Correlation of pre-operative nutritional condition with post-operative complications in surgical treatment for oesophageal carcinoma.

AIMS: The relationship between the pre-operative nutritional condition and the outcome of the surgical treatment in patients with oesophageal carcinoma has been discussed diversely. The aim of the current study was to demonstrate the relationship between pre-operative nutritional condition and post-operative complications and prognosis following surgical treatment for oesophageal carcinoma. METHODS: Two hundred and fifty-eight patients with oesophageal carcinoma treated with oesophageal resection and reconstruction were selected. The correlation of pre-operative values of prognostic nutritional index (PNI) with the incidence of post-operative complications and prognosis of the patients was investigated. RESULTS: The mean pre-operative value of PNI in patients with post-operative complications (41.8+/-5.4) was significantly lower than that in patients without post-operative complications (46.5+/-5.3; P<0.0001). The survival in patients with higher PNI value was significantly more favourable than that in patients with lower PNI value (P=0.0001). CONCLUSIONS: Pre-operative assessment of the nutritional condition could provide predictive information for post-operative complications in patients with oesophageal carcinoma.

Significance of allogenic blood transfusion on decreased survival in patients with esophageal carcinoma.

BACKGROUND: To the authors' knowledge, the significance of allogenic blood transfusion in the prognosis of patients with esophageal carcinoma remains controversial. The objective of the current study was to elucidate the correlation, if any, between intraoperative allogenic blood transfusion and prognosis in patients with esophageal carcinoma. METHODS: Two hundred fifty-nine patients with esophageal carcinoma who had undergone esophagectomy and reconstruction were studied. The clinicopathologic data and survival were compared between the 87 patients (33.6%) who received an intraoperative allogenic blood transfusion and the 172 patients (66.4%) who did not. RESULTS: Multivariate analysis demonstrated that the factors that appeared to independently determine prognosis in patients with esophageal carcinoma were the depth of the tumor (P = 0.0001), lymph node metastasis (P < 0.0001), lymphatic invasion (P = 0.0002), venous invasion (P = 0.0008), and the occurrence of postoperative complications (P = 0.034). Intraoperative allogenic blood transfusion was not found to be an independent prognostic indicator. CONCLUSIONS: In the current study, an advanced stage of disease at the time of surgery, which resulted in the need for blood transfusion and the occurrence of postoperative complications, appeared to worsen the prognosis in patients with esophageal carcinoma.

Defective mitogen-activated protein kinase (ERK2) signaling in gastric mucosa of portal hypertensive rats: potential therapeutic implications.

Portal hypertensive (PHT) gastropathy is a frequent, serious complication of liver cirrhosis. PHT gastric mucosa has numerous abnormalities such as reduced mucosal potential differences, reduced surface oxygenation, and increased susceptibility to injury caused by alcohol, aspirin, and other noxious factors. Because such mucosal injury is initially mediated by oxygen free radicals, and because mitogen-activated protein (MAP) kinase (ERK2) protects against cellular stress and induces cell proliferation, we postulated that oxidative stress-induced ERK2 activation is defective in PHT gastric mucosa. Here we show that in PHT gastric mucosa, ERK2 activation by oxidative stress is impaired. This impairment is mediated by overexpression of MAP kinase phosphatase-1 (MKP-1), which results from the underlying and continual oxidative state associated with portal hypertension, and is ameliorated by inhibiting MKP-1. Furthermore, we found that supplementing vitamin E, a free radical scavenger, reduces the oxidative state in PHT gastric mucosa, normalizes MKP-1 expression, and thereby reverses impairment of oxidative stress-induced ERK2 activation. Finally, we show that orally administered vitamin E completely reverses the increased susceptibility of PHT gastric mucosa to alcohol injury. Our findings point to a new molecular and mechanistic basis for PHT gastropathy and provide a new therapeutic modality for protection of PHT gastric mucosa.

Apoptosis and p53 overexpression in human rectal cancer; relationship with response to hyperthermo-chemo-radiotherapy.

