bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL)
Authors: Ottmann Oliver G. , Pfeifer Heike
Published: December 2009

The tyrosine kinase inhibitor (TKI) imatinib has become an integral part of front-line therapy for Ph+ ALL, with remission rates exceeding 90% irrespective of whether imatinib is given alone or combined with chemotherapy. Treatment outcome with imatinib-based regimens has improved compared with historic controls, but most patients who do not undergo allogeneic stem cell transplantation (SCT) eventually relapse. Acquired resistance on TKI treatment is associated with mutations in the bcr-abl tyrosine kinase domain in the majority of patients, and may be detected at low frequency prior to TKI treatment in a subset of patients. Second generation TKIs, eg, dasatinib and nilotinib, show activity against most of the bcr-abl tyrosine kinase domain (TKD) mutations involved in acquired imatinib resistance, but clinical benefit is generally short-lived. Accordingly, SCT in first complete remission (CR) is considered to be the best curative option. Molecular monitoring of minimal residual disease levels appears to have prognostic relevance and should be used to guide treatment. International standardization and quality control efforts are ongoing to ensure comparability of results. Mutation analysis during treatment relies increasingly on highly sensitive PCR techniques or denaturing HPLC and may assist in treatment decisions, eg, in case of molecular relapse. Results from current studies of second-generation TKI as front-line treatment for Ph+ ALL are promising and show high molecular response rates, but follow-up is still too short to determine their impact on remission duration and long-term survival. Strategies to improve outcome after SCT include the pre-emptive use of imatinib, which appears to reduce the relapse rate. In patients ineligible for transplantation, novel concepts for maintenance therapy are needed. These could involve novel immunotherapeutic interventions and combinations of TKI.
Independent prognostic factors for AML outcome
Authors: Grimwade David , Hills Robert K.
Published: December 2009

Over the last three decades there have been dramatic advances in deciphering the cytogenetic and molecular lesions underlying the pathogenesis of acute myeloid leukemia (AML). These have not only afforded greater insights into disease biology, but also provided useful information predicting the likelihood of any given patient achieving and maintaining remission following conventional chemotherapy, leading to the development of risk-stratified treatment approaches. However, it is becoming increasingly apparent that AML is highly heterogeneous at the molecular level. Defining the individual genetic abnormalities or combinations of markers that provide significant independent prognostic information and establishing their respective relationships to other pre-treatment characteristics that impact on outcome, such as age and presenting white blood cell count, presents a major ongoing challenge. Moreover, there is increasing evidence that risk of relapse and overall survival can be predicted by assessment of kinetics and depth of response following front-line therapy and monitoring of the leukemic burden using molecular or immunological approaches to minimal residual disease (MRD) detection. These advances present the exciting prospect that panels of pre-treatment parameters affording independent prognostic information can be integrated with precise measurement of treatment response using MRD technologies to provide greater refinement in risk-adapted management of AML. This could lead to further improvements in outcome and serve to identify in a more reliable fashion those patients most likely to benefit from allogeneic transplant in first remission.
What is the role of reduced-intensity transplantation in the treatment of older patients with AML?
Authors: Forman Stephen J.
Published: December 2009

Acute myelogenous leukemia (AML), either de novo or arising out of antecedent myelodysplasia, increases with age and is rarely curable by standard treatments used for younger patients. Recent clinical trials using reduced-intensity allogeneic transplantation regimens suggest that a proportion of patients with this disease can be cured, with results comparable to those achieved in younger patients undergoing fully ablative transplant. Although those patients who undergo transplant in a first remission often do well, the vast majority of older patients have not benefited because of the low successful remission achieved with standard therapy, the delay in initiating a donor search, and the lack of significant benefit from transplantation in patients who are not in remission. New approaches to induction, improvements in reduced-intensity regimens, and earlier donor identification will help expand the potential clinical benefit to a larger number of older patients with the disease.
Predicting clinical outcome in CLL: how and why
Authors: Shanafelt Tait D.
Published: December 2009

The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous, with some patients experiencing rapid disease progression and others living for decades without requiring treatment. Clinical features and molecular/biologic factors such as ZAP-70, immunoglobulin heavy chain (IGHV) gene mutation status, and cytogenetic abnormalities on fluorescent in situ hybridization (FISH) have been found to be robust predictors of treatment-free survival and overall survival among newly diagnosed patients. Beyond their widely recognized value for providing insight into disease biology and utility for stratifying patient risk in clinical trials, these prognostic tools play an important role in the current counseling and management of patients with CLL. Recent studies have focused on how to combine the results of multiple prognostic assays into an integrated risk stratification system and explored how these characteristics influence response to treatment. This chapter reviews the available tools to stratify patient risk and discusses how these tools can be used in routine clinical practice to individualize patient counseling, guide the frequency of follow-up, and inform treatment selection.
Initial treatment for patients with CML
Authors: Goldman John M.
Published: December 2009

