Contamination level, spatial distribution, and sources of potentially toxic elements in indoor settled household dusts in Tehran, Iran.

Tehran, the capital city of Iran, has been facing air pollution for several decades due to rapid urbanization, population growth, improper vehicle use, and the low quality of fuels. In this study, 31 indoor dust samples were collected passively from residential and commercial buildings located in the central and densely populated districts of the city. These samples were analyzed after preparation to measure the concentration of elements (As, Be, Cd, Co, Cr, Cu, Fe, Hg, Mn, Mo, Ni, Pb, Se, Sr, V, Zn). Statistical data analyses were employed to compare their relationship across various uses, variations, and for source identification. Geochemical indices of contamination factor (CF) and pollution load index (PLI) were utilized to evaluate the degree of contamination. The mean concentrations of Zn, Cu, and Pb (938, 206, and 176 µg g-1, respectively) are 6, 5, and 3 times higher than their mean values in worldwide urban soils. Additionally, Cd, Mo, and Ni showed concentrations about 1.5 times higher, while As, Co, Cr, Mn, and Sr fell within the range of reference soils. Be, V, and Sb displayed remarkably lower mean values. Building use did not significantly influence element levels in indoor deposited dust except for Pb and Zn. A comparison of indoor concentrations with previously published data for outdoor dusts revealed higher enrichments of Mo, Cu, Pb, and Ni, while As, Cd, and Zn showed lower enrichments in street dust samples. The order of CF values indicated Hg > Zn > Cd > Pb > Cu > As > Ni > Cr > Co > V. For Hg, Zn, Pb, Cd, and Cu, all or almost all samples exhibited very high contamination. PLI values were consistently higher than 1, indicating contamination in all samples. Multivariate statistical analysis and Tehran's specific geological location suggested that mafic-intermediate volcanic rocks are primary sources for Cr, Cu, Fe, and Ni (PC1). As, Pb, and V (PC2) were attributed to fossil fuel combustion in vehicles and residential buildings. Pb is a legacy metal remaining from the use of leaded gasoline, which was phased out in the 1990s. Zn (PC3) is derived from vehicle tires.

Clothing as a potential exposure source of trace elements during early life.

In recent years, the interest in determining the chemical composition of textile products has increased among the scientific community and regulatory agencies, driven by toxicological issues and environmental concerns. Chemical elements are naturally present in clothing as natural fibers or intentionally added during manufacture. Some of them show physical-chemical properties that allow their absorption through the skin. In addition, chronic situations increase the dermal exposure capacity. Because of age-specific behavioral characteristics and underdeveloped physiological function, children may be especially sensitive to exposure to trace elements. This study aimed to analyze the levels of twenty trace elements in 120 clothing items commercialized in Spain. Textile products for pregnant women and children <36 months old were included. The potential health implication of this dermal exposure in early life was also evaluated. Aluminum, zinc, and titanium showed the highest concentrations, with median levels of 27.6, 5.6, and 4.2 mg/kg, respectively. Since chromium is employed as a metal complex dye in synthetic fibers, high levels of this element were found in black polyester. Dermal exposure to titanium, which is a ubiquitous element in clothes made of synthetic fibers, was associated with a hazard quotient (HQ) higher than the threshold value (HQ > 1), with values of 1.13 for pregnant women and 1.22 for newborns. On the other hand, HQ values of other elements and cancer risks were lower than the recommended values. Assessing early-life exposure to toxic elements can help to identify potential sources and to prevent or reduce human exposure, mainly in vulnerable groups.

Multidrug-resistant Enterobacter spp. in wastewater and surface water: Molecular characterization of ß-lactam resistance and metal tolerance genes.

