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The escalating concerns about traditional reliance on fossil fuels and environmental issues associated with their exploitation have spurred efforts to explore eco-friendly alternative processes. Since then, in an era where the imperative for renewable practices is paramount, the aromatic synthesis industry has embarked on a journey to diversify its feedstock portfolio, offering a transformative pathway toward carbon neutrality stewardship. This Review delves into the dynamic landscape of aromatic synthesis, elucidating the pivotal role of renewable resources through syngas/CO 2 utilization in reshaping the industry's net-zero carbon narrative. Through a meticulous examination of recent advancements, the current Review navigates the trajectory toward admissible aromatics production, highlighting the emergence of Fischer-Tropsch tandem catalysis as a game-changing approach. Scrutinizing the meliorated interplay of Fe-based catalysts and HZSM-5 molecular sieves would uncover the revolutionary potential of rationale design and optimization of integrated catalytic systems in driving the conversion of syngas/CO 2 into aromatic hydrocarbons (especially BTX). In essence, the current Review would illuminate the path toward cutting-edge research through in-depth analysis of the transformative power of tandem catalysis and its capacity to propel carbon neutrality goals by unraveling the complexities of renewable aromatic synthesis and paving the way for a carbon-neutral and resilient tomorrow., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Biogas methanation emerges as a prominent technology for converting biogas into biomethane in a single step. Furthermore, this technology can be implemented at biogas plant locations, supporting local economies and reducing dependence on large energy producers. However, there is a lack of comprehensive studies on biogas methanation, particularly regarding the technical optimization of operational parameters and the profitability analysis of the overall process. To address this gap, our study represents a seminal work on the technical optimization of biogas methanation obtaining an empirical model to predict the performance of biogas methanation. We investigate the influence of operational parameters, such as reaction temperature, H 2 /CO 2 ratio, space velocity, and CO 2 share in the biogas stream through an experimental design. Based on previous research we selected a nickel supported on ceria-alumina catalyst; being nickel a benchmark system for methanation process such selection permits a reliable data extrapolation to commercial units. We showcase the remarkable impact of studied key operation parameters, being the temperature, the most critical factor affecting the reaction performance (ca. 2 to 5 times higher than the second most influencing parameter). The impact of the H 2 /CO 2 ratio is also noticeable. The response surfaces and contour maps suggest that a temperature between 350 and 450 °C and an H 2 /CO 2 ratio between 2.5 and 3.2 optimize the reaction performance. Further experimental tests were performed for model validation and optimization leading to a reliable predictive model. Overall, this study provides validated equations for technology scaling-up and techno-economic analysis, thus representing a step ahead towards real-world applications for bio-methane production., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This review discusses the importance of mitigating CO 2 emissions by valorizing CO 2 through high-pressure catalytic processes. It focuses on various key processes, including CO 2 methanation, reverse water-gas shift, methane dry reforming, methanol, and dimethyl ether synthesis, emphasizing pros and cons of high-pressure operation. CO 2 methanation, methanol synthesis, and dimethyl ether synthesis reactions are thermodynamically favored under high-pressure conditions. However, in the case of methane dry reforming and reverse water-gas shift, applying high pressure, results in decreased selectivity toward desired products and an increase in coke production, which can be detrimental to both the catalyst and the reaction system. Nevertheless, high-pressure utilization proves industrially advantageous for cost reduction when these processes are integrated with Fischer-Tropsch or methanol synthesis units. This review also compiles recent advances in heterogeneous catalysts design for high-pressure applications. By examining the impact of pressure on CO 2 valorization and the state of the art, this work contributes to improving scientific understanding and optimizing these processes for sustainable CO 2 management, as well as addressing challenges in high-pressure CO 2 valorization that are crucial for industrial scaling-up. This includes the development of cost-effective and robust reactor materials and the development of low-cost catalysts that yield improved selectivity and long-term stability under realistic working environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Today's rising energy costs, coupled with increasing energy demand, make it necessary to search for more efficient energy processes. In recent years, there have been increasing efforts to develop efficient catalysts based on waste-derived char, by a single step where the carbon precursor and the metallic active phase one undergo a single common thermal process under a reductant atmosphere at high temperature. The use of a reductant atmosphere drives the formation of carbonaceous materials with different characteristics than those obtained under the standard nitrogen-inert one. Our work evaluates the influence of the residence time and the heating rate on the physicochemical properties of the biochar obtained. Relatively long residence times and slow heating rates, improve the yield to the resulting biochar, without increasing production cost, making the subsequent char-based metallic catalyst synthesis more efficient. The heating rate was shown to be key in improving the properties of the char in a smoother and more controlled way, unlocking a new working pathway for the efficient design and production of char-based catalysts in a one-pot synthesis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

The Covid-19 pandemic and its dramatic worldwide impact have required global multidisciplinary actions to mitigate its effects. Mobile phone activity-based digital contact tracing (DCT) via Bluetooth Low Energy (BLE) technology has been considered a powerful pandemic monitoring tool, yet it sparked a controversial debate about privacy risks for people. In order to explore the potential benefits of a DCT system in the context of Occupational Risk Prevention, this paper presents the potential of Visual Analytics methods to summarize and extract relevant information from complex DCT data collected during a long-term experiment at our research centre. Visual tools were combined with quantitative metrics to provide insights into contact patterns among volunteers. Results showed that crucial actors such as participants acting as bridges between groups could be easily identified - ultimately allowing for making more informed management decisions aimed at containing the potential spread of a disease.

The number of adolescent refugees around the world has been continuously increasing over the past few years trying to escape war and terror, among other things. Such experience not only increases the risk for mental health problems including anxiety, depression, and post-traumatic stress disorder (PTSD), but also may have implications for socio-cognitive development. This study tested cognitive-affective processing in refugee adolescents who had escaped armed conflict in Syria and now resided in Istanbul, Turkey. Adolescents were split into a high trauma (n = 31, 12 girls, mean age = 11.70 years, SD = 1.15 years) and low trauma (n = 27, 14 girls, mean age = 11.07 years, SD = 1.39 years) symptom group using median split, and performed a working memory task with emotional distraction to assess cognitive control and a surprise faces task to assess emotional interpretation bias. The results indicated that high (vs. low) trauma symptom youth were ~ 20% worse correctly remembering the spatial location of a cue, although both groups performed at very low levels. However, this finding was not modulated by emotion. In addition, although all youths also had a ~ 20% bias toward interpreting ambiguous (surprise) faces as more negative, the high (vs. low) symptom youth were faster when allocating such a face to the positive (vs. negative) emotion category. The findings suggest the impact of war-related trauma on cognitive-affective processes essential to healthy development., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

