Pharmacological treatment options for mast cell activation disease

Abdulkadir H, Grootens J, Kjellander M, Hellstram Lindberg E, Nilsson G, Ungerstedt J (2015) Histone deacetylase inhibitor SAHA mediates epigenetic silencing of KIT D816V mutated systemic mastocytosis primary mast cells and selective apoptosis of mutated mast cells. Blood;126: abstract 2834 Adachi S, Maruyama T, Kondo T, Todoroki T, Fukao K (1999) The prevention of postoperative intraperitoneal adhesions by tranilast: N-(3′,4′-dimethoxycinnamoyl)anthranilic acid. Surg Today 29:51–54 Afrin LB (2010) Mast cell activation disorder masquerading as pure red cell aplasia. Int J Hematol 91:907–908 Afrin LB (2011) Polycythemia from mast cell activation syndrome: lessons learned. Am J Med Sci 342:44–49 Afrin LB (2012) Mast cell activation syndrome masquerading as agranulocytosis. Mil Med 177:113–117 Afrin LB (2013) Utility of hydroxyurea in mast cell activation syndrome. Exp Hematol Oncol 2:28 Afrin LB (2015) Utility of continuous diphenhydramine infusion in severe mast cell activation syndrome. Blood 126:5194 abstract Afrin LB, Molderings GJ (2014) A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 3:1–17 Afrin LB, Cichocki FM, Patel K, Molderings GJ (2015a) Successful treatment of mast cell activation syndrome with sunitinib. Eur J Haematol 95:595–597 Afrin LB, Pöhlau D, Raithel M, Haenisch B, Dumoulin FL, Homann J, Mauer UM, Harzer S, Molderings GJ (2015b) Mast cell activation disease: an underappreciated cause of neurologic and psychiatric symptoms and diseases. Brain Behav Immun 50:314–321 Aichberger KJ, Gleixner KV, Mirkina I, Cerny-Reiterer S, Peter B, Ferenc V, Kneidinger M, Baumgartner C, Mayerhofer M, Gruze A, Pickl WF, Sillaber C, Valent P (2009) Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs. Blood 114:5342–5351 Akhavein A, Patel NR, Minoyappa PK, Glover SC (2012) Allergic mastocytic gastroenteritis and colitis: an unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterol Res Pract 2012:950582 Akin C, Valent P, Metcalfe D (2010) Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 126:1099–1104 Aldi S, Takano KI, Tomita K, Koda K, Chan NY, Marino A, Salazar-Rodriguez M, Thurmond RL, Levi R (2014) Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via PKCε-dependent aldehyde dehydrogenase type-2 activation. J Pharmacol Exp Ther 349:508–517 Alexandrakis MG, Kyriakou DS, Kempuraj D, Huang M, Boucher W, Seretakis D, Theoharides TC (2003) The isoflavone genistein inhibits proliferation and increases histamine content in human leukemic mast cells. Allergy Asthma Proc 24:373–377 Aman J, van Bezu J, Damanafshan A, Huveneers S, Eringa EC, Vogel SM, Groeneveld AB, Vonk Noordegraaf A, van Hinsbergh VW, van Nieuw Amerongen GP (2012) Effective treatment of edema and endothelial barrier dysfunction with imatinib. Circulation 126:2728–2738 Anand P, Singh B, Jaggi AS, Singh N (2012) Mast cells: an expanding pathophysiological role from allergy to other disorders. Naunyn Schmiedeberg’s Arch Pharmacol 385:657–670 Baba A, Tachi M, Ejima Y, Endo Y, Toyama H, Matsubara M, Saito K, Yamauchi M, Miura C, Kazama I (2016) Anti-allergic drugs tranilast and ketotifen dose-dependently exert mast cell-stabilizing properties. Cell Physiol Biochem 38:15–27 Babaei S, Bayat M (2012) Effect of pentoxifylline administration on mast cell numbers and degranulation in a diabetic and normoglycemic rat model wound healing. Iran Red Crescent Med J 14:483–487 Bachelet I, Munitz A, Moretta A, Moretta L, Levi-Schaffer F (2005) The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells. J Immunol 175:7989–7995 Bae MH, Kim HK, Park CJ, Seo EJ, Park SH, Cho YU, Jang S, Chi HS, Lee KH (2013) A case of systemic mastocytosis associated with acute myeloid leukemia terminating as aleukemic mast cell leukemia after allogeneic hematopoietic stem cell transplantation. Ann Lab Med 33:125–129 Baek OS, Kang OH, Choi YA, Choi SC, Kim TH, Nah YH, Kwon DY, Kim YK, Kim YH, Bae KH, Lim JP, Lee YM (2003) Curcumin inhibits protease-activated receptor-2 and -4-mediated mast cell activation. Clin Chim Acta 338:135–141 Bairlein M (2010) Characterization of the small molecule kinase inhibitor SU11248 (sunitinib/SUTENT) in vitro and in vivo—towards response prediction in cancer therapy with kinase inhibitors. TU Munich, Munich, Germany, Medical thesis Barete S, Lortholary O, Damaj G, Hirsch I, Chandesris MO, Elie C, Hamidou M, Durieu I, Suarez F, Grosbois B, Limal N, Gyan E, Larroche C, Guillet G, Kahn JE, Casassus P, Amazzough K, Coignard-Biehler H, Georgin-Lavialle S, Lhermitte L, Fraitag S, Canioni D, Dubreuil P, Hermine O (2015) Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. Blood 126:1009–1016 Bell MC, Jackson DJ (2012) Prevention of anaphylaxis related to mast cell activation syndrome with omalizumab. Ann Allergy Asthma Immunol 108:383–384 Bibi S, Arslanhan MD, Langenfeld F, Jeanningros S, Cerny-Reiterer S, Hadzijusufovic E, Tchertanov L, Moriggl R, Valent P, Arock M (2014) Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy. Haematologica 99:417–429 Bidri M, Royer B, Averlant G, Bismuth G, Guillosson JJ, Arock M (1999) Inhibition of mouse mast cell proliferation and proinflammatory mediator release by benzodiazepines. Immunopharmacology 43:75–86 Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ, Muir JG, Gibson PR (2011) Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol 106:508–514 Böhm A, Sonneck K, Gleixner KV, Schuch K, Pickl WF, Blatt K, Peter B, Herrmann H, Schernthaner GH, Pehamberger H, Rabitsch W, Sperr WR, Valent P (2010) In vitro and in vivo growth-inhibitory effects of cladribine on neoplastic mast cells exhibiting the imatinib-resistant KIT mutation D816V. Exp Hematol 38:744–755 Borzutzky A, Morales PS, Mezzano V, Nussbaum S, Burks W (2014) Induction of remission of frequent idiopathic anaphylaxis with rituximab. AAAAI Meeting 28.2.