Hyperthermo-chemo-radio (HCR) therapy has been found to be effective for rectal cancer. Biomarkers for predicting the effect of HCR therapy are important in determining optimum treatment regimens. Hyperthermo-chemo-radiotherapy (HCR therapy), consisting of hyperthermia at 42 degrees C to 45 degrees C for 40 minutes (twice per week for two weeks), a total of 60 Gy irradiation and administration of 1-hexylcarbamoyl-5-fluorouracil (HCFU) (total 8400 mg), were prescribed pre-operatively for 29 patients with rectal cancer, using tissue specimens collected at pre-treatment biopsy. Apoptosis and overexpression of p53 protein were investigated histopathologically and immunohistochemically. On termination of HCR therapy, all the tumors were surgically resected and effectiveness of the therapy was evaluated histologically. Spontaneous apoptosis was evident in the pre-treatment cancer tissues of 14 patients (48.2%). In this apoptosis-positive group, the positive rate of expression of the p53 protein (21.4%, 3 out of 14) was lower as compared to findings in the apoptosis-negative group (66.7%, 10 out of 15). The response to HCR therapy was better in the apoptosis-positive group than in the apoptosis-negative group. We propose that spontaneous apoptosis is closely related to the function of wild-type p53 protein and is also a predictive biomarker of the effect of HCR therapy for patients with rectal cancer.

Retrospective study on the effects of lipiodolization before a potentially curative hepatectomy for colorectal liver metastases: long-term results of a pilot study.

BACKGROUND/AIMS: Lipiodolization, a selective regional cancer chemotherapeutic modality using lipiodol plus anticancer drugs, can prolong the survival time of patients with unresectable liver cancer. A preliminary study was conducted with adjuvant lipiodolization before a potentially curative hepatectomy for patients with metachronous colorectal liver metastases. The ultimate aim of this study was to improve the long-term survival after hepatectomy. METHODOLOGY: Twenty-one consecutive patients with colorectal hepatic metastases were included in this study. Seven patients underwent preoperative lipiodolization, while the remaining 14 patients did not receive any preoperative adjuvant therapy. The clinicopathological features and prognoses of these patients were investigated. The median follow-up period after a curative hepatectomy was 56 months. RESULTS: The clinicopathological factors did not differ markedly between the 2 groups. However, the cumulative survival rate of the 7 patients receiving preoperative lipiodolization was significantly (P < 0.05) better than that in those not receiving any preoperative treatment. CONCLUSIONS: Based on the above encouraging findings, we therefore propose that a prospective randomized trial should be carried out to confirm the beneficial effects of our adjuvant chemotherapeutic modality on patient survival following a curative hepatectomy for the patients with colorectal liver metastases.

Preclinical and therapeutic utility of HVJ liposomes as a gene transfer vector for hepatocellular carcinoma using herpes simplex virus thymidine kinase.

Although gene therapy has been suggested to be a novel strategy to treat hepatocellular carcinoma (HCC), no study showing the clinical feasibility of vectors to treat HCC has been reported. In this preclinical study, we show evidence indicating that hemagglutinating virus of Japan (HVJ) liposomes are a feasible vector to treat HCC in a clinical setting using ganciclovir (GCV) and herpes simplex virus thymidine kinase (HSV-tk), which is driven by the cytomegalovirus immediate early enhancer/promoter (plasmid pcDNA3/HSV-tk). In in vitro experiments, almost complete tumor cell regression was achieved with the optimal GCV concentration (100 microg/mL) and more than 1/3 regression was seen even with a 20% transduction ratio using HuH7 HCC cells stably transformed by HSV-tk. HVJ liposomes showed a 19.7% (mean) transduction rate of the lacZ gene in a relatively large mass of more than 300 mm3 in vivo, which is a clinically detectable size, implanted into SCID mice. Moreover, a single HSV-tk injection of HVJ liposomes followed by GCV treatment inhibited tumor growth at least within a week, and repeat administration was more effective. Furthermore, subcutaneous injection of an HVJ liposomes vehicle induced no apparent inflammatory response in C3H/HeN mice, whereas lacZ gene transfection resulted in inflammatory pathology, suggesting a lower immunogenicity of the HVJ envelope protein than those of bacteria-derived plasmid DNA or the beta-galactosidase gene product. From these findings, we conclude that HVJ liposomes are a clinically safe and effective gene transfer vector to treat HCC.