The exponential growth of greenhouse gas emissions and their associated climate change problems have motivated the development of strategies to reduce CO 2 levels via CO 2 capture and conversion. Reverse water gas shift (RWGS) reaction has been targeted as a promising pathway to convert CO 2 into syngas which is the primary reactive in several reactions to obtain high-value chemicals. Among the different catalysts reported for RWGS, the nickel-based catalyst has been proposed as an alternative to the expensive noble metal catalyst. However, Ni-based catalysts tend to be less active in RWGS reaction conditions due to preference to CO 2 methanation reaction and to the sintering and coke formation. Due to this, the aim of this work is to study the effect of the potassium (K) in Ni/CeO 2 catalyst seeking the optimal catalyst for low-temperature RWGS reaction. We synthesised Ni-based catalyst with different amounts of K:Ni ratio (0.5:10, 1:10, and 2:10) and fully characterised using different physicochemical techniques where was observed the modification on the surface characteristics as a function of the amount of K. Furthermore, it was observed an improvement in the CO selectivity at a lower temperature as a result of the K-Ni-support interactions but also a decrease on the CO 2 conversion. The 1K catalyst presented the best compromise between CO 2 conversion, suppression of CO 2 methanation and enhancing CO selectivity. Finally, the experimental results were contrasted with the trends obtained from the thermodynamics process modelling observing that the result follows in good agreement with the modelling trends giving evidence of the promising behaviour of the designed catalysts in CO 2 high-scale units., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gandara-Loe, Portillo, Odriozola, Reina and Pastor-Pérez.)

Background: The Mindfulness in Parenting Questionnaire (MIPQ) is a self-report instrument to measure how much parents practice mindful parenting. The main aim of this study was to analyze the psychometric properties of the Spanish version of the MIPQ., Method: A total of 271 parents of adolescents completed the MIPQ along with questionnaires about their mindfulness trait, parenting style, and their children's resilience and symptoms of depression. Their adolescent children completed questionnaires about their own depressive symptoms, their perception of their parents' parenting style, and their perceived stress., Results: Factor analyses suggested a two-factor structure corresponding to Being in the Moment with the Child and Mindful Discipline. Moreover, the MIPQ showed good internal consistency and was related to parent's dispositional mindfulness and positive parenting as well as to adolescents' resilience and (negatively) to their depressive symptoms., Conclusion: The Spanish version of the MIPQ exhibits good psychometric properties and is an easily applicable test for the assessment of mindful parenting.

This paper proposes a model-based methodology that allows synthesising the most appropriate strategies for optimising the operation of wastewater treatment plants (WWTPs). The methodology is applied with the aim of maximising the nitrogen removal in membrane bioreactors (MBRs). The proposed procedure is based on a systematic approach composed of four steps. First, a sensitivity analysis of the input variables is carried out in order to obtain a first assessment of the potential for operational improvements. Then, the optimum input variable values are calculated by a model-based optimisation algorithm that minimises a cost function associated with the effluent total nitrogen at different temperatures. Then, the optimum operational strategies are identified. Finally, these operational strategies form the conceptual knowledge base for designing automatic control laws. The obtained optimal control strategies have shown a significant improvement in performance in comparison with fixed operation for the studied case, reducing the total nitrogen by 40%.

Objective: To assess the indications and possible underlying causes of emergency peripartum hysterectomy (EPH) at the present hos- pital during the 2001-2011 period., Materials and Methods: A revision of the charts and pathology reports corresponding to 42,728 parturients., Results: During the study period, 25 peripartum hysterectomies were performed (0.61/1.000), of which 23 were EPHs (0.54/1.000) and two were planned cesarean hysterectomies. The indication for EPH was acute postpartum hemorrhage in 22 of 23 instances (95.7%). Roughly two-thirds of the operated uteri (16/25, 64%) showed placental site anomalies, half corresponding to different degrees of placental accretism and half to anomalies derived from the implantation site intermediate trophoblast. In five cases (31%), the anomaly was an exaggerated placental site and three cases corresponded to placental site trophoblastic tumors. Of the 16 cases showing placental site anomalies, ten (62.5%) were associated with one or more previous cesarean sections., Conclusions: Roughly one-third of EPHs performed at the present center during the last ten years were associated with placental site anomalies originating in the implantation site intermediate trophoblast (exaggerated placental site and placental site trophoblastic tumor). This association has not been described before, and should be taken into consideration when facing acute peripartum hemorrhage predisposing to EPH.

Graft-versus-host disease (GVHD) remains the greatest source of morbidity-mortality in allogenic transplant patients. Although in most cases the more easily obtainable clinical and laboratory test parameters suffice to confirm the diagnosis and establish the stage of the disease biopsies of the affected organ are sometimes needed. At present there is great Interest in the study of factors allowing a prognosis of the course and type of response to treatment in patients with CVHD. In this sense, It would be necessary to objectively Identify and validate biomarkers capable of predicting biological or pathological processes in patients with cVHD. To this effect we have performed serial analyses of skin tissue using peripheral blood and tissue biomarkers in a prospective observational study conducted in three transplant centers. The still preliminary results Indicate that certain histopathological findings classically attributed to CVHD ore also seen in patients not clinically affected by the disease--this probably being related to other physiopathological phenomena occurring during transplantation. The study of these findings, combined with biomarker analysis, will allow improved understanding of the underlying etiopathogenesis, as well as the definition of new diagnostic, prognostic and response-evaluating criteria.

Manganese oxides having 2 x 2 tunnel structures (cryptomelanes) have been synthesized by a milling method in order to test their efficiency as catalysts for the abatement of volatile organic compounds, using toluene as probe molecule. These materials present excellent textural properties, arising from the nanofiber morphology and were active for toluene total oxidation. DRIFTS of the adsorbed phase allow proposing the role of lattice oxygen in the catalytic reaction.

Photocatalytic oxidation of 2,4-dichlorophenoxyacetic acid was performed over ZrO2, Cu/ZrO2 and Fe/ZrO2 catalysts prepared by the sol-gel method. The samples were annealed at 400 degrees C. Textural and electronic characterization was carried out using BET and UV-Vis in order to establish the relationship between surface, pore volume and E(g) with the photoactivity of the materials. The degradation of the acid was followed by UV-Vis spectroscopy. The disappearance of the herbicide in solution follows approximately pseudo-first order kinetics. The apparent rate constants were calculated for the three catalysts. The results reveal that Fe/ZrO2 exhibits the best photoactivity for the degradation of 2,4-dichlorophenoxyacetic acid.

In the present work we synthesized inorganic oxide nanoparticle carriers of platinum compounds and tested their therapeutic effect on animal models in which C6 glioma cells have been inoculated. TiO(2)-containing Pt(NH(3))(4)Cl(2) complexes were synthesized using sol-gel methods. The platinum species are chemically bonded to the TiO(2) carrier, as shown by Fourier transform infrared spectroscopy of probe molecules. Treatment with TiO(2)-Pt nanoparticles reduces tumour growth rate by up to 56%, showing that a synergistic effect exists between the TiO(2) carrier and the platinum drug.