Among the ESKAPE group pathogens, Enterobacter spp. is an opportunistic Gram-negative bacillus, widely dispersed in the environment, that causes infections. In the present study, samples of hospital wastewater, raw and treated urban wastewater, as well as surface receiving water, were collected to assess the occurrence of multidrug-resistant (MDR) Enterobacter spp. A molecular characterization of ß-lactam antibiotic resistance and metal tolerance genes was performed. According to identification by MALDI-TOF MS, 14 isolates were obtained: 7 E. bugandensis, 5 E. kobei, and 2 E. cloacae. The isolates showed resistance mainly to ß-lactam antibiotics, including those used to treat infections caused by MDR bacteria. Multiple antibiotic resistance index was calculated for all isolates. It allowed verify whether sampling points showed a high risk due to antibiotic resistant Enterobacter spp., as well as to determine if the isolates have been in environments with a frequent antibiotic use. Twelve isolates showed ß-lactam antibiotic resistance gene, being the blaKPC widely detected. Regarding metal tolerance, 13 isolates showed at least two genes that encode metal tolerance mechanisms. Overall, metal tolerance mechanisms to silver, copper, mercury, arsenic and tellurium were found. New data on metal tolerance mechanisms dispersion and antibiotic-resistance characterization of the E. bugandensis and E. kobei species were here provided. The occurrence of MDR Enterobacter spp. in analyzed samples draws attention to an urgent need to put control measures into practice. It also evidences waterborne spread of clinically important antibiotic-resistant bacteria recognized as critical priority pathogens.

Optimising the management of patients with multiple myeloma in Spain: A measurement of the social return on investment.

OBJECTIVE: The aim of this study was to reach a consensus on a set of proposals to optimise the disease management of Multiple myeloma (MM) within the Spanish National Health System (SNHS) and to apply the Social Return on Investment (SROI) method to estimate their social impact. METHODS: A Multidisciplinary Working Team (MWT) including MM main stakeholders was organised. A survey was administered to gather information from patients regarding the impact of MM on different life domains. A forecast-type SROI analysis, with a 1-year timeframe, was applied. RESULTS: Fifteen proposals were selected, to optimise MM management, including actions for early diagnosis, psychological support, improvement of information for patients and quick access to palliative care, among others. The implementation of these proposals would benefit patients, their informal caregivers and the SNHS. The investment required would amount to 10.32 million euros with a social return of 43.31 million euros: 4.2 euros for each euro invested. According to the sensitivity analysis, this ratio could range from 3.38 to 5.20 euros from the worst to the best-case scenario. CONCLUSIONS: The current management of MM could be optimised by implementing a set of proposals that would most likely result in an overall positive social return.

Characterization of airborne particles and cytotoxicity to a human lung cancer cell line in Guangzhou, China.

Air pollution by airborne particles is a serious health problem worldwide. The present study was aimed at investigating the concentrations and composition of total suspended particles (TSPs) and PM2.5 at various industrial/commercial sites of Guangzhou, a megacity of Southern China. Major and trace elements, ions and carbonaceous fraction were determined and main components were calculated. In addition, in order to assess the potential toxic on the respiratory system of these PM, cytotoxicity of size-fractionated particles (PM10-5.6, PM5.6-3.3, PM3.3-1.1, PM1.1-0.43) for a human lung cancer cell line (A549) was also investigated. Correlations between PM constituents and toxicity were assessed. Median levels of TSPs and PM2.5 in industrial/commercial sites were 206 and 57.7 µg/m3, respectively. Nickel, Cu, Mo, Mn, Pb, and Ti were the most abundant metals in TSPs and PM2.5. Industrial activities and coal combustion were the most important sources of carbonaceous particles in the zone. MTT assays showed that PM10-5.6 and PM1.1-0.43 had the highest and the lowest cytotoxicity to A549 cell lines, respectively. Inhalable particles around the manufacturing of metal facilities and formal waste treatment plants showed a high cytotoxicity to A549 cell lines. In general terms, no significant correlations were found between main components of PM and toxicity. However, W showed a significant correlation with cell viability.

Correction to: Update on management and progress of novel therapeutics for R/R AML: an Iberian expert panel consensus.

After publication of this paper, the authors determined that an additional information in the funding section was missing.