Prognostic significance of lymphocyte infiltration following preoperative chemoradiotherapy and hyperthermia for esophageal cancer.

PURPOSE: Lymphocyte infiltration (LI) around cancerous lesions is an important immune response. The purpose of this study is to evaluate the prognostic significance of LI after preoperative treatment for esophageal cancer. METHODS AND MATERIALS: Preoperative chemoradiotherapy (CR therapy), either bleomycin 30 mg or cisplatin 120 mg/m(2) plus radiation 30 Gy, was performed on 51 cases with esophageal cancer, while hyperthermo-chemoradiotherapy (HCR therapy) was also indicated in 71 cases. Using resected specimens, both the histopathologic effectiveness and degree of LI to cancerous lesions were evaluated. RESULTS: The incidences of the cases in which preoperative treatment was effective were 56% and 92.3% in LI (-) and LI (++) group (p < 0.05). The presence of LI resulted in favorable prognosis; the 5-year survival rates of LI (++) and LI (+) patients were 75.5% and 46.1%, both of which were significantly better than LI (-) (27.8%, p < 0.05 and p < 0.01, respectively). Especially among cases whose preoperative treatment was moderately effective, a multivariate analysis revealed LI to be a favorable prognostic factor independent of other clinicopathologic factors (p = 0.0171). Regarding the preoperative treatment, the incidence of LI (++) was higher in the HCR group (16.9%) than in the CR group (2.0%, p < 0.01). CONCLUSIONS: LI appears to be a prognostic predictor after preoperative CR therapy while, in addition, simultaneous hyperthermia may stimulate LI in cases with esophageal cancer.

An individual patient data meta-analysis of long supported adjuvant chemotherapy with oral carmofur in patients with curatively resected colorectal cancer.

To reappraise the benefits of the long supported chemotherapy with carmofur, a meta-analysis based on individual patient data from the three clinical trials was performed by pooling 614 patients from three trials, there is a statistically significant survival benefit (2p=0.032) and disease-free survival (DFS) benefit (2p=0.021) for carmofur; and a highly significant advantage for carmofur in DFS (2p=0.0004) and in survival (2p=0.004) in Dukes' C patients. This IPD meta-analysis strongly suggested an effect of oral carmofur in a long supported chemotherapy for curatively resected colorectal carcinoma.

Effect of dietary conjugated linoleic acid on the in vivo growth of rat hepatoma dRLh-84.

We examined the effect of dietary conjugated linoleic acid (CLA) on the growth of injected hepatoma dRLh-84 in Donryu rats. After experimental diets containing 0% or 2% CLA were given to male Donryu rats for 3 wk, dRLh-84 cells were injected into the left lobe of the hepatic capsule, and the experimental diet was continued. The cells formed a solid tumor > or = 1 wk after the injection, and thereafter the tumor grew with feeding duration. In a morphological study, this tumor appeared to be a low-differentiated hepatoma, and there was no remarkable difference in the morphology of the tumor between 0% and 2% CLA groups. Tumor weight was significantly higher in the 2% CLA group than in the 0% CLA group throughout the feeding period after the injection. Serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase activities were significantly higher in 2% CLA-injected rats than in 0% CLA-injected rats at 3 wk after the injection. CLA upregulated acyl-CoA oxidase activity, especially 1 wk after the injection. However, dietary CLA did not activate carnitine palmitoyl transferase II, which is a rate-limiting enzyme in the mitochondrial beta-oxidation pathway. Natural killer cell activity in the spleen tended to be higher in injected rats, but a significant effect of dietary CLA was not recognized. Serum interferon-gamma and tumor necrosis factor-alpha levels were higher in injected than in sham rats. Moreover, these levels were higher in 2% CLA groups than in the respective 0% CLA groups.

