bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interferon Alpha May Improve the prognosis of Advanced Myeloproliferative Neoplasm Patients with JAK2V617F Mutations
Authors: Xiaoli Liu , Ding Li , Xu Na , Huang Bintao , Zhou Xuan , Qisi Lu , Huang Jixian 
Published: October 2019

Abstract
Objective Whetherinterferon alpha (IFN-α) has special therapeutic effect formyeloproliferative neoplasm (MPN) patients with JAK2V617F mutations was not widely confirmed. Our purpose was to evaluate the therapeutic effect of interferon alpha (IFN-α) in MPN patients with JAK2V617F mutations.
Methods A total of 99 advanced MPN patients (including 68 polycythemia vera (PV) patients with 34 JAK2V617F mutations and 68 essential thrombocytosis (ET) with JAK2V617F mutations) patients) were enrolled to the study during 2007 to 2013 with informed consent, then they were divided into two groups: the IFN-α group (patients received a standard dose of IFN-α with (30-50)ug/d ) and the Hydroxyurea (HU) group (patients received a a dose of (0.25-0.5)g/d for HU). The progression-free survival rate were analyzed for a median of 32.0 (6.0 to 60.0) months follow-up period.
Results The overall response rate between IFN-α and Hydroxyurea therapy groups of essential thrombocytosis (ET) patients with JAK2V617F mutations had no significant difference (88.2% vs 85.0%, P>0.05), but the 5-year progression-free survival rate of two groups showed significant difference (88.2% vs 55.0%, P<0.05). The overall response rate (78.6% vs 82.4% ) and 5-year progression-free survival rate (57.1% vs 58.8%) between IFN-α and Hydroxyurea therapy groups of ET patients without JAK2V617F mutations had no significant difference (P>0.05). The overall response rate between IFN-α and Hydroxyurea therapy groups of polycythemia vera (PV) patients with JAK2V617F mutations had no significant difference (80.0% vs 75%, P>0.05), but the 5-year progression-free survival rate of IFN-α and Hydroxyurea therapy groups showed significant difference (86.7% vs 50.0%, P<0.05). After the treatment of IFN-α and HU for six months, the ratio of Interferon-treated patients need to continue phlebotomy was significantly lower than hydroxyurea therapy group (8.3% vs 58.3%, P<0.05). The thromboembolic events,splenomegaly, bone marrow fibrosis of interferon treatment group were lower than hydroxyurea treatment group showed significant difference (P<0.05). The adverse reactions of IFN-α was moderate, most of the patients in this study could tolerate the therapy. The major side effect of hydroxyurea was hematologic adverse reactions (Grade 1-2) with mainly reduce of white blood cells and thrombocytopenia, which showed difference between IFN-α and hydroxyurea (P<0.05).
Conclusions IFN-α may improve the prognosis of ET and PV patients with JAK2V617F mutations. Moreover, patients with PV and JAK2V617F mutations may be benefit for the treatment of IFN-α and could be recommended for an effective choice.

Disclosures
No relevant conflicts of interest to declare.
Determination of Driver Mutations in JAK2, MPL, and Calreticulin in Coronary Patients with Suspected Essential Thrombocythemia
Authors: Gasser Klaus , Muendlein Axel , Kinz Elena , Leiherer Andreas , Steurer Michael , Fraunberger Peter , Drexel Heinz , Lang Alois 
Published: October 2019

