It is known that polyethyleneglycol (PEG) modification of the liposome surface leads to the formation of a fixed aqueous layer around the liposomes due to interaction between the PEG polymer and water molecules, which prevents the attraction of opsonins. When a combination of PEG-distearolyglycerol (PEG-DSG) whose characteristics are remarkably different is used, interaction between molecules occurs, leading to increased fixed aqueous layer thickness (FALT). From this speculation, we studied the effect of both modification of PEG900-DSG and PEG2000-DSG modified liposome on FALT, cell uptake and biodistribution. The FALT of mixed PEG modified liposome increased, compared to that of each single PEG modified liposome. In this mixed modification, maximum FALT was shown at liposome modified by added PEG-2000:PEG-900=2:1. This most suitable additional ratio was equal to actual incorporated ratio. On the other hand, cell uptake of mixed modified liposome containing doxorubicin (DOX) was similar with that of PEG2000 modified liposome. Furthermore, mixed PEG modification of liposome was tendency to increase cytotoxicity, compared to that of other modifications. After DOX contained liposome treatment, DOX distribution in the tumor and antitumor activity of DOX increase by mixed PEG modification. In conclusion, it was suggested that mixed PEG liposome (PEG-2000:PEG-900=2:1) was useful for cancer chemotherapy.

This study evaluated an in vitro assay for chemosensitivity test using a collagen-gel droplet-embedded culture drug sensitivity test (CD-DST) for hepatocellular carcinoma (HCC). In 25 patients with HCC, in vitro chemosensitivity to 5-fluorouracil (5-FU), epirubicin (EPI), and cisplatin (CDDP) was examined by CD-DST, and 5-FU, EPI, and paclitaxel (PTX) were examined in 38 patients with breast cancer. Successful rates of chemosensitive evaluation by CD-DST were 64% for HCC and 79% for breast cancers. Although chemosensitivities of breast cancer were 5-FU 23.1%, EPI 83.3%, and PTX 67.7%, only one HCC sample was sensitive to EPI. Growth rates of HCC for 7 days of culture were significantly lower than those of breast cancers (1.04 vs 3.61). The culture methods for HCC in CD-DST should be improved to estimate accurate results.

We measured total Pt concentration in serum and tongue tissue in CDGP intraarterial infusion with male rats. Subjects were 40 male rats sorted into intraarterial infusion (n=20), intravenous infusion (n=20), and CDGP infusion groups at a dose of 10 mg/kg. Total Pt concentration was measured every 30 minutes for 120 minutes after CDGP infusion was completed. Total Pt concentration in tongue tissue was measured on the dosage and nondosage side. Total Pt concentration on the dosage side of tongue tissue of the intraarterial infusion group was higher than in the intravenous infusion group for 120 minutes. Total Pt concentration in intraarterial infusion group tongue tissue on the dosage side was higher than on the nondosage side for 120 minutes. Serum total Pt concentration, total Pt concentration in nondosage side tongue tissue, AUC of total Pt in serum, elimination half-life (t1/2) did not show a difference in the intraarterial or intravenous infusion groups. Total Pt AUC in tongue tissue on the intraarterial infusion group dosage side was greater than in others. In intraarterial infusion of CDGP, Pt concentration in tongue tissue is higher than in intravenous infusion. Serum Pt concentration, did not differ by group. This study showed that intraarterial infusion of CDGP has the potency to become a chemotherapy indication the same as intravenous infusion, in addition to the target organ.

One of selective estrogen receptor modulators (SERMs), tamoxifen, has been widely used for prevention of breast cancer, postoperative adjuvant therapy and treatment of advanced breast cancer. The relation of a long-term administration of tamoxifen and its adverse effects have been extensively investigated. Favorable effects of tamoxifen are:the reduction in the risk of contralateral breast cancer, gain in bone density in postmenopausal women and decrease in serum low-density lipoprotein cholesterol. Unfavorable effects are: gynecologic problems and the increase in the risk of endometrial cancer and thromboembolism. In contrast, another SERM, raloxifene, has reported to have similar favorable adverse effects but no unfavorable effect on endometrium.

