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Unlabelled: Anticancer drugs may frequently induce host immunosuppression and symptomatic toxicities. Once symptomatic toxicity occurs, the patient's quality-of-life (QOL) is reduced. Since little is known of the relationship between host immunity and the toxicity of chemotherapy, the host immunity before and after chemotherapy was compared to assess whether it is related to symptomatic toxicity during chemotherapy., Patients and Methods: Fourteen patients with colorectal cancer underwent leucovorin /5-fluorouracil (LV/5-FU) treatment, or S-1/irinotecan (CPT-11). Host immunity (cytokine production of peripheral blood mononuclear cell (PBMC), serum soluble interleukin-2 receptor (sIL-2R) levels and phenotypic analyses of PBMC were measured before and after the first chemotherapy., Results: An increase of sIL-2R, CD4+CD25+ T-cells and the CD4/8 ratio in patients with symptomatic adverse reactions were found. These changes in the first chemotherapy were significantly different (p = 0.0211, p = 0.0087, p = 0.0234)., Conclusion: The current study indicated that there are some parameters correlated with toxicity during chemotherapy which effect QOL. In such patients, negative influences on host immunity, such as an increase of sIL-2R and regulatory T-cells, and a decrease of cytotoxic T-cells could occur.

S-1 is a novel oral anticancer drug, composed of tegafur (FT), gimestat (CDHP) and otastat potassium (Oxo), based on the biochemical modulation of 5-fluorouracil (5-FU). S-1 plus irinotecan (CPT-11) for advanced colorectal cancer as expected showed equally good results as these with CPT-11 plus infusional 5-FU/LV (FOLFIRI regimen). A case of unresectable lymph node metastasis from colon cancer successfully treated with S-1 plus CPT-11 is reported here. A 65-year-old man had metastasis to the lymph nodes in the left supra clavicular region and the superior mesenteric artery. S-1 plus CPT-11 was chosen for the treatment. After 2 courses, since grade 2 toxicity for dysgeusia was observed, S-1 administration was shortened. After 3 courses of the revised regimen, the enlarged lymph nodes disappeared on conventional CT and fluorine-18 fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT) and the case was assessed as a complete response (CR). Because CR was continued by an additional four courses of treatment, the regimen was changed to a single administration of S-1. Although eighteen months have passed since the induction of CR by S-1 plus CPT-11 therapy, no symptoms or findings of relapse have been observed.

We herein report a case of long-term surviving patient who was treated with intravenous administration of activated autologous lymphocytes and low-dose chemotherapy. The patient was an 82-year-old female. She underwent radical resection for sigmoid colon cancer in 1998 and right lobectomy of the liver for metastatic liver tumor in 2001. A follow up CT revealed the metastasis to the bilateral lung on November 2003. Then she received a treatment with UFT plus low-dose CPT-11/CDDP and activated autologous lymphocytes. Although the response of the treatment was SD, the serum CEA level decreased to a normal range. The treatment continued with delayed administration for 30 months while CEA and the size of the tumors increased very slowly. After that, her treatment was changed with a single administration of S-1. She obtained a 3.5 year survival with an inhibition of fast tumor growth by chemo-immunotherapy.

A 72-year-old woman, who had the carcinoma of cecum with unresectable multiple liver metastases, underwent ileocecal resection and insertion of hepatic arterial infusion catheter. Hepatic arterial infusion (HAI) chemotherapy using Leucovorin. 5-FU caused to decrease liver metastases after an initiation of HAI. However, the metastatic nodule at the right lobe of lung was found. Then systemic chemotherapy with CPT-11 CDDP was performed alternately with HAI chemotherapy. After the initiation of revised regimen, all metastatic lesions were shrunk. We here in present the case of extra- and intra-hepatic metastasis successfully treated with alternative chemotherapy with hepatic arterial infusion and systemic intravenous infusion after responding to hepatic metastasis from colon cancer by hepatic arterial infusion.

Background/aims: We have performed end-to-end anastomosis by the triangulating method using a linear cutter for the reconstruction in colectomy. In this report, we present our technique of triangle anastomosis and its convenience and merits., Methodology: Patients who underwent end-to-end anastomosis with the triangulating method, or the Gambee procedure, for reconstruction after colon cancer surgery from 1998 to 2003 in our department, were analyzed retrospectively. The anastomosis time and complications were compared in these two groups., Results: The mean anastomosis time was 14.7+/-3.5 minutes, which is 17+/-0.7 shorter than the 31.7+/-4.2 minutes it took for the Gambee anastomosis performed during the same period. There were no significant differences in the incidences and variety of complications., Conclusions: Triangulating anastomosis using a linear cutter is a safe and easy technique that can be performed in a short amount of time. It is, therefore, considered a useful method for reconstructive surgery for colon cancer.