Abstract
Patients with essential thrombocythemia (ET) are at increased risk towards atherothrombotic complications. The JAK2 V617F mutation is found in at least half of the patients with ET and screening for JAK2 V617F mutational status has been included in the World Health Organization diagnostic criteria for ET. Further somatic driver mutations including mutations in exon 12 of the JAK2 gene, MPL mutations W515L/W515K, as well as mutations in exon 9 of the calreticulin (CALR) gene have been suggested as diagnostic markers for ET. Due to the close relation of ET to thrombotic events, early diagnosis of ET is of high clinical relevance, especially in patients with increased cardiovascular risk, like coronary patients. However, elevated blood cell counts are often ascribed to a reactive genesis within an acute coronary event. For this reason mostly no further clarification concerning myeloproliferative neoplasms is done.
In the present study, therefore, we determined the prevalence of JAK2 V617F, JAK2 exon 12, MPL W515L, MPL W515K, and CALR exon 9 mutations in a cohort of patients undergoing coronary angiography for the evaluation of suspected or established stable coronary artery disease and suspected diagnosis of ET. We aimed at identifying those with occult ET proposing need for additional treatment.
From a total of 1,589 coronary patients, 12 patients had increased platelets (>450 x10 9/L) predisposing them to ET. Mutation analysis among these patients showed three individuals with the JAK2 V617F mutation and one with an ins/del mutation in exon 9 of the CALR gene confirming suspected diagnosis of ET. Consequently, frequency of ET was 0.25% among our coronary patients. For comparison, in the United States between 38 and 57 ET cases per 100,000 age-adjusted inhabitants have been reported. This corresponds to an up to 7-fold accumulation of ET cases in coronary patients compared to the general population.
We conclude that the prevalence of ET is increased in coronary patients compared to the general population. For this reason comprehensive mutation analysis should be considered in all cardiovascular risk patients with persistent elevation of thrombocytes, not only to identify patient subgroups at high risk but also to individualize therapeutic strategies.

Disclosures
No relevant conflicts of interest to declare.
Disparities in Utilization of Autologous Hematopoietic Progenitor Cell Transplantation for Multiple Myeloma in the US
Authors: Costa Luciano J , Huang Jia-Xing , Hari Parameswaran N. 
Published: October 2019

Abstract
Introduction: Autologous hematopoietic progenitor cell transplantation (AHPCT) is an established modality in the treatment of patients with multiple myeloma (MM) with impact in depth and duration of remission and, in some studies, overall survival. Utilization of AHPCT for treatment of MM in US is increasing but still low. Race-ethnicity, sex and age-disparities may affect AHPCT utilization, although they do not impact benefit from AHPCT.
Methods: MM incidence derived from Surveillance, Epidemiology and End Results (SEER-18) database and AHPCT for MM reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2005-2009 were analyzed. Cases were grouped in 4 racial-ethnic categories (REC): non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), Hispanics (irrespective of race) and Asians. We assessed utilization as the ratio between first AHPCT for MM and number of newly diagnosed cases in the period of interest and calculated the relative utilization ratio (RUR), as [utilization for a given category] / [utilization for the entire population].
Results: Data was obtained from 22,462 actual MM cases reported to SEER and 13,311 actual AHPCT reported to CIBMTR. NHW, NHB, Hispanics and Asians corresponded respectively to 72.0%, 18.7%, 6.7% and 2.6% of the new MM cases and 77.4%, 15.85, 5.2% and 1.6% of the AHPCT procedures. Median age at diagnosis of MM was higher in NHW (P=0.0002)and was higher in women than in men in all RECs. Age-adjusted RUR was 1.17 (95% C.I. 1.15-1.19) among NHW, higher than in NHB [0.69 (95% C.I. 0.67-0.72), P<0.0002], Hispanics [0.64 (95% C.I. 0.60-0.69), p<0.002] and Asians [0.65 (95% C.I. 0.58-0.73), P<0.0002]. There was higher utilization of AHPCT in men than in women detected among Hispanics (age adjusted RUR 0.72 vs 0.56, P=0.007), but not among NHW, NHB or Asians. Only 3.1% of the NHW patients younger than 65 were identified as uninsured vs. 8.1% of NHB, 11.9% of Hispanics and 3.2% of Asians (P<0.0001). Correction of sex disparity would lead to an overall increase of 1.3% in AHPCT for MM, higher among Hispanics (11.7%) but lower in the other categories (Figure, panel a). The hypothetical correction of racial-ethnic disparity would result in 15.9% increase in volume of AHPCT, with a pronounced increase among NHB, Hispanics and Asians (Figure, panel b). Increase in age at transplant will strongly affect AHPCT volumes with dissimilar impact in different RECs according to their age structure (Figure, panel c).
Conclusions: Race-ethnicity disparity greatly affects AHPCT utilization for management of MM in US. Sex disparity plays a much lesser role, except among Hispanics. The profound age disparity is decreasing over time and will likely continue to drive major increase of AHPCT activity.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Familiar JAK2 G571S Variant Not Linked with Essential Trombocythemia
Authors: Panovska-Stavridis Irina , Eftimov Aleksandar , Pivkova-Veljanovska Aleksandra , Ivanovski Martin , Cevreska Lidija , Dimovski Aleksandar J 
Published: October 2019

