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Lakes provide a wide range of ecosystem services that are increasingly at risk because of multiple anthropogenic pressures. Santa María del Oro crater lake lies in rural northwest Mexico and is of interest for global change studies and as a natural resource that sustains the economies of local communities. Temporal trends of trace element (As, Co, Cr, Cu, Ni, Pb, V, and Zn) concentrations over the past century were assessed in four 210Pb-dated sediment cores, under the hypothesis that recent anthropogenic activities have promoted increasing trace element inputs. Data were analyzed within three periods: (1) pre-1900s, from which background levels were estimated, (2) pre-1950, and (3) post-1950. Trace element provenance was determined through a chemometric approach. Most trace element concentrations varied little in the past ~ 100 years, with no Co, V, and Zn enrichment, and minor enrichment by Cr, Cu, Ni and Pb in a few sections of the cores collected from the deepest locations, within the hypolimnion, and by Pb along the shallowest core. In contrast, As enrichment in the deep cores reached moderately severe levels during the post-1950 period. Cobalt, Pb, V, and Zn input to the lake was related to terrigenous sources. Lead enrichment was mainly anthropogenic (the shallow coring site is close to human settlements). Copper and Cr variability were mostly the result of diagenetic reactions. Arsenic enrichment, however, was attributed to biogeochemical cycling processes, likely exacerbated by drought conditions and enhanced calcite precipitation. Contradicting our hypothesis, recent anthropogenic impact on the lake´s environmental quality was small. However, a preliminary assessment, based on international guidelines, indicated that As, Cr, and Ni concentrations could be harmful to benthic biota, even at background levels. High As concentrations could affect the aquatic food web and human health, the latter through fish consumption. Given predictions for increasing droughts in the area, which induce greater evaporation and lower water levels, this issue could worsen in the future. Further studies on As contamination in the lake are needed to better understand potential hazards and enhance response capacity. Such data must be part of conservation efforts and should be integrated into management policies to ensure the lake's sustainability. [ABSTRACT FROM AUTHOR]

Lakes are effective sentinels of global change owing to their sensitivity to land-use changes and climate variability in their catchment. Santa María del Oro Lake (SAMO, NW Mexico) is of interest both for global change studies and as a natural resource to sustain the economy of local communities. Four sediment cores were used to evaluate the temporal variations of sediment accumulation, under the hypothesis that changes in sediment input are mostly driven by anthropic activities developed in the lake surroundings. Radiocarbon (14C) dating of SAMO sediments was precluded by a large and variable reservoir effect, inducing an age offset of ~ 4000 years. Well-constrained chronologies over the past century were obtained by 210Pb dating, corroborated by the stratigraphic markers 137Cs, 239+240Pu, and 14C-fraction modern. Geochemical, magnetic susceptibility, and meteorological data were used to elucidate the main controls of sedimentation processes in the lake. Mass accumulation rates were high, likely because of the natural vulnerability of catchment soils to hydric and aeolian erosion. The highest values, observed towards the lakeshore, were attributed to the influence of seasonal runoff from the surrounding steep hills, and the proximity of human settlements and agricultural fields. Mean mass accumulation rates increased with time (from 0.03 ± 0.01 g cm−2 year−1 between 1900 and 1950, to 0.14 ± 0.10 g cm−2 year−1 after the 1950s), although the most recent values were comparable to the mean values during the pre-1950 period. Accumulation maxima across the lake, occurring mostly since the 1980s, concurred with precipitation minima and were related to terrigenous pulses associated with soil erosion, likely favored by lower soil humidity and the occurrence of wildfires during dryer years. Controls on the development of human settlement and agriculture practices should be included in the long-term environmental management plans for the conservation of the lake resources. [ABSTRACT FROM AUTHOR]

The article focuses on demographic declines of the Rapa Nui society. Topics discussed include the role of climate non-additive perturbations on the population dynamic of past food producer societies, the reduction and replacement of native palm forest by grasslands; and development of population dynamic models (PDMs).

Abstract: The present study focuses on the morphotectonic evolution of the axial portion of the Southern Apennine chain between the lower Calore River valley and the northern Camposauro mountain front (Campania Region). A multidisciplinary approach was used, including geomorphological, field‐geology, stratigraphical, morphotectonic, structural, 40Ar/39Ar and tephrostratigraphical data. Results indicate that, from the Lower Pleistocene onwards, this sector of the chain was affected by extensional tectonics responsible for the onset of the sedimentation of Quaternary fluvial, alluvial fan and slope deposits. Fault systems are mainly composed of NW‐SE, NE–SW and W‐E trending strike‐slip and normal faults, associated to NW‐SE and NE–SW oriented extensions. Fault scarps, stratigraphical and structural data and morphotectonic indicators suggest that these faults affected the wide piedmont area of the northern Camposauro mountain front in the Lower Pleistocene–Upper Pleistocene time span. Faults affected both the oldest Quaternary slope deposits (Laiano Synthem, Lower Pleistocene) and the overlying alluvial fan system deposits constrained between the late Middle Pleistocene and the Holocene. The latter are geomorphologically and chrono‐stratigraphically grouped into four generations, I generation: late Middle Pleistocene–early Upper Pleistocene, with tephra layers 40Ar/39Ar dated to 158±6 and 113±7 ka; II generation: Upper Pleistocene, with tephra layers correlated with the Campanian Ignimbrite (39 ka) and with the slightly older Campi Flegrei activity (40Ar/39Ar age 48±7 ka); III generation: late Upper Pleistocene–Lower Holocene, with tephra layers correlated with the Neapolitan Yellow Tuff (~15 ka); IV generation: Holocene in age. The evolution of the first three generations was controlled by Middle Pleistocene extensional tectonics, while Holocene fans do not show evidence of tectonic activity. Nevertheless, considering the moderate to high magnitude historical seismicity of the study area, we cannot rule out that some of the recognized faults may still be active. Copyright © 2018 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Relapsed and refractory (rel/ref) mantle cell lymphoma (MCL) portend a dismal prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potentially curative therapy in this setting. We analyzed the survival outcomes of 29 recipients of non-myeloablative allo-HSCT for rel/ref MCL, and studied possible prognostic factors in this setting. The cumulative incidences of disease progression and non-relapse mortality at 3 years were 28% (95% confidence interval (CI): 13-46%) and 29% (95% CI: 13-47%), respectively. The cumulative incidence of grade II-IV acute GvHD at days +100 and +180 was 34% (95% CI: 18-52%) and 45% (95% CI: 26-62%), respectively. With a median follow-up in survivors of 53 (range 24-83) months, the 3-year overall survival (OS) and PFS were 54% (95% CI: 38-76%) and 41% (95% CI: 26-64%), respectively. In vivo T-cell depletion with alemtuzumab (n=6) was associated with inferior 3-year PFS (0% vs 51%, P=0.007) and OS (17% vs 64%, P=0.014). Conversely, a second-line international prognostic index (sIPI) at transplantation equal to 0 (no risk factors) was associated with an improved 3-year PFS (52% vs 22%, P=0.020) and OS (71% vs 22%, P=0.006) compared with sIPI ⩾1. Performing an allo-HSCT before 2007 was associated with a decreased 3-year OS (25% vs 76%, P=0.015) but not with a significantly inferior PFS (17% vs 59%, P=0.058). In this single-center series, we report encouraging results with allo-HSCT for patients with rel/ref MCL. High alemtuzumab doses should probably be avoided in this context. [ABSTRACT FROM AUTHOR]