The patient was a 58-year-old man who suffered from non-resectable gastric cancer, staged intraoperatively for peritoneal dissemination and paraaorta lymph node metastasis at another hospital in December 2002. He was initially treated with TS-1 as an outpatient. However, he was readmitted on March 4, 2003 for hematuria, general fatigue, jaundice and dyspnea. He was diagnosed with gastric cancer duodenum invasion, obstructive jaundice and lymphangitis carcinomatosa, and began weekly TXL as second-line chemotherapy on March 26. TXL (70 mg/ m2) was infused once a week for 3 weeks followed by a 1-week interval as one cycle. One week after the first infusion therapy, the jaundice and dyspnea were greatly improved. CT scan showed the lymphangitis carcinomatosa had disappeared and paraaorta lymph node metastasis was reduced to 60% after one cycle of the treatment. The toxic events were leukopenia (grade 1) and alopecia (grade 1).

We measured docetaxel (TXT) concentrations in the blood and ascites after drip infusion into each vessel and intraperitoneal cavity of a patient with advanced gastric cancer. The peak concentration was reached immediately (first time 244 ng/ml, second time 215 ng/ml) after the infusion of TXT (25 mg/m2) into the vessels. The concentration of TXT for ascites peaked after 30 min of drip infusion (first time 26 ng/ml, second time 30 ng/ml). AUC ascites/AUC blood was 27.2% and 35.8% respectively. This is the first report demonstrating the concentration of TXT in ascites after drip infusion into vessels. When TXT was administered into the peritoneal cavity, the peak concentration of ascites was reached immediately (54,200 ng/ml). After 240 min, the TXT concentration in the peritoneal cavity was still high (14,200 ng/ml). In blood, the level peaked (64 ng/ml) at 120 min. After 240 min, the TXT level in the blood remained 44 ng/ml. AUC blood/AUC ascites was only 0.25%. These results suggested that the transition rate of TXT from blood to intraperitoneal cavity was excellent, and that TXT was suitable for the treatment of peritoneal dissemination of gastric cancer. Furthermore, infusion of TXT (25 mg/m2) into the peritoneal cavity may directly and systemically provide its antitumor effect. If we prefer the antitumor effect directly, a much lower dose infusion of TXT may be recommended.

The stomatitis accompanying chemotherapy reduces a patient's QOL. Many reports have suggested that some kinds of gargling agents for oral mucositis shorten the duration and severity of symptoms. This study tested the prevention and efficacy against stomatitis of a herbal medicine (Syousaikotou) as a gargling agent for patients receiving chemotherapy. Compared to gargling with providone-iodine and amphotericin B, the Syousaikotou gargle showed a significantly decreased incidence of stomatitis, and a painkilling effect. Stomatitis occurred in about 17.4% among 23 chemotherapy cycles with the Syousaikotou gargle, against about 40.8% among 71 chemotherapy cycles without the Syousaikotou gargle. Among the patients suffering stomatitis pain after 22 chemotherapy cycles, the painkilling effect was seen to be 76.2%, and continues for about 2 hours. Critical side effects were not seen, but in 4 cases there were complaints about foul smells, such as oil and grass smells. Syousaikotou gargle was considered to be one of the useful methods against the stomatitis prevention and sharp pain mitigation from the chemotherapy.

In Gemcitabine treatment, elderly patients with unresectable pancreatic cancer are more likely to suffer from haematological and non-haematological adverse effects than non-elderly patients. Forty percent of the elderly patients were dropped from the initial protocol due to the adverse effects, mainly because of non-haematological events or symptoms. To avoid adverse effects, the administration schedule for Gemcitabine tended to be less often and at a lower dose for elderly patients among members of the Nagano Pancreatic Cancer Study Group. However, the fact that some cases showed a limited effect from this administration schedule albeit without adverse effect, might suggest that the frequency of ordinary administration schedule should be maintained, although the Gemcitabine dose could be decreased in unresectable pancreatic cancer patients in poor condition.

