bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term effects of an iron heater and Äspö groundwater on smectite clays: Chemical and hydromechanical results from the in situ alternative buffer material (ABM) test package 2
Authors: Kumpulainen Sirpa , Kiviranta Leena , Korkeakoski Petri
Published: September 2016

Smectite-rich clays are to be used in nuclear repositories for sealing in the radioactive waste. As the radioactive decay produces heat it may affect the chemical, physical and hydromechanical properties of the clay components in the repository. An ‘alternative buffer material’ (ABM) experiment is a Svensk Kärnbränslehantering AB (SKB)-led in situ heating test placed in boreholes in the Äspö tunnel (Sweden). The 2nd ABM package was dismantled in April 2013, after 6.5 y of equilibration with Äspö groundwater and 5 y of heating. The objective was to investigate the long-term effects of the iron heater and Äspö groundwater on four of 31 compacted blocks made of MX-80, Deponit CaN and Friedland clays.

Compared to the starting materials, major changes in the exchangeable cation populations were observed. Within horizontal profiles, water-soluble sulfate, Ca, K and Mg increased; poorly crystalline Fe oxide contents decreased; total Mg, Ca and S increased; and a decrease in the amounts of total Na and K away from the host rock towards the heater was observed. At the boundary with the heater, an increase in the total Fe content, decreases in total Si and Al contents, precipitation of gypsum and anhydrite, dissolution of cristobalite and feldspars, and indications of the formation of trioctahedral clay minerals were observed. A decrease in swelling pressure for the Friedland clay (in drill-cored samples) was recorded which was recovered after grinding and recompaction. No effects of hydraulic conductivity were found, after 6.5 y of reaction time, in the subsurface of any of materials studied.
Time evolution of MX-80 bentonite geochemistry under thermo-hydraulic gradients
Authors: Gómez-Espina R. , Villar M.V.
Published: September 2016

Two 20-cm long columns of MX-80 bentonite compacted at a nominal dry density of 1.7 g/cm3with a water content of 17% were tested in thermo-hydraulic (TH) cells with the aim of simulating the conditions of a sealing material in a nuclear waste repository. On top of the columns a hydration surface simulated the host rock supplying groundwater and at the bottom a heater simulated the waste canister. The tests comprised two phases: a heating phase and a ‘heating + hydration’ phase. The temperatures at the ends of the columns were set during the last phase to 30°C at the top and 140°C at the bottom, respectively. The thermo-hydraulic treatment resulted in major changes along the bentonite columns. These changes led to significant gradients along the column with respect to the physical state (water content, dry density) and geochemistry of the bentonite. Smectite dissolution processes occurred. As a result, colloids were probably produced, particularly in the more hydrated areas. In the warmest part of the columns precipitation of carbonates took place, caused by their solubility decrease with temperature and the evaporation. The increase in water content reduced the ionic strength of the pore water in the more hydrated areas where species such as gypsum were dissolved. The solubilized ions were transported towards the bottom of the columns; Na+, Ca+, Mg2+and SO42−moved at a similar rate and K+and Cl−moved farther. These solubilized ions precipitated in the form of salts farther away along the columns as the test was longer. The TH treatment implied the loss of exchangeable positions in the smectite, particularly towards the heater. The cation exchange complex was also modified.
Methodology for studying the composition of non-interlamellar pore water in compacted bentonite
Authors: Järvinen Joonas , Matusewicz Michał , Itälä Aku
Published: September 2016

Many safety functions required of the compacted bentonite buffer in the KBS-3 concept rely on processes influenced by the composition of the pore water. Important safety-relevant processes are related to the bentonite buffer,e.g.swelling, precipitation and dissolution reactions, and transport of water, colloids and ions. One of the methods used in analysing pore water in compacted bentonite is the ‘squeezing technique’. Various possible artefacts which can occur during squeezing, such as mixing of different pore-water types, dissolution of accessory minerals and cation exchange, need special attention.

The present work describes the methodology for studying the composition of the non-interlamellar pore water by combining squeezing methods, chemical analyses, microstructure measurements and geochemical modelling. Four different maximum pressures were used to squeeze the compacted bentonite pore water. The origin of the pore water was studied by analysing the bentonite microstructure both before and after squeezing using SAXS and NMR, the cation exchange and dissolution reactions were studied by chemical analyses and geochemical modelling.