For adult patients who present with chronic myeloid leukemia (CML) in chronic phase it is now generally agreed that initial treatment should start with the tyrosine kinase inhibitor (TKI) imatinib at 400 mg daily. Five years after starting imatinib about 60% of these patients will be in complete cytogenetic response (CCyR), still taking imatinib; an appreciable proportion of these will have achieved a major molecular response, defined as a 3-log reduction in the level of BCR-ABL1 transcripts in their blood. The patients in CCyR seem to have a very low risk of relapse to chronic phase or of progression to advanced phase. Other patients may be resistant to imatinib or may experience significant side effects that require change of therapy. The best method of monitoring responding patients is to enumerate Philadelphia chromosome–positive marrow metaphases at 3-month intervals until CCyR and to perform RQ-PCR for BCR-ABL1 transcripts at 3-month intervals after starting imatinib. The recommendations for defining “failure” and “sub-optimal response” proposed by the European LeukemiaNet in 2006 have proved to be a major contribution to assessing responses in individual patients and are now being updated. Patients who fail imatinib may respond to second-generation TKIs, but allogeneic stem cell transplantation still plays an important role for eligible patients who fare badly with TKIs. Patients who present in advanced phases of CML should be treated initially with TKI alone or with TKI in conjunction with cytotoxic drugs, but their overall prognosis is likely to be much inferior to that of those presenting in early chronic phase.
Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance
Authors: Bixby Dale , Talpaz Moshe
Published: December 2009

Given its relative rarity, it may at first seem surprising that chronic myeloid leukemia (CML) has garnered so much attention over the last decade. Yet, the advances in molecular pathogenesis that have been derived from studying this leukemia have clearly benefited all of oncology. Moreover, the strides in drug design and development that have also ensued around CML have given rise to what others have called a molecular revolution in cancer therapy. While a majority of patients with chronic phase CML (CP-CML) have an excellent durable response to imatinib (Gleevec, Novartis, Basel, Switzerland), a clear minority will unfortunately have signs of primary or secondary resistance to therapy. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the biology of drug trafficking into and out of cells, epigenetic control of cellular processes, alterations in enzymatic structures, and the rational structural-based design of small molecule enzyme inhibitors. This review will describe the efforts at understanding the pathogenesis of imatinib resistance and the molecular rationale for the development of second- and now third-generation therapies for patients with CML.
Molecular biology of Hodgkin lymphoma
Authors: Küppers Ralf
Published: December 2009

Hodgkin lymphoma (HL) is derived from mature B cells and subdivided into classical HL and nodular lymphocyte predominant HL (NLPHL). HL is unique among human B cell lymphomas because of the rarity of the lymphoma cells, the Hodgkin and Reed-Sternberg (HRS) cells in classical HL and the lymphocyte-predominant (LP) cells in NLPHL, which usually account for 0.1% to 10% of the cells in the affected tissues. Moreover, HRS cells are unique in the extent to which they have lost their B cell–typical gene expression pattern. Deregulation of transcription factor networks plays a key role in this reprogramming process. HRS cells show strong constitutive activity of the transcription factor NF-κB. Multiple mechanisms likely contribute to this deregulated activation, including signaling through particular receptors and genetic lesions. Inactivating mutations in the TNFAIP3 tumor suppressor gene, encoding a negative regulator of NF-κB activity, were recently identified in about 40% of patients with classical HL. HRS cells are latently infected by Epstein-Barr virus in about 40% of patients, and an important role of this virus in HL pathogenesis—in particular for cases in which HRS cells had lost the capacity to express a B-cell receptor due to destructive somatic mutation—was recently substantiated.
Standard therapy of advanced Hodgkin lymphoma
Authors: Kuruvilla John
Published: December 2009

ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) continues to be the standard of care for patients with advanced-stage Hodgkin lymphoma (HL). Consolidation of primary chemotherapy with radiation or autologous stem cell transplantation (ASCT) has not demonstrated an improvement in overall survival in randomized controlled trials. Regimens such as escalated BEACOPP have more acute and late toxicities and survival benefits have yet to be confirmed.

Despite effective therapy, ultimately 30% to 40% of patients with advanced HL will relapse. ASCT has become the standard of care for patients with relapsed or refractory HL based on two randomized trials. The optimal salvage chemotherapy and high dose therapy regimen are not known. Similarly, non-ASCT strategies including salvage radiotherapy or non-ASCT chemotherapy strategies have been reported and have a potential role in selected clinical scenarios.

