bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral Blood Stem Cell (PBSC) Harvest Is More Expensive Following Bortezomib-Based Therapy in Multiple Myeloma (MM), Related to Increase Number of Days of Collect.
Authors: Barthelemy Matthieu , Boulanger Florence , Debarri Houria , Pascal Laurent , Samarcq Pierre , Cossement Colette , Jouet Jean-Pierre , Facon Thierry , Yakoub-Agha Ibrahim , Leleu Xavier 
Published: October 2019

Abstract
Abstract 1373
Poster Board I-395

Background:
High-dose therapy is the front line treatment of reference in young patients with Multiple Myeloma (MM). Although induction therapy remains a matter of controversy, bortezomib-based therapy is considered more and more as a standard of care. Prior to autologous stem cell transplantation (ASCT), patients undergo PBSC collect, usually starting after cycle 2 to 4 of the induction treatment. Currently, patients receive one transplant at front line, but most of the patients will benefit throughout the MM disease history of a second or a third ASCT procedure. We have noticed that the number of days of collection vary from patient-to-patient following bortezomib-based induction therapy. This increase in collection procedures might increase the cost of PBSC harvest with more patients discomfort and staff unavailability. We have therefore further studied the quality, yields and days of collection in myeloma patients following bortezomib-based therapy as compared to other regimens-based treatment courses.

Material and Method:
We retrospectively studied 70 patients with myeloma that underwent PBSC harvestsafter mobilization with GCSF following debulking with bortezomib-based therapy (58 days of procedures – 26 patients) versus other agents-based therapy [65 days of procedure – 44 patients; VAD vincristine, adriamycin, dexamethasone).

Results:
-Yields. CD34 Mobilization is lower following bortezomib-based therapy as compared to other regimen-based therapy. Similarly, more days of collection are also needed to collect the requested yield of PBSC.
-Engrafment. No significant differences regarding engraftment was noticed among the 2 groups studied. The days to neutrophil and platelet counts recovery, the number of days with fever and the number of red cell and platelet transfusions were not significantly different between the 2 groups, mobilization following bortezomib-based therapy versus other regimen-based therapy, respectively.

Conclusion:
In our series, bortezomib-based induction regimen does not increase the number of PBSC harvest failure and the quality of engraftment was identical to other regimen-based induction treatment. However, CD34 mobilization was lower following bortezomib-based therapy, which explains lower daily harvest counts and therefore an increase number of days of collection in bortezomib-based treated patients. Therefore, PBSC harvest procedure following bortezomib-based therapy significantly increases the cost of PBSC collection. These results need to be confirmed in larger studies. New agents in use for mobilization might be considered for future PBSC collection in bortezomib-based treated patients.

Disclosures:
Leleu: Janssen Cilag: Research Funding.
Outcome of Fungal Infection in Patients Undergoing Myelosuppressive Chemotherapy in a Tertiary Care Centre During 12 Years (1995-2006).
Authors: von Lilienfeld-Toal Marie , Glasmacher Axel , Marklein Günter , Brossart Peter , Hahn-Ast Corinna 
Published: October 2019

Abstract
Abstract 1384
Poster Board I-406
Invasive fungal infections (IFI) contribute significantly to mortality and morbidity in patients receiving myelosuppressive chemotherapy for hematological malignancies. The present study evaluates the incidence of IFI, the overall survival (OS), the infection-related mortality and changes in treatment of IFI in our department from 1995 until 2006. Data of all consecutive chemotherapy courses were retrospectively collected with a standard questionnaire. EORTC/MSG criteria for IFI were applied with a modification: A positive PCR-result for Aspergillus spp. in bronchoalveolar lavage was also defined as probable IFI. In total, 1693 courses of 592 patients were evaluated. Sixty-three percent were given to treat acute myeloid leukemia, the rest for acute lymphoblastic leukemia or aggressive lymphoma. IFI were observed in 139/592 patients (23%, 95% confidence interval (CI) 20-27%), and in 149/1693 (8.8%, 95%CI 8-10%) courses. IFI-related mortality was 57% in 1995-2001 and 29% in 2002-2006, p<0.001. Accordingly, median OS in patients with IFI increased in the later years: 54 days (95%CI 26–82 days) in 1995-2001 versus 229 days (95% CI 35–423 days) in 2002-2006, p=0.001, figure 1. By multivariate analysis, factors predictive for better OS were controlled disease after chemotherapy (hazard ratio (HR) 0.226, p<0.001), possible IFI (in contrast to proven/probable IFI, HR 0.511, p=0.002), age < 60 years (HR 0.611, p=0.015), and use of novel antifungals (HR 0.493, p=0.002). In conclusion, IFI-related mortality decreased and OS in patients with IFI increased significantly in recent years compared to 1995-2001. In our cohort improved OS was associated with controlled underlying disease, certainty of IFI diagnosis (possible), younger age, and the use of novel antifungal agents.
Figure 1 p=0.001 Figure 1. p=0.001
Time period ········ 2002-2006 —— 1995-2001 Number at risk 2002-2006 78 28 18 9 6 2 1995-2001 61 8 6 5 5 5

