Gemcitabine-cisplatin: a schedule finding study.
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PURPOSE: To evaluate the tolerability of four alternating cisplatin-gemcitabine schedules. A secondary aim was to evaluate the clinical efficacy of this combination. PATIENTS AND METHODS: Forty-one patients with advanced solid tumors received alternating sequences with a 4- and 24-hour interval of cisplatin and gemcitabine. Gemcitabine 800 mg/m2 was administered as a 30-min infusion on day 1, 8 and 15, and cisplatin 50 mg/m2 over 1 hour on day 1 and 8; in case of the 24-hour time interval the second drug was administered one day later. Four cisplatin-gemcitabine schedules were studied: gemcitabine four hour before cisplatin (10 patients), or vice versa (14 patients) and gemcitabine twenty-four hours before cisplatin (9 patients) or vice versa (8 patients). The sequence of drug administration was reversed in the second cycle of therapy in each individual patient, enabling the evaluation of sequence-dependent side effects. Twenty-six patients had received prior chemotherapy, of which twenty-one platinum-based. RESULTS: The main toxicity was myelosuppression. Overall, grade 3 and 4 thrombocytopenia was observed in 27 out of 41 patients (66%) and was not schedule dependent. No serious bleeding occurred. Leukopenia was significantly different between the 4 alternating schedules (P = 0.01); gemcitabine 24 hours before cisplatin was significantly less toxic compared to both cisplatin 4 hours and 24 hours before gemcitabine (P = 0.01 and P = 0.003, respectively). Furthermore, paired analysis of the 4-hour and 24-hour data sets showed that leukopenia was significantly more serious when cisplatin preceded gemcitabine (P = 0.005). Although most patients received prior treatment, both prior chemotherapy and radiotherapy were not related to toxicity. Overall, grade 3 and 4 leukopenia occurred in 19 out of 41 patients (46%). Anemia (Hb < or = 6.0 mmol/l) was not sequence dependent and was observed in 63% of patients. Myelotoxicity was cumulative between cycles and caused frequent omission of gemcitabine on day 15. Overall, in 51% of administered cycles there was no omission of gemcitabine. A mean of 3.5 therapy cycles was administered. Non-hematological toxicity was moderate, consisting mainly of grade 1 and 2 nausea/vomiting and fatigue, and was not schedule dependent. Recently, we described that the schedule in which cisplatin was administered 24 hours before gemcitabine produced the best pharmacological profile. Based on this and because toxicity was manageable, the schedule cisplatin 24 hours prior to gemcitabine was chosen for phase II evaluation. Nine out of thirty-six evaluable patients had an objective response. These responses were observed in head and neck squamous-cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC), melanoma, adenocarcinoma of unknown origin, ovarian and esophageal carcinoma. CONCLUSIONS: Myelosuppression was the most important toxicity. Leukopenia was schedule dependent: gemcitabine before cisplatin was less toxic than the reversed sequence, in this respect. Some encouraging responses were seen in patients with esophageal cancer. Currently, a phase II study with cisplatin 24 hours before gemcitabine is ongoing in patients with advanced upper gastro-intestinal tumors. (+info)
The accumulation of dendritic cells in the lung is impaired in CD18-/- but not in ICAM-1-/- mutant mice.
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Bone marrow-derived dendritic cell (DC) precursors migrate via the blood stream to peripheral tissues to adopt their sentinel function. To identify factors facilitating their emigration to the lung, mutant mice deficient in E-selectin, P-selectin, E/P-selectin, ICAM-1, or CD18 and their respective controls were examined. DCs and monocytes/macrophages were immunolabeled with M5/114 and MOMA-2 mAbs, respectively, and quantified morphometrically. Of these genotypes, the numbers of DC and MOMA-2+ cells were significantly less only in the lungs of CD18-/- mice by 68 and 35% in alveolar walls and by 28 and 26% in venous walls, respectively. DCs were reduced by 30 and 41% around large and small airways, respectively, but the number of MOMA-2+ cells in these locations was not significantly different from controls. Ablation of a single gene may be associated with augmented expression of other, related gene products. Therefore, we examined the expression of VCAM-1. Increased numbers of arteries exhibited continuous luminal VCAM-1 staining in both CD18-/- and ICAM-1-/- mutants. VCAM-1 expression was absent in pulmonary capillaries and unchanged in veins. These data suggest that under nonperturbing conditions, CD18-mediated adhesion is required for the full complement of DC precursors to accumulate in the lungs. However, the defect in CD18-/- mice is partial, suggesting that CD18-independent adhesion occurs. The alternative pathway may involve VLA-4/VCAM-1 in arteries and venules but not in capillaries. The smaller defect in ICAM-1-/- mice suggests that the CD11/CD18 complex recognizes ligands other than ICAM-1 at some sites. (+info)
Efficacy of liposomal amphotericin B with prolonged circulation in blood in treatment of severe pulmonary aspergillosis in leukopenic rats.