Three Spanish alpine lakes located in the Central Range (Peñalara Lake and Cimera Lake) and the Pyrenees (Redon Lake) are selected to understand the effects of the North Atlantic Oscillation (NAO) on ice phenology. A conceptual lake model is formulated based on Pearson's correlation coefficients obtained between season-scale time series of the NAO index, climatic data (i.e., precipitation, air temperature and snow data) and limnological variables (ice phenology records). The results suggest that the effects of the NAO are only reflected in the thawing process via the air temperature and the insulating effect of snow accumulation on the ice cover. An altitude component is evident in our survey because the effects of the NAO on Peñalara Lake (the lowest altitude studied lake) are restricted to winter, whereas for Redon Lake (the highest altitude studied lake), the effects extend into spring. A latitudinal component is also clear when comparing our data with northern European lakes. Snow accumulation primarily depends on the air temperature at high latitudes, and both precipitation and the air temperature control snow accumulation at lower latitudes. Consequently, in northern Europe, the NAO signal is primarily reflected in lake ice phenology via the air temperature, whereas our results confirm that in southern Europe, the strong dependence of precipitation on the NAO determines the importance of the NAO for lake ice cover. [ABSTRACT FROM AUTHOR]

At present, allo-SCT is the only curative treatment for patients with myelofibrosis (MF). Unfortunately, a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at the time of diagnosis. The approval of the first JAK inhibitor, ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support for assessing the drug's candidacy in the peritransplant period. The drug's precise impact on clinical outcome following allo-SCT is currently not known; nor are the drug's long-term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who undergo allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54th American Society of Hematology Annual Meeting in New Orleans, USA on 6 December 2013, and the European Hematology Association's Annual Meeting in Milan, Italy on 13 June 2014. This document summarizes the results of these efforts. [ABSTRACT FROM AUTHOR]

We compared outcomes of adult patients receiving T-cell-depleted (TCD) hematopoietic SCT (HCT) without additional GVHD prophylaxis at Memorial Sloan Kettering Cancer Center (MSKCC, N=52), with those of patients receiving conventional grafts at MD Anderson Cancer Center (MDACC, N=115) for ALL in CR1 or CR2. Patients received myeloablative conditioning. Thirty-nine patients received anti-thymocyte globulin at MSKCC and 29 at MDACC. Cumulative incidence of grades 2-4 acute (P=0.001, 17.3% vs 42.6% at 100 days) and chronic GVHD (P=0.006, 13.5% vs 33.4% at 3 years) were significantly lower in the TCD group. The non-relapse mortality at day 100, 1 and 3 years was 15.4, 25.0 and 35.9% in the TCD group and 9.6, 23.6 and 28.6% in the unmodified group (P=0.368). There was no difference in relapse (P=0.107, 21.3% vs 35.5% at 3 years), OS (P=0.854, 42.6% vs 43.0% at 3 years) or RFS (P=0.653, 42.8% vs 35.9% at 3 years). In an adjusted model, age >50, cytogenetics and CR status were associated with inferior RFS (hazard ratio (HR)=2.16, P=0.003, HR=1.77, P=0.022, HR=2.47, P<0.001), whereas graft type was NS (HR=0.90, P=0.635). OS and RFS rates are similar in patients undergoing TCD or conventional HCT, but TCD effectively reduces the rate of GVHD. [ABSTRACT FROM AUTHOR]

Antifungal prophylaxis with azoles is considered standard in allogeneic hematopoietic SCT (allo-HSCT). Although sirolimus is being used increasingly for the prevention of GVHD, it is a substrate of CYP3A4, which is inhibited by voriconazole, and concurrent administration can lead to significantly increased exposure to sirolimus. We identified 67 patients with hematologic malignancies who underwent allo-HSCT with sirolimus, tacrolimus and low-dose MTX and received concomitant voriconazole prophylaxis from April 2008 to June 2011. All patients underwent a non-myeloablative or reduced-intensity conditioned allo-HSCT. Patients received sirolimus and voriconazole concurrently for a median of 113 days. The median daily dose reduction of sirolimus at the start of coadministration was 90%. The median serum sirolimus trough levels before and at steady state of coadministration were 5.8 ng/mL (range: 0-47.6) and 6.1 ng/mL (range: 1-14.2) (P=0.45), respectively. One patient with an average sirolimus level of 6 ng/mL developed sirolimus-related thrombotic microangiopathy that resolved after sirolimus discontinuation. No sinusoidal obstructive syndrome was reported. Seventeen patients (25%) prematurely discontinued voriconazole because of the adverse events. Only two patients (3%) presented with possible invasive fungal infections at day 100. We demonstrate that sirolimus and voriconazole coadministration with an empiric 90% sirolimus dose reduction and close monitoring of sirolimus trough levels is safe and well tolerated. [ABSTRACT FROM AUTHOR]