Apatite and Portland/apatite composite cements containing steelwork dusts have been prepared using a low temperature hydrothermal method (200 degrees C, 48h). The produced solids were characterized by means of XRD, IR, and SEM-EDX, and the remaining liquid was analyzed by ICP. The results clearly show the capability of these cements to inertise the heavy metals contained in steelwork dusts, that is Fe, Pb, Mo, Cr, Mn, Ni, and Zn. In the case of apatitic cements, Fe, Mg, Cr, Mn, and Pb coming from steel dust replaced Ca in the divalent cation position of the apatite structure, while Si and Mo replaced P in tetrahedral position. The average crystal size of the apatite-containing dust is smaller than in pure apatite synthesized using the same procedure, which is related to the magnesium content of the dust, since magnesium seems to inhibit the crystal growth. XRD diagrams of composite cements show only peaks corresponding to phases observed in the single cements, and in that no new phases are found. However, EDX analysis reveals the introduction of cations coming from Portland cement into the apatite structure. From the results of water analysis it could be concluded that the capability of retention is higher in composite matrices than in the pure apatite one. In conclusion, the obtained data allow stating that the proposed method, the hydrothermal synthesis of steelwork dust containing cement, is a reliable one for immobilization of toxic residues containing heavy leachable cations.

The use of the tyrosine kinase inhibitor imatinib, which blocks the enzymatic action of the BCR-ABL fusion protein, has represented a critical advance in chronic myeloid leukemia (CML) treatment. However, a subset of patients initially fails to respond to this treatment. Use of complementary DNA (cDNA) microarray expression profiling allows the identification of genes whose expression is associated with imatinib resistance. Thirty-two CML bone marrow samples, collected before imatinib treatment, were hybridized to a cDNA microarray containing 6500 cancer genes, and analyzed using bootstrap statistics. Patients refractory to interferon-alpha treatment were evaluated for cytogenetic and molecular responses for a minimum of 12 months. A set of 46 genes was differentially expressed in imatinib responders and non-responders. This set includes genes involved in cell adhesion (TNC and SCAM-1), drug metabolism (cyclooxygenase 1), protein tyrosine kinases and phosphatases (BTK and PTPN22). A six-gene prediction model was constructed, which was capable of distinguishing cytogenetic response with an accuracy of 80%. This study identifies a set of genes that may be involved in primary resistance to imatinib, suggesting BCR-ABL-independent mechanisms.

A novel biomaterial (HA-SBA-15) has been developed based on the growth of calcium phosphate hydroxyapatite (HA) nanoparticles within an organized silica structure (SBA-15). Characterization of the material was carried out using a combination of X-ray diffraction, X-ray fluorescence, transmission electron microscopy, N2 adsorption-desorption isotherms and nuclear magnetic resonance. Transmission electron microscopy observations and N2 porosimetry revealed the crystallization of hydroxyapatite nanoparticles inside the mesopore cavities of the silica structure. Specific surface areas of 760 m2 g(-1) and 260 m2 g(-1) were measured for the SBA-15 and the HA-SBA-15 material, respectively. The hydroxyl groups present in the silica nanostructure surface have brought about cationic defects in the silicium sites, mainly with those of tetrahedral symmetry, and promoted the formation of siloxanes. 29Si MAS-NMR analysis shows a significant reduction of the silanol groups concentration with HA growing within the base (SBA-15) material. Studies and brain tissue biocompatibility tests were carried out. Histopathological studies on the SBA-15 implant material showed no changes to the tissue nearby. The results confirmed the synthesis of a silica-based composite containing HA nanoparticles with the potential for biomedical applications.

Interferon-alpha (IFN-alpha) is a therapy of unquestionable efficacy in chronic myeloid leukemia (CML) patients. The best dose of IFN-alpha in the treatment of CML still remains controversial. Our primary objective was to compare cytogenetic responses in patients treated with intermediate versus high doses of IFN-alpha. A multicenter randomized controlled trial was conducted involving 109 patients with untreated CML in chronic phase from 26 Spanish hospitals. Patients were assigned to receive either an intermediate (2.5 MU/m(2) per day) or high (5 MU/m(2) per day) target dose of IFN-alpha. Hydroxyurea was allowed in both groups. In total, 108 patients were analyzed, 53 in the intermediate- and 55 in the high-dose group. Median follow-up was 47.5 months. The dose of IFN-alpha actually given was lower in the intermediate-dose group (3.83 MU/day) than in the high-dose group (6.6 MU/day) ( p<0.001). The rate of complete cytogenetic response was 24.5% in the intermediate- and 12.7% in the high-dose group (NS). A partial cytogenetic response was obtained in 7.5% and 10.9%, respectively. Cox analysis did not reveal any influence of the randomization arm on cytogenetic response rate. Ten patients in each group discontinued IFN-alpha because of toxicity. Albeit not our primary objective, no differences were found in terms of survival or transformation rate between both groups. Median survival was 73 months; 64% of patients remained free of transformation at 5 years. In terms of cytogenetic response, intermediate doses of IFN-alpha are as effective as high doses in the treatment of CML.

Background and Objectives: Imatinib mesylate has recently been shown to be highly effective in chronic-phase chronic myeloid leukemia (CML). The results of imatinib treatment in chronic-phase CML patients resistant or intolerant to interferon (IFN) and the factors predicting therapeutic response and progression-free survival were analyzed., Design and Methods: One hundred and fifty patients with chronic-phase CML resistant (n=111) or intolerant (n=39) to IFN were treated with imatinib. Prognostic factors for response and disease progression were assessed by multivariate analysis., Results: The median time from diagnosis was 43 months (0.5-188), median IFN therapy 21.5 months (0.5-140) and median follow-up from starting imatinib 13.6 months (range: 3-23). Complete hematologic response was achieved in 96 of 97 patients. Complete, partial and minor cytogenetic responses were present in 44%, 22%, and 8% of patients at 12 months. Grade III-IV neutropenia, thrombocytopenia, and anemia developed in 33%, 16%, and 6% of patients, respectively. Sixty-five patients discontinued treatment for a median of 4 weeks (1-36) due to toxicity. The rate of progression-free survival (lack of accelerated/blastic phase with persistent response) was 89.2% (95% CI: 84-94.4) at 12 months and 80.2% (95% CI: 72.2-88.2) at 18 months. Platelets > 450x10(9)/L and treatment discontinuation > 4 weeks were associated with a lower rate of major (complete plus partial) cytogenetic response. Patients in Sokal's high-risk group and those who did not achieve a major cytogenetic response had significantly shorter progression-free survival., Interpretation and Conclusions: Imatinib is highly effective in chronic-phase CML patients resistant or intolerant to IFN, especially in those with normal platelet counts and in those not requiring prolonged treatment discontinuation due to neutropenia.

Purpose: To analyze patient cases of therapy-related acute promyelocytic leukemia (tAPL), occurring after chemotherapy (CT), radiotherapy (RT) or both for a prior disorder, diagnosed during the last 20 years in three European countries., Patients and Methods: The primary disorder and its treatment, interval from primary disorder to tAPL, characteristics of tAPL, and its outcome were analyzed in 106 patients., Results: Eighty of the 106 cases of tAPL were diagnosed during the last 10 years, indicating an increasing incidence of tAPL. Primary disorders were predominantly breast carcinoma (60 patients), non-Hodgkin's lymphoma (15 patients), and other solid tumors (25 patients). Thirty patients had received CT alone, 27 patients had received RT alone, and 49 patients had received both. CT included at least one alkylating agent in 68 patients and at least one topoisomerase II inhibitor in 61 patients, including anthracyclines (30 patients), mitoxantrone (28 patients), and epipodophyllotoxins (19 patients). Median interval from primary disorder to tAPL diagnosis was 25 months (range, 4 to 276 months). Characteristics of tAPL were generally similar to those of de novo APL. With treatment using anthracycline-cytarabine-based CT or all-trans-retinoic acid combined with CT, actuarial survival was 59% at 8 years., Conclusion: tAPL is not exceptional, and develops usually less than 3 years after a primary neoplasm (especially breast carcinoma) treated in particular with topoisomerase II-targeted drugs (anthracyclines or mitoxantrone and less often etoposide). Characteristics and outcome of tAPL seem similar to those of de novo APL.

