Fecoflowmetric analysis of anorectal motor function in postoperative anal-preserving surgery patients with low rectal cancer comparison with the wexner score and anorectal manometry.

The aim of this study was to elucidate whether fecoflowmetry (FFM) could evaluate more detailed evacuative function than anorectal manometry by comparing between FFM or anorectal manometric findings and the clinical questionnaires and the types of surgical procedure in the patients who received anal-preserving surgery. Fifty-three patients who underwent anal-preserving surgery for low rectal cancer were enrolled. The relationships between FFM or the manometric findings and the clinical questionnaires and the types of procedure of anal-preserving surgery were evaluated. There were significant differences between FFM markers and the clinical questionnaire and the types of the surgical procedure, whereas no significant relationship was observed between the manometric findings and the clinical questionnaire and the types of the surgical procedure. FFM might be feasible and useful for the objective assessment of evacuative function and may be superior to manometry for patients undergoing anal-preserving surgery.

Virchow lymph node metastatic recurrence of sigmoid colon cancer with severe lymph node metastases successfully treated using systemic chemotherapy combined with radiotherapy.

Metastatic recurrence of colon cancer in the left supraclavicular lymph node (Virchow lymph node) is rare, and to date there are no reports on radiotherapy as treatment. We report on a case of metastatic recurrence of sigmoid colon cancer in the Virchow lymph node with severe lymph node metastases successfully treated with a combined modality therapy of systemic chemotherapy and radiotherapy. The case is of a 58-year-old man, who underwent sigmoid excision and lymph node excision, and subsequently received systemic chemotherapy. After left supraclavicular lymph node recurrence appeared he later received radiotherapy. Complete response was achieved, and there has been no further recurrence, to date, 10 months after the radiotherapy. Radiotherapy was effective as a local treatment, and local control of distant metastasis of colonic cancer may lead to a good prognosis.

Amphiregulin is a prognostic factor in colorectal cancer.

Amphiregulin is an epidermal growth factor (EGF) which is a ligand of epidermal growth factor receptor (EGFR). Amphiregulin is the most enhanced EGFR ligand in colon cancer. Here we report on the expression of Amphiregulin using immunohistochemical staining in primary colorectal cancer, and the correlations between prognosis and various clinicopathological factors. We examined 174 consecutive patients who underwent curative resection of colorectal cancer, from January 2002 to December 2004. Amphiregulin was positive in 156 (90%) patients. Amphiregulin was found to be an independent predictor of overall survival [hazard ratio=6.25 (95% confidence interval=1.3-111.5; p=0.0144)] and relapse-free survival [hazard ratio=6.94 (95% confidence interval=1.5-123.2; p=0.0075)]. We conclude that the expression of Amphiregulin in a primary colorectal tumor is useful as an indicator of prognosis and as a predictor of recurrence.

[Treatment and outcome in small bowel cancer].

In adenocarcinoma of the small intestine, delays in diagnosis are frequent, and the majority of patients present with advanced- stage disease and either lymph node involvement or distant metastatic disease. Surgical resection is a mainstay in treatment of this disease, but the role of adjuvant therapy is unclear. Recent retrospective and prospective studies have helped to clarify the optimal chemotherapy approach for advanced small bowel adenocarcinoma. The combination of capecitabine and oxaliplatin is reportedly highly effective. Further clinical studies on this rare type of tumor are needed. This article reviews the focuses on recent advances in management. The 72nd Japanese Society for Cancer of the Colon and Rectum have conducted a retrospective review of Japanese patients with adenocarcinoma of the jejunum or ileum. The data indicated that although not statistically significant, there was a trend in median overall survival favoring the chemotherapy for advanced jejunal or ileal adenocarcinoma (17 months vs. 8 months, p=0.114).

[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.

Dosage escalation study of S-1 and irinotecan in metronomic chemotherapy against advanced colorectal cancer.

