Toshikazu Sakuyama

Predicting 5-FU sensitivity using human colorectal cancer specimens: comparison of tumor dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase activities with in vitro chemosensitivity to 5-FU

Abstract.Background: In tumor cells, the enzyme orotate phosphoribosyl transferase (OPRT) contributes to 5-fluorouracil (5-FU) phosphorylation and another enzyme, dihydropyrimidine dehydrogenase (DPD), is associated with 5-FU catabolic action. We measured OPRT and DPD activities and, to determine whether their levels might serve as indicators of 5-FU sensitivity, simultaneously assayed in vitro chemosensitivity to 5-FU. Methods: Tissue specimens were obtained from colorectal cancer patients and in vitro chemosensitivity was tested using fluorescein diacetate assay (FDA) or histoculture drug response assay (HDRA). DPD and OPRT activities were measured by radioassay. Results: The chemosensitivity assay was performed on 62 colorectal cancer specimens. Results were evaluable in 29 of 30 cases (96.7%) for FDA and 30 of 32 cases (98.3%) for HDRA. The positive sensitivity rate was 37.9% by FDA assay and 30% by HDRA assay. In positive specimens, the mean DPD activity was 44.9 ± 32.6 pmol/min per mg protein, and in negative specimens, it was 53.8 ± 33.7 pmol/min per mg protein (P = 0.875). In contrast, the mean OPRT value was significantly higher in positive specimens (0.418 ± 0.180 nmol/min per mg protein) than in negative specimens (0.325 ± 0.153 nmol/min per mg protein; P < 0.05). The chemosensitivity test proved positive in 60% of the specimens with ORPT activity of 0.413 or above and 50% of those with DPD activity of 30 or below. Of the patient specimens showing OPRT activity of 0.413 or above and DPD activity of 30 or below, 88.9% were positive for 5-FU sensitivity, suggesting the possibility that the combination of these two levels may be predictive of 5-FU positive sensitivity. Conclusion: DPD and OPRT activities within cancer cells may predict positive sensitivity to 5-FU.

Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial).

PURPOSE We compared biweekly irinotecan plus cisplatin (BIRIP) with irinotecan alone as the second-line chemotherapy (SLC) for advanced gastric cancer (AGC). METHODS Patients with metastatic or recurrent gastric cancer refractory to S-1-based first-line chemotherapy were randomly assigned to receive BIRIP (irinotecan 60mg/m(2) plus cisplatin 30mg/m(2), every 2weeks) or irinotecan alone (irinotecan 150mg/m(2), every 2weeks). The primary end-point was to show the superiority of BIRIP to irinotecan in terms of progression free survival (PFS). RESULTS 130 patients were enrolled. PFS was significantly longer in the BIRIP group (3.8months [95% confidence interval (CI) 3.0-4.7]) than in the irinotecan group (2.8months [2.1-3.3]; hazard ratio 0.68, 95% CI 0.47-0.98; P=0.0398). Median overall survival was 10.7months in the BIRIP group and 10.1months in the irinotecan group (HR 1.00, 95% CI 0.69-1.44, P=0.9823). The objective response rate was 22% in the BIRIP group and 16% in the irinotecan group (P=0.4975). However, the disease control rate was significantly better in the BIRIP group (75%) than in the irinotecan group (54%, P=0.0162). The incidences of grade 3 or worse adverse events did not differ between the two groups. Any grade elevation of serum creatinine was more common in the BIRIP group (25% versus 8%, P=0.009), but any grade diarrhoea (17% versus 42%, P=0.002) was more common in the irinotecan group. CONCLUSION BIRIP significantly prolonged PFS as compared with irinotecan alone and was tolerated as SLC, but did not demonstrate the survival benefit in this trial.

Second-line Chemotherapy with Biweekly Paclitaxel after Failure of Fluoropyrimidine-based Treatment in Patients with Advanced or Recurrent Gastric Cancer: a Report from the Gastrointestinal Oncology Group of the Tokyo Cooperative Oncology Group, TCOG GC-0501 Trial

OBJECTIVE A multicenter trial was conducted to evaluate the efficacy and safety of paclitaxel every 2 weeks in patients with advanced or recurrent gastric cancer who had previously received fluoropyrimidine-based chemotherapy. METHODS The subjects were patients with gastric cancer who had disease progression or recurrence while receiving fluoropyrimidine-based chemotherapy. All patients had adequate major organ functions with an Eastern Cooperative Oncology Group performance status (PS) of 0-2. Paclitaxel 140 mg/m(2) was administered intravenously on days 1 and 15 of a 4-week cycle. The primary endpoint was the response rate. Secondary endpoints were progression-free survival (PFS), overall survival and safety. RESULTS Response was assessable in 40 of 41 enrolled patients. Their median age was 63 (range: 48-77) years, and PS was 0 in 22 patients, 1 in 13 and 2 in 5. Previous treatment included S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) monotherapy in 32 patients and S-1-based combination therapy in 5. The median number of administered courses of paclitaxel was 3.5 (1-14). The response rate was 17.5% (95% confidence interval: 7.3-32.8%, partial response: 7, stable disease: 21, progressive disease: 10 and not evaluable: 2). The disease control rate was 70.0%, the median PFS was 111 days and the median overall survival was 254 days. Major adverse events of Grade 3 or 4 were neutropenia (27.5%), anemia (12.5%), diarrhea (2.5%) and sensory neuropathy (2.5%). CONCLUSIONS Biweekly paclitaxel seemed to be one of the useful chemotherapies after failure of fluoropyrimidine-based treatment in patients with advanced or recurrent gastric cancer.

