Midostaurin: a magic bullet that blocks mast cell expansion and activation.

Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediator-related symptoms, and organ damage resulting from mast cell (MC) infiltration in advanced forms of SM. Regardless of the SM variant, expansion of neoplastic MC in the skin and other organs is triggered by mutant forms of KIT, the most prevalent being D816V. Activation of MC with subsequent release of chemical mediators is often caused by IgE-dependent mechanisms in these patients. Midostaurin, also known as PKC412, blocks the kinase activity of wild-type KIT and KIT D816V, counteracts KIT-dependent growth of neoplastic MC, and inhibits IgE-dependent mediator secretion. Based on this activity-profile, the drug has been used for treatment of patients with advanced SM. Indeed, encouraging results have been obtained with the drug in a recent multi-center phase II trial in patients with advanced SM, with an overall response rate of 60% and a substantial decrease in the burden of neoplastic MC in various organs. Moreover, midostaurin improved the overall survival and relapse-free survival in patients with advanced SM compared with historical controls. In addition, midostaurin was found to improve mediator-related symptoms and quality of life, suggesting that the drug may also be useful in patients with indolent SM suffering from mediator-related symptoms resistant to conventional therapies or those with MC activation syndromes. Ongoing and future studies will determine the actual value of midostaurin-induced MC depletion and MC deactivation in these additional indications.

Preoperative anxiety and postoperative pain in patients undergoing septoplasty.

OBJECTIVE: The aim of the study was to determine whether psychological variables such as preoperative anxiety could serve as predictors of the postoperative pain response. METHODS: Sixty consecutive patients with deviated nasal septum were evaluated in the pre- and postoperative periods. A questionnaire that included sociodemographic features was administered to patients. Preoperative anxiety was assessed by the Spielberger State-Trait Anxiety Index. The severity of pain was recorded with a ten-point Visual Analog Scale at the immediate postoperative period (baseline) and at postoperative hours 2, 4, 6, 12, and 24. RESULTS: Sixty patients met the eligibility criteria for the study. Of the 60 patients (39 men and 21 women) whose charts were reviewed, the mean age was 30.9 ± 12.6 years for men and 32.8 ± 10.4 years for women. The mean State-Trait Anxiety Index score was 44.3 ± 7.5 (range 29-67). No significant relationship was found between the patients' self-reports of postoperative pain and sociodemographic variables such as age and educational status. Men and women showed significant differences with respect to pain in the immediate and late postoperative periods. Correlation tests identified a significant relationship between patients' preoperative anxiety and postoperative pain in both the immediate and late periods. CONCLUSIONS: The results of this study suggest that early interventions to minimize the preoperative anxiety stress response may affect the postoperative pain response.

Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal.

Mast cell leukemia (MCL), the leukemic manifestation of systemic mastocytosis (SM), is characterized by leukemic expansion of immature mast cells (MCs) in the bone marrow (BM) and other internal organs; and a poor prognosis. In a subset of patients, circulating MCs are detectable. A major differential diagnosis to MCL is myelomastocytic leukemia (MML). Although criteria for both MCL and MML have been published, several questions remain concerning terminologies and subvariants. To discuss open issues, the EU/US-consensus group and the European Competence Network on Mastocytosis (ECNM) launched a series of meetings and workshops in 2011-2013. Resulting discussions and outcomes are provided in this article. The group recommends that MML be recognized as a distinct condition defined by mastocytic differentiation in advanced myeloid neoplasms without evidence of SM. The group also proposes that MCL be divided into acute MCL and chronic MCL, based on the presence or absence of C-Findings. In addition, a primary (de novo) form of MCL should be separated from secondary MCL that typically develops in the presence of a known antecedent MC neoplasm, usually aggressive SM (ASM) or MC sarcoma. For MCL, an imminent prephase is also proposed. This prephase represents ASM with rapid progression and 5%-19% MCs in BM smears, which is generally accepted to be of prognostic significance. We recommend that this condition be termed ASM in transformation to MCL (ASM-t). The refined classification of MCL fits within and extends the current WHO classification; and should improve prognostication and patient selection in practice as well as in clinical trials.

Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis.

Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator-related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator-related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25-30 ng/ml) and/or (iii) other clinical or laboratory features suggest the presence of 'occult' mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis or another haematopoietic disease, no BM investigation is required, but the clinical course and tryptase levels are monitored in the follow-up. In paediatric patients, a BM investigation is usually not required, even if the tryptase level is increased. Although validation is required, it can be expected that the algorithm proposed herein will facilitate the management of patients with suspected mastocytosis and help avoid unnecessary referrals and investigations.

Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders.

KIT is a member of the tyrosine kinase family of growth factor receptors which is expressed on a variety of haematopoietic cells including mast cells. Stem cell factor (SCF)-dependent activation of KIT is critical for mast cell homeostasis and function. However, when KIT is inappropriately activated, accumulation of mast cells in tissues results in mastocytosis. Such dysregulated KIT activation is a manifestation of specific activating point mutations within KIT, with the human D816V mutation considered as a hallmark of human systemic mastocytosis. A number of other activating mutations in KIT have recently been identified and these mutations may also contribute to aberrant mast cell growth. In addition to its role in mast cell growth, differentiation and survival, localized concentration gradients of SCF may control the targeting of mast cells to specific tissues and, once resident within these tissues, mast cell activation by antigen may also be amplified by SCF. Thus, KIT inhibitors may have potential application in multiple conditions linked to mast cells including systemic mastocytosis, anaphylaxis, and asthma. In this review, we discuss the role of KIT in the context of mast cells in these disease states and how recent advances in the development of inhibitors of KIT activity and function may offer novel therapies for the treatment of these disorders.

Proposed diagnostic criteria and classification of basophilic leukemias and related disorders.

Basophils form a distinct cell lineage within the hematopoietic cell family. In various myeloid neoplasms, including chronic myeloid leukemia, basophilia is frequently seen. Acute and chronic basophilic leukemias, albeit rare, have also been described. However, no generally accepted criteria and classification of basophilic leukemias have been presented to date. To address this unmet need, a series of Working Conferences and other meetings were organized between March 2015 and March 2016. The current article provides a summary of consensus statements from these meetings, together with proposed criteria to delineate acute basophilic leukemia (ABL) from chronic basophilic leukemia (CBL) and primary forms of the disease where no preceding myeloid malignancy is detected, from the more common 'secondary' variants. Moreover, the term hyperbasophilia (HB) is proposed for cases with a persistent peripheral basophil count ⩾1000 per µl of blood. This condition, HB, is highly indicative of the presence of an underlying myeloid neoplasm. Therefore, HB is an important checkpoint in the diagnostic algorithm and requires a detailed hematologic investigation. In these patients, an underlying myeloid malignancy is often found and is then labeled with the appendix -baso, whereas primary cases of ABL or CBL are very rare. The criteria and classification proposed in this article should facilitate the diagnosis and management of patients with unexplained basophilia and basophil neoplasms in routine practice, and in clinical studies.

Pathogenesis, clinical features, and treatment advances in mastocytosis.

