bluuebunny/crossref_metadata_2025_split huggingface dataset:
Galectin-3 and Myocardial Fibrosis By Cardiac Magnetic Resonance in Thalassaemia Major
Authors: Ricchi Paolo , Meloni Antonella , Di Matola Tiziana , Spasiano Anna , Filosa Aldo , Costantini Silvia , Atripaldi Luigi , Esposito Salvatore , Cinque Patrizia , De Franceschi Lucia , Pepe Alessia 
Published: October 2019

Abstract
Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) technique is the only validated non-invasive approach used for detecting macroscopic myocardial fibrosis. Galectin-3 has been shown to participate in tissue fibrogenesis and was already associated with LGE-assessed myocardial replacement fibrosis in a cohort of patients with non-ischemic dilated cardiomyopathy (NICM).
Our aim was to investigate the relationships between galectin-3 circulating level and myocardial fibrosis in patients with thalassemia major (TM) who underwent CMR technique during the Myocardial Iron Overload in Thalassemia (MIOT) project.
All patients underwent also an extensive biohumoral characterization, including Troponin, NT Pro BnP, BNP, VES, PCR assay.
At UOSD Malattie rare del globule Rosso of Cardarelli hospital (Naples, Italia), between January 2015 and March 2016, all patients who underwent contrast-enhanced CMR were progressively enrolled to test Galectin-3.
Eighty-six patients were evaluated (males 43%; age 37, SD 8 years): six (7%) had diabetes mellitus (DM), 64 had anti-HCV antibodies and 28 (32%) were HCV RNA positive. Median galectin-3 value was 14.04ng/mL (5.26 ng/mL), and LGE was detected in 42 (49%) patients. Patients with LGE had higher galectin-3 than those without (14.48 ± 5.98, vs 13.63 ± 5.98), but without a statistically significant difference (p=0.109).
Galectin-3 was significantly associated with age (R=0.34; p=0.001), but not with sex.
Patients with DM, with anti-HCV antibodies and with HCV-RNA positivity, had significant higher level of Galectin 3 with respect to those without (22.5± 11.1 vs 13.4± 4, p=0.009; 14.9 ± 5.4 vs 11.5± 3.7, p=0.001; 16.2 ± 6.5 vs 13± 4.2, p=0.011, respectively).
No correlation was found between Galectin 3 and other tested biochemical variables and iron overload and cardiac parameters.
In conclusion, in our cohort of TM patients there was a great prevalence of myocardial fibrosis. In patients with myocardial fibrosis, the level of galectin-3 was higher and comparable to that found in a previous study performed in patients with NICM, but not significantly different with respect to those without fibrosis. The elevated prevalence of patients with previous exposure to HCV virus and/or DM and/or iron overload may significantly influence Galectin-3 level limiting the ability of the marker to identify patients without fibrosis.

Disclosures
De Franceschi: F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding. Pepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.
Association Between Cardiac Iron Clereance and Hepatic Siderosis
Authors: Pepe Alessia , Pistoia Laura , D'Ascola Domenico , Gamberini Maria Rita , Gagliardotto Francesco , Filosa Aldo , Cirotto Carla , Casini Tommaso , Maggio Aurelio , Riva Ada , Positano Vincenzo , Meloni Antonella 
Published: October 2019

Abstract
Introduction. The aim of this multicenter study was to evaluate in thalassemia major (TM) if the cardiac efficacy of the three iron chelators in monotherapy was influenced by hepatic iron levels over a follow up of 18 months.
Methods. Among the 2551 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we evaluated prospectively the 98 patients those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans and who showed evidence of significant cardiac iron (global heart T2*<20 ms) at the basal MRI. Iron overload (IO) was measured by T2* multiecho technique. We used cardiac R2* (equal to 1000/T2*) because cardiac R2* is linearly proportional to cardiac iron and hepatic T2* values were converted into liver iron concentration (LIC) values.
Results. We identified 3 groups of patients: 47 treated with deferasirox (DFX), 11 treated with deferiprone (DFP) and 40 treated with desferrioxamine (DFO).
Percentage changes in cardiac R2* values correlated with changes in LIC in both DFX (R=0.469; P=0.001) and DFP (R=0.775; P=0.007) groups. All patients in these 2 groups who lowered their LIC by more than 50% improved their cardiac iron (see Figure 1).
Percentage changes in cardiac R2* were linearly associated to the log of final LIC values in both DFX (R=0.437; P=0.002) and DFP groups (R=0.909; P<0.0001).
Percentage changes in cardiac R2* were not predicted by initial cardiac R2* and LIC values.
In each chelation group patients were divided in subgroups according to the severity of baseline hepatic iron overload (no, mild, moderate, and severe IO). The changes in cardiac R2* were comparable among subgroups (P=NS) (Figure 2).
Conclusion. In patients treated with DFX and DFP percentage changes in cardiac R2* over 18 months were associated with final LIC and percentage LIC changes.
In each chelation group percentage changes in cardiac R2* were no influenced by initial LIC or initial cardiac R2*.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..
Average Monthly Cost of Iron Chelator Treatment in Adult Patients with Sickle Cell Disease
Authors: Master Samip , Mansour Richard Preston 
Published: October 2019