Unlabelled: The aim was to assess the practical efficacy of low-dose chemotherapy in patients with intrapelvic recurrence of rectal cancer without radiotherapy., Patients and Methods: The records of 13 patients treated with low-dose chemotherapy for intrapelvic recurrence of rectal cancer between 1996 and 2003 were retrospectively reviewed. The patients had received low-dose leucovorin and 5-fluorouracil (LV/5-FU) as first-line and low-dose irinotecan and cisplatin regimen (CPT-11/CDDP) as second-line therapy without radiotherapy., Results: With the LV/5-FU treatment, no patients showed a complete response (CR), two patients showed a partial response (PR), three patients had stable disease (SD), and eight patients experienced progressive disease (PD), giving a response rate (RR) of 15.4% and a disease control rate (DCR) of 38.5%. With the CPT-1/CDDP treatment, no patients showed CR or PR, three patients had SD, and ten patients had PD, which results in a DCR of 23.1%. The progression-free survival (PFS) of LV/5-FU and CPT-11/CDDP were 4.7 months and 4.7 months respectively. The median survival time (MST) of all the patients was 17.3 months. There were no patients who experienced grade 3 or 4 of any adverse reaction during the course of these regimens., Conclusion: The results suggest that low-dose chemotherapy for intrapelvic recurrence of rectal cancer without radiotherapy could be acceptable. For patients who refused radiotherapy in order to avoid adverse effects, these low-dose low toxicity chemotherapy regimens might be recommended.

Aim: To assess the practical efficacy of low-dose leucovorin plus 5-fluorouracil (LV/5-FU) in elderly patients with metastatic colorectal cancer., Patients and Methods: The records of 20 patients treated with LV/5-FU for unresectable metastatic disease from colorectal cancer from 1999 to 2004 were retrospectively reviewed. The patients received LV/5-FU as first-line, and low-dose CPT-11 and CDDP regimen (CPT-11/CDDP) as second-line therapy., Results: In the treatment of LV/5-FU, no patients had CR, 3 patients had PR, 4 patients had SD and 13 patients had PD, which results in a response rate (RR) of 15% and in a disease control rate (DCR) of 35%. MST of all patients was 18.4 months. There was one patient who experienced grade 3 or 4 adverse reactions during the course of these regimens., Conclusion: Low-dose LV/5-FU chemotherapy in elderly patients with metastatic colorectal cancer could be acceptable in order to avoid adverse effects and to obtain quite a favorable survival time.

Background: S-1 is a novel oral anticancer drug, composed of tegafur (FT), gimestat (CDHP) and otastat potassium (Oxo) in a molar ratio of 1:0.4:1. S-1 plus irinotecan (CPT-11) administered for advanced colorectal cancer could be expected to show as equally good results as the infusional 5-fluorouracil/leucovorin (5-FU/LV) with CPT-11 (FOLFIRI) regimen. When toxicity is too severe preventing patients from receiving an intensive chemotherapeutic regimen, survival benefit might be forfeited. A pilot study of low-dose S-1 plus CPT-11 therapy with constant doses without consideration of body surface area (BSA) was therefore performed., Patients and Methods: Twenty-two patients were enrolled in this study. S-1 was given orally at 40 mg b.i.d. for 21 consecutive days followed by a 14-day rest period. CPT-11 was administered as a 90-minute intravenous infusion at a dose of 80 mg on days 1 and 15. Courses of treatment were repeated every 35 days., Results: The median age was 62.5 years (26-74). The median cycles were 8.5 (3-20). The overall response rate was 45.5% (complete response (CR), 1; partial response (PR), 9). Median progression-free survival (PFS) and median overall survival time (MST) were 9.0 and 20.2 months respectively. No grade 3 or 4 toxicities were observed. Eight patients (36.4%) did not have any sign or symptom of toxicity throughout all the treatment courses. The response, survival and toxicity were not significantly different according to BSA., Conclusion: These results suggest that simplified low-dose S-1 plus CPT-11 treatment might be of considerable advantage as first-line chemotherapy for patients with advanced colorectal cancer who would like to avoid toxicity.

Background: The clinical indications for hepatectomy and extrahepatic bile duct resection (EBDR) for pT2 gallbladder carcinoma (GBC) remains controversial. The aim of this study is to elucidate the therapeutic effect of hepatectomy and extrahepatic bile duct resection on the surgical treatment of pT2 GBC., Methods: Ninety-four patients with pT2 GBC who underwent a potentially curative resection were retrospectively analyzed regarding their pathological findings, surgical procedures, and survival., Results: The most powerful predicting factor for the survival is the nodal status. The 5-year survival rate was 87.1% for the pN0 patients and 55.7% for the pN1 patients. With respect to surgical procedures, the 5-year survival rate was 73.3% for the 51 patients with hepatectomy, and 87.2% for the 43 patients without hepatectomy. In addition, the 5-year survival rate was 66.7% for the 11 patients with EBDR, and 81.1% for the 83 patients without EBDR. When restricting the patients to those with pN1 disease, the 5-year survival rate of the patients who received these procedures did not surpass that of the patients who did not., Conclusion: There is no positive therapeutic effect besides providing surgical margins in hepatectomy and EBDR in the surgical treatment of pT2 GBC whereas lymph node dissection is most effective procedure for improving survival. Provided that the negative surgical margins are secured, a hepatectomy and an EBDR can therefore be withheld in the surgical treatment for the pT2 GBC.