Abstract
Somatic activating mutations in the JAK2 gene are one of the most important characteristics of the myeloproliferative neoplasams (MPNs). Moreover, JAK2 germline mutations occur in familiar MPN. However, the same JAK2 mutations are associated with different phenotypic MPNs and their exact role in the pathogenesis of the MPNs is not clear and well established.
Here, we report a family with a germline JAK2 G571S mutation associated with only one sporadic case of essential thrombocythaemia (ET). Our patient, male, born 1958, presented at the age of 54 with a marked and sustained thrombocythosis (platelets count higher than 1500x109per liter over a period of 3 months). The bone marrow biopsy sample revealed normocellular bone marrow with an increased number of megakaryocytes organized in clusters; the reticulin staining was negative. The molecular diagnostic work up towards MPNs included the analysis of BCR/ABL fusion transcript, JAK2, CALR and MPL mutations. These analyses showed that the patient had 2 variants which might account for the ET phenotype; a somatic CARL mutation (insertion p.K385fs*47) and a germline C-T substitution at codon 571 in exon 13 of the JAK2 gene. Extended family analysis showed that the G571 variant was also present in the patient’s father, brother and one daughter. All of them had normal hematological parameters and didn’t exhibit any abnormality in the serum ferritin, prolactin, lipids, fasting glucose levels, blood pressure, body mass index, skin and skeletal changes.
The JAK2 G571S mutation was already described in MPNs with a frequency <0.01 and was not recorded in the database of single nucleotide polymorphisam (SNP). Glycine at 571 is adjacent to Tyr570 which is one of the most important sites for autophosphorilation and downregulation of JAK2 signaling. The substitution of nonpolar Glycine for polar but non-charged Serine might affect this by altering the conformation of the protein and result in a constitutively active kinase. However, the absence of any hematological or other disorders in a wide age spectrum in carriers of this variant indicate that it is a silent nonfunctional polymorphism. Moreover, the ET phenotype present in the index case is reminiscent of other ET patients with somatic CALR p.K385fs*47 mutation, further demonstrating that the JAK2G571 variant is a non-functional silent polymorphism.
Our results support the need for routine screening for all mutations that might be involved in the pathogenesis of the MPNs since they are not always mutually exclusive and also not always responsible for the phenotypic expression of the MPNs.

Disclosures
No relevant conflicts of interest to declare.
Spectrum of Phenotypic Manifestations of a Novel c1339A>C, pS447R Germline GATA2 Mutation
Authors: Kochuparambil Samith T. , Jackson Amie E , Litzow Mark R. , Khan Shakila , Rodriguez Vilmarie , Hogan William J. , Abraham Roshini , Patnaik Mrinal M. 
Published: October 2019

