bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skin Malignancies Associated with HYDROXYUREA Use in MYELOPROLIFERATIVE DISORDERs and Sickle Cell Patients: Incidence and Significance.
Authors: Chiha Maguy , Younes Mohamad , Arnaout Karim , Hanbali Amr 
Published: October 2019

Abstract
Abstract 4969

BACKGROUND
Hydroxyurea (HU) is one of the mainstay agents used to treat myeloproliferative disorders as well as sickle cell anemia. There has been lately increasing reports of secondary skin malignancies in patients receiving Hydroxyurea therapy but the literature consists essentially of case reports. Current incidence of melanoma skin cancer in the general population in the United States is 15 per 100 000 person, and of non melanoma skin cancer is 230 per 100 000 lightly pigmented individuals and 3.4 per 100 000 darkly pigmented individuals.

METHODS
We reviewed 292 charts of patients treated with HU in our institution. 237 patients carried a diagnosis of myeloproliferative disorder, 14 patients were treated for sickle cell anemia and 41 patients were being treated with HU for HIV as part of a regimen to decrease viral load. Charts were reviewed looking for development of skin malignancies.

RESULTS
Among the patients with sickle cell anemia, the incidence of skin cancer was nil. Among the patients with HIV there were 2 cases of non melanoma skin cancer. Among patients with myeloproliferative disorders, there were 16 cases of skin cancer. The pathology was non-melanoma skin cancer. Subgroup analysis based on skin phenotype revealed that the incidence was higher than the general population in both dark and light-skinned individuals: the rate was 0.9434 per 100 among the dark skinned individuals, statistically significant when compared to the established rate of 0.0034 per 100 dark-skinned individual in the general population. Similarly among light-skinned individuals, the calculated rate was 12.0968 per 100-person, which is statistically significant compared to the rates in light-skinned individuals in the general population of 0.2300 per 100 person with a p-value of 0.001.

CONCLUSION
Our study showed a significantly higher incidence of non-melanoma skin cancer among patients treated with HU. While HU is well known to have cutaneous side effects in terms of hyperpigmentation, skin ulcers, scaling or skin atrophy, its implication in skin cancers had only been in the form of case reports. Our study thus highlights a true risk of skin malignancies with HU. It is worth noting though that there were only non-melanoma skin cancers, which are non-aggressive, localized and treatable. Thus this heightened incidence of skin cancer does not appear to bear a mortality or morbidity burden on patients treated with HU.

Disclosures
No relevant conflicts of interest to declare.
In Vitro Testing of Suppresion of T Regulatory Cells ( Treg) by Lenalidomide Is Correlated to Treatment Response of Lenalidomide in Patients with Primary Myelofibrosis ( PMF).
Authors: Wang Jen-Chin , Chen Chi , Rathnasabapathy Chentyl , Kafeel Muhammad I. , Singh Amrit , Sun Yiwu 
Published: October 2019

Abstract
Abstract 4987
Except allogenic bone marrow transplatation with either myeloblative or reduced intensity conditioning, there is no effective treatment for PMF. Age-related morbility and mortality factors limit this application. Anti-Jak2 treatment relieves splenomegaly but does not improve cytopenia. IMiDs on the other hand can improve anemia in up-to 20% of transfusion dependent anemic patients with PMF. In order to asses the underlying mechanism and to predict treatment responsiveness, in vitro suppression of Treg cells by lenalidomide correlated to clinical treatment response was performed. Six patients with transfusion dependent and ESD ( erythropoietin stimulating drugs) resistant PMF were studied. Mononuclear cells from blood in patients with PMF were cultured in the culture medium with FCS and Il-2 ( 100 IU/ml) in the presence of lenalidomide or DMSO for 6 days, the cells were then stained for Treg cells ( CD4+, CD 25 +,and FoxP3+,) and analyzed by flow cytometry using Treg Detection Kit from Miltenyi Biotec Inc (Auburn, CA). Treg cells were enumerated as percentage of selected CD4 + cells. The results showed that in the 4 patients who responded to lenalidomide treatment, Treg cells were suppressed by the in vitro testing by lenalidomide, while in the two patients who were clinically refractory to lenalidomide treatment, their Treg cells were not suppressed by in vitro lenalidomide treatment. These results suggest that in transfusion dependent PMF, Treg cells may play a role in the pathogenesis of anemia and that effectiveness of lenalidomide treatment may be partly related to its suppression of Treg cells. Further studies to recruit more patients and to explore the role of Treg cells in modulating erythroipoiesis in PMF using the erythroid methylcellulose culture systems are currently in progress