Alien species are often a major threat to native species. We consider optimal conservation strategies for a population whose viability is affected both by an alien species (such as a competitor, a predator, or a pathogen) and by random fluctuations of the environment (e.g. precipitation, temperature). We assume that the survivorship of the native population can be improved by providing resources such as food and shelter, and also by an extermination effort that decreases the abundance of the alien species. These efforts decrease the extinction probability of the native population, but they are accompanied by economic costs. We search for the optimal strategy that minimizes the weighted sum of the extinction probability and the economic costs over a single year. We derive conditions under which investment should be made in both resource-enhancement and extermination, and examine how the optimal effort levels change with parameters. When the optimal strategy includes both types of efforts, the optimal extermination effort level turns out to be independent of the density and economic value of the native species, or the variance of the environmental fluctuation. Furthermore, the optimal resource-enhancement effort is then independent of the density of the alien species. However, the parameter dependencies greatly change if one of the efforts becomes zero. We also examine the situation in which the impact of the alien species is uncertain. The optimal extermination effort increases with the uncertainty of this impact except when the cost of extermination is very high.

Background: Anticancer drugs may frequently show host immunosuppression. Low-dose chemotherapy has been used for unresectable cancer as a tumor dormancy therapy, and it has been reported that the patients treated this way demonstrated favorable survival without toxicity. In this study, host immunity before and after a low-dose leucovorin plus 5-fluorouracil regimen (low-dose LV/5-FU) and S-1 plus irinotecan regimen (S-1/CPT-11) was compared to assess whether low-dose chemotherapy can maintain host immunity., Patients and Methods: Fourteen patients with recurrent or metastatic colorectal cancer underwent low-dose LV/5-FU, or S-1/CPT-11 treatment. The host immunity (cytokine production of the peripheral blood mono-nuclear cells (PBMC), serum soluble interleukin-2 receptor (sIL-2R) levels and phenotypic analyses of the PBMC) was measured before and after the first chemotherapy treatment., Results: An increase of sIL-2R and CD4+CD25+ T cells with S-1/CPT-11 treatment, and a decrease with low-dose LV/5-FU treatment were observed and these changes in the first course were significantly different (p =0.0722 for the slL-2R, p=0. 0187for the CD4+CD25+ T cells)., Conclusion: The current study indicated that there is no change or an improvement in host immunity with the low-dose LV/5-FU treatment as compared with the S-1/CPT-11 treatment. Low-dose LV/5-FU treatment should be considered for metastatic colorectal cancer in order to maintain a host immunity during chemotherapy.

We review and synthesize recent developments in the study of the invasion of communities in heterogeneous environments, considering both the invasibility of the community and impacts to the community. We consider both empirical and theoretical studies. For each of three major kinds of environmental heterogeneity (temporal, spatial and invader-driven), we find evidence that heterogeneity is critical to the invasibility of the community, the rate of spread, and the impacts on the community following invasion. We propose an environmental heterogeneity hypothesis of invasions, whereby heterogeneity both increases invasion success and reduces the impact to native species in the community, because it promotes invasion and coexistence mechanisms that are not possible in homogeneous environments. This hypothesis could help to explain recent findings that diversity is often increased as a result of biological invasions. It could also explain the scale dependence of the diversity-invasibility relationship. Despite the undoubted importance of heterogeneity to the invasion of communities, it has been studied remarkably little and new research is needed that simultaneously considers invasion, environmental heterogeneity and community characteristics. As a young field, there is an unrivalled opportunity for theoreticians and experimenters to work together to build a tractable theory informed by data.

Background: Human X-box binding protein 1 (XBP-1) is a transcription factor essential for hepatocyte growth, as well as for plasma cell differentiation. Recently, overexpression of XBP-1 has been reported in breast cancer including non-invasive carcinomas, and was suggested to play an important role in breast carcinogenesis. To investigate the involvement of XBP-1 in colorectal tumorigenecity, the expression of XBP-1 was examined in four colon cancer cell lines, six colorectal polyps and five colorectal carcinomas., Materials and Methods: The study population consisted of eleven patients who had undergone resection for colorectal cancer or adenoma from 2000 to 2002. Four colon cancer cell lines, DLD1, SW480, HCT15 and WiDr, were also analyzed for expression of XBP-1. Reverse transcription-polymerase chain reaction was performed using eleven primary colon tumors. XBP-1 expression was then investigated using an immunohistochemical method for archived paraffin-embedded sections., Results: The XBP-1 gene was overexpressed in four cases out of five primary colorectal carcinomas and in four cases out of six colorectal adenomas. Also all four cancer cell lines expressed XBP-1 mRNA. Immunohistochemical staining demonstrated that XBP-1 protein was strongly stained in the cytoplasms of cancer cells, whereas it was unreactive in the normal colon epithelial cells and stromal cells., Conclusion: These data indicate that increased expression of XBP-1 gene may play some role in human colon carcinogenesis through impairment of cell differentiation regulation.