The pore-water yield increased from 32 to 48 wt.% from the initial amount of porewater in the samples when the maximum squeezing pressure was increased from 60 MPa to 120 MPa. About 35 wt.% of the water collected originated from the interlamellar (IL) pores. The ratio between IL and non-IL pore waters as well as the composition of the squeezed porewater was constant in the squeezing-pressure range used. The results of microstructural measurements by SAXS were in perfect agreement with previous studies (e.g.Muurinen & Carlsson, 2013). The dissolving accessory minerals have an effect on the ratio of the cations in the squeezed solution while the migration of anions in bentonite seems to be diffusion limited. According to geochemical modelling the chloride concentration of the non-IL pore water in compacted bentonite before squeezing was 0.34 Mgreater than in the squeezed pore water due to the mixing of two main water types.
Size distribution of FEBEX bentonite colloids upon fast disaggregation in low-ionic strength water
Authors: Mayordomo Natalia , Degueldre Claude , Alonso Ursula , Missana Tiziana
Published: September 2016

Bentonite colloids generated from the backfill barrier in nuclear waste repositories may act as radionuclide carriers, if they are stable and mobile. Repository scenarios with highly saline groundwater inhibit colloid stability as particles tend to aggregate but, in the time frame of repositories, groundwater conditions may evolve, promoting particle disaggregation and stabilization. The disaggregation of FEBEX bentonite colloids by fast dilution to lower ionic strength was analysed in this study. Time-resolved dynamic light-scattering experiments were carried out to evaluate the kinetics of bentonite colloid aggregation and disaggregation processes in Na+ and Na+-Ca2+ mixed electrolytes of low ionic strength. Attachment and detachment efficiencies were determined.

Aggregation is promoted by increasing ionic strength, being more efficient in the presence of divalent cations. Once bentonite colloids are aggregated, a decrease in ionic strength facilitates disaggregation, but the process is not fully reversible as the initial size of the stable bentonite colloids at low ionic strength is not fully recovered. Particle-size distribution and concentration in suspension were analysed on disaggregated samples by single particle-counting measurements. Small colloids were measured in the disaggregated samples but their population was smaller than in the initial stable sample, especially in the presence of Ca2+.
Formation of C-A-S-H phases from the interaction between concrete or cement and bentonite
Authors: Raúl Fernández  , Ruiz Ana Isabel , Cuevas Jaime
Published: September 2016

Concrete and bentonite are being considered as engineered barriers for the deep geological disposal of high-level radioactive waste in argillaceous rocks. Three hydrothermal laboratory experiments of different scalable complexity were performed to improve our knowledge of the formation of calcium aluminate silicate hydrates (C-A-S-H) at the interface between the two materials: concretebentonite transport columns, lime mortar-bentonite transport columns and a portlandite- (bentonite and montmorillonite) batch experiment. Precipitation of C-A-S-H was observed in all experiments. Acicular and fibrous morphologies with certain laminar characteristics were observed which had smaller Ca/Si and larger Al/Si ratios with increasing temperature and lack of accessory minerals. The compositional fields of these C-A-S-H phases formed in the experiments are consistent with Al/(Si+Al) ratios of 0.2– 0.3 described in the literature. The most representative calcium silicate hydrate (C-S-H) phase from the montmorillonite–cement interface is Al-tobermorite. Structural analyses revealed a potential intercalation or association of montmorillonite and C-A-S-H phases at the pore scale.
Interaction of titanium with smectite within the scope of a spent fuel repository: A spectroscopic approach
Authors: Grolimund Daniel , Wersin Paul , Brendlé Jocelyne , Huve Joffrey , Kiviranta Leena , Snellman Margit
Published: September 2016

The Swedish and Finnish nuclear waste repository design, KBS-3H, foresees horizontal emplacement of copper canisters-bentonite modules surrounded by a titanium shell. The interaction of titanium with bentonite was studied here using a combination of wet chemistry and a spectroscopic approach to evaluate the potential impact of Ti corrosion on the clay. For natural analogue clays with high Ti contents, spectroscopic investigations showed that titanium occurs as crystalline TiO2. In contrast, the Ti in the MX-80 bentonite occurs in the clay structure, presumably in the octahedral sheet. Hydrothermal tests conducted at 200°C using synthetic montmorillonite showed little if any change in the montmorillonite structure at near-neutral and acidic conditions. Under alkaline conditions, limited alteration was observed, including the formation of trioctahedral clay minerals and zeolite. These changes, however, occurred independently of the addition of Ti. In the batch tests conducted at 80°C, Ti did not occur as separate TiO2particles. The comparison of experimental data with spectroscopic simulations provides sound evidence that Ti was incorporated in a neoformed phyllosilicate structure.
Mineralogical changes and associated decrease in tritiated water diffusivity after alteration of cement–bentonite interfaces
Authors: Yamaguchi Tetsuji , Sawaguchi Takuma , Tsukada Manabu , Hoshino Seiichi , Tanaka Tadao
Published: September 2016