The anti-angiogenic efficacy of chemotherapy would seem to be optimized by administering comparatively lower doses of drugs on a more frequent (daily, several times a week, or weekly) or continuous schedule, with no extended interruptions - sometimes referred to as 'metronomic' chemotherapy. This phase I study was performed to determine the recommended dosage (RD) of metronomic chemotherapy using oral fluoropyrimidine S-1 plus weekly irinotecan (CPT-11) in patients with previously untreated advanced or recurrent colorectal cancer. Patients received first-line chemotherapy consisting of 80 mg/m(2) of S-1 given on days 3 to 7, 10 to 14, and 17 to 21 with escalating dosages of CPT-11 (from 40 mg/m(2)) administered intravenously on day 1, 8, and 15 of a 28-day cycle. Standard patient eligibility criteria were used. Based on the concept of metronomic chemotherapy, dose limiting toxicity (DLT) was defined any toxicity that resulted in skipping of CPT-11 administration, or more than 5 days suspension in S-1 administration, in addition to the conventional criteria. If the maximum tolerated dosage (MTD) was defined as the maximum dosage at which no suspension of CPT-11 or S-1 administration occurred, the RD was considered to be the dosage one rank lower than the MTD. On the other hand, in the present study the MTD was defined as the dosage at which at least one suspension of CPT-11 or S-1 administration occurred, the MTD was considered to be the RD. Two of the first 3 patients at level 4 received 60 mg/m(2) of CPT-11 and 80 mg/m(2) of S-1 experienced a suspension in CPT-11 administration, thus level 4 was defined as the MTD and RD. Sixty mg/m(2) of CPT-11 and 80 mg/m(2) of S-1 were the indicated RD for the following phase II study of metronomic chemotherapy.

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.

Oral fluoropyrimidines may not reduce the risk of postoperative recurrence in colorectal cancer associated with mesenteric lymph node metastasis.

To clarify the efficacy and problems of postoperative adjuvant chemotherapy using oral fluoropyrimidines, the clinicopathological data of 307 colorectal cancer patients treated with or without postoperative chemotherapy were analyzed retrospectively. Patients in the chemotherapy group (n=188) who underwent curative resection were followed by administration of oral fluoropyrimidine. The other 119 patients underwent surgery alone. The disease-free survival rates were compared between the two groups. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery alone. However, no significant difference in disease-free survival rate was found for those with tumors that were associated with mesenteric lymph node involvement and tumors with a high grade of lymphatic invasion or high grade of venous invasion. Postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT (litegafur +4:uracil) and 5'-DFUR (doxifluridine) might not reduce the risk of recurrence in colorectal cancer with mesenteric lymph nodes involvement.

The MMP-9 expression determined the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer.

BACKGROUND: The aim of this study was to determine any correlation between the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines and the matrix metalloproteinase 9 (MMP-9) expression in primary colorectal cancer tissues. PATIENTS AND METHODS: The data on 307 patients with colorectal cancer at stage II or III, who underwent potentially curative resection with lymphadenectomy, were reviewed. Of these, 188 received postoperative administration of oral fluoropyrimidines such as UFT and 5'-DFUR (chemotherapy group), while the other 119 patients underwent surgery alone (surgery-alone group). Immunostaining for MMP-9 was performed using surgical specimens of all 307 primary tumors and 18 recurrent tumors. RESULTS: Overall, MMP-9 was positively expressed in the primary tumor in 44% of patients. Multivariate analysis revealed that the MMP-9 expression was a worse prognostic factor with a second highest hazard ratio for recurrence. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery-alone group. However, no significant difference in disease-free survival rate between the two groups was found in patients with a tumor positive for MMP-9. There was a strong positive correlation of MMP-9 expression between the primary tumors and the recurrent liver or lung tumors. CONCLUSIONS: The efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT and 5'-DFUR may not be as great for patients with a tumor positive for MMP-9 having a greater risk to postoperative recurrence.

Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat.

We have investigated the antitumor effects of synthetic MMP inhibitor MMI270 against postoperative lung metastasis from colon cancer in nude rat. The KM12SM human colon cancer cells were injected into the cecal wall, and at 5 weeks after the injection, the cecum was removed including the tumor. Then, 30 mg/kg of MMI270 was administered perorally twice per day for 2 or 4 weeks, either immediately after removal or after week 2 after the removal. At week 7 after the removal, lung metastasis was significantly inhibited by the early administration of MMI270 immediately after the tumor removal but not by the late administration. The survival rates were significantly higher in the rats treated by early administration of MMI270 compared to the survival rate in untreated rats. Moreover, no lung metastasis was detected in some rats with 24-weeks' survival treated by early administration. Lower microvessel density, lower PCNA Index and higher Apoptotic Index in the lung metastases of the rats treated with MMI270 were found compared to those in untreated rats. A beneficial effect of by early administration of MMI270 against postoperative lung metastases may be expected through inhibiting neovascularization of metastases in nude rat.

Upregulation of thymidine phosphorylase in rectal cancer tissues by mitomycin C.

