Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Randomized clinical trial of 24 versus 72 h antimicrobial prophylaxis in patients undergoing open total gastrectomy for gastric cancer.

BACKGROUND: Open total gastrectomy carries a high risk of surgical-site infection (SSI). This study evaluated the non-inferiority of antimicrobial prophylaxis for 24 compared with 72 h after open total gastrectomy. METHODS: An open-label, randomized, non-inferiority study was conducted at 57 institutions in Japan. Eligible patients were those who underwent open total gastrectomy for gastric cancer. Patients were assigned randomly to continued use of ß-lactamase inhibitor for either 24 or 72 h after surgery. The primary endpoint was the incidence of SSI, with non-inferiority based on a margin of 9 percentage points and a 90 per cent c.i. The secondary endpoint was the incidence of remote infection. RESULTS: A total of 464 patients (24 h prophylaxis, 228; 72 h prophylaxis, 236) were analysed. SSI occurred in 20 patients (8·8 per cent) in the 24-h prophylaxis group and 26 (11·0 per cent) in the 72-h group (absolute difference -2·2 (90 per cent c.i. -6·8 to 2·4) per cent; P < 0·001 for non-inferiority). However, the incidence of remote infection was significantly higher in the 24-h prophylaxis group. CONCLUSION: Antimicrobial prophylaxis for 24 h after total gastrectomy is not inferior to 72 h prophylaxis for prevention of SSI. Shortened antimicrobial prophylaxis might increase the incidence of remote infection. Registration number: UMIN000001062 ( http://www.umin.ac.jp).

Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05).

BACKGROUND: In Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC. PATIENTS AND METHODS: Patients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40-60 mg/m(2)) on days 1-14 and intravenous irinotecan (150 mg/m(2)) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS). RESULTS: From February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78-1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group. CONCLUSION: The consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy. ClinicalTrials.gov ID: NCT00639327.

S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial).

BACKGROUND: S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV). PATIENTS AND METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. RESULTS: A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. CONCLUSION: Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. CLINICALTRIALSGOV: NCT00660894.

Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial.

BACKGROUND: The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis. METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m(-2) per day as tegafur; LV, 75 mg per day on days 1-28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1-28, every 42 days, 4 courses). Treatment status and safety were evaluated. RESULTS: Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of grade 3 AEs were 16% and 14%, respectively. CONCLUSION: Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.

Dynamic changes in RAS gene status in circulating tumour DNA: a phase II trial of first-line FOLFOXIRI plus bevacizumab for RAS-mutant metastatic colorectal cancer (JACCRO CC-11).

BACKGROUND: Few prospective studies have used liquid biopsy testing in RAS-mutant metastatic colorectal cancer (mCRC), and its clinical significance remains unknown. Therefore, this study aimed to carry out a biomarker analysis by liquid biopsy using updated data of the phase II trial of FOLFOXIRI plus bevacizumab as first-line chemotherapy for RAS-mutant mCRC. MATERIALS AND METHODS: A total of 64 patients who received modified FOLFOXIRI regimen (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2) plus bevacizumab biweekly were enrolled. The primary endpoint was the objective response rate (ORR). Plasma samples were collected at pre-treatment, 8 weeks after treatment, and progression in participants included in the biomarker study. The levels of circulating tumour DNA (ctDNA) and specific KRAS and NRAS variants were evaluated using real-time PCR assays. RESULTS: There were 62 patients (median age: 62.5 years, 92% performance status 0, 27% right side) who were assessable for efficacy and 51 for biomarker analysis. ORR was 75.8% (95% confidence interval 65.1% to 86.5%). The median progression-free survival was 12.1 months, and the median overall survival (OS) was 30.2 months. In 78% of patients, RAS mutations disappeared in the ctDNA at 8 weeks after treatment; these patients tended to have better outcomes than those with RAS mutations. Interestingly, RAS mutations remained undetectable during progression in 62% of patients. Survival analysis indicated that the median OS from progression was significantly longer in patients with RAS mutation clearance than in those with RAS mutation in the ctDNA at disease progression (15.1 versus 7.3 months, hazard ratio: 0.21, P = 0.0046). CONCLUSIONS: Our biomarker study demonstrated no RAS mutations in ctDNA at disease progression in 62% of patients with RAS-mutant mCRC. Both OS and post-progression survival were better in patients with clearance of RAS mutations in ctDNA after triplet-based chemotherapy.

