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  • 1
    ISSN: 1569-8041
    Keywords: bilirubin ; CPT-11 ; Gilbert's syndrome ; glucuronidation ; SN-38
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: CPT-11 is hydrolyzed to its active metabolite SN-38, which is mainly eliminated through conjugation by hepatic uridine diphosphate glucuronosyl transferases (UGTs) to the glucuronide (SN-38G) derivative. Preclinical studies showed that UGT*1.1 is the isozyme responsible for SN-38 glucuronidation. Patients with Gilbert's syndrome have deficient UGT*1.1 activity, therefore may have an increased risk for related CPT-11 toxicity. Patients and methods: Two patients with metastatic colon cancer and Gilbert's syndrome were treated with CPT-11 based chemotherapy. CPT-11, SN-38 and SN-38G pharmacokinetics parameters were obtained. Serum bilirubin was analysed by alkaline methanolysis and HPLC. Results: Both patients presented grade 4 neutropenia and/or diarrhea (NCI-CTC) in every treatment cycle. Biliary index (after Gupta et al) values were well above 4000. Conclusion: We present the first clinical evidence linking bilirubin glucuronidation status and CPT-11 related toxicity. The severe toxicity experienced by the two patients with Gilbert's syndrome treated with CPT-11 based chemotherapy has a genetic basis. Individuals with Gilbert's syndrome have an enhanced risk for CPT-11 toxicity. Unconjugated serum bilirubin could be predictive parameter of CPT-11 toxicity.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Vindesine (VDS) has been submitted to a phase-II trial, the results of which were assessed in terms of regression induction. VDS was given weekly IV in doses of 2 mg/m2 on two consecutive days to 59 patients, 55 of whom were evaluable. A high proportion of complete (36%) and over 50% partial regressions were obtained in acute lymphoid leukemias (ALL) (overall response 63%) whatever the perceptible phase, in blastic crisis of chronic myeloid leukemia (55%), and some responses were recorded in lymphosarcoma (40%). No effect has so far been seen in acute myeloid leukemia or in Hodgkin's disease. Malignant neoplasms of the immunoblastic type seem to be particularly sensitive to VDS. Continuous 48 h IV infusion can induce a remission where an IV push administration of the same dose has failed. One remarkable characteristic of VDS is the apparent absence of cross-resistance with VCR: in acute leukemic forms, 55% of patients who failed to obtain remission induction after three weekly injections of VCR (used in combination chemotherapy) achieved a complete or partial remission with VDS. The toxicity was mainly neurologic (paralytic ileus, constipation, paresthesias, loss of reflexes) and hematologic (leukopenia and thrombopenia), and was not more significant than with the other agents: four patients died of infection or hemorrhage.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The first 100 acute lymphoid (and undifferentiated) leukemias, (of which the smears at the first presentation of the disease are still available for typing), treated successively with remission induction chemotherapy, complementary cell-reducing chemoradiotherapy and then active immunotherapy with irradiated pooled allogeneic leukemic cells and fresh Pasteur Institute BCG applied on scarifications, have been reviewed, especially in connection with BCG application. Tolerance of BCG has been good. Its application had to be stopped due to a side effect (choroiditis) in only one patient. This toxic cost is negligible compared to that of so-called maintenance chemotherapy. No subject of our first control trial started in 1963 has relapsed between 3 and 13 years. In the overall group of the 100 patients studied, no relapse has been observed after 48 months, which is quite different to the observations of frequent relapses after that time in patients submitted to maintenance chemotherapy. Moreover, second remissions are obtained in 94% of the patients who relapsed early under immunotherapy, and their life expectancy after a second remission is as high as it is after the first remission. The median of survival is longer than 5 years. The action of active immunotherapy on the immune machinery has been followed by several assays, of which the increase of null cells (which include K-cells) may be the most interesting. Several prognostic factors have been demonstrated among which are sex, the volume of the neoplasia, meningeal localizations, and the cytological types. Age has no prognostic value in immunotherapy patients, contrary to maintenance chemotherapy patients. Also the cytological types behave differently under immunotherapy and under maintenance chemotherapy. The disease-free survival of more than 85% of the microlymphoblastic patients submitted to immunotherapy is not observed in J. Bernard's patients submitted to maintenance chemotherapy, which suggests that this high cure rate is due to active immunotherapy. Hence, these prognostic factors are probably factors of sensitivity to active immunotherapy. A statistical computerized study has shown that there is a link between the cytological types and other prognostic factors and that they all depend on the cytological type. Hence, our present protocol is adapted to this immunotherapy sensitivity factor. It comprises a nonrisk preimmunotherapy chemotherapy for the microlymphoblastic type, and a longer and more intensive chemotherapy for less immunotherapy sensitive types.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1335
