scholarly journals ASXL1 and CBL Mutations Are Independently Predictive of Inferior Survival in Advanced Systemic Mastocytosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 828-828 ◽  
Author(s):  
Animesh Pardanani ◽  
Terra L. Lasho ◽  
Christy Finke ◽  
Darci Zblewski ◽  
Ramy Abdelrahman ◽  
...  
Keyword(s):  
Deep Sequencing ◽  
Prognostic Value ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasm ◽  
Clinical Manifestations ◽  
World Health ◽  
Kit Mutation ◽  
Specific Pcr ◽  
Health Organization ◽  
Kit D816v

Abstract Background: KIT D816V is considered the driver mutation in systemic mastocytosis (SM) however this mutation alone does not explain the diverse clinical manifestations of SM. While mutations in other myeloid-relevant genes have been reported in SM, their pattern(s) of co-segregation and prognostic value, independent of age and SM subtype, have not been fully defined in a mature dataset. Objectives: In this pilot study of advanced SM patients, we sequenced a panel of myeloid-relevant genes for known pathogenic mutations, to ascertain: (i) the frequency of individual mutations; (ii) the pattern(s) of mutation co-segregation; and (iii) the prognostic value of mutations, both individually and in combination, on overall- (OS) and leukemia-free survival (LFS). Methods: The current study was approved by the Mayo Clinic institutional review board. SM was classified as per World Health Organization criteria. DNA was isolated from archived bone marrow (BM) cell pellets. Next-generation deep sequencing by HiSeq SBS chemistry (Illumina) was performed to investigate the coding regions of 22 genes: KIT, JAK2, CALR, SRSF2, U2AF1, SF3B1, ASXL1, TET2, EZH2, SETBP1, DNMT3A, IDH-1/2, SUZ12, CBL, NRAS, FLT3, PTPN11, RUNX1, CEBPA, TP53 and NPM1. Results: We studied 19 patients with advanced SM; 6 had aggressive SM (ASM) and 13 had SM with an associated hematological disease (SM-AHD). Of the latter, 5 patients (38%) had myeloproliferative neoplasm-unclassified (MPN-u), 3 (23%) chronic myelomonocytic leukemia (CMML), 2 (15%) acute myeloid leukemia (AML), and 1 (8%) each polycythemia vera, myelodysplastic syndrome, and multiple myeloma. The median follow up from diagnosis was 20 months (range 2 to 84). Over this period, 5 patients (26%) developed leukemic transformation and 12 patients (63%) have died. KIT D816V was identified in 9 (47%) patients; 9 of 10 patients who tested negative by deep sequencing were screened by allele-specific PCR (sensitivity ~0.01%), with 8 additional patients testing positive. Thus, overall KIT D816V frequency was 89%. Fourteen (74%) patients harbored at least one additional non-KIT mutation; of these 7 patients had one additional mutation (ASXL1/TET2/SF3B1 = 2 each and JAK2 =1), 3 patients each had two and three additional mutations, and 1 patient had 4 additional mutations. The most frequently mutated genes (other than KIT) were ASXL1/TET2 (5 patients each, 26%), CBL (4 patients, 21%), SETBP1/SF3B1/DNMT3A (2 patients each, 11%) and JAK2/CALR/FLT3/IDH-1/RUNX1/TP53 (1 patient each, 5%). There was no overlap between patients harboring TET2 and ASXL1 mutations however 2 and 1 CBL-mutated patients concurrently harbored TET2 and ASXL1 mutations, respectively. SETBP1 and SF3B1 but not DNMT3A mutations occurred independently of TET2 and ASXL1 mutations. The distribution of mutations was similar between ASM and SM-AHD subgroups. When considered individually, the following non-KIT mutated genes (present in at least 2 patients) were associated with significantly inferior OS: ASXL1, CBL and SETBP1 (p<0.05). When the 3 mutated genes were considered together, only ASXL1 and CBL maintained their significance, independent of age and SM subtype, for inferior OS (Hazard ratio (95% confidence interval)=34.8 (3.1-393.9) and 59.7 (4.1-861.5), respectively). Patients harboring ASXL1 and/or CBL mutations (n=8, 8 deaths, median OS=11 months) had a significantly worse OS as compared to those without either mutation (n=11, 4 deaths, median OS=84 months) (p=0.0002) (Fig 1). When considering the number of non-KIT mutations (zero, one, two, three and four mutations in 5, 7, 3, 3 and 1 patients, respectively), the group with ≥3 mutations (n=4, 4 deaths, median OS=7 months) had a significantly inferior OS as compared to those with <3 mutations (n=15, 8 deaths, median OS=48 months) (p=0.01) (Fig 2). Presence of mutations was not correlated with LFS in this analysis. Conclusions: In this cohort of advanced SM patients, non-KIT mutations were frequent (prevalence 74%). TET2, ASXL1, SETBP1 and SF3B1, but not CBL or DNMT3A, mutations were mutually exclusive. Presence of ASXL1 and CBL mutations was associated with significantly inferior OS (HR=35 and 60, respectively), independent of known prognostic factors. An increasing number of non-KIT mutations (≥3, HR=5.9) was also associated with a significantly worse survival outcome. Sequencing results from a larger cohort will be presented at the meeting. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Pardanani: Stemline: Research Funding.

