Development of an Algorithm to Predict Recurrences After Resection of Liver Metastases in Patients With Metastatic Colorectal Cancer.

BACKGROUND/AIM: Hepatic recurrences after resection of metastatic lesions in advanced colorectal cancer (CRC) have an enormous impact on patient prognosis. Response evaluation criteria in solid tumor (RECIST) or morphologic response on computed tomography (CT) have been reported as surrogate prognostication markers. This study assessed a novel algorithm for the prognostication of liver metastasis treatment. PATIENTS AND METHODS: Forty-seven patients with liver metastases from CRC who underwent liver resection after systemic chemotherapy were included. The CT values examined before and after chemotherapy were collected. The velocity of CT values (CTvΔ) was calculated, and the subjects were divided into CTvΔ_high and _low groups. Clinicopathological variables, recurrence-free survival (RFS), and overall survival (OS) were statistically compared between the two groups. In addition, the effect of the combined evaluation of CTvΔ and carcinoembryonic antigen (CEA) was evaluated. RESULTS: In univariate analyses, the hazard ratio (HR) for a recurrence after liver resection was relatively higher in the RECIST_stable disease (SD) or _progressive disease (PD) and the CTvΔ_low groups. In multivariate analysis, the HR was significantly higher in the CEA_high, the RECIST_SD or PD, and the CTvΔ_low groups. The RFS was significantly longer in the CTvΔ_high group. Furthermore, the combination of CTvΔ and CEA predicted the RFS and OS. CONCLUSION: Our algorithm using CTvΔ could be a useful tool to select patients suitable for liver resection of hepatic CRC metastases.

Correction to: S-1 and irinotecan plus bevacizumab as second-line chemotherapy for patients with oxaliplatin-refractory metastatic colorectal cancer: a multicenter phase II study in Japan (KSCC1102).

In the original publication, in Abstract, the sentence that reads as, "Oral S-1 at a dose of 80 mg/m2 was…………. drug-free interval" should read as, "Oral S-1 at a dose of 40 mg/m2 was administered twice daily for 2 weeks, followed by a 1-week drug-free interval.

S-1 and irinotecan plus bevacizumab as second-line chemotherapy for patients with oxaliplatin-refractory metastatic colorectal cancer: a multicenter phase II study in Japan (KSCC1102).

BACKGROUND: Combination chemotherapy with S-1 and irinotecan is one of the standard treatments for metastatic colorectal cancer (mCRC) in Japan. However, there are few alternative practical second-line therapies. We conducted a phase II trial to evaluate the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab as a second-line treatment for oxaliplatin-refractory mCRC. METHODS: Patients with mCRC who were previously treated with oxaliplatin-containing regimens were enrolled. Oral S-1 at a dose of 40 mg/m(2) was administered twice daily for 2 weeks, followed by a 1-week drug-free interval. Irinotecan at a dose of 150 mg/m(2) and bevacizumab at a dose of 7.5 mg/kg were administered on day 1. The primary endpoint was progression-free survival (PFS). RESULTS: Thirty-seven patients were enrolled, and 34 and 36 patients were assessed for response and safety, respectively. The overall response rate was 20.6 % (95 % confidence interval [CI] 8.7-37.9), and the disease control rate was 76.5 % (95 % CI 58.8-89.3). The median PFS was 5.6 months (95 % CI 3.8-7.0). The median overall survival was 16.4 months (95 % CI 8.1-20.0). The most common grade 3/4 adverse events included neutropenia (25.0 %), anorexia (22.2 %), anemia (16.7 %), and fatigue/malaise (16.7 %). The most common grade 3/4 adverse event of special interest for bevacizumab was hypertension (30.6 %). One treatment-related death caused by gastrointestinal bleeding occurred. CONCLUSIONS: The findings suggest that the combination of S-1 and irinotecan plus bevacizumab is effective and tolerable as second-line chemotherapy for patients with oxaliplatin-refractory mCRC.

Estimation of the number of metastatic lymph nodes in dukes' C colorectal cancer.