Disclosures
No relevant conflicts of interest to declare.
It is Different the Survival of Primary Extranodal Non Hodgkin Lymphoma?.
Authors: Giraldo Pilar , Franco-Garcia Esther , Alvarez Ramiro , Garcia-Carpintero Gloria , Martos Carmen 
Published: October 2019

Abstract
Abstract 5028

Introduction
There are few studies that evaluate the difference in incidence and survival of primary extranodal lymphomas (PEL) as compared to nodal lymphomas. In the Population Based Cancer Registry of Zaragoza (PCRZ) working since 1960, all incident cases of hematologic and non hematologic cancer are including. PCRZ is a data source for epidemiological studies.

Objectives
1. Review and reclassify cases of NHL diagnosed during the period 1992-2004. 2. Define the incidence of PEL in PCRZ during this period. 3. Analyze the survival of the PEL and compare it with that of nodal NHL.

Materials and methods
Based on the data PCRZ, we have reviewed and reclassified the patients with NHL according to REAL classification and the new WHO classification (2008), diagnosed during the period 1992-2004, to determine location and histology. The follow-up period of cases was completed by December 31, 2007 Data sources: medical records, histological reports and discharged hospital reports. Population at risk: 9,255,818 person-years. We have calculated crude incidence rates (IR) and standardized by age (SIR), using the European population as standard. For the calculation of survival and confidence intervals (95%) had used the Kaplan-Meier method and the log-rank test was used to compare survival curves.

Results
During the period of study a total of 4,570 primary hematological disorders were included in the PCRZ; 1,987 (43.4%) were NHL (IR: 19×105 person-years), 331 (16.6%) of them were classified as PEL, which represented a 2.7 SIR x105 person-years (male: 183 cases (55.2%), mean age 59.2 years, SIR: 3.1 ×105 person-years and women 148 cases (44.7%), mean age 66.8 years, SIR: 2,4 ×105 person-years. Only 10% of cases will be reclassified related to histology or location. The most common site was gastrointestinal tract (50.4%), skin (19.8%), glands (10.0%), oral cavity and pharynx (7.9%), lung (2.9%), CNS (2.4%), orbit (2.1%) and other locations (4.5%). Histological types: MALT 60.2%, BDLCNHL: 18.3%, FNHL: 4.7%, MCNHL: 3.2%, MZNHL: 6.5%, T-NHL: 7.1%. Median survival for PEL was 6.61 years (95% CI: 3.7-9.5) and 5.01 years for nodal lymphomas (95% CI: 4.1-5.9). The survival at 5 years was 53.5% and 50% respectively. There were no statistically significant differences between PEL group and the nodal NHL, according to the location or by gender. The differences in survival were associated with histological subtype of lymphoma. These results were similar to those in the data EUROCARE.

Conclusions
No differences in incidence in PEL and nodal NHL were observed according to gender and age. There were no statistically significant differences between the survival of the PEL and nodal NHL, survival is more influenced by histology than by location.
This work partially funded by the project HAEMACARE

Disclosures
No relevant conflicts of interest to declare.
The Value of D-Dimer in Patients with Increased C-Reactive Protein Suspected of Pulmonary Embolism.
Authors: Siemes Claire , Berendes Paul , van der Straaten Frans , Cleophas Ton , Levin Mark-David 
Published: October 2019

Abstract
Abstract 5056

OBJECTIVE
To investigate the relation between elevated levels of C-reactive protein (CRP) and D-dimer, and to study whether D-dimer levels can be interpreted in relation to elevated levels of CRP in the prediction of a pulmonary embolism in order to increase its specificity without decline in sensitivity.

METHODS
Between august 2004 and april 2007 (33 months) serum levels of C-reactive protein (mmol/L) and D-dimer (mmol/L) were cross-sectionally collected and pulmonary embolisms on CT-angiograms were scored within 48 hours. The study was devided into three parts. First, characteristics of excluded persons were studied. Second, the correlation between CRP and D-dimer level was considered in those with a defined (i.e. values with < and > symbols excluded) biomarker level. Finally, the effect of CRP level on the sensitivity of D-dimer for pulmonary embolisms was examined.