This review summarizes recent clinical trial results in the initial treatment of advanced HL and will focus on second-line treatment strategies for patients with relapsed or refractory disease.
Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma
Authors: Younes Anas
Published: December 2009

Although classical Hodgkin lymphoma (HL) is considered one of the most curable human cancers, the treatment of patients with relapsed and refractory disease, especially those who relapse after autologous stem cell transplantation, remains challenging. Furthermore, because the median age of the patients is in the mid-30s, the impact of early mortality on the number of years lost from productive life is remarkable. Patients with HL whose disease relapses after stem cell transplantation are rarely cured with current treatment modalities. New drugs and novel treatment strategies that are based on our understanding of the disease biology and signaling pathways are needed to improve treatment outcome for these patients. This review will focus on emerging new treatment modalities that are currently under investigation for patients with relapsed classical HL.
Novel therapies in sickle cell disease
Authors: Ataga Kenneth I.
Published: December 2009

Despite an increased understanding of the pathophysiology of sickle cell disease (SCD), there remains a paucity of available agents for the prevention and treatment of specific SCD-related complications. Recently, there has been significant progress in the development of novel drugs for this disease. These agents, which increase the production of fetal hemoglobin, improve red blood cell hydration, increase the availability of nitric oxide and possess anti-inflammatory effects, are in varying stages of clinical development. With the complex pathophysiology of SCD, it is unlikely that a single agent will prevent or treat all the sequelae of this disease. As a result, patients may benefit from treatment with a combination of agents that possess different mechanisms of action. This overview discusses selected novel agents that appear promising in SCD.
How to treat a newly diagnosed young patient with multiple myeloma
Authors: San-Miguel Jesús F. , Mateos María-Victoria
Published: December 2009

Survival rates of young patients with myeloma have increased markedly in the last decade, mainly due to the use of autologous stem cell transplantation (ASCT) and new, highly efficient rescue treatments. In order to improve the survival of newly diagnosed young patients further, the next steps need to focus on increasing the activity of upfront or debulking regimens, improving the efficacy of ASCT, mainly through the conditioning regimen, and increasing the duration of responses through more effective maintenance or consolidation therapies. Nevertheless, this approach is being challenged by the favorable results obtained with long-term treatment with novel agents and the possibility of reserving the ASCT until relapse. Allogeneic transplantation in newly diagnosed patients should be considered as an investigational procedure and used only in well-designed clinical trials. This review covers the new strategies that are currently under investigation with the aim of optimizing the outcome for newly diagnosed young patients with myeloma.
How to treat elderly patients with multiple myeloma: combination of therapy or sequencing
Authors: Palumbo Antonio , Gay Francesca
Published: December 2009

Patients with multiple myeloma aged older than 65 years have traditionally received an oral regimen combining melphalan and prednisone (MP). The introduction of novel agents, such as immunomodulatory drugs and proteasome inhibitors, has substantially changed the treatment paradigm of this disease. Five randomized phase III studies, comparing MP plus thalidomide (MPT) versus MP, have shown that MPT increased time to progression (TTP); however, only two of these five studies showed improvement in overall survival (OS). One randomized study has shown that MP plus bortezomib (MPV) increases both TTP and OS compared with MP. Both MPT and MPV are now regarded as the new standards of care for elderly patients. Other promising results have been reported with MP plus lenalidomide or lenalidomide plus dexamethasone, or the combination of cyclophosphamide, thalidomide, and dexamethasone. Reduced-intensity transplantation can be an option for some patients, especially when novel agents are incorporated into pre-transplant induction and post-transplant consolidation. For patients aged older than 75 years a gentler approach should be used, and doses of standard MPT or MPV should be reduced. An accurate management of treatment-related adverse events with prompt dose-reduction can greatly reduce the rate of early discontinuation and significantly improve treatment efficacy. The choice of treatment should be tailored according to the patient’s biologic age and comorbidities, and the expected toxicity profile of the regimen.
Novel therapies for relapsed myeloma
Authors: Stewart A. Keith
Published: December 2009

Treatment of myeloma relapse needs to be individualized to reflect the effectiveness and toxicities of prior therapies, with consideration given to pragmatic issues such as the tempo of relapse, age of the patient, access to drugs and patient preference. In general, combination therapies have been associated with higher response rates and improved progression-free survival and may be preferable when a rapid response is required. Nevertheless, in a slower-tempo relapse it is unclear at this juncture whether sequencing of drugs or multi-agent combinations offer superior overall survival results. Fortunately, active novel agents that offer further possibilities for some myeloma patients have become available in clinical trials. In this review we will describe the various classes of novel drugs being tested and the pros and cons of preclinical testing, and will particularly focus on two agents with single-agent activity in myeloma: carfilzomib, a proteasome inhibitor, and pomalidomide, a member of the immunomodulatory class of drugs.
Advances in the use of hydroxyurea
Authors: Ware Russell E. , Aygun Banu
Published: December 2009