BACKGROUND: Colorectal cancer staging is decided by the depth of tumor invasion and the node (N) category. Evaluation of the metastatic lymph node number (MLN) varies. The purpose of this study was to investigate the N-category as a function of MLN. PATIENTS AND METHODS: Patients with colorectal cancer (n=551) who underwent curative resection were grouped based on the MLN, and appropriate cut-off values were decided based on survival. The validity of the new cut-off values was analyzed as a prognostic factor. RESULTS: The median number of lymph nodes retrieved per patient was 19, and the median MLN was 2. The survival and recurrence rates allowed MLN groupings of 1-4, 5-7, and ≥8. In particular, when grouping was performed using MLN ≤4 and ≥5, the 5-year survival rate for patients with MLN ≥5 (56.8%) was significantly worse than that of these with MLN ≤4 (78.6%) (p<0.0001). Receiver operating characteristic (ROC) curve analysis showed the highest accuracy to be with MLN=5. Multivariate analysis using a Cox proportional hazard model identified MLN ≥5 as an independent adverse prognostic factor (hazard ratio=1.84; 95% confidence interval=1.2801-2.6295; p=0.0012). CONCLUSION: MLN ≥5 is an independent predictor of 5-year survival for patients with Dukes' C colorectal cancer. It is possible that tumor staging in colorectal cancer differs between facilities, with particular ramifications for patients with stage III disease.

Circulating endothelial progenitor cells in metronomic chemotherapy using irinotecan and/or bevacizumab for colon carcinoma: Study of their clinical significance.

The aim of the present study was to clarify the antitumor efficacy of metronomic chemotherapy using irinotecan (CPT-11) combined with or without bevacizumab against colon cancer, and the significance of circulating endothelial cell (CECs) and endothelial progenitor cells (CEPs) as a surrogate marker for metronomic chemotherapy. KM12SM cells were implanted into the subcutis of nude mouse. After confirming that the implanted tumors had grown 5 mm in size, group A received an intraperitoneal injection of 40 mg/kg CPT-11 every two weeks for 4 weeks [conventional maximum-tolerated dose (MTD)], group B received 10 mg/kg twice weekly (metronomic), group C received 10 mg/kg twice weekly combined with 5 mg/kg bevacizumab twice weekly (metronomic + anti-angiogenic), and the control group received 0.2 ml of PBS every week. Serial changes of CECs and CEPs in peripheral blood and microvessel density (MVD) in the tumor tissues were evaluated. The results showed that the antitumor activity in group B and in group C was significantly higher than that in group A. A significant inhibition in CEPs on day 15 in the metronomic therapy groups B and C was noted when compared to that in the control group, while there was no significant difference in CECs and CEPs between the groups on days 4 and 8. The MVD on day 15 in metronomic groups was significantly lower than that in group A. In conclusion, metronomic chemotherapy of CPT-11 with or without bevacizumab for colon cancer was more effective than the MTD therapy via anti-angiogenic effects. Sequential measurement of CEPs may be a predictive factor for the efficacy and a decisive factor for the optimal dose of metronomic therapy in colon cancer.

[Therapeutic results of hepatic resection using thermal ablation for unresectable colorectal liver metastases].

We have retrospectively reviewed the therapeutic results of hepatic resection with or without thermal ablation therapy (TA) for colorectal liver metastases in 138 patients between 1994 and 2006. A total of 88 unresectable liver metastatic lesions were selectively treated with TA as initial treatment (42 patients) basically in combination with hepatectomy. Overall, TA achieved a high local tumor control rate of 94.3%. Multivariate analysis revealed that initial TA therapy was not a significantly predictive factor of hepatic recurrence or any recurrence. TA therapies in combination with hepatectomy may offer improving resectability without risk to intrahepatic dissemination or to extrahepatic recurrence.

Elevated preoperative serum carcinoembrionic antigen level may be an effective indicator for needing adjuvant chemotherapy after potentially curative resection of stage II colon cancer.

