed gelatin zymography to estimate the degree of MMP-2 and MMP-9 activation. Microvessel density and vascular endothelial growth factor (VEGF) expression were also evaluated histologically. Results: RECK protein was detected in 30 of 53 (56.6%) specimens. Importantly, patients with tumors expressing relatively high levels of RECK (high-RECK group) had a significantly lower risk of recurrence than did patients with tumors expressing relatively low levels of RECK (low-RECK group; P = 0.011). Moreover, RECK-dominant (RECK score ≥ MMP-9 score) patients showed a significantly lower incidence of recurrence than did MMP-9-dominant patients (P = 0.0003). Multivariate analysis revealed that the RECK/MMP-9 balance was an independent prognostic factor (P = 0.0122). The expression of VEGF and microvessel density were inversely correlated with the level of RECK expression. Conclusions: RECK/MMP-9-balance is an informative prognostic indicator for colorectal cancer. Our data also suggest that RECK suppresses tumor angiogenesis, probably by limiting the availability of VEGF in tumor tissues.

Adenovirus-mediated gene transduction of truncated IκBα enhances radiosensitivity in human colon cancer cells

Nuclear factor kappa B (NF‐κB) is a transcription factor that is known to regulate apoptosis when cells are exposed to DNA‐damaging agents such as ionizing radiation and cytotoxic drugs. We sought to determine if inhibition of NF‐κB could enhance radiosensitivity in human colon cancer cells in vitro and in vivo. To inhibit NF‐κB activation specifically, we constructed a recombinant adenovirus vector expressing a truncated form of the inhibitor protein lκβα (lκBαΔN) that lacks the phosphorylation sites essential for activation of NF‐κB, and transfected two human colon cancer cell lines (HT29 and HCT15) with this vector. In vitro colony‐forming assays revealed that the overexpression of the stable IκBα by AxIκBαΔN infection significantly suppressed cell growth after irradiation in both cell lines as compared to infection with a control vector, AxLacZ. Treatment with AxIκBαΔN and irradiation successfully inhibited the growth of HT29 xenografted subcutaneous tumors in nude mice with an 83.8% volume reduction on day 38 as compared to the untreated tumors. Furthermore, it was demonstrated that apoptosis was increased by adenovirus‐mediated gene transduction of IκBaLΔN in vitro and in vivo. These results indicated that inhibition of NF‐κB could enhance radiosensitivity through an increase in radiation‐induced apoptosis. We believe that radio‐gene therapy using adenovirusmediated gene transduction of IκBαΔN could be an attractive candidate as a treatment strategy for colorectal cancer.

Long-term results of high-dose extracorporeal and endocavitary radiation therapy followed by abdominoperineal resection for distal rectal cancer.

PurposeTo examine the complications, local effects, survival, and prognostic factors of preoperative high-dose radiation therapy in patients with advanced carcinomas of the distal rectum.MethodsForty-one patients with tethered or fixed rectal cancer located a median distance of 3.0 cm from the anal verge were treated with extracorporeal and endocavitary radiation therapy (70 Gy), followed 2 weeks later by abdominoperineal resection (APR).ResultsThis combined radiotherapy achieved acceptable results. Postoperative complications developed in 18 patients (43.9%), 10 (24.3%) of which involved perineal dehiscence. Two patients (4.8%) suffered more than grade 3 toxicity. Destructive changes were histologically confirmed in all specimens, and there were four (9.8%) sterile specimens. Recurrence developed in 11 patients and there were 6 cancer-related deaths. Among six cases of local recurrence, three were found just outside of the radiation field. The 5-year survival and disease-free survival rates were 82.9% and 71.8%, respectively. Multivariate analysis revealed that nodal involvement was the sole independent prognostic factor for survival. Sexual function was maintained in the most recent patients who underwent APR with autonomic nerve-preserving surgery.ConclusionAlthough the original aim of our treatment focused on curability, this combination therapy may be an option for selected patients, because of potential prevention of local recurrence, relatively low morbidity, and promising autonomic nerve function.

Retrocaval liver lifting maneuver and modifications of total hepatic vascular exclusion for liver tumor resection

AIM To evaluate the efficacy of technical modifications of total hepatic vascular exclusion (THVE) for hepatectomy involving inferior vena cava (IVC). METHODS Of 301 patients who underwent hepatectomy during the immediate previous 5-year period, 8 (2.7%) required THVE or modified methods of IVC cross-clamping for resection of liver tumors with massive involvement of the IVC. Seven of the patients had diagnosis of colorectal liver metastases and 1 had diagnosis of hepatocellular carcinoma. All tumors involved the IVC, and THVE was unavoidable for combined resection of the IVC in all 8 of the patients. Technical modifications of THVE were applied to minimize the extent and duration of vascular occlusion, thereby reducing the risk of damage. RESULTS Broad dissection of the space behind the IVC coupled with lifting up of the liver from the retrocaval space was effective for controlling bleeding around the IVC before and during THVE. The procedures facilitate modification of the positioning of the cranial IVC cross-clamp. Switching the cranial IVC cross-clamp from supra- to retrohepatic IVC or to the confluence of hepatic vein decreased duration of the THVE while restoring hepatic blood flow or systemic circulation via the IVC. Oblique cranial IVC cross-clamping avoided ischemia of the remnant hemi-liver. With these technical modifications, the mean duration of THVE was 13.4 ± 8.4 min, which was extremely shorter than that previously reported in the literature. Recovery of liver function was smooth and uneventful for all 8 patients. There was no case of mortality, re-operation, or severe complication (i.e., Clavien-Dindo grade of III or more). CONCLUSION The retrocaval liver lifting maneuver and modifications of cranial cross-clamping were useful for minimizing duration of THVE.