[Usefulness of preadmission autologous blood donation and intraoperative autotransfusion using the "cell saver" for the patients with abdominal aortic aneurysm repair].

To evaluate the effectiveness of preadmission autologous blood donation (PABD) and intraoperative autotransfusion (IAT) in reducing the homologous transfusion requirement of abdominal aortic aneurysm (AAA) resection, we retrospectively reviewed 232 AAA cases from January 1991 to December 1999. The patients were separated into three groups. The group I (n = 101) received no PAPD and IAT. The group II (n = 58) received only IAT. The group III (n = 73) received both PAPD and IAT. Surgical data indicating operative time and intraoperative blood loss did not differ among the three groups. However, the incidence of requirement for homologous transfusion in group III (19.2%) is significantly less than those of group I (63.4%) or group II (51.7%), although there was no significant difference between group I and group II. We concluded that the combination of PAPD and IAT are useful for reducing the incidence of requirement for homologous transfusion in the patients with aneurysmal resection.

Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group.

This study set out to evaluate, in patients with metastatic colorectal carcinoma, the efficacy and toxicity of S-1, which contains tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate, based on a biochemical modulation of 5-fluorouracil (5-FU) targeted at inhibition of dihydropyrimidine dehydrogenase (DPD). Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled into the study. None of the patients had received prior chemotherapy except for adjuvant setting. S-1 was administered orally twice daily at a standard dose of 80 mg m(-2) day(-1) for 28 days followed by a 14-day rest. This agent is continued until disease progression, unaccepted toxicity, or patient refusal. Twenty-two (35%) of the 62 eligible patients achieved PR with a 95% confidence interval of 25-48%. Five of the 10 patients with a history of adjuvant chemotherapy achieved partial remission. The median survival time was 12 months. Major adverse reactions included myelosuppressive and gastrointestinal toxicities, though their incidence of grade 3 or 4 being 13% in neutropenia and less than 10% in the others. None of the 53 patients treated as outpatients required hospitalization due to adverse reactions: These results suggest that S-1 achieves similar responses to those of infusional 5-FU plus leucovorin and shows the potential of another biochemical modulation with easily manageable toxicity.

Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas.

The expression of ATP-binding cassette superfamily transporter genes, such as P-glycoprotein/multidrug resistance (MDR) 1 and MDR protein (MRP) 1, is often up-regulated in various tumor types and is involved in responses to some anticancer chemotherapeutic agents. Five human MRP subfamily members (MRP2-6) with structural similarities to MRP1 have been identified. The relationships between MRP2-6 mRNA levels and drug resistance are not well understood. Data on 45 patients with colorectal cancer were analyzed. Of the ATP-binding cassette superfamily genes, we asked whether mRNA levels of MDR1, MRP1, MRP2, and MRP3 correlated with drug resistance to anticancer agents. For this analysis, we used quantitative reverse transcription-PCR, and the sensitivity to anticancer agents in surgically resected colon carcinomas was determined using the in vitro succinate dehydrogenase inhibition test. MDR1, MRP1, and MRP3 were highly expressed in normal colorectal mucosa, and the relative mRNA levels of MDR1, MRP1, and MRP3 in cancerous tissues compared with noncancerous tissues were decreased or unchanged. By contrast, MRP2 mRNA expression was low in normal colorectal mucosa and specifically increased in cancer regions compared with noncancerous regions. Of the anticancer agents prescribed for patients with colorectal cancers, including doxorubicin, mitomycin C, cisplatin, 5-fluorouracil, etoposide, and a camptothecin derivative, mRNA expression of MRP2 was significantly associated with resistance to cisplatin. MRP2 may be important for resistance to cisplatin treatment in colorectal cancer.

Antiemetic effect of ramosetron during hyperthermo-chemo-radiotherapy for esophageal cancer.