Marine Isotope Stage 3 (MIS 3, 59.4-27.8 kyr BP) is characterized by the occurrence of rapid millennial-scale climate oscillations known as Dansgaard--Oeschger cycles (DO) and by abrupt cooling events in the North Atlantic known as Heinrich events. Although both the timing and dynamics of these events have been broadly explored in North Atlantic records, the response of the tropical and subtropical latitudes to these rapid climatic excursions, particularly in the Southern Hemisphere, still remains unclear. The Rano Aroi peat record (Easter Island, 27° S) provides a unique opportunity to understand atmospheric and oceanic changes in the South Pacific during these DO cycles because of its singular location, which is influenced by the South Pacific Anticyclone (SPA), the Southern Westerlies (SW), and the Intertropical Convergence Zone (ITCZ) linked to the South Pacific Convergence Zone (SPCZ). The Rano Aroi sequence records 6 major events of enhanced precipitation between 38 and 65 kyr BP. These events are compared with other hydrological records from the tropical and subtropical band supporting a coherent regional picture, with the dominance of humid conditions in Southern Hemisphere tropical band during Heinrich Stadials (HS) 5, 5a and 6 and other Stadials while dry conditions prevailed in the Northern tropics. This antiphased hydrological pattern between hemispheres has been attributed to ITCZ migration, which in turn might be associated with an eastward expansion of the SPCZ storm track, leading to an increased intensity of cyclogenic storms reaching Easter Island. Low Pacific Sea Surface Temperature (SST) gradients across the Equator were coincident with the here-defined Rano Aroi humid events and consistent with a reorganization of Southern Pacific atmospheric and oceanic circulation also at higher latitudes during Heinrich and Dansgaard--Oeschger stadials. [ABSTRACT FROM AUTHOR]

Disease relapse or progression is a major cause of death following umbilical cord blood (UCB) transplantation (UCBT) in patients with high-risk, relapsed or refractory acute lymphoblastic leukemia (ALL). Adoptive transfer of donor-derived T cells modified to express a tumor-targeted chimeric antigen receptor (CAR) may eradicate persistent disease after transplantation. Such therapy has not been available to UCBT recipients, however, due to the low numbers of available UCB T cells and the limited capacity for ex vivo expansion of cytolytic cells. We have developed a novel strategy to expand UCB T cells to clinically relevant numbers in the context of exogenous cytokines. UCB-derived T cells cultured with interleukin (IL)-12 and IL-15 generated >150-fold expansion with a unique central memory/effector phenotype. Moreover, UCB T cells were modified to both express the CD19-specific CAR, 1928z, and secrete IL-12. 1928z/IL-12 UCB T cells retained a central memory-effector phenotype and had increased antitumor efficacy in vitro. Furthermore, adoptive transfer of 1928z/IL-12 UCB T cells resulted in significantly enhanced survival of CD19+ tumor-bearing SCID-Beige mice. Clinical translation of CAR-modified UCB T cells could augment the graft-versus-leukemia effect after UCBT and thus further improve disease-free survival of transplant patients with B-cell ALL. [ABSTRACT FROM AUTHOR]

The vegetation of the southern Gran Sabana (SE Venezuela) consists primarily of a treeless savanna with morichales (Mauritia flexuosa palm stands), despite the prevailing climate being more favorable for the development of extensive rainforests. Here, we discuss the results of our 8700-year paleoecological reconstruction from Lake Encantada based on the analysis of pollen, algal remains, charcoal, and geochemical proxies. We use the findings to assess a number of hypotheses that seek to explain the dominance of savanna vegetation and consider the relative importance of factors such as climate, fire, and erosion on the landscape. The reconstruction of vegetation changes suggests the following trends: open savanna with scattered forest patches (8700–6700 yr BP), forest-savanna mosaic (6700–5400 yr BP), open savanna with forest patches (5400–1700 yr BP), and treeless savanna with morichales (1700 yr BP–the present). We conclude that the interplay between climate and fire and the positive feedback between the presence of grasses and increased fire frequency played a major role in the vegetation dynamics from the early to middle Holocene (8700–6700 yr BP). The synergistic action between reduced fires and wetter conditions appears to be a determinant in the development of rainforest around 6700 yr BP. Despite higher available moisture at ~5400 yr BP, the savanna expanded with the increased frequency of fire, potentially driven by human land-use practices. We also propose that the interplay between fire and erosion created forest instability during the middle and late Holocene. The current southern Gran Sabana landscape is the result of the complex interplay between climate, fire, erosion, and vegetation. [ABSTRACT FROM AUTHOR]

Optimal treatment approach continues to remain a challenge for systemic light chain amyloidosis (AL). So far, Auto-SCT is the only modality associated with long-term survival. However, failure to show survival benefit in randomized study raises questions regarding its efficacy. We present a comparative outcome analysis of Auto-SCT to conventional therapies (CTR) in AL patients treated over a 14-year period at our institution. Out of the 145 AL amyloidosis patients, Auto-SCT was performed in 80 patients with 1-year non-relapse mortality rate of 12.5%. Novel agents were used as part of induction therapy in 56% of transplant recipients vs 46% of CTR patients. Hematological and organ responses were seen in 74.6% and 39% in the Auto-SCT arm vs 53% and 12% in the CTR arm, respectively. The projected 5-year survival for Auto-SCT vs CTR was 63% vs 38%, respectively. Landmark analysis of patients alive at 1-year after diagnosis showed improved 5-year OS of 72% with Auto-SCT vs 65% in the CTR arm. In the multivariate analysis, age <60 years, induction therapy with novel agents, kidney only involvement and Auto-SCT were associated with improved survival. In conclusion, Auto-SCT is associated with long-term survival for patients with AL amyloidosis. [ABSTRACT FROM AUTHOR]

