scholarly journals Myeloproliferative Hypereosinophilic Syndrome with Concomitant Ischemic Events

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4640-4640
Author(s):  
Roxanne T Aleman ◽  
Spencer Deleveaux ◽  
Mauna B Pandya
Keyword(s):  
Mast Cells ◽  
Skin Biopsy ◽  
Hypereosinophilic Syndrome ◽  
Published Data ◽  
High Dose ◽  
Kit Mutation ◽  
Coronary Syndrome ◽  
Cardiac Symptoms ◽  
Wide Range ◽  
Ischemic Events

Abstract Background: Eosinophils are versatile reactionary cells that play a key role in the inflammatory response. Excessive proliferation and aggregation of eosinophils have been implicated in the pathogenesis of ischemic neurologic and cardiac events. We present a rare case of hypereosinophilic syndrome (HES) in a patient hospitalized for simultaneous acute cerebrovascular accident (CVA) and acute coronary syndrome. Case: A 53-year-old male with past medical history of hypertension and diabetes mellitus presented with new onset bifrontal headache, right arm numbness and apraxia, and concurrent typical angina. On physical examination, he had small non-tender raised nodules on the bilateral upper and lower limbs. MRI of the brain demonstrated multifocal infarcts in a watershed distribution. Biochemical investigation revealed rising troponins. Splenomegaly of 16.4 cm was found on CT imaging. He was admitted for management of acute CVA and non-ST segment elevation myocardial infarction (NSTEMI). Complete blood count (CBC) revealed leukocytosis (34.4 K/mcL) with an eosinophilia of 85% and an absolute eosinophil count (AEC) of 29.2 x 10 3 eosinophils/µL. Serum tryptase was 29.2 µg/L. The patient was started on a high dose steroid with subsequent resolution of his neurologic and cardiac symptoms. Due to high suspicion for HES, FISH panel and bone marrow biopsy were performed. A small focus of marrow on his biopsy showed abundant eosinophils and bland spindle cells (>15 mast cells in aggregate). FISH panel was positive for 4q12 rearrangement, consistent with a FIP1L1/PDGFRA fusion mutation. Skin biopsy of his lesions demonstrated superficial and deep inflammation with eosinophils. He was diagnosed with myeloproliferative HES with features of mastocytosis and started on imatinib. Discussion: The defining features of HES consist of eosinophilia greater than 1500/µL for greater than 6 months with evidence of eosinophil induced tissue infiltration and injury. The ability of eosinophils to induce pathologic outcomes is influenced by a variety of parameters, including the number of eosinophils present, their location, and the degree of activation. Published data suggests that neurologic and cardiac ischemic events occur in HES patients with a higher leukocyte count and AEC than what we present with in this case. Our patient meets the main lab criteria of HES and our case highlights that simultaneous clinical manifestations can occur in the absence of markedly elevated peripheral eosinophilia. As with most cases involving unexplained hypereosinophilia, a wide range of diagnostic testing was necessary. The presence of a PDGFRA fusion mutation established a clonal disorder, supporting the diagnosis of myeloproliferative HES variant. The presence of eosinophils and the lack of mast cells on skin biopsy further supports myeloproliferative HES variant rather than a true systemic mastocytosis. Despite recent advances in molecular and immunologic therapies, treatment for HES remains challenging due to the wide variety of etiological classifications necessitating targeted treatments. At the time of submission, KIT mutation analysis is pending. Identification of a KIT D816V mutation would support use of midostaurin or the recently approved avapritinib for treatment of overlap syndrome. Disclosures No relevant conflicts of interest to declare.