Systemic mastocytosis (SM) is characterized by the abnormal growth and accumulation of mast cells (MC) in one or more organs. The interaction between the cytokine stem cell factor (SCF) and its cognate receptor, the c-kit receptor tyrosine kinase (KIT), plays a central role in regulating MC growth and differentiation. Whereas germline and somatically acquired activating mutations of KIT have been identified in SM, the issue as to whether individual KIT mutation(s) are necessary and sufficient to cause MC transformation remains unclear based on currently available data. Activating mutations of platelet-derived growth factor receptor-alpha (FIP1 L1-PDGFRA) are identified in a significant number of SM cases that have associated eosinophilia. To date, as with gastrointestinal stromal tumors, activating mutations of KIT and PDGFRA appear to be alternative and mutually exclusive genetic events in SM. The World Health Organization has specified criteria for classification of SM into six major subtypes: cutaneous mastocytosis, indolent systemic mastocytosis (ISM), systemic mastocytosis with an associated clonal hematological non-mast-cell disorder (SM-AHNMD), aggressive systemic mastocytosis (ASM), mast cell leukemia, and mast cell sarcoma. The ability to molecularly classify individual SM cases based on the presence or absence of specific mutations allows for molecularly targeted therapy in a growing number of cases. Imatinib mesylate therapy might result in complete remission of SM cases with wild-type KIT, certain KIT mutations, such as F522C, or the FIP1L1-PDGFRA fusion gene, but not of D816V-KIT-bearing SM. For the latter, interferon-alpha and 2-CdA are potential first- and second-line therapeutic options. Other drugs under investigation include novel tyrosine kinase inhibitors, as well as NF-kappaB inhibitors, which might display greater selectivity towards D816V-KIT as compared to wild type KIT. The pathogenesis of mastocytosis, its major clinical subtypes, and recent treatment advances are discussed in this chapter.

A pilot study of nonmyeloablative allogeneic hematopoietic stem cell transplant for advanced systemic mastocytosis.

Systemic mastocytosis (SM) is a disease characterized by tissue infiltration of neoplastic mast cells originating from hematopoietic stem cells. Patients with advanced SM have a poor prognosis, and there is no mast cell ablative therapy available for most patients who carry an activating point mutation in the c-kit gene. We report results of a prospective study evaluating the safety, engraftment, and possibility of inducing a graft-versus-mast cell (GvMC) effect after allogeneic nonmyeloablative hematopoietic cell transplantation (HCT) from an HLA-identical sibling. Three patients with advanced SM were transplanted. All achieved complete donor T cell chimerism followed by clinical evidence for GvMC effect. However, all patients experienced disease progression with the longest response duration of 39 months. The GvMC effect can be observed after nonmyeloablative HCT with limited efficacy. Effective cytoreductive therapy prior to HCT may be required for long-term disease control and cure.

Analysis of the surface expression of c-kit and occurrence of the c-kit Asp816Val activating mutation in T cells, B cells, and myelomonocytic cells in patients with mastocytosis.

OBJECTIVE: The Asp816Val c-kit activating mutation is detectable in the peripheral blood cells of some patients with mastocytosis and in lesional skin biopsies obtained from adult patients with urticaria pigmentosa. These observations led to the conclusion that this mutation is present in mast cells and mast cell precursors that express c-kit. However, the distribution of the Asp816Val mutation among hematopoietic lineages is unknown. To determine the distribution of the Asp816Val mutation among hematopoietic lineages and to explore its relationship to clinical disease, we examined cells bearing differentiation markers for myelomonocytic cells as well as T and B lymphocytes, in both peripheral blood and bone marrow obtained from patients with mastocytosis. MATERIALS AND METHODS: The presence of Asp816Val c-kit mutation in cells magnetically sorted from peripheral blood or bone marrow according to surface differentiation markers was studied by reverse transcriptase polymerase chain reaction (RT-PCR) restriction fragment length polymorphism (RFLP) analysis. The surface expression of c-kit was determined by flow cytometry. RESULTS: The mutation was detectable by RT-PCR in at least one cell lineage in the bone marrow in 7 of 7 patients examined and in the peripheral blood of 11 of 11 adult patients with urticaria pigmentosa and indolent disease. The mutation was identified most frequently in B cells and myeloid cells. Flow cytometric analysis demonstrated that the differentiated cells expressing mutated c-kit were negative for surface KIT. CONCLUSION: These results are consistent with the conclusion that the c-kit Asp816Val mutation occurs in an early progenitor cell and is carried by myelomonocytic cells, T cells, and B cells in addition to mast cells. However, unlike mast cells, these myelomonocytic cells, T cells, and B cells do not concomitantly express surface c-kit and thus may be less susceptible to the effects of this mutation.

KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis.

Although acquired mutations in KIT are commonly detected in various categories of mastocytosis, the methodologies applied to detect and quantify the mutant type and allele burden in various cells and tissues are poorly defined. We here propose a consensus on methodologies used to detect KIT mutations in patients with mastocytosis at diagnosis and during follow-up with sufficient precision and sensitivity in daily practice. In addition, we provide recommendations for sampling and storage of diagnostic material as well as a robust diagnostic algorithm. Using highly sensitive assays, KIT D816V can be detected in peripheral blood leukocytes from most patients with systemic mastocytosis (SM) that is a major step forward in screening and SM diagnosis. In addition, the KIT D816V allele burden can be followed quantitatively during the natural course or during therapy. Our recommendations should greatly facilitate diagnostic and follow-up investigations in SM in daily practice as well as in clinical trials. In addition, the new tools and algorithms proposed should lead to a more effective screen, early diagnosis of SM and help to avoid unnecessary referrals.

Stimulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) production and its role as an autocrine inducer of CD14 upregulation in human myeloid leukemia cells.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that takes part in the growth and differentiation of normal and leukemic hematopoietic cells. Because of its potential significance in the etiopathogenesis of myeloid leukemia, we have studied the extracellular stimuli leading to GM-CSF secretion from a human myeloid leukemia cell line, K-562, and have demonstrated an important role for the cytokine in the differentiation process of this cell line. TNF-alpha, IL-1 beta, phorbol ester (PMA), and calcium ionophore A23187 were found to stimulate GM-CSF production from K-562 cells. PMA caused the cells to differentiate into megakaryocytic lineage, whereas treatment with A23187 resulted in increased expression of monocyte/macrophage marker CD14. Neutralization of the GM-CSF activity in the culture medium, as well as blocking of its receptors, resulted in suppression of the increase in CD14 expression and partially restored the proliferative capacity in cells exposed to A23187. Autocrine GM-CSF secretion did not appear to play an important role in PMA-induced megakaryocytic differentiation. These results suggest that autocrine GM-CSF secretion may be associated with differentiation of myeloid leukemic cells without any significant growth stimulatory activity.

Inhibition of murine splenic T lymphocyte proliferation by 2-deoxy-D-glucose-induced metabolic stress.

Female Swiss-Webster mice were injected with the glucose analogue 2-deoxy-D-glucose (2-DG), which when administered to rodents induces acute periods of metabolic stress. A single or multiple injections of 2-DG invoked a stress response, as evidenced by increases in serum corticosterone levels. The influence of this metabolic stressor on the blastogenic potential of splenic T lymphocytes was then examined. It was found that one, two, or three injections of 2-DG resulted in depressed T cell proliferative responses, with an attenuation of the effect occurring by the fifth injection. The 2-DG-induced inhibition of T cell proliferation was not attributable to 2-DG-induced cytolysis, as in vitro incubation of naive T cells with varying concentrations of 2-DG did not result in a reduction in cell number or viability, and flow cytometric analysis demonstrated that percentages of CD3, CD4, and CD8 splenic T cells were not altered as a result of 2-DG-induced stress. Incubating naive T cells in varying concentrations of 2-DG resulted in a dose-dependent inhibition of T cell blastogenic potential. Following in vivo exposure to 2-DG, T cell proliferation did not return to normal levels until 3 days after the cessation of 2-DG injections. Administering the beta-adrenergic receptor antagonist propranolol did not reverse the inhibited lymphoproliferation in 2-DG-treated mice. The inhibition in T cell proliferation was not observed, however, in mice that had been adrenalectomized or hypophysectomized and injected with 2-DG.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of transferrin receptor expression by insulin and granulocyte-macrophage colony stimulating factor in AML-193 leukemic cells.