BACKGROUND: The antiemetic effects of serotonin receptor antagonists during chemoradiotherapy for solid tumors have never been reported. We have developed hyperthermo-chemo-radiotherapy (HCR) for esophageal cancer. However, with this treatment, the more potent the chemotherapy was, the more frequently emesis was experienced. MATERIALS AND METHODS: Fifteen patients with esophageal cancer underwent HCR (6 courses of hyperthermia, cisplatin 20 mg/m2 x 6, 5-FU 300 mg/m2 x 15 and radiation 1.5 Gy x 30). Ramosetron was administered intravenously (0.3 mg x 15). The emesis inhibition rate was defined as the rate of patients having neither vomiting nor severe nausea. RESULTS: The incidence of patients without nausea gradually decreased to 60% at the end of chemotherapy. However, vomiting was completely avoided except in one patient for two days. The emesis inhibition rates of weeks 1, 2, 3 and 4 were 100.0, 93.3, 89.5 and 95.2%, respectively. The overall inhibition rate was 94.5% and the rate of "well inhibited" was 79.0%. There were no ramosetron-related adverse reactions. CONCLUSIONS: These findings suggest that ramosetron is a useful antiemetic agent for nausea and vomiting induced by chemoradiotherapy for solid tumors.

Experimental study of the effects of deletion variant of hepatocyte growth factor on hepatic ischaemia-reperfusion injury.

BACKGROUND: Hepatic ischaemia-reperfusion (IR) injury is still a serious complication following liver surgery. The effect of the deletion variant of hepatocyte growth factor (dHGF) on hepatic IR injury was examined in rats. METHODS: Male Wistar rats were divided into two groups after 90 min of partial liver ischaemia: the dHGF group which was given dHGF 0.5 mg/kg intravenously immediately after reperfusion, followed by 0.5 mg/kg every 12 h, and the control group, which received vehicle buffer only. Serum chemistry, histopathological findings and liver weights were compared between the groups. RESULTS: In the dHGF group, the increase in serum alanine transaminase and hyaluronic acid levels was significantly reduced, and the serum albumin level increased after reperfusion. The extent of hepatic necrosis 24 h after reperfusion was decreased in the dHGF group. Moreover, the proportion of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labelling-positive hepatocytes 6 h after reperfusion was reduced in the dHGF group. The non-ischaemic-, ischaemic- and whole-liver weight : body-weight ratio significantly increased in the dHGF group after reperfusion. The proportion of proliferating cell nuclear antigen-positive hepatocytes in the dHGF group markedly increased after 6 h after reperfusion in the non-ischaemic lobes, while in the ischaemic lobes it increased 24 h after reperfusion. CONCLUSION: These data suggest that dHGF not only improves recovery from IR injury, but also accelerates recovery from these injuries. dHGF may be an effective pharmacological agent for prevention and treatment of hepatic IR injury.

The p53 tumor suppressor gene in anticancer agent-induced apoptosis and chemosensitivity of human gastrointestinal cancer cell lines.

PURPOSE: While the target of many anticancer agents has been identified, the processes leading to killing of the cancer cells and the molecular basis of resistance to the drugs are not well understood. We used human gastrointestinal cancer cell lines and examined how anticancer agents induced cell killing and how the chemosensitivity of these lines was determined. METHODS: Twelve gastrointestinal cancer cell lines were examined for the presence of either a wild-type or mutant p53 gene by direct sequencing. We also determined whether or not cell killing would occur when the cell lines were exposed to anticancer drugs. The sensitivity to the anticancer agents was determined based on colony formation. RESULTS: All 12 gastrointestinal cancer cell lines carried either a wild-type or mutant p53 gene. Three lines, MKN45, MKN74 and COLO320, carried the wild-type p53 gene, and nine carried the mutant p53 gene. When three lines were exposed to the anticancer agents etoposide, doxorubicin (DXR) or 5-fluorouracil (5-FU), cell death ensued. In these cells, the population of cells in G1 phase increased after exposure to high-dose anticancer agents, but cells in G2 phase increased when exposed to low-dose anticancer agents. Our observations support the concept that cells carrying the wild-type p53 gene tend to be sensitive to etoposide and DXR and, in particular, deletion of the p53 function results in a greater resistance to anticancer agents. CONCLUSION: Based on our findings, human gastrointestinal cancer-related cell death apparently occurs via a p53-dependent pathway. A relationship was observed between the induction of cell death and chemosensitivity.

