ALBERT

Description: We used environmental niche modelling along with the best available species occurrence data and environmental parameters to model habitat suitability for key cold-water coral and commercially important deep-sea fish species under present-day (1951-2000) environmental conditions and to forecast changes under severe, high emissions future (2081-2100) climate projections (RCP8.5 scenario) for the North Atlantic Ocean (from 18°N to 76°N and 36°E to 98°W). The VME indicator taxa included Lophelia pertusa , Madrepora oculata, Desmophyllum dianthus, Acanela arbuscula, Acanthogorgia armata, and Paragorgia arborea. The six deep-sea fish species selected were: Coryphaenoides rupestris, Gadus morhua, blackbelly Helicolenus dactylopterus, Hippoglossoides platessoides, Reinhardtius hippoglossoides, and Sebastes mentella. We used an ensemble modelling approach employing three widely-used modelling methods: the Maxent maximum entropy model, Generalized Additive Models, and Random Forest. This dataset contains: 1) Predicted habitat suitability index under present-day (1951-2000) and future (2081-2100; RCP8.5) environmental conditions for twelve deep-sea species in the North Atlantic Ocean, using an ensemble modelling approach.  2) Climate-induced changes in the suitable habitat of twelve deep-sea species in the North Atlantic Ocean, as determined by binary maps built with an ensemble modelling approach and the 10-percentile training presence logistic (10th percentile) threshold. 3) Forecasted present-day suitable habitat loss (value=-1), gain (value=1), and acting as climate refugia (value=2) areas under future (2081-2100; RCP8.5) environmental conditions for twelve deep-sea species in the North Atlantic Ocean. Areas were identified from binary maps built with an ensemble modelling approach and two thresholds: 10-percentile training presence logistic threshold (10th percentile) and maximum sensitivity and specificity (MSS). Refugia areas are those areas predicted as suitable both under present-day and future conditions. All predictions were projected with the Albers equal-area conical projection centred in the middle of the study area. The grid cell resolution is of 3x3 km.

Description: Background: Although clearly unsatisfactory, melphalan and prednisone remains the gold standard for elderly MM patients. Therefore new treatment strategies are needed for these patients. The proteasome inhibitor bortezomib (VELCADE) has shown significant activity in refractory/relapsed MM patients. Moreover, in vitro synergy has been reported when bortezomib is combined with cytotoxic agents such as melphalan. Aim: To define the appropriate dose of bortezomib in combination with MP and to analyse the toxicity and efficacy of V-MP (in terms of response) in untreated MM pts ≥ 65 years old. Methods: Treatment schedule consisting of four 6-week cycles followed by five 5-week cycles. First, two sequential dose levels of bortezomib (1.0 and 1.3 mg/m2) (6 pts each) were explored, administered on days 1,4,8,11,22,25,29 and 32 in combination with oral melphalan, 9 mg/m2 and prednisone, 60mg/m2 once daily on days 1 to 4. When maximum tolerated dose (MTD) of bortezomib in combination with MP was defined, the cohort of pts at the MTD was expanded to up to 60 patients to further refine estimates of efficacy and toxicity (PhaseII). Results: Median age of the 60 enrolled pts was 74(65–85) and the median number of cycles so far received is 3(1–9). During PhaseI, no dose limiting toxicity(DLT) was observed in the two cohorts of pts, and the recommended dose for phaseII was 1.3 mg/m2 of bortezomib in combination with MP. 53pts are evaluable for efficacy since they have already completed at least the first cycle. Analysis of response after cycle 1 revealed a Response Rate(RR) of 72%(6%CR with Immunofixation negative(CRIF-), 2%CRIF+ and 64%Partial Response(PR)). Analysis of best response after a median of 3 cycles revealed a RR of 85%(28%CRIF-, 11%CRIF+ and 45%PR); an additional pt(2%) achieved Minor Response(MR) and 7(13%) stable disease. The toxicity was manageable. Adverse events G3-4 reported for 60 pts included: Gastrointestinal toxicity, such as nauseas(2%), vomiting(2%), diarrhoea(15%) and constipation(8%); haematological toxicity, such as anemia(12%), neutropenia(G3 in 26% and G4 in 13%) and thrombocytopenia(G3 in 33% and G4 in 13%); infection(G3 en 12% and G4 in 2%) and peripheral neuropathy(G3 in 13% and G4 in 2%). Bortezomib and melphalan dose modification was required in 6 and 2 pts, respectively. Eight pts so far have been discontinued due to toxicity related to study medication: peripheral neuropathy in 5(G2 in 1, G3 in 2 and G4 in 2), diarrhoea in 1(G3), infection in 1(G3) and prolonged thrombocytopenia in 1(G4). With a median follow up of 7 months (range:3–15), two responding pts have progressed (months +9and+10), 54(90%) are alive and 6(10%) have died. Cause of death was lung cancer diagnosed 1 month after start of study treatment(1), progressive disease(1), septic shock(2), pulmonary thromboembolism (1) and pulmonary hypertension with right ventricular insufficiency and multiorganic failure(1). Conclusion: V-MP shows a high response rate(85% with 28%CRIF-) and manageable toxicities and could replace MP as the standard of care for elderly MM pts. An international phase 3 randomized trial is in progress to examine this.

