Among patients undergoing surgical resection for extrahepatic cholangiocarcinoma, invasive carcinoma at the ductal resection margins appears to have a significant relation to local recurrence and also a significant negative impact on survival, whereas residual carcinoma in situ does not. Discrimination whether carcinoma in situ or invasive carcinoma is present is important in clinical setting in which the resection margin at the ductal stump is positive.

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Background: Cisplatin is widely used in combination chemotherapy against a variety of tumors; however, the optimal administration schedule of cisplatin is still controversial. To clarify the pharmacokinetic differences according to the administration schedules of cisplatin, we compared three different administration schedules of cisplatin such as single short-term infusion, daily short-term infusion and daily continuous infusion in combination with 5-fluorouracil. Preliminary clinical responses and toxicities were also investigated. Methods: A total of 12 courses in combination of cisplatin and 5-fluorouracil therapy was studied. The schedules of cisplatin tested were as follows: single short-term infusion (80 mg/m 2 , day 1,2 h div., n =4),daily short-term infusion (20mg/m 2 , days 1 to 5, 2 h div., n =4), daily continuous infusion (100 mg/m 2 , 120 h, n = 4). In all schedules, 5-fluorouracil was continuously administered at a dose of 800 mg/m 2/day on days 1 to 5. The area under the time-concentration curve (AUC) and the maximum concentration (C max ) of total and free Pt were investigated. Results: The highest AUC of total and free Pt and the lowest C max of free Pt were observed in the daily continuous infusion (total AUC; 162.53± 18.39~g h/ml, free AUC; 5.50±0.9~g h/ml, free Cmax; 0.07±0.01 Ilg /ml, mean ± SEM).Two patients in the single short-term infusion and one patient in the daily continuous infusion indicated partial responses clinically. No nephrotoxicity or ototoxicity was observed. All toxicities were mild and tolerable in all regimens; however, the incidence of GI toxicity in daily continuous infusion seemed to be relatively higher. Conclusions: Daily continuous infusion of cisplatin gave the best pharmacokinetic results and to evaluate the clinical advantage of this schedule a prospective randomized trial should be conducted with sufficient numbers of patients.

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These results suggest that AngII-EGFR cross-talk signaling mediated by ADAMs is involved in the proliferation and invasion activities of several HCC cell lines.