Alteration of cement–bentonite interfaces and accompanying changes in diffusivity of tritiated water (HTO) was investigated experimentally using intact, hardened cement-paste specimens. The alteration by carbonate solution was accompanied by mineralogical changes at the interface and a decrease in the HTO diffusivity to ∼70 ± 7%of the initial value after a 180-day period. Another alteration in contact with compacted bentonite was accompanied by mineralogical changes at the interface and a decrease in the HTO diffusivity to ∼71 ± 10% of the initial value after a 600-day period. The changes in the diffusivity were considerably less than those observed for mixed specimens of ground, granulated hardened cement paste and bentonite where the diffusivity decreased to 20% of the initial value over 180 days. The results were extrapolated to 15 y under simple assumptions and showed good agreement with those observed in the cement–argillite interface at Tournemire URL (France). Such an explanation enhances confidence in the assessment of the alteration of cement-bentonite systems and might be a basis for using the data and models obtained in the long-term assessment of radioactive waste disposal.
Distinguishing between more and less suitable bentonites for storage of high-level radioactive waste
Authors: Kaufhold S. , Dohrmann R.
Published: September 2016

One of today's big challenges is to store safely the increasing amount of high-level radioactive waste (HLRW) in the world. In some of the concepts devised for this challenge, bentonite, a natural swelling clay, plays a key role in encasing the canisters containing the waste. The use of bentonite as a geotechnical barrier in HLRWrepositories is a new venture; specifications to ensure either optimum performance or that a minimum standard is reached at least do not exist yet. The present study summarizes relevant research and discusses possible HLRW-bentonite specifications. The importance of these specifications for any given repositories has to be assessed on a case by case basis, depending on the concept being employed and any special circumstances for the individual repositories.

Ten key issues were identified which were used to discuss bentonite specifications. In some of these key issues the optimum bentonite performance depended more on processing and production (compaction) than on the bentonite type (e.g.swelling pressure and thermal conductivity). In contrast, in some of the other key issues, the type of bentonite was found to influence possible specifications: the bentonite should not alter its mineral composition or its geotechnical parameters such as the swellability. Therefore, the bentonite should contain neither soluble nor reactive phases (e.g.organic matter, pyrite, gypsum). The structural Fe content of the smectites should be small because of the lesser stability and greater reactivity of the Fe-rich bentonites. Also, a large layer-charge density of the swelling clay minerals leads to less corrosion at the iron–bentonite interface (relevant if iron canisters are used). The hydraulic conductivity and swelling pressure can be tailored by compaction of the bentonite resulting in different dry densities. From an engineering point of view, a bentonite with least dependence of the hydraulic conductivity/swelling pressure on the dry density would be best. Using a bentonite which has been investigated extensively over many years means less uncertainty compared to unknown materials.
Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis
Authors: Allen Carl E. , McClain Kenneth L.
Published: September 2016

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by extreme immune activation, resulting in pathologic inflammation. The diagnosis includes a spectrum of inherited or acquired defects in cytotoxic lymphocyte function, often with uncontrolled infections. HLH may also arise as the result of persistent antigen stimulation due to autoimmune disease or malignancy. HLH is often described in binary terms as “primary,” indicating Mendelian inheritance of gene mutations resulting in cytotoxic lymphocyte dysfunction, or “secondary” indicating an acquired reactive disorder. Increasing evidence describes HLH as more complex phenomenon, resulting from specific immune challenges in patients with a susceptible genetic background. Early recognition of HLH and evaluation of potential causes is critically important, as survival generally requires urgent treatment with immune suppression and resolution of the activating antigen. However, the diagnosis of HLH is challenged by the myriad of pathways that lead to pathologic inflammation and the clinical overlap with other conditions. Further improvements in therapy will require prospective trials to define optimal strategies for each patient based on the individual paths that lead to pathologic inflammation.
Venous clot lysis and stenting
Authors: Vedantham Suresh
Published: September 2016

Venous thromboembolism (VTE) continues to represent a major source or mortality and morbidity. Although anticoagulation is the mainstay of therapy, adjunctive catheter-based interventions have shown substantial potential to improve clinically meaningful patient outcomes in patients with deep vein thrombosis (DVT), pulmonary embolism (PE), and the post-thrombotic syndrome (PTS). Catheter-directed thrombolysis (CDT) has been shown in a randomized trial to reduce the risk of PTS in patients with acute proximal DVT; data from a larger NIH trial is expected shortly. The use of CDT is being increasingly used for patients with submassive or massive pulmonary embolism. Preliminary studies suggest that endovascular stent placement and ablative therapies can improve quality-of-life in carefully selected patients with established PTS. In this article, we summarize the current status of thrombus removal and stent placement procedures for VTE and PTS, with the main purpose being to guide clinicians in individualizing treatment decisions for their challenging patients.
Use of alternative donors for allogeneic stem cell transplantation
Authors: Anasetti Claudio
Published: September 2016