    Keywords: Key words Oxaliplatin ; Germ cell tumors ; salvage treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Only 20–30% of patient with advanced germ cell tumors, relapsing after standard first-line therapy, are curable with current second-line cisplatin-based regimens. New salvage combinations incorporating new active agents are needed. We report the toxicity/tolerance of a new salvage regimen based on the oxaliplatin (Eloxatin)/cisplatin combination, evaluated in patients with recurrent, mostly cisplatin-refractory germ cell tumors. Patients and methods: Thirteen patients were enrolled in this study. All except one had received cisplatin-based chemotherapy. Eight had progressive disease as the best response on their last platinum-based chemotherapy, and three had potentially sensitive tumors. The median interval since the last platinum-based chemotherapy was 6 months (range: 1–36 months). One untreated patient with poor prognosis was also enrolled. Twelve patients had pathological markers [median α-fetoprotein 14 800 ng/ml (58–106), median human chorionic gonadotrophin β subunit 7000 IU/ml (37–723 700)]. Patients received either oxaliplatin (130 mg/m2) and cisplatin (100 mg/m2) every 3–4 weeks (Bi regimen, four patients), or the same regimen combined with one to four of the following cytotoxic agents: ifosfamide, epirubicin, vinorelbine, methotrexate, dactinomycin, etoposide and bleomycin (BiC regimen, 9 patients). Treatment was individualized according to each individual patient's pretreatment and clinical characteristics. Results: Seven objective responses were obtained (overall response rate = 54%), all with the BiC regimens (two complete and five partial responses). Two patients with recurrent disease achieved a long-term complete response lasting over 5 years. Four partial responders were seen in the eight cisplatin-refractory tumors, lasting 4–8 months. All objective responses had a corroborating major decrease in tumor marker blood levels (median decrease: 99.7%). The median survival for the whole group was 8 months. The commonest severe toxicity was hematological (grade 4 neutropenia in 78% and thrombopenia in 74% of the BiC cycles). Conclusion: Our combined salvage regimen induced significant antitumoral activity in recurrent, cisplatin-refractory germ cell tumors. Oxaliplatin merits further evaluation as a component of combination therapy for this disease.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A phase II trial of which preliminary results are available for 22 patients indicates that aclacinomycin applied in a continuous modality induced complete and partial remission in four of nine patients with acute lymphoid leukaemia that was resistant to all previously available drugs, and in four of eight patients with stage V lymphosarcoma (leukaemic). Bone-marrow toxicity was the major side-effect. Only one patient of 20 suffered from cardiac toxicity; no one had alopoecia. This very low incidence of myocardial lesions and the absence of hair loss had been predicted, respectively, by our electron microscope study of the myocardium and the light electron microscope study of the skin of golden hamsters [7], a test that detects frequent severe myocardium and skin toxicities for adriamycin and some anthracyclin analogues such as detorubicin, which was found to be toxic in a high percentage of patients in a clinical trial conducted by the E.O.R.T.C. Clinical Screening Group [8].
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We treated 101 patients with advanced (stage III and IV) lymphosarcoma and reticulosarcoma at first presentation of the disease or in relapse according to a protocol combining initial chemotherapy, complementary radiotherapy on icebergs, supplementary chemotherapy, and, finally, active immunotherapy. The overall complete remission rate was about 79% for lymphosarcoma and 73% for reticulosarcoma. About 50% of the patients were still in remission in each of the two diseases at 2 years; 60% of lymphosarcoma and 44% of reticulosarcoma patients achieved 2-year survival. This study shows the prognostic value of the WHO classification for lymphosarcoma and reticulosarcoma: the prognosis of prolymphocytic (centrofollicular) lymphosarcoma is far better than that of the lymphoblastic type, which is in turn better than that of the very poor prognosis of the immunoblastic type. The prognosis of reticulosarcoma is intermediate between that of the best-prognosis and that of the poorest-prognosis type of lymphosarcoma.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Protocol ICIG-ALL 9 with only nine months' remission chemotherapy followed by active immunotherapy has given a proportion of about 50% of the patients on the plateau of the first remission curve, while 60% of the children are on the plateau of survival curve. These results do not differ from those of another protocol (ICIG-ALL 10) conducted on an identical population of patients and comprising a 25 month remission chemotherapy before immunotherapy. This observation, confirmed by a randomized trial of the EORTC Haemopathy Working Party, suggests that between the 9th and the 25th month, active immunotherapy is as efficient as maintenance chemotherapy. The overall results of this protocol with short chemotherapy followed by active immunotherapy have been compared with those of another prolonged maintenance chemotherapy before