Disclosures:
von Lilienfeld-Toal: MSD: Honoraria, Research Funding. Glasmacher: Celgene: Employment, Equity Ownership. Hahn-Ast: MSD: Research Funding.
Development of Personal Health Records (PHR) for Patiets with Malignancies Using Interactive Internet Service: Experience at National Center for Hematology in Moscow.
Authors: Shklovskiy-Kordi Nikita E , Zingerman Boris V , Varticovski Lyuba , Kremenetskya Alexandra , Vorobjov Andrei 
Published: October 2019

Abstract
Abstract 1407
Poster Board I-429

Purpose.
To compare the requirements of physicians and patients for the Internet interactive service which allows patients to manage their own medical records and communicate with physician via the Internet.

Background.
USA federal rule defining “the Meaningful Use of Electronic Health Records” is similar to that of the National Standard of Russian Federation “The Electronic Case History (EHR)”, operating since 2008. This National Standard was developed based on experience of EHR system at the National Center for Hematology in Moscow (NCH). In 2009, we started the Personal Health Records service (PHR service) that allows patients to manage their own medical records and have internet-based communication with physicians. Simple interface for patients which blocks the full capacity of the PHR service is similar to that of EHR system of NCH. It permits integrated data presentations on a uniform axis of time and access to additional information (reported to ASH in 2001). The PHR service raises question of “meaningful use” requirements not only for EHR provider organization, but for the service users - patients and doctors.

Methods.
Using questionnaires and interviews, we compared expectations and acceptance of the PHR service by doctors and their patients.

Results and Discussion.
Preliminary results indicate that doctors are more likely to use the PHR service than the System of HER. Although the entire format of PHR service is familiar to physicians at NCH, they mostly use its information capabilities (viewing the results of the analysis, making appointments for research and planning patient's visits). The patients use PHR service with great enthusiasm (increasing with younger age and higher level of education). The complexity of integration interfaces, which we leave for the patients in the second term, gives them more inspiration than that the physicians. However, few patients take seriously the responsibilities that exist in relation to the accurate maintenance of their records.

Conclusion.
PHR can be widely used if integration of sources for medical information and unification format can simplify the “manual” work of PHR management. Key Words: Telemedicine, PHR, EHR

Disclosures:
No relevant conflicts of interest to declare.
Deletion of the Protein Tyrosine Phosphatase Gene PTPN2 in T-Cell Acute Lymphoblastic Leukemia.
Authors: Kleppe Maria , Lahortiga Idoya , El Chaar Tiama , De Keersmaecker Kim , Mentens Nicole , Graux Carlos , Van Roosbroeck Katrien , Ferrando Adolfo A. , Langerak Anton W , Meijerink Jules P.P. , Sigaux Francois , Haferlach Torsten , Wlodarska Iwona , Vandenberghe Peter , Soulier Jean , Cools Jan 
Published: October 2019

Abstract
Abstract 141

Introduction:
T-cell lymphoblastic leukemia (T-ALL) arises from clonal expansion of a lymphoid progenitor that has undergone stepwise alteration at distinct stages of differentiation. It is suggested that a set of cooperative mutations that affect different pathways are required before thymocytes become fully malignant. Despite major improvements in our understanding of the molecular genetics of T-ALL, the underlying mechanisms that lead to the abnormal proliferation and enhanced survival of the leukemic cells remain largely unknown.