For patients without a human leukocyte antigen (HLA)-matched sibling or unrelated donor, options include transplantation from HLA-mismatched related donors, HLA-mismatched unrelated donors, or unrelated cord blood units. Graft failure remains a problem in 10%-20% of cord blood transplants that contain a limited number of hematopoietic cells. Many approaches are tested in clinical trials to offset the risk of graft failure after cord blood transplantation. GVHD remains a hurdle with any HLA mismatched graft. The use of post-transplant cyclophosphamide holds the promise to overcome the HLA barrier and prevent GVHD despite donor mismatch for a full HLA haplotype. Priority should be given to enrolling patients onto transplant protocols addressing the fundamental problems of engraftment, GVHD, relapse or treatment-related mortality tested with one or more of the alternative stem cell sources. Principles for prioritization of alternative stem cell sources are discussed separately for children and adults who cannot be enrolled on clinical trials. It is difficult ranking currently available sources in the face of multiple factors affecting outcomes, rapidly changing transplant technology and without results from comparative trials.
Graft-versus-host disease versus graft-versus-leukemia
Authors: Negrin Robert S.
Published: September 2016

Graft-versus-host disease (GVHD) is a significant clinical problem after allogenic hematopoietic cell transplantation (HCT) associated with substantial morbidity and mortality that limits the potential utility of transplantation. Associated with GVHD is the well-recognized phenomenon of the graft-versus-leukemia (GVL) effect that results in reduced risk of disease relapse. GVL effects have been observed after treatment for a broad range of hematological malignancies. Both GVHD and GVL are the results of T cell–effector functions that frames a major question in the field of how linked are these two phenomena. A major goal of basic science and translational research has been to develop strategies to reduce the risk of GVHD while maintaining or enhancing GVL. In this review, a number of different strategies developed from preclinical animal models will be explored with a focus on those approaches that have been extended to the clinic in an attempt to achieve this goal. Needless to say, there is no proven strategy; however, with the use of modern technology and clinical translation, there has been substantial progress toward this goal of reducing the risks of GVHD while promoting and enhancing GVL responses.
What's different about atypical CML and chronic neutrophilic leukemia?
Authors: Dao Kim-Hien T. , Tyner Jeffrey W.
Published: September 2016

Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare myeloid neoplasms defined largely by morphologic criteria. The discovery of CSF3R mutations in aCML and CNL have prompted a more comprehensive genetic profiling of these disorders. These studies have revealed aCML to be a genetically more heterogeneous disease than CNL, however, several groups have reported that SETBP1 and ASXL1 mutations occur at a high frequency and carry prognostic value in both diseases. We also report a novel finding—our study reveals a high frequency of U2AF1 mutations at codon Q157 associated with CSF3R mutant myeloid neoplasms. Collectively, these findings will refine the WHO diagnostic criteria of aCML and CNL and help us understand the genetic lesions and dysregulated signaling pathways contributing to disease development. Novel therapies that emerge from these genetic findings will need to be investigated in the setting of a clinical trial to determine the safety and efficacy of targeting various oncogenic drivers, such as JAK1/2 inhibition in CSF3R-T618I–positive aCML and CNL. In summary, recent advances in the genetic characterization of CNL and aCML are instrumental toward the development of new lines of therapy for these rare leukemias that lack an established standard of care and are historically associated with a poor prognosis.
Reclassifying myelodysplastic syndromes: what's where in the new WHO and why
Authors: Arber Daniel A. , Hasserjian Robert P.
Published: September 2016

A revision to the 4th edition of the WHO Classification of myelodysplastic syndromes (MDSs), originally published in 2008, is expected in mid-2016. Based on recommendations of a Clinical Advisory Committee, the revision will aim to incorporate new discoveries in MDS that impact existing disease categories. Although the basic diagnostic principles of the WHO classification remain unchanged, several changes to the classification are proposed. All revisions are considered preliminary until the actual publication of the monograph and online document. Proposals for change include abandoning the routine use of “refractory anemia/cytopenia” in the various disease names, including the prognostic significance of gene mutations in MDS, revising the diagnostic criteria for MDS entities with ring sideroblasts based on the detection of SF3B1 mutations, modifying the cytogenetic criteria for MDS with isolated del(5q), reclassifying most cases of the erythroid/myeloid type of acute erythroleukemia, and recognizing the familial link in some cases of MDS. This review will provide details of the major proposed changes as well as rationale for the revisions.
The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP)
Authors: Malcovati Luca , Cazzola Mario
Published: September 2016

The WHO classification provides the best diagnostic approach to myelodysplastic syndromes (MDS). However, biologic and analytic limitations have emerged in the criteria currently adopted to establish the diagnosis and to classify MDS. The provisional category of idiopathic cytopenia of undetermined significance (ICUS) has been proposed to describe patients in whom MDS is possible but not proven. To formulate a diagnosis of ICUS, a thorough diagnostic work-up is required and repeated tests should be performed to reach a conclusive diagnosis. Recent studies provided consistent evidence of age-related hematopoietic clones (clonal hematopoiesis of indeterminate potential; CHIP), driven by mutations of genes that are recurrently mutated in myeloid neoplasms and associated with increase in the risk of hematologic cancer. A subset of mutated genes, mainly involved in epigenetic regulation, are likely initiating lesions driving the expansion of a premalignant clone. However, in a fraction of subjects the detected clone may be a small malignant clone expanding under the drive of the detected and additional undetected mutations. In addition, several experimental evidences suggest the potential relevance of an abnormal bone marrow environment in the selection and evolution of hematopoietic clones in MDS. The spreading of massively parallel sequencing techniques is offering translational opportunities in the clinical approach to myeloid neoplasms. Although several issues remain to be clarified, targeted gene sequencing may be of potential value in the dissection between clonal myelodysplasia, nonclonal cytopenia, and clonal hematopoiesis arising upon aging or in the context of acquired marrow failure.
Nine years without a new FDA-approved therapy for MDS: how can we break through the impasse?
Authors: DeZern Amy E.
Published: September 2016