BACKGROUND: To determine the prognostic factors and to rationalize adjuvant therapy, the clinicopathologic data of patients with a stage II colon cancer were analyzed retrospectively. PATIENTS AND METHODS: A total of 392 patients underwent potentially curative resection at the Kurume University Hospital between 1982 and 2005. Postoperative adjuvant chemotherapy using oral fluoropyrimidines was administered in 163 patients, and the other 229 patients underwent surgery alone. Univariate and multivariate analyses for prognostic factors were carried out. RESULTS: Invasive type in gross features, elevated preoperative CEA level, and surgery alone were each an independently significant factor for shorter relapse-free survival, and tumor size <50 mm, invasive type in gross features, elevated preoperative CEA level, and surgery alone were each an independently significant factor for shorter overall survival. The relapse-free survival rate and overall survival rate in the patients who received postoperative adjuvant chemotherapy were significantly higher than those in the patients treated with surgery alone even after stratifying to the preoperative CEA level. CONCLUSION: Patients with an elevated preoperative CEA may be candidates for adjuvant chemotherapy after curative resection in stage II colon cancer. These findings warrant clinical trials to test out the efficacy of adjuvant chemotherapy in stage II colon cancer with an elevated preoperative CEA.

Efficacy of the combined use of bevacizumab and irinotecan as a postoperative adjuvant chemotherapy in colon carcinoma.

We evaluated the efficacy of anti-human VEGF antibody (bevacizumab) with or without irinotecan (CPT-11) against lung metastases in which neovascularization was already induced, as a postoperative adjuvant therapy using orthotopically implanted colon cancer in rat. The high VEGF productive KM12SM human colon cancer cells were injected into the cecal wall. At 5 weeks after the injection, the cecum was removed including the tumor. Then, 5 mg/kg of bevacizumab and 40 mg/kg of CPT-11 were administered, alone or in combination, intravenously once a week for 3 weeks, from day 15 after the cecal removal. The results show that the incidences of macroscopic and/or microscopic lung metastases in the bevacizumab-alone group (B) and in the combination group (C) were significantly lower (B, p=0.001 and C, p=0.037) than that in the control group at day 35 after the cecal removal. The number of lung metastases in B was 0.8+/-0.8 (p=0.024) and in C 2.4+/-1.8 (p=0.060), each value lower than the 12.4+/-4.2 of the control group. The growth of a subcutaneously implanted tumor was significantly inhibited in the combination group compared to either the CPT-alone (p=0.003) or the bevacizumab-alone groups (p=0.027). Apoptosis was significantly (p<0.001) induced in the combination group. In conclusion, a beneficial effect of bevacizumab against postoperative lung metastases may be expected even after the establishment of neovascularization in metastatic foci in nude rat. The results from the present subcutaneously implanted tumor model suggested that a higher efficacy may be expected when bevacizumab is combined with the cytotoxic agent CPT-11, compared to bevacizumab alone, against tumors with a variety of VEGF production levels in clinical situations.

Significance of thymidine phosphorylase in metronomic chemotherapy using CPT-11 and doxifluridine for advanced colorectal carcinoma.

BACKGROUND: A phase II study was designed to evaluate the efficacy, safety and predictors for response of metronomic chemotherapy using weekly low-dosage CPT-11 and doxifluridine (5'-DFUR) in 45 patients with metastatic colorectal cancer. PATIENTS AND METHODS: Forty mg/m2 of CPT-11 was administered for 3 consecutive weeks in a 4-week treatment cycle, with 5'-DFUR (800 mg/day) given orally. RESULTS: One or more adverse effects were seen in 42 patients. However, most of these were mild at grade 1 or 2, including only leucopenia in 2, neutropenia in 1, diarrhea in 1 and nausea in 1 as grade 3. The objective response rate was 36% with a median overall survival of 452 days. The response rate in patients with a high expression of thymidine phosphorylase (dThdPase) in tumor cells (47%) was higher (p=0.092) than that (19%) in patients with a low expression. CONCLUSION: The efficacy of metronomic chemotherapy using low-dosage weekly CPT-1 and 5'-DFUR is worthy of further clinical study, especially in patients with a high expression of dThdPase in primary tumor cells.

