Search

The individual risk of infection and requirements for medical treatment after high-dose chemotherapy have been unpredictable. In this prospective, multicenter, open-label study we investigated the potential of granulocyte colony-stimulating factor (G-CSF) responsiveness as a predictor. A total of 168 patients with multiple myeloma or lymphoma received a single dose of subcutaneous G-CSF (lenograstim, 263 μg) after high-dose chemotherapy. Highly variable leukocyte peaks were measured and grouped as low (quartile 1; leukocytes 100-10 100/μL), medium (quartile 2; leukocytes > 10 100-18 300/μL), and high (quartiles 3/4; leukocytes > 18 300-44 800/μL). G-CSF responsiveness (low vs medium vs high) was inversely correlated with febrile neutropenia (77% vs 60% vs 48%; P = .0037); the rate of infection, including fever of unknown origin (91% vs 67% vs 54%; P < .0001); days with intravenous antibiotics (9 vs 6 vs 5; P < .0001); and antifungal therapy (P = .042). In multivariate analysis, G-CSF responsiveness remained the only factor significantly associated with infection (P = .016). In addition, G-CSF responsiveness was inversely correlated with grade 3/4 oral mucositis (67% vs 33% vs 23%; P < .0001). G-CSF responsiveness appears as a signature of the myeloid marrow reserve predicting defense against neutropenic infection after intensive chemotherapy. This study is registered at http://www.clinicaltrials.gov as NCT01085058.

Purpose: To assess the impact of allogeneic hematopoietic stem-cell transplantation (HSCT) from matched related donors (MRDs) and matched unrelated donors (MUDs) on outcome in high-risk patients with acute myeloid leukemia (AML) within a prospective multicenter treatment trial., Patients and Methods: Between 1998 and 2004, 844 patients (median age, 48 years; range, 16 to 62 years) with AML were enrolled onto protocol AMLHD98A that included a risk-adapted treatment strategy. High risk was defined by the presence of unfavorable cytogenetics and/or by no response to induction therapy., Results: Two hundred sixty-seven (32%) of 844 patients were assigned to the high-risk group. Of these 267 patients, 51 patients (19%) achieved complete remission but had adverse cytogenetics, and 216 patients (81%) had no response to induction therapy. Allogeneic HSCT was actually performed in 162 (61%) of 267 high-risk patients, after a median time of 147 days after diagnosis. Graft sources were as follows: MRD (n = 62), MUD (n = 89), haploidentical donor (n = 10), and cord blood (n = 1). The 5-year overall survival rates were 6.5% (95% CI, 3.1% to 13.6%) for patients (n = 105) not proceeding to HSCT and 25.1% (95% CI, 19.1% to 33.0%; from date of transplantation) for patients (n = 162) receiving HSCT. Multivariable analysis including allogeneic HSCT as a time-dependent covariable revealed that allogeneic HSCT significantly improved outcome; there was no difference in outcome between allogeneic HSCT from MRD and MUD., Conclusion: Allogeneic HSCT in younger adults with high-risk AML has a significant beneficial impact on outcome, and allogeneic HSCT from MRD and MUD yields similar results.

The present study investigated the effects of CD34(+) cell selection in 102 patients using the CliniMACS device. Patients were at high risk for the development of graft versus host disease (GvHD) because of age, or the use of a haploidentical, mismatched or unrelated donor (UD). The median age of the patients was 44 years. The CliniMACS procedure yielded 8.0 x 10(6) CD34(+) cells/kg and the number of residual T cells was 1.3 x 10(4)/kg (median). The median follow up was 20.6 months. The probability of graft failure was 7%. The rate of acute GvHD was low (compatible family donors 10%, UDs 17%, and haploidentical donors 26%) with no patient enduring more than grade II disease. The cumulative incidence of chronic GvHD at the median follow up after transplant was 15% for the compatible family donor group, 40% for the UD group and 78% in the group transplanted from a haploidentical donor Treatment failure was mainly because of transplant-related mortality, especially aspergillus infection, and not due to relapse. The probability of disease-free survival, stratified for the risk of treatment failure, was 27% for the high risk, 46% for the intermediate risk and 83% for the low risk group.