Introduction:
Iron overload in adult patients with sickle cell disease (SCD) can lead to variety of complications like liver dysfunction/cirrhosis, cardiac enlargement, diabetes mellitus, hypogonadism and arthropathy. These complication can be prevented by iron chelation therapy .We did retrospective analysis to find incidence of iron over load in this population and also did a survey to find the insurance status in this population.
Methods:
We take care of approximately 300 adult patients with SCD at out hematology clinic. We did retrospective analysis to investigate the prevalence of iron overload in this population. We also did survey on 100 adult patients with SCD to find out about the insurance converge for them. Web search was done to find out the average monthly cost of iron chelators.
Results:
On retrospective analysis of 458 adult patients with SCD, we found that 117/458(25.58%) had iron over load. Majority of them, 93/117 were SS type of SCD. Results of survey done on 100 adult patients with SCD showed that 61 had Medicaid, 2 were free care, 25 had Medicare and 12 had private insurance. The average monthly cost of Deferiprone is $ 18762, while that of Deferasirox is $ 13,082.
Conclusions:
Iron over load is a common complication affecting a quarter of the adult patients with SCD. The treatment of iron overload is expensive, as just the iron-chelator therapy costs approximately 160 to 220 K per year. In an attempt to minimize additional iron accumulation in our chronically transfused patient population we encourage the schedule of exchange of 1 unit phlebotomy and 1 unit of red cell infusion every two weeks.

Disclosures
No relevant conflicts of interest to declare.
Successful Management of a Left-Sided Endocarditis Patient Complicated with Hemophagocytic Lymphohistiocytosis---a Rare Case Report and Literature Review
Authors: Zhang Qiguo , Zeng Hui , Xu Peipei , Wang Jing , Yang Ronggong , Xu Jingyan , Zhou Rongfu , Ouyan Jian , Chen Bing 
Published: October 2019

Abstract
Objective: To increase the knowledge and experience of treating left-sided endocarditis patients complicated with hemophagocytic lymphohistiocytosis.
Method: One case with left-sided endocarditis and secondary hemophagocytic lymphohistiocytosis was reported and related PubMed literatures were reviewed.
Results: A 40-year-old Asian female came to hospital with uncontrolled repeated fever that had lasted for more than one month. Prior to this admission, the patient suffered a sub-acute liver failure of unknown cause and received artificial liver support and intravenous hepatic protectants in the local hospital, and the patient responded well. At that time echocardiography revealed congenital heart disease. After admission to our hospital, her lab results showed pancytopenia, coagulation abnormal and significantly elevated levels of total bilirubin, soluble CD25 and serum ferritin. Bone marrow biopsy was negative for hemaphagocytosis. The full body PET-CT was performed and the results demonstrated hepato-splenomegaly and relatively increased standard uptake value (SUV) of the spleen, with no signs of malignancies. Several sets of blood cultures were all positive for methicillin-resistant Staphylococcus epidermidis (MRSE). Two weeks later, cardiac ultrasound images were obtained and showed a completely well-shaped vegetation attached to the aorta valve, which confirmed the diagnosis of definite infectious endocarditis (IE). So the final diagnosis was the MRSE-related left-sited infectious endocarditis and acquired HLH. The Multi-disciplinary team (MDT) discussed this critical case, since the allergic reaction of vancomycin and no therapeutic effect of tecolplanin for 10 days, the patient was treated by high dose daptomycin(10 mg/kg once daily) and chemotherapy according to HLH-2004 protocol, afterwards the patient's condition was improved, cardiothoracic surgery was performed smoothly and the vegetation on the aortic valve was successfully removed. Till now the patient has been in good condition for more than 2 years. There are only 4 case reports pertinent to endocarditis with HLH published in PubMed and these related cases were also reviewed.
Conclusion: This case report is the description of another rare and complicated condition in which the patient concurrently developed left-sided infectious endocarditis and acquired HLH. High dose daptomycin monotherapy was effective for controlling MRSE-related left-sided IE. Early diagnosis and intervention is very important for the successful treatment of HLH. Our case also highlights the importance of the multi-disciplinary team (MDT) model in dealing with similar critical cases in the clinic work.