An integrated multiproxy analysis from westernmost Mediterranean hemipelagic sediments has provided further insights into natural climate variability and forcing mechanisms in this region during the last two millennia. Two deep-sea marine records, with a robust age model provided by the activity–depth profiles of 210Pb and 137Cs, together with 14C dating, allowed us to perform a detailed reconstruction of paleoenvironmental and paleoceanographic responses during the ‘Medieval Climate Anomaly’ (MCA), the ‘Little Ice Age’ (LIA), the Industrial period (IP) and the second-half of the 20th century. Decreasing trends of fluvial-derived element (Si) and a increasing eolian input (Zr/Al ratio) characterized the MCA and the second-half of the 20th century as prevalent dry periods, while generally humid conditions are evidenced during the LIA and the IP, in accordance to a positive and a negative mode of the North Atlantic Oscillation (NAO), respectively (Trouet et al., 2009). The LIA developed as a sequence of successive short and abrupt dry–humid phase alternation. Furthermore, a noteworthy and sharp decrease of redox-sensitive elements (V/Cr and Ni/Co ratios) and coarser sortable silt at ad 1450 and 1950 yr, support more energetic hydrodynamic conditions at this time (oxygenated bottom waters and faster bottom currents), likely promoted by strengthened cooler waters flowing into the Mediterranean Sea. [ABSTRACT FROM AUTHOR]

Light-chain amyloidosis is a plasma cell dyscrasia characterized by the production of fibrillar proteins comprised of monoclonal light chains, which deposit in tissues causing multiorgan dysfunction and death. The diagnosis is challenging and requires a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains, which improve organ function and extend survival. Standard treatment approaches have included high-dose melphalan followed by autologous hematopoietic SCT or oral melphalan with dexamethasone. The use of novel agents (thalidomide, lenalidomide and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. A risk-adapted approach to SCT followed by novel agents as consolidation, reduces treatment-related mortality with promising activity. Immunotherapy targeting pathologic plasma cells and amyloid fibrils is being developed and could potentially eliminate visceral amyloid deposits. Improved understanding of the biology that renders light-chains amyloidogenic and a commitment to refer patients to specialized centers conducting well-designed clinical trials is essential to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Thalidomide, lenalidomide and bortezomib have increasingly been incorporated in first-line induction therapies for multiple myeloma. Concerns regarding the impact of these agents, especially lenalidomide, on stem cell mobilization prompted us to re-evaluate the risk factors that impact mobilization, including exposure to novel induction regimens. Among 317 patients who proceeded to stem cell collection after induction therapy between 2000 and 2009, the rate of mobilization failure, defined as the inability to collect 5 × 106 CD34+ cells/kg following the first collection attempt, was 13%. By multivariate analysis, independent risk factors associated with mobilization failure included older age (P=0.04), lower platelet count (P=0.002) and use of single-agent G-CSF for mobilization (P<0.0001). When considering for outcome measurement stem cell collection efficiency measured by the number of CD34+ cells yielded per pheresis performed during first collection attempt, lower platelet count, use of single-agent G-CSF and older age were also associated with lower efficiency. In this population mobilized mostly with cyclophosphamide and G-CSF, the use of lenalidomide during induction was not associated with a lower stem cell collection efficiency by multivariate analysis. The data support the current International Multiple Myeloma Working Group guidelines recommending the use of cyclophosphamide and G-CSF based mobilization for patients previously exposed to lenalidomide. [ABSTRACT FROM AUTHOR]

To improve the efficacy of risk-adapted melphalan (MEL) in patients with amyloidosis (AL), we conducted a phase II trial using bortezomib and dexamethasone (BD) as consolidation. Forty untreated patients with renal (70%), cardiac (65%), liver/gastrointestinal (15%) or nervous system (13%) AL were assigned MEL 100, 140 or 200 mg/m2 based on age, renal function and cardiac involvement. Hematological response was assessed at 3 months post stem cell transplant (SCT); patients with less than complete hematological response (CR) received BD consolidation. Four patients with advanced cardiac AL died within 100 days of SCT (10% treatment-related mortality). Survival at 12 and 24 months post treatment start was 88 and 82% overall and was 81 and 72% in patients with cardiac AL. At 3 months post SCT, 45% had  partial response (PR) including 27% CR. Twenty-three patients received consolidation and in 86% response improved; all patients responded in one cycle. At 12 and 24 months, 79 and 60% had  PR, 58 and 40% CR. Organ responses occurred in 55 and 70% at 12 and 24 months. Eight patients relapsed/progressed. One patient with serologic progression had organ impairment at time of progression. In newly diagnosed AL, BD following SCT rapidly and effectively improves responses resulting in high CR rates and maintained organ improvement. [ABSTRACT FROM AUTHOR]

