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.

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.

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.

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.

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.

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.

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.

Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria.

Although a classification for mastocytosis and diagnostic criteria are available, there remains a need to define standards for the application of diagnostic tests, clinical evaluations, and treatment responses. To address these demands, leading experts discussed current issues and standards in mastocytosis in a Working Conference. The present article provides the resulting outcome with consensus statements, which focus on the appropriate application of clinical and laboratory tests, patient selection for interventional therapy, and the selection of appropriate drugs. In addition, treatment response criteria for the various clinical conditions, disease-specific symptoms, and specific pathologies are provided. Resulting recommendations and algorithms should greatly facilitate the management of patients with mastocytosis in clinical practice, selection of patients for therapies, and the conduct of clinical trials.

Interobserver reliability of the Nail Psoriasis Severity Index.

BACKGROUND: Because the Psoriasis Area and Severity Index (PASI) does not consider the severity of nail disease, a scale that assesses the extent of involvement of psoriatic nails is needed. A new grading system, the Nail Psoriasis Severity Index (NAPSI) has been proposed. AIMS: The purpose of this study was to assess the interobserver reliability of NAPSI. Methods. The nail features of 25 patients with psoriasis with nail involvement were evaluated and graded by three dermatologists for total NAPSI scores and nail scores. The quadrants of all nails were examined for the presence of matrix and bed features. Total NAPSI score (0-160) of patients and nail score (0-32) of the individual nails were calculated. Interobserver reliability assessments were performed by computing intraclass correlation coefficients (ICC; two-way mixed model, consistency definition). RESULTS: The ICC((3,1)) results for total NAPSI score and nail score were found to be 0.781 and 0.649, respectively. The ICC((3,1)) for nail-bed and nail-matrix features were 0.869 and 0.584, respectively, in the total NAPSI scoring system, and 0.705 and 0.603, respectively, in the nail scoring system. CONCLUSION: Moderate to good agreement of scoring with the NAPSI was determined among the observers in this study. Our results suggest that scoring for nail-bed features seems to be more reliable than scoring for nail-matrix features.

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.

On the way to targeted therapy of mast cell neoplasms: identification of molecular targets in neoplastic mast cells and evaluation of arising treatment concepts.

Several emerging treatment concepts for myeloid neoplasms are based on novel drugs targeting cell surface antigens, signalling pathways, or critical effector molecules. Systemic mastocytosis is a haematopoietic neoplasm that behaves as an indolent myeloproliferative disease in most patients, but can also present as aggressive disease or even as an acute leukaemia. In patients with aggressive disease or mast cell leukaemia, the response to conventional therapy is poor in most cases, and the prognosis is grave. Therefore, a number of attempts have been made to define novel treatment strategies for these patients. One promising approach may be to identify novel targets and to develop targeted drug therapies. In this article, we support the notion that neoplastic mast cells indeed express a number of potential molecular targets including immunoreactive CD antigens, the microphthalmia transcription factor (MITF), and members of the Bcl-2 family. In addition, the tyrosine kinase receptor KIT and downstream signalling pathways have been proposed as targets of a specific pharmacological intervention. A particular challenge is the disease-related D816V-mutated variant of KIT, which is resistant against diverse tyrosine kinase inhibitors including STI571, but may be sensitive to more recently developed targeted compounds. The therapeutic potential of target-specific approaches in malignant mast cell disorders should be evaluated in forthcoming clinical trials in the near future.

Mastocytosis: current concepts in diagnosis and treatment.

Mastocytosis consists of a group of disorders characterized by a pathologic increase in mast cells in tissues including skin, bone marrow, liver, spleen, and lymph nodes. Mastocytosis is a rare disease. Because of this, general practitioners have limited exposure to its clinical manifestations, diagnosis, classification, and management. Diagnosis of mastocytosis is suspected on clinical grounds and is established by histopathologic examination of involved tissues such as skin and bone marrow. The most common clinical sign of mastocytosis is the presence of typical skin lesions of urticaria pigmentosa. Most patients experience symptoms related to mast cell mediator release, and prevention of the effects of these mediators on tissues constitutes the major therapeutic goal in the management of mastocytosis. Despite recent advances in knowledge about the pathophysiology, diagnosis, and classification of mastocytosis, a curative treatment for mastocytosis does not now exist. Management of patients within all categories of mastocytosis includes: (1) a careful counseling of patients (parents in pediatric cases) and care providers, (2) avoidance of factors triggering acute mediator release, (3) treatment of acute mast cell mediator release, (4) treatment of chronic mast cell mediator release, and if indicated (5) an attempt to treat organ infiltration by mast cells. The goal of this manuscript is to provide an overview of the mediators produced and released by mast cells, the diagnostic criteria for the different variants of mastocytosis, and the treatment options currently available.

