bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation and management of stroke
Authors: Cucchiara Brett L. 
Published: December 2009

AbstractIn contrast to myocardial infarction, stroke is a heterogeneous disease with multiple different causes. Determination of stroke mechanism is critical to choosing optimal therapy to prevent recurrence. This article reviews the diagnostic approach to stroke and prognostic and treatment implications of specific stroke mechanisms. Data on the role of antiplatelet and anticoagulant therapy in secondary stroke prevention, as well as the role of these agents and thrombolytic therapy in acute stroke treatment are reviewed. Situations of particular relevance to the practicing hematologist—stroke in the young, patients with multiple recurrent strokes, patients with abnormal hypercoagulable laboratory testing, and treatment of intracerebral hemorrhage following thrombolytic therapy—are discussed.
Darwin and evolutionary tales in leukemia
Authors: Greaves Mel 
Published: December 2009

AbstractAll cancers evolve by a process of genetic diversification and “natural selection” akin to the process first described by Charles Darwin for species evolution. The evolutionary, natural history of childhood acute lymphoblastic leukemia (ALL) is almost entirely covert, clinically silent and well advanced by the point of diagnosis. It has, however, been possible to backtrack this process by molecular scrutiny of appropriate clinical samples: (i) leukemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukemia; and (iii) stored, viable cord blood cells. These studies indicate prenatal initiation of leukemia by chromosome translocation and gene fusion (or hyperdiploidy) and the post-natal acquisition of multiple, gene copy number alterations (CNAs), mostly deletions. The prenatal or first “hit” occurs very commonly, exceeding the clinical rate of ALL by some 100× and indicating a low rate of penetrance or evolutionary progression. The acquisition of the critical, secondary CNAs requires some Darwinian selective advantage to expand numbers of cells at risk, and the cytokine TGF beta is able to exercise this function. The clonal architecture of ALL has been investigated by single cell analysis with multicolor probes to mutant genes. The data reveal not a linear sequence of mutation acquisition with clonal succession but rather considerable complexity with a tree-like or branching structure of genetically distinct subclones very reminiscent of Darwin’s original 1837 evolutionary divergence diagram. This evolutionary pattern has important implications for stem cells in ALL, for the origins of relapse and for therapeutic targeting.
The bridge between patient and doctor: the shift from CAM to integrative medicine
Authors: Diehl Volker 
Published: December 2009

Abstract
Integrative medicine (IM) has become a major challenge for doctors and nurses, as well as psychologists and many other disciplines involved in the endeavor to help patients to better tolerate the burden of toxic therapies and give patients tools so they can actively participate in their “salutogenesis.” IM encompasses psycho-oncology, acupuncture, and physical and mental exercises to restore vital capacities lost due to toxic therapies; furthermore, it aims to replenish nutritional and metabolic deficits during and after cancer treatment. IM gains an ever increasing importance in the face of the rapidly growing number of cancer survivors demanding more than just evidence-based diagnostic and therapeutic strategies. IM has to prove its value and justification by filling the gap between unproven methods of alternative medicine, still used by many cancer patients, and academic conventional medicine, which often does not satisfy the emotional and spiritual needs of cancer patients.
Clinical approach to marrow failure
Authors: Shimamura Akiko 
Published: December 2009

Abstract
The treatment and medical management of aplastic anemia fundamentally differ between patients with inherited versus acquired marrow failure; however, the diagnosis of an inherited bone marrow failure syndrome is frequently obscure. Recent exciting advances in our understanding of the molecular pathophysiology of the inherited bone marrow failure syndromes have resulted in a profusion of new tests to aid in diagnosis. This in turn has raised questions regarding the appropriate choice of testing for the patient presenting with aplastic anemia. Important clues to the diagnosis of an inherited marrow failure syndrome may be gleaned from careful attention to the clinical history, physical exam, and laboratory workup.
Telomeres and marrow failure
Authors: Calado Rodrigo T. 
Published: December 2009

AbstractTelomeres, repeat sequences at the ends of chromosomes, are protective chromosomal structures highly conserved from primitive organisms to humans. Telomeres inevitably shorten with every cell cycle, and telomere attrition has been hypothesized to be fundamental to normal senescence of cells, tissues, and organisms. Molecular mechanisms have evolved to maintain their length and protective function; telomerase (TERT) is a reverse transcriptase enzyme that uses an RNA molecule (TERC) as the template to elongate the 3′ ends of telomeres. Shelterin is a collection of DNA-binding proteins that cover and protect telomeres. The recent discovery of inherited mutations in genes that function to repair telomeres as etiologic in a range of human diseases, which have clinical manifestations in diverse tissues, including the hematopoietic tissue, suggests that defects in telomere repair and protection can cause organ failure. Dyskeratosis congenita is the prototype of telomere diseases; it is characterized by bone marrow failure, mucocutaneous abnormalities, pulmonary fibrosis, liver cirrhosis, and increased susceptibility to cancer, including acute myeloid leukemia. Aplastic anemia, acute myeloid leukemia, and idiopathic pulmonary fibrosis also are associated with inherited mutations in telomere repair or protection genes. Additionally, telomere defects associate with predisposition to hematologic malignancy and epithelial tumors. Telomere erosion is abnormally rapid in patients with mutations in telomerase genes but also after hematopoietic stem cell transplant, and telomeres are naturally shorter in older individuals—all conditions associated with higher rates of malignant diseases. In human tissue culture, short telomeres produce end-to-end chromosome fusion, nonreciprocal translocations, and aneuploidy.
Management of Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL)
Authors: Ottmann Oliver G. , Pfeifer Heike 
Published: December 2009

AbstractThe 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

AbstractOver 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

AbstractAcute 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

Abstract
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

AbstractFor 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

AbstractGiven 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

Abstract
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

AbstractABVD (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

AbstractAlthough 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

AbstractDespite 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

AbstractSurvival 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

AbstractPatients 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.