Auto-SCT (ASCT) is widely used in first-line treatment of multiple myeloma (MM). However, most patients eventually relapse or have progression of disease (R/POD). Although precise knowledge of R/POD patterns would be important to generate evidence-based surveillance recommendations after ASCT, such data is limited in the literature, especially after introduction of the free light chain assay (FLCA). This retrospective study examined the patterns of R/POD after first-line ASCT in 273 patients, using established criteria. At the time of R/POD, only 2% of patients had no associated serological evidence of R/POD. A total of 85% had asymptomatic R/POD, first detected by serological testing, whereas 15% had symptomatic R/POD with aggressive disease, early R/POD and short survival, with poor cytogenetics and younger age identified as risk factors. Although occult skeletal lesions were found in 40% of asymptomatic patients tested following serological R/POD, yearly skeletal surveys and urine testing were poor at heralding R/POD. We found a consistent association between paraprotein types at diagnosis and R/POD, allowing informed recommendations for appropriate serological monitoring and propose a new needed criterion using FLCA for patients relapsing by FLC only. Our findings provide important evidence-based recommendations that strengthen current monitoring guidelines after first-line ASCT in MM. [ABSTRACT FROM AUTHOR]

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Delayed or failed engraftment remains a concern after cord blood transplantation (CBT) even when using double-unit grafts. Therefore, we analyzed the association between BM assessment performed approximately 21 days after transplantation, and the speed and success of sustained donor-derived neutrophil engraftment in 56 myeloablative double-unit CBT (DCBT) recipients. Overall, the cumulative incidence of sustained neutrophil engraftment was 95% (95% confidence intervals (CI): 89-100). Of the percentage of myeloid precursors, the BM cellularity and the total donor chimerism the total donor chimerism percentage had the most critical association with the speed and success of engraftment. DCBT recipients who were 100% donor achieved a 98% engraftment rate at a median of 22 days. This compared with 100% engraftment in patients who were 90-99% donor, but at a delayed median of 29 days and only 68% engraftment in patients <90% donor at a median of 37 days (P=0.001). Multivariate analysis was performed in the subgroup of patients who had not engrafted at the time the BM analysis was performed, the subgroup of most clinical concern. This confirmed donor chimerism was predictive of subsequent neutrophil recovery (P=0.004). These findings demonstrate the importance of the day 21 BM chimerism determinations after DCBT. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic SCT is an effective treatment in accelerated (AP) or blast phase (BP) CML. Imatinib (IM) has transient but significant activity in advanced phases of CML, which may permit early allografting for responding patients. To identify prognostic factors in allograft recipients previously treated with IM, we analyzed 449 allogeneic hematopoietic SCTs performed from 1999 to 2004 in advanced-phase CML, using the data reported to the Center for International Blood and Marrow Transplant Research. CML patients in second chronic phase (CP2, n=184), AP (n=185) and BP (n=80) received HLA-identical sibling (27%), related (3%), or matched or mismatched unrelated donor (70%), peripheral blood (47%) or BM (53%) hematopoietic SCT after myeloablative (78%) or non-myeloablative (22%) conditioning. In all, 52% in CP2, 49% in AP and 46% in BP received IM before hematopoietic SCT. Disease-free survival was 35-40% for CP2, 26-27% for AP and 8-11% for BP. Cumulative incidence of acute and chronic GVHD and TRM were not affected by the stages of CML or pre-hematopoietic SCT IM exposure. Multivariate analyses showed that conventional prognostic indicators remain the strongest determinants of transplant outcomes. In conclusion, there are no new prognostic indicators of the outcomes of allogeneic hematopoietic SCT for advanced-phase CML in the IM era. [ABSTRACT FROM AUTHOR]

A total of 36 consecutive patients with AML in CR underwent reduced-intensity allogeneic hematopoietic SCT (RISCT) with fludarabine and melphalan conditioning. All patients were ineligible for myeloablative transplantation because of age or comorbidity. In total, 30 patients were in first CR and six patients were in second CR. Donors were siblings in 21 (58%) patients and were unrelated in 15 (42%) patients. Hematopoietic cell transplant specific comorbidity scores 3 were present in 26 (72%) patients. With a median follow-up of 52 months (range, 34-103 months), OS and PFS rates at 4 years were 71% (s.e., 8%) and 68% (s.e., 8%), respectively. At 4 years, the cumulative incidence of non-relapse mortality was 20% (s.e., 7%) and of relapse mortality was 8% (s.e., 5%). Neither OS nor PFS was affected by older age (>60 years), unrelated donor, melphalan dose, or comorbidity score. At last follow up, of the 24 surviving patients, 21 (88%) had performance status (ECOG) of 0 without any active chronic GVHD requiring steroids. Hence, RISCT with fludarabine and melphalan conditioning produces durable long-term remission in older patients with AML. [ABSTRACT FROM AUTHOR]

Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning. [ABSTRACT FROM AUTHOR]

One challenge in designing clinical trials for treatment of acute GVHD (aGVHD) is the lack of an established standardized end point to measure the success of therapies. To facilitate assessment of end points in clinical trials for treatment of aGVHD in the current allo-SCT era, a national workshop was recently organized. In this study, which was presented at the workshop, we evaluated the prognostic value of response to upfront therapy in a cohort of 83 patients who had been enrolled on two clinical trials testing novel therapies for aGVHD at our institution. Our results indicate that patients whose aGVHD has a CR or PR by day 28 after initiation of systemic therapy have a significantly lower 6-month cumulative incidence of non-relapse mortality (NRM) (16%) than patients whose aGVHD did not respond to therapy by day 28 (48%, P=0.005). Multivariate analysis based on the Cox proportional hazards regression analysis showed that the impact of response on NRM is independent of patient and aGVHD characteristics. Our data confirm the validity of using day-28 response as a primary end point in clinical trials for upfront therapy for aGVHD. [ABSTRACT FROM AUTHOR]