The effects of insulin and granulocyte-macrophage colony stimulating factor (GM-CSF) on the expression of transferrin receptors in AML-193 myeloid leukemia cell line were investigated. Insulin, alone or in combination with GM-CSF, caused an increase in surface transferrin receptors within 5 min. This increase was inhibited by hyperosmolarity but not by cycloheximide suggesting the involvement of receptor recycling from internal pools. In contrast, receptor increase after 18 h of incubation with insulin and GM-CSF was sensitive to cycloheximide indicating that long term effects of these growth factors are mediated through protein synthesis. These results may have implications on combined GM-CSF + antitransferrin receptor antibody therapy of leukemias.

Mastocytosis: molecular mechanisms and clinical disease heterogeneity.

Systemic mastocytosis has one unifying feature: an unexplained and pathologic increase in mast cells in specific tissues. This observation, along with clinical disease heterogeneity has long suggested that mastocytosis is a disease of complex etiology. At the same time, the last decade has witnessed significant progress in identifying the critical elements that regulate mast cell growth and development. Human mast cells are now known to arise from CD34(+) progenitors, particularly under the influence of stem cell factor (SCF). This information in turn led to the critical observation that a substantial number of patients with mastocytosis exhibit activating mutations in c-kit, the receptor for SCF. And while this observation may well be key in understanding mastocytosis, this mutation alone does not explain all heterogeneity. It now appears that other influences such as genetic polymorphisms within the host may influence the course of disease in those with KIT mutations; and that the search for additional molecular events capable of creating disease diversity must continue.

Slowly progressive systemic mastocytosis with high mast-cell burden and no evidence of a non-mast-cell hematologic disorder: an example of a smoldering case?

A 43-year-old man with extensive systemic mastocytosis with poor prognostic indicators but no overt hematologic abnormality is described. This patient's clinical presentation and course are consistent with the newly proposed 'smoldering mastocytosis' category. Long-term follow-up of patients is needed to determine whether they may be at higher risk for progression into more aggressive categories.

Diagnostic criteria and classification of mastocytosis: a consensus proposal.

The term 'mastocytosis' denotes a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MC) in one or more organ systems. Over the last 20 years, there has been an evolution in accepted classification systems for this disease. In light of such developments and novel useful markers, it seems appropriate now to re-evaluate and update the classification of mastocytosis. Here, we propose criteria to delineate categories of mastocytosis together with an updated consensus classification system. In this proposal, the diagnosis cutaneous mastocytosis (CM) is based on typical clinical and histological skin lesions and absence of definitive signs (criteria) of systemic involvement. Most patients with CM are children and present with maculopapular cutaneous mastocytosis (=urticaria pigmentosa, UP). Other less frequent forms of CM are diffuse cutaneous mastocytosis (DCM) and mastocytoma of skin. Systemic mastocytosis (SM) is commonly seen in adults and defined by multifocal histological lesions in the bone marrow (affected almost invariably) or other extracutaneous organs (major criteria) together with cytological and biochemical signs (minor criteria) of systemic disease (SM-criteria). SM is further divided into the following categories: indolent systemic mastocytosis (ISM), SM with an associated clonal hematologic non-mast cell lineage disease (AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL). Patients with ISM usually have maculopapular skin lesions and a good prognosis. In the group with associated hematologic disease, the AHNMD should be classified according to FAB/WHO criteria. ASM is characterized by impaired organ-function due to infiltration of the bone marrow, liver, spleen, GI-tract, or skeletal system, by pathologic MC. MCL is a 'high-grade' leukemic disease defined by increased numbers of MC in bone marrow smears (>or=20%) and peripheral blood, absence of skin lesions, multiorgan failure, and a short survival. In typical cases, circulating MC amount to >or=10% of leukocytes (classical form of MCL). Mast cell sarcoma is a unifocal tumor that consists of atypical MC and shows a destructive growth without (primary) systemic involvement. This high-grade malignant MC disease has to be distinguished from a localized benign mastocytoma in either extracutaneous organs (=extracutaneous mastocytoma) or skin. Depending on the clinical course of mastocytosis and development of an AHNMD, patients can shift from one category of MC disease into another. In all categories, mediator-related symptoms may occur and may represent a serious clinical problem. All categories of mastocytosis should be distinctively separated from reactive MC hyperplasia, MC activation syndromes, and a more or less pronounced increase in MC in myelogenous malignancies other than mastocytosis. Criteria proposed in this article should be helpful in this regard.

