[A trial of TS-1 administration on the basis of the pharmacokinetic study for an advanced gastric cancer patient with impaired renal function].

TS-1 is an antitumor drug including 5-chloro-2,4 dihydroxypyridine (CDHP), which inhibits dihydriopyrimidine dehydrogenase (DPD) activity selectively in metabolism of 5-FU. However, TS-1 therapy tends to increase adverse events for patients with impaired renal function due to excessively high blood concentration of 5-FU, because CDHP is mainly excreted into the urine. In a 67-year-old male with advanced gastric cancer, renal dysfunction occurred during TS-1 administration as its adverse event. We studied the pharmacokinetics of 5-FU, which were analyzed on the T1/2 value and the AUC (0-infinity) of 5-FU with a single and consecutive TS-1 administration, and estimated an optimal TS-1 administration regimen for this patient. The regimen is 60 mg/body/day given in one divided dose for 28 days consecutively followed by 14 days rest. This regimen enabled a continuation of TS-1 treatment for the patient. In conclusion, individual dose adjustment using pharmacokinetic study of 5-FU might be beneficial to patients with impaired renal function.

[A case of peritoneal dissemination disappeared by CPT-11 + TS-1 combination chemotherapy].

A patient is a 35-year-old man. By a diagnosis of descending colon cancer, descending colon ablative operation and D1 lymph node dissection were performed on April 22, 2004. It was P3H0N1SE, Stage IV in perioperative findings. Abdominal CT showed peritoneal dissemination of 1.7 cm at the right under the abdominal wall wound and 1.2 cm in the rectovesical pouch on May 18, 2004. CPT-11 + TS-1 combination chemotherapy was started on June 22nd. In the five weeks of the combination chemotherapy, continuous infusion of CPT-11 (150 mg/body day 1 and 15) was twice administered, and oral administration of TS-1 (120 mg/body/day) was given for 3 weeks (day 1-21). Peritoneal dissemination disappeared after the two-course end, and we judged it as CR. Furthermore, we were certain that we obtained CR after the three course end. The adverse event was only neutropenia of grade 1. The fourth course was not administered, but recurrence has not been observed. Abdominal CT showed no recurrence on March 3, 2005 since the combination chemotherapy ended 6 months ago.

Ki-67 and CEA expression as prognostic markers in Dukes' C colorectal cancer.

This study investigated the relationship between clinicopathological or immunohistochemical factors and postoperative prognosis for Dukes' C colorectal cancer. Short-term survivors died from cancer within 2 years of surgery, whereas long-term survivors were disease-free for over 10 years. The groups differed in Ki-67 antigen and CEA expression in colon cancer, and CEA expression in rectal cancer that was limited to the metastatic lymph nodes. The immunohistochemical scores were higher in short-term survivors. Our data suggest that the characteristics of metastatic lymph nodes are important as a predictor of the aggressiveness of tumor behavior and that the expression of Ki-67 antigen or CEA there may be a useful indicators of patients' survival in Dukes' C colorectal cancer.

Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor agent in animal model and in patients with impaired renal function.

PURPOSE: S-1 is a novel oral fluorouracil antitumor drug that combines tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD), and potassium oxonate (Oxo). As 50% of CDHP is excreted in the urine, renal dysfunction may directly affect the DPD inhibitory effect and lead to increased 5-fluorouracil (5-FU) concentrations. We sought to determine the influence of impaired renal function on the pharmacokinetics of S-1 in an animal model and in patients with gastric cancer. METHODS: An experimental renal failure model induced by cisplatin was developed in rabbits, and plasma concentrations of FT, 5-FU, CDHP and Oxo were determined after S-1 injection. Four patients with various degrees of renal impairment with unresectable gastric cancer were recruited to the study, and the pharmacokinetics in these four patients were analyzed following single and consecutive S-1 administrations. RESULTS: In experimental renal failure, plasma clearance of CDHP and 5-FU was retarded corresponding to the degree of renal impairment and there was a close correlation between creatinine clearance (CLcr) and plasma CDHP and 5-FU clearance. In the single administration study, half standard dose was used in three patients (CLcr > or = 50 ml/min) and one-third in the other (CLcr <50 ml/min). In patients with CLcr more than 75 ml/min, C(max), T(max), AUC((0-infinity)), and T(1/2) of 5-FU and CDHP were not different between single and consecutive administrations. In contrast, in patients with mild and moderate renal dysfunction (CLcr 55 and 36 ml/min, respectively), the T(1/2) values of CDHP with consecutive administrations (7.6 and 15.3 h, respectively) were longer than the values with single administration (4.6 and 8.2 h, respectively). The T(1/2) of 5-FU was 5.7 h with single administration and 8.5 h with consecutive administration in patients with moderate renal impairment. The AUC((0-infinity)) of 5-FU with consecutive administrations (3089.7 ng.h/ml) was far greater than with single administration (430.4 ng.h/ml). There was also a strong correlation between CLcr and plasma CDHP clearance. Based on the pharmacokinetics following multiple consecutive administrations, S-1 administration resulted in no severe adverse reactions in any of the four patients. CONCLUSIONS: CDHP clearance was prolonged in the presence of renal impairment, leading to a delayed T(1/2), and high AUC of 5-FU. These findings demonstrate that administration of S-1 to patients with impaired renal function may need individualized dosing and pharmacokinetic monitoring.