Administration of cimetidine after curative surgery can improve prognosis of patients with colorectal cancer. In this study, we analyzed whether cimetidine can influence the survival of patients with a recurrent disease after colorectal surgery. The subjects were 29 patients with recurrent disease: 14 patients were administered with cimetidine and 15 patients were not. In the cimetidine administered group, seven cases were recurrent in the liver, 5 cases in a local site and 1 case in the lymph node, whereas 7 cases were recurrent in the liver, 4 cases in a local site and 3 cases in the lung for the non-cimetidine administered group. There were no significant differences for both groups in terms of patient's survival after recurrence. Although it was not significant, the patient's survival after curative resection of recurrent disease for the cimetidine administered group was better than the non cimetidine administered group. Although the results did not show cimetidine could influence the overall survival of the patients after recurrence, it might be possible to improve the survival of the patients after resection of the recurrent disease.

Hepatic arterial infusion (HAI) chemotherapy for unresectable liver metastases from colorectal cancer (CRC) is generally indicated to patients without extrahepatic lesions. This study was performed to examine whether or not it was possible to obtain a comparable survival time, response rate (RR) and modest toxicity combining low-dose LV and 5-FU (LV/5-FU) with HAI for the patients with unresectable liver metastases from CRC. Twenty two patients with unresectable multiple liver metastases were enrolled in the study. These were patients who had been admitted from 1994 to 2003 in our hospital. Patients were given LV at 25 mg/body immediately followed by 5-FU at 500 mg/body as a 2-hour HAI daily for 5 consecutive days every 5 weeks. The median survival time (MST) of HAI patients was 24.5 months. According to the treatment in the HAI patients, one patient was CR, 6 were PR, 9 were NC, 6 were PD, and the response rate (RR) was 31.8% (7 of 22 patients). The toxicities to this regimen on HAI were observed in 12 patients, and grades 3 or 4 were in 3 patients only. These results suggested that HAI with LV/5-FU can be useful for unresectable liver metastases from CRC.

Background: Identifing patients prone to colorectal cancer recurrence is of importance in providing appropriate adjuvant chemotherapy. In this retrospective study on Dukes' B colorectal cancer, patients at high risk of recurrence were identified by clinicopathological factors, and the efficacy of adjuvant chemotherapy with oral fluoropyrimidines was evaluated., Patients and Methods: The subjects were 229 patients with Dukes' B colorectal cancer who had undergone curative surgical resection. The relationship between each factor and cancer-related survival was examined., Results: In all the patients, the 5-year cumulative survival rate was 83.5% and the recurrence rate was 20.1%. The multivariate analyses indicated that the depth of invasion was the most significant prognostic factor. The cases with tumor exposed at the serosa or which invaded other organs were considered as a high-risk group. The 5-year survival rate in high-risk patients with adjuvant chemotherapy was significantly better than those without chemotherapy (75.8% and 44.0%, respectively, p=0.0008). The patients who received chemotherapy tended to show a decrease in the recurrence rate, especially in the liver and lung (p=0.0346)., Conclusion: In Dukes' B colorectal cancer, the cases with invasion depth se or si were considered to be at high risk of recurrence or death. Adjuvant chemotherapy was effective for such high-risk patients, especially decreasing recurrence in the liver and lung.

Unlabelled: In the present study, a retrospective investigation was conducted to determine whether or not it was possible to obtain a comparable survival time, response rate (RR) and modest toxicity combining low-dose leucovorin (LV) and 5-Fluorouracil (5-FU) (LV/5-FU) with hepatic arterial infusion (HAI) or systemic intravenous infusion (SI) for patients with unresectable liver metastasis from colorectal cancer (CRC)., Patients and Methods: Patients were given LV at 20 mg/m2 immediately followed by 5-FU at 370 mg/m2 with a 2-hour SI or HAI daily for 5 consecutive days with courses repeated every 5 weeks. Twenty patients received HAI and 16 patients received SI. Survival, response and toxicity were assessed., Results: The median survival time (MST) of all patients was 20.0 months. The MST of the HAI and SI patients was 24.5 and 18.9 months, respectively. Two patients had complete remission (CR), 8 partial response (PR) and 14 no change (NC), which resulted in an RR of 28%. The MST according to the responses of CR/PR, NC and progressive disease (PD) patients was 45.5, 20.2 and 11.2 months, respectively. Severe toxicity (grades 3 or 4) to this regimen occured only in 0-10% of the cases, and there were no treatment-related deaths., Conclusion: There was no difference in response and survival between HAI and SI, which could be interpreted as a favorable result. Regardless of the route of administration, low-dose LV/5-FU treatment should be considered for patients with liver metastasis from CRC.