-04.03, abstract 91 Boyce JA (2007) Mast cells and eicosanoid mediators: a system of reciprocal paracrine and autocrine regulation. Immunol Rev 217:168–185 Breslow RG, Caiado J, Castells MC (2009) Acetylsalicylic acid and montelukast block mast cell mediator-related symptoms during rapid desenesitization. Ann Allergy Asthma Immunol 102:155–160 Broesby-Olsen S, Kristensen T, Vestergaard H, Brixen K, Møller MB, Bindslev-Jensen C, Mastocytosis Centre Odense University Hospital (MastOUH) (2013) KIT D816V mutation burden does not correlate to clinical manifestations of indolent systemic mastocytosis. J Allergy Clin Immunol 132:723–728 Broyd H, Koffer A, Assem ESK (2005) Effect of cyclosporin-A on secretion from intact and permeabilised mast cells. Inflamm Res 54(Supplement 1):7–8 Butterfield JH (2005) Interferon treatment for hypereosinophilic syndromes ans systemic mastocytosis. Acta Haematol 114:26–40 Butterfield JH (2009) Survey of aspirin administration in systemic mastocytosis. Prostaglandins Other Lipid Mediat 88:122–124 Butterfield JH, Chen D (2016) Response of patients with indolent systemic mastocytosis to tamoxifen citrate. Leuk Res 40:10–16 Butterfield JH, Weiler CR (2008) Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D(2) production. Int Arch Allergy Immunol 147:338–343 Butterfield JH, Tefferi A, Kozuh GF (2005) Successful treatment of systemic mastocytosis with high- dose interferon-alfa: long-term follow-up of a case. Leuk Res 29:131–134 Cardet JC, Akin C, Lee MJ (2013) Mastocytosis: update on pharmacotherapy and future directions. Expert Opin Pharmacother 14:2033–2045 Carter MC, Robyn JA, Bressler PB, Walker JC, Shapiro GG, Metcalfe DD (2007) Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Clin Immunol 119:1550–1551 Casassus P, Caillat-Vigneron N, Martin A, Simon J, Gallais V, Beaudry P, Eclache V, Laroche L, Lortholary P, Raphaël M, Guillevin L, Lortholary O (2002) Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients. Br J Haematol 119:1090–1097 Caughey GH (2016) Mast cell proteases as pharmacological targets. Eur J Pharmacol 778:44–55 Chan IJ, Kasprowicz S, Tharp MD (2013) Distinct signalling pathways for mutated KIT(V560G) and KIT(D816V) in mastocytosis. Clin Exp Dermatol 38:538–544 Chandesris MO, Damaj G, Canioni D, Brouzes C, Cabaret L, Hanssens K, Durieu I, Durupt S, Besnard S, Beyne-Rauzy O, Launay D, Schiffmann A, Niault M, Ranta D, Agape P, Faure C, Chantepie SP, Daguindau N, Bourgeet P, Dubreuil P, Lortholary O, Hermine O (2014) Treatment of advanced systemic mastocytosis with PKC412: the French compassionate use programme experience and historical comparison. ASH Meeting, abstract 3193 Chatterjee IB, Gupta SD, Majumder AK, Nandi BK, Subramanian N (1975) Effect of ascorbic acid on histamine metabolism in scorbutic guinea-pigs. J Physiol 251:271–279 Church MK, Gradidge CF (1980) Inhibition of histamine release from human lung in vitro by antihistamines and related drugs. Br J Pharmacol 69:663–667 Cikler E, Ersoy Y, Cetinel S, Ercan F (2009) The leukotriene d4 receptor antagonist, montelukast, inhibits mast cell degranulation in the dermis induced by water avoidance stress. Acta Histochem 111:112–118 Clemons A, Vasiadi M, Kempuraj D, Kourelis T, Vandoros G, Theoharides TC (2011) Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: possible relevance to chronic fatigue syndrome. J Clin Psychopharmacol 31:385–387 Cohen SS, Skovbo S, Vestergaard H, Kristensen T, Møller M, Bindslev-Jensen C, Fryzek JP, Broesby-Olsen S (2014) Epidemiology of systemic mastocytosis in Denmark. Br J Haematol 166:521–528 Cooper K, Young J, Wadsworth S, Cui H, diZerega GS, Rodgers KE (2007) Reduction of post-surgical adhesion formation with tranilast. J Surg Res 141:153–161 Corbin AS, Griswold IJ, La Rosée P, Yee KW, Heinrich MC, Reimer CL, Druker BJ, Deininger MW (2004) Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970. Blood 104:3754–3757 Correia O, Duarte AF, Quirino P, Azevedo R, Delgado L (2010) Cutaneous mastocytosis: two pediatric cases treated with topical pimecrolimus. Dermatol Online J 16:8 Damaj G, Bernit E, Ghez D, Claisse JF, Schleinitz N, Harlé JR, Canioni D, Hermine O (2008) Thalidomide in advanced mastocytosis. Br J Haematol 141:249–253 De Filippis D, D’Amico A, Iuvone T (2008) Cannabinomimetic control of mast cell mediator release: new perspective in chronic inflammation. J Neuroendocrinol 20(Suppl 1):20–25 Dix S, Cord M, Howard S, Coon J, Belt R, Geller R (1999) Safety and efficacy of a continuous infusion, patient controlled anti-emetic pump to facilitate outpatient administration of high-dose chemotherapy. Bone Marrow Transplant 24:561–566 Droogendijk HJ, Kluin-Nelemans HJC, van Doormaal JJ, Oranje AR, van de Loosdrecht AA, van Daele PLA (2006) Imatinibmesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer 107:345–351 Dueñas-Laita A, Ruiz-Muñoz P, Armentia A, Pinacho F, Martín-Armentia B (2009) Successful treatment of chronic drug-resistant urticaria with alprazolam. J Allergy Clin Immunol 123:504–505 Duffy SM, Lawley WJ, Kaur D, Yang W, Bradding P (2003) Inhibition of human mast cell proliferation and survival by tamoxifen in association with ion channel modulation. J Allergy Clin Immunol 112:965–972 Edwards AM, Hagberg H (2010) Oral and inhaled sodium cromoglicate in the management of systemic mastocytosis: a case report. J Med Case Rep 4:193 Edwards AM, Stevens MT, Church MK (2011) The effects of topical sodium cromoglicate on itch and flare in human skin induced by intradermal histamine: a randomised double-blind vehicle controlled intra-subject design trial. BMC Res Notes 4:47 El-Agamy DS (2012) Anti-allergic effects of nilotinib on mast cell-mediated anaphylaxis like reactions. Eur J Pharmacol 680:115–121 El-Feki G, X Zhou, LC Lau, J Pedersen, AF Walls (2011) Inhibitors of dipeptidyl peptidase I (DPPI) as mast cell stabilising agents: the contribution of DPPI in mast cell activation. J Allergy Clin Immunol 127, Suppl. – Abstracts Erben P, Schwaab J, Metzgeroth G, Horny HP, Jawhar M, Sotlar K, Fabarius A, Teichmann M, Schneider S, Ernst T, Müller MC, Giehl M, Marx A, Hartmann K, Hochhaus A, Hofmann WK, Cross NC, Reiter A (2014) The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis. Ann Hematol 93:81–88 Escribano L, Akin C, Castells M, Schwartz LB (2006) Current options in the treatment of mast cell mediator-related symptoms in mastocytosis. Inflamm Allergy Drug Targets 5:61–77 Eskandari N, Bastan R, Peachell PT (2015) Regulation of human skin mast cell histamine release by PDE inhibitors. Allergol Immunopathol (Madr) 43:37–41 Estévez MD, Vieytes MR, Botana LM (1996) Mitoxantrone induces nonimmunological histamine release from rat mast cells. Inflamm Res 45:113–117 Evans E, Gardino A, Hodous B, Davis A, Zhu J, Kohl NE, Lengauer C (2015) Blu-285, a potent and selective inhibitor for hematologic malignancies with KIT exon 17 mutations. ASH Annual Meeting: abstract 568 Evora PR, Simon MR (2007) Role of nitric oxide production in anaphylaxis and its relevance for the treatment of anaphylactic hypotension with methylene blue. Ann Allergy Asthma Immunol 99:306–313 Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A (1995) Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A 92:3376–3380 Finn DF, Walsh JJ (2013) Twenty-first century mast cell stabilisers. Br J Pharmacol 170:23–37 Frenkel A, Roy-Shapira A, Evgeni B, Leonid K, Borer A, Klein M (2015) Life threatening idiopathic recurrent angioedema responding to cannabis. Case Rep Immunol 2015:780824 Friedman BS, Santiago ML, Berkebile C, Metcalfe DD (1993) Comparison of azelastine and chlorpheniramine in the treatment of mastocytosis. J Allergy Clin Immunol 92:520–526 Frieri M, Alling DW, Metcalfe DD (1985) Comparison of the therapeutic efficacy of cromolyn sodium with that of combined chlorpheniramine and cimetidine in systemic mastocytosis. Results of a double-blind clinical trial. Am J Med 78:9–14 Fujimoto T, Nishiyama T, Hanaoka K (2005) Inhibitory effects of intravenous anesthetics on mast cell function. Anesth Analg 101:1054–1059 Fumo G, Akin C, Metcalfe DD, Neckers L (2004) 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. Blood 103:1078–1084 Galli SJ, Costa JJ (1995) Mast-cell-leukocyte cytokine cascades in allergic inflammation. Allergy 50:851–862 Gibbs BF, Schmutzler W, Vollrath IB, Brosthardt P, Braam U, Wolff HH, Zwadlo-Klarwasser G (1999) Ambroxol inhibits the release of histamine, leukotrienes and cytokines from human leukocytes and mast cells. Inflamm Res 48:86–93 Giraldo Castellano P, García-Erce JA, Alvarez Alegret R, Arroyo Rubio A, Mayayo Artal P, Vicente Cámara P, Rubio-Félix D, Giralt RM (1998) Interferon alpha and systemic mastocytosis. Analysis of therapeutic efficacy in 6 cases. Rev Clin Esp 198:345–350 Gleixner KV, Mayerhofer M, Cerny-Reiterer S, Hörmann G, Rix U, Bennett KL, Hadzijusufovic E, Meyer RA, Pickl WF, Gotlib J, Horny HP, Reiter A, Mitterbauer-Hohendanner G, Superti-Furga G, Valent P (2011) KIT-D816V-independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk-activation and disruption by dasatinib and bosutinib. Blood 118:1885–1898 Gleixner KV, Peter B, Blatt K, Suppan V, Reiter A, Radia D, Hadzijusufovic E, Valent P (2013) Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V. Haematologica 98:1450–1457 Gotlib J, George TI, Corless C, Linder A, Ruddell A, Akin C, DeAngelo DJ, Kepten I, Lanza C, Heinemann H, Yin O, Gallagher N, Graubert T (2008) The KIT tyrosine kinase inhibitor midostaurine (PKC412) exhibits a high response rate in aggressive systemic mastocytosis (ASM): interim results of a phase II trial. Blood 110:1039A Gotlib J, Kluin-Neelemans HC, George TI et al. (2014) Midostaurin (PKC412) demonstrates a high rate of durable responses in patients with advanced systemic mastocytosis: results from the fully accrued global phase 2 CPKC412D2201 trial. Blood;124: ASH Annual Meeting Abstracts; Abstract 636 Gri G, Frossi B, D’Inca F, Danelli L, Betto E, Mion F, Sibilano R, Pucillo C (2012) Mast cell: an emerging partner in immune interaction. Front Immunol 3:120 Gromke T, Elmaagacli AH, Ditschkowski M, Hegerfeldt Y, Koldehoff M, Hlinka M, Ottinger H, Trenschel R, Beelen DW (2013) Delayed graft-versus-mast-cell effect on systemic mastocytosis with associated clonal haematological non-mast cell lineage disease after allogeneic transplantation. Bone Marrow Transplant 48:732–733 Gruson B, Lortholary O, Canioni D, Chandesris O, Lanternier F, Bruneau J, Grosbois B, Livideanu C, Larroche C, Durieu I, Barete S, Sevestre H, Diouf M, Chaby G, Marolleau JP, Dubreuil P, Hermine O, Damaj G (2013) Thalidomide in systemic mastocytosis: results from an open-label, multicentre, phase II study. Br J Haematol 161:434–442 Gurgel JA, Lima-Júnior RC, Rabelo CO, Pessoa BB, Brito GA, Ribeiro RA (2013) Amitriptyline, clomipramine, and maprotiline attenuate the inflammatory response by inhibiting neutrophil migration and mast cell degranulation. Rev Bras Psiquiatr 35:387–392 Hadzijusufovic E, Peter B, Herrmann H, Schuch, Thaiwong T, Yuzbasiyan-Gurkan V, Pickl W, Willmann M, Valent P (2010) Mutations in KIT predict resistance to several TKI (sorafenib, sunitinib, and masitinib) in neoplastic human and canine mast cell lines. Haematologica 95(suppl.2):357 abs. 0857 Haenisch B, Nöthen MM, Molderings GJ (2012) Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 137:197–205 Haenisch B, Fröhlich H, Herms S, Molderings GJ (2014) Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation disease. Immunogenetics 66:287–297 Hagel AF, Layritz CM, Hagel WH, Hagel HJ, Hagel E, Dauth W, Kressel J, Regnet T, Rosenberg A, Neurath MF, Molderings GJ, Raithel M (2013) Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases. Naunyn Schmiedeberg’s Arch Pharmacol 386:789–793 Hagenlocher Y, Kießling K, Schäffer M, Bischoff SC, Lorentz A (2015) Cinnamaldehyde is the main mediator of cinnamon extract in mast cell inhibition. Eur J Nutr 54:1297–1309 Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ (2011) Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 128:147–152 Hantschel O, Rix U, Schmidt U, Bürckstümmer T, Kneidinger M, Schütze G, Colinge J, Bennett KL, Ellmeier W, Valent P, Superti-Furga G (2007) The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci U S A 104:13283–13288 Harvima IT, Levi-Schaffer F, Draber P, Friedman S, Polakovicova I, Gibbs BF, Blank U, Nilsson G, Maurer M (2014) Molecular targets on mast cells and basophils for novel therapies. J Allergy Clin Immunol 134:530–544 Hauswirth AW, Simonitsch-Klupp I, Uffmann M, Koller E, Sperr WR, Lechner K, Valent P (2004) Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. Leuk Res 28:249–257 Heinrich MC, Joensuu H, Demetri GD, Corless CL, Apperley J, Fletcher JA, Soulieres D, Dirnhofer S, Harlow A, Town A, McKinley A, Supple SG, Seymour J, Di Scala L, van Oosterom A, Herrmann R, Nikolova Z, McArthur AG, Imatinib Target Exploration Consortium Study B2225 (2008) Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin Cancer Res 14:2717–2725 Hennessy B, Giles F, Cortes J, O’brien S, Ferrajoli A, Ossa G, Garcia-Manero G, Faderl S, Kantarjian H, Verstovsek S (2004) Management of patients with systemic mastocytosis: review of M. D. Anderson Cancer Center experience. Am J Hematol 77:209–214 Hermine O, Lortholary O, Leventhal PS, Catteau A, Soppelsa F, Baude C, Cohen-Akenine A, Palmérini F, Hanssens K, Yang Y, Sobol H, Fraytag S, Ghez D, Suarez F, Barete S, Casassus P, Sans B, Arock M, Kinet JP, Dubreuil P, Moussy A (2008) Case-control cohort study of patients’ perceptions of disability in mastocytosis. PLoS One 3:e2266 Hochhaus A, Ottmann OG, Lauber S, Hughes T, Verhoef G, Schwarer AP, Gratwohl A, Rafferty T, Resta D, Gattermann N (2006) A phase II study of nilotinib, a novel inhibitor of c-Kit, PDGFR, and Bcr-Abl, administered to patients with systemic mastocytosis. Blood 108: Abstract 2703 [ASH Annual Meeting Abstracts] Hochhaus A, Baccarani M, Giles FJ, le Coutre PD, Müller MC, Reiter A, Santanastasio H, Leung M, Novick S, Kantarjian HM (2015) Nilotinib in patients with systemic mastocytosis: analysis of the phase 2, open-label, single-arm nilotinib registration study. J Cancer Res Clin Oncol 141:2047–2060 Hoffmann K, Xifró RA, Hartweg JL, Spitzlei P, Meis K, Molderings GJ, von Kügelgen I (2013) Inhibitory effects of benzodiazepines on the adenosine A(2B) receptor mediated secretion of interleukin-8 in human mast cells. Eur J Pharmacol 700:152–158 Horan RF, Sheffer AL, Austen KF (1990) Cromolyn sodium in the management of systemic mastocytosis. J Allergy Clin Immunol 85:852–855 Ibelgaufts H. (2016.) “Mast Cells” in COPE: cytokines and cells online pathfinder encyclopaedia, Available at http://www.cells-talk.com (accessed March 21, 2016) Jensen BM, Beaven MA, Iwaki S, Metcalfe DD, Gilfillan A (2008) Concurrent inhibition of KIT- and FcεRI-mediated signaling: coordinated suppression of mast cell activation. J Pharmacol Exp Ther 324:128–138 Jin B, Ding K, Pan J (2014) Ponatinib induces apoptosis in imatinib-resistant human mast cells by dephosphorylating mutant D816V KIT and silencing beta-catenin signaling. Mol Cancer Ther 13:1217–1230 Johnston CS, Martin LJ, Cai X (1992) Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis. J Am Coll Nutr 11:172–176 Joks R, Durkin HG (2011) Non-antibiotic properties of tetracyclines as anti-allergy and asthma drugs. Pharmacol Res 64:602–609 Jones E, Koyama T, Ho RH, Kuttesch J, Shankar S, Whitlock JA, Cartwright J, Frangoul H (2007) Safety and efficacy of a continuous infusion, patient-controlled antiemetic pump for children receiving emetogenic chemotherapy. Pediatr Blood Cancer 48:330–332 Kaneko I, Suzuki K, Matsuo K, Kumagai H, Owada Y, Noguchi N, Hishinuma T, Ono M (2009) Cysteinyl leukotrienes enhance the degranulation of bone marrow-derived mast cells through the autocrine mechanism. Tohoku J Exp Med 217:185–191 Karlberg M, Ekoff M, Labi V, Strasser A, Huang D, Nilsson G (2010a) Pro-apoptotic Bax is the major and Bak an auxiliary effector in cytokine deprivation-induced mast cell apoptosis. Cell Death Dis 1:e43 Karlberg M, Ekoff M, Huang DC, Mustonen P, Harvima IT, Nilsson G (2010b) The BH3-mimetic ABT-737 induces mast cell apoptosis in vitro and in vivo: potential for therapeutics. J Immunol 185:2555–2562 Katoh N, Hirano S, Yasuno H (1996) Solitary mastocytoma treated with tranilast. J Dermatol 23:335–339 Kay LJ, Yeo WW, Peachell PT (2006) Prostaglandin E-2 activates EP2 receptors to inhibit human lung mast cell degranulation. Br J Pharmacol 147:707–713 Kempna P, Reiter E, Arocks M, Azzi A, Zingg JM (2004) Inhibition of HMC-1 mast cell proliferation by vitamin E. J Biol Chem 279:50700–50709 Kempuraj D, Castellani ML, Petrarca C, Frydas S, Conti P, Theoharides TC, Vecchiet J (2006) Inhibitory effect of quercetin on tryptase and inetrleukin-6 release, and histidine decarboxylase mRNA transcription by human mast cell-1 cell line. Clin Exp Med 6:150–156 Kettelhut BV, Berkebile C, Bradley D, Metcalfe DD (1989) A double-blind, placebo-controlled, crossover trial of ketotifen versus hydroxyzine in the treatment of pediatric mastocytosis. J Allergy Clin Immunol 83:866–870 Kibsgaard L, Skjold T, Deleuran M, Vestergaard C (2014) Omalizumab induced remission of idiopathic anaphylaxis in a patient suffering from indolent systemic mastocytosis. Acta DermVenereol 94:363–364 Kinney SR, Carlson L, Ser-Dolansky J, Thompson C, Shah S, Gambrah A, Xing W, Schneider SS, Mathias CB (2015) Curcumin ingestion inhibits mastocytosis and suppresses intestinal anaphylaxis in a murine model of food allergy. PLoS One 10:e0132467 Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ, Van’t Wout JW, Verhoef G, Gerrits WB, van Dobbenburgh OA, Pasmans SG, Fijnheer R (2003) Cladribine therapy for systemic mastocytosis. Blood 102:4270–4276 Kluin-Nelemans HC, Ferenc V, van Doormaal JJ, van Iperen C, Peters WG, Akin C, Valent P (2009) Lenalidomide therapy in systemic mastocytosis. Leuk Res 33:e19–e22 Knapper S, Cullis J, Drummond MW, Evely R, Everington T, Hoyle C, McLintock L, Poynton C, Radia D (2011) Midostaurin a multi-targeted oral kinase inhibitor in systemic mastocytosis: report of an open-label compassionate use program in the United Kingdom. Blood 118:5145 Koelink PJ, Overbeek SA, Braber S, de Kruijf