BACKGROUND AND OBJECTIVES: We have investigated the regulation by mitomycin C (MMC) of thymidine phosphorylase (dThdPase) and dihydropyrimidine dehydrogenase (DPD), which enhances or reduces the efficacy of capecitabine and its metabolite 5'-deoxy-5-fluorouridine (5'-DFUR), in rectal cancer tissues. MATERIALS AND METHODS: In 31 patients with a rectal cancer, tumor biopsies were performed before and after pre-operative venous administration of 4 mg/m2, 6 mg/m2, or 10 mg/m2 of MMC. The dThdPase and DPD levels in the biopsy and surgical specimens were measured using ELISA, and immunostaining for dThdPase was performed. RESULTS: The fitting multiple linear regression models indicated that the dThdPase levels increased after MMC administration, in particular in the patients with a pre-treatment dThdPase level less than 56.2 U/mg protein (median value). The time course analysis indicated that the increase in the dThdPase level by 4 mg/m2 of MMC administration continued for 3 weeks. The dThdPase/DPD ratio was increased after MMC administration in patients with a pre-treatment dThdPase/DPD ratio less than 1.79 (median value). MMC enhanced the expression of dThdPase protein both in the tumor cells and in the stromal cells. The disease free-survival rate in the Dukes B or C patients with a high dThdPase/DPD ratio in surgical specimen who received 5'-DFUR based adjuvant chemotherapy tended to be higher than that in those with a low dThdPase/DPD ratio. CONCLUSION: MMC may upregulate the dThdPase level and the dThdPase/DPD ratio in rectal cancer tissues. Combined use of MMC with capecitabine or 5'-DFUR may offer a more effective colorectal cancer therapy.

The benefit of post-operative adjuvant chemotherapy using oral fluoropyrimidines in rectal cancer.

Recent meta-analysis has shown that oral fluoropyrimidenes is effective as post-operative adjuvant therapy in stage II or III colorectal cancer. However, because the efficacy of oral fluoropyrimidines was expected to be mild, it is important to know patients who respond to this mild chemotherapy for reasonable adjuvant therapy for rectal cancer. To clarify the benefit and problems of the post-operative adjuvant chemotherapy using oral fluoropyrimidines, the clinicopathological data of 169 rectal cancer patients treated with or without the post-operative chemotherapy were analyzed retrospectively. Patients in chemotherapy group (n = 100) underwent curative resection with lymphadenectomy were followed by administration of oral fluoropyrimidine. Other 69 patients underwent surgery alone. The disease-free survival rates were compared between the two groups. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery alone. However, no significant difference in disease-free survival rate was found for those with tumor which was associated with metastasis of mesenteric lymph node or node belonging to the internal iliac artery, and tumor with lymphatic invasion or venous invasion. Post-operative adjuvant chemotherapy using oral fluoropyrimidines such as UFT and 5'-DFUR might not reduce the risk of recurrence in rectal cancer with metastasis of mesenteric lymph node or node belonging to the internal iliac artery, and with lymphatic permeation and venous invasion.

Repeat pulmonary resection for isolated recurrent lung metastases yields results comparable to those after first pulmonary resection in colorectal cancer.

Pulmonary resection for colorectal metastases is well accepted. However, the main cause of death after pulmonary resection is recurrence in the lung. The aim of this study was to clarify whether a repeat pulmonary resection was warranted in patients with recurrent lung metastases. The records of 76 patients undergoing initial pulmonary resection, including 14 patients undergoing a repeat operation for lung metastases, were reviewed for survival, operative morbidity, and mortality. Overall, pulmonary resection was performed 96 times in this group of patients. The operative mortality was 0%, morbidity involved only one case of major postoperative hemorrhage associated with the first operation. The cumulative 5-year survival rate for the 76 patients was 32%. After the second pulmonary operation, recurrence was identified in 79% (11 of 14) of the patients. In 10 patients with isolated lung recurrence after a first pulmonary resection, who showed no extrapulmonary disease before or at the time of first thoracotomy, the 3-year, and 5-year-survival rate after the second pulmonary resection was 67%, and 33%, respectively, comparing favorably with the survival rate in those who underwent primary pulmonary resection. In contrast, all 4 patients with extrapulmonary disease before or at the time of thoracotomy had poor prognosis. Repeat pulmonary operation for isolated recurrent colorectal metastases to the lung yielded results comparable to those after the first pulmonary resection in terms of operative mortality and survival in the absence of hilar/mediastinal lymph node or extrathoracic involvement.