Disclosures
No relevant conflicts of interest to declare.
Rationale for Investigator-Assigned Prophylaxis Dosing Frequency in the Leopold I Study
Authors: Humphries Thomas J. , Church Nikki , Lalezari Shadan , Poulsen Lone H. , Yoon Mia , Maas Enriquez Monika 
Published: October 2019

Abstract
The LEOPOLD I study (part B) in severe hemophilia A was a multicenter, phase II/III, open-label trial to assess the safety, tolerability, and efficacy of prophylaxis treatment with BAY 81-8973, an unmodified recombinant factor VIII product. Dose and dose frequency of the prophylaxis regimen during the study were at the investigators' discretion. A questionnaire was sent to sites poststudy to determine what elements led to the assignment of patients to a twice-weekly regimen rather than 3 times weekly. Seventeen specific questions were posed, plus 1 labeled as "other," allowing the investigator to insert a rationale not otherwise specified.
Responses to the questionnaire were received for 13 of 17 patients (76%) assigned to twice-weekly prophylaxis. The 2 most frequent responses were "treatment options were discussed with the patients" (67%) and "patient preference" (61%). Additional responses in descending frequency included "prophylaxis regimen was adapted to the patient's physical activity and schedule" (28%) and "already on a twice-weekly regimen before the study," "sedentary lifestyle," "noncompliance with a 3-times-weekly regimen," and "other" (17% each). "Minimal arthropathy," "no target joints," and "patient's age" were included at 11% each.
These results demonstrate that discussions between patient and doctor are appropriately considered paramount to treatment decisions. The other elements mentioned are known parameters thought to contribute to bleeding phenotype in hemophilia.

Disclosures
Humphries: Bayer: Employment. Church:Bayer: Employment. Lalezari:Pfizer: Honoraria; Bayer: Honoraria; TEVA pharmaceuticals: Consultancy. Poulsen:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Investigator for Clinical Trials; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Investigator for Clinical Trials, Mentor, Speakers Bureau; SOBI: Speakers Bureau; Ferring: Speakers Bureau; Pfizer: Consultancy. Yoon:Bayer Inc: Employment. Maas Enriquez:Bayer Pharma AG: Employment.
Type 3 Von Willebrand Disease: A Case Report of a Rare Entity
Authors: Phillips Stephanie , Lazarchick John , Bergmann Shayla 
Published: October 2019

Abstract
Background:
Von Willebrand Factor (VWF) is essential for proper hemostasis. It serves as a carrier protein for factor VIII and also aids in platelet adherence to damaged endothelium. Von Willebrand Disease (VWD) may result from congenital absence of VWF, structural or functional abnormalities or mutations leading to mild decreases in expression of VWF. Type 3 VWD is an autosomal recessive disorder, which accounts for only 1% of patients with VWD and is characterized by a virtual absence of VWF and low levels of Factor VIII.
Objective:
To describe a case of Type 3 VWD including the presentation, diagnosis and clinical course.
Design/Method: Case Report.
A 4 month old female presented with a history of 8 hours of persistent bleeding from an injection site following vaccination administration. At that time, the patient's platelet count and PT/PTT were normal. She had a few intermittent episodes of persistent bleeding with minor abrasions and had labs repeated at the age of 4 months which were significant for a prolonged PTT of 59.5 seconds with normal PT and platelet count. Factor VIII level was <1% and VWF activity was <15%.
Results:
A complete Von Willebrand panel was sent to Mayo Medical Labs and showed a Factor VIII level of 2%, VWF antigen 6%, VWF activity of 8, and an absence of VWF multimers. Confirmatory VWF full gene sequence analysis testing was sent to Blood Center of Wisconsin and showed a heterozygous sequence variant, c.2435delC, in the VWF gene consistent with a diagnosis of VWD Type 3. VWF full gene sequence analysis was also sent on both parents. Mother's results showed that she is a carrier of the same VWF gene sequence variant. Father's results were negative. Given the patient only has a heterozygous sequence variant yet still has expression of VWD, gene duplication testing was sent to Blood Center of Wisconsin to look for possible duplication of this area. Results of this testing showed that the patient had two pathogenic variants, one on each allele: heterozygous c.243delC in exon 18 and a deletion involving exon 6 in the VWF gene.
Conclusion:
This case represents the clinical presentation and diagnosis of a patient with Type 3 VWD. While VWD is not uncommon, diagnosis of VWD Type 3 is quite rare. VWD Type 3 is inherited in an autosomal recessive fashion. In the case of our patient, only one parent was identified as a carrier of the same gene sequence mutation. Therefore, the second pathogenic variant resulting in VWD Type 3 was found to be a de novo deletion, further adding to the uniqueness of this case.

