[Preliminary study of Peptide vaccine with UFT/LV as adjuvant setting for stage III colorectal cancer].

cDNA microarray technology has been used to identify HLA-A24-restricted epitope peptides as potential targets for cancer vaccination in metastatic colorectal cancer patients. We conducted a clinical trial of two novel cancer-specific peptides( RNF43, TOMM34) with UFT/LV for the treatment of recurrent colorectal cancer. Among 23 patients, 21 patients had completed the protocol. All patients were well tolerated with no severe toxicities. The median survival time was 24.4 months. Furthermore, we investigated the relationship between CTL response to both antigens and overall survival. The best long-term survival was observed in the group with CTL responses against both antigens, followed by the group showing CTL responses against only RNF43 or TOMM34. The patients with no response had the lowest survival. Based on the results, we started a randomized trial of the current protocol, as adjuvant immunochemotherapy in following curative resection of Stage III colorectal cancer patients.

Osteopontin induced by macrophages contribute to metachronous liver metastases in colorectal cancer.

Even after radical surgery for stage II and stage III colorectal cancer, metachronous liver metastasis is frequently observed. The aim of this study was to identify the risk of metachronous liver metastasis with retrospective clinicopathological study. Immunohistochemistry was performed to evaluate the expression of Osteopontin (OPN), CD-68, and CD105 in 41 cases of stage II and stage III colorectal cancer tissue. Stage II and stage III colorectal cancer patients who had undergone R0 resection were classified into two groups: with metachronous liver metastasis (m-LM; n = 17) and without liver metastases (control; n = 24). Additionally, double-immunofluorescence staining was performed using antibodies to OPN and CD68. OPN-positive cells were frequently colocalized with CD68 immunoreactivity. OPN and microvascular density expression in the central area were significantly higher in the m-LM (OPN; control 4.3 ± 0.56, m-LV 10.8 ± 1.48, P < 0.05; microvascular density control 18.5 ± 2.86, m-LV 31.4 ± 4.39, P < 0.05), while CD68 expression in the invasive margin was significantly higher in the control group (control 98.9 ± 7.31, m-LV 28.2 ± 3.18, P < 0.05). These results suggest that the risk of metachronous liver metastasis could be well predicted by immunohistochemical staining of OPN in the central areas, and CD68 in the invasive margins of tumors.

Phase I clinical trial of a novel peptide vaccine in combination with UFT/LV for metastatic colorectal cancer.

To test the safety and immune responses of a novel peptide vaccine derived from RNF43 (ring finger protein 43) and TOMM34 (34-kDa translocase of the outer mitochondrial membrane) administered in combination with chemotherapy in patients with metastatic colorectal cancer, a phase I clinical trial with 21 HLA-A2402-positive metastatic colorectal cancer patients was conducted. Patients received a weekly peptide vaccine (1 mg of each peptide in incomplete Freund's adjuvant) in combination with oral UFT (300 mg/m(2)/day) and UZEL (75 mg/day) for 4 weeks, followed by 1 week of rest. The protocol consisted of at least two cycles of this regimen. After the 2nd cycle, vaccinations were given biweekly or monthly, depending on the condition of the patient. Clinical responses were judged 10 weeks after the 2nd cycle by performing computed tomography (CT) scans and assessing the cytotoxic T lymphocyte (CTL) responses against RNF43 and TOMM34 in peripheral lymphocytes. The vaccinations were well tolerated without any serious adverse events. CTL responses were induced against both antigens in 8 patients and against one antigen in 12 patients, while 1 patient had no CTL response. The rate of stable disease was 83%. The group with CTL responses against both antigens had the most long-term survivors, followed by the group showing CTL responses against one antigen (p=0.0079). The patients with no CTL responses had the lowest survival. The safety and immunological responsiveness of the present combination therapy suggests that it is clinically beneficial for metastatic colorectal cancer. Further clinical trials are warranted.

Increased osteopontin-positive macrophage expression in colorectal cancer stroma with synchronous liver metastasis.