Dasatinib (Sprycel™) Therapy for Patients with Systemic Mastocytosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3627-3627 ◽  
Author(s):  
Srdan Verstovsek ◽  
Hagop Kantarjian ◽  
Jorge Cortes ◽  
Farhad Ravandi-Kashani ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Interferon Alpha ◽  
Systemic Mastocytosis ◽  
Performance Status ◽  
Hypereosinophilic Syndrome ◽  
In Vivo Models ◽  
Recombinant Interferon ◽  
Kit Mutation

Abstract Background Systemic mastocytosis (SM) is characterized by abnormal proliferation and accumulation of neoplastic mast cells. Patients (pts) with SM are treated with recombinant interferon-alpha or cladribine. Responses to these agents are poor. Malignant mast cells in SM carry, in most cases, a mutation involving codon 816 of the c-KIT gene (D816V) resulting in constitutively activated c-kit receptor tyrosine kinase believed to be important for disease progression. Agents that antagonize this mutated form of c-kit may have clinical benefit in SM. Dasatinib is one such agent, proven effective in pre-clinical in vitro and in vivo models of SM. Study Design In pilot Phase II trial for SM, Dasatinib was administered at 70mg PO BID. Response was assessed after minimum of 3 months (3 cycles) of therapy. Therapy was discontinued in pts who showed no response after 6 cycles of therapy. Response was evaluated following guidelines proposed by Valent et al. (Leuk Res. 25;603–625, 2001). In addition, all symptoms related to SM were recorded and monitored. Results Thus far, a total of 30 pts have been treated; 24 are evaluable for response and toxicity, including 6 with aggressive SM (ASM), 4 with SM and associated hematologic non-mast cell disease (SM-AHNMD; 2 with chronic myelomonocytic leukemia and one each with myelofibrosis [SM-MF; JAK2 mutation positive and abnormal cytogenetics] and hypereosinophilic syndrome [SM-HES; FIP1L1-PDGFRa negative]) and 14 with indolent SM (ISM) with uncontrolled symptoms despite optimal supportive care measures. Median age is 57 years (range, 35–73); these were 10 males and 14 females; time from diagnosis to dasatinib therapy 49 months (range, 0–233), performance status 1 in 23 and 2 in 1 pt. Eleven patients were previously treated: imatinib mesylate in 6; denileukin diftitox in 4; and erythropoietin, interferon-alpha, or cladribine in 2 each. One pt, who had undergone splenectomy, had hepatomegaly prior to start of therapy. Median Hb 12.4g/dL (range, 8.5–15.4), WBC 6.7×109/L, (range, 3.5–53.3), and platelets 263×109/L (range, 60–377); no patient was transfusion dependent. Percent bone marrow mast cell varied from <10% in 9 pts, to 60% in 4 pts; blood tryptase level was ≤20ng/mL (not significant) in 7 pts and >200ng/mL (upper limit of the test) in 7 pts. A total of 94 cycles of therapy were administered. The median number of cycles was 4 (range, 1–8). Ten patients stopped therapy: 1 due to progression of AHNMD to acute leukemia, 1 lost a response (symptomatic improvement), 2 had no response after 3 months of therapy, and 6 due to toxicity. No grade 4 toxicity was observed. Twelve patients decreased the dose of dasatinib to 50mg PO BID, of which four to 40mg PO BID. Two patients (8%) achieved complete remission, one with SM-MF, and one with SM-HES. Both were c-KIT mutation negative and had low, not significant tryptase levels. Both were anemic (Hb 9.4g/dL) and failed erythropoietin therapy, and had abnormal WBC differential; one had low platelets (90×109/L). No significant response in % bone marrow mast cells (4 pts are too early in therapy) or blood tryptase levels have been observed in other patients so far. Symptoms related to SM improved significantly in 7 patients (29%). Conclusion Dasatinib is active in SM (overall response rate 37%). Updated clinical and molecular results will be presented.

Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4660-4666 ◽  
Author(s):  
Amy D. Klion ◽  
Pierre Noel ◽  
Cem Akin ◽  
Melissa A. Law ◽  
D. Gary Gilliland ◽  
...  
Keyword(s):  
Mast Cells ◽  
Poor Prognosis ◽  
Systemic Mastocytosis ◽  
Hypereosinophilic Syndrome ◽  
Elevated Serum ◽  
Clinical Manifestations ◽  
Serum Tryptase ◽  
Bone Marrow Biopsies ◽  
Kit Mutation ◽  
Tissue Fibrosis

Abstract Since serum tryptase levels are elevated in some patients with myeloproliferative disorders, we examined their utility in identifying a subset of patients with hypereosinophilic syndrome (HES) and an underlying myeloproliferative disorder. Elevated serum tryptase levels (&gt; 11.5 ng/mL) were present in 9 of 15 patients with HES and were associated with other markers of myeloproliferation, including elevated B12 levels and splenomegaly. Although bone marrow biopsies in these patients showed increased numbers of CD25+ mast cells and atypical spindle-shaped mast cells, patients with HES and elevated serum tryptase could be distinguished from patients with systemic mastocytosis and eosinophilia by their clinical manifestations, the absence of mast cell aggregates, the lack of a somatic KIT mutation, and the presence of the recently described fusion of the Fip1–like 1 (FIP1L1) gene to the platelet-derived growth factor receptor α gene (PDGFRA). Patients with HES and elevated serum tryptase were more likely to develop fibroproliferative end organ damage, and 3 of 9 died within 5 years of diagnosis in contrast to 0 of 6 patients with normal serum tryptase levels. All 6 patients with HES and elevated tryptase treated with imatinib demonstrated a clinical and hematologic response. In summary, elevated serum tryptase appears to be a sensitive marker of a myeloproliferative variant of HES that is characterized by tissue fibrosis, poor prognosis, and imatinib responsiveness.

Eosinophilic vasculitis: an inhabitual and resistant manifestation of a vasculitis

VASA ◽  
2010 ◽  
Vol 39 (4) ◽  
pp. 344-348 ◽  
Author(s):  
Jandus ◽  
Bianda ◽  
Alerci ◽  
Gallino ◽  
Marone
Keyword(s):  
Skin Biopsy ◽  
Intravenous Iron ◽  
Small Vessel Vasculitis ◽  
High Dose ◽  
Raynaud Phenomenon ◽  
The Third ◽  
Left Elbow ◽  
Right Hand ◽  
The Right ◽  
Trunk Skin

A 55-year-old woman was referred because of diffuse pruritic erythematous lesions and an ischemic process of the third finger of her right hand. She was known to have anaemia secondary to hypermenorrhea. She presented six months before admission with a cutaneous infiltration on the left cubital cavity after a paravenous leakage of intravenous iron substitution. She then reported a progressive pruritic erythematous swelling of her left arm and lower extremities and trunk. Skin biopsy of a lesion on the right leg revealed a fibrillar, small-vessel vasculitis containing many eosinophils.Two months later she reported Raynaud symptoms in both hands, with a persistent violaceous coloration of the skin and cold sensation of her third digit of the right hand. A round 1.5 cm well-delimited swelling on the medial site of the left elbow was noted. The third digit of her right hand was cold and of violet colour. Eosinophilia (19 % of total leucocytes) was present. Doppler-duplex arterial examination of the upper extremities showed an occlusion of the cubital artery down to the palmar arcade on the right arm. Selective angiography of the right subclavian and brachial arteries showed diffuse alteration of the blood flow in the cubital artery and hand, with fine collateral circulation in the carpal region. Neither secondary causes of hypereosinophilia nor a myeloproliferative process was found. Considering the skin biopsy results and having excluded other causes of eosinophilia, we assumed the diagnosis of an eosinophilic vasculitis. Treatment with tacrolimus and high dose steroids was started, the latter tapered within 12 months and then stopped, but a dramatic flare-up of the vasculitis with Raynaud phenomenon occurred. A new immunosupressive approach with steroids and methotrexate was then introduced. This case of aggressive eosinophilic vasculitis is difficult to classify into the usual forms of vasculitis and constitutes a therapeutic challenge given the resistance to current immunosuppressive regimens.