Effect of a selective neutrophil elastase inhibitor on early recovery from body water imbalance after transthoracic esophagectomy.

The objective of the study was to evaluate the efficacy of sivelestat, a selective neutrophil elastase inhibitor, on body fluid balance after transthoracic esophagectomy. Esophagectomy with elective lymphadenectomy may induce excessive release of neutrophil elastase, which then promotes vascular permeability and an excessive water shift from the intravascular space to the peripheral compartment. Body fluid imbalance after esophagectomy often leads to circular instability, a decrease of urine output, and a delay in the shift to a diuretic state. The study was designed as a case-control study with a historical control group. A retrospective analysis was performed to examine our hypothesis that sivelestat improves abnormal body fluid retention and prevents subsequent pulmonary complications. To reveal the direct influence of sivelestat on the postoperative course, we avoided using steroids or other diuretic agents. Eighty-eight patients who underwent thoracic esophagectomy with extended lymphadenectomy from 2000 to 2008 were divided into two groups: those treated from 2003 to 2008, who all received postoperative administration of sivelestat (n=60); and those treated from 2000 to 2002, who did not receive sivelestat and were used as the control group (n=28). Both groups received fluid management using the same protocol. The time to reach a diuretic state, time until extubation of the tracheal tube, and development of delayed respiratory dysfunction were compared between the groups using univariate and multivariate analysis. The time until a shift to a diuretic state was significantly shorter after treatment with sivelestat (p<0.0001) and with a shorter operation time (p<0.0001). The tracheal tube was extubated significantly earlier in the sivelestat group (p<0.0001) and the incidence of delayed respiratory dysfunction was also significantly lower (p=0.0028) in this group. Multivariate logistic regression analysis showed that a delay in a shift to a diuretic state was a strong independent risk factor for the time to tracheal extubation (odds ratio 2.539, p=0.0056) and occurrence of delayed respiratory dysfunction (odds ratio 1.989, p=0.0104). Sivelestat treatment was not independently associated with reduced pulmonary complications, but the diuretic state was strongly regulated by sivelestat treatment (odds ratio 0.044, p=0.0003). Thus, administration of sivelestat has a beneficial influence on recovery from body water imbalance through a more rapid return to a diuretic state after esophagectomy, which contributes to prevention of subsequent pulmonary complications.

Role of thymidine phosphorylase and dihydropyrimidine dehydrogenase in tumour progression and sensitivity to doxifluridine in gastric cancer patients.

This study was designed to investigate the role of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) on tumour progression and sensitivity to 5'-deoxy-5-fluorouridine (5'-DFUR). Tumour tissue was obtained from surgically resected samples from 93 patients with primary gastric cancer. Tumour TP and DPD expression levels were determined by the enzyme-linked immunosorbent assay (ELISA) system and compared with several clinicopathological factors and in vitro sensitivity to 5'-DFUR. DPD showed no correlation with any clinicopathological factors. However, the TP level was significantly correlated with the depth of tumour, lymphatic invasion and venous invasion. In comparison with 5'-DFUR sensitivity, there was a weak inverse correlation between the DPD level and the sensitivity to 5'-DFUR (r(s)=-0.361). Furthermore, the TP/DPD ratio showed a significant correlation with 5'-DFUR sensitivity (r(s)=0.634). In a subgroup of patients with postoperative 5'-DFUR administration, the survival rate was significantly better in patients with a high TP/DPD ratio (n=8) than in those with low TP/DPD ratio (n=14) (P=0.0140). These results suggest that sensitivity to 5'-DFUR is predictable by measurement of both TP and DPD levels.

Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity.

