Therapeutic progress--review VIII. Do the newer cytotoxic drugs represent a significant advance in the treatment of cancer?
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Biomedical subjects
Publications and source records attributed to G Blackledge.
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121 CT scans were obtained in 75 women with ovarian cancer, including 108 scans of the abdomen and pelvis and 13 of the pelvis alone. 70 patients had epithelial carcinoma. In 48 cases, pelvic CT was performed within 3 weeks after surgery, confirming the operative findings in all but 6. In the abdomen, CT identified intrahepatic deposits and minimal ascites not seen at surgery; however, small peritoneal deposits not usually shown by CT were readily found at surgery. CT was superior to clinical examination, detecting unsuspected disease and delineating areas of known disease more accurately. It was also helpful in assessing suitability for repeat laparotomy. In 7 cases, CT demonstrated an operable lesion which had been thought to be inoperable. In 65 cases (59%), CT contributed additional information which was helpful in management, proving it to be an important noninvasive investigation in patients with ovarian carcinoma.
The binding of fluorescein-conjugated lentil lectin and concanavalin A to the surface membrane of human peripheral blood lymphocytes was studied by flow cytometry. The lymphocytes bound 3-fold more lentil lectin molecules compared with concanavalin A molecules and lentil lectin binding approached saturation at a much lower concentration than did that of concanavalin A. Lentil lectin identified two groups of lymphocytes: a low-binding T-cell fraction and a high-binding B-cell-enriched fraction. Concanavalin A did not discriminate between these populations in unseparated lymphocytes. Competition studies indicated that lentil lectin and concanavalin A were bound to different sites on the lymphocyte surface, although about 50% of lentil lectin sites were in close proximity to concanavalin A sites.
The effects of Hodgkin's disease and quadruple chemotherapy on gonadal function have been investigated in 92 male patients with Hodgkin's disease. Nineteen men were studied before they received chemotherapy. Fifteen of the 19 had a sperm count of 20 million/ml or greater and motility was at least 40% in all 15. In the remaining 74 men, gonadal function was studied after completion of chemotherapy (6 months--8 years). Semen was obtained from 49 men who had received six of more courses of MVPP. Forty-two were azoospermic and five of the remaining seven had a sperm count below 1 million/ml. Decreased libido and sexual activity was common during treatment but in the majority of men these returned to normal after completion of chemotherapy. The median FSH and LH levels and the median increments in serum FSH and LH levels after LHRH administration were significantly elevated compared with an age-matched control group. The mean testosterone level of the patients was significantly lower than in controls suggesting Leydig cell damage but androgen replacement therapy was not indicated in any individual patient. No evidence of hyperprolactinaemia as a result of MVPP therapy was found. These results suggest that sperm storage before chemotherapy represents the main possibility for these patients to have children after completing chemotherapy. Before starting chemotherapy, advice should be given to these patients concerning possible changes in sexual behavior during treatment and the very high incidence of permanent infertility following treatment.
Human natural killer (NK) cells separated initially by density centrifugation of lymphocytes (E+) forming rosettes with sheep red blood cells (SRBC), were further fractionated on gradients of bovine serum albumin (BSA). Low density fractions contained effector cells which displayed high cytotoxicity against the NK-sensitive erythroleukaemic cell line, K562. These low density cells, which expressed receptors for Fc and the monoclonal antibody OKMI, showed enhanced cytotoxicity when treated with lymphoblastoid interferon (IFN-alpha). They also showed an increased response to phytomitogen in comparison with unseparated cells or those recovered from high density fractions. Two lymphocyte subsets one of high and one of low lectin binding capacity were identified in the E+ populations by their reactivity with Lens culinaris agglutinin (LCA). High LCA binding was observed only in low density fractions and was associated with a marked enrichment of NK activity. This property was used to separate the NK active population in E+ cells by fluorescence-activated cell sorting (FACS). These data add a new dimension to the cell surface properties of human NK cells and suggest the presence of LCA-reactive glycoproteins which are either enriched in, or uniquely associated with, cells of the NK subset. The experiments indicate that lectins can serve as useful probes of lymphocyte function and provide the basis for effective cell sorting.
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Two hundred and six patients with biopsy-proven lymphoma, 74 with Hodgkin's disease and 132 with non-Hodgkin's lymphoma had abdominal computed tomography for assessment of remission status (108 patients) or for investigation of relapse (98 patients). In 43 patients with diffuse large cell lymphomas scanned at a time of apparent complete remission CT was abnormal in 21. Sixteen of these patients have relapsed and died. Only one patient has relapsed in the group who have normal CT scans. This difference was significant (p=0.00001). This difference was not seen in nodular lymphomas. There were very few patients with Hodgkin's disease in whom the CT scan was abnormal and there is a suggestion that many abnormalities following treatment may represent inactive Hodgkin's disease or fibrosis only. CT played a major role in diagnosing the full extent of relapse in both non-Hodgkin's lymphoma and Hodgkin's disease. Over 50% of the abnormal sites detected by CT would not have been shown by any other non-invasive investigation. Five patients with treated Hodgkin's disease who had "B" symptoms only suggesting relapse were all shown by CT to have extensive intra-abdominal disease.