Imatinib mesylate (STI571) is a highly effective and well-tolerated treatment for patients with chronic-phase chronic myeloid leukaemia (CML), but information on its efficacy and tolerance in intensively pretreated patients is scarce. Thirty-three chronic-phase CML patients who were resistant or intolerant to interferon (IFN) and had been previously submitted to autologous stem cell transplantation were treated with imatinib for a median of 14 months (range: 6-19 months). Seven patients were in haematological response (HR) at the start of treatment; the remaining 26 attained a HR at a median of 3 weeks (range: 1-4 weeks). Major cytogenetic response rates at 3, 6 and 12 months were 42%, 45% and 55%, respectively, including 21%, 24% and 33% complete responses. Grade 3-4 neutropenia, thrombocytopenia and anaemia developed in 33%, 27% and 12% of patients respectively. Non-haematological toxicity included superficial oedema (21% of patients), gastrointestinal symptoms (18%), muscle cramps (15%), skin rash and liver enzyme increase (3% each). These results were not significantly different from those in 65 chronic-phase CML patients, resistant or intolerant to interferon without a previous ASCT, who were included in the same protocol. Imatinib mesylate is effective and safe in chronic-phase CML patients with a previous history of intensive treatment.

A study on 315 patients undergoing transplantation with CD34+ selected blood cells from HLA-identical siblings was performed to determine risk factors for acute GVHD (aGVHD). Recipients of a dose of CD34+ cells (x 10(6)/kg) of 2 or less, more than 2 to 4, and more than 4 had a cumulative incidence of aGVHD grades I-IV of 21%, 35%, and 43%, respectively (log-rank P =.01); similarly, recipients of a dose of CD3+ cells (x 10(6)/kg) of 0.05 or less, more than 0.05 to 0.1, and more than 0.1 had a cumulative incidence of aGVHD grades I-IV of 18%, 35%, and 44%, respectively (log-rank P =.007). Using a Cox regression model, 4 independent factors for aGVHD I-IV were identified: increased CD34+ cell dose (P =.02), increased CD3+ cell dose (P =.02), female patients (P =.01), and higher patient age (> 42 years) (P =.007). This study shows, for the first time in T-cell-depleted transplantations, a positive correlation between the number of CD34+ cells and aGVHD and, also, that the number of CD3+ cells necessary to initiate aGVHD is lower than previously reported.

Standard allogeneic stem cell transplantation (SCT) has been associated with a high transplant-related mortality (TRM) in patients who have failed a prior autologous SCT (ASCT). Reduced-intensity conditioning (RIC) regimens may reduce the toxicities and TRM of traditional myeloablative transplants. We report 46 adults who received a RIC peripheral blood SCT from an HLA-identical sibling in two multicenter prospective studies. The median interval between ASCT and allograft was 16 months, and the patients were allografted due to disease progression (n = 43) and/or secondary myelodysplasia (n = 4). Conditioning regimens consisted of fludarabine plus melphalan (n = 41) or busulphan (n = 5). The 100-day incidence of grade II-IV acute graft-versus-host disease (GVHD) was 42% (24% grade III-IV), and 10/30 evaluable patients developed chronic extensive GVHD. Early complete donor chimerism in bone marrow and peripheral blood was observed in 35/42 (83%) patients, and 16 evaluable patients had complete chimerism 1 year post transplant. With a median follow-up of 358 days (450 in 29 survivors), the 1-year incidence of TRM was 24%, and the 1-year overall (OS) and progression-free survival were 63% and 57%, respectively. Patients who had chemorefractory/ progressive disease, a low performance status or received GVHD prophylaxis with cyclosporine A alone (n = 32) had a 1-year TRM of 35% and an OS of 46%, while patients who had none of these characteristics (n = 32) had a 1-year TRM of 35% and an OS of 46% while patients who had none of these characteristics (n = 14) had a TRM of 0% and an OS of 100%. Our results suggest that adult patients who fail a prior ASCT can be salvaged with a RIC allogeneic PBSCT with a low risk of TRM, although patient selection has a profound influence on early outcome.

A retrospective multicenter study was performed to assess the clinical results in patients with acquired aplastic anemia (AA) allografted over a 19 year period and to identify prognostic factors influencing survival. From April 1978 to December 1997, 176 patients were transplanted. Records from 160 receiving related matched bone marrow transplantation (BMT) were reviewed. Fifty-two percent of the patients were older than 20 years, 5% older than 40; 6.3% were untransfused at BMT and 56.2% had received prior treatments. Conditioning regimens were with chemotherapy in 43.7% of the procedures and with additional irradiation in 56.3%. Graft-versus-host disease (GVHD) prophylaxis was based on cyclosporin A (CsA) in 58.1% of the patients while methotrexate (MTX) was administered to 41.9%. Transplantation earlier on, a longer interval from diagnosis to BMT, GVHD prophylaxis with MTX, graft failure/rejection and acute severe GVHD were adverse factors for survival. The use of CsA emerged as the main factor for the improvement, inducing a significant decrease in graft failure/rejection rate and severe acute GVHD when compared with MTX alone. Radiation-containing regimens decreased the graft failure/rejection rate without improving survival due to the increased risk of acute GVHD. Age and number of transfusions pretransplant did not influence outcome. Survival achieved since 1991 is 79.79%, and graft failure and acute severe GVHD rates are 6.0% and 11.8%, respectively. In conclusion, CsA-based post-graft immunosuppression has been crucial in achieving improved survival in patients with acquired AA up to 40 years of age. Regardless of CsA use, further improvement in survival was apparent with time, probably due to better skills in patient care.

Reduced-intensity conditioning (RIC) regimens for allogeneic haematopoietic stem cell transplantation (SCT) have been shown to lead to engraftment of donor stem cells without the severe extra-haematological toxicities of traditional myeloablative transplants. Between December 1998 and December 2000, 76 patients underwent a RIC peripheral blood SCT in a prospective multicentre study. The median age was 53 years, and 57 patients were beyond the early phase of their disease. The conditioning regimens consisted of fludarabine (150 mg/m2) plus melphalan (140 mg/m2) or busulphan (10 mg/kg). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A plus short-course methotrexate. The preparative regimens were well tolerated. All patients experienced severe pancytopenia, but haematological recovery was prompt in all but two cases (early deaths). The 100-d probability of developing grade II-IV acute GVHD was 32% (10% grade III-IV), and the 1-year probability of developing chronic extensive GVHD was 43%. Early complete donor chimaerism was observed in 52/68 patients, and 16 evaluable patients were in complete chimaerism 1 year post transplant. With a median follow-up of 283 d (355 in 48 survivors), the 1-year probability of transplant-related mortality was 20%, and the 1-year overall and progression-free survivals were 60% and 55% respectively. In conclusion, RIC regimens lead to low early toxicity after allografting, with stable donor haematopoietic engraftment, with an apparent low risk of acute GVHD. Chronic GVHD, however, develops in a significant proportion of patients.