Clinical experience with hydroxyurea for patients with sickle cell disease (SCD) has been accumulating for the past 25 years. The bulk of the current evidence suggests that hydroxyurea is well-tolerated, safe, and efficacious for most patients with SCD. Hydroxyurea has proven clinical efficacy for reducing acute vaso-occlusive events including pain episodes and acute chest syndrome. Salutary effects on hematological parameters include increases in fetal hemoglobin (HbF), hemoglobin, and MCV; also significant decreases occur in WBC, ANC, reticulocytes, LDH, and bilirubin. Treatment with hydroxyurea is usually considered for patients with recurrent vaso-occlusive events, but additional indications for treatment may include laboratory markers of disease severity and evidence of chronic organ dysfunction. Ten years ago, the US Food and Drug Administration approved hydroxyurea for adult patients with clinically severe SCD; however, its use in children remains off-label. Despite the large body of evidence regarding its efficacy and safety, hydroxyurea is currently prescribed only sparingly for patients with SCD and therefore has only limited effectiveness for this disorder; barriers to its use need to be identified and overcome.
Pathogenesis and management of essential thrombocythemia
Authors: Beer Philip A. , Green Anthony R.
Published: December 2009

The last four years have seen an explosion in our understanding of the myeloproliferative neoplasms. Important and often unexpected insights into the molecular mechanisms responsible for these disorders have been accompanied by the development of new diagnostic tests and by an improved understanding of the relationship between the different disease entities. This review will focus on recent developments in the pathogenesis and management of essential thrombocythemia with a particular emphasis on its phenotypic overlap with polycythemia vera and primary myelofibrosis.
Idiopathic erythrocytosis: a disappearing entity
Authors: McMullin Mary Frances
Published: December 2009

Erythrocytosis results when there is an increased red cell mass and thus an increased hemoglobin. The causes can be divided into primary intrinsic defects of the erythroid progenitor cell and secondary defects, where factors external to the erythroid compartment are responsible. Both can then be further divided into congenital and acquired categories. Congenital causes include mutations of the erythropoietin receptor and defects of the oxygen-sensing pathway including VHL, PHD2 and HIF2A mutations. When fully investigated there remain a number of patients in whom no cause can be elucidated who are currently described as having idiopathic erythrocytosis. Investigation should start with a full history and examination. Having eliminated the common entity polycythemia vera, further direction for investigation is guided by the erythropoietin level. Clinical consequences of the various erythrocytoses are not clear, but in some groups thromboembolic events have been described in young patients. Evidence is lacking to define best management, but aspirin and venesection to a target hematocrit should be considered.
Treatment of MDS: something old, something new, something borrowed…
Authors: Sekeres Mikkael A.
Published: December 2009

As opposed to the treatment landscape for myelodysplastic syndromes (MDS) two decades ago, potential therapies now abound for the treatment of lower-risk and higher-risk populations. In lower-risk patients, decision tools can be used to determine the likelihood of response to erythropoiesis stimulating agents (ESAs), which have demonstrated survival advantages in retrospective studies in patients with MDS, and whether these patients should be treated initially with ESAs or non-growth factor (“active”) therapies. Lenalidomide has shown good activity in transfusion-dependent patients with the del(5q) cytogenetic abnormality and modest activity in other lower-risk patients. In higher-risk patients, the DNA methyltransferase inhibitors produce complete and partial responses in 20% to 30% of patients, and for the first time, the MDS drug azacitidine has demonstrated a survival advantage when compared with conventional therapies. Newer therapies stimulate platelet production and target novel pathways, while a panoply of combination studies are underway or recently completed and that likely represent the next frontier in MDS therapy.
Hematopoietic stem cell gene transfer for the treatment of hemoglobin disorders
Authors: Persons Derek A.
Published: December 2009

Hematopoietic stem cell (HSC)–targeted gene transfer is an attractive approach for the treatment of a number of hematopoietic disorders caused by single gene defects. Indeed, in a series of gene transfer trials for two different primary immunodeficiencies beginning early in this decade, outstanding success has been achieved. Despite generally low levels of engrafted, genetically modified HSCs, these trials were successful because of the marked selective advantage of gene-corrected lymphoid precursors that allowed reconstitution of the immune system. Unlike the immunodeficiencies, this robust level of in vivo selection is not available to hematopoietic repopulating cells or early progenitor cells following gene transfer of a therapeutic globin gene in the setting of β-thalassemia and sickle cell disease. Both preclinical and clinical transplant studies involving bone marrow chimeras suggest that 20% or higher levels of engraftment of genetically modified HSCs will be needed for clinical success in the most severe of these disorders. Encouragingly, gene transfer levels in this range have recently been reported in a lentiviral vector gene transfer clinical trial for children with adrenoleukodystrophy. A clinical gene transfer trial for β-thalassemia has begun in France, and one patient with transfusion-dependent HbE/β-thalassemia has demonstrated a therapeutic effect after transplantation with autologous CD34+ cells genetically modified with a β-globin lentiviral vector. Here, the development and recent progress of gene therapy for the hemoglobin disorders is reviewed.
Imaging circulating cells and lymphoid tissues with iron oxide nanoparticles
Authors: Elias Andrew , Tsourkas Andrew
Published: December 2009