The Kit-activating mutation D816V enhances stem cell factor--dependent chemotaxis.

The D816V mutation of c-kit has been detected in patients with mastocytosis. This mutation leads to constitutive tyrosine kinase activation of Kit. Because stem cell factor (SCF), the ligand for Kit (CD117(+)), is a chemoattractant for CD117(+) cells and one feature of mastocytosis is an abnormal collection of mast cells in tissues derived from CD34(+)CD117(+) mast cell precursors, the hypothesis was considered that the D816V mutation would enhance chemotaxis of these precursor cells. Constructs encoding wild-type Kit or Kit bearing the D816V mutation were transfected into Jurkat cells, labeled with Calcein-AM, and migration to SCF assessed in the presence or absence of tyrosine kinase inhibitors. Chemotaxis to SCF was enhanced in D816V transfectants compared to wild-type Kit transfectants (P <.002). Migration of both transfectants was inhibited by tyrosine kinase inhibitors, although D816V transfectants were more sensitive. Chemotaxis was next performed on CD34(+)CD117(+) circulating mast cell precursors obtained from patients with mastocytosis. Analysis of prechemotaxis and migrated cells showed that whereas less than 10% in the prechemotaxis sample had the D816V mutation, 40% to 80% of migrated cells had this mutation. These results demonstrate that the D816V Kit mutation enhances chemotaxis of CD117(+) cells, offering one explanation for increased mast cells observed in tissues of patients with mastocytosis. (Blood. 2001;98:1195-1199)

Association of the Q576R polymorphism in the interleukin-4 receptor alpha chain with indolent mastocytosis limited to the skin.

Gain-of-function mutations in c-kit, which appear to contribute to mast cell hyperplasia, have been detected in both limited and aggressive forms of mastocytosis, suggesting that other mutations or polymorphisms may contribute to the clinical phenotype. Because addition of interleukin-4 (IL-4) to mast cell cultures is reported to induce apoptosis, the hypothesis was considered that individuals carrying the gain-of-function polymorphism Q576R in the cytoplasmic domain of the alpha-subunit of the IL-4 receptor (IL-4R) might be relatively resistant to the gain-of-function mutation in c-kit. To assess this possibility, 36 patients with either cutaneous or systemic mastocytosis were studied for association with the Q576R polymorphism. The Q576R polymorphism was found more frequently in those with disease limited to skin and who exhibited lower levels of surrogate disease markers. These data suggest that the Q576R IL-4R alpha- chain polymorphism may mitigate disease expression and confer a better prognosis in patients with mastocytosis. (Blood. 2001;98:880-882)

Human mast cell apoptosis is regulated through Bcl-2 and Bcl-XL.

It is well established that human mast cell proliferation and maturation are regulated by kit ligand (stem cell factor). Little is known, however, about how these two processes are negatively regulated and thus, how mast cell number is controlled in normal and pathologic conditions. We therefore first hypothesized that SCF-dependent human mast cells would undergo programmed cell death (apoptosis) on removal of SCF as has been shown for growth factor-dependent rodent mast cells. We then examined whether SCF acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. As hypothesized, elimination of SCF from primary peripheral blood-derived human mast cell cultures resulted in a significant apoptotic process. During apoptosis, down-regulation of the two apoptosis-regulatory proteins Bcl-2 and Bcl-XL was observed. Moreover, a deregulated expression of these two proteins was found in two human mast cell lines which are SCF-independent. Thus, SCF functions as a survival factor by repressing apoptosis of human mast cells through Bcl-2 and Bcl-XL. Deregulated expression of these antiapoptotic proteins may contribute to proliferation and accumulation of mast cells in certain forms of systemic mast cell disorders.

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.

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.