scholarly journals Rare and unknown canine systemic mastocytosis: clinical and laboratory features of an aberrant c-Kit mutation neoplasia

2021 ◽  
Vol 58 ◽  
pp. e175896
Author(s):  
Carla Sofia Soares ◽  
Leonor Delgado ◽  
Sónia Morgado ◽  
Pedro Pires Carvalho ◽  
Luís Carlos Barros
Keyword(s):  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasms ◽  
World Health ◽  
Base Pairs ◽  
Kit Mutation ◽  
Laboratory Features ◽  
Exon 11 ◽  
Serra Da Estrela ◽  
Health Organization ◽  
Reported Data

Systemic mastocytosis (SM) pathology is extremely rare in canine practice, with insufficient reported data. The knowledge of the clinical behavior of this pathology is scarce. In human medicine, SM has been widely investigated, being defined as a rare hematopoietic disorder by the World Health Organization (2016), within the type of myeloproliferative neoplasms. Herein, we describe a systemic mastocytosis case in a Portuguese Serra-da-Estrela dog, where a cutaneous grade III/high-grade MCT was also diagnosed. The clinical decline of the animal and owner’s insistence throughout anamnesis that the dog was markedly different after the cytologic exam performed in another clinic, along with both severe eosinophilia and hepatomegaly, led to the clinical suspicion of SM. The animal passed away 7 days later. Post-mortem investigation confirmed SM pathology, and a deletion of 15 base pairs change on c-Kit gene exon 11 was identified. Contemplating the low number of cases described in the literature, this publication aims to disclose clinical and laboratory features of rare and poorly described canine SM, taking into consideration human outcomes described in the literature.

Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies

Blood ◽  
2009 ◽  
Vol 114 (18) ◽  
pp. 3769-3772 ◽  
Author(s):  
Animesh Pardanani ◽  
Ken-Hong Lim ◽  
Terra L. Lasho ◽  
Christy Finke ◽  
Rebecca F. McClure ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasm ◽  
Cell Lineage ◽  
Chronic Myelomonocytic Leukemia ◽  
World Health ◽  
Primary Data ◽  
Myeloid Neoplasm ◽  
Health Organization ◽  
Myelomonocytic Leukemia

Abstract The prognostic heterogeneity of the World Health Organization category of “systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease” (SM-AHNMD) has not been systematically validated by primary data. Among 138 consecutive cases with SM-AHNMD, 123 (89%) had associated myeloid neoplasm: 55 (45%) myeloproliferative neoplasm (SM-MPN), 36 (29%) chronic myelomonocytic leukemia, 28 (23%) myelodysplastic syndrome (SM-MDS), and 4 (3%) acute leukemia. Of the myeloid subgroups, SM-MPN displayed a 2- to 3-fold better life expectancy (P = .003), whereas leukemic transformation was more frequent in SM-MDS (29%; P = .02). The presence of eosinophilia, although prevalent (34%), was prognostically neutral, and the overall results were not affected by exclusion of FIP1L1-PDGFRA-positive cases. We conclude that it is clinically more useful to consider specific entities, such as SM-MPN, systemic mastocytosis with chronic myelomonocytic leukemia, SM-MDS, and systemic mastocytosis with-acute leukemia, rather than their broad reference as SM-AHNMD.

scholarly journals The new tool “KIT” in advanced systemic mastocytosis

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 127-136 ◽  
Author(s):  
William Shomali ◽  
Jason Gotlib
Keyword(s):  
Cell Activation ◽  
Systemic Mastocytosis ◽  
Symptom Burden ◽  
Organ Damage ◽  
Mast Cell Activation ◽  
World Health ◽  
Hematologic Neoplasm ◽  
Health Organization ◽  
Kit D816v