The use of nanometer-sized iron oxide nanoparticles and micron-sized iron oxide particles as magnetic resonance (MR) contrast agents has garnered a high degree of interest in diverse areas of biology and medicine. Applications such as cell tracking, molecular imaging, gene detection, and lymphography are being explored to provide insight into disease mechanisms, monitor therapeutic efficacy, and facilitate diagnostic imaging. What makes iron oxide so appealing is a number of favorable properties including high detectability by MR, biodegradability and low toxicity. Here we describe the recent progress on the use of magnetic nanoparticles in imaging circulating cells and lymphoid tissues. The study of the lymph system and the biodistribution of various circulating immune cells is important in the diagnosis, prognosis, and treatment of a wide range of diseases and is expected to have a profound effect on patient outcome.
Finding the right academic job
Authors: Ghobrial Irene M. , Laubach Jacob P. , Soiffer Robert J.
Published: December 2009

The career path in academic medicine is full of exciting opportunities as well as great achievements and discoveries. In this review, we discuss various obstacles that fellows face as they explore career opportunities in academic hematology/oncology. We also share thoughts on what might be considered steps for success in maneuvering through a search for the “right” position. We discuss several aims including how to define career goals early on, keys to success in an academic career, how to look for an academic job, successful points for the interview process, and how to negotiate a job offer. Finally, we discuss some roadblocks and limitations of academic careers and promotions. These limitations, frustrations and roadblocks should not be a deterrent from pursuing such a great role in the scientific field. This is a new generation of scientific discovery, improvement in healthcare and great advances in research.
The academic job offer: what to expect and how to negotiate
Authors: Schafer Andrew I.
Published: December 2009

In contrast to the familiar college, medical school, residency and fellowship application mechanisms, securing the first academic faculty position has no ground rules and no timelines. The open-ended and idiosyncratic nature of securing a job can be frustrating. Negotiating a competitive start-up package when continuing on the faculty of one’s training institution can be particularly challenging. Deciding which offer to accept should be determined less by the “best deal” that can be negotiated and more by the short-term and long-term opportunities for career success.
Academic promotion and tenure: a user’s guide for junior faculty members
Authors: Buchanan George R.
Published: December 2009

Securing a junior faculty position is an important early step in an academic career in hematology. Shortly thereafter one should begin to plan for eventual promotion and possible tenure. The process is not straightforward, as the “rules of the road” regarding academic positions, academic tracks, assessment and evaluation metrics, and timelines vary immensely from one institution to another. It is critically important, therefore, for the new junior faculty member to become knowledgeable about the institutional policies and “culture” regarding this process. This understanding includes the definition of and criteria for achieving tenure, the academic tracks and the policies for advancement on each track, and the process by which the institutional committee responsible for promotion and tenure conducts its activities. Learning the rules and successfully navigating the academic pathway will help ensure success by achieving the desired promotion and the self-satisfaction, prestige, and financial awards that may accompany it.
Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia
Authors: Muramatsu Hideki , Makishima Hideki , Jankowska Anna M. , Cazzolli Heather , O'Keefe Christine , Yoshida Nao , Xu Yinyan , Nishio Nobuhiro , Hama Asahito , Yagasaki Hiroshi , Takahashi Yoshiyuki , Kato Koji , Manabe Atsushi , Kojima Seiji , Maciejewski Jaroslaw P.
Published: December 2009

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. When we investigated the presence of recurrent molecular lesions in a cohort of 49 children with JMML, neurofibromatosis phenotype (and thereby NF1 mutation) was present in 2 patients (4%), whereas previously described PTPN11, NRAS, and KRAS mutations were found in 53%, 4%, and 2% of cases, respectively. Consequently, a significant proportion of JMML patients without identifiable pathogenesis prompted our search for other molecular defects. When we applied single nucleotide polymorphism arrays to JMML patients, somatic uniparental disomy 11q was detected in 4 of 49 patients; all of these cases harbored RING finger domain c-Cbl mutations. In total, c-Cbl mutations were detected in 5 (10%) of 49 patients. No mutations were identified in Cbl-b and TET2. c-Cbl and RAS pathway mutations were mutually exclusive. Comparison of clinical phenotypes showed earlier presentation and lower hemoglobin F levels in patients with c-Cbl mutations. Our results indicate that mutations in c-Cbl may represent key molecular lesions in JMML patients without RAS/PTPN11 lesions, suggesting analogous pathogenesis to those observed in chronic myelomonocytic leukemia (CMML) patients.
A CD8 T cell–intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo
Authors: Fehr Thomas , Lucas Carrie L. , Kurtz Josef , Onoe Takashi , Zhao Guiling , Hogan Timothy , Vallot Casey , Rao Anjana , Sykes Megan
Published: December 2009

