bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Oral Mtor Inhibitor Everolimus in Relapsed and Refractory Hodgkin Lymphoma- Compassionate Use in 8 Centers in Brazil
Authors: Da Rocha Talita Silveira , Fortier Sergio Costa , de Castro Nelson Siqueira , Delamain Marcia T , Oliveira José Salvador , Perini Guilherme , Buccheri Valeria , Gaiolla Rafael Dezen , Fogliato Laura , Laranja Andressa , Pinto Maeva , Chiattone Carlos 
Published: October 2019

Abstract
Purpose- Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin Lymphoma (HL). The goal of this study was to evaluate the response, time of response, toxicity and overall survival in patients with refractory disease using everolimus out of clinical trial, in a compassionate use.
Patients and Methods- Patients were eligible if they had refractory and active Hodgkin disease. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Time to response assessement was defined by each center until progression (this was defined by each doctor, some have considered to keep the drug until clinical progression and not radiological progression of the disease). Patients could remain on drug until progression or toxicity.
Results- Thirty three patients were enrolled. Median age at the time of everolimus start was 29 years (range, 20-70). Patients had received a median of 5 prior therapies (range, 3-7) , 81% had undergone prior autologous stem cell transplant and 4 patients had undergone alogenic trasnplantation. The ORR was 51% (95% CI: 24-71%) with 14 patients achieving a PR, 3 patient achieving a CR and 10 with stable disease. Thirteen patients used the drug for more than 1 year. Patients received a median of 14 cycles of therapy and 3 remains on therappy at 36 months showing a great tolerability of the drug. The median DR for the responders (CR/PR) was 10 months. The most commons site effects were trombocitopenia and hypercholesterolemia. Three patients had pulmonar toxicity. The adverse events grade III and IV ocurred in 30% of the patients.
Conclusions- Everolimus has single-agent activity in relapsed/refractory HL, even in real lyfe and clinical practice and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant.

Disclosures
Off Label Use: everolimus for refractory hodgkin lymphoma.
Clinical and Haematological Features of Genetic Mutations in MPN Patients with Diagnosis of Prefibrotic Idiopathic Myelofibrosis (MF0)
Authors: Martino Bruno , Labate Claudia , Greve Bruna , Ielo Domenica , Rotilio Domenico , Mammì Corrado , Laganà Carmelo , Ronco Francesca 
Published: October 2019

Abstract
Background: Diagnosis of a prefibrotic state (MF0) presents histological diagnostic difficulties. MF0 has a worst prognostic impact than Essential Thrombocythemia (TE) as regard the thrombotic risk and a higher risk towards Idiopathic Myelofibrosis (MI) and acute leukemia evolution. For this reason it is very useful to identify this group of patients.
Aims: The aim of this study was to evaluate clinical and hematological impact of the mutational status in patients with an MF0 diagnosis.
Methods: A retrospective chart review was performed from January 2010 to July 2015 in a single center in 317 patients affected by Ph negative chronic myeloproliferative neoplasms. Polycythemia vera cases were excluded. Thirty-three patients have been classified as MF0 on the base of the bone marrow histological examination. Onset features include cytogenetics, blood counts, peripheral CD34-positive cells, spleen and liver size, thrombotic events (prior to and post-diagnosis) and thrombotic risk. Fragment analysis was performed to study exon 9 CALR mutation, Real-time PCR was applied for exon 14 JAK2 V617F mutation and Sanger sequencing was used to identify exon 10 MPL mutations for 505 and 515 codons. According to genetic results, patients were identified into four groups according to a positivity for JAK2, MPL, CALR and for triple negativity.
Results: The 33 patients with MF0 were: 11 (33%) JAK2 positive, 10 (30%) CALR positive, (10) 30% triple negative and 2 (7%) MPL positive. The latter group was not further considered for analysis due to the low number of cases. Eighty percent of CALR positive patients had a deletion on the exon 9 of the gene (8 del52bp and 2 del46bp), while 20% had the type 2 mutation (ins5bp). The average of JAK2 allelic burden was 20%. The 3 groups of patients were comparable for age, white blood counts and hemoglobin values. There was a female prevalence (23 vs 10 males). Platelet count was higher (median 875.500 103 µl, interquartile range 303.000 103 µl , p = 0.008) in CALR positive patients compared to JAK2 positive (median 569.000 103 µl, interquartile range 433.000 103 µl) and to triple negative patients (median PLT count 629.500 103 µl, interquartile range 378.250 103 µl). Noteworthy, bone marrow cytogenetic exam was normal in all patients. JAK2 positive patients had a larger spleen compared to the other two groups. Pre-diagnosis thrombotic events were exclusive for JAK2 positive patients and absent in the other groups. Triple negative patients do not have a negative prognostic impact for the thrombotic risk.
Conclusions: CALR deletion could be considered as an MF0 marker and should be included in diagnostic work-up. JAK2 positivity in MF0 is associated with a high thrombotic risk.