It is better an approximate answer to the right question than the exact answer to the wrong question : the case of the psychometric analysis of the ASQ:SE

2020 ◽  
Author(s):  
Luis Anunciacao ◽  
janet squires ◽  
J. Landeira-Fernandez
Keyword(s):  
Internal Structure ◽  
Statistical Methods ◽  
Principal Component ◽  
Psychological Theory ◽  
Published Data ◽  
Multivariate Statistical ◽  
Exact Answer ◽  
Wide Range ◽  
Ages And Stages Questionnaire ◽  
The Right

One of the main activities in psychometrics is to analyze the internal structure of a test. Multivariate statistical methods, including Exploratory Factor analysis (EFA) and Principal Component Analysis (PCA) are frequently used to do this, but the growth of Network Analysis (NA) places this method as a promising candidate. The results obtained by these methods are of valuable interest, as they not only produce evidence to explore if the test is measuring its intended construct, but also to deal with the substantive theory that motivated the test development. However, these different statistical methods come up with different answers, providing the basis for different analytical and theoretical strategies when one needs to choose a solution. In this study, we took advantage of a large volume of published data (n = 22,331) obtained by the Ages and Stages Questionnaire Social-Emotional (ASQ:SE), and formed a subset of 500 children to present and discuss alternative psychometric solutions to its internal structure, and also to its subjacent theory. The analyses were based on a polychoric matrix, the number of factors to retain followed several well-known rules of thumb, and a wide range of exploratory methods was fitted to the data, including EFA, PCA, and NA. The statistical outcomes were divergent, varying from 1 to 6 domains, allowing a flexible interpretation of the results. We argue that the use of statistical methods in the absence of a well-grounded psychological theory has limited applications, despite its appeal. All data and codes are available at https://osf.io/z6gwv/.

scholarly journals Flow and Particle Modelling of Dry Powder Inhalers: Methodologies, Recent Development and Emerging Applications

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 189
Author(s):  
Zhanying Zheng ◽  
Sharon Shui Yee Leung ◽  
Raghvendra Gupta
Keyword(s):  
Dry Powder Inhaler ◽  
Research Direction ◽  
Particle Methods ◽  
Future Research ◽  
High Dose ◽  
Dry Powder ◽  
Multi Scale ◽  
Wide Range ◽  
Computational Fluid Dynamics Cfd ◽  
Discrete Element Methods

Dry powder inhaler (DPI) is a device used to deliver a drug in dry powder form to the lungs. A wide range of DPI products is currently available, with the choice of DPI device largely depending on the dose, dosing frequency and powder properties of formulations. Computational fluid dynamics (CFD), together with various particle motion modelling tools, such as discrete particle methods (DPM) and discrete element methods (DEM), have been increasingly used to optimise DPI design by revealing the details of flow patterns, particle trajectories, de-agglomerations and depositions within the device and the delivery paths. This review article focuses on the development of the modelling methodologies of flow and particle behaviours in DPI devices and their applications to device design in several emerging fields. Various modelling methods, including the most recent multi-scale approaches, are covered and the latest simulation studies of different devices are summarised and critically assessed. The potential and effectiveness of the modelling tools in optimising designs of emerging DPI devices are specifically discussed, such as those with the features of high-dose, pediatric patient compatibility and independency of patients’ inhalation manoeuvres. Lastly, we summarise the challenges that remain to be addressed in DPI-related fluid and particle modelling and provide our thoughts on future research direction in this field.

scholarly journals Regulation of Cytochrome c Oxidase by Natural Compounds Resveratrol, (–)-Epicatechin, and Betaine

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1346
Author(s):  
Icksoo Lee
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Model Systems ◽  
Health Improvement ◽  
Published Data ◽  
Mitochondrial Electron Transport Chain ◽  
Naturally Occurring ◽  
Transport Chain ◽  
Wide Range ◽  
Experimental Model Systems

