An early phase II study of a new camptothecin analog and an inhibitor of topoisomerase I, CPT-11, was conducted in 62 patients with refractory leukemia and lymphoma by four different treatment schedules in a multiinstitutional cooperative study. CPT-11 therapy resulted in four complete remissions (CRs) and three partial remissions (PRs) in 29 assessable non-Hodgkin's lymphoma (NHL) patients, one PR in three Hodgkin's disease (HD), one CR and one PR in 11 acute lymphoblastic leukemia (ALL), and one PR in 15 acute myelogenous leukemia (AML) patients. Single infusion of 200 mg/m2 every 3 to 4 weeks produced no response in both leukemia and lymphoma patients. Sixty-minute infusions of 40 mg/m2/d for 5 days every 3 to 4 weeks or for 3 days weekly produced four CRs (17%) and four PRs (17%) in 24 patients with malignant lymphoma. Sixty-minute infusions of 20 mg/m2 twice a day for 7 days every 3 to 4 weeks resulted in one CR and two PRs in 12 patients with acute leukemia. No response was seen in an acute leukemia patient by another treatment schedule. CPT-11 was effective in two (15%) of 13 primarily refractory leukemia and lymphoma cases, in two of four relapsed cases, and in seven (17%) of 41 relapsed and refractory cases. Major side effects were leukopenia (91%) and gastrointestinal (GI) (76%). CPT-11 was shown to be effective against refractory leukemia and lymphoma, and thus deserves further clinical study; the novel antitumor activity mode of this drug predicts no cross-resistance to presently available antitumor drugs.

Summary Chemical structures of the sugar chains of various human ax-fetoprotein (AFP) species with different affinity for Concanavalin A (Con A) and Lens culinaris agglutinin (LCA) were examined by pyridylamination of their oligosaccharides and stepwise exoglycosidase digestion. Using reversed-phase and size-fractionation high performance liquid chromatography systems we identified six pyridylamino-sugar chains. The Con A-reactive and LCA-nonreactive species of AFP from patients with hepatocellular carcinoma contained a biantennary sugar chain, and the Con A-reactive and LCA-reactive species had a biantennary one with a fucose residue at the innermost N-acetylglucosamine residue. The Con A-nonreactive and LCA-reactive species contained a biantennary sugar chain both with a bisecting-N-acetylglucosamine residue at the trimannosyl core and with a focuse residue at the innermost N-acetylglucosamine residue. The Con A-nonreactive and LCA-nonreactive species contained a fucosylated triantennary sugar chain as a major component, and two minor components: a triantennary sugar chain and a biantennary sugar chain with a bisecting-N-acetylglucosamine residue at the trimannosyl core. Thus, the fucosylated and non-fucosylated triantennary sugar chains were newly identified in human AFP. Essentially identical results were obtained for AFP from the patient with gallbladder carcinoma which metastasises to the liver. These results indicate that the increment in fucosylation and branching to form new antennae is a characteristic feature of the carbohydrate chains of AFP from patients with neoplastic diseases of the liver.

The degrees of glucosaminylation (glucosaminylation index) and fucosylation (fucosylation index) of alpha-fetoprotein (AFP) were determined in serum samples of 351 patients with hepatocellular carcinoma (HCC), 47 with carcinoma metastatic to the liver from digestive organs, five with mixed cholangiocellular and HCC, and 176 with benign liver diseases. The glucosaminylation index of AFP in patients with carcinoma metastatic to the liver (42 +/- 23%, mean +/- SD) was significantly higher than that in patients with HCC (5 +/- 7%, P less than 0.001) or that in patients with benign liver diseases (2 +/- 4%, P less than 0.001). The fucosylation indices of AFP in patients with carcinoma metastatic to the liver, with HCC, and with benign liver diseases were 76 +/- 25%, 42 +/- 30%, and 4 +/- 6%, respectively. Thus, the fucosylation indices of AFP were high in two neoplastic liver diseases (carcinoma metastatic to the liver and HCC) and low in benign liver diseases, whereas the glucosaminylation indices were high in carcinoma metastatic to the liver but low in HCC and benign liver diseases. When the values of 30% and 80% were used as the level of the glucosaminylation and fucosylation indices, respectively, to discriminate carcinoma metastatic to the liver from HCC, 40 of 47 patients with carcinoma metastatic to the liver (85%) were able to be discriminated from HCC (sensitivity). The specificity, the positive predictive value, and the overall accuracy were 86% (302/351), 45% (40/40 + 47 + 3 - 2) and 86% (40 + 302/47 + 351), respectively. These data suggest that the combined information in these two indices provides a potent criterion for the diagnosis of neoplastic diseases of the liver.

Thirty-eight patients with adult acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) were treated intravenously with (2"-R)-4'-o-Tetrahydropyranyladriamycin (THP) at a dose of 10 mg/m2 for 5 consecutive days. Seven complete and 15 partial responses were observed in 35 evaluable patients (overall response rate, 62.8%). Both antitumor activity and antitumor spectrum were similar to those for doxorubicin. Since the patients who had had chemotherapy previously, including other kinds of anthracycline, responded rather poorly to THP, cross-resistance between THP and other anthracyclines may be present. Leukopenia and thrombocytopenia were dose-limiting factors. Nausea and vomiting episodes were mild, and epilation was also minimal. Although the observation period was short and a cumulative dose was not large enough to evaluate cardiotoxicity, there were no abnormal EKG changes or clinical signs of cardiotoxicity in this study. THP is a potent antitumor agent in the treatment of lymphoid malignancies.

We report here on three patients with cirrhosis for whom an early recognition of hepatocellular carcinoma was made possible by the measurement of the degree of fucosylation (fucosylation index) of alpha-fetoprotein. Increased levels of this index associated with a moderate increment of serum concentration of alpha-fetoprotein were observed in three patients with cirrhosis who showed no indication of hepatocellular carcinoma by several imaging modalities. Four years after the onset of an increase in the fucosylation index, small hepatocellular carcinoma with a tumor diameter less than 2 cm was revealed in case 1. In cases 2 and 3, small hepatocellular carcinomas were detected 24 mo and 9 mo, respectively, after the first sign of the increase in the index. However, the development to hepatocellular carcinoma was not detected in five patients with cirrhosis in whom continuous increments of serum concentration of alpha-fetoprotein with low levels of fucosylation index were observed during the prospective follow-up from 3 to 9 yr. These findings indicated that the fucosylation index of alpha-fetoprotein can be used as an aid in an early recognition of hepatocellular carcinoma, especially in patients with cirrhosis during the follow-up process in which the moderate increment of serum concentration of alpha-fetoprotein is noted.