Monthly limnological monitoring in Lake Sanabria (Spain) since 1986 provided a unique opportunity to test relationships among climate, hydrology and lake dynamics and how they are recorded in the lake sediments. Four datasets were employed: (1) meteorological (monthly maximum and minimum air temperature and total precipitation), (2) limnological (Secchi disk, water temperature, conductivity, pH, dissolved oxygen, nitrate, silicon, total and reactive phosphorus, and total chlorophylls and chlorophyll a), (3) hydrological (Tera River water input and output), and (4) XRF core scanner measurements carried out in short cores. Linear models between the different dataset variables allowed us to characterize the climate signal transmission from one to the other and cross-correlation analyses permitted us to identify the different response times (if any) between them. Principal Component Analyses (PCA) of the limnological and geochemical datasets allowed us to identify the main processes that link lake dynamics, primarily nutrient supply and organic productivity, with some sedimentological processes, e.g. organic matter and phosphorus accumulation. Sediment chronology was established by gamma spectrometry (Pb). Water input to Lake Sanabria is controlled mostly by the Tera River input and is linked directly to precipitation. Response of the Lake Sanabria water budget to climate oscillations is immediate, as the strongest correlation between these two datasets occurs with no lag time. PCA of the limnological dataset indicated that most of the variance is related to nutrient input, and comparison with the Tera River water discharge shows that nutrient input was controlled mainly by oscillations in the hydrological balance. The lag time between the hydrological and limnological datasets is 1 month. The PCA of the XRF core scanner dataset showed that the principal process that controls the chemical composition of the Lake Sanabria sediments is related to sediment and nutrient delivery from the Tera River and organic productivity. Comparison of the nutrient input reconstructed using the limnological dataset and the XRF core scanner data indicated that the sediments act as a low-pass filter, smoothing the climate signal. It was, however, possible to establish the link between these datasets, and obtain a quantitative reconstruction of precipitation for the 1959-2005 AD period that captures the regional variability. This quantitative precipitation reconstruction suggests it is possible to obtain accurate climate reconstructions using non-laminated sediments. [ABSTRACT FROM AUTHOR]

Climate variability in the western Mediterranean is reconstructed for the last 4000 yr using marine sediments recovered in the west Algerian-Balearic Basin, near the Alboran Basin. Fluctuations in chemical and mineralogical sediment composition as well as grain size distribution are linked to fluvial-eolian oscillations, changes in redox conditions and paleocurrent intensity. Multivariate analyses allowed us to characterize three main groups of geochemical and mineralogical proxies determining the sedimentary record of this region. These three statistical groups were applied to reconstruct paleoclimate conditions at high resolution during the Late Holocene. An increase in riverine input (fluvial-derived elements - Rb/Al, Ba/Al, REE/Al, Si/Al, Ti/Al, Mg/Al and K/Al ratios), and a decrease in Saharan eolian input (Zr/Al ratio) depict the Roman Humid Period and the Little Ice Age, while drier environmental conditions are recognized during the Late Bronze Age-Iron Age, the Dark Ages and the Medieval Climate Anomaly. Additionally, faster bottom currents and more energetic hydrodynamic conditions for the former periods are evidenced by enhanced sortable silt (10- 63 µm) and quartz content, and by better oxygenated bottom waters - as reflected by decreasing redox-sensitive elements (V/Al, Cr/Al, Ni/Al and Zn/Al ratios). In contrast, opposite paleoceanographic conditions are distinguished during the latter periods, i.e. the Late Bronze Age-Iron Age, the Dark Ages and the Medieval Climate Anomaly. Although no Ba excess was registered, other paleoproductivity indicators (total organic carbon content, Br/Al ratio, and organometallic ligands such as U and Cu) display the highest values during the Roman Humid Period, and together with increasing preservation of organic matter, this period exhibits by far the most intense productivity of the last 4000 yr. Fluctuations in detrital input into the basin as the main process managing deposition, reflected by the first eigenvector defined by the Principal Component Analyses, point to solar irradiance and the North Atlantic Oscillation variability as the main driving mechanisms behind natural climate variability over decadal to centennial time-scales for the last 4000 yr. [ABSTRACT FROM AUTHOR]

In spite of high-dose chemotherapy followed by autologous hematopoietic SCT multiple myeloma (MM) eventually recurs, highlighting the need for more effective treatment approaches. Patients received topotecan 3.5 mg/m2 intravenously on days -6 to -2, melphalan 70 mg/m2 intravenously on days -3 and -2 and CY 1 g/m2 intravenously on days -6, -5 and -4. Overall response rate (ORR) consisting of complete response and partial response (CR+PR, PFS, OS and toxicity are reported. Between August 2002 to March 2004, 60 patients (34 men and 26 women) with a median age of 61 years (range 45-72) were enrolled. Forty-one patients were treated for consolidation of first remission, while 19 patients had relapsed/refractory disease. ORR was 85% (CR 12%, very good PR 43% and PR 30%). Median time to neutrophil (ANC>0.5 × 109/L) and plt engraftment (>20 × 109/L) was 10 (range 7-12 days) and 9 days (range 6-79 days), respectively. A majority of the common adverse events were grade 1-3 mucositis/stomatitis (65%), grade 1 or 2 nausea (59%) and grade 1 or 2 diarrhea (41%). Median PFS was 18.5 months and median OS has yet not been reached. In conclusion, topotecan, melphalan and CY is a safe and active conditioning regimen for auto hematopoietic SCT in MM. The ORR and PFS were comparable to high-dose melphalan. [ABSTRACT FROM AUTHOR]