The effectiveness of chemotherapy for metastatic gastric cancer has been already revealed. But a standard chemotherapy has not been established yet. New agents such as TS-1, CPT-11 and taxanes are improving the response rates and also the survivals for gastric cancer. Including these new drugs, several randomized phase III trials are ongoing in Japan. In the near future, the candidate for standard resume will be sent abroad. In this article, we described the current state of CPT-11 combined chemotherapy for gastric cancer. Among various CPT-11- combined chemotherapy, CPT-11 + TS-1 is the most effective and less toxic treatment.

A 67-year-old woman visited our hospital with a chief complaint of epigastralgia. The patient was diagnosed as having unresectable pancreatic cancer because abdominal CT and angiography revealed a tumor that had invaded a common bile duct, portal vein and superior mesenteric vein. A palliative operation was performed because of obstructive jaundice. Peritoneal dissemination was observed and confirmed pathologically. The patient was treated with gemcitabine after the palliative operation. A gemcitabine 30 min i.v. infusion at a starting dose of 1,000 mg/m2 was administered once a week for 3 weeks with a 1-week rest. The patient experienced grade 2 leukocytopenia, so the dose of gemcitabine was reduced to continue the chemotherapy. The patient continued to undergo the palliative chemotherapy without severe adverse effects. As a result, the patient was in tumor dormancy for 15 months. It is important for the patient to induce an acceptable level of toxicity in clinical practice and to continue the chemotherapy.

A 69-year-old female patient underwent total gastrectomy with a D2 lymph node dissection. Her final findings were of pT2, pN0, sP0, sH0, sM0 and Stage IB. After thirty-five months from the operation, peritoneal recurrence with ascites, bilateral hydronephrosis and stenosis of colon was found. TS-1 (80 mg/day/body) was administered for four weeks followed by a 2-week rest after DJ stents were inserted into bilateral ureters. At the end of two courses of TS-1, ascites disappeared and the decrease of tumor marker was observed. During the seventh course, symptoms such as abdominal fullness and ascites became worse. She underwent a weekly administration of paclitaxel (90 mg/body) as a second-line chemotherapy. This regimen was continued for three weeks followed by a 1-week rest. After four courses of paclitaxel, ascites disappeared and the tumor marker was gradually reduced. However, multiple bone metastases were found during the eighth course, and she died about two years after the recurrence. The toxic events were mucositis (grade 1) in TS-1, and alopecia (grade 2) and leukopenia (grade 1) in paclitaxel. No major adverse effects were observed. Although the prognosis of recurrent gastric cancer with peritoneal dissemination was extremely poor, this case might suggest a possibility that intensive therapies are useful in maintaining the quality of life and improving survival.

We evaluated the safety of paclitaxel (TXL) via intraperitoneal (i.p.) administration in 6 patients with peritoneal dissemination of gastric cancer. Four patients were treated with TXL via i.p. administration at a dosage of 80-90 mg/m2 every 1 to 2 weeks. Grade 4 leukopenia was observed in 1 patient, accompanied with massive ascites. Two other patients, who also had malignant peritoneal effusion, were treated with TXL via i.p. administration at a dosage of 60 mg/m2 every 1 to 2 weeks. All toxicities were mild in those two patients. TXL via i.p. administration at a dosage of less than 90 mg/m2 has never been reported to cause a grade 4 leukopenia. These results suggest that a phase I/II study of TXL via i.p. administration should be tried in gastric cancer patients with malignant peritoneal effusion.