Essential and toxic elements in human milk concentrate with human milk lyophilizate: A preclinical study.

Concentrated human milk (HM-concentrate) can be obtained from the simple and inexpensive method of donated breast milk direct lyophilization. A previous study reported that HM-concentrate contains the adequate amount of main macro- and micronutrients for use as a nutritional resource for preterm infants with very low birth weight admitted to neonatal intensive care units. However, further details need to be elucidated about HM-concentrate composition, particularly its content of essential and potentially toxic trace elements. Therefore, this study aimed to determine the concentration of essential and toxic elements in human milk considered baseline (HM-baseline) and HM-concentrate, as well as to quantify changes in concentration of these elements after the HM concentration process. The concentration of Aluminum, Arsenic, Cadmium, Chromium, Iron, Mercury, Manganese, Nickel, Lead, Selenium, Tin, and Thallium was analyzed by inductively coupled plasma-mass spectrometry (ICP-MS). Moreover, Bayesian linear mixed effect models were applied to estimate the mean difference between HM-baseline and HM-concentrate samples. After comparison (HM-concentrate versus HM-baseline), a significant increase in concentration was observed only for Manganese (0.80 µg/L; 95% CrI [0.16; 1.43]) and Selenium (6.74 µg/L; 95% CrI [4.66; 8.86]), while Lead concentration (-6.13 µg/L; 95% CrI [-8.63; -3.61]) decreased. This study provides latest and reliable information about HM composition. After milk concentration by lyophilization, there was a significant increase only in the essential elements Manganese and Selenium. The essential micronutrient content in HM-concentrate was similar or higher than that in preterm mothers' milk, which suggests it is viable for nutritional support of preterm infants. In addition, the low concentrations of potentially toxic elements in HM-concentrate indicates that it is safe for consumption by premature newborns.

Update on management and progress of novel therapeutics for R/R AML: an Iberian expert panel consensus.

A significant proportion of adult patients with acute myeloid leukemia (AML) fail to achieve complete remission or will relapse later on after achieving it. Prognosis for relapsed or refractory (R/R) AML patients remains discouraging, with the main curative option still relying on hematopoietic stem cell transplant (HSCT) for those who are eligible. Beyond morphological bone marrow and peripheral blood assessment, evaluation of patient performance status and comorbidities, as well as genetic/molecular characterization, is crucial to make an accurate diagnosis and prognosis, which will be useful to select the most appropriate treatment. Emerging strategies are mainly focusing on the development of immune- and molecular-based approaches. Novel targeted therapies are generally well tolerated, potentially allowing them to be administered alone or in combination with classical chemotherapy agents. Enrolment in clinical trials should be considered first option for R/R AML patients, either as a bridge to HSCT or to benefit from novel therapies that eventually may prolong survival and improve quality of life. An Iberian expert panel has reviewed the recent advances in the management of R/R AML with the aim to develop updated evidence and expert opinion-based recommendations.

Seasonal characterization and dosimetry-assisted risk assessment of indoor particulate matter (PM10-2.5, PM2.5-0.25, and PM0.25) collected in different schools.

Inhalation of particulate matter (PM) has been linked to serious adverse health effects, such as asthma, cardiovascular diseases and lung cancer. In the present study, coarse (PM10-2.5), accumulation mode (PM2.5-0.25), and quasi-ultrafine (PM0.25) particulates were collected inside twelve educative centers of Tarragona County (Catalonia, Spain) during two seasons (cold and warm). Chemical characterization of PM, as well as risk assessment were subsequently conducted in order to evaluate respiratory and digestive risks during school time for children. Levels and chemical composition of PM were very different among the 12 centers. Average PM levels were higher during the cold season, as well as the concentrations of most toxic metals. In most schools, PM levels were below the daily PM10 threshold established in the regulation (50 µg/m3), with the exception of school number 1 during the cold season. On average, and regardless of season, coarse PM was highly influenced by mineral matter, while organic matter and elemental carbon were prevalent in quasi-ultrafine PM. The concentrations of the toxic elements considered by the legislation (As, Cd, Pb, and Ni) were below their correspondent regulatory annual limits. Calculated risks were below the safety thresholds, being fine fractions (PM2.5-0.25 and PM0.25) the main contributors to both digestive and respiratory risks.