Disclosures
No relevant conflicts of interest to declare.
SIRT6 Inhibition As a Novel Approach for Treating Acute Myeloid Leukemia
Authors: Cea Michele , Cagnetta Antonia , Soncini Debora , Minetto Paola , Lovera Davide , Guolo Fabio , Colombo Nicoletta , Ballerini Filippo , Clavio Marino , Miglino Maurizio , Gobbi Marco , Lemoli Roberto M 
Published: October 2019

Abstract
Currently available therapeutics against Acute Myeloid Leukemia (AML) have improved patient outcome. However, resistance develops even to novel therapies and patient overall survival remains low, especially for patients who are not eligible for allogeneic bone marrow transplantation. Therefore, there is an urgent need to overcome the biologic mechanisms underlying drug resistance in AML, to enhance the efficacy of existing treatments and to facilitate the design of novel approaches. Recently, our group has demonstrated that SIRT6, a NAD+-dependent histone deacetylase involved in genome maintenance, is frequently up-regulated in Multiple Myeloma and its targeting induces cancer cell killing (Cea M. et al, Blood 2016). Furthermore, gene expression analyses performed by our groups show that SIRT6 is also up-regulated in AML and confers poor prognosis in a series of 200 primary AML cases from our Hematology Clinic. Thus, these data suggested a role for SIRT6 in AML biology. High SIRT6 expression was typically observed in AML cell lines characterized by constitutive DNA damage and intense replicative stress. Likewise, primary AML cases exhibiting an intermediate-to-high chromosome instability (CIN) gene expression signature were also those with the highest SIRT6 expression, and worst prognosis. Subsequent studies demonstrated that SIRT6 silencing or its chemical inhibition, as observed in Multiple Myeloma exacerbates DNA damage in response to genotoxic agents, sensitizing AML cells to cytarabine (ARA-C) and idarubicin in vitro. Overall, enhancing genotoxic stress while concomitantly blocking DNA double-strand breaks (DSBs) repair response, may represent an innovative strategy to increase chemosensitivity of AML cells. Mechanistic studies revealed that SIRT6 acts as a genome guardian in AML cells by binding DNA damage sites and activating DNA-PKcs and CtIP by deacetylation, which in turn promotes DNA repair. Overall our data suggest that genomic instability is present in all hematologic malignancies including AML. Strategies aimed to shift the balance towards high DNA damage and reduced DNA repair by SIRT6 inhibition can decrease AML growth and may benefit patients with otherwise unfavorable outcomes.

Disclosures
Gobbi: Gilead: Honoraria; Takeda: Consultancy; Janssen: Consultancy, Honoraria; Roche: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.
FOXC1 Expression in Acute Myeloid Leukemia: Potential Predictor of Disease Relapse and/or Refractory Disease
Authors: Swaminathan Mahesh , Jensen Tor W , Ray Tania , Andruska Neal D , Shah Anit , Egner James R. , Ray Partha S. 
Published: October 2019