RESULTS
CRP and D-dimer levels were positively correlated ( r = 0.37; p < 0.001), and both were increased in persons with a pulmonary embolism (CRP: p = 0.02; D-dimer: p < 0.001). 14 % of variability in D-dimer level was explained by CRP level. Median D-dimer levels were increased in the pulmonary embolism (PE) group, however, the increase in D-dimer level by CRP quartile as was found in the non-PE was not seen in de PE-group. Adding the interaction term of CRP and D-dimer to the statistical model showed some influence on the area under the curve (AUC). Nevertheless, this was not significantly different from the model with only D-dimer levels. However, when stratified for CRP quartile, ROC-curves of the predictive effect of D-dimer on pulmonary embolisms showed a decrease in AUC by increment of CRP quartile.

CONCLUSION
CRP and D-dimer are positively correlated, and both predictive of PE. The predictive value of D-dimer for PE declines by increment of CRP, although this seems to be safely for a broader range of accompanied CRP levels.

Disclosures
No relevant conflicts of interest to declare.
RhoA Effector mDia1 Is Required for PI 3-Kinase-Dependent Actin Remodeling and Spreading by Thrombin in Platelets.
Authors: Chen Xiequn , Gao Guangxun , Wang Jishi 
Published: October 2019

Abstract
Abstract 5077
The RhoA effector mDia1 is involved in controlling the balance between filamentous and monomeric actin, but its role in modulating thrombin-induced actin remodeling and platelet spreading on fibrinogen matrices remains unclear. In this study, mDia1 was shown to translocate to the platelet cytoskeleton following thrombin stimulation, in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner. AntimDia1 loading or pretreatment with PI 3-kinase inhibitors essentially abrogated thrombin-elicited actin stress fiber formation, with a corresponding decrease in the proportion of platelets exhibiting a fully spread morphology. We also investigated the mechanisms underlying the effects of mDia1 on thrombin-induced actin remodeling and platelet spreading, and found that these involved PI 3-kinase-mediated induction of mDia1 interaction with RhoA. Collectively, these results suggest that the PI 3-kinase/RhoA/mDia1 axis is a critical pathway for coupling thrombin signaling to actin cytoskeletal remodeling during platelet spreading.

Disclosures
No relevant conflicts of interest to declare.
Phenobarbital for Long-Term Management of Marked Hyperbilirubinemia.
Authors: Shojania A. Majid 
Published: October 2019

Abstract 5089
Gilbert's syndrome (GS) is associated with a mild chronic unconjugated hyperbilirubinemia, due to partial deficiency of bilirubin uridine diphosphate glucuronyl transferase (UDPGT). Phenobarbital is a known inducer of hepatic UDPGT and has been used in hyperbilirubinemia of newborns. It has also been used as a test for support of the diagnosis of GS. However, because hyperbilirubinemia of GS is mild and harmless, phenobarbital is not used for treatment of hyperbilirubinemia in adults. I report a case of a 46-year-old woman who, because of having chronic hereditary hemolytic anemia and GS, had marked hyperbilirubinemia with psychosocial problems, as the result of her hyperbilirubinemia and her skin color, which responded well to chronic phenobarbital treatment. Case report- CH was diagnosed to have hereditary high phosphatidylcholine hemolytic anemia (HHPCHA) at the age of 23. She was seen again at the age of 30 because of very high serum ferritin and iron saturation which seemed disproportionally high for the degree of her mild hemolytic anemia (51Cr RBC survival T½ of 16.5 days). Further investigation revealed that she had hereditary hemochromatosis due to homozygosity for H63D HFE gene. She was started on phlebotomies initially weekly and later on every 2-3 months to control her iron overload. During the follow-up it was noted that her serum unconjugated bilirubin (SUB) was persistently much higher than is expected from her mild hemolytic anemia (up to 288 μmol/L). Since she had no abnormality of liver function tests, I suspected that she also has Gilbert's syndrome. In September 2008 her blood was sent for genetic testing which showed that she has an additional TA repeat [(TA)7/(TA)7], confirming the diagnosis of GS. On January 21, 2009 when her SUB was 149 μmol/L, she expressed concern that her friends and coworkers keep making fun of her, because of the orange color of her face and sclera. She was started on phenobarbital 30 mg daily for a month and then 60 mg daily. This therapy rapidly brought her bilirubin down and changed the color of her face to normal, making her very happy. Her SUB on February 20, March 20 and June 30, 2009 were 103, 63 and 37 μmol/L, respectively.

