W R Sperr

..The serum tryptase level is used as a diagnostic marker in mastocytosis and is considered to reflect the burden of (neoplastic) mast cells (MC)...

..Karyotype-based multiparameter systems appear to be particularly effective in defining MDS patients who are at high risk of transforming to leukemia...

..Blast cell persistence or regrowth was associated with a persistently elevated level or recurrent increase of tryptase. Together, tryptase is expressed in myeloblasts in a group of AML and may serve as a useful disease-related marker...

..No general guidelines for the treatment of patients with SM-AHNMD have been established so far. A reasonable straightforward approach may be to treat the AHNMD in those patients in the same way as if no coexisting SM exists...

..We hypothesize that tryptase-positive AMLs arise from a leukemic progenitor that exhibits a limited potential to differentiate into mast cells and/or basophils...

..In the present article, the concomitant occurrence of mastocytosis and leukemia is discussed in the light of the literature and of concepts proposed to explain the biologic basis of this phenomenon...

..Whether such autoantibodies are recurrently produced in patients with Schnitzler's syndrome and play a role in the pathophysiology of the disease remains to be determined...

..The therapeutic efficiency and toxicity-profiles of these novel drugs are currently under investigation in clinical trials...

..The present article gives an overview of our knowledge about AML stem cells, their phenotype, and their role as a 'therapy-target' in new concepts to treat and to cure patients with AML...

..In addition, serum tryptase levels appear to correlate with MDS variants. Follow up studies should clarify whether an elevated tryptase concentration in MDS is of prognostic significance...

..High-dose intermittent cytarabine is an effective postremission treatment for patients with acute myeloid leukemia (AML). This regimen is a safe approach in patients < 60 years but produced severe neurotoxicity in the elderly...

....

..Criteria proposed in this article should be helpful in this regard...

..Furthermore, MCs could be desensitized specifically by pre-incubation of MCs with rhSCF in Ca-free medium. Together, these data suggest that SCF triggers mediator secretion from MCs in various organs via binding to the c-kit receptor...

..This is the first definitive demonstration that mast cells are replenished directly from early hemopoietic progenitors and thus form a unique cell lineage within the hemopoietic system...

..The present article gives an overview of MC phenotypes in health and disease, and attempts to provide explanations for the phenotypic variability of MC...

..These data suggest that cytomorphological assessment of bm MC in SM is an important diagnostic approach that may help to delineate between variants of the disease...

..The other statins tested (simvastatin, pravastatin) did not affect mediator release or growth of MCs. CONCLUSIONS: Cerivastatin and atorvastatin act as inhibitors of growth and function of human MCs...

..Whether these neoplasms display aberrant gene expression (or gene defects) or represent 'pre-pre-mast cell leukemias', remains unknown...

..However, little is known so far about basophil granulocytes in MDS...

..Thus, by combining isolation techniques including elutriation, magnetic cell depletion and cell sorting with mAb, functionally intact normal human basophils and mast cells can be enriched to homogeneity...

....

..Because of the 'intermediate' clinical signs and absence of progression to aggressive disease, we proposed the term 'smouldering mastocytosis'...

..We thus demonstrate that synthetic hypoallergenic peptides derived from B cell epitopes of major allergens represent safe vaccine candidates for the treatment of IgE- mediated allergies...

..The LDH activity should be considered as an important prognostic factor in MDS...

..Apart from these, CD2 may be a novel useful marker because MCs in mastocytosis frequently express this antigen, whereas MCs in other pathologic conditions are CD2 negative...

..In the present study, we asked whether leukaemic stem cells in patients with AML express CD33...

..Therefore, tryptase should not be regarded as specific for mast cells when neoplastic myeloid cells are analyzed...

..Almost 100 million allergic patients are sensitized to the major birch pollen allergen, Bet v 1, a 17 kDa protein containing most of the IgE epitopes present in pollens of trees belonging to the Fagales order and plant-derived food...

..Therefore, monitoring of minimal residual disease (MRD) during treatment with imatinib is important. However, most MRD-parameters are expensive and require special technology. We determined the value of histamine as MRD-marker in CML...

..In a screen program searching for dynamic prognostic determinants, we have identified lactate dehydrogenase (LDH) as a most suitable follow-up parameter...

..Compared to FcepsilonRI-mediated cell activation, IL-3-induced upregulation of CD203c is a late(r) event and is not accompanied by upregulation of CD63...

..Basophilic crisis and eosinophilia are well recognized features of advanced chronic myeloid leukaemia. In other myeloid neoplasms, however, transformation with marked basophilia and eosinophilia is considered unusual...