To elucidate the mechanism of the enhanced antitumour activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2, 4-dihydroxypyridine, and 1 M potassium oxonate) in terms of the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism, we investigated tumoral thymidylate synthase (TS) content, dihydropyrimidine dehydrogenase (DPD) activity, the TS inhibition rate (TS-IR), and 5-FU incorporated into RNA (F-RNA) in four human gastric cancer xenografts (MKN-28, MKN-74, GCIY and GT3TKB) and compared the results obtained with S-1 with those obtained with 5-FU and UFT (1 M tegafur, 4 M uracil). 5-FU was administered intraperitoneally (i.p.) to mice at a dose of 50 mg/kg, three times, on days 0, 4 and 8. S-1 and UFT were administered orally at doses of 10 and 24 mg/kg, respectively, once a day, for 9 consecutive days. Antitumour activity was evaluated as the maximum inhibition of tumour growth in each animal. S-1 showed a better antitumour activity than 5-FU and UFT in tumours with a high DPD activity (GCIY and GT3TKB). There were inverse correlations between the antitumour activity and both TS content and DPD activity in the 5-FU and UFT groups. However, no such correlations were observed in the S-1 group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-1 group than in the 5-FU or UFT groups. In GT3TKB xenografts, the F-RNA level was significantly higher in the S-1 group than in the 5-FU or UFT groups. The superior cytotoxicity of S-1 appears to be attributable to both an increased inhibition of DNA synthesis and an enhanced blockade of RNA function against tumours with a high DPD activity.

Carcinoembryonic antigen level in peritoneal washing is a prognostic factor in patients with gastric cancer.

This study was designed to evaluate the usefulness of carcinoembryonic antigen (CEA) and sialyl-Tn antigen (STN) levels in peritoneal washings in gastric cancer patients. At the time of laparotomy, peritoneal washings were collected from 96 gastric cancer patients and CEA and STN levels were determined. Patients with elevated CEA (100 ng/g protein) had a high incidence for peritoneal metastasis, lymph node metastasis and serosal invasion. In addition, prognosis in patients with high CEA level was significantly poorer than in those without it. The peritoneal CEA is a prognostic factor in patients with gastric cancer.

Roles of thymidylate synthase and dihydropyrimidine dehydrogenase in tumor progression and sensitivity to 5-fluorouracil in human gastric cancer.

BACKGROUND: The role of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) enzyme activities in tumor progression and sensitivity to 5-fluorouracil (5-FU) were evaluated. MATERIALS AND METHODS: TS and DPD activities were measured in 81 clinical samples of gastric cancer. TS and DPD activities were determined by 5-fluorodeoxyuridine monophosphate binding assay and by radioenzymatic assay, respectively. Sensitivity to 5-FU was determined by in vitro ATP assay. RESULTS: There was no correlation between TS activity and sensitivity to 5-FU. However, a weak correlation was found between DPD activity and sensitivity to 5-FU. In a subgroup of patients who did not receive adjuvant chemotherapy, overall survival was poorer in patients with high TS activity (p=0.0265). Conversely, in a subgroup of patients who received 5-FU-based adjuvant chemotherapy, overall survival was poorer in patients with high DPD activity (p=0.0465). CONCLUSION: These results suggest that TS has an important role in tumor progression and DPD may be the dominant predictor of 5-FU sensitivity in gastric cancer.

Telomerase assay as a possible predictor of the response to anticancer chemotherapy.

BACKGROUND: The correlation between telomerase activity and antitumor effects was investigated in cell lines of human gastric (MKN-28, MKN-45, and MKN-74) and breast (T-47D, MCF-7, ZR75-1) cancers to evaluate the possibility of utilizing this enzyme to predict tumor response to chemotherapy. MATERIALS AND METHODS: After culture with various concentrations of 5-fluorouracil (5-FU) or doxorubicin (DOX) for 3 days, cell viability (trypan blue exclusion), cell cycle distribution (flow cytometry), and telomerase (TRAP-EZE) were measured. RESULTS: Telomerase activity correlated significantly with the number of viable cells. After drug exposure, this activity decreased rapidly in a dose-dependent fashion in most cell lines. There was no correlation between telomerase activity and the distribution of cells in the cell cycle. CONCLUSIONS: As the assay for telomerase activity is extremely sensitive and is virtually specific to cancer cells, this method may prove useful for the sensitivity testing of small specimens of human tumors.