Description: Background: Darbepoetin alfa (Aranesp®) is a unique erythropoiesis-stimulating protein effective for the treatment of CIA when administered weekly (QW), every 2 weeks (wks) or every 3 wks. Fixed dosing of darbepoetin alfa is routinely used in clinical practice, but little data are available on its patterns of use and the impact of iron status on its effectiveness. Methods: This was a subanalysis of LPM pts included in a prospective, single-arm, multicenter study conducted in Spain. Pts were ≥ 18 yrs old, anemic (hemoglobin [Hb] ≤11 g/dL), scheduled to receive ≥ 12 wks of chemotherapy, and without iron, vitamin B12, or folate deficiencies. Pts were treated with darbepoetin alfa 150 mcg QW; the dose was to be doubled to 300 mcg QW if Hb increased

Description: Introduction: Justification and Objectives There are little epidemiologic data about Myeloma Multiple in Spain. The heterogeneity and complexity of this pathology, and the several sociodemographic factors, justify the interest of this type of studies. On the other hand, this disease needs a high assignement of welfare and therapeutic resources, and besides new strategies have arisen for its treatment. The Spanish Leukaemia and Lymphoma Foundation (FLL)has analyzed the actual situation of Myeloma Multiple in Spain, compiling several epidemiologic and welfare parameters about the disease in a Multiple Myeloma “White Book” for Spain. Patients and Methods The period of analysis was 10 years, from 1.991 to 2.001. The information was compiled from a Hospital Based Survey about MM and the following official sources: International Agency for Research on Cancer (IARC): “Cancer incidence in Five continents” and “Incidence and Mortaliity for Cancer In Spain, Patterns and Tendences” Data Base of EUCAN and GLOBOCAN (Cancer Incidence, Mortality and Prevalence Worldwide) EUROCARE III study, (IARC Cancer Base Number 5, Lyon, IARCPress). “Natural Changes of Population and Demography. Spanish National Statistic Institute (INE) and National Spanish Center for Epidemiology (CNE.) Official Records for Mortality Rates by MM in Spain in Spanish Regions (CCAA) (death records Demograhy Records of INE). INE Hospital Case Rate Inquest. CMBD Data Base of Department of Health (Inmunoproliferative Neoplasm and Multiple Myeloma, CIE-9 Diagnosis Code: 203.0)The indicators used were: Deaths number, median of age, proportional mortality, mortality rates, mortality rates adjusted by age, gender and potential years of life lost due to multiple myeloma, (item 203 of ICD-10, OMS) during the last ten years in Spain. Results The incidence rates of MM, adjusted to the European population were: 3,54 cases by 100.000/year for men and 2,54 cases by 100.000/year for women. The global incidence rate were 4,44 cases by 100.000/year for men and 4,22 cases by 100.000/year for women. These rates were similar in all geographic regions. Performed predictions show a prevalence increase during the following five years, which means more than 2.400 cases in men and more than 2.100 in women MM cases per year. Regarding mortality, rates, myeloma is a very slightly frequent cause of death: 3.23 cases by 100.000/years of men and 2.3 cases of women. A whole an increase of mortality of 45.2 per cent was observed for the period of time between 1992 and 2001. Comments and Conclusions The MM incidence and mortality rates in Spain for this period were lower than expected in comparison with other European epidemiology studies. Nevertheless we observed that the MM mortality and prevalence rates present a continuous and uniform increment in the last years. Part of these increases can be due to the incorporation of new technologies, more sensitive for diagnosis, and to the increase of aging of the population. Furthermore certain occupational and chemical exposures and other environmental changes could explain these trends.