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The therapeutic efficacy of long-circulating polyethylene glycol-coated liposomal amphotericin B (AMB) (PEG-AMB-LIP) was compared with that of AMB desoxycholate (Fungizone) in a model of severe invasive pulmonary aspergillosis in persistently leukopenic rats as well as in temporarily leukopenic rats. PEG-AMB-LIP treatment (intravenous administration) consisted of a single, or double (every 72 h), or triple (every 72 h) dose of 10 mg of AMB/kg of body weight, a double dose (every 72 h) of 14 mg of AMB/kg, or a 5-day treatment (every 24 h) with 6 mg/kg/dose. AMB desoxycholate was administered for 10 consecutive days at 1 mg of AMB/kg/dose. Treatment was started 30 h after fungal inoculation, at which time mycelial growth was firmly established. Both persistently and temporarily leukopenic rats died between 4 and 9 days after Aspergillus fumigatus inoculation when they were left untreated or after treatment with a placebo. In persistently leukopenic rats, a single dose of PEG-AMB-LIP (10 mg/kg) was as effective as the 10-day treatment with AMB desoxycholate (at 1 mg/kg/dose) in significantly prolonging the survival of rats infected with A. fumigatus and in reducing the dissemination of A. fumigatus to the liver. Prolongation of PEG-AMB-LIP treatment (double or triple dose or 5-day treatment) did not further improve efficacy. For temporarily leukopenic rats no major advances in efficacy were achieved compared to those for persistently leukopenic rats, probably because the leukocyte numbers in blood were restored too late in the course of infection. (+info)
Combination chemotherapy with irinotecan and adriamycin for refractory and relapsed non-Hodgkin's lymphoma.
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Twenty-five patients with relapsed or refractory non-Hodgkin's lymphoma were treated by combination chemotherapy with irinotecan hydrochloride (CPT-11) and adriamycin (ADM): CPT-11, 25 mg/m2 on days 1 and 2; ADM, 40 mg/m2 on day 3. Nine (36%) of twenty-five patients achieved CR. Fairly good responses were seen in relapsed B-cell lymphomas (4 of 8 in diffuse large B-cell lymphoma and 2 of 2 in follicular lymphoma grade 1), and substantial responses in T-cell lymphomas (1 of 4 in peripheral T-cell lymphoma and 2 of 7 in adult T-cell leukemia/lymphoma). Leukopenia was frequent but tolerable, and diarrhea minimal. Combination chemotherapy with a reduced dose CPT-11 and ADM was useful in the treatment of relapsed non-Hodgkin's lymphoma. (+info)
Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer.
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A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (90Y-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m2 (mean administered dose, 106.5 +/- 10.3 mCi/m2) of 90Y-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered approximately 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients received biotin-DOTA-labeled with 110 mCi/m2 90Y. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs. (+info)
Protective effects of leukopenia and tissue plasminogen activator in microvascular ischemia-reperfusion injury.