Relationship between the expression of HLA-DR antigen and the effectiveness of preoperative hyperthermo-chemo-radiotherapy in oesophageal cancer.

Based on the hypothesis that tumour cells expressing HLA-DR antigen would easily be damaged by the local immune response during preoperative treatments, the relationship was investigated between the expression of HLA-DR antigen in the oesophageal cancer and the effectiveness of the preoperative treatment. Immunohistochemical staining for the detection of HLA-DR antigen in cancer cells from biopsy specimens obtained before undergoing preoperative hyperthermo-chemo-radiotherapy (HCR therapy) in patients with oesophageal squamous cell carcinoma was performed, and the relationship between the expression of HLA-DR antigen and the effectiveness of HCR therapy was evaluated according to a histopathologic examination of resected specimen. A total of 35 cases were examined in which 14 showed strongly positive staining (+2), 14 weakly positive staining (+) and seven negative staining (-). No significant differences in the clinicopathologic factors between the groups were observed. In the 14 strongly positive HLA-DR antigen cases, nine were markedly effective (grade 3) (64.3%), four were moderately effective (grade 2) (28.6%) and one was slightly effective or ineffective (grade 1, 0) (7.1%). In the 14 weakly positive HLA-DR antigen cases, the markedly, moderately and slightly or ineffective cases numbered four (28.6%), eight (57.1%) and two (14.3%), respectively. On the other hand, in the seven patients showing no HLA-DR expression, the markedly, moderately and slightly effective cases numbered one (14.3%), two (28.6%) and four (57.1%), respectively. A statistical difference was observed between the cases of strongly positive and negative staining for HLA-DR antigen (p < 0.05). The expression of HLA-DR antigen in oesophageal cancer cells is thus considered to potentially be a valuable factor for predicting the effectiveness of preoperative treatment.

Clinicopathologic features of patients with oesophageal cancer obtaining a histological complete response for preoperative hyperthermo-chemo-radiotherapy.

From 1979 to 1993, 151 patients with resectable oesophageal cancer underwent preoperative hyperthermo-chemo-radiotherapy (HCR) followed by a subtotal esophagectomy. All resected specimens were histopathologically evaluated, and then were classified into two groups according to the efficacy of the preoperative HCR. Group A included 33 patients whose resected oesophagus was free of any cancer cells (grade 3). Group B included 118 patients, in which viable cancer cells remained in the resected specimens to various degrees (grade 1,2). The incidence of patients with well differentiated squamous cell carcinoma, node negative cases, or TNM stage I/II was significantly higher in group A than in group B (27.3% versus 9.3%, 72.7% versus 50.8%, 72.7% versus 50.8%, respectively). The recurrence rate was 33.3% (11/33) in group A, while it was 65.3% (77/118) in group B (p < 0.005). There was no case with any local recurrence in the former, while it was 8.5% (10/118) in the latter. The 1-, 3- and 5-year survival rates were 87.2%, 65.9% and 46.1% in group A, while they were 54.8%, 26.7% and 18.8% in group B (p < 0.005), respectively. Preoperative HCR may be expected of decreasing in the recurrence rate, including regional relapse when a grade 3 is obtained. Complete local control would further positively influence the prognosis.

Recent advances in preoperative hyperthermochemoradiotherapy for patients with esophageal cancer.