Background and Objectives: To analyze in patients with de novo acute promyelocytic leukemia (APL) treated with an ATRA plus anthracyclin-based protocol if the presence of additional cytogenetic aberrations to the t(15;17) influences: 1. clinical and biological presenting features; 2. disease outcome., Design and Methods: One hundred and thirteen patients with newly diagnosed APL enrolled in the APL-96 protocol of the Spanish PETHEMA group were studied by conventional karyotyping, FISH and RT-PCR for the PML-RARa fusion. Treatment was homogeneous in all cases and consisted of anthracyclines and ATRA., Results: Additional chromosome aberrations were observed in 30% of cases. The most frequent secondary changes were +8 (14 cases), and abnormalities of chromosomes 9 or 3 (4 patients each), and of chromosomes 1 and 8 (3 cases each). No clinical, biological, morphological, immunophenotypic or molecular differences were observed between the group of APLs with t(15;17) alone and the group of patients with additional changes. Patients with additional changes had a higher rates of complete remission (CR) and 4-year disease-free survival (DFS) (97%, and 97%, respectively) than patients with t(15;17) alone (CR, 70% and DFS, 84%) but these differences were not statistically significant., Interpretation and Conclusions: Patients with APL and additional cytogenetic abnormalities do not show different clinical, biological, morphological or molecular features as compared to patients with t(15;17) alone. The prognosis of patients with APL and t(15;17) alone and those with additional changes is similar in both groups. This study indicates that there is no rationale for administering more intensive treatment in APL patients with additional cytogenetic abnormalities receiving ATRA plus anthracycline-based chemotherapy.

An allogeneic transplantation of CD34(+)-selected cells from peripheral blood (allo-PBT/CD34(+)) from HLA-identical sibling donors was performed in 50 adult patients with acute myeloid leukemia in first complete remission (AML CR1) (n = 29), myelodysplastic syndrome (MDS) (n = 4), or chronic myeloid leukemia in first chronic phase (CML CP1) (n = 17). Clinical results were compared to a concurrent group of 50 patients transplanted with unmodified peripheral blood progenitor cells (allo-PBT), matched for age, diagnosis, and disease stage. The median follow-up period was 29 months (range 1-69). The actuarial probability of developing acute GVHD clinical grade II to IV was 16% (95%CI: 6-26) for the allo-PBT/CD34(+) group and 41% (95%CI: 29-57) for the allo-PBT group (P = 0.002). The actuarial probability of developing extensive chronic GVHD was 22% (95%CI: 8-36) for the allo-PBT/CD34(+) group and 47% (95%CI: 31-63) for the allo-PBT group (P = 0.02). Recipients of allo-PBT/CD34(+) had less toxicity associated with the transplant and better Karnofsky index at the last follow-up. For AML/MDS patients, the actuarial probability of disease-free survival (DFS) for recipients of allo-PBT/CD34(+) and allo-PBT was 65% (95%CI: 45-85) vs43% (95%CI: 28-58) (P = 0.05), respectively. These data provide a rationale for a randomised trial of allo-PBT/CD34(+) vs allo-PBT in AML/MDS patients in early stage of the disease.

The objective of the present study was to analyze whether veno-occlusive disease (VOD) is based on specific findings or whether this syndrome is the exacerbation of changes in hemostatic parameters that develop following hematopoietic stem cell transplantation (HSCT). 40 patients undergoing HSCT were enrolled (6 allogeneic bone marrow transplantation and 34 peripheral stem cell rescue-2 allogeneic, 32 autologous). Measurements of hemostatic parameters (endothelial, hypercoagulability and fibrinolytic markers) were obtained prior to chemotherapy and weekly thereafter for 3 weeks. The incidence of VOD was 15%. HSCT showed a state of moderate hypercoagulability (increase of thrombin-antithrombin complex and fibrinogen, and decrease of Factor VII, Protein C, and antithrombin-III), probably as a consequence of marked endothelial damage (increase of von Willebrand Factor and tissue plasminogen activator). All these alterations create a potentially prothrombotic state, more pronounced in VOD. The decreasing incidence of VOD and the moderate disease in all patients suggest that increasing improvements in transplant strategies have reduced the risk and severity of a syndrome that at the beginning of the transplantation era was a leading cause of morbidity/mortality.

Hereditary thrombocythaemia (HT) is an autosomal dominant disorder with clinical presentation and complications resembling sporadic essential thrombocythaemia (ET). Mutations in the thrombopoietin (TPO) gene causing overproduction of TPO and elevated TPO serum levels have been found previously in three families with HT. Here, we present evidence for genetic heterogeneity by demonstrating that HT in a Spanish and a US family is caused by genes other than TPO. Affected family members in both families had normal TPO serum levels. Genetic linkage analysis with TPO microsatellite markers excluded TPO as the disease gene in the Spanish HT family, and sequencing of the TPO gene revealed no mutations in the propositus of the US family. To test a role for MPL, the gene for the TPO receptor, we identified three single nucleotide polymorphisms (SNP) and a novel polymorphic CA microsatellite marker. By linkage analysis, we excluded MPL as the cause of HT in the Spanish family. Interestingly, mapping of the CA microsatellite marker to a region 40.5 kb upstream of MPL revealed the presence of sequences from the TIE gene, which encodes a tyrosine kinase receptor expressed on megakaryocytes and endothelial cells. Thus, MPL and TIE are in close physical proximity, and the CA microsatellite described here will be a useful genetic marker for both genes.

Introduction: This study analyses the factors affecting mobilisation and engraftment in autologous peripheral blood progenitor cell transplantation according to the number of CD34(+) re-infused., Materials and Methods: A total of 190 patients underwent mobilisation with G-CSF alone (n=113) or in combination with chemotherapy (n=77). A total of 116 patients (61%) were autografted with <2 x 10(6) CD34(+) cells/kg and 74 patients were transplanted with >2 x 10(6) CD34(+) cells/kg. Rates of granulocyte and platelet recovery were estimated using the product-limit method of Kaplan-Meier and compared using a log-rank test. The Cox regression model was used for the multivariate analysis of factors influencing engraftment. Differences between cohorts were evaluated by one-way ANOVA or Mann-Whitney tests, and multivariate analysis was performed using a stepwise lineal regression., Results: Neutrophil and platelet engraftment was significantly longer with <2 x 10(6)/CD34(+)/kg (12 vs 10 days, P=0.014 and 16 vs 13 days, P=0.0001 respectively). Platelet recovery was affected by exposure to alkylating agents (P=0.04), refractory disease (P=0.02) and AML (P=0.0001), but only the last two variables remained significant in Cox regression (P<0.01). Granulocyte engraftment was longer in CML (univariate, P=0.04) and in refractory disease (multivariate, P=0.02). In patients re-infused with >2 x 10(6)/CD34(+)/kg, the Cox model did not identify prognostic factors for haematopoietic recovery., Conclusion: Although mobilisation schedules and disease status influenced not only the yield of progenitor cells, but also the engraftment kinetics, the number of CD34(+) re-infused was the main predictor of haematopoietic recovery. While engraftment succeeded in most of the cases, the re-infusion of >2 x 10(6)/CD34(+)/kg resulted in significantly shorter recovery times.