Disclosures
No relevant conflicts of interest to declare.
United Kingdom Experience of Intracranial Bleeds in Childhood Immune Thrombocytopenia
Authors: Grainger John D. , Harrison Louise , Bolton-Maggs Paula H. B 
Published: October 2019

Abstract
Childhood immune thrombocytopenia (ITP) is an uncommon disease that is usually self-limiting and resolves spontaneously without treatment. Less than 1% of children with ITP will develop an intracranial haemorrhage (ICH). The aim of this project was to review data from all available cases of ICH and identify features associated with an increased risk of intracranial bleeding. The data were obtained from three main resources: patient notes, the UK ITP Registry and surveys sent out to centres across the UK. 19 cases were reviewed, occurring over a period of 12 years from 2004 to 2016.
Platelet counts below 20x109/L were associated with severe bleeding, as were moderate or severe bleeding manifestations beyond cutaneous bleeding in the 28 days leading up to an ICH. Patient comorbidity was also reviewed and a significant number of patients had co-existing issues, including positive autoantibody tests. Presentations of ICH varied. In 10 patients, headache was a presenting feature. 3 patients presented with seizures, and 5 with vomiting. The majority of patients also had at least one active bleeding site in the 28 days before the episode of ICH. The mouth and nose were the most common bleeding sites. The mortality rate was 4/19, 21%. Neurological disability on discharge was present in 4/15, 27% of the patients who survived. Most identified risk factors for ICH were consistent with previous research, however none had an arteriovenous malformation and only three of 19 cases were documented to have experienced head trauma prior to ICH. Based on UK ITP registry data the incidence of ICH is estimated to bet 0.14-0.57% of paediatric ITP patients.

Disclosures
Grainger: Amgen: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bolton-Maggs:Novartis: Honoraria; Grifols: Honoraria.
Clinicopathologic Comparison of Plasmablastic Lymphoma in HIV-Positive Versus HIV-Negative Patients: Single-Center Experience
Authors: Vasquez Jule , Huamanchumo Jorge , Quintana Shirley 
Published: October 2019

Abstract
Background: Plasmablastic lymphoma (PBL) is an aggressive lymphoma associated mainly to HIV infection, although cases in immunocompetent patients are described as well.
Objective: To describe the prevalence, the clinicopathologic features and determine the overall survival of lymphoma patients according human immunodeficiency virus (HIV) status.
Methods: We reviewed the pathology database at Instituto Nacional de Enfermedades Neoplasicas (INEN), the leading cancer center of Peru from 2005 to 2014. 6218 cases were lymphomas, 5031 cases were Non-Hodgkin lymphoma and 3905 cases were B-cell lineage. 22 met diagnosis of PBL, 4 patients were excluded (1 prior treatment, 1 synchronous malignancy and 2 incomplete medical records). Finally, we had 18 cases for evaluation. Survival curves were estimated by Kaplan Meier. Statistical analysis was based on SPSS Program version 22.
Results: The prevalence of PBL was 0.004% of all Non-Hodgkin lymphomas and 0.005% of B-cell lymphomas. 13 of 18 cases (72.2%) were HIV-positive patients (PBL-HIV+). The median age for PBL-HIV+ was 37 years (range 22-67 years) and 58 years (range 53-74 years) for HIV-negative patients (PBL-HIV-).The extra-oral primary was the most frequent primary site in both groups. The advanced stage was 80% in PBL-HIV- patients. Presence of B-symptoms and Ki-67>80% were greater in PBL-HIV- patients. CHOP or CHOP-like regimen was the common treatment in both groups, only one patient received DA-EPOCH (PBL-HIV+ group). HAART-naïve patients were 77%. The median OS time was 43 months (range 1-84 months) in PBL-HIV+ patients and 13 months (range 0-15 months) in PBL-VIH- patients, the 5-yrs-OS was 26.9% y 0% respectively.
Conclusions: Plasmablastic lymphoma is a rare lymphoma, either associated or not to HIV infection. Advanced and aggressive disease is a distinctive feature in both lymphomas. The PBL-HIV- has a worse prognosis with shorter overall survival compared to the PBL-HIV+ patients.