P, Folkerts G, Smit MJ, Kraneveld AD (2012) Targeting chemokine receptors in chronic inflammatory diseases: an extensive review. Pharmacol Ther 133:1–18 Kohno M, Yamasaki S, Tybolewicz VLJ, Saito T (2005) Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen. Blood 105:2059–2065 Kontou-Fili K, Filis CI, Voulgari C, Panayiotidis PG (2010) Omalizumab monotherapy for bee sting and unprovoked “anaphylaxis” in a patient with systemic mastocytosis and undetectable specific IgE. Ann Allergy Asthma Immunol 104:537–539 Krauth MT, Majlesi Y, Sonneck K, Samorapoompichit P, Ghannadan M, Hauswirth AW, Baghestanian M, Schernthaner GH, Worda C, Muller MR, Sperr WR, Valent P (2006) Effects of various statins on cytokine-dependent growth and IgE-dependent release of histamine in human mast cells. Allergy 61:281–288 Krauth MT, Böhm A, Agis H, Sonneck K, Samorapoompichit P, Florian S, Sotlar K, Valent P (2007) Effects of the CD33-targeted drug gemtuzumab ozogamicin (Mylotarg) on growth and mediator secretion in human mast cells and blood basophils. Exp Hematol 35:108–116 Krug U, Lübbert M, Büchner T (2010) Maintenance therapy in acute myeloid leukemia revisited: will new agents rekindle an old interest? Curr Opin Hematol 17:85–90 Kurosawa M, Amano H, Kanbe N, Igarashi Y, Nagata H, Yamashita T, Kurimoto F, Miyachi Y (1999) Response to cyclosporin and low-dose methylprednisolone in aggressive systemic mastocytosis. J Allergy Clin Immunol 103:S412–S420 Kurzen H. (2009) Neramexane for the treatment of mast cellmediated diseases. Patent application WO2010/069595 Kvasnicka HM, Thiele J, Bueso-Ramos CE, Kamalanabhaiah S, Cortes JE, Kantajian H, Verstovsek S (2014) Changes in activated bone marrow macrophages and mast cells in patients with myelofibrosis following ruxolitinib therapy. ASH Meeting abstract 3184 Laengle UW, Markstein R, Pralet D, Seewald W, Roman D (2006) Effect of GLC756, a novel mixed dopamine D1 receptor antagonist an dopamine D2 receptor agonist, on TNF-alpha release in vitro from activated rat mast cells. Exp Eye Res 83:1335–1339 Laroche M, Livideanu C, Paul C, Cantagrel A (2011) Interferon alpha and pamidronate in osteoporosis with fracture secondary to mastocytosis. Am J Med 124:776–778 Lasho T, Tefferi A, Pardanani A (2010) Inhibition of JAK-STAT signaling by TG101348: a novel mechanism for inhibition of KITD816V-dependent growth in mast cell leukemia cells. Leukemia 24:1378–1380 Lasho T, Finke C, Zblewski D et al. (2016) Concurrent activating KIT mutations in systemic mastocytosis. Br J Haematol 173:153–156 Lau HY, Kam MF (2005) Inhibition of mast cell histamine release by specific phosphodiesterase inhibitors. Inflamm Res 54(Supplement 1):05–06 Lechowski S, Feilhauer K, Staib L, Coëffier M, Bischoff SC, Lorentz A (2013) Combined arginine and glutamine decrease release of de novo synthesized leukotrienes and expression of proinflammatory cytokines in activated human intestinal mast cells. Eur J Nutr 52:505–512 Lee YS, Kim MS, Lee DH, Kwon TH, Song HH, Oh SR, do Yoon Y (2015) Luteolin 8-C-β-fucopyranoside downregulates IL-6 expression by inhibiting MAPKs and the NF-κB signaling pathway in human monocytic cells. Pharmacol Rep 67:581–587 Lieberoth S, Thomsen SF (2015) Cutaneous and gastrointestinal symptoms in two patients with systemic mastocytosis successfully treated with omalizumab. Case Rep Med 2015:903541 Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A (2009) Cytoreductive therapy in 108 adults with systemic mastocytosis: outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol 84:790–794 Lin TY, Bear M, Du Z, Foley KP, Ying W, Barsoum J, London C (2008) The novel HSP90 inhibitor STA-9090 exhibits activity against KIT-dependent and -independent malignant mast cell tumors. Exp Hematol 36:1266–1277 Lin TY, Fenger J, Murahari S, Bear MD, Kulp SK, Wang D, Chen CS, Kisseberth WC, London CA (2010) AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated KIT. Blood 115:4217–4225 Lock AD, McNamara CJ, Rustin MH (2015) Sustained improvement in urticaria pigmentosa and pruritus in a case of indolent systemic mastocytosis treated with cladribine. Clin Exp Dermatol 40:142–145 Lundequist A, Pejler G (2011) Biological implications of preformed mast cell mediators. Cell Mol Life Sci 68:965–975 Ma Z, Tovar JP, Kwong KY, Paek D (2010) Pimecrolimus induces apoptosis of mast cells in a murine model of cutaneous mastocytosis. Int Arch Allergy Immunol 153:413–418 Mallet AI, Norris P, Rendell NB, Wong E, Greaves MW (1989) The effect of disodium cromoglycate and ketotifen on the excretion of histamine and N tau-methylimidazole acetic acid in urine of patients with mastocytosis. Br J Clin Pharmacol 27:88–91 Marech I, Patruno R, Zizzo N, Gadaleta C, Introna M, Zito AF, Gadaleta CD, Ranieri G (2014) Masitinib (AB1010), from canine tumor model to human clinical development: where we are? Crit Rev Oncol Hematol 91:98–111 Marquardt DL, Gruber HE, Walker LL (1987) Ribavirin inhibits mast cell mediator release. J Pharmacol Exp Ther 240:145–149 Marton I, Pósfai É, Borbényi Z, Bödör C, Papp G, Demeter J, Korom I, Varga E, Bata-Csörgő Z (2015) Therapeutic challenge during the long-term follow-up of a patient with indolent systemic mastocytosis with extensive cutaneous involvement. Eur Rev Med Pharmacol Sci 19:1607–1609 Matsubara S, Li G, Takeda K, Loader JE, Pine P, Masuda ES, Miyahara N, Miyahara S, Lucas JJ, Dakhama A, Gelfand EW (2006) Inhibition of spleen tyrosine kinase prevents mast cell activation and airway hyperresponsiveness. Am J Respir Crit Care Med 173:56–63 Mattace Raso G, Russo R, Calignano A, Meli R (2014) Palmitoylethanolamide in CNS health and disease. Pharmacol Res 86:32–41 Maurer M, Magerl M, Metz M, Weller K, Siebenhaar F (2013) Miltefosine: a novel treatment option for mast cell-mediated diseases. J Dermatolog Treat 24:244–249 McNeil BD, Pundir P, Meeker S, Han L, Undem BJ, Kulka M, Dong X (2015) Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 519:237–241 Meeran SM, Ahmed A, Tollefsbol TO (2010) Epigenetic targets of bioactive dietary