bluuebunny/crossref_metadata_2025_split huggingface dataset:
Congenital neutropenia
Authors: Klein Christoph 
Published: December 2009

Abstract
Congenital neutropenia comprises a variety of genetically heterogeneous phenotypic traits. Molecular elucidation of the underlying genetic defects has yielded important insights into the physiology of neutrophil differentiation and function. Non-syndromic variants of congenital neutropenia are caused by mutations in ELA2, HAX1, GFI1, or WAS. Syndromic variants of congenital neutropenia may be due to mutations in genes controlling glucose metabolism (SLC37A4, G6PC3) or lysosomal function (LYST, RAB27A, ROBLD3/p14, AP3B1, VPS13B). Furthermore, defects in genes encoding ribosomal proteins (SBDS, RMRP) and mitochondrial proteins (AK2, TAZ) are associated with congenital neutropenia syndromes. Despite remarkable progress in the field, many patients with congenital neutropenia cannot yet definitively be classified by genetic terms. This review addresses diagnostic and therapeutic aspects of congenital neutropenia and covers recent molecular and pathophysiological insights of selected congenital neutropenia syndromes.
Alpha thalassemia major—new mutations, intrauterine management, and outcomes
Authors: Vichinsky Elliott P. 
Published: December 2009

AbstractAlpha thalassemia disorders are a group of hereditary anemias caused by absent or decreased production of the alpha chain of hemoglobin. Hemoglobin Bart’s hydrops fetalis is usually a fatal in-utero disease caused by absence of the alpha genes. However, the molecular and genotypic expression of hemoglobin Bart’s varies and increasing numbers of births are being reported. Population screening and prenatal diagnosis of at-risk couples is essential but often not performed. Most affected pregnancies are often undetected, resulting in severe fetal and maternal complications. Noninvasive monitoring by Doppler ultrasonagraphy with intrauterine transfusion therapy has changed the prognosis for this disorder. These advances in intrauterine and postnatal therapy have resulted in ethical dilemmas for the family and the provider.
The role of NOTCH1 signaling in T-ALL
Authors: Ferrando Adolfo A. 
Published: December 2009

AbstractThe identification of activating mutations in NOTCH1 in over 50% of T-cell acute lymphoblastic leukemias (T-ALL) has generated major interest in the elucidation of the mechanisms of transformation downstream of oncogenic NOTCH and in the targeting of the NOTCH signaling pathway in this disease. Small molecule γ-secretase inhibitors (GSIs) block NOTCH1 signaling in T-ALL lymphoblasts, yet the clinical development of GSIs has been held back by the development of gastrointestinal toxicity and their weak antileukemic effects against human T-ALL. However, new therapeutic strategies aiming to optimize the use of anti-NOTCH1 therapies for T-ALL, including combination therapies with molecularly targeted drugs and glucocorticoids, have started to emerge as a result of improved understanding of the molecular mechanisms that mediate the effects of GSIs in leukemic cells and the intestinal epithelium. This review focuses on the molecular basis of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 and clinical significance of NOTCH1 mutations in T-ALL.
Evolving paradigms in the therapy of Philadelphia chromosome–negative acute lymphoblastic leukemia in adults
Authors: Litzow Mark R. 
Published: December 2009

AbstractImportant studies challenging previous approaches to the treatment of adults with Philadelphia chromosome–negative acute lymphoblastic leukemia (ALL) have emerged in the past decade. Donor versus no donor comparisons of allogeneic transplant highlight a potent graft-versus-leukemia effect in ALL, and the application of reduced-intensity conditioning transplants may exploit this effect while reducing non-relapse mortality. The adoption of the use of pediatric intensity-type regimens in adolescents and young adults shows promise to improve outcomes in this population. New therapeutic targets such as mutations in NOTCH1 in T-cell ALL and CD22 in pre-B ALL are being exploited in clinical trials. The application of molecular techniques and flow cytometry to quantitate minimal residual disease will allow further stratification of patients by risk. Although the outcomes of adults with ALL lag behind the stunningly successful results seen in children, new paradigms and new discoveries bring hope that this disparity will steadily lessen.
Optimal induction and post-remission therapy for AML in first remission
Authors: Rowe Jacob M. 
Published: December 2009