Metals risk assessment for children's health in water and particulate matter in a southeastern Brazilian city.

Ribeirão Preto City is supplied by the Guarani Aquifer System and suffers with intense environmental degradation due to growth of the vehicle fleet, burning of cane fields and also with water contamination by agricultural products, such as pesticides and fertilizers. The aim of the present study was to assess the human health risk derived from the exposure to metals through water and air (PM10) for two population groups (adults and children) of the municipality of Ribeirão Preto during the dry and wet seasons. Seasonal and spatial assessments of the metal concentrations in supply wells and household waters and the concentrations of PM10 and its metals were also performed. Element concentrations were determined by inductively coupled plasma spectrometry. Environmental exposure to metals were assessed under a residential scenario and estimated considering the three main routes of exposure: ingestion, dermal contact and inhalation. The results showed a higher concentration of PM10 during the dry season, which may be due to the lower precipitation and higher number of burns in this period. Copper in household waters presented a great increase when compared with the concentrations of the supply wells, probably related to the contamination during the route from its source until the residences supply. Although presenting levels in accordance with the national legislation, household waters in the municipality of Ribeirão Preto may be a concern for human exposure to metals for children during the wet season as well as the levels found for the carcinogenic risk (ELCR).

Main components of PM10 in an area influenced by a cement plant in Catalonia, Spain: Seasonal and daily variations.

Particulate matter (PM) composition has a key role in a wide range of health outcomes, such as asthma, chronic obstructive pulmonary disease, lung cancer, cardiovascular disease, and death, among others. Montcada i Reixac, a municipality located in the Barcelona metropolitan area (Catalonia, Spain), for its location and orography, is an interesting case- study to investigate air pollution. The area is also characterized by the presence of different industrial emission sources, including a cement factory and a large waste management plant, as well as an intense traffic. In this study, PM10 levels, trace elements, ions, and carbonaceous particles were determined for a long time period (2013-2016) in this highly polluted area. PM10 samples were collected during six consecutive days in two campaigns (cold and warm) per year. A number of elements (As, Ba, Be, Bi, Ca, Cd, Ce, Co, Cr, Cs, Cu, Dy, Er, Eu, Fe, Ga, Gd, Ge, Hf, Hg, Ho, K, La, Li, Hg, Mg, Mn, Mo, Nb, Nd, Ni, Pb, Pr, Rb, Sb, Sc, Se, Sm, Sn, Sr, Tb, Th, Ti, Tl, U, V, W, Y, Yb, and Zr), ions (Cl-, SO42-, NO3-, and NH4+), and carbonaceous content (total carbon, organic plus elemental carbon, and CO32-), were analysed. These data were used to identify the PM10 main components: mineral matter, sea spray, secondary inorganic aerosols, organic matter plus elemental carbon, trace elements or indeterminate fraction. Although a clear seasonality (cold vs. warm periods) was found, there were no differences between working days and weekends. Obviously, the cement plant influences the surrounding environment. However, no differences in trace elements related with the cement plant activity (Al, Ca, Ni and V) between weekdays and weekends were noted. However, some traffic-related elements (i.e., Co, Cr, Mn, and Sb) showed significantly higher concentrations in weekdays.

Water Quality Assessment of the Pardo River Basin, Brazil: A Multivariate Approach Using Limnological Parameters, Metal Concentrations and Indicator Bacteria.