components for cancer prevention and therapy. Clin Epigenetics 1:101–116 Min YD, Choi CH, Bark H, Son HY, Park HH, Lee S, Park JW, Park EK, Shin HI, Kim SH (2007) Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-kappaB and p38 MAPK in HMC-1 human mast cell line. Inflamm Res 56:210–215 Molderings GJ (2015) The genetic basis of mast cell activation disease—looking through a glass darkly. Crit Rev Oncol Hematol 93:75–89 Molderings GJ (2016) Transgenerational transmission of systemic mast cell activation disease-genetic and epigenetic features. Transl Res. Molderings GJ, Kolck UW, Scheurlen C, Brüss M, Homann J, Von Kügelgen I (2007) Multiple novel alterations in KIT tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder. Scand J Gastroenterol 42:1045–1053 Molderings GJ, Meis K, Kolck UW, Homann J, Frieling T (2010) Comparative analysis of mutation of tyrosine kinase KIT in mast cells from patients with systemic mast cell activation syndrome and healthy subjects. Immunogenetics 62:721–727 Molderings GJ, Brettner S, Homann J, Afrin LB (2011a) Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol 4:10 Molderings GJ, Raithel M, Kratz F, Azemar M, Haenisch B, Harzer S, Homann J (2011b) Omalizumab treatment of systemic mast cell activation disease: experiences from four cases. Intern Med 50:1–5 Molderings GJ, Haenisch B, Bogdanow M, Fimmers R, Nöthen MM (2013a) Familial occurrence of systemic mast cell activation disease. PLoS One 8:e76241 Molderings GJ, Haenisch B, Homann J, Wilhelm T, Huber M (2013b) Neue Angriffspunkte der 1-4-Benzodiazepine in der mastzelspezifischen immunsuppressiven Therapie der sytemischen Mastzellüberaktivitätserkrankung. Gastroenterologe 8:170 abstract Molderings GJ, Homann J, Brettner S, Raithel M, Frieling T (2014) Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Dtsch Med Wochenschr 139:1523–1534 Moon PD, Lee BH, Jeong HJ, An HJ, Park SJ, Kim HR, Ko SG, Um JY, Hong SH, Kim HM (2007) Use of scopoletin to inhibit the production of inflammatory cytokines through inhibition of the IkB/NF-kB signal cascade in the human mast cell line HMC-1. Eur J Pharmacol 555:218–225 Mousli M, Hugli TE, Landry Y, Bronner C (1994) Peptidergic pathway in human skin and rat peritoneal mast cell activation. Immunopharmacology 27:1–11 Moussy A, Kinet JP (2014) Treatment of mastocytosis with masitinib. US Patent Application Mühlenberg T, Zhang Y, Wagner AJ, Grabellus F, Bradner J, Taeger G, Lang H, Taguchi T, Schuler M, Fletcher JA, Bauer S (2009) Inhibitors of deacetylases suppress oncogenic KIT signaling, acetylate HSP90, and induce apoptosis in gastrointestinal stromal tumors. Cancer Res 69:6941–6950 Nader MA (2011) Inhibition of anaphylaxis like reaction and mast cell activation by sitagliptin. Int Immunopharmacol 11:1052–1056 Nakamura R, Chakrabarti S, Akin C, Robyn J, Bahceci E, Greene A, Childs R, Dunbar CE, Metcalfe DD, Barrett AJ (2006) A pilot study of nonmyeloablative allogeneic hematopoietic stem cell transplant for advanced systemic mastocytosis. Bone Marrow Transplant 37:353–358 Nolte H, Stahl Skov P (1988) Inhibition of basophil histamine release by methotrexate. Agents Actions 23:173–176 Nurmatov UB, Rhatigan E, Simons FE, Sheikh A (2015) H1-antihistamines for primary mast cell activation syndromes: a systematic review. Allergy 70:1052–1061 Oppong E, Flink N, Cato AC (2013) Molecular mechanisms of glucocorticoid action in mast cells. Mol Cell Endocrinol 380:119–126 Otani IM, Bhagat M, Newbury RO, Dohil R, Broide DH, Aceves SS (2012) The effect of anti-IL-5 therapy on esophageal mastocytosis in pediatric eosinophilic esophagitis. J Allergy Clin Immunol 129:AB202 Paez P, Ryan J, Taruselli M, Ndaw V (2015) Fluvastatin elicits apoptosis in primary and transformed mast cells (INC6P.305). J Immunol 194(Suppl. 1):197.7 Pagano L, Valentini CG, Caira M, Rondoni M, Van Lint MT, Candoni A, Allione B, Cattaneo C, Marbello L, Caramatti C, Pogliani EM, Iannitto E, Giona F, Ferrara F, Invernizzi R, Fanci R, Lunghi M, Fianchi L, Sanpaolo G, Stefani PM, Pulsoni A, Martinelli G, Leone G, Musto P (2008) Advanced mast cell disease: an Italian Hematological Multicenter experience. Int J Hematol 88:483–488 Paivandy A, Calounova G, Zarnegar B, Ohrvik H, Melo FR, Pejler G (2014) Mefloquine, an anti-malaria agent, causes reactive oxygen species-dependent cell death in mast cells via a secretory granule-mediated pathway. Pharmacol Res Perspect 2:e00066 Pan J, Quintas-Cardama A, Kantarjian HM, Akin C, Manshouri T, Lamb P, Cortes JE, Tefferi A, Giles FJ, Verstovsek S (2007) EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation. Blood 109:315–322 Papaetis GS, Syrigos KN (2009) Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies. BioDrugs 23:377–389 Papayannidis C, Soverini S, Benedittis CD, Abbenante MC, Sartor C, Iacobucci I, Baldazzi C, Ottaviani E, Ferrari A, Guadagnuolo V, Conficoni A, Paolini S, Parisi S, Frabetti F, Piccari S, Grilli S, Lani E, Martinelli G (2014) PKC412 (midostaurin) is safe and highly effective in systemic mastocytosis patients: follow up of a single-center Italian compassionate use. Cancer Res 74:746 Pardanani A (2013) Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. Am J Hematol 88:612–624 Pardanani A, Elliott M, Reeder T, Li CY, Baxter EJ, Cross NC, Tefferi A (2003) Imatinib for systemic mast-cell disease. Lancet 362:535–536 Pardanani A, Hoffbrand AV, Butterfield JH, Tefferi A (2004) Treatment of systemic mast cell disease with 2-chlorodeoxyadenosine. Leuk Res 28:127–131 Parikh SA, Kantarjian HM, Richie MA, Cortes JE, Verstovsek S (2010) Experience with everolimus (RAD001), an oral mammalian target of rapamycin inhibitor, in patients with systemic mastocytosis. Leuk Lymphoma 51:269–274 Park TH (2013) The effects of botulinum toxin A on mast cell activity: preliminary results. Burns 39:816–817 Paul C, Sans B, Suarez F, Casassus P, Barete S, Lanternier F, Grandpeix-Guyodo C, Dubreuil P, Palmérini F, Mansfield CD, Gineste P, Moussy A, Hermine O, Lortholary O (2010) Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study. Am