Abstract
Background: Haploinsufficiency of GATA2 results in familial immunodeficiency and MDS/ AML. We identified a family with a novel c1339A>C, pS447R germline GATA2 mutation. Unlike most other disease-causing GATA2 mutations, this mutation occurred in the non-zinc finger domain. Methods: After due IRB approval, clinical and laboratory data were retrospectively abstracted.
Results: Seven family members with the mutation are being followed at our institution. (Table 1), of whom two have MDS, one MDS/AML and one with isolated neutropenia. At the time of diagnosis 5/7(71%) pt had decreased monocyte count. 4/7(57%) patients had decreased NK cell count and/or function. Only 1/7(14%) patient had decreased CD4 count. 3/7(42%) patients had reduced B cell numbers and 5/7(71%) patients had persistent HPV warts. Other infections include invasive Absidia sinusitis, infectious mononucleosis, pertussis, and blood stream infections with S. maltophilia and S.aureus. One patient had the Emberger's syndrome presenting with lymphedema and congenital pulmonary stenosis. Pulmonary manifestation included a patient each with decreased DCLO and hyperreactive airway disease. Genitourinary manifestations included pelvic kidney/dysplastic kidney, posterior urethral valve, dermoid cyst and hydrocele. Two female patients developed primary infertility. One patient had a history of appendicular carcinoid. 4/7(57%) patients have successfully undergone allogenic stem-cell transplantation.
Conclusion: Germline GATA2 mutations are associated with a high frequency of MDS/AML. We describe a family with a non-zinc finger GATA2 mutation causing MDS/AML, with a spectrum of hematological and non-hematological manifestations, once again, highlighting the heterogeneity of this syndrome and expanding the genotype-phenotype correlation in this disease. Abstract 5614. Table#Age/sexHemDAbso . MonoCount Abso. CD4 TCellNK cyto-toxicityAbso. NK CountAbso.B cell CountInfectiousDermCoag/VascularCVS/LungOthersNo.137/MAMLSeverely DecreasedNormalAbsentSeverely DecreasedAbsentAbsidia S.maltop- hilia S.aureusHPV WartsITP -Hydrocele 10 hyperparathyroidismNo.231/FMDSDecreasedNormalAbsentDecreasedNormalInfectious MonoHPV Warts-Hyper- reactive airwayInfertilityNo.317/FMDSSeverely DecreasedNormalUnknownDecreasedDecreasedHerpes stomatitisHPV Warts-Dec-DCLOPosterior urethral valveNo.49/MNeutropeniaSeverely DecreasedNormalNormalNormalNormalHSV-1HPV Warts Embergers syndrome Pul. Stenosis Congenital dysplastic Rt. Kidney Pelvic Lt. KidneyNo.531/F-DecreasedNormalDecreasedNormalNormal- -Qualitative platelet defectNoneInfertilityNo.635/F-NormalNormalDecreasedDecreasedDecreasedPertussisHPV Warts--Dermoid appendicular carcinoid No.756/F-NormalNormalNormalNormalNormalFrequent PNA----

Disclosures
No relevant conflicts of interest to declare.
Early Diagnosis of Multiple Myeloma - Project CRAB of Czech Myeloma Group(CMG)
Authors: Straub Jan , Hajek Roman , Scudla Vlastimil , Maisnar Vladimir , Gregora Evzen , Schutzova Miroslava , Adam Zdenek , Bacovsky Jaroslav , Spicka Ivan 
Published: October 2019

Abstract
Introduction: Multiple myeloma is one of the most frequent hematological malignancies. The prognosis of patients has substantially improved due to new treatment options. However, the early diagnosis is still a crucial factor for prognosis. First symptoms of myeloma are different and mostly unspecific - therefore many patients are diagnosed late with serious organ and/or tissue damage. Czech Myeloma Group initiated the program for early diagnosis of MM in 2007. Program (named due to educational reasons„CRAB“) was focused on general practitioners (GPs) and key specialists responsible for recognizing the symptoms related to MM (neurology, orthopedics, nephrology). We present results of the final analysis.
Methods: a/ telephonic survey for healthcare professionals, b/ written information for primary care providers, c/ brochures containing definition of clinical symptoms and recommended diagnostic methods, d/ patient questionnaire, e/ presentations at medical meetings in Czech republic, f/ presentation in non-hematological medical journals, g/ e-learning.
Primary objectives were: 1) decrease risk of late diagnosis ( > 3 month after first symptoms of myeloma) from 50% to 30% , 2) reduction of irreversible deterioration at the time of diagnosis from 20% to <10%. Secondary objectives were: 3) improve knowledge of the first-contact care providers about the initial symptoms of multiple myeloma 4) inform them about diagnostic methods applicable in first-contact care 5) inform them about new treatment modalities and improving prognosis of myeloma patiens.
Planned project duration was 7 years (2007-2013). The first interim analysis was done in 2010.
Results: 76,4% patients was diagnosed < 3 month after first contact with healthcare professionals according to the second analysis in 2013. Probability of early diagnosed patients increased from 53,5% in 2007 to 68,8%, ,i.e. by 29% , in 2013 However, incidence of the osteolytic lesions and renal failure at time of diagnosis remained similar.
Conclusion: The 7-year project leads to the increase of early diagnosis of MM by almost one third. Long-term analysis will show whether better knowledge of medical society about myeloma is transient (just during information campaign) or permanent.
Project was supported by Czech Myeloma Group and Jansen-Cillag.