Located in the southeast of Brazil, the Pardo River Basin has a large population and an economy focused on agriculture, with a strong predominance of the sugarcane agro-industry. The purpose of the study was to assess the water quality of the Pardo River Basin under a multivariate approach using limnological parameters, metal concentrations, and indicator bacteria. Nine sampling campaigns were performed during both the dry and rainy seasons. Element concentrations were determined by inductively coupled plasma spectrometry (ICP-MS, Perkin Elmer Elan 6000). A battery of test to determine limnological parameters was performed (in situ). Total coliforms and Escherichia coli were detected and quantified using Defined Substrate Technology Colilert® and multiple tube dilutions. Principal component analysis and hierarchical cluster analysis were used as multivariate exploratory analysis. In general, the results suggest the influence of rain, possible sewage discharges into the watercourse, and the input of organic matter in some sampling points in both seasons, besides the absence of riparian vegetation in much of the Pardo River. The likely influence of industrial activities that do not have great prominence in the region was supported by temporal/spatial assessment of Cr and V. The water quality monitoring of Pardo River is an important tool for environmental management, and its continuity is indicated to obtain a consistent series of systematic data and thereby support concretely the actions of planning and controlling the use of water from the Pardo River and soil around them.

Do Patients and Physicians Agree When They Assess Quality of Life?

Patient and physician agreement on the most significant symptoms is associated with treatment outcomes and satisfaction with care. Thus, we sought to assess patient and physician agreement on patient-reported quality of life (QoL), and whether patient-related variables predict disagreement. In this cross-sectional, multisite study, patients and physicians completed the FACT-BMT at day 90. Agreement was analyzed with the intraclass coefficient correlation (ICC). Rates of underestimation and overestimation were calculated. Logistic regression models identified predictors of disagreement. We analyzed 96 pairs of questionnaires completed by 96 patients and 11 physicians. The patients' median age was 54 years, 52% were men, and 52% had undergone allogeneic hematopoietic cell transplantation (HCT). The physicians' median age was 42, 64% were men, and they had worked in the HCT field for an average of 12 years. Agreement on QoL was moderate (ICC = .436). Exploratory analyses revealed poor agreement for emotional (ICC = .092) and social (ICC = .270) well-being and moderate agreement for physical (ICC = .457), functional (ICC = .451), and BMT concerns (ICC = .445). Patients' well-being was underestimated by physicians in 41% to 59% of the categories of well-being parameters, and overestimated in 10% to 24%. Patient's anxiety predicted less disagreement in all scales except in social well-being, for which nonsignificant associations were observed. Patient-related variables explained 12% to 19% of the variance in disagreement across well-being scales. Patient and physician agreement on QoL was suboptimal, particularly in emotional and social well-being. The implementation of patient-reported outcomes in the daily care of HCT recipients may contribute to improving patient-centered care.

Concentrations of polycyclic aromatic hydrocarbons and trace elements in Arctic soils: A case-study in Svalbard.

A combined assessment on the levels and distribution profiles of polycyclic aromatic hydrocarbons (PAHs) and trace elements in soils from Pyramiden (Central Spitsbergen, Svalbard Archipelago) is here reported. As previously stated, long-range atmospheric transport, coal deposits and previous mining extractions, as well as the stack emissions of two operative power plants at this settlement are considered as potential sources of pollution. Eight top-layer soil samples were collected and analysed for the 16 US EPA priority PAHs and for 15 trace elements (As, Be, Cd, Co, Cr, Cu, Hg, Mn, Mo, Ni, Pb, Sn, Tl, V and Zn) during late summer of 2014. The highest levels of PAHs and trace elements were found in sampling sites located near two power plants, and at downwind from these sites. The current PAH concentrations were even higher than typical threshold values. The determination of the pyrogenic molecular diagnostic ratios (MDRs) in most samples revealed that fossil fuel burning might be heavily contributing to the PAHs levels. Two different indices, the Pollution Load Index (PLI) and the Geoaccumulation Index (Igeo), were determined for assessing soil samples with respect to trace elements pollution. Samples collected close to the power plants were found to be slightly and moderately polluted with zinc (Zn) and mercury (Hg), respectively. The Spearman correlation showed significant correlations between the concentrations of 16 PAHs and some trace elements (Pb, V, Hg, Cu, Zn, Sn, Be) with the organic matter content, indicating that soil properties play a key role for pollutant retention in the Arctic soils. Furthermore, the correlations between ∑16 PAHs and some trace elements (e.g., Hg, Pb, Zn and Cu) suggest that the main source of contamination is probably pyrogenic, although the biogenic and petrogenic origin of PAHs should not be disregarded according to the local geology.