The hydroalcoholic extract of Tinnevelli senna is widely used as a laxative phytomedicine. In order to improve the knowledge of the chemical composition of this extract, LC/MS and LC/MS(n) studies were performed, allowing the on-line identification of most of the known constituents, i. e., flavonoids, anthraquinones and the typical dianthronic sennosides. However, the identity of four compounds could not be ascertained on-line under the given LC/MS conditions. These substances were isolated and their structures elucidated as kaempferol, the naphthalene derivative tinnevellin 8-glucoside and two new carboxylated benzophenone glucosides.

The conditioning regimen prior to stem cell transplantation in 36 patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) was intensified by treating patients with a rhenium 188-labeled anti-CD66 monoclonal antibody. Dosimetry was performed prior to therapy, and a favorable dosimetry was observed in all cases. Radioimmunotherapy with the labeled antibody provided a mean of 15.3 Gy of additional radiation to the marrow; the kidney was the normal organ receiving the highest dose of supplemental radiation (mean 7.4 Gy). Radioimmunotherapy was followed by standard full-dose conditioning with total body irradiation (12 Gy) or busulfan and high-dose cyclophosphamide with or without thiotepa. Patients subsequently received a T-cell-depleted allogeneic graft from a HLA-identical family donor (n = 15) or an alternative donor (n = 17). In 4 patients without an allogeneic donor, an unmanipulated autologous graft was used. Infusion-related toxicity due to the labeled antibody was minimal, and no increase in treatment-related mortality due to the radioimmunoconjugate was observed. Day +30 and day +100 mortalities were 3% and 6%, respectively, and after a median follow-up of 18 months treatment-related mortality was 22%. Late renal toxicity was observed in 17% of patients. The relapse rate of 15 patients undergoing transplantation in first CR (complete remission) or second CR was 20%; 21 patients not in remission at the time of transplantation had a 30% relapse rate. (Blood. 2001;98:565-572)

The syntheses of new cycloalkyl- and cycloalkylalkyl-substituted 3-(4-aminophenyl)-piperidine-2,6-diones and their evaluation as aromatase inhibitors is described. Seven of the new compounds were more active in vitro than the cyclohexyl compound (CHAG), a former clinical candidate: cycloheptyl (1), cycloheptylmethyl (2), cyclohexylmethyl (3), cyclopentylmethyl (4), 1-adamantylmethyl (6), 2-cyclohexylethyl (7) and 2-cyclopentylethyl (8). Compound 3 was the most active, exceeding the potency of aminoglutethimide (AG) and CHAG by factors of 356 and 3, respectively, and reaching the activity of fadrozole. With the exception of 4, the other highly potent aromatase inhibitors were less active towards P450 scc compared with AG. Selected compounds showed only little inhibition of P450 18. In a QSAR study including analogous non-cyclic alkyl-substituted piperidinediones a linear relationship between logP and -logIC50 was found. Tested in vivo, compounds 1, 3, 4, 6 and 7 inhibited androgen-stimulated uterine growth in immature Sprague-Dawley rats as potently as CHAG. At a dose of 8.6 micromol/kg body wt compound 2 was superior to CHAG and thus might be a candidate for the treatment of breast cancer.

Toxicological studies indicate that two hydroxyanthraquinones (HAs), aloe-emodin and emodin, present as minor components in senna, might represent a genotoxic or cancerogenetic risk for man. Since aloe-emodin and emodin occur in senna in the free form as well as their glucosides and dianthrone glucosides, a HPLC method was established to allow the quantification of all free and glycosidic 1,8-dihydroxy anthranoids. The sum of the free HAs and their calculated content in each of their prodrug forms is defined as the potential HA content. For the comparison of different senna drugs in respect to the genotoxic risk arising from their potential aloe-emodin or emodin contents, a risk index has been established.

The stability of rhein-9-anthrone, one of the main and most active metabolites of the sennosides A + B, was studied under physiological conditions. A high-pressure liquid chromatographic method for the determination of rhein-9-anthrone and its oxidation products, rhein and sennidins A + B, was developed. Rhein-9-anthrone, dissolved in Tyrode buffer at pH 6.5 or 7.5 at a concentration of 10(-4) mol/l, completely disappeared from a solution warmed to 37 degrees C within 30 min. More than 90% were transformed into rhein and sennidins A + B. Pharmacological experiments in rats showed that net water absorption in the small intestine was reversed to net secretion by rhein-9-anthrone, whereas rhein and sennidins in corresponding concentrations were ineffective. As at least rhein is known to stimulate secretion under different experimental conditions, all pharmacological results with rhein-9-anthrone must be interpreted with caution and should be checked whether they essentially differ from those of its main oxidation products.