J Hematol 85:921–925 Peter B, Hadzijusufovic E, Blatt K, Gleixner KV, Pickl WF, Thaiwong T, Yuzbasiyan-Gurkan V, Willmann M, Valent P (2010) KIT polymorphisms and mutations determine responses of neoplastic mast cells to bafetinib (INNO-406). Exp Hematol 38:782–791 Peter B, Gleixner KV, Cerny-Reiterer S, Herrmann H, Winter V, Hadzijusufovic E, Ferenc V, Schuch K, Mirkina I, Horny HP, Pickl WF, Mullauer L, Willmann M, Valent P (2011) Polo-like kinase-1 as novel target in neoplastic mast cells: demonstration of growth-inhibitory effects of siRNA and the Polo-like kinase-1 targeting drug BI 2536. Haematologica 96(5):672–680 Picard M, Giavina-Bianchi P, Mezzano V, Castells M (2013) Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther 35:548–562 Purtill D, Cooney J, Sinniah R, Carnley B, Cull G, Augustson B, Cannell P (2008) Dasatinib therapy for systemic mastocytosis: four cases. Eur J Haematol 80:456–458 Quintás-Cardama A, Jain N, Verstovsek S (2011) Advances and controversies in the diagnosis, pathogenesis, and treatment of systemic mastocytosis. Cancer 117:5439–5449 Quintás-Cardama A, Sever M, Cortes J, Kantarjian H, Verstovsek S (2013) Bone marrow mast cell burden and serum tryptase level as markers of response in patients with systemic mastocytosis. Leuk Lymphoma 54:1959–1964 Radojković M, Ristić S, Colović N, Terzić T, Colović M (2011) Response to cladribine in patient with systemic mastocytosis. Vojnosanit Pregl 68:444–446 Randall N, Courville EL, Baughn L, Afrin L, Ustun C (2015) Bosutinib, a lyn/btk inhibiting tyrosine kinase inhibitor, is ineffective in advanced systemic mastocytosis. Am J Hematol 90:E74 Ritter M, El-Nour H, Hedblad MA, Butterfield JH, Beck O, Stephanson N, Holst M, Giscombe R, Azmitia EC, Nordlind K (2012) Serotonin and its 5-HT1 receptor in human mastocytosis. Immunopharmacol Immunotoxicol 34:679–685 Rodrigo L, Perez-Martinez I, Lucendo AJ (2013) Urticaria pigmentosa in a female patient wth celiac disease: response to a gluten-free diet. Allergol Immunopathol (Madr) 41:128–130 Rodrigues JM, Pazin Filho A, Rodrigues AJ, Vicente WV, Evora PR (2007) Methylene blue for clinical anaphylaxis treatment: a case report. Sao Paulo Med J 125:60–62 Rodriguez T, Pfeffer M, Levy BD, Castells M (2011) Lipid mediators in cutaneous and systemic mastocytosis and the impact of 5-LO inhibition. J Allergy Clin Immunol 127(Suppl):AB132 Rosen H, Goetzl EJ (2005) Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 5:560–570 Ruano I, Gargini R, Izquierdo M (2010) Combination of KIT gene silencing and tocopherol succinate may offer improved therapeutic approaches for human mastocytosis. Br J Haematol 148:59–68 Sagi L, Solomon M, Baum S, Lyakhovitsky A, Trau H, Barzilai A (2011) Evidence for methotrexate as a useful treatment for steroid-dependent chronic urticaria. Acta Derm Venereol 91:303–306 Sandler C, Nurmi K, Lindstedt KA, Sorsa T, Golub LM, Kovanen PT, Eklund KK (2005) Chemically modified tetracyclines induce apoptosis in cultured mast cells. Int Immunohistopharmacol 5:1611–1621 Schittenhelm MM, Akmut F, Illing B, Frey J, Schuster K, Ramachandran A, Kanz L, Kampa-Schittenhelm KM (2014) Gain-of-function KIT mutations sensitize the mutant isoform to the type I tyrosine kinase inhibitor crenolanib: a rationale for the therapeutic use in systemic mastocytosis (SM) and core binding factor leukemias (CBFL). ASH-Meeting abstract 2230 Seifert R (2015) How do basic secretagogues activate mast cells? Naunyn Schmiedeberg’s Arch Pharmacol 388:279–281 Shimoda T, Liang Z, Suzuki H, Kawana S (2010) Inhibitory effects of antipsychotic and anxiolytic agents on stress-induced degranulation of mouse dermal mast cells. Clin Exp Dermatol 35:531–536 Sido B, Dumoulin FL, Homann J, Hertfelder HJ, Bollmann M, Molderings GJ (2014) Surgical interventions in patients with mast cell activation disease. Aspects relevant for surgery using the example of a cholecystectomy. Chirurg 85:327–333 Siebenhaar F, Förtsch A, Krause K, Weller K, Metz M, Magerl M, Martus P, Church MK, Maurer M (2013) Rupatadine improves quality of life in mastocytosis: a randomized, double-blind, placebo-controlled trial. Allergy 68:949–952 Simhadri VR, Andersen JF, Calvo E, Choi SC, Coligan JE, Borrego F (2012) Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells. Blood 119:2799–2809 Simon J, Lortholary O, Caillat-Vigneron N, Raphael M, Martin A, Briere J, Barete S, Hermine O, Casussus P (2004) Interest of interferon alpha in systemic mastocytosis. The french experience and review of the literature. Pathol Biol 52:294–299 Soter NA, Austen KF, Wasserman SI, Soter NA, Austen KF, Wasserman SI (1979) Oral disodium cromoglycate in the treatment of systemic mastocytosis. N Engl J Med 301:465–469 Spirkoski J, Melo FR, Grujic M, Calounova G, Lundequist A, Wernersson S, Pejler G (2012) Mast cell apoptosis induced by siramesine, a sigma-2 receptor agonist. Biochem Pharmacol 84:1671–1680 Spyridonidis A, Thomas AK, Bertz H, Zeiser R, Schmitt-Graff A, Lindemann A, Waller CF, Finke J (2004) Evidence for a graft-versus-mast-cell effect after allogeneic bone marrow transplantation. Bone Marrow Transplant 34:515–519 Strati P, Kantarjian H, Ravandi F, Nazha A, Borthakur G, Daver N, Kadia T, Estrov Z, Garcia-Manero G, Konopleva M, Rajkhowa T, Durand M, Andreeff M, Levis M, Cortes J (2015) Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J Hematol 90:276–281 Suzuki-Nishimura T, Sano T, Uchida MK (1989) Effects of benzodiazepines on serotonin release from rat mast cells. Eur J Pharmacol 167:75–85 Tachibana M, Wada K, Katayama K, Kamisaki Y, Maeyama K, Kadowaki T, Blumberg RS, Nakajima A (2008) Activation of peroxisome proliferator-activated receptor gamma suppresses mast cell maturation involved in allergic diseases. Allergy 63:1136–1147 Tanaka A, Konno M, Muto S, Kambe N, Morii E, Nakahata T, Itai A, Matsuda H (2005) A novel NF-kappa B inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-Kit receptors. Blood 105:2324–2331 Tang C, Lan C, Wang C, Liu R (2005) Amelioration of the development