ALBERT

Description: Glutathione S-transferases (GSTs) are enzymes involved in the detoxification of several environmental mutagens, carcinogens, and anticancer drugs. GST polymorphisms resulting in decreased enzymatic activity have been associated with several types of solid tumors. We determined the prognostic significance of the deletion of 2 GST subfamilies genes, M1 and T1, in patients with acute myeloid leukemia (AML). Using polymerase chain reactions, we analyzed theGSTM1 and GSTT1 genotype in 106 patients with AML (median age, 60.5 years; range, 19-76 years). The relevance ofGSTM1 and GSTT1 homozygous deletions was studied with respect to patient characteristics, response to therapy, and survival. Homozygous deletions resulting in null genotypes at theGSTM1 and GSTT1 loci were detected in 45 (42%) and 30 (28%) patients, respectively. The double-null genotype was present in 19 patients (18%). GST deletions predicted poor response to chemotherapy (P = .04) and shorter survival (P = .04). The presence of at least one GST deletion proved to be an independent prognostic risk factor for response to induction treatment and overall survival in a multivariate analysis including age and karyotype (P = .02). GST genotyping was of particular prognostic value in the cytogenetically defined intermediate-risk group (P = .003). In conclusion, individuals with GSTM1 or GSTT1 deletions (or deletions of both) may have an enhanced resistance to chemotherapy and a shorter survival.

Description: The existence of an association between infection with hepatitis C virus (HCV) and B-cell non-Hodgkin lymphoma (B-NHL) remains controversial, largely because previous studies were based on prevalent case series or comparisons with less than optimal control groups. This hospital-based case-control study was conducted from January 1998 through February 2001 to evaluate the association between HCV infection and B-NHL of different types. Cases were consecutive patients with a new diagnosis of B-NHL; controls were patients from other departments of the same hospitals. Both groups were interviewed using a standardized questionnaire. The prevalence of HCV infection was calculated by histologic type of B-NHL and clinical behavior (indolent or aggressive). Adjusted odds ratio (OR) and HCV-attributable risk (AR) were estimated. HCV prevalence was 17.5% among the 400 lymphoma patients and 5.6% among the 396 controls. The OR of B-NHL (patients vs controls), adjusted by age, sex, level of education, and place of birth, was 3.1 (95% confidence interval [CI], 1.8-5.2); an OR indicative of positive association was found for indolent and aggressive B-NHL. The estimated AR was 4.6%. This study confirms an association between HCV and B-NHL. In Italy, 1 of 20 instances of B-NHL may be attributable to HCV infection and may, thus, benefit from antiviral treatment.

Description: Several studies showed that the response rate to standard dose of recombinant Human Erythropoietin (rHuEPO) in MDS patients is generally low, with only few cases presenting a significant increase of haemoglobin (Hb) levels. So, currently, the interest has focused on the use of high dose rHuEPO. The rationale for using high dose rHuEPO was elucidated: residual normal stem cells and/or abnormal clone of MDS stem cells, unresponsive to low levels of endogenous EPO, might respond to high doses of rHuEPO. The aim of this study was to assess the efficacy and safety of high dose rHuEPO treatment. EPO alfa 40.000 IU was given subcutaneously twice weekly for 4 weeks. Twenty-five patients with low-risk MDS (17 RA and 8 RARS) and Hb levels ≤ 10 g/dL were included in this study; sixteen patients were female and 9 male; mean age of enrolled patients was 74 years (range 66 – 85). Twenty-two of 25 patients completed the scheduled treatment and were evaluated for response. At 4 weeks eighteen of 22 patients (81%) showed a Hb mayor response (Hb increase ≥ 2 g/dL); Hb mean value at baseline was 8,15 g/dL (range 7 – 10), at 4 weeks was 13,15 g/dL (range 10 – 14,6). In 4 of 22 patients (19%) the high dose rHuEPO did not induce an increase of Hb levels after 4 weeks of treatment; in addition, these patients needed of RBC transfusions to maintain Hb levels ≥ 8 g/dL. The failure of treatment with rHuEPO occurred in patients with diagnosis of RARS. In our study there were no statistically significant differences between the group of patients with erythroid hyperplasia and the group of patients with normal percent of bone marrow erythroid cells (P = 0,4); no significant difference was noted in response rates between patients with RBC pre-treatment transfusion need and those with stable anaemia without prior transfusion (P = 0,09). In our study, Hb mayor response occurred also in one patient with marked marrow fibrosis. In this study all patients presented defective endogenous EPO production related to their degree of anaemia, with serum EPO levels ≤ 100 mU/ml (mean value 43,5; range 6 – 98). The responder patients need continuous maintenance treatment to maintain their response; EPO alfa 40.000 IU was given subcutaneously once a week; at 12 weeks overall response rate was 77%: 13/18 patients maintained their mayor response, 4/18 patients showed decreased Hb levels in comparison to initial response (Hb decrease 〉 1 〈 2 g/dL), 1 patient progressed on RAEB. Hb mean value at 12 weeks was 11,8 g/dL (range 9,2 – 13,5). The median duration of maintenance of the erythroid response was 7,5 months (range 2 – 24 months). Treatment with high dose of rHuEPO is well tolerated; only one adverse event of arterial hypertension of moderate severity was reported as possible episode related to treatment. In conclusion, our study shows that, in low-risk MDS patients with defective endogenous EPO production, EPO alfa 40.000 IU, given subcutaneous twice weekly for 4 weeks, induces rapid, significant and persistent increase of Hb, without important adverse events; continuous maintenance treatment with 40.000 IU/w is necessary for the majority of the responding patients to maintain their response.