immunotherapy protocol (ICIG-ALL 11), and with published protocols comprising only long maintenance chemotherapy: protocol 9 is, as far as the first remission plateau and the survival plateau are concerned, superior to most of these protocols (if not all their branches). Lethal toxicity of active immunotherapy is nil, in contrast to the proportion of deaths (4–28%) occurring during remission in the patients submitted to maintenance chemotherapy. However, not all patients with so-called acute lymphoid leukaemias should be treated identically: our early prognosis parameters (WHO cytological types and volume of the tumour, in this study) allow us to distinguish a good prognosis group in which protocol 9 gave an 80% cure expectancy. The patients with a poor prognosis should be the object of further research for a more efficient therapy. Even if this should be more intensive, the risk is justified in this group, while it is not so for the good prognosis group.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Cancer immunology immunotherapy 1 (1976), S. 193-196 
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary BCG was injected directly into multiple metastatic cutaneous melanomas. Individual metastases were excised sequentially at planned intervals. We found that a progressive necrosis of tumor cells was followed first by a severe exudative reaction and subsequently by the formation of BCG granulomas which completely replaced the tumor mass. No changes were observed in noninjected subcutaneous nodules excised simultaneously with injected nodules at 36 hrs.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1335
    Keywords: Ifosfamide ; Metabolism ; Continuous infusion ; Chemotherapy ; Toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ifosfamide is an analogue of cyclophosphamide active in the treatment of numerous tumours. Although its use by continuous infusion seems to be responsible for less toxicity, differences of efficacy and toxicity, observed according to its doses and schedules of administration, still remain debated. The objective of this study was to assess the toxicity of high-dose ifosfamide given by continuous infusion over 6 days and its therapeutic activity in various advanced tumours. Twenty-six patients were treated with 14 g/m2 ifosfamide, an equal dose of MESNA, and routine granulocyte- or granulocyte/macrophage-colony-stimulating factor during the intercycle. Courses were repeated every 3 weeks until disease progression or unacceptable toxicity occurred; 75 cycles were administered. The mean number of cycles per patient was 3 (range 1–11). Extrahaematological toxicity was manageable in most patients, WHO grade II or more neurological (5 patients) and renal (5 patients) toxicities occurring in those heavily pretreated with platinum compounds and presenting peritoneal disease. WHO grade III or more neutropenia occurred in 60% of cycles, while grade III–IV thrombocytopenia and anaemia were observed in 19% of them. Three partial responses (germ-cell tumour, chondrosarcoma, soft-tissue sarcoma) and one complete response (metastatic osteosarcoma) were assessed, all in patients with tumours refractory or resistant to standard-dose ifosfamide, which underlines the possibility of circumventing the resistance to ifosfamide given in conventional schedules. The present results confirm previous reports of changes in the therapeutic index of ifosfamide according to its dose and administration schedule.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1335
    Keywords: Key words Ifosfamide ; Metabolism ; Continuous ; infusion ; Chemotherapy ; Toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Ifosfamide is an analogue of cyclophosphamide active in the treatment of numerous tumours. Although its use by continuous infusion seems to be responsible for less toxicity, differences of efficacy and toxicity, observed according to its doses and schedules of administration, still remain debated. The objective of this study was to assess the toxicity of high-dose ifosfamide given by continuous infusion over 6 days and its therapeutic activity in various advanced tumours. Twenty-six patients were treated with 14 g/m2 ifosfamide, an equal dose of MESNA, and routine granulocyte- or granulocyte/macrophage-colony-stimulating factor during the intercycle. Courses were repeated every 3 weeks until disease progression or unacceptable toxicity occurred; 75 cycles were administered. The mean number of cycles per patient was 3 (range 1–11). Extrahaematological toxicity was manageable in most patients, WHO grade II or more neurological (5 patients) and renal (5 patients) toxicities occurring in those heavily pretreated with platinum compounds and presenting peritoneal disease. WHO grade III or more neutropenia occurred in 60% of cycles, while grade III–IV thrombocytopenia and anaemia were observed in 19% of them. Three partial responses (germ-cell tumour, chondrosarcoma, soft-tissue sarcoma) and one complete response (metastatic osteosarcoma) were assessed, all in patients with tumours refractory or resistant to standard-dose ifosfamide, which underlines the possibility of circumventing the resistance to ifosfamide given in conventional schedules. The present results confirm previous reports of changes in the therapeutic index of ifosfamide according to its dose and administration schedule.
    Type of Medium: Electronic Resource
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