AbstractMastocytosis is a rare disease characterized by KIT-driven expansion and accumulation of neoplastic mast cells in various tissues. Although mediator symptoms related to mast cell activation can impose a symptom burden in cutaneous disease and across the spectrum of systemic mastocytosis subtypes, the presence of an associated hematologic neoplasm and/or organ damage denotes advanced disease and the potential for increased morbidity and mortality. In addition to the revised 2016 World Health Organization classification of mastocytosis, a new diagnostic and treatment toolkit, tethered to enhanced molecular characterization and monitoring, is poised to transform the management of patients with advanced systemic mastocytosis (advSM). Although the efficacy of midostaurin and novel selective KIT D816V inhibitors, such as avapritinib (BLU-285), have validated KIT as a therapeutic target, the clinical and biologic heterogeneity of advSM requires that we reimagine the blueprint for tackling these diseases and use tools that move beyond KIT-centric approaches.

COVID 19: REALS AND CHALLENGES AGAINST DOCTORS

2020 ◽  
Vol 2 (1) ◽  
pp. 65-87
Author(s):  
Zen Ahmad
Keyword(s):  
Virus Disease ◽  
Clinical Manifestations ◽  
World Health ◽  
Unknown Etiology ◽  
Wuhan City ◽  
Traditional Markets ◽  
Pneumonia Case ◽  
The World ◽  
New Type ◽  
Health Organization

Corona Virus Disease (Covid-19) is a contagious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which was discovered in December 2019 in China. This disease can cause clinical manifestations in the airway, lung and systemic. The World Health Organization (WHO) representative of China reported a pneumonia case with unknown etiology in Wuhan City, Hubei Province, China on December 31, 2019. The cause was identified as a new type of coronavirus on January 7, 2020 with an estimated source of the virus from traditional markets (seafood market). ) Wuhan city

Possible role of Unani Pharmacology in COVID-19 – a narrative review

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Md Anzar Alam ◽  
Mohd Abdul Gani ◽  
G. Shama ◽  
Ghulamuddin Sofi ◽  
Mohd Aleemuddin Quamri
Keyword(s):  
Clinical Manifestations ◽  
Public Health Problem ◽  
World Health ◽  
Santalum Album ◽  
Boswellia Serrata ◽  
Unani Medicine ◽  
Significant Public Health Problem ◽  
Significant Public Health ◽  
Novel Coronavirus ◽  
Health Organization

AbstractAccording to the World Health Organization (WHO), viral diseases continue to rise, and pose a significant public health problem. Novel coronavirus disease (COVID-19) is an infectious disease caused by SARS-CoV-2. The pathogenesis and clinical manifestations of COVID-19 is close to Amraz-e-Wabai (epidemic diseases) which was described by Hippocrates, Galen, Aristotle, Razes, Haly Abbas, Avicenna, Jurjani etc. Presently, there is no specific or challenging treatment available for COVID-19. Renowned Unani Scholars recommended during epidemic situation to stay at home, and fumigate the shelters with aromatics herbs like Ood kham (Aquilaria agallocha Roxb.), Kundur (Boswellia serrata Roxb), Kafoor (Cinnamomum camphora L.), Sandal (Santalum album L), Hing (Ferula foetida L.) etc. Use of specific Unani formulations are claimed effective for the management of such epidemic or pandemic situation like antidotes (Tiryaqe Wabai, Tiryaqe Arba, Tiryaqe Azam, Gile Armani), Herbal Decoction (Joshandah), along with Sharbate Khaksi, Habbe Bukhar, Sharbate Zanjabeel, Khamira Marwareed, Jawarish Jalinus, and Sirka (vinegar). Such drugs are claimed for use as antioxidant, immunomodulatory, cardiotonic, and general tonic actions. The study enumerates the literature regarding management of epidemics in Unani medicine and attempts to look the same in the perspective of COVID-19 prevention and management.