Background/aims: We analyzed how many lymph nodes should be examined to establish the presence or absence of lymph node metastasis, a staging factor, based on cumulative survival rate in colorectal cancer., Methodology: Among those who had undergone curative resection of colorectal cancer and lymphadenectomy exceeding D2, 94 patients with Dukes' B colorectal cancer (group B) and 108 patients with Dukes' C colorectal cancer (group C) were investigated, excluding obvious deaths from other diseases. Group B was divided into two groups by the number of lymph nodes examined, and the minimum number of retrieved lymph nodes yielding significant difference in survival rate was determined., Results: Dividing group B into two groups by the number of lymph nodes examined, survival rate was studied. The minimum number of retrieved lymph nodes yielding significant difference in survival rate between the two groups was observed when group B was divided into one group with 9 or more lymph nodes (72 patients) and the other with less than 9 (22 patients), with cumulative five-year survival rate of 86.7% and 66.7%, respectively. More favorable prognoses were observed in the 9 or more group compared with the less than 9 group or Dukes' C group (p=0.0284, p=0.0032, respectively). On the other hand, survival rate of the less than 9 group was similar to that of the Dukes' C group (p=0.8167)., Conclusions: Based on survival rate, 9 or more lymph nodes should be examined in order to correctly ascertain nodal negativity in lymphadenectomy exceeding D2 for Dukes' B colorectal cancer.

TS-1/CPT-11 treatment for the patients with advanced colorectal cancer is expected to be equal to FOLFOX and FOLFIRI regimen. The aim of this study was to investigate the relationship between host immunity and this regimen. Four patients were enrolled in this study. Host immunity was investigated before and after chemotherapy. PHA response, serum IAP level and the productions of any cytokines did not change significantly before and after the chemotherapy. Although these changes were not significant: both Th1/Th2 ratio and NK cells ratio were decreased, and the ratio of suppressor T cells was increased. These results suggest that TS-1/CPT-11 regimen may influence host immunity a little bit worse.

We encountered two cases of concurrent multiple liver metastases of colorectal cancer in two patients who achieved a complete response (CR) to hepatic arterial infusion (HAI) chemotherapy. The first case is a 64-year old man who was found to have anemia, and a diagnosis of ascending colon cancer was made. There were 6 metastatic lesions in both lobes of the liver. A right hemicolectomy was performed. Postoperative chemotherapy consisted of 2 g of oral UFT-E as well as 3 mg of CDDP and 500 mg of 5-FU administered by HAI. The metastatic lesions disappeared after 9 courses of chemotherapy were carried out. A partial hepatectomy was performed in the scarred area. Histopathological examination revealed no cancer cells. No recurrence has been observed for 4 years and 10 months since achieving CR. The second case is a 69-year-old man who had thin stool and bloody stool. Rectal cancer was diagnosed. Five metastatic lesions were noted in both lobes of the liver. A low anterior resection was performed. l-LV 25 mg and 5-FU 500 mg were given postoperatively by HAI. After three courses of chemotherapy postoperatively, metastatic lesions disappeared. No recurrence has been noted for 2 years and 1 month since achieving CR. HAI chemotherapy is considered one of the useful treatment options for patients with multiple liver metastases of colorectal cancer.

Mate-choice copying by females has been reported in fishes (e.g., guppies) and lekking birds. Presumably, females assess males' quality using both information from direct observation of males and information acquired by observing other females' choices. Here, we study mathematically the conditions under which mate-choice copying is advantageous on the basis of Bayesian decision theory. A female may observe the mate choice of another female, called the model female, who has performed an optimal choice based on her own judgment. The conditions required for the focal female to choose the same mate as that chosen by the model female should depend on the male's appearance to her, the reliability of her own judgment of male quality, and the reliability of the model females. When three or more females are involved, the optimal mate choice critically depends on whether multiple model females make decisions independently or they themselves copy the choices of others. If two equally reliable females choose different males, the choice of the second female, made knowing the choice of the first, should have a stronger effect on the choice of the third (focal) female. This "last-choice precedence" should be tested experimentally.

In colorectal cancer, low-dose Leucovorin plus 5-FU therapy does not induce any severe adverse effects, and patients could receive this therapy for many cycles. The aim of this study was to investigate the relationship between host immunity and this regimen. Seven patients were enrolled in this study. Host immunity was investigated before and after chemotherapy. The ratio of Th1/Th2, PHA response, serum IAP level and the productions of IL-6, IL-10 and soluble IL-2 receptor did not change significantly before and after chemotherapy. Since low-dose Leucovorin plus 5-FU therapy might not influence host immunity, patients could receive the therapy for a long duration without toxicity.

We consider optimal conservation strategies for an endangered population. We assume that juvenile survival is affected by unpredictable environmental fluctuation and can be improved by costly conservation effort. The initial population size is not accurately known at the time that the conservation effort level is chosen, but the uncertainty of its estimate can be reduced by a costly monitoring effort. In a previous paper, we analysed the optimal management strategy that minimizes a weighted sum of extinction probability and economic costs when only a single year is considered. Here we examine the case in which the conservation period lasts for several years by dynamic programming with incompletely observed process states. We study the optimal levels of the conservation and the monitoring efforts, and their dependence on the length of the conservation period and other parameters. The main conclusions are: (1) The optimal conservation effort in the first year depends on the accuracy of the information on the population size in the first year, but is almost independent of the accuracy of the information in later years. (2) When the risk of population extinction is small, the optimal conservation effort increases with the uncertainty of the population size. In contrast when the population is endangered, the optimal conservation effort decreases with the uncertainty of the population size. (3) The optimal conservation and monitoring efforts both increase with the length of the conservation period, provided that the population is relatively safe. However, if the population is endangered, both types of effort become smaller when the conservation period increases.