BACKGROUND AND OBJECTIVES: Hyperthermochemoradiotherapy (HCR) has been performed on numerous patients with esophageal cancer. The purpose of this study is to demonstrate the recent advances in HCR. METHODS: From 1965 to 1997, 294 patients given preoperative chemoradiotherapy (CR) or HCR were classified according to the anticancer agent that was administered (CR; group A given bleomycin (BLM); group B given cis-diamminedichloroplatinum (II) (CDDP), HCR; group C given BLM; and Group D given CDDP). The local response and the long-term results were investigated. RESULTS: The cases in which CR or HCR was evaluated to be effective numbered 44 (48.4%) in group A, 22 (73.3%) in group B, 79 (63.7%) in group C, and 36 (73.5%) in group D. A significant difference was observed between groups A and B (P < 0.05). The highest incidence of markedly effective cases was observed in group D. The 5-year survival rates for the group A and B patients were 17.2% and 43.9%, respectively (P < 0.01), while the same rates for those of groups C and D were 25.6% and 57.8%, respectively (P < 0.05). Our results thus showed CDDP to have a greater effect than BLM, while HCR had a greater effect than CR. CONCLUSIONS: Preoperative HCR has improved thanks to recent advances in anticancer agents.

Postoperative adjuvant chemotherapy with 1-hexylcarbamoyl-5-fluorouracil in patients with colorectal cancer and at a high risk for recurrence.

We examined the effects of postoperative 5-fluorouracil (5-FU) infusions and oral treatment with 1-hexylcarbamoyl-5-fluorouracil (HCFU) on patients curatively resected for stages II-IV colorectal cancer. The study was prospectively randomized, and 251 (93.3%) of 269 patients were valid candidates for statistical assessment. The inductive regimen for group A included 5-FU 10 mg intravenous (i.v.) injections on days 0, 1, 2, 7, 8 and 9, postoperatively. For maintenance therapy, group A received HCFU 300 mg orally and daily for 52 weeks beginning 2 weeks after surgery. The regimen for group B included only 5-FU injections. The effects of this chemotherapy were also retrospectively analyzed for groups at a high risk for recurrence, stages III-IV, transmural invasion-positive and lymph node metastasis-positive cases. There was no statistical difference in survival time between the groups for 251 eligible cases (p = 0.079). In group A given 5-FU plus HCFU, there was a reduction in the recurrence rate for patients with stages III-IV or lymph node metastasis-positive colorectal cancers (p < 0.05) and prolongation of the survival time for patients with stage III-IV, transmural invasion-positive or lymph node-positive colorectal cancers (p < 0.05). Our findings show that the combination of 5-FU infusion and the continuous administration of HCFU is effective in treating patients with surgically resected colorectal cancer who are at high risk for a recurrence.

Potentiation of the cytotoxicity of carboquone by flavone acetic acid combined with hyperthermia.

Flavone acetic acid (FAA) has shown the effectiveness of vasoactive drugs in the selective reduction of tumor blood flow. A FAA-mediated decrease in tumor blood flow may produce sufficient hypoxic conditions within the tumor. Carboquone (CQ), a naturally occurring prototype bioreductive alkylating agent like mitomycin C (MMC), has been shown to be selectively more cytotoxic toward hypoxic tumor cells. We have reported enhancement of the combined antitumor effects of MMC plus FAA and hyperthermia (HT). In this study, we examined the combined effects of FAA, CQ and HT. In vitro, although HT (43 degrees C, 60 min) reduced the colonogenicity to 0.58 in CQ (0.01 microg/ml) alone, the combined cytotoxicity of CQ and HT was not enhanced with exposure to FAA at a concentration of 100 microg/ml. In vivo, the tumor growth time, calculated as the time required to reach twice the initial tumor volume, for CQ (2 mg/kg) alone, FAA (150 mg/kg) alone, CQ+FAA, CQ+HT (43 degrees C, 15 min), FAA+HT and FAA+CQ+HT was 6.1, 5.1, 7.1, 8.0, 7.6 and 13.4 days, respectively. A significant enhancement of antitumor effects by trimodality therapy with CQ, FAA and HT was observed, when compared to the treatment with CQ and FAA (p < 0.05). The possible mechanisms of an increased antitumor response achieved with the combination of CQ, FAA and HT may be explained in the following way: the FAA-mediated decrease in tumor blood flow produced sufficient hypoxic conditions within the tumor, and these resulted in a significant increase of the antitumor effects of CQ and HT.