The myelodysplastic syndromes (MDSs) are a heterogeneous collection of clonal hematopoietic malignancies that compromise a large subgroup of the myeloid neoplasms and collectively are the most common acquired adult bone marrow failure syndromes. Currently, only 3 agents are approved for the treatment of MDS by the US Food and Drug Administration (FDA): azacitidine, decitabine, and lenalidomide. The latter drug, approved in 2006, is the most recent agent approved by the FDA for MDS and there has been mediocre success with novel agents for the past 9 years. The heterogeneity of MDS as a disease group is likely to be a strong contributor to this slow progress but recent developments in molecular characterization of MDS are improving diagnostic accuracy, providing insights into pathogenesis and refining our prognostic ability in the field. With the advent of these developments, appropriately chosen therapeutics or even targeted agents may be able to improve patient outcomes in the future.
Looking forward: novel therapeutic approaches in chronic and advanced phases of myelofibrosis
Authors: Mascarenhas John
Published: September 2016

Myelofibrosis (MF) is complex at the pathobiologic level and heterogeneous at the clinical level. The advances in molecular characterization of MF provide important insight into the mechanisms driving this chronic myeloid malignancy, refine risk stratification, offer novel therapeutic targets, and serve to measure therapeutic response. Although JAK2 inhibition has been the focus of laboratory and clinical efforts over the last decade, current experimental therapeutic approaches have broadened to include inhibitors of key alternative signaling pathways, epigenetic modulators, anti-fibrotics, and immunotherapies. Based on compelling preclinical rationale, a number of JAK2 inhibitor based combination therapies are now actively being evaluated in the clinic with the goal of disease course modification. The role and timing of hematopoietic stem cell transplant (HSCT) for MF has been challenged with the availability of commercial ruxolitinib and the plethora of experimental treatment options that exist. Integration of preconditioning JAK2 inhibition, reduced intensity conditioning regimens, and alternative donor sources are all being explored in an attempt to optimize this potentially curative modality. This review will summarize modern MF risk stratification, current clinical research approaches to chronic and advance phase MF focusing on novel agents alone and in combination, and update the reader on new directions in HSCT.
Emerging genetic and pharmacologic therapies for controlling hemostasis: beyond recombinant clotting factors
Authors: Monahan Paul E.
Published: September 2016

For more than 3 decades, the scientific community has pursued gene correction of hemophilia, with the goal that an individual with congenitally deficient factor VIII or factor IX might synthesize adequate endogenous clotting factor to be relieved of burdensome repeated clotting factor infusions, as well as the emotional weight of continuous hemorrhage risk. Recent reports of successful factor IX gene therapy and partial correction of the bleeding phenotype have raised the bar for success for a robust crop of new clinical gene therapy efforts for both hemophilia A and B. At the same time that gene therapy is gaining momentum, suggesting the possibility of relief from regular intravenous coagulation protein replacement, a number of innovative technologies that enhance hemostatic potential independently of replacement factor administration are demonstrating success in human clinical application. Human clinical trial progress is reviewed regarding a recombinant bispecific IgG antibody to factors IXa and X that mimics factor VIII cofactor activity, as well as monoclonal antibody and short interfering RNA strategies that demonstrate hemostatic efficacy via opposing inhibitors of coagulation. These strategies, associated with prolonged hemostatic potential following subcutaneous (ACE910, ALN-AT3, Concizumab) or single administration (eg, gene therapy) make it possible to imagine a day when recombinant clotting factor administration, rather than being a daily preoccupation, is relegated to an adjunctive role in supporting more novel standard of care therapies.
Management of symptoms in polycythemia vera and essential thrombocythemia patients
Authors: Radia Deepti , Geyer Holly L.
Published: September 2016

The BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal stem cell derived malignancies, which include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). The MPNs are characterized by dysregulated JAK-STAT signaling pathways. PV and ET are associated with an increased risk of thrombo-hemorrhagic complications, risk of progression to MF and leukemia. Presentation of patients with PV and ET is variable and usually as a result of abnormal full blood count indices (raised hemoglobin and hematocrit, leukocytosis, and thrombocytosis). Presentation with thrombosis or splenomegaly occurs in ∼30% of patients. Historically thought of as indolent compared with MF, patients with PV and ET have significant disease symptom burden which does not directly correlate to the current clinical prognostic classifications. The mainstay of therapy is reserved for patients with high-risk disease and thus excludes a population of patients with significant symptom related morbidity impacting their quality-of-life and survival. Recent treatment strategies have aimed to incorporate disease burden assessment into the selection of therapeutic interventions such as JAK2 inhibitors and HDAC inhibitors. We will review the advances in the field of MPN symptom assessment and symptom burden experienced by ET and PV patients. We will also discuss the risk-stratified management of ET and PV patients alongside symptom assessment and the impact of potential novel therapies, for patients who fail to respond to conventional treatment.
Management of prolymphocytic leukemia
Authors: Dearden Claire
Published: September 2016

B-cell (B-PLL) and T-cell (T-PLL) prolymphocytic leukemias are rare, poor-prognosis lymphoid neoplasms with similar presentation characterized by symptomatic splenomegaly and lymphocytosis. They can be distinguished from each other and from other T- and B-cell leukemias by careful evaluation of morphology, immunophenotyping, and molecular genetics. The clinical behavior is typically aggressive, although a subset of patients may have an indolent phase of variable length. First-line therapy for T-PLL is with intravenous alemtuzumab and for B-PLL is with combination purine analog-based chemo-immunotherapy. New B-cell receptor inhibitors, such as ibrutinib and idelalisib, may have a role in the management of B-PLL, especially for the patients harboring abnormalities of TP53. Allogenic stem cell transplantation should still be considered for eligible patients and may be the only current therapy capable of delivering a cure. In the past few years, many of the molecular mechanisms underlying disease pathogenesis and progression have been revealed and are likely to lead to the development of novel targeted approaches.
Diagnosis and management of rare congenital nonimmune hemolytic disease
Authors: Gallagher Patrick G.
Published: September 2016

Rare, congenital nonimmune hemolytic disorders of the erythrocyte, although uncommon, are important causes of anemia in the child and adult. These are a heterogeneous group of diseases that disrupt normal erythrocyte structure and function in varying ways. Predominant are abnormalities of hemoglobin stability, defects of erythrocyte metabolism, and disorders of erythrocyte hydration. Unstable hemoglobinopathies may lead to chronic or episodic hemolysis. Perturbation of critical enzymes of the Embden–Meyerhof pathway lead to altered erythrocyte metabolism and chronic hemolysis. Disorders of erythrocyte hydration are an under-recognized cause of hemolytic anemia. Beyond pathophysiologic mechanisms of disease, clinical, laboratory, and genetic heterogeneity characterize this group of disorders. Often, they are underdiagnosed or misdiagnosed. This review discusses pathophysiology, inheritance, clinical findings, laboratory manifestations, and management considerations in several rare nonimmune hemolytic diseases including the unstable hemoglobins, disorders of erythrocyte metabolism, and abnormalities of erythrocyte hydration.
The use of novel monoclonal antibodies in the treatment of acute lymphoblastic leukemia
Authors: DeAngelo Daniel J.
Published: September 2016

Regardless of age, patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have extremely poor outcomes. The success of reinduction chemotherapy remains dismal, because complete remission rates are low and seldom durable. Clearly, new and novel strategies are needed to improve the outcome of patients with relapsed or refractory ALL. Patients with early relapse, especially those still receiving chemotherapy, tend to have a much poorer outcome and are often chemotherapy resistant. Although high-dose approaches may overcome chemotherapy resistance, long-term disease-free and overall survival remains limited. Several approaches have been used to target antigens, including cluster of differentiation (CD) 19, CD20, CD22, and CD52, on the surface of the malignant lymphoblast with striking efficacy. This review will focus on the clinical application of the major classes of antibodies, including naked antibodies, drug–antibody conjugates, immunotoxins, and T cell–engaging bispecific antibodies. Hopefully, these novel monoclonal antibodies will result in a significant improvement in the outcome of patients with relapsed or refractory ALL.
Can selectin and iNKT cell therapies meet the needs of people with sickle cell disease?
Authors: Field Joshua J.
Published: September 2016

Recent insights into the pathogenesis of microvascular occlusion downstream of the sickled red cell have revealed new therapeutic targets for sickle cell disease (SCD). After the formation of sickle cells, tissue injury spurs inflammation, which leads to receptor-mediated contacts between sickle cells, leukocytes, and vascular endothelium. Specifically, selectins decelerate sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other cell–cell interactions, ultimately leading to vascular occlusion. Invariant NKT (iNKT) cells, activated during reperfusion, generate a broad inflammatory response, which further increases cellular adhesion and vascular occlusion. Novel therapies are in development that target selectins and iNKT cells to prevent or interrupt the vicious cycle of adhesion and inflammation. Although the therapies hold promise for the treatment of SCD, an underappreciated threat to their development is poor access to care for people with SCD. Unless the majority of people with SCD have access to consistent, high-quality care, they will not have the opportunity to participate in a clinical trial or receive any new therapy, regardless of its efficacy.
Palliative care in pediatric patients with hematologic malignancies
Authors: Humphrey Lisa , Kang Tammy I.
Published: September 2016