An autopsy case of pseudosarcoma of the common bile duct

An autopsy case of pseudosarcoma in the common bile duct is reported. An 82-year-old Japanese male complaining of jaundice was admitted to our hospital; he was examined by abdominal ultrasonography (US), revealing biliary calculus, dilatation of the common bile duct, and choledocholithiasis, considered to be the possible cause of the obstructive jaundice.Endoscopic retrograde biliary drainage (ERBD) and cholangioscopy were performed concurrently, revealing a vaguely whitish tumor near the papilla of Vater. Two months later, the patient died from complications of the liver, infection, and disseminated intravascular coagulation (DIC). An autopsy study revealed tumor cells with extreme pleomorphic changes, growing diffusely, very like sarcoma. Further examination revealed epithelioid arrangements in the metastatic lymph node. Twelve kinds of immunohistochemical examination showed a positive reaction, reflecting the presence of an epithelioid cytoskeleton. Of 28 cases of true and pseudosarcoma of the biliary system reported in the Japanese literature, only 1 case was reported, in 1990, to involve the common bile duct. We therefore report the present case of pseudosarcoma of the common bile duct.

Early measurement of urinary N-acetyl-β-glucosaminidase helps predict severe hyponatremia associated with cisplatin-containing chemotherapy

BACKGROUND Although cisplatin is a widely used anticancer drug for treating various types of cancer, its clinical application is limited by severe systemic toxicities, such as nephropathy, hematologic toxicity, and gastrointestinal toxicity. There are no reliable and validated biomarkers to predict adverse events caused by cisplatin. METHODS Sixty-six patients who underwent cisplatin-containing first-line chemotherapy between June 2010 and November 2013 were retrospectively analyzed. Data on urinary N-acetyl-β-glucosaminidase activities measured 24-48 h after cisplatin infusion were retrieved, and adverse events during the first course of chemotherapy were recorded according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS Patient characteristics were: male/female 60/6, median age 65 (range 36-78) years, esophageal/gastric/other cancer 60/4/2, chemotherapy regimen docetaxel-cisplatin-fluorouracil/fluorouracil-cisplatin/S-1-cisplatin 54/8/4, cisplatin dose (mg/sm) 60/70/80 16/43/7. Grade 3/4 adverse events were leukopenia (40.9%), neutropenia (54.4%), febrile neutropenia (37.9%), hyponatremia (28.8%), and acute kidney injury (37.9%). Patients with 20 units/gram creatinine or higher urinary N-acetyl-β-glucosaminidase developed statistically lower minimum serum sodium concentration (median 126 vs. 134 mEq/L, p = 0.0053). There were no significant correlations between urinary N-acetyl-β-glucosaminidase and the development of other severe adverse events. CONCLUSION Early significant increase in urinary N-acetyl-β-glucosaminidase predicts subsequent development of severe hyponatremia after cisplatin-containing chemotherapy.

Complete response of esophageal small cell carcinoma amrubicin treatment

Small cell carcinoma of the esophagus (SmCCE) is a rare and aggressive disease known to have a poor prognosis. SmCCE patients are generally treated with a chemotherapeutic regimen for small cell lung cancer. Salvage therapy for patients with relapsed or refractory tumors has not yet been established. A 63-year-old man with extensive SmCCE was treated with chemotherapy consisting of cisplatin (CDDP) and irinotecan (CPT-11). After the second course of CPT-11/CDDP, the celiac lymph node increased in size. Amrubicin (AMR) as second-line chemotherapy was started. The patient had a complete response after the fifth course of AMR, resulting in an 8-month progression-free survival after initial administration. This case suggests that, as in small cell lung cancer, AMR is effective for SmCCE.

Randomized phase III trial of irinotecan plus cisplatin versus irinotecan alone after S-1 based chemotherapy failure for patients with advanced and recurrent gastric cancer (AGC) (TCOG GI-0801).

61 Background: S-1based chemotherapy is the standard first-line chemotherapy for AGC in Japan. Currently, there is no high level evidence established for second-line treatment. Irinotecan (CPT-11) plus cisplatin (CDDP) are active in AGC. The combination of these 2 agents is synergistic effect in preclinical and clinical studies. We conducted a phase III study of CPT-11 plus CDDP (CP) compared with CPT-11 alone (C) in patients with AGC refractory to S-1 based chemotherapy. Methods: Patients with previously treated with S-1-based chemotherapy for AGC, an ECOG PS of 0-1 and adequate organ functions were randomly assigned to receive either CPT-11 60 mg/m2 plus CDDP 30 mg/m2 on day 1 every 2 weeks or CPT-11 150mg/m2on day 1 every 2 weeks. The primary endpoint is progression free survival (PFS). The statistical design is based on superiority hypothesis; PFS is 110days in CP, 65days in C; two-sided α=0.05, 1-β=0.8; and planed accrual is 130 pts. Secondary endpoints include Overall Survival (OS), Time to Treatmen...

Drug delivery system in pain control Methods, procedures, and techniques for the pain control

疼痛管理の最大の目的は, 傷害された組織による痛みのストレスを最小限にすることである. 本稿では, 疼痛管理によく用いられている, 神経ブロック, 薬物療法, 種々の持続注入ポンプによる薬物投与方法について, 最近の調査結果を交えて概説した. 近年, 携帯型精密輸液ポンプは, いずれも持続投与機能に患者自己管理鎮痛法(PCA)機能をプラスし, 小型化し在宅患者にも使用可能になった. また, ディスポーザブル注入ポンプは携帯型輸液ポンプにくらべ, 機器購入の初期費用が不要で, 導入しやすい利点がある.