[A case of lymph node recurrence after curative operation of type 4 gastric cancer, successfully treated with TS-1].

A 74-year-old male underwent left upper abdomen excision (LUAE) and D3 lymph node dissection for type 4 gastric cancer. Nine months after the surgery, abdominal computed tomography (CT) revealed paraportal lymph node recurrence (#8p), 22 mm in size. One hundred mg/body/day of TS-1 was administrated for 14 days, followed by 7 days rest, as one course. A complete response was obtained after the second course. This treatment was stopped after the 11 course because the patient suffered prolonged grade 1 fatigue. The patient has been in good health without a recurrence for 1 year and 5 months after the recurrence. Adverse effects included rash (grade 1), diarrhea (grade 2), fatigue (grade 2) and neutrophils neutropenia (grade 2).

[Limits of surgical therapy for pulmonary metastasis from breast cancer].

Sixteen cases of first pulmonary metastasis from breast cancer were reexamined. There was no significant difference between the operated and non-operated cases. The prognoses of both groups were unfavorable due to aggravation of the lung, including the pleural focus or other distant metastases. We found a surgical benefit in only selected cases such as comparatively advanced breast cancers with long disease-free intervals, and cases in which the differentiation with the primary lung cancer was difficult. We recommend a mildly invasive operation using video-assisted thoracic surgery in these cases.

[A case of metastatic gastric cancer treated with CDDP plus TS-1 and surgical resection].

UNLABELLED: Advanced gastric cancer (AGC) with liver metastasis has a poor prognosis. We encountered a case of AGC with multiple liver metastasis treated with chemotherapy and surgery. CASE: A 54-year-old male. He was admitted to our hospital with epigastric pain. Gastrointestinal fiberscope examination revealed gastric cancer. A CT scan showed regional and para-aortic lymph node (LN) swelling and multiple hepatic metastasis in the left hepatic lobe. The serum CEA level was 100.6 ng/dl. He was administered 4 courses of CDDP (100 mg (day 8 i.v.)) plus TS-1 (120 mg/day day 1-21 p.o.). After the chemotherapy, CT showed a reduction of liver metastasis and disappearance of the LN swelling. The serum CEA levels were normalized. Distal gastrectomy, partial hepatectomy, and microwave coagulation therapy were performed. After operation, he was administered 4 courses of CDDP/TS-1 additionally. Surgery may be one of therapeutic option for AGC with liver metastasis that has responded to chemotherapy, as in the present case.

[A case responding to weekly paclitaxel therapy as second-line chemotherapy for gastric cancer previously treated with TS-1].

A 58-year-old male patient with the recurrence of para-aortic lymphnodes after TS-1 treatment was treated by a weekly infusion of paclitaxel as second-line chemotherapy. Paclitaxel was administered at a weekly dose of 70 mg/m2/day for three weeks followed by a one week interval. After 2 courses, the tumor was reduced, and the reduction was judged as PR. Moreover, after 5 courses, the tumor was more remarkably reduced and the reduction was judged as CR. The grade 2 leukopenia, neutropenia, and grade 1 alopecia were observed as adverse events. Recently, we treated 11 patients of advanced or recurrent gastric cancers with measurable lesions, using the weekly paclitaxel therapy after TS-1 treatment. The response rate was 36.4%. The median duration of PR was 130 days. Therefore, a weekly paclitaxel regimen was considered to be one of the promising regimens for advanced or recurrent gastric cancer as the second-line chemotherapy after TS-1 treatment.