Climate variability in the western Mediterranean is reconstructed for the last 4000 yr using marine sediments recovered in the west Algerian-Balearic basin, near the Alboran basin. Fluctuations in chemical and mineralogical sediment composition as well as grain size distribution are linked to fluvial-eolian oscillations, changes in redox conditions and paleocurrent intensity. Multivariate analyses allowed us to characterize three main groups of geochemical and mineralogical proxies determining the sedimentary record of this region. These three statistical groups were applied to reconstruct paleoclimate conditions at high resolution during the Late Holocene. An increase in fluvial-derived elements (Rb/Al, Ba/Al, REE/Al, Si/Al, Ti/Al, Mg/Al and K/Al ratios), finer grain size, slower flows and oxygen-poor bottom waters - as suggested by sortable silt (10-63 µm), clays (<2 µm) and redox-sensitive elements (V/Al, Cr/Al, Ni/Al and Zn/Al ratios) - depict the Roman Humid Period (RHP) and the Little Ice Age (LIA), while drier environmental conditions are recognized during the Late Bronze Age-Iron Age (LBA-IA) and the Medieval Warm Period (MWP). Although no Ba excess was registered, other paleoproductivity indicators (total organic carbon content, Br/Al ratio, and organometallic ligands such as U and Cu) display the highest values during the RHP, this period exhibiting by far the most intense productivity of the last 4000 yr. These marine sediments evidence oscillations that support the link of the westernmost Mediterranean climate with the North Atlantic coupled ocean-atmosphere climatic system, pointing to solar irradiance and the North Atlantic Oscillation (NAO) variability as the main driving mechanisms behind natural climate variability over decadal to centennial time-scales for the last 4000 yr. [ABSTRACT FROM AUTHOR]

Background: Recurrence is a major cause of treatment failure after allogeneic transplantation for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and treatment options are very limited. Azacitidine is a DNA methyltransferase inhibitor with activity in myeloid disease. The authors hypothesized that low-dose azacitidine administered after transplant would reduce recurrence rates, and conducted a study to determine a safe dose/schedule combination.Methods: Forty-five high-risk patients were treated. Median age was 60 years; median number of comorbidities was 3; 67% were not in remission. By using a Bayesian adaptive method to determine the best dose/schedule combination based on time to toxicity, the authors investigated combinations of 5 daily azacitidine doses, 8, 16, 24, 32, and 40 mg/m2, and 4 schedules: 1, 2, 3, or 4 cycles, each with 5 days of drug and 25 days of rest. Cycle 1 started on Day +40.Results: Reversible thrombocytopenia was the dose-limiting toxicity. The optimal combination was 32 mg/m2 given for 4 cycles. Median follow-up was 20.5 months. One-year event-free and overall survival were 58% and 77%, justifying further studies to estimate long-term clinical benefit. No dose significantly affected DNA global methylation.Conclusions: Azacitidine at 32 mg/m2 given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pretreated AML/MDS patients. The trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with greater benefit. [ABSTRACT FROM AUTHOR]

Background: Resistance to tyrosine kinase inhibitor (TKIs) therapy is associated with the development of kinase domain mutations. Although many imatinib-resistant mutations respond well to second-generation TKIs, the threonine-to-isoleucine mutation at codon 315 of the breakpoint cluster region/v-abl Abelson murine leukemia viral oncogene protein fusion Bcr-Abl (T315I) is insensitive to all currently available TKIs. The outcome in such patients after stem cell transplantation (SCT) is unknown.Methods: Eight patients with TKI-resistant CML who had T315I mutations underwent 9 transplantations. At the time of SCT, 2 patients were in chronic phase, 3 patients were in accelerated phase; and 3 patients were in second chronic phase.Results: The best responses after SCT were a complete molecular response (CMR) in 3 patients, a complete cytogenetic response (CCyR) in 4 patients, and a complete hematologic response (CHR) in 1 patient, and 1 patient had no response. The best outcome was for patients who underwent transplantation in chronic phase, and both of those patients remained alive and in complete molecular remission 14 months and 42 months after SCT. After a median follow-up of 13 months from SCT, 5 patients remained alive, including 3 patients in CMR, 1 patient in CCyR, and 1 patient in CHR.Conclusions: The current results indicated that SCT is an effective strategy for patients with CML who have the T315I mutation, particularly in earlier stages. [ABSTRACT FROM AUTHOR]

Between April 2006 and June 2009, 34 newly diagnosed patients with multiple myeloma received one to three courses of bortezomib 1.3 mg/m2 i.v. four times, lenalidomide 25 mg p.o. daily for 21 days and dexamethasone 20 mg/m2 p.o. for 4 days beginning on days 1, 9 and 17 (BLD). There was rapid onset of remission in 30 patients (88%) similar to the frequency of 87% induced by a previous combination of bortezomib–thalidomide–dexamethasone (BTD). After a median of 3.6 months, 28 patients received intensive therapy with high-dose melphalan supported by autologous blood stem cells, so that the overall frequency of complete remission (CR) was 44%, similar to the frequency of 37% observed previously. Side effects due to thalidomide with previous BTD were less frequent and severe with BLD. The combination of BLD given for one or two courses was an effective primary treatment for newly diagnosed patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

To assess the impact of CR on survival in multiple myeloma. Retrospective evaluation of response and survival among 758 consecutive patients with multiple myeloma treated at a single center, of whom 395 patients received intensive therapy supported by autologous stem cells within the first year. Survival times were calculated after 1 and 2 years from the start of chemotherapy. On the basis of the response status after a 2-year landmark, the subsequent median survival was 9.7 years for patients with CR, 4.4 years for those with PR and 2.7 years for patients with NR (P<0.001). Longer survival was attributed in part to intensive therapy that converted the myeloma of 67% of patients with NR to PR or CR, and induced CR in 26% of patients with PR. Intensive therapy did not prolong survival for patients with CR after primary therapy. For patients with multiple myeloma, Cox regression analyses showed that CR was the dominant prognostic factor for long survival, followed by stage I disease, PR and intensive treatment as independent factors. A cure fraction of 2% was identified for nine patients who have remained in CR >10 years. [ABSTRACT FROM AUTHOR]