Conclusion
Gilbert's syndrome is a common hereditary disorder that can aggravate hyperbilirubinemia of chronic hemolytic anemia. However, this association is often unrecognized, because many physicians attribute the hyperbilirubinemia to hemolysis and do not look for associated GS. In chronic hemolytic anemias, if hyperbilirubinemia is more than expected, the possibility of an associated GS should be considered. If such association exists, small daily doses of phenobarbital can markedly reduce this hyperbilirubinemia and improve the psychosocial effects of hyperbilirubinemia. Furthermore, marked reduction of bilirubin, following the therapeutic trial of Phenobarbital, will confirm the association of GS with hemolytic anemia.

Disclosures
No relevant conflicts of interest to declare.
Molecular Characterization in Two Families Bearing Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD) IN Rosario, Argentina.
Authors: del Luján Irma , Pérez Susana Mabel SMP , Botta Sabrina SB , Rescia Virginia VR , Davoli Mauro MD , Milani Angela Cristina ACM 
Published: October 2019

Abstract
Abstract 5093

Introduction:
G6PD deficiency is a frequent worldwide enzymopathy, with sex-linked inheritance, the gene that codifies the enzyme localizes at the X chromosome. Males are hemizygous (Hem) for disease, while women are heterozygous (Het), i.e. carriers, and very rarely homozygous, or double heterozygous and consequently, develop disease. There are over 120 deficient molecular variants observed in Afro-Americans and in the malaria endemic region of the Mediterranean Basin. In previous studies in Argentina we have reported a low prevalence, 0,2-0,3 %, although the predominant molecular variants are unknown. Most of deficiencies are clinically detected when the patient is submitted to oxidative stress produced by infections, therapeutic drugs, or Vicia fava ingestion, develops an acute hemolytic anemia (AHA) of variable severity.

Materials and Methods:
Two male patients and their families were studied. 1) A1: 45y aged male, with AHA after bean ingestion, as well as the following relatives: mother (M1); sister (S1); three nephews (N1, N2, N3) and a niece (N4) without positive AHA history. 2) A2: 55y aged male, with two AHA episodes in childhood and adolescence, one of them associated with an infection, and the mother (M2). The evaluation clinical and hematological of the patients were normal Laboratory assays: Hemogram, Hemoglobin (Hb) (Coulter AcT10); Reticulocytes (Ret); Brewer test (B.T.); Heinz bodies (HB); Cytochemical method modified (Gurbuz, N; et al): NV: 86,8 % positive cells (CYT); Enzymatic activity (EA) Kinetic Method (Beutler-OMS): NV: 8.0±1.6 G6PD/gHb IU and Polymerase Chain Reaction with Enzyme Restriction (PCR-ER) for characterization of different variants: G6PDMed(563G□T), G6PD A376(A□G), G6PD A376(A□G) 202(G□A); G6PD A 376(A□G) 680 (G□T) y G6PD A 376(A□G) 968 (T□C).

Results:

Conclusions:
The EA confirmed the deficit of probands and nephews N1 and N3 without previous AHA history. The heterozygous character of females was not defined by this method but PCR-ER and CYT mod. supported the obliged carriers heterozygosis and the potential ones, demonstrating that CYT is more sensitive for carrier detection than other screening techniques or EA. The deficient phenotype was correlated with the detected variants, since the Mediterranean G6PD: G6PD Med(563G□T) (Type II, OMS) and G6PD A376(A□G) 202(G□A) (Type III, OMS) are associated with AHA induced by infections or Vicia Fava ingestion. The finding in Argentina of these two variants, that are frequent in the Mediterranean region, it is in accordance with the fact that our population has mainly Italian, Spanish (family 1) and Jewish (family 2) ancestors. The detection of deficient without hemolysis, as well as carriers is of the utmost importance in genetic counseling.

Disclosures:
No relevant conflicts of interest to declare.
Is There a Difference in the Preclinical Safety Parameters of Different Intravenous Iron Compounds?.
Authors: Toblli Jorge , Cao Gabriel , Oliveri Leda , Angerosa Margarita 
Published: October 2019

Abstract
Abstract 5097

Background
Intravenous (i.v.) iron has been effectively used to manage anemia in hemodialysis, chemotherapy-induced anemia and cardiac failure patients. However, i.v. iron preparations may cause different degree of oxidative stress and tissue inflammation. In the current study the effects of five i.v. iron preparations on haemodynamic, oxidative stress and inflammatory response were examined.

