[Complications after high dose therapy and autologous stem cell transplantation. Retrospective study of an unselected patient sample]. / Komplikationen nach Hochdosistherapie und autologer Stammzelltransplantation. Retrospektive Untersuchung an einem nicht selektionierten Patientenkollektiv.

BACKGROUND: High-dose therapy (HDT) with autologous blood stem cell transplantation (ASCT) has become the therapy of choice for patients with specific hematologic neoplasms. Although pancytopenia after HDT with stem cell support is of relatively short duration, complications may be severe and life-threatening. In unselected patients with hematologic and solid tumor malignancies, only few data have been published regarding complications. We therefore analyzed the rate of infection and toxicity in patients with different neoplasms undergoing HDT and ASCT. PATIENTS AND METHODS: From 6/96 to 12/99 42 patients received 54 HDT and ASCT (nine tandem transplants and one triple transplant). The median age was 55 years (range 25-74 years) with equal sex distribution. 30 patients suffered from hematologic malignancies and twelve from solid tumors. RESULTS: Infections were the major cause for complications followed by mucositis, pain and diarrhea. In four patients a positive cytomegalovirus polymerase chain reaction (CMV-PCR) was detected. In two patients this positive test result was accompanied by clinical symptoms of CMV infection. One patient developed lung fibrosis due to busulfan (WHO 4 degrees) and additionally a veno-occlusive disease (VOD) of the liver (WHO 4 degrees). Two patients (4%) died due to CMV pneumonia and multiple organ failure after idiopathic pneumonia, respectively. Four patients developed secondary neoplasms (two patients myelodysplastic syndromes, two patients solid tumors). Three of them had been heavily pretreated. We further analyzed whether the following parameters had an influence on the rate of complications: tumor diagnosis (hematologic vs. solid), number of pretreatment protocols (< 2 vs. > or = 2), CD34+ cell count (< median CD34+ cell count vs. > or = median CD34+ cell count), age (< or = 55 years vs. > 55 years), mucositis (WHO 1-2 degrees vs. 3-4 degrees) and conditioning regimen (myeloablative vs. myelosuppressive). The infection rate was higher in patients receiving myeloablative therapy compared to patients with myelosuppressive conditioning and the platelet count recovery was slower. In patients receiving a higher CD34+ cell count, time until platelets reached > 50/nl was shorter than in patients with a lower CD34+ cell count. Patients with > or = 2 pretreatment protocols had a higher infection rate than patients with < 2 pretreatments. Patients suffering from severe mucositis (WHO 3-4 degrees) exhibited a slower platelet recovery and a higher infection rate. No difference was noted in the complication rate for the other parameters (tumor diagnosis, age). CONCLUSION: Complication rate and mortality in this heterogeneous patient group were not different from the data of other authors describing selected patients receiving a uniform conditioning regimen or having a distinct disease. The complication rate is influenced by the number of pretreatment protocols, conditioning regimens and the number of transplanted CD34+ cells.

Metabolism of S-nicotine in noninduced and aroclor-induced rats.

The urinary excretion of nicotine and its metabolites in noninduced and Aroclor-induced male and female rats has been determined following intravenous administration of 2'-[14C]-labeled S-nicotine at a dose of 4.6 mumol/kg. Complete recovery of the administered radioactivity was achieved: 95% in urine and 4% in feces over 96 h and 1% remaining in the body. More than 40 nicotine metabolites were found by radio-HPLC; 19 were identified including the cis/trans-diastereomers of nicotine-N'-oxide and 3'-hydroxycotinine. The urinary metabolite profile and excretion kinetics of nicotine and its metabolites were significantly different between noninduced and Aroclor-induced rats. The major urinary nicotine metabolite in the noninduced rat was cis-nicotine-N'-oxide. In the Aroclor-induced rat, cotinine metabolites were the major metabolites found. Sex differences were found for the urinary nicotine metabolite profile, mainly expressed in the excretion of cis-nicotine-N'-oxide, 29% in the male and 17% in the female noninduced rat, and the excretion of cotinine, 5% in the male and 12% in the female noninduced rat. High stereoselectivity was found for the formation of the cis/trans-diastereomers of nicotine-N'-oxide as well as of 3'-hydroxycotinine, the stereoselectivity being more pronounced in male rats.

Mouse skin bioassay of smoke condensates from cigarettes containing different levels of cocoa.

Smoke condensates derived from three cigarette types of identical blend to which 0, 1 and 3% cocoa powder was added to the filler were assayed on mice by chronic dermal application (skin painting). For each cigarette type, three condensate doses were applied: 60, 90 and 125 mg dry condensate/mouse/week. The results obtained in this study do not provide evidence that the biological activity of the condensates, as indicated by the occurrence of non-tumorous and tumorous lesions, is enhanced by the addition of cocoa.

Chromosomal abnormalities and sister-chromatid exchange in bone marrow cells of mice and Chinese hamsters after inhalation and intraperitoneal administration. II. Cyclophosphamide.

The genotoxic effects of cyclophosphamide (CPP), a human and animal carcinogen requiring metabolic activation, were studied in bone marrow cells of mice and Chinese hamsters, analyzing chromosome abnormalities (CA) and sister-chromatid exchange (SCE) after a 2-h inhalation or a single intraperitoneal administration. In order to compare the genotoxicity after the different routes of administration in the dose range of 10-110 mg CPP/kg body weight, the systemic dose obtained by inhalation was calculated from blood concentrations and the inhalation duration after an analysis of the CPP blood kinetics. In NMRI mice the frequency of bone marrow cells with chromosome abnormalities was higher after aerosol exposure than after intraperitoneal administration of comparable CPP doses. In Chinese hamsters the CA frequency was similar with both exposure routes. Inhaled CPP was found to induce a higher frequency of CA and SCE in the bone marrow cells of mice compared to those of Chinese hamsters. The findings suggest that for genotoxins requiring metabolic activation species differences exist with respect to the influence of the route of entry and the sensitivity of bone marrow cells.

Chromosomal abnormalities and sister-chromatid exchange in bone marrow cells of mice and Chinese hamsters after inhalation and intraperitoneal administration: I. Diepoxybutane.

Diepoxybutane (DEB), a direct-acting animal carcinogen, was found to increase the frequency of structural chromosomal abnormalities (CA) and sister-chromatid exchange (SCE) in bone marrow cells of mice and Chinese hamsters, when inhaled from an aerosol during a 2-h head-only exposure or administered as a single intraperitoneal injection. For the purpose of comparing the genotoxicity in the 2 species, both after inhalation and intraperitoneal administration, the systemic DEB dose obtained by inhalation was determined on the basis of blood concentrations and inhalation duration after the investigation of the blood kinetics. The bone marrow cells of male and female NMRI mice were found to be more sensitive than those of Chinese hamsters to the genotoxic activity of DEB.