Twenty-five patients with advanced squamous cell carcinoma of the head and neck were entered into this study. All patients had previously been irradiated and the majority had also undergone surgery for recurrent tumor. A low-dose regimen consisting of adriamycin, bleomycin, 5-fluorouracil, methotrexate, and vitamin A was prescribed, the median number of courses was four and a total of 95 were administered. Ten patients (40%) achieved objective responses (7 partial, 3 complete). The median duration of response was 14 weeks (range, nine to 60 weeks) with a median survival time of 38.5 weeks (range, eight to 72 weeks). The nonresponding patient group's survival time was significantly reduced (P = 0.002; median, 12 weeks; range, three to 40 weeks). The treatment was given on an outpatient basis and no serious hematologic toxic reactions were encountered. Mucositis was uncommon. This regimen produced an acceptable response rate without serious side-effects. The use of Vitamin A may have helped to prevent further impairment of the patient's nutritional status by ameliorating drug-induced mucositis.
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An interface between a commercial flow cytometer (Ortho Cytofluorograf 4800) and a Desk Top Computer (H.P. 9845S) is described. Programs for data acquisition and analysis have been developed. These include cell DNA content analysis, 2-parameter (3D) histograms and sophisticated sub-population selection. Although cell sorting is not possible using the facility, the data acquired per cell is optimised and detailed analysis can be carried out. The system represents a flexible, easily controlled and economical method for storing and analysing flow cytometric data.
One hundred and thirty-six patients with biopsy proven Hodgkin's disease (HD) had conventional staging investigations and CT carried out at presentation. CT did not detect 20 out of 24 positive spleens and did not detect disease at 16 involved lymph node sites proven at laparotomy. In 60 cases in whom lymphography was performed, CT detected all disease shown by lymphography and showed additional disease in 13 other cases (three within the lymphogram area). In 43 patients CT was the only investigation of the abdomen that could be performed and identified 31 unexpected areas of disease in this group. CT altered the stage of the patients in 16% of cases compared with 8% (lymphography) and 34% (laparotomy). The importance of CT as a baseline investigation for the subsequent monitoring of the complete remission of all known disease is discussed, and the routine use of CT when available as the primary non-invasive staging investigation of the abdomen in HD is recommended.
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During July 1976 to Demember 1977, 150 patients with Hodgkin's disease and 138 with non-Hodgkin's lymphoma were examined by computed tomography (CT). In 45 cases 50 repeat examinations were conducted. Concurrent laparotomy and lymphography were performed on 68 and 56 patients respectively. The overall incidence of false-positive CT examinations as confirmed by laparotomy was 7.4%. In 18 patients with non-Hodgkin's lymphoma in the abdomen there was good correlation between the two techniques. Of the 50 patients with Hodgkin's disease who underwent laparotomy, 17 had splenic disease and 14 minimally enlarged lymph nodes in 20 areas; CT, however, detected only four diseased spleens and five minimally enlarged lymph nodes. Nevertheless, CT often detected enlarged lymph nodes missed by lymphography and was 23% more efficient than lymphography in detecting unsuspected disease. CT also detected unsuspected disease in patients with relapse of lymphoma. CT may replace other non-invasive investigations of abdominal disease in patients with lymphoma and give a reliable guide to prognosis. It does not, however, eliminate the need for laparotomy in staging Hodgkin's disease.
Mitozolomide (NSC-353451; CCRG 81010; M and B 39565) is a novel potential anticancer agent that was selected for phase I study on the basis of broad spectrum activity in mouse tumors. Initially, mitozolomide was given iv as a short infusion to 37 patients in doses ranging from 8 to 153 mg/m2. Nausea and vomiting was dose-related but was not severe. The dose-limiting toxic effect was thrombocytopenia at doses greater than 115 mg/m2, and recovery from the thrombocytopenia was delayed up to 8 weeks. Partial responses were seen in two patients with adenocarcinoma of the ovary. The pharmacokinetics of mitozolomide showed that the half-life of the intact drug in the plasma was between 1 and 1.3 hours. The area under the curve was proportional to the dose administered. Mitozolomide is well-absorbed; therefore, future studies are recommended using a single-dose schedule orally or iv. In the phase I study reported here, a dose of 115 mg/m2 appeared to be safe, but additional studies have shown that when given orally to an older population, most patients experienced thrombocytopenia less than 50,000 cells/mm3. The recommended dose using current data is 90 mg/m2 iv or orally.