Disclosures
No relevant conflicts of interest to declare.
Impact of Additional Chromosomal Abnormalities in Philadelphia-Positive Clone on Prognosis of CML Patients Treated with Tyrosine Kinase Inhibitors
Authors: Liu Bingcheng , Wang Ying , Wei Hui , Liu Kaiqi , Lin Dong , Zhou Chunlin , Mi Yingchang , Wang Jianxiang 
Published: October 2019

Abstract
Background: To investigate the impact of additional chromosomal abnormalities(ACA) in Philadelphia-positive clone on response to TKIs and long-term survival of CML patients treated with tyrosine kinase inhibitors (TKIs) in the real world.
Methods:In this retrospective study, patients with chronic myelogenous leukemia (CML) in chronic phase treated with TKIs were recruited. The chromosome banding analysis was performed on bone marrow cells at baseline and during the TKIs therapy.The clinic response to TKIs was evaluated according to the recommendation of ELN2013. The overall survival (OS), events free survival (EFS) and progression free survival (PFS) were analyzed. Events were defined as treatment failure, progression to accelerate phase or blast crisis and death. The progression was defined according to criteria of ELN2013 CML recommendation.
Results:
The characters and cytogenetic analysis of the patients:A total of 451 patients (281 males and 170 females) were enrolled from Jun 2004 to March 2015.The median age was 42 (range 18-79) years old. 414 subjects hadevaluable information of karyotypeat baseline.351 patients (84.4%) had the standard Philadelphia chromosome (Ph), 8(1.9%) showed variant translocation of Ph, 19 had ACA in Ph+ cells (Ph+ACA), only 2(0.5%) showed ACA in Ph- cells (Ph-ACA)£¬11(2.7%) had normal karyotype. 29 patients (6.4%) developed Ph+ACA during the TKIs treatment. Ph-ACA occurred in 8 subjects (6.4%).The response to TKIs: Comparing to the patients without Ph+ACA at baseline, the patients with Ph+ACA had lower cumulative rate of complete cytogenetic response (CCyR) (92.4% vs 68.4%, P=0.038) and prolonger median time to achieving CCyR (19 vs 7 months, P=0.016).The Ph+ACA at diagnosis had no effect on achieving major molecular response (MMR). The OS, EFS and PFS at 7 years for the whole cohort were 91%¡¢54% and 83% respectively. The patients with baseline Ph+ACA had significant inferior survival comparing to the subjects without Ph+ACA (Figure 1). The median time of OS, EFS, PFS for Ph+ACA patients were 108, 50 and 91 months, whereas the patients without Ph+ACA were not reached ( P=0.003 for OS, P<0.001 for EFS, and P=0.004 for PFS). The patients developed Ph+ACA during treatment had similar OS comparing to the subjects with Ph-ACA or without ACA (P=0.115), but they had significant shorter EFS (31 vs 90 months vs not reached£¬P<0.001)and PFS(59 vs 120 months vs not reached£¬P<0.001).
Conclusion: The Ph+ACA emergence at diagnosis and during treatment had negative impact on prognosis of CML patients treated with TKIs.

Disclosures
No relevant conflicts of interest to declare.
Retrospective Case Series Study of Hypomethylating Therapy in IPSS Lower-Risk Myelodysplastic Syndrome
Authors: Park Han-Seung , Lee Je-Hwan , Kim Yoo-Jin , Sohn Sang Kyun , Yoon Sung-Soo , Kim Hawk , Cheong June-Won , Lee Won-Sik , Lee Gyeong-Won , Joo Young-Don , Kim Min Kyoung , Kim Yang Soo , Kim Hyeoung-Joon 
Published: October 2019