Description: We have analysed the influence of age on survival after a tandem hematopoietic stem cell transplantation prospective protocol (GEM-2000) in patients diagnosed of multiple myeloma (MM). From 870 patients with symptomatic MM aged 〈 70 years and prospectively included in the GEM-2000 protocol, we have analysed the outcome of a group of 637 patients [351 males, median age of 59 (range, 32 – 70) years] and treated with at least one autologous stem cell transplantation (ASCT). Sixteen patients (2.5%) were between 31 and 40 years of age (group A), 96 patients (15%) between 41 and 50 years (group B), 244 patients (38%) between 51 and 60 years (group C) and the remaining 281 patients (44.5%), between 61 and 70 years (group D). In 325 patients the M component at diagnosis was an IgG (51%). Fifty three patients (8%) had stage I at diagnosis, 232 patients (37%) stage II and 352 patients (55%), stage III. One hundred and one patients (16%) presented with renal insufficiency at diagnosis. Significantly lower levels of serum albumin at diagnosis were observed in the older group of patients (3.88 g/L vs 4.46 g/L, p = 0.05). Most of the patients (612, 96%) were initially treated with the alternating protocol VBCMP/VBAD. The response rate to the first line therapy was of 84% (n = 533), without differences between group D and the rest of the groups. The BUMEL protocol (busulfan 10 mg/kg po plus melphalan 140 mg/m2 iv) and MEL200 (melphalan 200 mg/m2 iv) were the two conditioning regimens used for the first intensive procedure. Although the proportion of older patients (group D) who received MEL200 was higher than in the younger groups of patients (groups A – C) (35% vs 44%), these differences did not reach a statistical significance. At three months after the first ASCT, 30% of the patients had reached a complete remission with negative immunofixation (CR IF-); this percentage was significantly superior in the younger group of patients (groups A – C) with respect to group D (32% vs 27%, p = 0.02). Transplant related mortality (TRM) was also significantly superior in group D (8% vs 3%, p = 0.01). At the time of follow-up, 124 patients (19%) have received a second transplantation; a second intensive procedure was more frequently performed in the younger group with respect to group D (25% vs 12%, p = 0.0001). This second transplant was an ASCT in 73% of the patients (65% in groups A – C vs 94% in group D, p = 0.04). With a median follow-up of 24 months, 508 patients are alive. Actuarial 2-year overall survival (OS) and event free survival (EFS) for the whole population of patients are 75%±2% and 57%±2%, respectively, with statistically significant differences between groups A - C and group D (77%±3% vs 72%±3%, p = 0.05 and 62%±3% vs 52%±4%, p = 0.02, respectively). The overall benefit of the intensification procedure seems to be less in the older group of MM patients (61 – 70 years) included in the GEM-2000 protocol. These results could be related to the achievement of a significant lower rate of CR IF- after the first ASCT and a higher TRM in this older population of patients.

Description: Some studies have suggested that mycophenolate mofetil (MMF) offers a similar efficacy in terms of GVHD prophylaxis as compared to methotrexate (MTX) but a faster engraftment and a lower incidence of mucositis. We have analyzed the results of fludarabine (150 mg/m2) and melphalan (140 mg/m2) or busulphan (10 mg/m2) plus Cyclosporine (CsA) and MMF instead of MTX as GVHD prophylaxis in a series of 30 patients undergoing unrelated allogeneic transplantation. Median age was 44 years (18–60). Patients younger than 40 were required to have a previous comorbid condition (8 had a previous autologous transplant; 2 had proven fungal infection; 1 had severe altered lung capacity). Twelve patients were diagnosed with AML, 4 had ALL, 4 MDS, 2 CML, 3 CLL, 3 NHL, 2 MM/WM. Disease status at transplant was 1st or 2nd CR in 12 patients, 〉2nd CR or PR in 11 patients while the remaining patients had active disease at the time of transplant (relapse, refractory, untreated diasease). Median day to reach 〉 0,5 x 109 granulocytes / L was +17 and to reach 〉 20 x 109 platelets / L was +13. At a median follow up of 445 days among patients alive, projected overall survival (OS) and event free survival at 3 years are 47% and 30%, respectively. Overall TRM was 32%. Cumulative incidence of grades 2–4 and 3–4 aGVHD was 67% and 33%, respectively while cumulative incidence of extensive cGVHD was 70%. Gut was the organ most severely involved in aGVHD in 10 out of 16 patients while liver was involved in only 3 cases. Interestingly, among patients who developed aGVHD, incidence of skin (80%) and liver (22%) involvement were similar to that observed in a similar series of patients receiving related donor transplant using the same RIC plus CsA and MTX instead of MMF while the incidence of gut involvement was significantly higher (64% vs 42%). In conclusion, the RIC used in the current study plus CsA and MMF offers promising results in high risk patients. In terms of GVHD prophylaxis, MMF shows a good efficacy at skin and liver but poor at the gastrointestinal tract.