BACKGROUND: The macrophages that infiltrate the tumor stroma are termed tumor-associated macrophages (TAMs). TAMs contribute to hematogenous spread of cancer cells especially liver metastasis. Osteopontin (OPN) is also related to tumor metastasis and proliferation of tumors. OPN is mainly expressed in macrophages of stroma other than that of tumor cells. The aim of the present study was to investigate differences in OPN-positive TAMs between cases of colorectal cancer with synchronous liver metastasis and those without liver metastasis. METHODS: A total of 54 subjects who had undergone resection of a primary tumor of advanced colorectal cancer were classified into two groups: synchronous colorectal liver metastasis group (s-CLM group; n = 30) and no liver metastasis group (controls; n = 24). The number of OPN- and CD68-positive cells and the microvascular density (MVD) were determined using the CD105 antibody in the stroma of the invasive margin of the tumor and in the stroma of the central area. RESULTS: There was no difference in the patient profiles between the two groups. OPN and MVD expression in the central area were significantly higher in the s-CLM group (OPN: control 4.3 +/- 1.42, s-CML 12.1 +/- 1.42, P < 0.05; MVD: control 18.5 +/- 2.86, s-CML 27.5 +/- 2.94, P < 0.05), whereas CD68 expression in the invasive margin was significantly higher in the control group (control 98.9 +/- 7.31, s-CML 29.0 +/- 4.44, P < 0.05). CONCLUSIONS: These data suggest that OPN in the central area may have induced high microvascular density, which led to liver metastasis. Thus, OPN might be a potential target for novel antiangiogenesis therapy for treating colorectal cancer.

Immunohistochemical expression of osteopontin in gastric cancer.

BACKGROUND/AIMS: Osteopontin (OPN) is significantly overexpressed in a variety of malignancies. However, little is known concerning the significance of OPN expression in human cancers. Thus, the aim of this study was to determine the relationship between the degree of OPN expression, the proliferative activity of cancer cells, and the clinicopathological findings for surgically resected gastric cancer. METHODOLOGY: We evaluated the immunohistochemical expression of OPN in 85 specimens of cancer. Additionally, we investigated a cancer cell proliferative index using an anti-MIB-1 antibody and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling staining. Levels of OPN expression in gastric cancers were classified into three groups. To compare the relationship between OPN expression and clinicopathological findings, the features of cancer lesions were classified using the TNM Classification of Malignant Tumors, 6th Edition. RESULTS: Immunohistochemical examination of OPN expression in gastric cancer revealed diffuse granular staining in the cytoplasm. High OPN expression was observed in 37 of 85 carcinomas. Strong OPN expression was significantly associated with a low apoptotic index, a high proliferative index, depth of invasion, lymphatic invasion, and venous invasion. Pathologically, intestinal type carcinoma showed strong expression of OPN. CONCLUSIONS: These data suggested that OPN may play an important role in the invasiveness and the progressive nature of gastric cancer.

Depth of mesorectal invasion has prognostic significance in T3N0 low rectal cancer.

BACKGROUND/AIMS: To investigate mesorectal fat invasion as a prognostic factor for T3N0 low rectal adenocarcinoma following sharp mesorectal excision. METHODOLOGY: Subjects consisted of 26 patients who had a potential curative excision of a T3N0 low rectal adenocarcinoma without neoadjuvant therapy between August 1988 and April 2003. Histological preparations were used to measure depth of mesorectal invasion, which was analyzed for associations with disease-free survival and recurrence. RESULTS: Five-year overall survival and disease-free survival were 64.8% and 57.1%, respectively. Ten patients developed recurrent disease; 3 had local recurrence, 3 had distant metastasis, and 4 had both local and distant recurrence. Rectal cancers were stratified by depth of mesorectal invasion using 4 cutoff values (2, 3, 4, 5 mm), and examined by Cox proportional hazard model. At a cutoff of 3 mm, multivariate analyses confirmed depth of mesorectal invasion to be an independent prognostic factor for 5-year disease-free survival (< 3mm, 90.9%; > or = 3mm, 32.0%; p = 0.023). Distant metastasis differed significantly (< 3mm, 0%; > or = 3mm, 46.7%; p = 0.01), but local recurrence did not (< 3 mm, 9.1%; > or = 3mm, 40%; p = 0.17). CONCLUSIONS: Patients with advanced low T3N0 rectal cancer are at high risk of distant metastases. Depth of mesorectal invasion may be valuable in decisions regarding intensive adjuvant therapy.