AbstractApproximately 300,000 patients in the world are diagnosed annually with acute myeloid leukemia (AML). The median age at presentation has been steadily increasing over the past few decades and now is approaching 70 years. Although considerable progress has been made over the past 3 decades in the therapy of AML, two thirds of young adults still die of their disease. The therapy of AML, unlike acute lymphoblastic leukemia (ALL), is based on maximally tolerated induction and post-remission therapy, all given within a few months from diagnosis. While complete remission can be achieved in the majority of young patients, ultimate cure of the disease depends on disease eradication through the administration of post-remission therapy. This is most often done with intensive chemotherapy. Harnessing the immunologic effect of graft-versus-leukemia, as in allogeneic transplantation, has further improved the outcome for many patients. Treatment of older adults, representing the majority of patients with AML, remains quite unsatisfactory. While 40% to 50% can achieve a complete remission, less than 10% are long-term survivors, and the cure rate of older patients has only minimally improved over the past three decades. Significant progress in the treatment of this age group is urgently required. New and targeted agents have much promise, but a definitive clinical role for these has yet to be conclusively established.
Monoclonal B-cell lymphocytosis
Authors: Rawstron Andy C. 
Published: December 2009

AbstractThe incidence and presenting features of chronic lymphocytic leukemia (CLL) have changed significantly over the last century. Routine diagnostic techniques can now detect very low levels of CLL phenotype cells. Monoclonal B-cell lymphocytosis (MBL) is a relatively recent diagnostic category encapsulating individuals with an abnormal B-cell population but not meeting the diagnostic criteria for a B-cell malignancy. This review focuses on CLL-type MBL, which represents the majority of MBL cases identified in diagnostic laboratories. CLL-type MBL has a phenotype identical to CLL and shares the same chromosomal abnormalities even at the lowest levels detectable. Recent evidence suggests that the immunoglobulin gene usage plays a key role in whether the abnormal cells will develop in significant numbers. In most cases, CLL-type MBL is a stable condition with only 1% per year among those presenting for clinical attention developing progressive disease requiring treatment, although suppressed immune function may have a more significant impact on outcome.
State-of-the-art treatment of chronic lymphocytic leukemia
Authors: Hallek Michael 
Published: December 2009

AbstractThe last decade has produced rapid progress in the management of chronic lymphocytic leukemia (CLL). Fludarabine, bendamustine and two monoclonal antibodies, alemtuzumab and rituximab, have been approved by the European and/or American regulatory agencies. Several, novel monoclonal antibodies targeting CD20, CD23 or CD40, as well as drugs designed to interfere with proteins regulating the cell cycle, apoptotic machinery, or leukemic microenvironment (eg, flavopiridol, oblimersen, or lenalidomide), are currently being tested in clinical trials. Furthermore, the increased experience with reduced-intensity allogeneic progenitor cell transplantation allows offering this option to physically fit patients. In addition, new prognostic markers that may influence therapeutic decisions have been identified. This review attempts to summarize the current use of these different modalities in CLL therapy.
Asthma and sickle cell disease: two distinct diseases or part of the same process?
Authors: Field Joshua J. , DeBaun Michael R. 
Published: December 2009

Abstract
A physician diagnosis of asthma in children and adults with sickle cell disease (SCD) has been associated with increased rates of pain and acute chest syndrome (ACS) episodes and premature death. Despite the clinical significance of a doctor’s diagnosis of asthma in individuals with SCD, the criteria for a physician diagnosis of asthma are not well defined. Many features of asthma are common in individuals with SCD, including symptoms of wheezing, obstructive lung disease and airway hyper-responsiveness. However, it is not clear if these signs and symptoms of asthma reflect a physician diagnosis of asthma, or if these asthma features are related to SCD. Further complicating the diagnosis of asthma in children with SCD is the significant overlap in clinical manifestations between an asthma exacerbation and an ACS episode. Evidence supporting the concept that asthma and SCD are separate co-morbid conditions includes a similar prevalence of asthma between children with SCD and those in the general population and the observation that asthma is inherited in a familial pattern in the families of children with SCD. In contrast, there is significant evidence that asthma-like features may be associated with SCD without a diagnosis of asthma, including a higher than expected prevalence of airway hyper-responsiveness and obstructive lung disease. Regardless of whether SCD and asthma are distinct or overlapping co-morbid conditions, we recommend a systematic and complete evaluation of asthma when the diagnosis is suspected or when patients have multiple episodes of pain or ACS.
Monitoring disease response to tyrosine kinase inhibitor therapy in CML
Authors: Hughes Timothy P. , Branford Susan 
Published: December 2009