Previous studies have indicated that blockade of signaling through the T-cell receptor (TCR)/calcineurin/nuclear factor of activated T cells (NFAT) pathway impairs transplantation tolerance induced with anti-CD154 antibody. By using an allogeneic bone marrow transplantation model, we examined the role of the TCR/calcineurin/NFAT pathway for tolerance induction with anti-CD154. Calcineurin blockade by cyclosporine A led to a failure of CD8 but not CD4 tolerance, and experiments in NFAT1−/− mice replicated this effect. Studies in thymectomized mice demonstrated that blockade of the calcineurin/NFAT pathway after bone marrow transplantation led to a failure of peripheral CD8 tolerance. Moreover, CD8 adoptive transfer studies demonstrated that NFAT1 is cell-intrinsically required for peripheral CD8 tolerance. NFAT1 deficiency did not impair CD8 T-cell up-regulation of PD1, which is required for CD8 tolerance in this model. NFAT1 has previously been shown to have a role in CD4 cells for anergy induction and for programming CD4 cells to become regulatory cells. By generating mice lacking NFAT1 in CD4 but not CD8 cells, we demonstrate that NFAT1 is neither required for CD4 tolerance induction nor for their regulatory function on CD8 T cells. Thus, our study reveals a CD8 T cell–intrinsic NFAT1 requirement for CD8 tolerance in vivo.
FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML
Authors: Pratz Keith W. , Sato Takashi , Murphy Kathleen M. , Stine Adam , Rajkhowa Trivikram , Levis Mark
Published: December 2009

We examined 6 different FMS-like tyrosine kinase-3 (FLT3) inhibitors (lestaurtinib, midostaurin, AC220, KW-2449, sorafenib, and sunitinib) for potency against mutant and wild-type FLT3, as well as for cytotoxic effect against a series of primary blast samples obtained from patients with acute myeloid leukemia (AML) harboring internal tandem duplication (FLT3/ITD) mutations. We found that inhibition of FLT3 autophosphorylation in a FLT3/ITD specimen does not always induce cell death, suggesting that some FLT3/ITD AML may not be addicted to FLT3 signaling. Relapsed samples and samples with a high mutant allelic burden were more likely to be responsive to cytotoxicity from FLT3 inhibition compared with the samples obtained at diagnosis or those with a low mutant allelic burden. These FLT3 inhibitors varied to a considerable degree in their selectivity for FLT3, and this selectivity influenced the cytotoxic effect. These results have important implications for the potential therapeutic use of FLT3 inhibitors in that patients with newly diagnosed FLT3-mutant AML might be less likely to respond clinically to highly selective FLT3 inhibition.
A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell–mediated responses that are differentially sensitive to therapy
Authors: Chow Leola , Aslam Rukhsana , Speck Edwin R. , Kim Michael , Cridland Norman , Webster Michelle Lee , Chen Pingguo , Sahib Kim , Ni Heyu , Lazarus Alan H. , Garvey M. Bernadette , Freedman John , Semple John W.
Published: December 2009

Immune thrombocytopenia (ITP) is a bleeding disorder characterized by antibody-opsonized platelets being prematurely destroyed in the spleen, although some patients with ITP may have a cell-mediated form of thrombocytopenia. Although several animal models of ITP have been developed, few mimic primary chronic ITP nor have any shown cell-mediated platelet destruction. To create this type of model, splenocytes from CD61 knockout mice immunized against CD61+ platelets were transferred into severe combined immunodeficient (SCID) (CD61+) mouse recipients, and their platelet counts and phenotypes were observed. As few as 5 × 104 splenocytes induced a significant thrombocytopenia and bleeding mortality (80%) in recipients within 3 weeks after transfer. Depletion of lymphocyte subsets before transfer showed that the splenocyte's ability to induce thrombocytopenia and bleeding completely depended on CD4+ T helper cells and that both CD19+ B cell (antibody)– and CD8+ T cell (cell)–mediated effector mechanisms were responsible. Treatment of the SCID mouse recipients with intravenous γ-globulins raised platelet counts and completely prevented bleeding mortality induced by antibody-mediated effector mechanisms but did not affect cell-mediated disease. This novel model not only shows both antibody- and cell-mediated ITP and bleeding but also suggests that these 2 effector mechanisms have a differential response to therapy.
Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia
Authors: Silverman Lewis B. , Supko Jeffrey G. , Stevenson Kristen E. , Woodward Christina , Vrooman Lynda M. , Neuberg Donna S. , Asselin Barbara L. , Athale Uma H. , Clavell Luis , Cole Peter D. , Kelly Kara M. , Laverdière Caroline , Michon Bruno , Schorin Marshall , Schwartz Cindy L. , O'Brien Jane E. , Cohen Harvey J. , Sallan Stephen E.
Published: December 2009