Abstract

Introduction: The IPSS has been widely used for risk stratification in myelodysplastic syndromes (MDS), and patients with IPSS low and intermediate-1 scores are designated as having lower-risk (LR) MDS. Despite its utility, the outcomes of patients with LR disease defined by IPSS are variable and a subset of patients experience inferior than expected outcomes. Treatment with hypomethylating agents is the standard of care in higher-risk MDS, but there have been little data for hypomethylating therapy in LR MDS. We retrospectively collected and analyzed the data related to hypomethylating therapy in IPSS LR MDS from 12 Korean institutes.
Patients and Methods: A total of 610 patients, who were treated with azacitidine or decitabine for IPSS LR MDS, were included in this retrospective case series study. All patients received azacitidine (7-day) or decitabine (5-day). Both regimens were repeated every 4 weeks. The overall response rate (ORR) included rates for complete response (CR), partial response (PR), marrow CR (mCR), and stable disease (SD) with hematologic improvements (HI). For 139 patients who underwent allogeneic hematopoietic cell transplantation (HCT), all survival data were censored at the time of HCT.
Results: Median age was 63 (19-84) years. IPSS category was low in 44 and intermediate-1 in 566. The patients were reclassified with other scoring systems including revised IPSS (R-IPSS), WPSS, and LR-PSS, and between 21.8% and 37.7% of patients were identified as having high or very high risk features by the other prognostic indices. Patients received azacitidine (n=436) or decitabine (n=174) for a median of 5 (1-46) courses. ORR was 51.3% (CR 78, PR 12, mCR with HI 27, mCR without HI 20, and SD with HI 176). 294 patients (48.2%) showed any HI. Median OS was 2.35 years and patients with HI had significantly longer OS than those without HI (P=0.001). Our case series patients were well stratified in terms of OS by R-IPSS (P=0.001), WPSS (P<0.001), and LR-PSS (P<0.001).
Conclusion: IPSS LR MDS included a broad range of prognostic implications. Hypomethylating therapy brought varying degrees of response in about half of the patients with IPSS LR MDS. The patients who had high risk features with other prognostic indices showed poor OS and allogeneic HCT should be considered during the course of hypomethylating therapy in these patients.

Disclosures
No relevant conflicts of interest to declare.
Nicotinamide N-Methyltransferase Expression Decreases in Iron Overload Exacerbating Iron-Induced Hepatotoxicity
Authors: Koppe Tiago De Bone , Patchen Bonnie , Cheng Aaron , Bhasin Manoj , Vulpe Chris D. , Fernandez-Real Jose M. , Schwartz Robert K. , Pissios Pavlos , Fraenkel Paula G. 
Published: October 2019

Abstract
Iron overload causes the generation of reactive oxygen species, which can lead to liver failure, particularly when it occurs in conjunction with nonalcoholic fatty liver disease (NAFLD) or viral hepatitis. Previously, we studied the effects of iron deficiency and iron overload on the hepatic transcriptional and metabolomic profile in mice. We found that iron overload induced significant changes in the expression of genes and metabolites involved in glucose and nicotinamide metabolism in both a dietary model, high iron diet, and a genetic model, hemojuvelin knockout mice. In particular, we discovered that the transcript, Nicotinamide N-methyltransferase (NNMT), was significantly downregulated in both models of iron overload. NNMT methylates nicotinamide, a form of vitamin B3, and has recently been shown to play a critical role in hepatic glucose and cholesterol metabolism by stabilizing Sirtuin 1, a nicotinamide-dependent deacetylase. For the current study, we evaluated 63 morbidly obese human subjects who gave written informed consent, validated and approved by the ethical committee of the Hospital Universitari Dr. Josep Trueta (Comitè d'Ètica d'Investigació Clínica, approval number 2009046), for the collection of liver biopsy samples and sera at the time of bariatric surgery after 8 hours of fasting. In these subjects, we found that log hepatic transcript levels of NNMT negatively correlated with measures of body iron stores, including log serum ferritin levels (R=-0.39, p=0.002) and log percent transferrin saturation (R=-0.21, p=0.02). We then performed experiments in primary hepatocytes to evaluate the interaction of iron overload and NNMT. We found that treatment with ferric ammonium citrate significantly decreased NNMT transcript levels in either primary human or mouse hepatocytes. We manipulated NNMT expression in primary mouse hepatocytes using adenoviral vectors and discovered that NNMT knockdown exacerbated iron-induced cytotoxicity and enhanced iron-induced expression of transcriptional markers of oxidative and endoplasmic reticulum stress, while NNMT overexpression protected against iron-induced cytotoxicity. In future studies, we would like to elucidate the mechanisms by which NNMT modulates hepatocyte sensitivity to iron overload. A deeper understanding of the relationship of the pathways involved in maintaining iron and energy homeostasis may reveal new therapeutic targets for patients with iron overload disorders, obesity, and NAFLD.

