Stephen Davis

A randomized trial of three cisplatin-containing regimens in advanced non-small-cell lung cancer (NSCLC) : a study of the Umbrian Lung Cancer Group

SummarySurvival in patients with locally advanced (stage III Mo) and metastatic (M1) non-small-cell lung cancer (NSCLC) is short. Phase II studies have reported objective responses ranging from 20% to 60% using cisplatin-based chemotherapeutic regimens, yet few have shown improvement in median survival. In our phase II pilot studies with cisplatin (CDDP) and etoposide (VP-16), we observed a 26% response rate; with CDDP, VP-16, and mitomycin-C, a 38% response rate was obtained in advanced NSCLC patients. A total of 156 consecutive patients with locally advanced and metastatic NSCLC were randomized to one of three treatment arms to determine whether the chemotherapy protocols had any effect on response rate and median survival in a large, randomized study. Arm 1 consisted of CDDP (120 mg/m2 × 3 weeks); arm 2, of CDDP (120 mg/m2) and VP-16 (100 mg/m2 given i.v. on days 1–3), repeated every 3 weeks; and arm 3, of CDDP (120 mg/m2) and VP-16 (100 mg/m2 on days 1–3) given every 3 weeks, plus mitomycin C (10 mg/m2 on days 1, 21, and 42, then every 6 weeks, for a maximal dose of 100 mg). After 71 patients had been enrolled in the study, we stopped accrual in the CDDP arm due to a lack of response [1 complete response (CR) in 24 patients; 4%] and continued enrollment in the two combination-chemotherapy arms. In the CDDP/VP-16 arm a 30% response rate [1 CR, 18 partial responses (PRs)] was obtained, and in the CDDP/VP-16 mitomycin C arm a 26% response rate (4 CRs, 11 PRs) was seen among a total of 150 evaluable patients. Responses were observed in 31% of patients with favorable performance status (PS) (ECOG 0–1) vs 14% in patients with a poor PS (ECOG 2–3). Of patients with locally advanced disease (III Mo), 17 (33%) obtained an objective response, compared with 20 patients (20%) with metastatic disease. Median survival was 18 weeks in the CDDP arm, 35 weeks in the CDDP/VP-16 arm, and 37 weeks in the CDDP/VP-16/mitomycin C arm. The median survival in the multimodal chemotherapy arms was significantly greater than that obtained with CDDP alone. Toxicity was predominantly myelosuppression in the mitomycin C-containing arm (27%, wtto grade 3–4). Our study shows that combination chemotherapy using CDDP/VP-16 is active and safe in the treatment of advanced NSCLC patients with a good performance status. The addition of mitomycin C did not improve the therapeutic response.

Expression of aphidicolin-induced fragile sites in lymphocytes of patients with breast cancer

The expression of fragile sites induced by aphidicolin (APC) was evaluated on metaphase chromosomes obtained from the peripheral blood lymphocytes of 26 women with breast cancer and 15 sex- and age-matched normal controls. Both the proportion of damaged cells (P < 0.001) and the mean number of gaps and breaks per cell (0.02 < P < 0.05) were significantly higher in the patient group. There were no differences in either the age-related fragile site levels or the expression of single fragile sites between patients and controls. Our findings indicate an increased genetic instability in women with breast carcinoma.

A distinct β-hexosaminidase isoenzyme separated from human leukemic lymphocytes and myelocytes

The beta-hexosaminidase (EC 3.2.1.30) isoenzymes were separated on the basis of their carbohydrate moieties by an affinity chromatography using immobilized phenylboronate. Normal lymphocytes and granulocytes contain two major forms of beta-hexosaminidase, acute lymphoblastic, acute myeloblastic, chronic lymphocytic and chronic myelocytic leukemic cells contain an extra, distinct isoenzyme of beta-hexosaminidase. This extra isoenzyme may be a marker for the leukemic conversion of hematopoietic tissue.

A mature thymocyte-like phenotypic pattern on human cord circulating T-lymphoid cells

Cord blood samples from healthy full-term newborns were tested with antimature and antiimmature lymphoid-cell monoclonal antibodies, as well as more traditional markers, in order to identify the phenotype of circulating precursor cells. The results demonstrated that human cord blood contains a lower number of OKT3+, E-rosetting mature T cells than adult blood, very high levels of OKT10+ cells, and few OKT9+, OKT8+OKT3−, and OKT4+OKT3− cells. Although the finding of OKT9+ and OKT10+ cord circulating cells could be indicative of cell activation, double marker studies in newborn blood pointed to phenotypically immature lymphoid subsets at different stages of maturation, according to Reinherzs hypothesis. In addition, the absence of nuclear Tdt-positive and hot-rosetting cells, together with the fact that most of these are OKT3+, OKT10+, OKT4+, or OKT8+ cells, suggests that the surface phenotype of newborn lymphocytes is similar to that of mature thymocytes.