Over the past several decades, L-asparaginase, an important component of therapy for acute lymphoblastic leukemia (ALL), has typically been administered intramuscularly rather than intravenously in North America because of concerns regarding anaphylaxis. We evaluated the feasibility of giving polyethylene glycosylated (PEG)–asparaginase, the polyethylene glycol conjugate of Escherichia coli L-asparaginase, by intravenous infusion in children with ALL. Between 2005 and 2007, 197 patients (age, 1-17 years) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-01 and received a single dose of intravenous PEG-asparaginase (2500 IU/m2) over 1 hour during remission induction. Serum asparaginase activity more than 0.1 IU/mL was detected in 95%, 88%, and 7% of patients at 11, 18, and 25 days after dosing, respectively. Toxicities included allergy (1.5%), venous thrombosis (2%), and pancreatitis (4.6%). We conclude that intravenous administration of PEG-asparaginase is tolerable in children with ALL, and potentially therapeutic enzyme activity is maintained for at least 2 weeks after a single dose in most patients. This trial was registered at www.clinicaltrials.gov as #NCT00400946.
Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis
Authors: Santos Fabio P. S. , Kantarjian Hagop M. , Jain Nitin , Manshouri Taghi , Thomas Deborah A. , Garcia-Manero Guillermo , Kennedy Debra , Estrov Zeev , Cortes Jorge , Verstovsek Srdan
Published: December 2009

Few treatment options exist for patients with myelofibrosis (MF), and their survival is significantly shortened. Activating mutation of the JAK2 tyrosine kinase (JAK2V617F) is found in approximately 50% of MF patients. CEP-701 is a tyrosine kinase inhibitor that inhibits JAK2 in in vitro and in vivo experiments. We conducted a phase 2 clinical study of CEP-701 in 22 JAK2V617F-positive MF patients (80 mg orally twice daily), and 6 (27%) responded by International Working Group criteria (clinical improvement in all cases): reduction in spleen size only (n = 3), transfusion independency (n = 2), and reduction in spleen size with improvement in cytopenias (n = 1). Median time to response was 3 months, and duration of response was more than or equal to 14 months. No improvement was seen in bone marrow fibrosis or JAK2V617F allele burden. Phosphorylated STAT3 levels decreased from baseline in responders while on therapy. Eight patients (36%) experienced grade 3 or 4 toxicity, and 6 (27%) required dose reduction. Main side effects were myelosuppression (grade 3 or 4 anemia, 14%; and thrombocytopenia, 23%) and gastrointestinal disturbances (diarrhea, any grade, 72%; grade 3 or 4, 9%; nausea, grade 1 or 2 only, 50%; vomiting, grade 1 or 2 only, 27%). In conclusion, CEP-701 resulted in modest efficacy and mild but frequent gastrointestinal toxicity in MF patients. The study was registered at http://clinicaltrials.gov as NCT00494585.
The transcriptional programme of Salmonella enterica serovar Typhimurium reveals a key role for tryptophan metabolism in biofilms
Authors: Hamilton Shea , Bongaerts Roy JM , Mulholland Francis , Cochrane Brett , Porter Jonathan , Lucchini Sacha , Lappin-Scott Hilary M , Hinton Jay CD
Published: December 2009

Background

Biofilm formation enhances the capacity of pathogenic Salmonella bacteria to survive stresses that are commonly encountered within food processing and during host infection. The persistence of Salmonella within the food chain has become a major health concern, as biofilms can serve as a reservoir for the contamination of food products. While the molecular mechanisms required for the survival of bacteria on surfaces are not fully understood, transcriptional studies of other bacteria have demonstrated that biofilm growth triggers the expression of specific sets of genes, compared with planktonic cells. Until now, most gene expression studies of Salmonella have focused on the effect of infection-relevant stressors on virulence or the comparison of mutant and wild-type bacteria. However little is known about the physiological responses taking place inside a Salmonella biofilm.

Results

We have determined the transcriptomic and proteomic profiles of biofilms of Salmonella enterica serovar Typhimurium. We discovered that 124 detectable proteins were differentially expressed in the biofilm compared with planktonic cells, and that 10% of the S. Typhimurium genome (433 genes) showed a 2-fold or more change in the biofilm compared with planktonic cells. The genes that were significantly up-regulated implicated certain cellular processes in biofilm development including amino acid metabolism, cell motility, global regulation and tolerance to stress. We found that the most highly down-regulated genes in the biofilm were located on
S

almonella
P athogenicity I sland 2 (SPI2), and that a functional SPI2 secretion system regulator (ssrA) was required for S. Typhimurium biofilm formation. We identified STM0341 as a gene of unknown function that was needed for biofilm growth. Genes involved in tryptophan (trp) biosynthesis and transport were up-regulated in the biofilm. Deletion of trpE led to decreased bacterial attachment and this biofilm defect was restored by exogenous tryptophan or indole.

Conclusions

Biofilm growth of S. Typhimurium causes distinct changes in gene and protein expression. Our results show that aromatic amino acids make an important contribution to biofilm formation and reveal a link between SPI2 expression and surface-associated growth in S. Typhimurium.
The expressed needs of people with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A systematic review
Authors: Drachler Maria de Lourdes , Leite Jose Carlos de Carvalho , Hooper Lee , Hong Chia Swee , Pheby Derek , Nacul Luis , Lacerda Eliana , Campion Peter , Killett Anne , McArthur Maggie , Poland Fiona
Published: December 2009

Background

We aimed to review systematically the needs for support in managing illness and maintaining social inclusion expressed by people with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

Methods

We carried out a systematic review of primary research and personal ('own') stories expressing the needs of people with CFS/ME. Structured searches were carried out on Medline, AMED, CINAHL, EMBASE, ASSIA, CENTRAL, and other health, social and legal databases from inception to November 2007. Study inclusion, data extraction and risk of bias were assessed independently in duplicate. Expressed needs were tabulated and a conceptual framework developed through an iterative process.