..The evaluation of comorbidity is of increasing importance in patients with hematologic disorders...

..Cladribine (2CdA) and dasatinib are two drugs that counteract the in vitro growth of neoplastic mast cells in SM. However, only little is known about the in vivo effects of these drugs in SM...

..The role of redistributed MC and their mediators in the pathophysiology of atrial thrombosis requires further investigation...

..In conclusion, CD203c is a novel activation-linked surface antigen on MC that is upregulated in response to IgE receptor cross-linking and is overexpressed on neoplastic MC in patients with SM...

..Whereas IL-3R and GM-CSFRs are lost during differentiation of MC, these cells may acquire complement receptors (CD35, CD88) under the influence of distinct cytokines...

..Almost 4% of the population suffer from food allergy which is an adverse reaction to food with an underlying immunological mechanism...

..Three mTOR-targeting drugs, rapamycin, everolimus (RAD001) and CCI-779, were applied. The effects of these drugs on growth, survival, apoptosis and VEGF expression in primary AML cells and various AML cell lines were examined...

..CONCLUSION: Immunoelectron microscopy may be a helpful approach in confirming the identity of neoplastic MC in myeloid neoplasms...

..An elevated CFU level in SM should raise the suspicion of an associated MPD (CMML) or smouldering SM, a novel SM-subtype that shares several features with MPD and sometimes progresses to an overt SM-MPD...

..037) and in the IPSS intermediate-1-risk group (p=0.015). The CD44s-adjusted IPSS defines a cohort of MDS patients with unfavorable prognosis, which might be helpful in risk stratification and in therapeutic algorithms...

..In summary, Ba and MC express a unique profile of homing molecules. Apparently, Ba differ from MC in expression of recognition receptors relevant for binding to endothelium and consecutive transmigration...

..The therapeutic potential of target-specific approaches in malignant mast cell disorders should be evaluated in forthcoming clinical trials in the near future...

..Recent data suggest that tryptase, a mast cell enzyme, is expressed in neoplastic cells in myeloid leukaemias. In several of these patients, increased serum tryptase levels are detectable...

..A major disadvantage of deferoxamine is that the drug has to be applied as continuous subcutaneous infusion. Therefore, novel oral agents have been developed. One of these drugs is deferasirox (Exjade)...

..In conclusion, our results indicate that both karyotype and the duration of first CR are independent prognostic factors for patients with de novo AML in first relapse...

..Whether an altered availability of components of this cellular repair system can predispose for thrombophilia remains to be determined...

..018) to predict survival in our patients. After inclusion of the IPSS risk categories, mCFU levels remained a highly predictive parameter for survival ( p=0.0056) and acute myeloblastic leukemia (AML) transformation ( p=0.0003)...

..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...

..Recent data suggest that the mammalian target of rapamycin (mTOR) is involved in the regulation of growth of neoplastic cells in chronic myeloid leukaemia (CML)...

..CONCLUSION: Fab12 represents a candidate molecule for therapy of atopy and asthma because it can be used for the depletion of circulating IgE antibodies, as well as for the depletion of IgE-bearing cells...

..Recent data indicate that detection of BCR/ABL1 mutant subclones does not permit prediction of their expansion dynamics and their potential to become drivers of resistant disease...

..The aim of this analysis was to study age and gender as interacting variables for individualized prognostication...

..Together, our data suggest that Hsp32 plays an important role as a survival factor in leukemic stem cells and as a potential new target in AML...

..Recombinant arginine kinase may be used to identify a group of polysensitized indoor allergic patients and for immunotherapy of these individuals...

..The BCR/ABL tyrosine kinase inhibitor imatinib is highly effective in patients with CML, but hardly crosses the blood-brain barrier...

..These blocking antibodies may have protective effects by inhibiting immediate-type reactions and systemic increases of IgE responses caused by seasonal allergen exposure...

..Recent data suggest that, among other factors, comorbidity may be an important prognostic variable in patients with myelodysplastic syndromes (MDS) who are eligible for haematopoietic stem cell transplantation (SCT)...

..The C-KIT 1642A-->C polymorphism is not associated with myelodysplastic syndrome or systemic mastocytosis...

..These recommendations should facilitate and assist in recognition of iron overload, selection of patients, timing of treatment, drug selection and the measurement of treatment responses...

..01), but thrombopoietin levels were not significantly different. Taken together, thrombopoietin levels are significantly higher in the sera of SLE patients than in healthy controls and anti-thrombopoietin antibodies are frequently found...

....