Children with advanced cancer, including those with hematologic malignancies, can benefit from interdisciplinary palliative care services. Palliative care includes management of distressing symptoms, attention to psychosocial and spiritual needs, and assistance with navigating complex medical decisions with the ultimate goal of maximizing the quality-of-life of the child and family. Palliative care is distinct from hospice care and can assist with the care of patients throughout the cancer continuum, irrespective of prognosis. While key healthcare organizations, including the Institute of Medicine, the American Academy of Pediatrics and the American Society of Clinical Oncology among many others endorse palliative care for children with advanced illness, barriers to integration of palliative care into cancer care still exist. Providing assistance with advance care planning, guiding patients and families through prognostic uncertainty, and managing transitions of care are also included in goals of palliative care involvement. For patients with advanced malignancy, legislation, included in the Patient Protection and Affordable Health Care Act allows patients and families more options as they make the difficult transition from disease directed therapy to care focused on comfort and quality-of-life.
Patient-reported outcomes in drug development for hematology
Authors: Acquadro Catherine , Regnault Antoine
Published: September 2016

Patient-reported outcomes (PROs) are any outcome evaluated directly by the patient himself and based on the patient's perception of a disease and its treatment(s). PROs are direct outcome measures that can be used as clinical meaningful endpoints to characterize treatment benefit. They provide unique and important information about the effect of treatment from a patient's view. However, PROs will only be considered adequate if the assessment is well-defined and reliable. In 2009, the FDA has issued a guidance, which defines good measurement principles to consider for PRO measures intended to give evidence of treatment benefit in drug development. In hematologic clinical trials, when applied rigorously, they may be used to evaluate overall treatment effectiveness, treatment toxicity, and quality of patient's well-being at short-term and long-term after treatment from a patient's perspective. In situations in which multiple treatment options exist with similar survival outcome or if a new therapeutic strategy needs to be evaluated, the inclusion of PROs as an endpoint can provide additional data and help in clinical decision making. Given the diversity of the hematological field, the approach to measurement needs to be tailored for each specific situation. The importance of PROs in hematologic diseases has been highlighted in a number of international recommendations. In addition, new perspectives in the regulatory field will enhance the inclusion of PRO endpoints in clinical trials in hematology, allowing the voice of the patients with hematologic diseases to be taken into greater consideration in the development of new drugs.
Acute myeloid leukemia in children and adolescents: identification of new molecular targets brings promise of new therapies
Authors: Kolb E. Anders , Meshinchi Soheil
Published: September 2016

Recent reports of recurrent mutations in childhood acute myeloid leukemia (AML) have identified potential targets for new therapeutic strategies. Acute promyelocytic leukemia (APL) is characterized commonly by a fusion between the PML gene and the RARA gene, genes targetable by arsenic (ATO) and retinoic acid (ATRA), respectively. A mutation in GATA1, common in AML of Down syndrome (ML-DS), renders cells more susceptible to cytarabine and anthracyclines, thus permitting targeted dose reductions to preserve high survival rates while reducing toxicity. In all other patients, Ras pathway mutations, KMT2A and other methyltransferase mutations, FLT3 mutations, and KIT mutations are all relatively common in childhood AML and all are potentially “druggable”. The focus of this review is on those therapies likely to be clinically available in the near future. The preclinical and clinical data providing a rationale for testing in children of specific agents in children is discussed. Whether the expression of a potential target is sufficient to predict response to a targeted therapy is an open question in childhood AML. Development of clinical trials to evaluate targeted therapies in small molecularly defined subsets of AML will be the next great challenge for all cooperative groups in North America and Europe.
Molecularly targeted therapies for acute myeloid leukemia
Authors: Stein Eytan M.
Published: September 2016

The past 15 years have seen major leaps in our understanding of the molecular genetic mutations that act as drivers of acute myeloid leukemia (AML). Clinical trials of agents against specific mutant proteins, such as FLT3-internal tandem duplications (ITDs) and isocitrate dehydrogenase mutations (IDHs) are ongoing. This review discusses agents in clinical trials that target specific gene mutations and/or epigenetic targets.
Antigen-specific immunotherapies for acute myeloid leukemia
Authors: Buckley Sarah A. , Walter Roland B.
Published: September 2016

