Fred H. Hsieh

Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis.

We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A) and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM). SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS) was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04) and sole TET2 mutations (P<0.001). In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients.

Initial experience with a novel desensitization strategy for carboplatin-associated hypersensitivity reactions: carboplatin-hypersensitivity reactions.

PurposeCarboplatin hypersensitivity is an increasingly recognized toxicity in individuals receiving >6 cumulative courses of this important antineoplastic agent. We wished to determine if a novel multi-pronged approach to re-treating patients with a high risk for this potentially serious side effect could permit the safe delivery of this class of cytotoxic drugs.MethodsFive patients with gynecologic malignancies who had either experienced a documented carboplatin hypersensitivity reaction (n =4) or had a “positive” carboplatin skin test (n =1), received a multi-drug oral regimen administered over several days which was designed to block known mediators of anaphylaxis. Four of these individuals subsequently underwent treatment with either cisplatin or carboplatin employing a “dose escalation” desensitization schema.ResultsFour patients underwent successful treatment with either cisplatin or carboplatin (3, 4, 5, 6+ total additional courses) without any further evidence of hypersensitivity.ConclusionIn this preliminary report of a limited patient population, we have demonstrated the ability to safely deliver a platinum agent to individuals with either documented carboplatin hypersensitivity, or a high risk for this potentially serious toxicity of carboplatin. Further exploration of this novel management strategy in a larger group of patients is indicated.

Current approaches to the diagnosis and treatment of systemic mastocytosis

OBJECTIVE To review the clinical manifestations of mastocytosis and examine the recommended diagnostic procedures and therapeutic options available for the treatment of this condition. DATA SOURCES PubMed searches were performed for articles published regarding presentation and classification of mastocytosis and the diagnostic criteria and treatment options for this condition using the keywords mastocytosis, clinical features, World Health Organization diagnostic criteria, management, pathogenesis, and urticaria pigmentosa. Retrieved articles were surveyed for additional citations. STUDY SELECTION Articles were reviewed for relevance to the study objectives, and more recent articles were preferentially included. Prospective studies were preferentially included when available. RESULTS Mastocytosis is a heterogeneous disorder that results from clonal mast cell proliferation. Symptoms are typically limited to the skin in the pediatric population, requiring only symptomatic treatment with spontaneous resolution by puberty. Disease course in adults ranges from minimally symptomatic in most to highly aggressive but tends to be persistent. Symptoms can be protean and nonspecific. The mainstay of treatment consists of avoidance of triggers of mast cell degranulation and symptom-based therapy. CONCLUSIONS Mastocytosis should be suspected in patients who present with a constellation of symptoms, including flushing, abdominal pain, diarrhea, unexplained syncope, and classic urticaria pigmentosa lesions. Diagnosis should be established by a bone marrow biopsy in all adults. Staging should be performed to assess disease burden and evidence of end-stage organ damage. Patients should be offered symptom-based treatment and cytoreductive therapy only for aggressive systemic mastocytosis or an associated hematologic malignant neoplasm.

Detection of phospho‐STAT5 in mast cells: a reliable phenotypic marker of systemic mast cell disease that reflects constitutive tyrosine kinase activation

Systemic mastocytosis (SM) is characterized by the abnormal proliferation and accumulation of mast cells (MCs). Constitutive activation of kit, a receptor tyrosine kinase (TK), has been associated with all types of SM. Signal transducers and activators of transcription (STATs), such as STAT5, mediate downstream kit signalling. We hypothesized that nuclear phospho‐STAT5 (pSTAT5) in MCs might reflect TK activation and would be a marker of abnormal MCs in SM. Expression of tryptase, CD25, CD2 and pSTAT5 was evaluated by immunohistochemistry (IHC) on archival cases of SM and cutaneous mastocytosis (CM). pSTAT5 was detected in 23/23 of SM and 1/9 of CM MC nuclei. 23/23 SM had CD25 + MCs. Control tissue MCs were negative for pSTAT5. Nuclear pSTAT5 in MCs from SM reflects abnormal TK activation. We propose nuclear pSTAT5 positivity in MCs as an additional minor phenotypic criterion for diagnosis of SM in future World Health Organization classification schemes.

SF3B1 mutations are infrequently found in non-myelodysplastic bone marrow failure syndromes and mast cell diseases but, if present, are associated with the ring sideroblast phenotype

The bone marrow failure syndromes (BMFS) are hematologic disorders characterized by impaired production and sometimes function of peripheral blood (PB) cells. While they can be either acquired or inherited, the majority are acquired and include myelodysplastic syndromes (MDS), aplastic anemia (AA),

Glatiramer acetate: successful desensitization for treatment of multiple sclerosis