[Long-term arterial infusion chemotherapy in advanced and recurrent gastric cancer patients at home and an interesting autopsy case].

Arterial infusion therapy was applied to 92 patients with 40 unresectable, 30 non-curatively resected and 22 recurrent gastric cancers. 5-Fluorouracil (5-FU) was administered by arterial continuous infusion, Adriamycin (ADM) and mitomycin C (MMC) were given by bolus infusion in the hospital, and continuous arterial 5-FU infusion and ADM low-dose intermittent bolus infusion chemotherapy (AF therapy) were used for outpatients at home. The clinical effectiveness was evaluated. One-year cumulative survival rate of primary case by Kaplan-Meier method was 21.6%, and that of recurrent gastric cancer was 4.5%. In primary cases, the arterial infusion therapy was more effective in non-curatively resected cases than in unresectable ones. Total periods of infusion for outpatients were longer in efficacious cases. A long-surviving autopsy case was reported. AF therapy was considered an effective supportive treatment without any serious side effects for unresectable, non-curatively resected and recurrent gastric cancer, especially responders.

[Changes of cytokine levels in ascitic fluid after intraperitoneal administration of OK-432 or CDDP].

In order to evaluate the biological response after intraperitoneal administration of OK-432 and CDDP, we studied the changes of cytokine levels in ascitic fluid. A total of 53 gastric cancer patients were included in this study. OK-432 20KE was administered in 7 patients and CDDP was administered in 4 patients intraperitoneally during operation. The IL-6, IL-8, TNF-alpha and sTNF RI levels in ascitic fluid were measured from 0 to 5 postoperative day. These results were compared with those obtained from the control groups (42 patients). The ascitic level of IL-6 increased immediately after operation, then gradually decreased. The elevations of IL-6 from 0 to 5 postoperative day were remarkably higher in the OK-432 treated group, and those on 0 and 1 postoperative days were remarkably lower in CDDP treated group than in the control group. Similarly, the ascitic level of IL-8 elevated soon after operation and then decreased gradually. In the OK-432 treated group, the ascitic level of IL-8 was significantly higher than in the control group from 0 to 2 postoperative day. Ascitic TNF-alpha was detectable only in the ascites soon after operation in the OK-432 treated group. The ascitic level of sTNF RI peaked on 2 postoperative day in the control and the OK-432 treated group and 1 postoperative day in the CDDP treated group. There were no significant differences between these groups.

[Intraperitoneal administration of cis-platin with arterial infusion chemotherapy of advanced and recurrent gastric cancer].

Arterial infusion therapy was used for 97 patients with AMF therapy. Forty were unresectable, 30 non-curatively resected and 22 recurrent gastric cancers. 5-fluorouracil (5-FU) was administered by arterial continuous infusion, adriamycin (ADM) and mitomycin C (MMC) by bolus infusion in the hospital, and continuous arterial 5-FU infusion and ADM low dose intermittent bolus infusion chemotherapy (AF therapy) was used for outpatients. The clinical effectiveness was evaluated. One year cumulative survival rate of primary case by Kaplan Meier method was 21.6%, and that of recurrent gastric cancer was 4.5%. The median survival periods were 7 months in primary cases and 4 months in recurrent cases. In primary cases, the arterial infusion therapy was more effective in non-curatively resected cases than in unresectable ones. Intraperitoneal administration of cisplatin with AF intraarterial infusion therapy (AF-CDDP therapy) was applied in 11 cases with 9 primary and 2 recurrent cases. The clinical effectiveness of each was evaluated. One-year cumulative survival rate of primary case by Kaplan-Meier method was 28.6% and the median survival periods were 10 months. AF-CDDP therapy was considered more effective for unresectable gastric cancer with carcinomatous peritonitis. In conclusion, our method is considered to be advantageous in the treatment of carcinomatous peritonitis of gastric cancer patients.

[Changes in cytokine levels in ascitic fluid after intraperitoneal administration of OK-432].