Feasibility and efficacy of outpatient therapy with intermediate dose cytarabine, fludarabine and idarubicin for patients with acute myeloid leukaemia aged 70 or older.

OBJECTIVES: A multicentre prospective non-randomised study of de novo acute myeloid leukaemia (AML) in patients aged ≥70 yr was designed to reduce toxicity and achieve acceptable complete remission (CR) rates. METHODS: The outpatient treatment included induction with oral fludarabine, subcutaneous cytarabine and subcutaneous filgrastim (FAG). The patients received more induction cycles according to the response achieved. If there was no response to induction with FAG, the following induction cycle included oral idarubicin, subcutaneous cytarabine and subcutaneous filgrastim (IAG). Patients achieving CR received one intensification (FAG on response to previous FAG or alternatively IAG) and one consolidation cycle (IAG). RESULTS: Thirty patients were enrolled from April 2004 to June 2007. The median age was 73 yr (range 70-77). Fifteen patients (50%) achieved CR. The 2-yr DFS was 29% (95% CI, 5-47%), and the 2-yr OS was 23% (95% CI, 12-35%). Twenty-five of 69 cycles (36%) were managed on a completely outpatient basis. The median hospital stay per cycle was 10 d (95% CI, 3-25). CONCLUSIONS: This study demonstrates the tolerability and efficacy of a semi-intensive treatment in elderly de novo patients with AML managed on an outpatient basis, without substantial toxicity.

Quantitative structure-activity relationship (QSAR) prediction of (eco)toxicity of short aliphatic protic ionic liquids.

Ionic liquids (ILs) are considered as a group of very promising compounds due to their excellent properties (practical non-volatility, high thermal stability and very good and diverse solving capacity). The ILs have a good prospect of replacing traditional organic solvents in vast variety of applications. However, the complete information on their environmental impact is still not available. There is also an enormous number of possible combinations of anions and cations which can form ILs, the fact that requires a method allowing the prediction of toxicity of existing and potential ILs. In this study, a group contribution QSAR model has been used in order to predict the (eco)toxicity of protic and aprotic ILs for five tests (Microtox®, Pseudokirchneriella subcapitata and Lemna minor growth inhibition test, and Acetylcholinestherase inhibition and Cell viability assay with IPC-81 cells). The predicted and experimental toxicity are well correlated. A prediction of EC50 for these (eco)toxicity tests has also been made for eight representatives of the new family of short aliphatic protic ILs, whose toxicity has not been determined experimentally to date. The QSAR model applied in this study can allow the selection of potentially less toxic ILs amongst the existing ones (e.g. in the case of aprotic ILs), but it can also be very helpful in directing the synthesis efforts toward developing new "greener" ILs respectful with the environment (e.g. short aliphatic protic ILs).

Set up and validation of a method to analyse microplastics in stool and small intestine samples.

The contamination of microplastics in humans is of increasing concern. Therefore, the aim of this study was to develop effective methods to determine the concentration and types of microplastics entering human digestive system. To study levels of MPs contamination in humans, an excellent indicator are stools. Indeed, stools, and thus the digestive system, can be an excellent indicator of the level of MPs contamination in humans. Hence, objective was to find effective methods to extract, quantify and characterize microplastics in stool and small intestine samples. The samples studied were human stools and pig jejunum (which has human-like characteristics). The methods were optimized by observing extraction efficiency, compatibility by Fourier-transform infrared spectroscopy (FTIR) characterization and non-deformation of the microplastics. The steps of the procedure were: • Sampling to avoid plastic contamination • Non-aggressive chemical and enzymatic digestion • Counting and characterization The methods were optimized and validated, observing recovery and repeatability. Therefore, two simple, effective methods with high analytical performance have been developed. The MPs present in the stool and intestine samples were counted by stereoscopic microscope and characterized by FTIR, finding several types of MPs such as synthetic cellulose, polyethylene, polypropylene, polystyrene, and polyethylene terephthalate, among others.