BACKGROUND Glatiramer acetate is an immunomodulatory drug that is widely prescribed for the treatment of multiple sclerosis. It is frequently associated with local injection site reactions and generalized urticaria. It is also associated with immediate postinjection systemic reactions in approximately 10% of patients. To our knowledge, no desensitization protocols for glatiramer acetate have been published to date. OBJECTIVES To evaluate the safety and efficacy of glatiramer acetate desensitization in a series of patients with multiple sclerosis. METHODS Six patients with multiple sclerosis and glatiramer acetate-associated local or systemic reactions underwent a 4-hour outpatient desensitization procedure at Cleveland Clinic between 2003 and 2008. Beginning with 20 ng, we administered subcutaneous glatiramer acetate suspension in increasing dosages every 15 minutes. Patient outcomes were monitored by return clinic visit and telephone follow-up. RESULTS No episodes of anaphylaxis or serious adverse reactions occurred during or immediately after desensitization. One patient suspended therapy after 14 months due to persistent local injection site reactions. All other patients successfully continued glatiramer acetate therapy. CONCLUSION Glatiramer acetate offers significant benefit to patients with multiple sclerosis. Our experience suggests that patients who suspend its use owing to local or systemic reactions can be successfully and safely desensitized and can resume medication use. To our knowledge, this is the first report of successful desensitization to glatiramer acetate in patients with multiple sclerosis.

Oral food immunotherapy and iatrogenic eosinophilic esophagitis: an acceptable level of risk?

Given the perplexing increase in food allergy during the past 10 considered, were not included. This bias is recognized by authors to 15 years, there has been tremendous interest in offering new treatment options other than the standard-of-care approach of identification, avoidance, and emergency therapy. In the absence of new pharmaceuticals that target mechanisms of sensitization, tolerance, and immune cell activation or treatment of symptoms after exposure, the most pioneering work has been performed in the area of food allergenespecific immunotherapy performed under the direct guidance of the allergist. Because preliminary trials of injection immunotherapy to food were associated with an unacceptable systemic reaction rate,1 modalities such as oral, sublingual, or transcutaneous food desensitization are being explored with oral food desensitization or oral immunotherapy (OIT), the method currently attracting the most clinical research interest.2e4 More than 40 studies of OIT to a variety of food allergens have been reported. The studies involve mostly pediatric but also some adult patients, using a variety of study designs and with varying sample sizes. Despite some promising efficacy outcomes, many studies report significant adverse events, including not only systemic reactions that require epinephrine administration but also cutaneous, respiratory, and gastrointestinal symptoms, and notable dropout rates.5 The identification of newly diagnosed eosinophilic esophagitis in patients undergoing food OIT has been recognized in numerous OIT studies. In this issue of the Annals, Lucendo et al6 report a systematic review and meta-analysis to attempt to address the association between OIT and eosinophilic esophagitis with the available data. Using a reference search strategy that encompassed OIT studies in which at least one case of eosinophilic esophagitis was reported, the investigators identified 12 publications (8 being abstracts only) for analysis. This report included data from 711 patients undergoing OIT to peanut, egg, cow’s milk, or wheat, with most of the patients being children, in retrospective studies, randomized clinical trials, or case reports. On the basis of this available data set, the investigators calculate a 2.72% (95% confidence interval, 1.7%e4.0%) prevalence of eosinophilic esophagitis in patients with IgE-mediated food allergy undergoing specific food OIT. Because of the study design, individual studies of OIT were excluded from the meta-analysis if no cases of eosinophilic esophagitis were reported; this 2.72% figure may overestimate the overall prevalence. The OIT studies not reporting eosinophilic esophagitis, either because there was no eosinophilic gastrointestinal disease or because eosinophilic esophagitis was not

The Utility of Serum Tryptase as a Marker in Chronic Spontaneous Urticaria

© 2013 The Authors. doi: 10.2340/00015555-1486 Journal Compilation

Mast cell phenotypes in the allograft after lung transplantation

The burden of mast cell (MC) infiltration and their phenotypes, MC‐tryptase (MCT) and MC‐tryptase/chymase (MCTC), after lung transplantation (LT) has not been evaluated in human studies.

Year in review: urticaria and angioedema

Defects in filaggrin gene expression have been associated with skin epithelial barrier dysfunction and have been implicated in the pathogenesis of atopic dermatitis; Ye et al1 studied the expression of filaggrin in patients with chronic urticaria (CU). In skin biopsies from patients with CU, patients with atopic dermatitis, and normal controls, filaggrin expression was significantly increased only in patients with CU. This increase in filaggrin expression in CU was correlated with higher urticaria activity scores, increased transepidermal water loss, and decreased skin pH, suggesting that alterations in filaggrin expression in CU are associated with altered skin barrier function. Palikhe et al2 measured soluble P-selectin and the expression of P2Y12, a G-protein coupled purinergic receptor, on platelets derived from 14 aspirin-intolerant and 29 aspirin-tolerant patients with CU and 25 normal controls. P2Y12 expression was higher in patients with CU and soluble P-selectin levels were higher in aspirin-intolerant patients with CU compared with aspirin-tolerant patients. This preliminary study proposes a role for platelet activation in CU, although a direct mechanism by which platelet activation affects CU pathogenesis remains to be elucidated.