Mastocytosis complicating pregnancy.

OBJECTIVE: To review the experience of women who conceived after developing mastocytosis and who were observed at the National Institutes of Health. METHODS: We reviewed our patient database for the years 1984-1998 to identify women with mastocytosis who had conceived. We then reviewed each woman's record, asked each woman to complete a questionnaire, and with permission wrote outside hospitals to obtain records of each labor and delivery. RESULTS: We identified eight women who had become pregnant. These women delivered a total of 11 live infants. In approximately a third of the pregnancies, patients experienced worsening of symptoms. They often used fewer medications during pregnancy because of safety concerns, and no greater incidence of adverse reactions was noted. Antihistamines were used most commonly, followed by oral prednisone. Medications used during delivery were well tolerated and included epidural analgesics. Neonates were generally healthy. None to date have developed urticaria pigmentosa or systemic mastocytosis. CONCLUSION: A subset of women with mastocytosis might have had exacerbated mastocytosis during and after pregnancy, but labor and delivery progressed normally. Infants were born generally healthy and were without mastocytosis. Thus there appears to be no absolute contraindication to pregnancy for women with mastocytosis, although women should be aware that the choice to have a child is not without some added risk.

Developing the Guide to Community Preventive Services--overview and rationale. The Task Force on Community Preventive Services.

When the GUIDE TO COMMUNITY PREVENTIVE SERVICES: Systematic Reviews and Evidence-Based Recommendations (the Guide) is published in 2001, it will represent a significant national effort in encouraging evidence-based public health practice in defined populations (e.g., communities or members of specific managed care plans). The Guide will make recommendations regarding public health interventions to reduce illness, disability, premature death, and environmental hazards that impair community health and quality of life. The Guide is being developed under the guidance of the Task Force on Community Preventive Services (the Task Force)-a 15-member, nonfederal, independent panel of experts. Subject matter experts, methodologists, and scientific staff are supporting the Task Force in using explicit rules to conduct systematic literature reviews of evidence of effectiveness, economic efficiency, and feasibility on which to base recommendations for community action. Contributors to the Guide are building on the experience of others to confront methodologic challenges unique to the assessment of complex multicomponent intervention studies with nonexperimental or nonrandomized designs and diverse measures of outcome and effectiveness. Persons who plan, fund, and implement population-based services and policies to improve health at the state and local levels are invited to scrutinize the work in progress and to communicate with contributors. When the Guide is complete, readers are encouraged to consider critically the value and relevance of its contents, the implementation of interventions the Task Force recommends, the abandonment of interventions the Task Force does not recommend, and the need for rigorous evaluation of the benefits and harms of promising interventions of unknown effectiveness.

Prolymphocytic leukemia: diagnosis and treatment. A case report.

A patient with B-cell prolymphocytic leukemia (PLL) who has had a prolonged survival is presented. The patient was diagnosed incidentally while asymptomatic, but later developed progressive disease. He was refractory to alkylating agents and fludarabine, but responded to treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone. This patient's prolonged survival may be due partly to his diagnosis at an indolent phase, possibly representing the early phase of the natural course of the disease. Diagnosis, clinical course, and treatment options for PLL are discussed.