Background: Stomatitis in cancer chemotherapy manifests with pronounced subjective symptoms, lowers the patient's quality of life (QOL) and may necessitate the discontinuation of chemotherapy. There have been few effective therapies established to date for chemotherapy-induced stomatitis., Patients and Methods: We used frozen allopurinol solution (allopurinol ice balls) in the prevention of stomatitis associated with leucovorin (LV)/5-fluorouracil (5-FU) therapy for colon cancer., Results: Among 32 patients undergoing LV/5-FU therapy, without the use of the allopurinol ice balls, 15 patients developed stomatitis. On the other hand, only 3 patients developed stomatitis among 20 patients receiving the chemotherapy in conjunction with allopurinol ice balls (p=0.0187). Seven patients who developed stomatitis during a course of chemotherapy without allopurinol ice balls were administered the ice balls in the subsequent course; 6 of these patients responded with lessened severity of stomatitis. In 2 of these responders, stomatitis of comparable severity recurred on discontinuation of the medication., Conclusion: Concomitant use of allopurinol ice balls is effective in preventing stomatitis in patients undergoing LV/5-FU therapy.

It was once considered that the T cell response is an all or nothing type event, but recent studies have clearly indicated that T cells show many different types of activation in recognition of altered ligands for T cell receptors (TCR). In this review, we summarize our recent findings on the response of human CD4+ helper T (Th) cell clones to altered peptide ligands (APL); peptides carrying single or multiple residue substitutions in antigenic peptides. The extensive analyses revealed that TCR-antagonism and partial agonism are frequently observed by the stimulation with APLs substituted at particular amino acid residues of antigenic peptides. We observed unique partially agonistic APLs inducing prolongation of T cell survival without cell proliferation. Superagonistic APLs stimulated enhanced proliferation and production of cytokines in Th cell clones reactive to tumor-associated antigens. The other APL induced enhanced production of interleukin-12 by antigen presenting cells and subsequent enhancement of IFN-gamma production by T cells reactive to allergens. By utilizing an HLA-DR-restricted T cell epitope library generated by mutated invariant chain genes, it was revealed that human Th cell clones recognize a more diverse array of peptides with multiple and simultaneous amino acid substitutions in an antigenic peptide. APLs also induced altered intracellular signaling events including intracellular calcium increase and phosphorylation of signaling molecules. This information provides basic knowledge regarding the characteristics of antigen recognition by human Th cells and the subsequent activation, and a novel method for manipulation of human Th cell responses by APLs, as a possible candidate for antigen-specific immuno-potentiating or immunosuppressive therapy.

Purpose: With the aim of reducing the toxicities of irinotecan (CPT-11) while maintaining its antitumor effect, we treated colorectal cancer patients resistant to chemotherapy based on 5-fluorouracil (5-FU) with low-dose CPT-11 and cisplatin (CDDP)., Methods: CPT-11 (27 mg/m2) and CDDP (6 mg/m2) were administered on days 1, 8 and 15 every 4 weeks to 20 patients with recurrent or metastatic colorectal cancer. When toxicities were noted, administrations were delayed or the dose was reduced., Results: No severe toxicity (i.e. grade 3 or more) was observed in this study. Nausea was observed in 50% of patients (10/20) and fatigue in 30% (6/20). Only four patients developed leukopenia (three grade 1 and one grade 2). Although the overall response rate was 15% (three partial response, seven no change, and ten progressive disease), the median time to progression was 7.0 months and the median survival time was 18.0 months. The treatment was well tolerated as outpatient therapy., Conclusion: Low-dose CPT-11 and CDDP treatment should be considered as second-line chemotherapy for patients with recurrent or metastatic colorectal cancer resistant to 5-FU-based chemotherapy.

The expression of Fas ligand (Fas L) was investigated in sixty-seven patients with colorectal cancer for possible correlation with liver metastasis. Fas L expression was positive in 48 and negative in 19 cases. In Fas L-positive cases, 14 patients had liver metastasis including metachronous metastasis. However, only one case had liver metastasis in Fas L-negative patients (p = 0.0344). In colorectal cancer with venous invasion, 13 from 25 Fas L-positive cases had liver metastasis but only one in 19 negative cases (p = 0.0003). In the cases without venous invasion, no liver metastasis was observed in Fas L-negative cases. These results suggest that Fas L expression may be a predictive factor for liver metastasis in colorectal cancer with venous invasion.

We herein report the result of a prospective study to investigate the efficacy of cimetidine administration in conjunction with chemotherapy for stage IV colorectal cancer. Sixty-two patients treated with Leucovorin/5-fluorouracil therapy were enrolled from 1996 to 2000. Both groups were well matched for pre-treatment characteristics. There was no difference in survival in cur B patients. However, the cimetidine group had significantly prolonged survival in the patients with cur C or non-resectable carcinoma. This study suggests that cimetidine treatment may improve the survival of patients with non-curative surgery for stage IV colorectal cancer.