Haploidentical SCT (HaploSCT) has been most commonly performed using a myeloablative, TBI-based preparative regimen; however, the toxicity with this approach remains very high. We studied the feasibility of a reduced-intensity conditioning regimen in a phase II clinical trial using fludarabine, melphalan and thiotepa and antithymocyte globulin (ATG) for patients with advanced hematological malignancies undergoing T-cell depleted HaploSCT. Twenty-eight patients were entered in the study. Engraftment with donor-derived hematopoiesis was achieved in 78% of patients after a median of 13 days. Six patients experienced primary graft failure, three out of four tested patients had donor-specific anti-HLA antibodies (DSA) (P=0.001). Toxicity included mostly infections. A total of 21 out of 22 patients with AML/myelodysplastic syndrome (MDS) achieved remission after transplant (16 with relapsed/refractory AML). Five out of the 12 patients (42%) with AML/MDS with <15% BM blasts survived long term as compared with none with more advanced disease (P=0.03). HaploSCT with this fludarabine, melphalan and thiotepa and ATG RIC is an effective, well-tolerated conditioning regimen for patients with AML/MDS with low disease burden at the time of transplant and allowed a high rate of engraftment in patients without DSA. Patients with overt relapse fared poorly and require novel treatment strategies. [ABSTRACT FROM AUTHOR]

In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM. [ABSTRACT FROM AUTHOR]

Multiple myeloma is the most common indication for high-dose chemotherapy with autologous stem cell support (ASCT) in North America today. Stem cell procurement for ASCT has most commonly been performed with stem cell mobilization using colony-stimulating factors with or without prior chemotherapy. The target CD34+ cell dose to be collected as well as the number of apheresis performed varies throughout the country, but a minimum of 2 million CD34+ cells/kg has been traditionally used for the support of one cycle of high-dose therapy. With the advent of plerixafor (AMD3100) (a novel stem cell mobilization agent), it is pertinent to review the current status of stem cell mobilization for myeloma as well as the role of autologous stem cell transplantation in this disease. On June 1, 2008, a panel of experts was convened by the International Myeloma Foundation to address issues regarding stem cell mobilization and autologous transplantation in myeloma in the context of new therapies. The panel was asked to discuss a variety of issues regarding stem cell collection and transplantation in myeloma especially with the arrival of plerixafor. Herein, is a summary of their deliberations and conclusions. [ABSTRACT FROM AUTHOR]

Decitabine is a hypomethylating agent with activity in myelodysplastic syndrome (MDS). It is largely unknown whether treatment with this drug before allo-SCT will increase the toxicity of the preparative regimen or otherwise affect the results of the transplant. We report the outcome of 17 patients with MDS with a median age of 55.5 years (range, 36–66 years) who underwent an allo-SCT (12 siblings, 5 unrelated) after prior therapy with decitabine. Preparative regimens consisted of fludarabine in combination with BU (n=8) or melphalan (n=9). The source of stem cells was marrow in four patients and peripheral blood (PB) in 13 patients. Thirteen patients were in CR within 100 days of transplant. With a median follow-up of 12 months (range, 3–35 months), 11 patients are alive; eight in CR and three with progressive disease. Prior therapy with hypomethylating agents did not increase toxicity and may improve the outcome of allogeneic transplant in MDS and should be evaluated in a prospective trial.Bone Marrow Transplantation (2009) 43, 839–843; doi:10.1038/bmt.2008.400; published online 19 January 2009 [ABSTRACT FROM AUTHOR]

Lymphocyte and platelet recovery may influence outcomes of allo-SCT for treatment of AML. It is not clear, however, if this impact is independent of patient and transplant characteristics. To investigate this question, we evaluated the influence of pre- or post transplant factors on day +30 absolute lymphocyte count (ALC) and the speed of platelet engraftment. We studied 106 AML patients treated with fludarabine and melphalan reduced-intensity conditioning and allo-SCT. Twenty nine percent of patients were in CR at the initiation of the conditioning, 39% had active disease with circulating blasts and 32% had active disease without circulating blasts. The graft source was peripheral blood from a matched sibling donor in 55% and BM from a matched unrelated donor in 45%. Our data showed that the presence of circulating blasts before transplantation is significantly correlated with low post-SCT day +30 ALC and slow platelet engraftment. This finding suggests that the impact of early ALC and platelet recovery on transplant outcome may not be independent of disease status at transplantation.Bone Marrow Transplantation (2009) 43, 685–692; doi:10.1038/bmt.2008.376; published online 17 November 2008 [ABSTRACT FROM AUTHOR]

Donor leukocyte infusions (DLI) can reverse relapse of hematologic malignancy following allogeneic hematopoietic stem cell transplant (HSCT) in some cases. Little is known regarding the effectiveness of DLI in children who relapse after HSCT. We report outcomes of 49 children who received DLI for relapse after allogeneic transplant. Prognosis was particularly poor (0/14 responses) for patients relapsing within 6 months from transplant. DLI rarely induced remission when given as sole therapy for marrow relapse. One-year disease-free survival was 30% (6/20) in patients who received DLI as consolidation following chemotherapy. The development of GVHD grades 1–2 was associated with superior 3-year survival than patients who developed GVHD grades 3–4 (P<0.002). To determine the benefit of DLI, 45 children who received DLI for relapse (four children without matches were excluded) were compared to 1229 children with similar characteristics whose relapse was not treated with DLI. There was no difference in survival (P=0.30) once adjustments were made to account for the time from relapse to DLI. Although a few children achieved durable remissions when DLI was used as part of a post-relapse treatment strategy, DLI was unsuccessful in the majority of cases. Strategies may be better directed at preempting post transplant relapse.Bone Marrow Transplantation (2008) 42, 201–205; doi:10.1038/bmt.2008.135; published online 19 May 2008 [ABSTRACT FROM AUTHOR]

The article focuses on the role of vertebral augmentation in the treatment of multiple myeloma. The study shows that vertebral augmentation is most likely to benefit those myeloma patients with mechanical pain and can be used for both acute and chronic fractures. However, it is not recommended for asymptomatic fractures unless there is documented increased collapse and deformity progression. A consensus statement from the International Myeloma Working Group is also presented.