[Distilled water pleurodesis for two breast cancer patients suffering from carcinomatous pleurisy].

Pleural effusion of carcinomatous pleurisy is relatively common and a significant problem in recurrent breast cancer patients. It's very important to control it to keep a good quality of life for those patients. Two recurrent breast cancer patients, suffering from carcinomatous pleurisy and dyspnea due to pleural effusion, were treated with distilled water. As they have been treated with many kinds of hormonal therapy or chemotherapy for their several distant metastases, the performance status of these therapies has not been good. After one or two distilled water pleurodesis, pleural effusion was well controlled and dyspnea had disappeared. No adverse events, such as high fever and chest pain concerning this distilled water therapy were experienced. Taking its efficacy and a rarity of adverse events, distilled water plerodesis is a useful treatment for pleural effusion of carcinomatous pleurisy.

[Surgical indication and significance of local therapy for first pulmonary metastases from colorectal cancer].

We often observe pulmonary metastases in patients following advanced colorectal cancer, especially rectal cancer. The prognoses of LM3 patients and patients with histological v2 factor in the primary site were unfavorable. Surgery was not indicated in these cases. Some patients experienced rapid progression during the standby period for surgery. For the surgery group, we recommend systemic reexaminations after several months. Pulmonary resections for metastatic colorectal cancer are beneficial to the selected patients and 5-year survival rate was 52.6%. New pulmonary relapses were also encountered which were the cause of death among the surgical patients. Close follow-up and multimodal therapy including surgery contributed to longer survival for postoperative pulmonary metastatectomy patients with colorectal cancer.

Surgery for gastric cancer increases plasma levels of vascular endothelial growth factor and von Willebrand factor.

BACKGROUND: Angiogenesis and hemostatic activation are important factors in tumor progression and metastasis. Because surgical intervention induces tissue hypoxia and hemostatic activation, we analyzed the effect of gastric surgery on the plasma concentrations of vascular endothelial growth factor (VEGF), soluble P-selectin (sP-selectin), and von Willebrand factor (vWf). METHODS: Plasma VEGF, sP-selectin, and vWf concentrations were measured in 14 patients with gastric cancer before operation and on postoperative day 1 (POD 1). Correlations between disease stage and the effect of surgical intervention were analyzed. RESULTS: The plasma concentrations of these three factors did not correlate with the disease stage. Plasma levels of sP-selectin did not change after operation (before surgery, 87.6 +/- 34.1 ng/ml; on POD 1, 101.1 +/- 48.1 ng/ml; P = 0.123). Plasma VEGF and vWf concentrations were significantly elevated on POD 1 (VEGF, 33.3 +/- 20.5 pg/ml before surgery and 61.9 +/- 35.6 pg/ml on POD 1; P = 0.0013; vWf, 164 +/- 31.1% before surgery and 211.1 +/- 66.1% on POD 1; P = 0.027). CONCLUSION: Because VEGF and vWf are involved in angiogenesis, tumor-platelet adhesion, and tumor-endothelial cell adhesion, surgical intervention could influence tumor growth and metastasis.

The novel germline mutation of hMSH2 gene in a case of a colon cancer patient without family history.

Hereditary non-polyposis colorectal cancer (HNPCC) is generally found from the patient's family history. The functional disorder of mismatch repair genes has been reported to be responsible for HNPCC. The proband was a 28-year-old Japanese female who was admitted to our hospital with a diagnosis of descending colon cancer. Although there was no previous or family history of malignant disorders within the first- and second-degree relatives, the early onset of colon cancer prompted genetic analysis with suspicion of HNPCC. PCR analysis of the primary tumor showed DNA replication errors at the six microsatellite regions. PCR/direct sequential analysis of the peripheral lymphocytes revealed a germline frameshift mutation due to deletion of TTCAA at nt. position from 650 to 654 in exon 4 of the hMSH2 gene. According to the Human Mutation Database and International Collaborative Group on HNPCC Database, this type of the frameshift mutation is the first report in the hMSH2 gene.