In order to evaluate the biological response after intraperitoneal administration of OK-432, we studied the changes of cytokine levels in ascitic fluid. In 6 advanced gastric cancer patients with peritoneal dissemination or extensive lymph node metastases, OK-432 20 KE was administered intraperitoneally during operation and the IL-6, IL-8 and IFN-gamma levels in ascitic fluid were measured from 0 to 5 postoperative days. These results were compared with those obtained from non-OK-432 administered control groups (17 cases). The ascitic level of IL-8 increased immediately after operation and gradually decreased. In the OK-432 treated group, the elevation of IL-8 on 0 and 1 postoperative days was remarkable, and there were statistically significant differences with the control group. Similarly, the ascitic level of IL-6 elevated soon after operation and then decreased gradually. In the OK-432 treated group, the ascitic level of IL-6 was significantly higher than in the control group after 3 postoperative days. There were no differences in changes of ascitic IFN-gamma levels between the groups. From these results, IL-6 and IL-8 appeared to be induced in ascitic fluid by intraperitoneal administration of OK-432.

[A study of 6-day subrenal capsule assay with cyclophosphamide pretreatment--histological evaluation of clinical samples].

In order to suppress the host immune reaction in subrenal capsule assay (SRCA), effect of cyclophosphamide (CPM) was evaluated histologically in 25 fresh clinical samples. In 21 out of 25 clinical samples, the extent of lymphocyte infiltration was minimal, and in all samples the host reaction was suppressed significantly by CPM pretreatment. However, tumor cells were well preserved in only 10 out of 20 samples obtained from esophageal cancer patients. With the samples obtained from gastric and colorectal cancer patients, there were no tumor cells in the subrenal space on day 6. Persistence of tumor cells was well recognized in the samples having rich tumor and less stromal cells. The xenografts with moderately to well-preserved cancer cells showed an increase of the tumor size as expressed by delta TS. Though many xenografts showed a positive delta TS, preservation of tumor cells was poor. In each of the drug treated groups, a decrease of the tumor size and the histological effects were well correlated. It is suggested that 6-day SRCA with CPM pretreatment is useful as a chemosensitivity test, especially for the esophageal cancer whose tumor cells were well preserved.

[A novel fibrin clot with a sustained release of cis-platinum (CDDP)].

The authors devised a novel fibrin clot (FC) using an ultra-violet (UV)-crosslinking method. CDDP was impregnated into FCs, and the release profiles of the CDDP were examined in vitro. The microstructures of the FCs were studied with scanning electron microscopy (SEM). The release of CDDP from the FC-UV-CDDP was maintained for 10 days, while that from the FC-CDDP showed initial bursting with a following plateau of CDDP concentrations. SEM of UV-crosslinked FCs revealed highly organized, close and homogeneous micropore structures. Native FCs and non-crosslinked FCs showed rough fibrin networks with entangling fibrin fibers. These microstructural differences may play important roles in the release profiles of CDDP. Our newly devised UV-crosslinked material is promising as a drug carrier for sustained release.

[Clinical effectiveness of arterial infusion chemotherapy in advanced and recurrent gastric cancer].

Arterial infusion therapy was applied to 77 patients with 18 unresectable, 29 non-curatively resected and 20 recurrent gastric cancers. 5-fluorouracil (5-FU) was administered by arterial continuous infusion, and adriamycin (ADM) and mitomycin C (MMC) by bolus infusion. The clinical effectiveness of each was evaluated. One-year cumulative survival rate of primary case by Kaplan-Meier method was 19.2%, and that of recurrent gastric cancer was 5.3%. Median survival time of primary case was 6.5 months, showing prolongation compared with recurrent ones. Also, in primary cases, the arterial infusion therapy was more effective in non-curatively resected cases than in unresectable ones. Two of the patients are now alive and another is apparently free of tumor and the remaining one had a recurrence. Continuous arterial 5-FU infusion and ADM low-dose intermittent bolus infusion chemotherapy (AF therapy) were considered an effective supportive treatment without any serious side effects for unresectable, noncuratively resected and recurrent gastric cancer.