Numerous naturally occurring molecules have been studied for their beneficial health effects. Many compounds have received considerable attention for their potential medical uses. Among them, several substances have been found to improve mitochondrial function. This review focuses on resveratrol, (–)-epicatechin, and betaine and summarizes the published data pertaining to their effects on cytochrome c oxidase (COX) which is the terminal enzyme of the mitochondrial electron transport chain and is considered to play an important role in the regulation of mitochondrial respiration. In a variety of experimental model systems, these compounds have been shown to improve mitochondrial biogenesis in addition to increased COX amount and/or its enzymatic activity. Given that they are inexpensive, safe in a wide range of concentrations, and effectively improve mitochondrial and COX function, these compounds could be attractive enough for possible therapeutic or health improvement strategies.

scholarly journals A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2840
Author(s):  
Dana M. Zaher ◽  
Wafaa S. Ramadan ◽  
Raafat El-Awady ◽  
Hany A. Omar ◽  
Fatema Hersi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cell ◽  
Xenograft Model ◽  
Mitochondrial Metabolism ◽  
High Dose ◽  
Anticancer Effect ◽  
Safety Margins ◽  
Wide Range

(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer.

PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 752-759 ◽  
Author(s):  
Karoline V. Gleixner ◽  
Matthias Mayerhofer ◽  
Karl J. Aichberger ◽  
Sophia Derdak ◽  
Karoline Sonneck ◽  
...  
Keyword(s):  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Drug Effects ◽  
Kit Mutation ◽  
Growth Inhibitory ◽  
Ic50 Values ◽  
Tk Inhibitors ◽  
Mast Cell Leukemia ◽  
Kit D816v

AbstractIn most patients with systemic mastocytosis (SM), including aggressive SM and mast cell leukemia (MCL), neoplastic cells express the oncogenic KIT mutation D816V. KIT D816V is associated with constitutive tyrosine kinase (TK) activity and thus represents an attractive drug target. However, imatinib and most other TK inhibitors fail to block the TK activity of KIT D816V. We show that the novel TK-targeting drugs PKC412 and AMN107 counteract TK activity of D816V KIT and inhibit the growth of Ba/F3 cells with doxycycline-inducible expression of KIT D816V as well as the growth of primary neoplastic mast cells and HMC-1 cells harboring this KIT mutation. PKC412 was a superior agent with median inhibitory concentration (IC50) values of 50 to 250 nM without differences seen between HMC-1 cells exhibiting or lacking KIT D816V. By contrast, AMN107 exhibited more potent effects in KIT D816V- HMC-1 cells. Corresponding results were obtained with Ba/F3 cells exhibiting wild-type or D816V-mutated KIT. The growth-inhibitory effects of PKC412 and AMN107 on HMC-1 cells were associated with induction of apoptosis and down-regulation of CD2 and CD63. PKC412 was found to cooperate with AMN107, imatinib, and cladribine (2CdA) in producing growth inhibition in HMC-1, but synergistic drug interactions were observed only in cells lacking KIT D816V. Together, PKC412 and AMN107 represent promising novel agents for targeted therapy of SM. (Blood. 2006;107: 752-759)

Lateral skull base surgery: a complicated pursuit?

2007 ◽  
Vol 122 (3) ◽  
pp. 221-229
Author(s):  
V C Cousins
Keyword(s):  
Skull Base ◽  
Skull Base Surgery ◽  
Treatment Modalities ◽  
Published Data ◽  
Know How ◽  
Team Assessment ◽  
Pathological Conditions ◽  
Lateral Skull Base ◽  
Wide Range ◽  
Multi Disciplinary Team

AbstractThe management of lesions of the lateral skull base is a highly sophisticated branch of surgery generally performed by otolaryngology–head and neck surgeons as part of a multi-disciplinary team. Assessment of patients with diseases affecting the lateral skull base can be complex, as can the application of the various treatment modalities and the management of the expected and unexpected side effects of that treatment.A wide range of pathological conditions occur in the lateral skull base. Many operations and procedures have been described for dealing with them. There is not necessarily one correct solution to the management of any particular problem in the skull base, with multiple factors to be considered in planning and intervention.As surgeons, we need to know how our own results and outcomes compare with pooled, published data concerning the implications and complications occurring as a result of intervention, in order to better advise our patients on their management.

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