We consider optimal conservation strategies for endangered populations. We assume that the survival of the population is affected by unpredictable environmental fluctuation and can be improved by conservation effort. Furthermore, the exact value of the initial population size is assumed to be unknown. The conservation strategy involves two aspects: investment of assessment effort, to improve the estimate of the initial population size and investment of conservation effort. Both types of effort imply economic costs. The optimal management strategy is assumed to minimize the weighted sum of extinction probability and the economic cost of the conservation and the assessment effort. (1) We first analyse the optimal conservation effort when the current population size is known accurately. (2) Next, we consider the situation in which there is limited information (i.e. a cue) on population size. (3) We subsequently discuss the cases where the cue accuracy can be improved by assessment of the population. We study the optimal level of the assessment effort and discuss its dependence on various parameters.

We study the optimal conservation effort for a population in a fluctuating environment. The survivorship of a population is affected by unpredictable environmental fluctuation (noise) and can be improved by conservation effort accompanied by a cost. The optimal effort level is the one that minimizes the total cost, defined as the weighted sum of the population extinction risk and the economic cost of conservation effort. The optimal effort depends on the variance and the probability distribution of the noise, the relative importance of the population's survival vs. the economic cost, the effectiveness of conservation effort, and the time scope over which we optimize. The analysis of dynamic programming illustrates that the choice of extinction risk function greatly affects the optimal effort level. The conservation effort level that is the best solution of a multiple-year optimization may be higher than that for the corresponding single-year optimization, if the population is relatively safe. However, the conservation level for the multiple-year optimization becomes lower than for the single-year optimization if the population is endangered. In a similar manner, the optimal conservation effort level for the problem with a short time scope is either higher or lower than that for the problem with a long time scope, depending on the extinction risk of the population. Next, for each parameter of the model, we define five different sensitivities of extinction probability or of the total cost. We then study the mean increase in the total cost caused by the uncertainty of parameters. To achieve the best conservation result, we need to invest the limited research effort to the parameter with the largest effect to the optimal effort level, rather than to those with large impacts on the extinction probability or on the total cost. The recommended policy should depend critically on the choice of the criterion to optimize, which shows the importance of theoretical study of the relationship in performing proper decision making in conservation practice.

We describe here a method of affinity capillary electrophoresis in which oligodeoxynucleotide (ODN) was immobilized onto the inner surface of the capillary. The immobilized ODN functioned successfully as an affinity ligand for sequence-based DNA separation. Six- or 12-mer ODN with a sequence complementary to one of the c-K-ras gene was used as an immobilized ligand. When the 12-mer ODN was used, the detection peak for the complementary ODN disappeared selectively, while the single-base mutant was detected as usual. In contrast, when the 6-mer ODN was used as the affinity ligand with a mixture of the complementary ODN and its single-base mutant, it was possible to detect both as completely separate peaks. That is, the separation mode was dependent on the base number of the immobilized ODN used as an affinity ligand.

We report a rare case of an epidermoid cyst in an accessory spleen at the pancreatic tail. Only 12 cases have been reported. Among the different diagnostic modalities, magnetic resonance imaging was most useful for the differential diagnosis. Precise imaging of the cyst wall and its comparison with the surrounding organs are essential.

Human CD4+ T-cells recognize antigenic peptides in the context of human leukocyte antigen (HLA) class II molecules and produce various lymphokines to proliferate and activate other cells. It was once considered that the T-cell response is an all or nothing type event, but recent studies have clearly indicated that T-cells show many different types of activation in recognition of altered ligands for T-cell receptors (TCR). In this review, we summarize our recent findings on the human CD4+ T-cell response to altered peptide ligands (APL); peptides carrying single residue substitutions in antigenic peptides. We observed the following: 1) TCR antagonism for T-cell clones reactive to non-self or autoantigenic peptides, 2) partial activation (agonism) without cell proliferation, including production of lymphokines and increases in cell size, and in expression levels of several cell surface proteins or survival time in the absence of antigenic stimulus, 3) augmentation in cell proliferation and production of interferon-gamma (IFN-gamma) and granulocyte monocyte colony stimulating factor (GM-CSF), 4) augmentation of interleukin (IL)-12 production by antigen presenting cell (APC) and the subsequent augmented production of IFN-gamma by T-cells. This information provides basic knowledge regarding the characteristics of T-cell recognition of antigens and the subsequent activation, and a novel method for modification of human T-cell responses by altered peptide ligands (APLs), as a possible candidate for antigen-specific immunopotentiating or immunosuppressive therapy against autoimmune diseases, allergies, infectious diseases and malignant tumors.

A new alignment method for Helmholtz coils is proposed. This method is based on a probe, whose axis is the same as the alignment axis. This probe includes one magnetic sensor, whose position is slightly shifted from the probe axis, and which is set perpendicular to the axis. Using this probe, the tilt and shift of the magnetic centre of Helmholtz coils can be aligned to within an order of 0.1 mrad and 0.1 mm, respectively. Moreover, by this method, effects of terrestrial magnetism and tilt of the magnetic sensor can be removed from the measurement. This alignment method is presented along with an estimate of the alignment accuracy of the SPring-8 linac injector.