Disclosures
Hajek: Merck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria.
Generation of a Predictive Score for Ixazomib Response in Multiple Myeloma
Authors: Mitra Amit Kumar , Dey Sanjoy , Hangsleben Andrew , Steinbach Michael , Kumar Vipin , Van Ness Brian 
Published: October 2019

Abstract
Multiple myeloma (MM) is the second-most common hematopoietic malignancy in the United States accounting for 1% of all cancers and 10% of all hematologic malignancies. Despite recent improvements in treatment strategies including the emergence of proteasome inhibitors (PIs) as effective chemotherapeutic agents, MM still remains difficult to cure with median survival rate of around 7 years, primarily due to wide inter-individual variation in response to treatment. We believe such heterogeneity in response to PIs is governed by the underlying molecular characteristics of the tumor including alterations in gene expression profile (GEP).
In the current study, we used a panel of Human Myeloma Cell Lines (HMCLs) representing the gamut of biological and genetic heterogeneity in MM to evaluate the gene expression signatures associated with response to the second-generation PI Ixazomib and produced a predictive score (PI score) for Ix response.
HMCLs (n=45) were treated with increasing concentrations of Ixazomib used as single agent and half maximal inhibitory concentration (IC50) values were determined using cell viability equation. Gene expression profiling data was obtained as publicly available data from the Keats lab website at TGen (http://www.keatslab.org/myeloma-cell-lines).
Genes with high expression value and high standard deviation beyond the median values were pre-filtered and log expression values were normalized by subtracting mean expression of individual genes across all the samples and the housekeeping genes (GAPDH). Subsequently, analysis of correlation between Ix IC50 data and GEP data and the False Discovery Rate (FDR) based on 1000 random permutations were performed to identify true patterns of genes that are highly predictive of Ix response and to look for the top genes that could discriminate between the top sensitive and top resistant cell lines. Gene clusters were identified that correlated with response and will be presented. Our results will demonstrate in vitro modeling of response using GEP approaches that may provide predictive scoring algorithms of a defined set of genes that will be useful in clinical evaluation of drug choice in treating individual patients.

Disclosures
No relevant conflicts of interest to declare.
CSF1R-Inhibition and Reduction of Macrophages Delays Multiple Myeloma Growth in a Non-T-Cell-Dependent Manner
Authors: Schjesvold Fredrik H. , Haabeth Ole Audun , Bogen Bjarne , Tveita Anders 
Published: October 2019

Abstract
Macrophages are important tumor-promoting cells, and can constitute up to half of the tumor mass, orchestrating remodeling, inducing angiogenesis and suppressing the immune system to terminate local inflammatory responses. Colony stimulating factor (CSF-1), also known as macrophage colony-stimulating factor (M-CSF), is the most important cytokine involved in survival, proliferation and differentiation of tissue macrophages and their precursors. Previous experiments from our group has shown that amount of CSF-1 in the tumor bed correlates with successful rejection of cancer cells in a TCR-transgenic model where CD4+ T cells recognize a tumor specific antigen produced by multiple myeloma cells. We therefore tested if reduced signaling via CSF-1R, and thereby a decrease in tumor infiltrating macrophages, would results in decreased growth of multiple myeloma cells. .
PLX3397, a tyrosine kinase inhibitor with specificity for CSF1R and KIT, has been demonstrated to delay tumor growth in a CD8+ T-cell-dependent manner after chemotherapeutic treatment in a murine model of mammary carcinogenesis. Here, we show that MOPC315 multiple myeloma cells implanted subcutaneously in matrigel plugs in SCID mice become infiltrated with M2 phenotype macrophages that enhances their growth. When given chow containing PLX3397, recruitment of macrophages is strikingly reduced, with significant delay in tumor growth. Importantly, this delay in tumor development is not T cell dependent, since the anti-tumor effect is seen in T cell deficient SCID-mice as well as in BALB/c mice. Importantly, treatment with PLX3397 does not abrogate efficient tumor killing, and does not affect survival, when tested in a TCR-transgenic model where CD4+ T cells via induction of M1 macrophages reject multiple myeloma.
In conclusion, PLX3397 delays tumor growth by reducing amounts of tumor infiltrating M2 macrophages, while rendering effective tumor killing by M1 macrophages uninhibited. Thus, drugs that inhibit signaling of CSF-1 could be of value in treatment of multiple myeloma.

Disclosures
No relevant conflicts of interest to declare.