AbstractThe remarkable progress made in the treatment of chronic myeloid leukemia (CML) over the past decade has been accompanied by steady improvements in our capacity to accurately and sensitively monitor response to therapy. After the initial target of therapy, complete cytogenetic response (CCR), is achieved, peripheral blood BCR-ABL transcript levels measured by real-time quantitative reverse transcriptase PCR (RQ-PCR) define the subsequent response targets, major and complete molecular response (MMR and CMR). The majority of patients on first-line imatinib therapy achieve a “safe haven” defined as a confirmed MMR, but 20% to 30% stop imatinib due to intolerance and/or resistance. Many imatinib-resistant patients can be effectively treated with second generation tyrosine kinase inhibitors (TKIs), but the actual drug selected should be based on the resistance profile of each inhibitor, in addition to issues of tolerance and disease phase. The main purpose of monitoring response with cytogenetics and RQ-PCR is to identify patients likely to achieve better long-term outcome if they are switched early to second-line therapy, either another TKI or an allograft. Mutation screening is most valuable in cases of loss of response to imatinib or a second-line TKI, but there are other settings where a high yield of mutations may justify regular mutation screening.
The 2008 WHO classification of lymphomas: implications for clinical practice and translational research
Authors: Jaffe Elaine S. 
Published: December 2009

AbstractThe 4th edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues published in 2008 builds upon the success of the 2001 3rd edition; new entities are defined, and solutions for problematic categories are sought. Recent studies have drawn attention to the biological overlap between classical Hodgkin lymphoma (CHL) and diffuse large B-cell lymphomas (DLBCL). Similarly, there is a greater appreciation of the borderlands between Burkitt lymphoma and DLBCL. Strategies for the management of these borderline lesions are proposed. Additionally, age-specific and site-specific factors play an important role in the definition of several new entities, which also have biological underpinnings. Among the peripheral T-cell lymphomas (PTCL), more precise definitions were introduced for several entities, including anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. Several new variants of primary cutaneous T-cell lymphomas are proposed. Finally, the subclassification and categorization of the most common lymphoma subtypes, follicular lymphoma (FL) and DLBCL, were altered to enhance diagnostic accuracy and aid in clinical management. The 2008 WHO classification also draws attention to early events in lymphomagenesis. These lesions help delineate the earliest steps in neoplastic transformation and generally mandate a conservative therapeutic approach. The 2001 classification was rapidly adopted for clinical trials and successfully served as a common language for scientists comparing genetic and functional data. The modifications made in the 2008 classification are the result of this successful partnership among pathologists, clinicians, and biologists, but are only a stepping stone to the future.
Current treatment standards and emerging strategies in mantle cell lymphoma
Authors: Dreyling Martin , Hiddemann Wolfgang ,   for The European MCL Network
Published: December 2009

AbstractMantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphomas characterized by the chromosomal translocation t(11;14)(q13;q32) and nuclear cyclin D1 overexpression in the vast majority of cases. Most patients present with advanced stage disease, often with extranodal dissemination, and pursue an aggressive clinical course in the majority of cases. Recent improvement has been achieved by the successful introduction of monoclonal antibodies and dose-intensified approaches including autologous stem cell transplantation (ASCT) strategies. With the exception of allogeneic hematopoietic stem cell transplantation, current treatment approaches are non-curative and the corresponding survival curves are characterized by a delayed, but continuous decline and a median survival of 4 to 6 years. However, recently a subset (15%) of long-term survivors have been identified with a rather indolent clinical course even after conventional treatment strategies only. Emerging strategies such as proteasome inhibitors, IMIDs, mTOR inhibitors and others are based on the dysregulated control of cell cycle machinery and impaired apoptotic pathways. Monotherapy of these compounds achieves efficacy comparable to conventional chemotherapy in relapsed MCL, and combination strategies are currently being investigated in numerous trials; however, their introduction into clinical practice and current treatment algorithms remains a challenge.
Transplantation in adult ALL
Authors: Goldstone Anthony H. , Rowe Jacob M. 
Published: December 2009

AbstractThe value of the allogeneic graft-versus-leukemia effect in adult acute lymphoblastic leukemia (ALL) has now been conclusively demonstrated and confirmed. While this is true for adults in all age groups, it may not be the best clinical option for young adults for whom increasingly intensive pediatric protocols are clearly of benefit. On the other hand, there is potentially wider applicability of allogeneic donor transplantation for adults 25 to 45 years old, for whom matched unrelated donors may be as safe and effective as sibling donors, and for the patient older than 45 years for whom reduced-intensity conditioning may be a promising way forward.Since the treatment-related mortality of allogeneic transplantation remains significant, careful selection of patients is mandatory. Patients with the Philadelphia chromosome, those with t(4;11) and those with a complex karyotype remain transplant candidates, and allogeneic transplantation remains the best option for salvage, where achievable, in a remission beyond first.As in childhood ALL minimal residual disease studies may be extremely useful in predicting outcome and, therefore, strategy, but at present there are less definite data in adults. Clinical indications to harness the allogeneic effect will mature as the true value of pediatric protocols in adult patients and the safety and efficacy of a sibling, unrelated and reduced intensity transplant emerge in this disease.
Allotransplantation for chronic lymphocytic leukemia
Authors: Dreger Peter 
Published: December 2009