Abstract
Background:
The mesenchymal transcription factor Forkhead Box C1 (FOXC1), derepressed in hematopoietic stem progenitor cells (HSPCs) in the setting of acute myeloid leukemia (AML), but not in normal HSPCs, was recently demonstrated to play an important role in AML disease onset and progression by blocking myeloid lineage differentiation and enhancing clonogenic potential. Herein we sought to further examine the prognostic value of FOXC1 in AML and whether FOXC1 expression is a potential predictor of disease relapse and/or lack of response to induction chemotherapy in AML.
Methods:
Expression of FOXC1 mRNA in mixed karyotype AML bone marrow samples was examined using publicly available microarray datasets (n=521, n=244). The clinical significance of FOXC1 gene expression as a prognostic biomarker was evaluated using censored overall survival (OS) and event-free survival (EFS) data. Degree of statistical significance in the univariate and multivariate analyses performed was assessed using log-rank test and Cox regression model, respectively.
Results:
FOXC1 mRNA expression was a significant predictor of OS on univariate (hazard ratio [HR] 1.592 95% confidence interval [CI] 1.263-2.007, P = 0.0001) and multivariate (HR 1.755 95% CI 1.355-2.273, P < 0.0001) analyses. This effect on OS could be attributed to disease relapse and/or lack of response to induction chemotherapy as FOXC1 mRNA expression also proved to be a significant predictor of EFS on univariate analysis (hazard ratio [HR] 1.539 95% confidence interval [CI] 1.208-1.961, P = 0.0002) and multivariate analysis (HR 1.678 95% CI 1.280-2.201, P = 0.0001), independent of age, FLT3 ITD status, NPM1 status or cytogenetic risk status. Compared to patients who experienced disease remission, FOXC1 expression was significantly elevated in patients experiencing disease relapse following induction chemotherapy (P<0.02), and in patients who were non-responders to induction chemotherapy (P<0.002)
Conclusions:
FOXC1 expression in AML is an independent prognostic predictor of decreased OS and EFS and is significantly associated with disease relapse and/or refractoriness to induction chemotherapy. A risk of relapse/non-response score that incorporates FOXC1 expression status may prove to be of value in identifying patients at the time of initial diagnosis who are likely to fail induction chemotherapy. Further studies are warranted to explore the prognostic and predictive utility of FOXC1 expression in the clinical management of AML.
Figure Figure.

Disclosures
Ray: Onconostic Technologies, Inc.: Employment. Shah:Onconostic Technologies, Inc.: Employment. Ray:Onconostic Technologies, Inc.: Consultancy, Equity Ownership; 3N Diagnostics Ltd.: Consultancy, Equity Ownership.
Massive Parallel Sequencing and Mutations Analysis of Mismatch Repair Genes in Recurrent Childhood Acute Lymphoblastic Leukemia Cases-Identification of Possible Molecular Signature of Poor Clinical Outcome
Authors: Kato Keisuke , Yoshimi Ai , Matsushima Satoru , Kobayashi Chie , Fukuda Kunio , Koike Kazutoshi , Tsuchida Masahiro 
Published: October 2019

Abstract
[Introduction] Mechanism of recurrence is fully characterized and is significant to improve prognosis in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and T lymphoblastic leukemia (T-ALL).. We have analyzed recurrent cases of childhood BCP-ALL and T-ALL. [Procedure] We analyzed clinical samples of 18 cases with BCP-ALL and 3 cases with T-ALL, who had been treated in our institution. We have investigated gene status of IKZF1, CRLF2, CDKN2A/2B, JAKs, IL7RA, and TP53 using RT-PCR and MLPA methods and IGH/TCR on genomic PCR. Whole exome analysis was done using Ion AmpliSeq Exome in seven cases. [Result] We analyzed clinical samples of 21 cases with ALL, who had been treated in our institution. The cases were 18 cases with BCP-ALL and 3 cases with T-ALL. We have investigated gene status of IKZF1, CRLF2, CDKN2A/2B,JAKs,IL7RA, NOTCH (for T-ALL), and TP53. Whole exome analysis was done in two cases, particularly for a case from which we have established cell line. < Result > Eight BCP-ALL cases with P2RY8-CRLF2 chimeric transcript: four cases of which had P2RY8-CRLF2 chimeric transcript only at initial diagnosis; two cases obtained transcript at recurrence. This was confirmed employing LD-PCR genomic analysis. Ten BCP-ALL cases had deletion of IKZF1; two showed deletion at relapse and a case demonstrated deletion at diagnosis only. Two BCP-ALL cases showed mutation of IL7RA. One of T-ALL cases from which we have established cell line showed mutation of MSH2 and more than 200 non-synonymous mutations on whole exome analysis. One T-ALL cases showed mutation of JAK3 at diagnosis. One BCP-ALL case had MLH1 mutation < Discussion > The present study has suggested acquisition of complex genetic change at different point of evolution may work in recurrence of ALL. The present study has indicated P2RY8-CRLF2 works not as simple growth advantage but rather as manifestation of genomic instability. This may be also illustrated by recurrent cases with T-ALL having mutation of MSH2 and BCP-ALL having mutation of MLH1.
Mutation of mismatch repair gene may be driver of gene mutation acquisition and consequently alterations of CREBBP and RAS or IKZF1, TP53, mismatch repair genes, or emergence of P2RY-CRLF2 chimeric transcript may be prognostically relevant in childhood acute lymphoblastic leukemia.

Disclosures
No relevant conflicts of interest to declare.