The expression of vascular endothelial growth factor determines the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer.

The aim of this study was to determine any correlation between the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines and the vascular endothelial growth factor (VEGF) expression in primary colorectal cancer tissues. The data were reviewed retrospectively on 342 patients with colorectal cancer at stage II or III, who underwent potentially curative resection between 1988 and 1998. Of these, 225 received post-operative administration of oral fluoropyrimidines such as UFT and 5'-DFUR, while the other 117 patients underwent surgery alone. Immunostaining for VEGF was performed using colorectal tumours. Overall, VEGF was positively expressed in primary tumour cells in 48% of patients. The disease-free survival rate and the overall survival rate in the chemotherapy group were higher than those in the surgery-alone group, although not significantly. However, the disease-free survival rate and the overall survival rate were similar between the two groups in patients with a tumour positive for VEGF. Multivariate analysis revealed that the VEGF expression was an independent factor for post-operative recurrence, and the VEGF expression and post-operative adjuvant chemotherapy were an independent factor for overall survival, in addition to the lymph node metastasis and the venous invasion. In conclusion, the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines may not be as great for patients with a tumour positive for VEGF having a greater risk of post-operative recurrence. The results support further investigation on efficacy of molecular targeting therapy for VEGF in combination with oral fluoropyrimidines as post-operative adjuvant therapy in colorectal cancer positive for VEGF.

A role of anti-verotoxin antibody immunoreactive peptide, Virp5, from rat spinal cord.

An anti-verotoxin 2 (VT2) antibody immunoreactive 5-kDa polypeptide (Virp5), has been obtained through screening of the rat spinal cord cDNA library with the aid of anti-VT2 antibody. Virp5 was mainly expressed in the central nervous system, liver and kidney, and localized at glia-like cells and nerve fibers in the central nervous system, vascular endothelial cells and hepatic cells in the liver, as well as epithelial cells of distal tubules in the kidney. Intravenous administration of purified Virp5 elicited a dose-dependent increase in blood pressure. These results suggest that Virp5 commonly exists in the body, being partly playing a role in regulating the blood pressure.

Differences in the effects of Na+-H+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts.

The protective effects of the Na+-H+ exchange (NHE) inhibitors SM-198110 (2-[[(aminoiminomethyl) amino] carbonyl]-4-chloro-1H-indole-1-propanesulfonic acid monohydrate) and SM-197378 (N-(aminoiminomethyl)-1-methyl-7-(sulfooxy)-4-(trifluoromethyl)-1H-indole-2-carboxamide monohydrate) were investigated in perfused Langendorff guinea-pig hearts subjected to ischemia (40 min) and reperfusion (40 min). The recovery of left ventricular developed pressure (LVDP) from ischemia by reperfusion was 39.0% in the control, while in the hearts pretreated with SM-198110 or SM-197378 (10(-7) M), it was about 100%. The ATP level, monitored simultaneously by (31)P-nuclear magnetic resonance spectrometry, was already higher than the control value at the end of the ischemic period, and the elevation in Na+ or Ca2+ fluorometric signals induced during ischemia was suppressed. In post-treated hearts, the LVDP recovery rate was significantly higher with SM-198110 than with SM-197378. By in vitro electron paramagnetic resonance spectrometry, SM-197378 was found to directly quench the active oxygen radical, whereas SM-198110 had no effect. Numbers of apoptotic cardiomyocytes after ischemia (1 h) followed by reperfusion (5 h) were significantly lower in SM-197378-treated than in SM-198110-treated hearts, consistent with the level of activity of caspase-3. These results suggest that the antioxidant effects of NHE inhibitors have an important role in apoptosis during ischemia-reperfusion, but apoptosis is not a major manifestation of cardiac function during postischemic recovery, and that NHE-sensitive mechanisms of reperfusion injury promote both necrotic and apoptotic processes death.