Results

Thirty two quantitative and qualitative studies, including the views of over 2500 people with CFS/ME with mainly moderate or severe illness severity, met the inclusion criteria. The following major support needs emerged: 1) The need to make sense of symptoms and gain diagnosis, 2) for respect and empathy from service providers, 3) for positive attitudes and support from family and friends, 4) for information on CFS/ME, 5) to adjust views and priorities, 6) to develop strategies to manage impairments and activity limitations, and 7) to develop strategies to maintain/regain social participation.

Conclusions

Although the studies were heterogeneous, there was consistent evidence that substantial support is needed to rebuild lives. Gaining support depends - most importantly - on the ability of providers of health and social care, colleagues, friends and relatives, and those providing educational and leisure services, to understand and respond to those needs.
Breast cancer in kurdish women of northern Iraq: incidence, clinical stage, and case control analysis of parity and family risk
Authors: Majid Runnak A , Mohammed Hazha A , Saeed Heshu M , Safar Banaz M , Rashid Rekawt M , Hughson Michael D
Published: December 2009

Background

Breast cancer in the Middle-East occurs in relatively young women and frequently presents as advanced disease. A protective effect of multiparity is not apparent, and high familial risk is reported in some countries. This study investigates breast cancer rates and clinical stage related to age in the Kurdish region of Iraq and evaluates risk associated with parity and family history. Findings are compared with nearby countries and the West.

Methods

Sulaimaniyah Directorate of Health records identified 539 women diagnosed with breast cancer during 2006-2008. Clinical survey forms were completed on 296 patients and on 254 age-matched controls. Age specific incidence rates were calculated from Directorate of Health population estimates.

Results

Average patient age was 47.4 ± 11 years and 59.5% were pre-menopausal. Diagnosis was at clinical stage 1 for 4.1%, stage 2 for 43.5%, stage 3 for 26.0%, and stage 4 for 8.1% of patients. For 18.2%, stage was unknown. Annual breast cancer incidence rates per 100,000 women peaked at 168.9 at age 55 to 59 and declined to 57.3 at 60 and above. Patients had an average of 5.0 ± 3.3 children compared to 5.4 ± 3.5 for controls, P = 0.16. A first degree family member had breast cancer among 11.1% of patients and 2.1% of controls (P < 0.001) with > 50% of these patients and controls being ≥50 years old. No statistically significant relationship was found between tumor stage and age, P = 0.59.

Conclusions

In Kurdish Iraq, breast cancer is predominantly a disease of pre-menopausal women having multiple pregnancies. For younger patients, breast cancer incidence was similar to the West and possibly higher than many Middle-Eastern countries, but unlike the West, the estimated rates declined markedly in the elderly. The familial breast cancer risk for both older and younger women was within the general population risk of Western countries. Clinical stages were advanced and indicated delays in diagnosis that were unrelated to patient age.
Fall-related injuries in a nursing home setting: is polypharmacy a risk factor?
Authors: Baranzini Federico , Diurni Marcello , Ceccon Francesca , Poloni Nicola , Cazzamalli Sara , Costantini Chiara , Colli Cristiano , Greco Laura , Callegari Camilla
Published: December 2009

Background

Polypharmacy is regarded as an important risk factor for fallingand several studies and meta-analyses have shown an increased fall risk in users of diuretics, type 1a antiarrhythmics, digoxin and psychotropic agents. In particular, recent evidence has shown that fall risk is associated with the use of polypharmacy regimens that include at least one established fall risk-increasing drug, rather than with polypharmacy per se. We studied the role of polypharmacy and the role of well-known fall risk-increasing drugs on the incidence of injurious falls.

Methods

A retrospective observational study was carried out in a population of elderly nursing home residents. An unmatched, post-stratification design for age class, gender and length of stay was adopted. In all, 695 falls were recorded in 293 residents.

Results

221 residents (75.4%) were female and 72 (24.6%) male, and 133 (45.4%) were recurrent fallers. 152 residents sustained no injuries when they fell, whereas injuries were sustained by 141: minor in 95 (67.4%) and major in 46 (32.6%). Only fall dynamics (p = 0.013) and drugs interaction between antiarrhythmic or antiparkinson class and polypharmacy regimen (≥7 medications) seem to represent a risk association for injuries (p = 0.024; OR = 4.4; CI 95% 1.21 - 15.36).

Conclusion

This work reinforces the importance of routine medication reviews, especially in residents exposed to polypharmacy regimens that include antiarrhythmics or antiparkinson drugs, in order to reduce the risk of fall-related injuries during nursing home stays.