Human exposure to elements through consumption of raw and cooked fish in an urban region of the central Brazilian Amazon biome: Health risks.

Fish is an important source of animal protein for local communities in the Amazon basin, whose food safety must be assured. However, certain potential toxicants elements, can bioaccumulate in fish species, which inhabit anthropogenically polluted waters, ultimately posing a risk to human health. In the present study, the concentrations of nine elements (Al, As, Cd, Cr, Cu, Hg, Ni, Pb and Zn) were determined in raw and cooked samples of eight fish species consumed in Santarém (northern Brazil, Amazon biome). The potential for non- carcinogenic human health risks linked to the consumption of cooked fish were evaluated for adults and children in two different scenarios. Four carnivores, three omnivores and one detritivore, all of them regularly marketed and consumed by the Santarém population, were the target species. The safety reference values set by national and international guidelines for humans, in both raw and cooked preparations, were used. In most cases, the cooking process showed a trend to increase elements concentrations compared to raw samples, however the differences were not significant. Moreover, the risk assessment showed danger for children in relation to Hg from the consumption of fish, in both scenarios evaluated. For adults, in one of the scenarios, there was a health risk associated to Hg as a result of carnivorous fish consumption. In a context of combined exposure to all elements, children were at risk when consuming fish, especially carnivorous and omnivorous species. For adults, the mixture of elements posed a risk to health human only for carnivorous fish consumption. The results reveal an environmental scenario of Hg contamination, which requires monitoring actions to preserve the aquatic biodiversity and human health in the Brazilian Amazon biome.

The combination of sirolimus plus tacrolimus improves outcome after reduced-intensity conditioning, unrelated donor hematopoietic stem cell transplantation compared with cyclosporine plus mycofenolate.

Different types of graft-versus-host disease prophylaxis have been proposed in the setting of reduced intensity and non-myeloablative allogeneic stem cell transplantation. An alternative combination with sirolimus and tacrolimus has recently been tested although comparative studies against the classical combination of a calcineurin inhibitor and mycophenolate mofetil or methotrexate are lacking. We describe the results of a prospective, multicenter trial using sirolimus + tacrolimus as immunoprophylaxis, and compare this approach with our previous experience using cyclosporine + mycophenolate in the setting of unrelated donor transplantation setting after reduced-intensity conditioning. Forty-five patients received cyclosporine + mycophenolate between 2002 and mid-2007, while the subsequent 50 patients, who were transplanted from late 2007, were given sirolimus + tacrolimus. No significant differences were observed in terms of hematopoietic recovery or acute graft-versus-host disease overall, although gastrointestinal acute graft-versus-host disease grade ≥ 2 was more common in the cyclosporine + mycophenolate group (55% versus 21%, respectively, P=0.003). The 1-year cumulative incidence of chronic graft-versus-host disease was 50% versus 90% for the patients treated with the sirolimus- versus cyclosporine-based regimen, respectively (P<0.001), while the incidence of extensive chronic disease was 27% versus 49%, respectively (P=0.043). The 2-year non-relapse mortality rate was 18% versus 38% for patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively (P=0.02). The event-free survival and overall survival at 2 years were 53% versus 29% (P=0.028) and 70% versus 45% (P=0.018) among patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively. In conclusion, in the setting of reduced intensity transplantation from an unrelated donor, promising results can be achieved with the combination of sirolimus + tacrolimus, due to a lower risk of chronic graft-versus-host disease and non-relapse mortality, which translates into better event-free and overall survival rates, in comparison with those achieved with cyclosporine + mycophenolate.