Description: Autologous stem cell transplantation (ASCT) is widely used in young/adult patients with acute myeloid leukemia (AML). However, ASCT is also feasible in elderly AML patients with encouraging results in terms of relapse rate reduction. The combination of fludarabine (F) with cytarabine (ARA-C) is effective in poor risk AML and advanced myelodysplastic syndromes (MDS); however, the administration of F can result in insufficient collection of CD34+ cells. We investigated the mobilization capacity from 28 untreated non M3 elderly AML patients who achieved complete remission (CR) after F plus ARA-C given as continuous sequential infusion (CI-FLA). F was administered at a loading dose of 10 mg/sqm over 15 min at day 0 followed by a continuous infusion (CI) of 20 mg/sqm/24h for 72 hours. ARA-C was given at a loading dose of 390 mg/sqm over 15 min three hours and half after F and then as CI over 96 hours at 1440 mg/sqm/24h. G-CSF was added at day +15 at 5 microg/kg. Patients in CR were programmed to receive an identical course. However, after the first 20 patients, consolidation was reduced by one day because of excessive toxicity. G-CSF at 10 microg/kg was added at day +15 with the aim of shortening neutropenia and mobilizing CD34+ cells. Between December 2001 and April 2004, 62 patients with a median age of 69 years (61–81) received the therapeutic program. In 24 cases (39%) a previously diagnosed MDS preceded the onset of AML. According to MRC criteria, 29 patients (47%) had intermediate karyotype, 23 (37%) adverse karyotype, 1 (2%) favorable karyotype and 9 (14%) no evaluable metaphases. Overall, 41 patients (66%) achieved CR, all following one course of CI-FLA. Among these, 34 (83%) received the programmed consolidation, while in 7 cases therapy was discontinued due to toxicity (n=5), death from cerebral hemorrage (n=1), loss to follow-up (n=1). There were 6 deaths after consolidation (4 from infections and 2 from miocardial infarction apparently unrelated to chemotherapy). Finally, 28 patients were monitorized for the mobilization which was successful in 22/28 patients (78%), with a median collection of 7.5x10E6 CD34+ cells (2,1–60,3). The median number of apheresis was 2 (1–3). The median age of mobilizers was 68 years (61–77); of note, 12/28 of them (43%) had secondary AML and 9 (41%) were aged over 70 years. There was no difference in CD34+ mobilization between patients consolidated with three or four days of therapy (p=0.78). Median time from the beginning of consolidation to first collection was 19 days (17–29). Overall, 17 patients (27% of the whole population, 41% of remitters and 77% of mobilizers) received ASCT, in absence of transplant related death. The median age of autografted patients was 66 years (61–77). Reasons for not autografting included early relapse (n=1), refusal (n=1), infection (n=2), severe uncontrolled diabetes resulting in left foot gangrene (n=1). In conclusion, this study demonstrates that continuous sequential infusion of F + ARA-C is effective in elderly AML patients with acceptable toxicity and high rate of CD34+ cell mobilization. In particular, our results compare favorably with classical combination of anthracyclines plus ARA-C or conventional F+ARA-C in terms of mobilization. We suggest that F, when given as continuous infusion, results in negligible stem cell damage and therefore in less impairment of mobilization capacity.

Description: The major biomarker compounds in surface (0.95 meters below seafloor [mbsf]) and deep (579.92 mbsf) sediment samples from the Benguela Current coastal upwelling system off Lüderitz, Namibia (Leg 175 Hole 1084A), have been identified and quantified. Lipids of marine origin (especially long-chain alkenones) dominate the solvent-soluble extracts of both samples with minor constituents of terrestrially derived lipids. The paleoenvironmental significance of the more labile biomarker distributions (sterols) is limited by losses from depth-related diagenetic transformations. These losses may have led to the relative enrichment of the more refractory biomarkers (alkenones) with depth.

Description: A multiproxy approach including the use of stable isotopes, magnetic characterization analyses, and organic geochemistry has been adopted to consider factors such as productivity and terrigenous input over the past 1.5 m.y. at two areas off the western coast of Africa. These factors can, in turn, be used to consider variability in ocean circulation and upwelling in addition to changes in climate on the African continent. In particular, studies focused on the influence of glacial-interglacial cycles and evidence for the mid-Pleistocene revolution (MPR), a complex change in climate that occurred at ~1 Ma. A comparison of the records from the two areas drilled during Ocean Drilling Program Leg 175, the Congo Basin, at a latitude of 5°S (Holes 1076A and 1077A), and the Walvis Ridge, at 17°S (Hole 1081A), demonstrates that these sites are affected by different localized factors. The sites in the Congo Basin are strongly influenced by freshwater and sediment from the Congo River, whereas the site at the Walvis Ridge is located in the center of oceanic upwelling and contains a more marine signal. Evidence also suggests that the two sites responded differently to both long- and short-term climatic variations. In particular, the response at the Walvis Ridge to the MPR occurred over an extended period, from 1.1 to 0.8 Ma, and was associated with a change in the dominant source of terrigenous input to the site in conjunction with a change in the productivity signal. In the Congo Basin, the response to the MPR was more rapid, occurring between 0.9 and 0.8 Ma. During this period, the influence of the Congo River became significant. However, productivity records only began to respond toward the end of this interval, at 0.8 Ma.