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)

Prognostic value of initial magnetic resonance imaging growth rates for World Health Organization grade II gliomas

2006 ◽  
Vol 60 (3) ◽  
pp. 380-383 ◽  
Author(s):  
Johan Pallud ◽  
Emmanuel Mandonnet ◽  
Hugues Duffau ◽  
Michèle Kujas ◽  
Rémy Guillevin ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
World Health Organization ◽  
Growth Rates ◽  
Prognostic Value ◽  
World Health ◽  
Resonance Imaging ◽  
Grade Ii ◽  
Health Organization

scholarly journals Comparative Analysis of Pediatric COVID-19 Infection in Southeast Asia, South Asia, Japan, and China

2021 ◽  
Author(s):  
Judith Ju Ming Wong ◽  
Qalab Abbas ◽  
Soo Lin Chuah ◽  
Ririe Fachrina Malisie ◽  
Kah Min Pon ◽  
...  
Keyword(s):  
Risk Factors ◽  
South Asia ◽  
Cultural Practices ◽  
Severe Disease ◽  
Clinical Manifestations ◽  
World Health ◽  
Logistic Regression Models ◽  
Clinical Presentations ◽  
The Common ◽  
Health Organization

There is a scarcity of data regarding coronavirus disease 2019 (COVID-19) infection in children from southeast and south Asia. This study aims to identify risk factors for severe COVID-19 disease among children in the region. This is an observational study of children with COVID-19 infection in hospitals contributing data to the Pediatric Acute and Critical Care COVID-19 Registry of Asia. Laboratory-confirmed COVID-19 cases were included in this registry. The primary outcome was severity of COVID-19 infection as defined by the World Health Organization (WHO) (mild, moderate, severe, or critical). Epidemiology, clinical and laboratory features, and outcomes of children with COVID-19 are described. Univariate and multivariable logistic regression models were used to identify risk factors for severe/critical disease. A total of 260 COVID-19 cases from eight hospitals across seven countries (China, Japan, Singapore, Malaysia, Indonesia, India, and Pakistan) were included. The common clinical manifestations were similar across countries: fever (64%), cough (39%), and coryza (23%). Approximately 40% of children were asymptomatic, and overall mortality was 2.3%, with all deaths reported from India and Pakistan. Using the multivariable model, the infant age group, presence of comorbidities, and cough on presentation were associated with severe/critical COVID-19. This epidemiological study of pediatric COVID-19 infection demonstrated similar clinical presentations of COVID-19 in children across Asia. Risk factors for severe disease in children were age younger than 12 months, presence of comorbidities, and cough at presentation. Further studies are needed to determine whether differences in mortality are the result of genetic factors, cultural practices, or environmental exposures.

scholarly journals The clinical features of COVID-19 patients with positive viral RNA stool test results and possibility of fecal-oral transmission : A Systematic Review

2021 ◽  
Vol 22 (1) ◽  
pp. 42-51
Author(s):  
Selina Natalia ◽  
Felicia Imanuella Thorion ◽  
Luky Adlino ◽  
Clifford Eltin John ◽  
Andree Kurniawan ◽  
...  
Keyword(s):  
Systematic Review ◽  
Gastrointestinal Tract ◽  
Demographic Data ◽  
Clinical Manifestations ◽  
Viral Rna ◽  
World Health ◽  
Test Results ◽  
Oral Transmission ◽  
Positive Stool ◽  
Health Organization

Objective : Coronavirus disease 2019 (COVID-19) has been declared as an international public health emergency by the World Health Organization (WHO), with outbreaks in over 200 countries and causing over 390,000 deaths globally. ACE-2 receptors are highly expressed in the upper and lower gastrointestinal system, providing a prerequisite for SARS-CoV-2 infection in the gastrointestinal tract. In addition, over half of the COVID-19 patients have viral nucleic acid detected in their feces and almost one-quarter of the cases, the stool samples test positive even when respiratory samples are negative. The aim of this systematic review is to summarize literature and to evaluate the clinical characteristics of patients with positive viral RNA stool test for COVID-19 and if there is a possibility of fecal-oral transmission of SARS-CoV-2 virus.Method : This systematic review has been registered in PROSPERO (CRD42020183049). A systematic search of the literature for observational study and randomized control trial was conducted in PubMed central and Google Scholar through May 5th, 2020. Three reviewers independently searched and selected. The risk of bias was evaluated using Newcastle-Ottawa Quality assessment tool.Results : 340 articles were screened, then from which eight articles were selected. Of eight articles that were included in this study, we sought for three main categories of the clinical manifestation; gastrointestinal, respiratory, and others. Each study was reviewed systematically to gain demographic data and evidence regarding the possibility of fecal oral transmission in SARS-CoV-2. Two studies reported prolongation of positive stool test results after the respiratory specimen conversion to negative which support the theory of fecal oral transmission.Conclusion : In conclusion, diarrhea, cough, and fever are the most common clinical manifestations in COVID-19 patients with positive RNA stool test results. Fecal oral transmission may be possible due to the ACE-2 receptors in the lining of the gastrointestinal tract. RNA stool test should be used as addition in discharging COVID-19 patients.

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