Prognostic factors after potentially curative resection in stage II or III colon cancer.

It is important to identify factors that are predictive of outcome after a curative resection in colon cancer in order to optimize adjuvant therapy. To investigate these prognostic factors we conducted a retrospective analysis of our clinicopathological data. A total of 190 patients with a pathological stage II or III colon cancer underwent potentially curative resection with lymphadenectomy at our hospital between 1990 and 1998. These patients received no preoperative chemotherapy, immunotherapy or radiotherapy. Postoperative adjuvant chemotherapy using oral fluoropyrimidines was performed in 127 patients, and the other 63 patients underwent surgery alone. Univariate and multivariate analyses for prognostic factors were carried out. The univariate analysis revealed that invasion to adjacent organs, N1-2, positive mesenteric lymph node metastasis (MLN+), lymphatic permeation (ly)1-3, venous invasion (v)1-3, and v2-3 were each significant factors indicating worse disease-free survival, and that N1-2, MLN+, ly1-3, v1-3 and v2-3 were each significant factors for worse overall survival. In the multivariate analysis, MLN+ and vl-3 were significant factors for worse disease-free survival, and for worse overall survival. In conclusion, stage II or III colon cancer patients positive for mesenteric lymph node metastasis or for venous invasion have a greater risk of recurrence and death after potentially curative resection. Postoperative adjuvant chemotherapy using oral fluoropyrimidines did not significantly reduce the risk of recurrence and death in these patients. More effective adjuvant chemotherapy than oral fluoropyrimidine should be considered, especially in such high-risk patients.

[The repetitive immune cell transfer therapy combining non-myelosuppressive chemotherapy for patients with advanced and refractory cancer].

Autologous tumor cells stimulated with T lymphocytes (AuTL) were generated ex vivo from peripheral blood lymphocytes over a two-week co-culturing process with autologous tumor cells. These AuTLs were capable of lysing established tumor cell lines and may have a potential for efficacy as an adoptive immunotherapy (IT) in advanced and metastatic refractory cancer patients (pts). We investigated the feasibility of a combination of AuTL transfer and chemotherapy (ChT) based on the conventional conditioning regimen in order to take advantage by both the anticancer effects and reconstruction of antitumor immunity. Nineteen patients were enrolled in a pilot clinical trial. The two administrations of AuTL were given prior to chemotherapy (ChT) for one treatment cycle. The treatment was repeated at least for three cycles over a one-week interval. The conventional ChT regimen was based on the standard dosage. The pts consisted of 3 of gastric cancer, colon cancer, lung adenocarcinoma, respectively, 6 of esophageal cancer, and 2 of breast and pancreas carcinoma, respectively. AuTLs were administered 1x/2 weeks using direct injection or intraarterial infusion. The median duration of the treatment was over 11.5 months, and the median survival time was 14.8 months. Adverse events related to both the ChT and AuTL transfers at all dosages were minimal. Four of the 13 pts achieved major tumor responses (2 CR: complete regression and 2 PR: partial regression) in this study. Three pts showed progressive disease, and 6 pts had stable disease for over 90 days. PBMC were evaluated for cytokine production prior to the treatment and after 3 treatments. Two and one of 4 CR/PR pts had increased IFN-gamma and TNF-alpha production with no TGF-beta1 responses by their PBMC after 3 treatments, respectively. Two out of 6 pts who experienced stable disease after the treatment had high IFN-gamma and TNF-alpha responses and no TGF-beta1 or IL-4 response. TGF-beta1 and IL-4 secretion increased in parallel in 3 out of 3 pts that experienced progressive disease after the treatment. These data show that combination therapy of AuTL transfer and non-myeloablative ChT is a feasible option for patients with refractory advanced cancers without serious adverse events and without reducing Th1 cytokine responses in peripheral blood for most of the pts that responded to the treatment. According to each mechanism of IT and ChT, a more stringent evaluation of AuTL transfer combined with non-myeloablative ChT for various kinds of cancers should be performed to manage the immunodeficiency in the pts with advanced cancer and to improve the effect of antitumor AuTLs.

Humoral responses to peptides correlate with overall survival in advanced cancer patients vaccinated with peptides based on pre-existing, peptide-specific cellular responses.