NK4 suppresses invasion and metastasis of tumor cells by means of dual actions as HGF antagonist and angiogenesis inhibitor. Our previous studies showed that NK4 suppresses the implantation of tumor cells to the peritoneal milky spots (MS) by intraperitoneal injection (i.p.) of adenovirus vector expressing NK4 (Ad-NK4) or NK4 gene-transfected tumor cells. In the present study, we investigated the antitumor mechanisms of NK4 in the suppression of peritoneal implantation. When evaluated by a fluorescent microscopy, a prior injection of Ad-NK4 suppressed peritoneal implantation immediately after the injection of GFP-expressing tumor cells. DNA microarray analyses also demonstrated a reduced expression of some adhesion molecules in NK4 gene-transfected tumor cells as compared to neomycin gene-trasfected cells (control). In the in vitro adhesion assay, the adhesion to some types of the extra cellular matrixs (ECM) was significantly decreased in NK4 gene-transfected cells as compared to the control. These results suggest that NK4 may suppress peritoneal implantation by inhibiting adhesion of tumor cells to ECM around MS.

We report the case of a 79-year-old female with gastric cancer accompanied by liver metastasis that was successfully treated by TS-1, a novel oral fluoropyrimidine derivative. Abdominal CT scan showed a low-density area in the lateral segment of the liver and lymph node swelling in the right side of the abdominal aorta. One treatment course consisted of 4 weeks of TS-1 administration (100 mg daily) followed by a 2-week break. After 2 courses of this treatment, an abdominal CT scan showed no evidence of liver metastasis and a reduction of lymph nodes metastasis. The serum level of CA19-9 was reduced from 780 U/ml to within a normal range. Grade 1-2 toxicity (nausea and diarrhea) was seen after 2 courses. We conclude that TS-1 may be beneficial in the treatment of the liver metastasis of gastric cancer.

A 60-year-old male was referred to our hospital because of cervical lymphadenopathy and a left hilar abnormal shadow seen on chest X-ray in May 1999. The pathological findings of the cervical lymph nodes revealed that the patient had a malignant lymphoma, of the diffuse large B cell type, at clinical stage IIIB. Immunohistochemistry demonstrated that the lymphoma cells were positive for CD11a, CD19, CD20, CD23, CD25, CD45, IgM, IgD and lambda, but negative for CD5. Although a complete remission was obtained after 8 courses of CHOP therapy, the patient relapsed 32 months later. Two courses of a half dose of CHASE therapy consisting of CPM, ara-C, VP-16 and dexamethasone, followed by rituximab (600 mg/week x4) resulted in a transient re-induction of complete remission. However, multiple cutaneous tumors became apparent just 10 days after the last rituximab therapy. Immunohistochemistry of the cutaneous tumors revealed infiltration of CD20-negative lymphoma cells. A series of chemotherapy including high-dose MTX was ineffective, and the patient died in August 2003. Autopsy findings revealed the systemic intra-capillary infiltration of CD20 negative-lymphoma cells into multiple organs, including the lungs, liver, and kidneys. A CD20 negative-clone selected by rituximab therapy appeared to have expanded in this case.

We report a case of 5-year-old boy with acute lymphoblastic leukemia who developed interstitial pneumonitis induced by methotrexate (MTX). The patient was hospitalized with fever, cough, dyspnea and hypoxemia during maintenance treatment with low dose MTX and 6-mercaptopurine. A diagnosis of MTX pneumonitis was made based on the clinical findings, viral and serologic studies, negative microbiology and the radiological features. The patient recovered after cessation of the MTX treatment. Interstitial pneumonitis caused by MTX is well-recognized and the prevalence has been estimated to be 0.3-7.5% among patients with adult rheumatoid arthritis. However, there are few reports in the literature regarding this adverse effect in patients with leukemia. Furthermore, very few cases of childhood leukemia have been reported regarding MTX induced interstitial pneumonitis. Physicians should be aware of this rare complication during maintenance treatment with weekly low dose MTX for acute lymphoblastic leukemia in children.