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Ischemia shifts the anticoaugulant/procoagulant balance of the endothelium in favor of activation of coagulation. We studied whether cheek pouch microcirculation of leukopenic hamsters was protected by tissue plasminogen activator (tPA) (50 microg/100 g body wt) against ischemia-reperfusion injury. Adherent leukocytes, total perfused capillary length (PCL), permeability increase, and arteriolar and venular red blood cell (RBC) velocity were investigated by fluorescence microscopy. Measurements were made at control, 30 or 60 min of ischemia, and at 30 or 60 min of reperfusion. Hamsters were made leukopenic by treatment with cyclophosphamide (20 mg/100 g body wt ip, 4 days before the experiment), which decreased circulating leukocyte count by 85-90%. Leukopenic hamsters undergoing 30 min of ischemia followed by 30 min of reperfusion showed no significant decrease in PCL or increased permeability. Leukopenic hamsters undergoing 60 min of ischemia followed by 60 min of reperfusion presented a significant decrease in microvascular perfusion where PCL was 28 +/- 7% of baseline, low-flow conditions, and increased permeability. In leukopenic hamsters treated with tPA there was complete protection of capillary perfusion with no significant changes in permeability or arteriolar and venular RBC velocity. In conclusion, thrombus formation may be an additional and independent factor that with leukocyte-mediated mechanisms determines ischemia-reperfusion injury. (+info)
In vivo activity and pharmacokinetics of ziracin (SCH27899), a new long-acting everninomicin antibiotic, in a murine model of penicillin-susceptible or penicillin-resistant pneumococcal pneumonia.
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The effectiveness of ziracin (SCH27899), a novel everninomicin, was at first investigated against lethal pneumonia caused by a penicillin-susceptible Streptococcus pneumoniae strain. A single intravenous injection of ziracin at a dose of 60 mg/kg of body weight given at 18 h postinfection protected 100% mice and led to the complete clearance of bacteria from their lungs. The activity of ziracin was observed to be the same as that of ceftriaxone: the 50% protective doses (PD(50)s) of ziracin and ceftriaxone were 24.8 and 24.6 mg/kg, respectively. Evaluation of this therapy with leukopenic mice showed that a single injection of ziracin protected 75% of these mice. A delay in therapy with ziracin, which was initiated at 48 h postinfection with 30 mg/kg given once daily for 3 days, resulted in an 83% survival rate of immunocompetent mice. The efficacy of ziracin was further compared to that of vancomycin against lethal pneumonia caused by a penicillin-resistant S. pneumoniae strain in leukopenic mice. The PD(50)s of ziracin and vancomycin were 40.5 and 44.2 mg/kg, respectively. Treatment with ziracin at 30 mg/kg once daily for 2 days (initiated 18 h postinfection) yielded an 83% survival rate and achieved complete eradication of the bacteria. The results were the same as those obtained with vancomycin administered at 15 mg/kg twice daily for 2 days. It is notable that the high survival rates for mice treated with ziracin were associated with effective eradication of the bacteria and rapid recovery of pulmonary tissues from pneumonia. The pharmacokinetic properties of ziracin, ceftriaxone, and vancomycin were estimated following intravenous administration of a single dose of 30 mg/kg to immunocompetent mice. The half-life of ziracin was observed to be longer than those of ceftriaxone and vancomycin (2.3 h versus 1.0 and 0.36 h in the bloodstream and 3 h versus 1.9 and 0. 45 h in lung tissues). The areas under the concentration-time curves (AUCs) in lung tissue for ziracin versus those for ceftriaxone and vancomycin were 36 microg. h/g versus 20 and 9.5 microg. h/g. The prolonged half-life and high AUC for ziracin in tissue contributed to its excellent in vivo activities. (+info)
Trichosporon beigelii: a life-threatening pathogen in immunocompromised hosts.
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Patients undergoing bone marrow transplantation are profoundly immunosuppressed as a result of their intensive myeloablative chemotherapy and are at high risk for opportunistic fungal infections mainly caused by Candida spp and Aspergillus spp. Trichosporon beigelii (T beigelii) has emerged as a life-threatening opportunistic pathogen in granulocytopenic and immunocompromised hosts and there is a marked increase in cases reported in the literature. Response to antifungal agents is poor, mortality is high and immunological recovery is the most important factor for a favorable outcome in patients with trichosporonosis. We present three cases of T. beigelii infection in patients undergoing allogeneic bone marrow transplantation in our center and we review cases described in the literature. (+info)