Antigen-specific immunotherapies have emerged as important components of curative treatment algorithms for many cancers. In acute myeloid leukemia (AML), success has been less obvious. Nonetheless, among the few drugs shown to improve survival in recent randomized trials is the CD33 antibody–drug conjugate gemtuzumab ozogamicin. Significant antileukemic activity is also well documented for radioimmunoconjugates targeting CD33, CD45, or CD66. These therapeutics can intensify conditioning before hematopoietic cell transplantation, but their effect on patient outcomes needs clarification. Emerging data now suggest clinical antileukemic activity of several novel antibodies and perhaps some adoptive T-cell immunotherapies and vaccines. In parallel, numerous other agents targeting a wider variety of antigens are currently being explored. However, the antigenic heterogeneity characteristic of AML is a considerable limitation for all these therapeutics, and many important questions related to the ideal target antigen(s), disease situation in which to use these therapies, most suitable patient populations, exact treatment modalities, and details of supportive care needs remain open. Addressing such questions in upcoming studies will be required to ensure that antigen-directed therapies become an effective tool in AML, a disease for which outcomes with standard “3 + 7”-based chemotherapy have remained unsatisfactory in many patients.
New approaches to transplantation in acute myelogenous leukemia
Authors: de Lima Marcos
Published: September 2016

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapeutic option for acute myelogenous leukemia (AML). This is due to the combined effect of chemo/radiation therapy and the immunologic graft-versus-leukemia effect. The field of HSCT has benefited from advances in a variety of “fronts,” including our increasing ability to break the human leukocyte antigen barrier, which has led to greater access to transplantation. Furthermore, progress in the biologic, genetic, and pharmacologic arenas is creating a scenario where traditional borders between transplant and non-transplant therapies are less clear. This overlap is exemplified by new approaches to pharmacologic maintenance of remission strategies after HSCT. In addition, cellular adoptive immunotherapy has the potential to exploit narrowly targeted anti-tumor effects within or outside the allogeneic HSCT “frame,” holding the promise of avoiding off target side effects, such as graft-versus-host disease. Here we discuss these and other lines of active investigation designed to improve outcomes of HSCT for AML.
Treatment of patients with transformed lymphoma
Authors: Montoto Silvia
Published: September 2016

Histologic transformation (HT) is a frequent event in the clinical course of patients with indolent lymphoma. Most of the available data in the literature comes from studies on transformation of follicular lymphoma (FL), as this is the most common indolent lymphoma; however, HT is also well documented following small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL), lymphoplasmacytic lymphoma (LPL), or marginal zone lymphoma (MZL), amongst other types of lymphoma, albeit most of the studies on transformation in these subtypes are case reports or short series. The outcome of patients with HT has traditionally been considered dismal with a median overall survival (OS) of around 1 year in most of the published studies. This prompted many authors to include stem cell transplant (SCT) as part of the treatment strategy for young and fit patients with HT. However, recent articles suggest that the outcome of patients with transformed lymphoma might be improving, questioning the need for such intensive therapies. The management of patients with HT is challenged by the heterogeneity of the population in terms of previous number and type of therapy lines and from their exclusion from prospective clinical trials. This review will examine whether the advent of new therapies has impacted on the prognosis of HT and on current treatment strategies.
Development of a prediction system for tail-anchored proteins
Authors: Shigemitsu Shunsuke , Cao Wei , Terada Tohru , Shimizu Kentaro
Published: September 2016

Background

“Tail-anchored (TA) proteins” is a collective term for transmembrane proteins with a C-terminal transmembrane domain (TMD) and without an N-terminal signal sequence. TA proteins account for approximately 3–5 % of all transmembrane proteins that mediate membrane fusion, regulation of apoptosis, and vesicular transport. The combined use of TMD and signal sequence prediction tools is typically required to predict TA proteins.

Results

Here we developed a prediction system named TAPPM that predicted TA proteins solely from target amino acid sequences according to the knowledge of the sequence features of TMDs and the peripheral regions of TA proteins. Manually curated TA proteins were collected from published literature. We constructed hidden markov models of TA proteins as well as three different types of transmembrane proteins with similar structures and compared their likelihoods as TA proteins.

Conclusions

Using the HMM models, we achieved high prediction accuracy; area under the receiver operator curve values reaching 0.963. A command line tool written in Python is available at https://github.com/davecao/tappm_cli.
Sierra platinum: a fast and robust peak-caller for replicated ChIP-seq experiments with visual quality-control and -steering
Authors: Müller Lydia , Gerighausen Daniel , Farman Mariam , Zeckzer Dirk
Published: September 2016

Background

Histone modifications play an important role in gene regulation. Their genomic locations are of great interest. Usually, the location is measured by ChIP-seq and analyzed with a peak-caller. Replicated ChIP-seq experiments become more and more available. However, their analysis is based on single-experiment peak-calling or on tools like PePr which allows peak-calling of replicates but whose underlying model might not be suitable for the conditions under which the experiments are performed.

Results

We propose a new peak-caller called ‘Sierra Platinum’ that allows peak-calling of replicated ChIP-seq experiments. Moreover, it provides a variety of quality measures together with integrated visualizations supporting the assessment of the replicates and the resulting peaks, as well as steering the peak-calling process.

Conclusion

We show that Sierra Platinum outperforms currently available methods using a newly generated benchmark data set and using real data from the NIH Roadmap Epigenomics Project. It is robust against noisy replicates.