By stimulating peripheral blood mononuclear cells of four healthy donors with a mixture of overlapping peptides representing the core domain of p53, we established two CD4+ alphabeta T cell clones and four lines that recognized wild-type and mutant p53 proteins as well as p53 self peptides in an HLA class II-restricted fashion. Two T cell lines established from two unrelated donors reacted to the p53 peptide (p)153-166 and p108-122, respectively, in the context of DP5 molecules. Two T cell clones established from two other unrelated donors were specific for p193-204 in the context of DRB1*1401 and for p153-165 in the context of DP5, respectively. These two T cell clones responded almost equally to both wild-type and four mutant recombinant p53 proteins. The proliferative responses of these T cell clones to p53 recombinant proteins were augmented by heat denaturing, thereby suggesting that altered conformation of the protein facilitates proteolytic processing to produce antigenic peptides. The DRB1*1401-restricted T cell clone specific for p193-204 killed a B lymphoblastoid cell line homozygous for HLA-DRB1*1401 when the cell line was pre-pulsed with p53 protein as well as peptide. These results indicate that CD4+ T cells reactive to p53 do exist in healthy individuals and the epitopes are probably ignored by the immune system under physiological conditions. It is suggested that such epitopes stimulate T cells to induce anti-p53 antibody production in cancer patients as previously reported by others. The possible involvement of p53-reactive T cells in anti-tumor immunity is discussed.

Choroid plexus carcinoma (CPC) is a rare tumor with poor prognosis, whose optimal treatment has not yet been established. We report a case of a one-year-old infant who has been treated with successive combined therapy. The therapy involved two operations for partial removal, interrupted radiotherapy up to 12Gy, 2 cycles of salvage chemotherapy, followed by an operation for total removal, and then a further 3 cycles of chemotherapy. CT scan after the preoperative salvage chemotherapy showed remarkable shrinkage of the residual tumor, which made operative procedure easier. The patient was disease-free for ten months after the last operation. Patients with combined preoperative chemotherapy and total resection seem to enjoy prolonged progression-free survival, so preoperative chemotherapy for choroid plexus carcinoma seems to be of benefit, despite the fact that its optimal recipe has not yet been established.

T-cells that recognize mutated p21 Ras are relevant to immune surveillance systems against cancer. We report here evidence that immune responses of a T-cell clone recognizing mutated p21 Ras can be augmented by an analog peptide. Using spleen cells from a gastric cancer patient, we established the CD4+ alpha beta Th1-like clone C27 that recognizes wild-type (3EYKLVVVGAGGVGKS17) and mutated p21 Ras protein molecules and peptides, in an HLA-DR1-restricted manner. C27 responded prominently to mutated Ras peptides carrying Val or Ala at position 12, as compared to wild-type and other mutated peptides. C27 also exhibited a much stronger response to a mutated p21 Ras whole-protein molecule-carrying Val at position 12, as compared with the wild-type protein. The proliferative response and production of GM-CSF, TNF-alpha, and IFN-gamma by C27 were further augmented by replacing the possible first DR anchor 4Tyr of the mutated Ras peptide with Trp, a more potent anchor residue for the DR1 molecule. Enhancement of peptide antigenicity by substituting the HLA anchor residue of an antigenic peptide recognized by tumor-reactive T-cells may prove to be a novel strategy for antigen-specific cancer immunotherapy.

We investigated binding of p53- and Ras-derived peptides with frequently observed missense mutations, to various L cell transfectants expressing a single species of HLA-DR complex, and found that: (i) all the synthetic peptides bound to various DR complexes with a variable affinity; (ii) some DR allelic products had a high affinity for both p53- and Ras-derived peptides (e.g., DRB1*1502), whereas others almost no affinity (e.g., DRB1*1101); and (iii) DR-binding motifs described in the literature can explain some of the allele-specific interactions between mutated peptides and DR complexes. Therefore, some mutated Ras- and p53-derived peptides could be tumor-specific antigens recognized by CD4+ T cells in an HLA-DR allele-specific manner.

The unfolding pathway of lysozyme was investigated by carrying out the computer simulation. Taking into account the simultaneous change of both the dihedral angels phi and psi of a residue, we explore the detailed features of the conformational energy profiles. The triangle distance map shows that the lysozyme molecule is divided into three domains, 1-40, 41-101 and 102-129 in amino acid residue numbers (referred to as the domains I, II and III, respectively). The calculated unfolding process indicates that in the early stage of unfolding domain III located at the C-terminal begins to be detached from the other two, and then domain I can be unfolded. The long-range interactions between domains I and III stabilize the whole molecule and give the cooperative nature of the folding. The calculated unfolding pathway of lysozyme is consistent with the folding pathway proposed by Anderson & Wetlaufer [J. Biol. Chem. (1976). 251, 3147-3153] who identified the disulfide bondings in the early stage of the glutathione regeneration. A simplified treatment of unfolding for myoglobin is also discussed in the Appendix.