Background and Objective: Interferon-a (IFN) is increasingly being used as the drug of choice in chronic myeloid leukemia patients. The main objectives of the study were to study the influence of the classic prognostic variables and response to IFN, and to assess the influence of this response on the course of the disease and survival., Design and Methods: Single arm, prospective, multicenter study, without a control group. Only Ph1-positive CML patients were included. The treatment scheme was biphasic: the patients first received standard chemotherapy and thereafter IFN-a2a was used as monotherapy, with a target dose of 9 MU/d/s.c., Results: Twenty-one centers in Spain enrolled 132 patients (72 men, 60 women). The median dose of IFN given was 5.8 MU/d, and the median treatment duration was 431 days (range: 18-2,597). Seventy-two percent of patients obtained a hematologic response in the first six months of IFN treatment. Genetic response was obtained in 47% of the patients, and the response was major or complete in 27% and 19%, respectively. The median time to obtain this response was 7, 9, and 18 months for minimal, partial and complete genetic response, respectively. Multivariant analysis showed that only a higher percentage of basophils at diagnosis was associated with a worse hematologic response at six months (p=0.001) (OR: 1.23) and with a worse cytogenetic response in the first year of IFN therapy (p=0.018) (OR: 1.4). Over an observation period of 8 years, 35.6% of the patients died, and 85 (64.4%) remained alive. With a median follow-up of 42 months (3.7-98), the 6-year projected probabilities of survival and transformation-free survival were 0.61+/-0.07 vs. 0.54+/-0.07, respectively. Patients with Kantarjian's stage 3 disease or in a high-risk Sokal group had lower probabilities of survival, but these systems did not adequately discriminate in our series. Obtaining a complete hematologic response in the first six months of IFN therapy was favorable in terms of overall survival (p=0.05; HR=0.33). Cox's analysis demonstrated that obtaining a cytogenetic response in the first year was independently associated with better overall survival (p=0.04; HR=0.19) and better transformation-free survival (p=0.0035; HR=0.11)., Interpretation and Conclusions: Nearly half of the patients obtained some degree of Philadelphia suppression, which was major in 27%, and complete in 19%. A higher percentage of basophils at diagnosis was the only variable associated with a lower probability of cytogenetic response. Obtaining a cytogenetic response during the first year of IFN treatment was a favorable and independent variable in terms of survival and transformation-free survival. Obtaining a major cytogenetic response during this period decreased the risk of transformation twenty times. Our results suggest that the effect of IFN on survival is independent of the classic prognostic variables.

Stem cell factor (SCF) has been shown to synergize with filgrastim to mobilize CD34(+) cells into the peripheral blood. To determine if addition of SCF to chemotherapy and filgrastim reduces the number of leukaphereses required to achieve a target yield of 5 x 10(6) CD34(+) cells/kg, 102 patients with multiple myeloma were randomized to receive mobilization chemotherapy with cyclophosphamide (4 g/m(2)) and either SCF (20 micrograms/kg/d) combined with filgrastim (5 micrograms/kg/d) or filgrastim alone (5 micrograms/kg/d), administered daily until leukaphereses were completed. After collection, patients were treated with myeloablative therapy supported by autologous peripheral blood progenitor cell (PBPC) infusion and filgrastim (5 micrograms/kg/d). There was a significant difference between the treatment groups in the number of leukaphereses required to collect 5 x 10(6) CD34(+) cells/kg (median of 1 v 2 for SCF + filgrastim and filgrastim alone, respectively, P =.008). Patients receiving the combination of SCF plus filgrastim had a 3-fold greater chance of reaching 5 x 10(6) CD34(+) cells/kg in a single leukapheresis compared with patients mobilized with filgrastim alone. The median CD34(+) cell yield was significantly increased for the SCF group in the first leukapheresis (11.3 v 4.0 x 10(6)/kg, P =.003) and all leukaphereses (12.4 v 8.2 x 10(6)/kg, P =.007). Total colony-forming unit-granulocyte-macrophage (CFU-GM) and mononuclear cell counts were also significantly higher in the SCF group in the first leukapheresis and in all leukaphereses. As expected for patients mobilized to an optimal CD34(+) cell yield, the time to engraftment was similar between the 2 treatment groups. Cells mobilized with the combination of SCF plus filgrastim were thus considered effective and safe for achieving rapid engraftment. Treatment with SCF plus filgrastim was well tolerated, with mild to moderate injection site reactions being the most frequently reported adverse events. There were no serious allergic-like reactions to SCF. The addition of SCF to filgrastim after cyclophosphamide for PBPC mobilization resulted in a significant increase in CD34(+) cell yield and a concomitant reduction in the number of leukaphereses required to collect an optimal harvest of 5 x 10(6) CD34(+) cells/kg.

Background: This study compares the immune reconstitution of total T cells, CD4 and CD8 cell subsets, activated T cells, NK cells and B cells in 66 patients who underwent allogeneic or autologous bone marrow transplantation (BMT)., Patients, Material and Methods: The reconstitution of peripheral lymphocytes subsets was studied using two-color flow cytometry. The study group consisted of 39 patients who received allogeneic BMT compared with 27 patients who received autologous BMT. Peripheral blood was examined at different time intervals. As a measure of immune function, the response to the mitogen phytohemaglutinin (PHA) was determined., Results: The pattern of recovery of CD3+, CD4+ and CD8+ T cells, as well as the PHA response, was similar for each type of transplant. CD3+CD5- cells were significantly higher following autologous BMT than after allogeneic BMT and during more time. An overexpression of DR on T cells following autologous or allogeneic BMT demonstrates an increasing degree of T-lymphocyte activation. This activated T-cell subset was more stable in patients transplanted with allogeneic BM than in patients treated with autologous BM. The levels of total B cells and CD19+CD5+ B-cells were increased during 2 to 12 months following autologous MBT, remaining normal afterwards; in contrast, the levels of CD19+ lymphocytes and CD19+CD5+B-cells remained higher than normal ranges until 36 months in patients transplanted with allogeneic BM. The percentage of NK cells was significantly increased following both autologous and allogeneic BMT. The highest percentage of NK cells were detected about 2 and 6 months post-transplant in patients treated with autologous or allogeneic BM, respectively., Conclusions: Allogeneic BMT appears to induce a slight delay recovery of B and NK cells in comparison to autologous BMT. In contrast, T-cells recovery was similar for each type of transplant, although a higher percentage of CD3+CD5- T cells and a faster recovery of activated CD3+DR+ cells to normal levels were observed in patients transplanted with autologous BM.