Disclosures
No relevant conflicts of interest to declare.
Geophagia: A Scientific Approach to a Historical Practice to Sustainably Treat Endemic Iron Deficiency in a Rural Community in Nepal
Authors: Lama Binay , Jones Rachael , Barlow Nicola , Keenan Russell D 
Published: October 2019

Abstract
Geophagia is the practice of eating earth or clay and is nearly universal around the world in traditional rural societies. Many animals across genera are known to eat mineral rich soil. Some animals travel long distances to seek specific soils that are rich in minerals that they are deficient. According to the WHO dietary iron deficiency is a documented threat to public health in Nepal and iron deficiency anaemia affects 60-85% in the general population. Iron deficiency holds developing communities back with reduced growth, reduced academic achievement and reduced physical productivity. While it would be possible to simply provide iron medications, the long term delivery to remote areas would make this logistically difficult to be sustainable and in our view would provide the wrong sort of aid.
We analysed local Nepalise hill clays in Kavre District to assess feasibility of use as an iron supplement. Providing a manual pill press would allow communities to make their own clay iron tablets facilitating more precise dosing in a truly sustainable way at ongoing zero cost. 23 mineral elements were measured by Inductively Coupled Mass Spectrometry in the two common clays, white and red, following a protocol based on the UK Environmental Protection Agency method "Acid digestion of sediments, sludges and soils (Method 3050B)".
Iron was present in useful amounts in both white and red clays; 33,485 μg/g and 35,091 μg/g respectively. All other mineral elements were present at low levels and unlikely to pose a health threat, with the exception of aluminium. Aluminium was present at 20,577 μg/g in white clay and 53,125 μg/g in red clay, which is above UK recommended dietary intake levels. However, in the absence of dialysis dependant renal failure, excess aluminium is excreted in urine and there are no documented cases of environmental aluminium toxicity. Aluminium levels in antacid tablets can be 20% with no toxicity documented even with chronic use.
This is a project with local Nepali community leaders working together with UK laboratories and haematologists. Further work will assess the homogeneity of the clay composition over a wider area. We are currently developing methods to facilitate the production of clay pills with a hand press alongside developing a school based education and iron supplementation programme. Iron deficiency is a worldwide problem in developing countries. We believe this approach could be used to empower communities to improve iron nutrition across the globe.

Disclosures
No relevant conflicts of interest to declare.
Iron Metabolism before Allo-HSCT in Patients with Acute Leukemia and Impact of Iron Overload on Transplantation
Authors: Shi Jimin , Pei Xuying , Luo Yi , Tan Yamin , Zhao Yanmin , He Jingsong , Zheng Weiyan , Lai Xiaoyu , Zheng Gaofeng , Zhang Jie , Lin Maofang , Cai Zhen , Huang He 
Published: October 2019

Abstract

Objective: Iron overload is common in patients with acute leukemia who undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT). We performed a comprehensive analysis of iron parameters to assess these patients' iron metabolism, and studied the prognostic impact of pretransplant iron overload on the outcome of transplantation.
Methods: In this retrospective study, we studied 124 patients undergoing myeloablative allo-HSCT between 2012 and 2014. Serum iron (SI), serum ferritin (SF), hepcidin (Hepc) and soluble transferrin receptor (sTfR) were measured before transplant. We analyzed the effect of elevated pretransplant ferritin on acute graft versus host disease (aGVHD), infectious complications, overall survival (OS) and non-relapse mortality (NRM).
Results: Date of 124 patients (including 56 cases of acute lymphocytic leukemia and 68 cases of acute myeloid leukemia) were analyzed. Median SI, SF, Hepc and sTfR values were 12.15 umol/L, 667.05 ng/ml, 369.50 ng/L and 7.69 ng/ml, respectively. Iron overload (defined as SF>1000 ng/ml) were observed in 27.42% of patients. Pretransplant iron overload was significantly associated with increased risk of bacterial infections during the early post-transplant period, and with reduced risk of aGVHD. Pretransplant iron overload increased NRM and reduced OS, but there were no significant differences.
Conclusion: Patients with acute leukemia regularly develop iron overload before they undergoing allo-HSCT. Pretransplant iron overload was correlated with transplantation outcome.

Disclosures
No relevant conflicts of interest to declare.