of multiple organ dysfunction syndrome by somatostatin via suppression of intestinal mucosal mast cells. Shock 23:470–475 Tanimoto A, Ogawa Y, Oki C, Kimoto Y, Nozawa K, Amano W, Noji S, Shiozaki M, Matsuo A, Shinozaki Y, Matsushita M (2015) Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm Res 64:41–51 Tefferi A, Li CY, Butterfield JH, Hoagland HC (2001) Treatment of systemic mast-cell disease with cladribine. N Engl J Med 344:307–309 Tolar J, Tope WD, Neglia JP (2004) Leukotriene-receptor inhibition for the treatment of systemic mastocytosis. N Engl J Med 350:735–736 Topar G, Staudacher C, Geisen F, Gabl C, Fend F, Herold M, Greil R, Fritsch P, Sepp N (1998) Urticaria pigmentosa: a clinical, hematopathologic, and serologic study of 30 adults. Am J Clin Pathol 109:279–285 Trojan TD, Khan DA (2012) Calcineurin inhibitors in chronic urticaria. Curr Opin Allergy Clin Immunol 12:412–420 Turner PJ, Kemp AS, Rogers M, Mehr S (2012) Refractory symptoms successfully treated with leukotriene inhibition in a child with systemic mastocytosis. Pediatr Dermatol 29:222–223 Uchida K, Mitsui M, Kawakishi S (1989) Monooxygenation of N-acetylhistamine mediated by L-ascorbate. Biochim Biophys Acta 991:377–379 Ustun C, Reiter A, Scott BL, Nakamura R, Damaj G, Kreil S, Shanley R, Hogan WJ, Perales MA, Shore T, Baurmann H, Stuart R, Gruhn B, Doubek M, Hsu JW, Tholouli E, Gromke T, Godley LA, Pagano L, Gilman A, Wagner EM, Shwayder T, Bornhäuser M, Papadopoulos EB, Böhm A, Vercellotti G, Van Lint MT, Schmid C, Rabitsch W, Pullarkat V, Legrand F, Yakoub-Agha I, Saber W, Barrett J, Hermine O, Hagglund H, Sperr WR, Popat U, Alyea EP, Devine S, Deeg HJ, Weisdorf D, Akin C, Valent P (2014) Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol 32:3264–3274 Vaali K, Lappalainen J, Lin AH, Mäyränpää MI, Kovanen PT, Berstad A, Eklund KK (2012) Imatinib mesylate alleviates diarrhea in a mouse model of intestinal allergy. Neurogastroenterol Motil 24:e325–e335 Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, Marone G, Nuñez R, Akin C, Sotlar K, Sperr WR, Wolff K, Brunning RD, Parwaresch RM, Austen KF, Lennert K, Metcalfe DD, Vardiman JW, Bennett JM (2001) Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 25:603–625 Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K, Castells M, Sperr WR, Kluin-Nelemans HC, Hamdy NA, Lortholary O, Robyn J, van Doormaal J, Sotlar K, Hauswirth AW, Arock M, Hermine O, Hellmann A, Triggiani M, Niedoszytko M, Schwartz LB, Orfao A, Horny HP, Metcalfe DD (2007) Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Investig 37:435–453 Valent P, Sperr WR, Akin C (2010) How I treat patients with advanced systemic mastocytosis. Blood 116:5812–5817 Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, Castells M, Escribano L, Hartmann K, Lieberman P, Nedoszytko B, Orfao A, Schwartz LB, Sotlar K, Sperr WR, Triggiani M, Valenta R, Horny HP, Metcalfe DD (2012) Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 157:215–225 van Doormaal JJ, Idema IG, de Monchy JG, Breukelman H, Keyzer JJ, Doorenbos H (1986) Effects of isoprenaline and terbutaline on urinary excretion of histamine and its two main metabolites in systemic mastocytosis. Agents Actions 18:269–272 van Doormaal JJ, Arends S, Brunekreeft KL, et al. (2013) Prevalence of indolent systemic mastocytosis in a Dutch region. J Allergy Clin Immunol 131:1429–1431 Vega-Ruiz A, Cortes JE, Sever M, Manshouri T, Quintás-Cardama A, Luthra R, Kantarjian HM, Verstovsek S (2009) Phase II study of imatinibmesylate as therapy for patients with systemic mastocytosis. Leuk Res 33:1481–1484 Verstovsek S, Tefferi A, Cortes J, O’Brien S, Garcia-Manero G, Pardanani A, Akin C, Faderl S, Manshouri T, Thomas D, Kantarjian H (2008) Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis. Clin Cancer Res 14:3906–3915 Vrugt B, Wilson S, Bron A, Shute J, Holgate ST, Djukanovic R, Aalbers R (2000) Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation. Eur Respir J 15:478–485 Welch EA, Alper JC, Bogaars H, Farrell DS (1983) Treatment of bullous mastocytosis with disodium cromoglycate. J Am Acad Dermatol 9:349–353 Weller K, Artuc M, Jennings G, Friedrichson T, Guhl S, Dos Santos RV, Sünder C, Zuberbier T, Maurer M (2009) Miltefosine inhibits human mast cell activation and mediator release both in vitro and in vivo. J Invest Dermatol 129:496–498 Weng Z, Zhang B, Asadi S, Sismanopoulos N, Butcher A, Fu X, Katsarou-Katsari A, Antoniou C, Theoharides TC (2012) Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One 7:e33805 Weng Z, Patel AB, Panagiotidou S, Theoharides TC (2015) The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells. J Allergy Clin Immunol 135:1044–1052 Worobec AS, Kirshenbaum AS, Schwartz LB, Metcalfe DD (1996) Treatment of three patients with systemic mastocytosis with interferon alpha-2b. Leuk Lymphoma 22:501–508 Yacoub A, Prochaska L (2016) Ruxolitinib improves symptoms and quality of life in a patient with systemic mastocytosis. Biomark Res 4:2 Yamaguchi S, Okada Y, Matsunaga Y, Nambu F (2016) Effect of ONO-4053 on FcεRI stimulated mast cell activation. J Allergy Clin Immunol 137:AB77 Yamaki K, Yoshino S (2012) Tyrosine kinase inhibitor sunitinib relieves systemic and oral antigen-induced anaphylaxes in mice. Allergy 67:114–122 Yang Y, Lu JY, Wu X, Summer S, Whoriskey J, Saris C, Reagan JD (2010) G-protein-coupled receptor 35 is a target of the asthma drugs cromolyn disodium and nedocromil sodium. Pharmacology 86:1–5 Yoshida C, Takeuchi M, Tsuchiyama J, Sadahira Y (2009) Successful treatment of KIT D816V-positive, imatinib-resistant systemic mastocytosis with interferon-alpha. Intern Med 48:1973–1978 Zachariae H, Herlin T, Larsen PO (1981) Oral disodium cromoglycate in mastocytosis. Acta Derm Venereol 61:272–273 Zen M, Canova M, Campana C, Bettio S, Nalotto L, Rampudda M, Ramonda R, Iaccarino L, Doria A (2011) The kaleidoscope of glucorticoid effects on immune system. Autoimmun Rev 10:305–310 Zhang T, Finn DF, Barlow JW, Walsh JJ (2016) Mast cell stabilisers. Eur J Pharmacol 778:158–168