Background: This study is aimed at establishing the possible associations between the number of admissions through the emergency room at the "Juan Canalejol" Hospital in Corunna in 1994-1994 due to organic, circulatory and respiratory reasons and the weather variables introduced as being exogenous for the purpose of preparing a prediction model., Methods: The Box-Jenkins methodology is used for obtaining univariate ARIMA models of the time-based series taken into consideration. Cross-Correlation Functions (CCF's) are established among the series of residuals which afford the possibility of establishing weights and lags among the variables for a subsequent modeling by means of multivariate ARIMA models which include environmental variables., Results: The emergency admissions for organic reasons significantly increase 0-2 days following a rise in temperature. The admissions due to respiratory ailments are associated with drops in temperature with 10-14 lags, whilst the admissions for circulatory reasons increase significantly due to long-lasting spells of hot weather (10 lags). For people over age 65, significant increases in emergency admissions for circulatory reasons are also recorded with cold snaps. The multivariate ARIMA models that take into account the effect of environmental variables provided the best adjustment for all of the admissions variables., Conclusions: The number of emergency room admissions at the "Juan Canalejo" Medical Center Complex in Corunna due to organic, respiratory and circulatory causes shows a seasonal behavior pattern. The admissions for respiratory reasons are associated with a drop in temperature, whilst the admissions for circulatory reasons are affected fundamentally by hot weather, although also by cold weather as regards people over age 65. The multivariate ARIMA models including climate-related variables provide a system for predicting admissions in terms of said variables that can be useful from the standpoint of hospital management.

Background and Objective: Cryopreservation of hemopoietic progenitors for transplantation has been traditionally performed by the use of a controlled-rate freezer. Several groups have reported successful cryopreservation of progenitor cells at -80 degrees C without a controlled-rate freezer. In an attempt to elucidate whether both methods are equally efficient, we compared controlled-rate versus uncontrolled cryopreservation of peripheral blood progenitor cells (PBPC) in a prospective, multicenter study., Design and Methods: Apheresis products from patients undergoing PBPC mobilization were split into two aliquots, and cryopreserved simultaneously by both methods, in autologous plasma plus 10% dimethylsulfoxide. Controlled-rate samples were placed into a programmable freezer with a cooling rate of 1-2 degrees C/min. Uncontrolled-rate samples were directly introduced into a -80 degrees C mechanical freezer. After thawing, cell counts, assays for viability, clonogenic cultures and CD34+ cell enumeration were performed., Results: A total of 105 cases were included. No significant differences were found in viability (mean 88.8 +/- 13% in the controlled-rate group vs. 89.7 +/- 12% in the uncontrolled-rate group), nucleated cell loss (23.5 +/- 23% vs. 23 +/- 22%), mononuclear cell loss (19 +/- 23% vs. 19.1 +/- 22%), and loss of CD34+ cells (34.3 +/- 33% vs. 28.6 +/- 34%). On the other hand, recovery of granulomonocytic colony-forming units (CFU-GM), was significantly better with the controlled-rate technique, than with the non-controlled-rate method (104.3 +/- 95 vs. 86.5 +/- 80, respectively; p = 0.048)., Interpretation and Conclusions: Our results indicate that both techniques are suitable for cryopreservation of PBPC, although a better recovery of committed progenitors is achieved by the controlled-rate method. Therefore, the use of controlled-rate freezer should probably be recommended.

Objective: To assess the relationship, if any, between air pollutant (sulfur dioxide and total suspended particulate) levels and mortality in the city of Madrid during the period 1986-1992, controlling for weather, season, and influenza epidemics., Methods: Daily death counts were obtained from the Regional Mortality Registry. Pollution data were supplied by the Municipal Monitoring Network. Time-series analysis methodology was used to assess the link between non-accidental as well as circulatory- and respiratory-disease mortality, on the one hand, and mean daily concentrations of SO2 and total suspended particulate (TSP), on the other. Multivariate autoregressive integrated moving-average (ARIMA) models were used to adjust for season, temperature, relative humidity, and influenza. A sensitivity analysis was run to assess the robustness of the estimators., Results: Graphical analysis revealed a linear relationship between mortality and TSP. The relationship was logarithmic in the case of SO2. TSP lagged 1 day and SO2 lagged 3 days with an independent effect on mortality. This relationship was produced without the detection of a minimal threshold in emission values., Conclusions: These results support the hypothesis of an association between pollution levels and mortality between 1986-1992 in Madrid. Additional measures designed to reduce pollution levels without compromising thermal comfort should be implemented.

Objective: The aim of the study is to quantify the relationship between sulphur dioxide (SO2), total suspended particulate (TSP) and daily mortality in Madrid., Methods: Data were plotted to exhibit the functional relationship between SO2, TSO and mortality. Box-Jenkins prewhitening method was used to detect lags and weights from the transfer function. Multivariate ARIMA models were built to control for confounding variables (air temperature and influenza epidemics)., Results: Graphic analysis suggested a logarithmic relationship between SO2 and mortality, and lineal relationship with TSP. No evidence of a threshold was found for each pollutant. Cross-correlation functions showed a statistically significant relationship between daily mortality caused by organic, cardiovascular and respiratory diseases and air pollution. The first lag was statistically significant for TSP and the third lag for SO2. Multivariate models gave a coefficient beta = 0.039 for TSP and beta = 1.04 for SO2 indicating a 6.6% increase in mortality for each 100 micrograms/m3 increase in TSP and a 2.2% for SO2., Conclusions: The result suggest a causal relationship between daily mortality and air pollution in Madrid.

The objective of this study was to analyze CD34+ cell recovery and T cell depletion (TCD) achieved in CD34+ cell grafts using either immunoadsorption or immunomagnetic methods applied to leukapheresis products from healthy donors. We also wanted to determine the kinetics of engraftment and incidence and severity of graft-versus-host disease (GVHD) after allogeneic transplantation of selected CD34+ cells. HLA-identical sibling donors received G-CSF. After leukapheresis, peripheral blood progenitor cells were selected using immunoadsorption (Ceprate SC) (n = 38) or immunomagnetic (Isolex 300) (n = 24) methods. Sixty-two patients, with a median age of 42 years (range 17-60) diagnosed with hematological malignancies were conditioned with either cyclophosphamide and total body irradiation (n = 43) or busulphan and cyclophosphamide (n = 19). GVHD prophylaxis consisted of cyclosporin A (CsA) and prednisone (n = 48), CsA alone (n = 11) and CsA and methotrexate (n = 3). The median yield and purity of CD34+ cells after the procedure was 65 and 66% with immunoadsorption, and 48 and 86% with immunomagnetic method, respectively. The median number (range) of CD34+ cells infused into the patients was 3.5 x 10(6)/kg (1-9.6). The median number (range) of CD3+ cells administered was 0.4 x 10(6)/kg (0.01-2) using immunoadsorption and 0.14 x 10(6)/kg (0.03-2.5) using immunomagnetic methods. Neutrophil recovery >500 and >1000/microl was achieved at a median (range) of 13 days (8-22) and 14 days (9-31), respectively. Platelets recovered to >20000 and >50000/microl at a median (range) of 13 days (0-128) and 18 days (0-180), respectively. Two patients developed graft failure. Acute GVHD in patients at risk was clinical grade 0 (n = 43), I (n = 8), II (n = 4) and III (n = 1). No patient developed acute GVHD grade IV. Chronic GVHD was limited in two cases and extensive in four cases. The actuarial probability of acute GVHD II-IV was 10% (95% CI, 1-19%), and of extensive chronic GVHD was 12% (95% CI, 11-13%). The cumulative incidence of transplant-related mortality was 12.6%, and this figure was 9% at 6 months. In conclusion, with the immunomagnetic procedure, a lower recovery and higher purity of CD34+ cells, and stronger TCD is obtained as compared to immunoadsorption (P = 0.008, P < 0.0001 and P = 0.0002, respectively). Our results also indicate that allogeneic transplantation of selected CD34+ cells is associated with a very rapid engraftment and with a low incidence of severe GVHD.