Monoclonal antibody-defined T-cell phenotypes and phytohemagglutinin reactivity of E-rosette-forming circulating lymphocytes from untreated chronic myelocytic leukemia patients

T‐cell phenotypes, as defined by murine monoclonal antibodies, (OKT3, OKT4, OKT8, OKIaI), and phytohemagglutinin (PHA) reactivity, were evaluated in E‐rosette forming cells (T‐cells) from 10 untreated chronic myelocytic leukemia patients. The proportion of T4+ cells was lower in patients than in controls (41.6 versus 61.7%, P < 0.02); whereas the proportion of T8+ cells was similar in patients and controls. The decrease in T4+ cells in CML resulted in a decrease in circulating T4+/T8+ ratio (P < 0.02). The la1+ T‐cells were increased in most CML (8 of 9) patients, white control subjects never displayed la1+ T‐lymphocytes (P < 0.01). The PHA reactivity of E‐rosette forming lymphocytes was significantly impaired in CML patients with respect to controls (P < 0.02). The presence of la antigen on T‐cells was positively correlated with the T8+ cell phenotype (P < 0.001) and inversely correlated with the T4+ (helper) cell phenatype (P < 0.05). Furthermore, there was a trend towards an inverse correlation between the PHA response and the level of lal+ or T8+ cells, there is no correlation between PHA reactivity and T4+ phenotype. The results suggest that the T‐lymphocyte population from untreated CML patients is intrinsically abnormal.

Cisplatin, etoposide, and mitomycin in the treatment of non-small cell carcinoma of the lung. A pilot study.

A total of 39 patients with non‐small cell carcinoma of the lung (NSCL) were treated with cisplatin, etoposide, and mitomycin. A major response rate (complete response + partial response) was seen in 15 patients (39%). Median survival for all patients was 340 days; median survival of the responding group was 514 days. Toxic effects included moderate hematologic toxicity, nausea, and vomiting. There were no treatment‐related deaths. This regimen clearly is effective in treating NSCL. Cancer 58:1018‐1019, 1986.

Microangiopathic Hemolytic Anemia and Pulmonary Small-Cell Carcinoma

Excerpt To the editor: Microangiopathic hemolytic anemia (1) is a rare but well-documented complication of malignant diseases. According to Horne and Cooper (2) only 59 cases have been reported, al...

Distinct α-L-Fucosidase Isoenzyme Profiles in Human Leukemic Cells

alpha-L-Fucosidase (EC 3.2.1.51; FUS) activity and isoenzyme characteristics were analyzed in normal lymphocytes, normal granulocytes (PMNs) and myeloid and lymphoid leukemic cells, (AML, AMMoL, ALL, CLL and CML). CLL lymphocytes had a lower mean specific activity than normal lymphocytes (2.5 v 4.0, p less than 0.05). ALL blasts had a higher mean specific activity compared to normal lymphocytes (9.7 v 4.0; p less than 0.001), CLL lymphocytes (9.7 v 2.5; p less than 0.001) and AML blasts (9.7 v 7.6 p = NS). Normal PMNs had a higher mean specific activity than normal lymphocytes (7.0 v 4.0 p less than 0.05) but similar activity when compared to CML cells or AML blasts. Blasts from AMMoL patients had higher activity than normal PMNs (9.0 v 7.0; p less than 0.05). The isoenzyme patterns of normal and leukemic granulocytes and lymphocytes were obtained by automated chromatofocusing on PBE-94 microcolumns with normal and leukemic lymphocyte lysates. With normal and leukemic lymphoid lysates two major isoenzyme components (B and A) were isolated. The isoenzyme pattern of PMN, AML, CML and AMMoL revealed 3 major peaks (B, A, I), totally different from that seen in lymphoid cells. The patterns of AML, CML and PMN appeared to be similar to each other; however, the isoenzyme pattern obtained from AMMoL cells could be distinguished from the others by a prominent I peak. Thus the FUS isoenzyme profile distinguishes the blasts of AMMoL from AML, and AMMoL and AML from ALL.

Vindesine and mitomycin C in chemotherapy: refractory advanced breast cancer.

Thirty‐five unselected postmenopausal women with metastatic breast carcinoma, refractory to hormonal manipulation and/or chemotherapy, were treated with vindesine (3 mg/m2 day 1, then weekly for 6 weeks, then every other week) and mitomycin (12 mg/m2 day 1, then every 6 weeks). Thirty‐one patients were evaluable for response. Two patients obtained a complete response (CR), three patients a partial response. Duration of the response in the two patients with CR was 24 and 16 months, respectively. Toxicity was mild, consisting of leukopenia and neurologic toxicity. Thrombocytopenia was not a significant clinical problem. Vindesine with mitomycin C, as administered in this study, is a safe, but marginally effective regimen for previously treated patients with metastatic breast cancer.

Alteration of β-hexosaminidase activity and isoenzymes in human leukemic cells

Abstract β-Hexosaminidase (EC 3.2.1.20; Hex) activity and isoenzyme characteristics were analyzed in human normal and leukemic leukocytes. Unseparated CLL and CML cells had a specific activity that was lower, whereas ALL and AML blasts had a higher specific activity than normal lymphocytes and granulocytes. CLL B-cells had a lower specific activity compared with that in normal non-T-lymphocytes; CLL T-cells and normal T-cells had similar activity. Isoenzyme separation was performed by chromatofocusing on PBE-94 coupled with an automated enzyme assay. When using a single linear pH elution gradient, normal leukocytes and all leukemia cells contained two forms of isoenzyme (B and A). When a double pH elution gradient was performed, an extra distinct form of Hex (I) was recorded. Hex I was present in small amounts in normal granulocytes and PHA-stimulated normal lymphocytes; isoenzyme I was found in high amounts in all leukemias tested. The activity ratios I/B and I/A, as well as the I isoenzyme profile, may facilitate differentiation between normal and leukemic cells and between lymphoblastic and myeloblastic leukemias.