PURPOSE: The aim of this study is to find a laboratory marker for overall survival in advanced cancer patients who were vaccinated with peptides based on pre-existing, peptide-specific CTL precursors in the circulation. EXPERIMENTAL DESIGN: A group of 113 patients with advanced cancer (28 colorectal, 22 prostate, 15 lung, 14 gastric, and 34 other cancers) was enrolled in a Phase I clinical study of peptide vaccination in which peptide-specific CTL precursors of prevaccination peripheral blood mononuclear cells were measured, followed by vaccination with these peptides (maximum of four). For cellular responses, pre and postvaccination (sixth) peripheral blood mononuclear cells were provided for measurement of both peptide-specific CTL precursors by IFN-gamma release assay and tumor reactivity by (51)Cr release assay. Delayed type hypersensitivity was also measured. For humoral response, pre and postvaccination (sixth) sera were provided for measurement of peptide-reactive IgG by an ELISA. RESULTS: The median survival time and 1-year survival rate of the total cases were 346 +/- 64.9 days and 44.6%, respectively, and those of patients vaccinated more than six times (n = 91) were 409 +/- 15 days and 54.4%, respectively. In these 91 patients, the overall survival of patients whose sera showed increased levels of peptide-reactive IgG (n = 60) was significantly more prolonged (P = 0.0003) than that of patients whose sera did not (n = 31), whereas none of cellular responses correlated with overall survival. CONCLUSIONS: Peptide-specific IgG in postvaccination sera could be a suitable laboratory maker for the prediction of prolonged survival in advanced cancer patients vaccinated with peptides based on pre-existing CTL precursors.

[Autologous tumor specific immunotherapy of refractory cancers with ex vivo-generated T cells stimulated by autologous tumor cell].

OBJECTIVES: Autologous tumor-cell stimulated cytotoxic T lymphocytes (AuTLs) were prepared from peripheral blood T cells and the T cells were activated ex vivo over a 2-week culturing process in the presence of IL-2 and autologous biopsied tumor-cells from advanced cancer patients. These AuTLs may have potential for efficacy as a locoregional therapy in patients with refractory cancer. METHODS: Twenty-nine of 35 cancer patients (13 esophagus, 5 lung, 3 stomach, 4 breast, 1 melanoma) were enrolled in an early Phase II clinical trial. The patients received direct locoregional intratumoral injection of AuTLs biweekly through medical endoscope or intraarterial infusion reservoir system. Mean 0.25 x 10(9) AuTLs were injected 1 x /2 weeks for 6 weeks. RESULTS: Adverse events related to AuTL were minimal. AuTLs specific for autologous tumor cells were observed in 12 of 29 patients. Seven of these 12 patients (58.3%) had partial response (PR) or stable disease (SD). In contrast, 8 of 23 (34.8%) remaining patients treated by non-specific AuTLs had SD. Infiltration of T effector cells was significantly increased on the biopsied tumor specimens in the immunohistological studies. Furthermore, 11 patients receiving systemic infusion of non-specific LAK/NK T cells without autologous tumor-cell stimulation only had 2 SDs (18.2%). CONCLUSIONS: Our results demonstrated the clinical potential of intra-peritumoral administration of AuTLs. Thus, locoregional immunotherapy with autologous tumor specific AuTLs may be more effective than systemic adoptive immunotherapy using intravenous infusion of autologous tumor non-specific LAK/NK T cells for the treatment of solid cancers.

Up-regulation in dihydropyrimidine dehydrogenase activity by raltitrexed causes antagonism in combination with 5-fluorouracil.

BACKGROUND AND METHODS: We have studied the influence of raltitrexed, a specific thymidylate synthase (TS) inhibitor, on dihydropyrimidine dehydrogenase (DPD) activity in cultured cancer cells and in transplanted tumors in nude mice. Further, we investigated the combined effect of raltirexed and 5-fluorouracil (5-FU) on the in vitro anti-tumor effect and its correlation to the DPD activity and mRNA level. RESULTS: By raltitrexed treatment, the DPD activity and mRNA level were increased in HuTu-80 small intestine carcinoma cells, and in its transplanted tumors. On the other hand, raltitrexed showed no influence on DPD activity in MIAPaCa2 pancreatic carcinoma cells. In the study of cell growth activity, the results showed that in MIAPaCa2, the Combination Index (CI) was 0.57 +/- 0.03, representing a synergistic effect, while in HuTu-80, the CI was 1.26 +/- 0.09, representing an antagonistic effect. CONCLUSION: Raltitrexed may up-regulate DPD activity in tumor cells, resulting in antagonism when combined with 5-FU.