Methods
Sixty rats (n=10/group) received high molecular weight (HMW) iron dextran (Dexferrum®, American Regent, Inc., USA), low molecular weight (LMW) iron dextran (INFeD®, Watson Pharmaceuticals, USA/CosmoFer®, Vitaline Pharma, UK), ferric gluconate (Ferrlecit®, Watson Pharmaceuticals, USA), ferric carboxymaltose (Ferinject®, Vifor Pharma, Switzerland), iron sucrose (Venofer®, Vifor Pharma, Switzerland) or isotonic saline solution (control) in a blinded controlled study. Five i.v. doses of iron (40 mg iron/kg) or saline were administered over 4 weeks.

Results
Systolic blood pressure was significantly reduced in the LMW dextran group, whereas serum iron and percentage transferrin saturation were significantly elevated in all treatment groups. Creatinine clearance was reduced and proteinuria increased in the ferric gluconate group only (p<0.01) (day 1 to 29). Liver enzyme levels in the blood were significantly increased in the ferric gluconate and two dextran groups on days 1, 8 and 29 compared with the ferric carboxymaltose and iron sucrose groups. Analysis of liver, heart and kidney homogenates on day 29 showed a significant increase in catalase and malondialdehyde levels in the ferric gluconate group, and an increase in CuZn-superoxide dismutase and glutathione peroxidase activity accompanied with a decrease in the reduced-to-oxidized glutathione ratio in the ferric gluconate and two dextran groups (p<0.01). TNF-α and IL6 levels were significantly elevated in liver, heart and kidney samples from the ferric gluconate and two dextran groups but not the ferric carboxymaltose, iron sucrose or control groups on day 29.

Discussion
In this study, there was a difference in the hemodynamic and functional response to the different i.v. iron preparations. These findings indicate that HMW/LMW iron dextran and ferric gluconate have less favourable safety profiles in rats than ferric carboxymaltose and iron sucrose.

Disclosures
Toblli: Vifor Pharma: Research Funding.
Serum Ferritin Levels Are Associated with Vascular Damage in Patients with Nonalcoholic Fatty Liver Disease.
Authors: Valenti Luca , Swinkels Dorine W. , Burdick Larry , Dongiovanni Paola , Tjalsma Harold , Fargion Silvia , Fracanzani Anna Ludovica 
Published: October 2019

Abstract
Abstract 5098

Background and Aims
Increased ferritin and body iron stores are frequently observed in nonalcoholic fatty liver disease (NAFLD), associated with heightened susceptibility to vascular damage. Conflicting data have been reported on the role of iron in atherosclerosis, with recent data suggesting that excess iron induces vascular damage by increasing levels of the hormone hepcidin, which would determine iron trapping into macrophages, oxidative stress, and promotion of transformation into foam cells. Aim of this study was to investigate the relationship between iron status and cardiovascular damage in NAFLD.

Methods and Results
Vascular damage was evaluated by common carotid arteries intima-media thickness (CC-IMT) measurement and plaque detection by ecocolor-doppler ultrasonography in 506 patients with clinical and ultrasonographic diagnosis of NAFLD, HFE mutations by restriction analysis in 342 patients. Serum hepcidin-25 was measured by time-of-flight mass spectrometry in 143 patients. At multivariate analysis CC-IMT was associated with systolic blood pressure, glucose, LDL cholesterol, abdominal circumference, age, and ferritin (p=0.048). Carotid plaques were independently associated with age, ferritin (p=0.0004), glucose, and hypertension. Ferritin reflected iron stores and metabolic syndrome components, but not inflammation or liver damage. Hyperferritinemia was associated with increased vascular damage only in patients with HFE genotypes associated with hepcidin upregulation by iron stores (p<0.0001), and serum hepcidin-25 was independently associated with carotid plaques (p=0.05).

Conclusion
Ferritin levels, reflecting iron stores, are independent predictors of vascular damage in NAFLD. The mechanism may involve upregulation of hepcidin levels by increased iron stores in patients not carrying HFE mutations, and iron compartmentalization into macrophages.

Disclosures
No relevant conflicts of interest to declare.