This report summarizes the Spanish experience of 62 cases of allogeneic transplantation of purified CD34+ cells from peripheral blood. HLA-identical sibling donors received G-CSF. After leukapheresis, peripheral blood progenitor cells were purified using one of two methods: Ceprate (n = 38), or Isolex 300 (n = 24). Sixty-two patients median age 42 years (range 17-60) diagnosed with hematological malignancies were conditioned with either cyclophosphamide and total body irradiation (n = 43) or busulphan and cyclophosphamide (n = 19). GVHD prophylaxis consisted of cyclosporin A (CsA) and prednisone (n = 48), CsA alone (n = 11), and CsA and methotrexate (n = 3). The median yield and purity of CD34+ cells after the procedure was 65% and 66% with Ceprate, and 48% and 86% with Isolex, respectively. The median number of CD34+ cells infused into the patients was 3.5 x 10(6)/kg (range 1-9.6). The median number of CD3+ cells administered was 0.4 x 10(6)/kg (range 0.01-2) using Ceprate and 0.14 x 10(6)/kg (range 0.03-2.5) using Isolex. Neutrophil recovery >500 and >1000/microl was achieved at a median of 13 days (range 8-22) and 14 days (range 9-31), respectively. Platelets recovered to >20,000 and >50,000/microl at a median of 13 days (range 0-128) and 18 days (range 0-180), respectively. The actuarial probability of acute GVHD II-IV was 10% (95% CI, 1-19%), and of extensive chronic GVHD 12% (95% CI, 11-13%).

Between January 1989 and November 1995, 259 patients with multiple myeloma (MM), 22 stage I, 57 stage II and 180 stage III at diagnosis were treated with myeloablative high-dose therapy followed by autologous peripheral blood stem cell (PBSC) transplantation. The median time from diagnosis to transplantation was 17 months (6-112). At the time of transplant, 56 patients were in CR, 153 in PR, 25 were nonresponders and 25 had progressive disease. Mobilization of stem cells was performed with G-CSF alone in 141 cases, chemotherapy plus G-CSF in 65, chemotherapy plus GM-CSF in 36 and chemotherapy alone in 17 patients. The conditioning regimen consisted of high-dose melphalan alone in 96 patients, melphalan plus TBI in 73, busulfan plus melphalan in 56, busulfan plus cyclophosphamide in 27 and cyclophosphamide plus TBI in seven. The median durations of neutropenia (>0.5 x 10(9)/l) and thrombocytopenia (>20 x 10(9)/l) were 12 (5-118) and 13 days (5-360), respectively. Transplant-related mortality occurred in 11 patients (4%). Once a stable graft was achieved, 114 patients (44%) received maintenance treatment with recombinant alpha interferon (IFN-alpha). Among the 248 patients evaluable for response 125 (51%) had a CR and 100 had a PR (40%). The median duration of progression-free survival (PFS) and overall survival (OS) after transplantation was 23 and 35 months, respectively. Univariate analysis showed that response status pretransplant, only one line of primary induction treatment and IFN-alpha maintenance treatment post-transplant significantly influenced OS. Female sex, pretransplant responsive disease, and treatment with IFN-alpha post-transplant were the factors significantly influencing PFS. The conditioning regimen and method of stem cell mobilization had no significant impact on OS and PFS. On multivariate analysis the only independent factors associated with a longer survival were the number of chemotherapy courses prior to autologous PBSC transplantation and the pretransplant response status. The present analysis from the Spanish Registry confirms the feasibility of autologous PBSC transplantation in myeloma patients with a very low toxicity (4% toxic deaths). The high complete response rate after transplantation is encouraging. The best results are obtained when the procedure is performed early after the first line of induction therapy and in patients with chemosensitive disease. Whether early high-dose therapy followed by autotransplantation in responding patients is superior to conventional chemotherapy is currently being investigated in prospective randomized studies.

We report the case of a BMT recipient who developed blindness 22 months after BMT. Microvascular retinopathy, cortical blindness and other ocular pathologies were excluded with appropriate tests. Electrophysiological studies showed retinal damage without excluding an optic nerve lesion. The patient, who had several risk factors for neurologic-induced cyclosporine toxicity, improved with cyclosporine withdrawal. Our findings stress the need of electrophysiological tests to exclude neuroretinal damage in patients receiving cyclosporine after BMT.

Objective: To investigate the influence of environmental variables on daily mortality, due to respiratory and cardiovascular diseases, in the C.M. from 1986 to 1991., Methodology: The environmental and mortality variables are correlated between cold and heat effects, checking the possible coincidence of models between temperature and mortality by Box-Jenkins models. The filtered mortality is correlated to the daily average temperatures, for 0-15 lags., Results: The minimum daily mortality is produced in an average temperature of 23.9 degrees. There exists a correlation (p < 0.001) between cold temperature and all the mortality causes in the 15 analysed lags. A correlation (p < 0.01) to vascular diseases appears with hot temperature and, among them, with cerebrovascular accidents (ACVA) in women for 0-3 lags., Conclusions: Cold temperatures increase the mortality for all the analysed lags and causes. The heat produces immediate effects on the mortality by ACVA in women.

We evaluated the role of high-dose granulocyte colony stimulating factor (G-CSF) in vitro, in inducing the generation of high-proliferative potential colony forming cells (HPP-CFC), from either mononuclear cells or purified CD34+ cells. Both normal controls and patients undergoing peripheral blood stem cell (PBSC) mobilization and transplantation were studied. In serum-driven agar cultures, G-CSF stimulated the proliferation of HPP-CFC in a dose dependent manner (r = 0.92). The number of HPP-CFC was four-fold greater in mobilized patients than in normal controls. Purified CD34+ cells yielded 11-fold more colonies than mononuclear cells. HPP-CFC from mobilized patients showed replating capacity, giving rise to secondary colonies of more mature appearance. In serum-free cultures, the effect of G-CSF appeared to be mediated by synergistic interaction with stem cell factor. Our results suggest that G-CSF stimulates primitive hematopoietic cells that are detectable in increased amounts in patients receiving mobilization therapy. Therefore, determination of G-CSF induced HPP-CFC could be a useful tool in the evaluation of mobilization strategies.