AbstractEfforts to develop curative treatment strategies for chronic lymphocytic leukemia (CLL) in recent years have focused on allogeneic stem cell transplantation (alloSCT). The crucial anti-leukemic principle of alloSCT in CLL appears to be the immune-mediated anti-host activities conferred with the graft (graft-versus-leukemia effects, GVL). Evidence for GVL in CLL is provided by studies analyzing the kinetics of minimal residual disease on response to immune modulation after transplantation, suggesting that GVL can result in complete and durable suppression of the leukemic clone. AlloSCT from matched related or unrelated donors can overcome the treatment resistance of poor-risk CLL, ie, purine analogue refractory disease and CLL with del 17p-. Even with reduced-intensity conditioning, alloSCT in CLL is associated with significant mortality and morbidity due to graft-versus-host disease, which has to be weighed against the risk of the disease when defining the indication for transplantation. Therefore, it can be regarded as a reasonable treatment option only for eligible patients who fulfill accepted criteria for poor-risk disease. If alloSCT is considered, it should be performed before CLL has advanced to a status of complete refractoriness to assure an optimum chance for a successful outcome. Prospective trials are underway to prove whether allo-SCT can indeed change the natural history of poor-risk CLL.
Allogeneic stem cell transplantation in follicular lymphoma: recent progress and controversy
Authors: van Besien Koen 
Published: December 2009

Abstract
Allogeneic stem cell transplantation (allo HCT) is a curative treatment for follicular lymphoma, but is hampered by a relatively high treatment-related mortality and by difficulties in identifying high-risk groups for whom transplant is warranted. Results with myeloablative conditioning have improved, but the field has shifted largely to reduced-intensity conditioning and non-myeloablative transplantation, though morbidity and mortality are also substantial. Some groups have investigated T cell–depleted transplantation, which results in a low rate of chronic graft-versus-host disease (GVHD) and, in most studies, excellent rates of disease control. Overall, outcome after alloHCT for follicular lymphoma correlates more with disease status, with performance status and with comorbidities than with any particular conditioning regimen used. For patients with chemotherapy-sensitive disease, the treatment-related mortality has stabilized in the 15% to 20% range and, depending on the method of GVHD prophylaxis and the donor type, there is an additional 20% to 60% incidence of chronic GVHD. For patients with chemotherapy-refractory disease, both treatment-related mortality and recurrence rates are much higher, but their prognosis is dismal with other treatments and some may be cured, particularly with myeloablative transplants. Ongoing studies focus on improving conditioning regimens, on prevention of disease recurrence and on decreasing chronic GVHD.
Therapeutic potential of JAK2 inhibitors
Authors: Verstovsek Srdan 
Published: December 2009

AbstractThe discovery of an activating tyrosine kinase mutation JAK2V617F in myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has resulted in the development of JAK2 inhibitors, of which several are being evaluated in phase I/II clinical studies. It is important to recognize that because the V617F mutation is localized in a region outside the adenosine triphosphate (ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase (like the current JAK2 inhibitors in the clinic) are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme. While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones. On the other hand, JAK inhibitors may have great therapeutic benefit by controlling the disease for patients with MPNs who suffer from debilitating signs (eg, splenomegaly) or constitutional symptoms (which presumably result from high levels of circulating cytokines that signal through JAK enzymes). Indeed, the primary clinical benefits observed so far in MF patients have been significant reduction is splenomegaly, elimination of debilitating disease-related symptoms, and weight gain. Most importantly, patients with and without the JAK2V617F mutation appear to benefit to the same extent. In this review we summarize current clinical experience with JAK2 inhibitors in MPNs.
The changing classification of myelodysplastic syndromes: what’s in a name?
Authors: Steensma David P. 
Published: December 2009

AbstractWhat is the most sensible way of organizing the disorderly spectrum of acquired marrow failure states collectively known as the myelodysplastic syndromes (MDS)? While the 2008 version of the World Health Organization classification is the current standard, the recent proliferation of MDS prognostic tools illustrates the usefulness of supplemental information for clinical purposes. Many cases of acquired bone marrow failure do not fit cleanly into established MDS categories, yet an alternative diagnosis is not apparent. The term “idiopathic cytopenias of undetermined significance” (ICUS) has been proposed to describe these cases, but there is a paucity of information about the natural history of ICUS. New data on the natural history of MDS associated with a broad range of cytogenetic abnormalities that were not included in the International Prognostic Scoring System (IPSS), as well as the emerging picture of karyotypically occult DNA changes, promise to inform future classifications.