..Patients with mastocytosis may suffer from severe hypotension after wasp or bee stings. In these patients, no specific IgE is detectable, but they usually have skin lesions and an elevated serum tryptase level...

..Whether these drugs, alone or in combination, are also effective in patients with MCL, remains to be determined...

....

..In summary, our data show that the spleen can be a primary site of disease in rare cases of SM. Mastocytosis should therefore be considered as a (rare) differential diagnosis in patients with splenomegaly of unknown etiology...

..Together, tryptase is secreted from AML blasts as a biologically active molecule that may exhibit paracrine rather than autocrine effects in AML...

..In summary, VEGF expression in the bone marrow is restricted to certain stages of differentiation and maturation of myeloid cells and correlates with the FAB category...

..IDAC is a superior protocol in this regard and may therefore be most suitable for elderly patients and those at high risk for severe infections...

..Respective algorithms and recommendations should facilitate diagnostic and prognostic evaluations in MDS, selection of patients for therapies, and the conduct of clinical trials...

..The phrase "idiopathic cytopenia of undetermined significance (ICUS)", as also suggested by Mufti and co-workers, is proposed and long term follow-up is recommended to assess the evolution...

..Together, these data identify cerivastatin and atorvastatin as novel inhibitors of growth and activation of human basophils...

..The notion that SM is associated with increased BM angiogenesis and vascular endothelial growth factor expression may have implications for the biology of disease and development of new treatment strategies...

..Based on our case and similar cases mimicking mastocytosis, it seems of importance to apply recently established SM criteria in order to discriminate between reactive MC hyperplasia and true mastocytosis with certainty...

..These data show that some patients with SM can remain in a clinically indolent smouldering state over years even when presenting with marked eosinophilia and lymphadenopathy...

..The use of novel CD antibodies may help to isolate MC and basophils and to study their functional properties...

..In the few patients recorded so far, a complex karyotype without recurring anomaly was found. The prognosis appears to be grave, although complete remission in response to chemotherapy has been described...

..The KIT mutation D816V was detected in sorted CD34(+) cells and unfractionated marrow cells but not in CD5(+) SLL cells, confirming the coexistence of 2 distinct neoplasms...

....

....

..Together, our data show that BCR/ABL induces VEGF- and HIF-1alpha gene expression through a pathway involving PI3-kinase and mTOR. BCR/ABL-induced VEGF expression may contribute to the pathogenesis and increased angiogenesis in CML...

..Because of the availability of a superior targeted drug (imatinib), it is of importance to screen for FIP1L1/PDGFRalpha in suspected CEL with or without co-existing SM...

..05). Taken together, these data show that aplastic anemia is associated with reduced angiogenesis and reduced VEGF expression...

..Finally, our case further shows that mastocytosis can be an important differential diagnosis to be considered in patients with unexplained anaphylactoid or other mediator-related symptoms...

..In contrast to solid tumors, venous thromboembolism before or at diagnosis of acute leukemia is not associated with poor prognosis...

..Whether these strategies will lead to curative drug therapy in CML in the future remains at present unknown...

..These data suggest that Imatinib is a useful agent for long term treatment of relapsed CML after allogeneic SCT...

..05). Together, our data suggest that the BM-MVD could be a prognostic parameter concerning survival in patients with AML undergoing allogeneic BMT...

..Recently established scoring systems aimed at predicting survival and evolution of leukemia in MDS may be helpful in this regard...

..In patients with SM-AHNMD, the SM should be treated as if no AHNMD is present, and the AHNMD should be treated as if no SM had been diagnosed...

..In this situation quantitative RT-PCR might help to define individual relapse risk and to improve as well as facilitate clinical decision-making...

..The current review provides an overview of mastocytosis and its subvariants and a practical guide that might help to delineate mastocytosis from unrelated systemic disorders...

..In the current article, the biochemical, functional, and technical background of these basophil tests is discussed...

..Our data show that VEGF is expressed in immature myeloid cells in CML. The extent of VEGF expression depends on the phase of disease and the cell type involved in disease progression...

..Our finding that rabbit anti-rPhl p 13 Abs blocked patients' IgE binding to the allergen suggests that rPhl p 13 may be used for immunotherapy of sensitized patients...

..Together, our data identify HO-1 as a novel BCR/ABL-driven survival molecule and potential target in leukemic cells in patients with CML. The pathogenetic and clinical implications of this observation remain to be elucidated...

..It is hypothesized that CD172 and CD47 contribute to MC clustering and that the "lack" of SHP-1 in MC may facilitate KIT-dependent signaling in a subgroup of patients...