Description: Introduction: Stem cell (SC) based therapy in ischemic heart disease is actually in development with the aim of improving cardiac regeneration. The way of administration, source of SC and the mechanisms of its clinical effects are yet not well defined. We present preliminary results of a group of patients treated with laser revascularization and autologous bone marrow (BM) cells administration, evaluating cells immunophenotype and clinical results. Patients and methods: Fourteen patients (57–78 y) with diffuse coronary disease and medically refractory class III/IV angina were prospectively evaluated for cell-based therapy combined with laser transmyocardial revascularization (TMR) PHOENIX-TM (Cardiogenesis, Irvine, CA, USA). BM mononuclear cells (MC), were obtained by BM aspiration (120 mL) and processed for concentration using HARVEST-TM system (Harvest Technologies Inc. GMBH, Munich). Immunophenotypic characterization of the final infused product was performed by standard four-color flow cytometry with monoclonal antibodies directed against the human surface antigens CD29, CD49a, CD105, CD106, CD117, CD34, CD133 and CD45, to evaluate different cell populations. Results and conclusions: Patients received a median of 56.8×106 (43.7–79) BMMC/ mL 0.5×106 (0.05–1) CD34+ cells/mL and 0.23×106 (0.001–0.7) CD133+ cells/mL. All the patients are alive after this treatment: median of 9 months, (1–15), with improvement of their cardiological clinical status and QoL. As observed (Table 1) the BMMC used in the therapy contained a significant proportion of CD133+ and CD34+ hematopoietic SC. In addition, the samples contained cells with CD105+ CD45− or CD29+ CD45− CD34− phenotypes which have been described as mesenchymal stem cells (MSC). Bone marrow CD106+ positive cells represent a multipotent subpopulation of MSC including endotelial. Correlation between the relative quantity of the different cell subsets and clinical results of the patients will be presented. TABLE 1 CD34 CD133 CD117 CD29 CD49a CD105 CD106 Mean 3.53 2.42 7.37 2.23 0.75 6.75 0.33 Std. Deviation 1.72 1.68 2.60 0.97 0.75 3.34 0.23 25% Percentile 1.95 0.85 4.95 1.25 0.15 3.10 0.2 Median 3.20 2.15 6.70 2.30 0.40 7.05 0.25 75% Percentile 5.45 4.25 10.45 3.15 1.70 10.10 0.55

Description: Introduction In spite of the favourable results observed after autologous PBSCT in MM there is no clear plateau in the survival curve and eventually most patients relapse with a median EFS between 40–50 months postransplant. To improve these results and sustain remission, various maintenance treatments have been proposed with minimal and discrepant benefits. Interpheron alpha2b s.c. at low dose and steroids on alternate days, have demonstrated modest improvements in EFS and OS times (5–12 months) after standad-dose therapya but its role in the setting of high dose therapy (HDT) needs confirmation. Recently a new formulation of interpheron alpha2b is available conjugated with polietilenglicol (Pegintron®), that need only one dose weekly and has not been evaluated in MM. We present the preliminary and interim results of a spanish, open study, no comparative, multicentric with Pegintron® (Schering-Plough) as maintenance treatment after autologous PBSCT. Patients y Methods 17 patients with MM received Pegintron® once wekly subcutaneously as maintenance treatment after favourable response post-HDT with autologous PBSCT when the engraftement was completed (7 CR and 10 PR). The initial dose was 15 mg/week x 2 week and this dose was escalated to 25 mg/week and then 35 mg/week. The final dose was adopted according clinical and hematological tolerance. Intermitent oral steroids were allowed. The maintenance treatment was continued until toxicity, relapse or progressión. Results Of the 17 patients included so far in the study, 2 patients suspended the treatment. One case by personal decision an the other for progression, 14 months after transplant. The remainder 15 patients follow the treatment with a median of 10.7± 5 months (1.5–18.6). Most patients received also zolendronate iv/months and oral low dose dexamethasone (20 mg x 4 x months) associated to Pegintron. Mild bone pain, “flu-lyke syndrome” and grade I thrombopenia and neutropenia, were the most common adverse effect.. The best tolerated dose was 15 mg/week. With the exception of one case, all patients maintain the response achieved with HDT with a median of 15 months (3–22) after transplant. Comments and Conclusions These prelimiar results show that maintenance treatment with a weekly dose of Interpheron-a2b conjugated with Polietilenglicol (Pegintron®) is effective and well tolerated after autologous PBSCT in MM. No major adverse effects were observed and no relevant negative effecst was presented on the autologous graft. Pegintron® could be an alternative to sc standar interpheron with the main advantage of therapy simplification (one dose weekly). More experience and longer follow up are needed to evaluate the role of this strategy in the global treatment of MM and new approaches for maintenance have to be investigated, including new drugs as bortezomib, thalidomide an lenalidomide, associated or not with bisphosphonates, Pegintron and steroids.