Results:
Array CGH analysis revealed an acquired homozygous microdeletion at chromosome 18p11 in 6 % of T-ALL cases. The deleted region was only 125 kb in size and restricted to the PTPN2 (protein tyrosine phosphatase, non-receptor type 2) locus. PTPN2 encodes an intracellular non-transmembrane tyrosine-specific phosphatase that functions as a negative regulator of a variety of signaling proteins including several members of the janus kinase (JAK) and of signal transducer and activator of transcription (STAT) families, growth factor receptors and SRC family kinases. Homozygous deletion of PTPN2 was specifically found in cases with aberrant expression of the TLX1 transcription factor, with two cases also harboring the NUP214-ABL1 fusion. Analysis of additional TLX1 positive cases by quantitative PCR identified loss of one copy of PTPN2 in 5 out of 20 cases. No mutations were detected in the coding region of PTPN2. To determine the effect of loss of PTPN2 in T-cells, we downregulated the expression of PTPN2 using RNAi technology. siRNA mediated knock-down of PTPN2 affected activation of JAK1 associated cytokine receptors implicated in T-cell development. Ligand stimulation of IL7 and interferon gamma receptor resulted in an augmented and prolonged phosphorylation of JAK1 as well as downstream targets STAT1 and STAT5 in T-ALL cell lines with knock-down of PTPN2. In addition, knock- down of Ptpn2 sensitized the pro B-cell line Ba/F3 to transformation by wild type JAK1 confirming a clear relationship between loss of PTPN2 and JAK1 activation. Knock-down of PTPN2 expression also provided a proliferative advantage and reduced sensitivity to kinase inhibitors in lymphoblastic leukemia cell lines HSB-2 and ALL-SIL.

Conclusion:
In conclusion, our data provide genetic and functional evidence for a tumor suppressor role of PTPN2 in T-ALL and warrant testing of JAK inhibitors for the treatment of this specific subset of T-ALLs as well as further analysis of a potential negative impact of loss of PTPN2 on responsiveness to anti-cancer treatments.

Disclosures:
Ferrando: Merck, Pfizer: Research Funding.
The Humanized Multiple Myeloma Mouse Model: Opportunities for Studying the Pathogenesis of MM in Its Natural Environment.
Authors: Groen Richard W.J. , Hofhuis Frans M. , Prins Henk-Jan , Rozemuller Henk , van Kessel Berris , de Weers Michel , Lokhorst Henk , Martens Anton C.M. 
Published: October 2019

Abstract
Abstract 1847
Poster Board I-873
Multiple myeloma (MM), one of the most common hematological malignancies in adults, is a neoplasm of terminally differentiated B cells, i.e. plasma cells. The transition of a plasma cell to a fully transformed, aggressive myeloma is a multistep process, which requires the acquisition of mutations in multiple genes. Most of this evolution takes place in the bone marrow (BM). Studying the pathogenesis of MM is seriously hampered by the lack of appropriate conditions for the engraftment of patient derived MM cells (pMM) which, unlike MM cell lines, strongly depend on a human microenvironment to engraft, survive and expand, indicating that the interaction of MM cells with the cellular and extracellular components of the human BM microenvironment plays a crucial role in the growth behavior of MM cells. To date only few animal models are described that facilitate the outgrowth of pMM, however, they depend on the co-implantation of human fetal tissues or prior implantation of rabbit bone. Moreover, these do not represent the human adult BM microenvironment in which MM cells normally exist (e.g. in the SCID-Rab model and in the NOD-SCID mouse model) or there are ethical concerns (e.g. the SCID-Hu model).
Here we report the development of a unique mouse model to study the pathobiology of MM by implementing a technology for creating a natural human bone environment in the immune deficient RAG2−/−γc−/− mouse. To this end we combined a procedure to culture-expand human BM-derived mesenchymal stromal cells (MSC) that were seeded on biphasic calcium phosphate (BCP) particles and subsequently implanted subcutaneously in RAG2−/−γc−/− mice. Within 6 to 8 weeks this leads to the formation of so-called ossicles that contain substantial amounts of human bone, while the remaining open structures are filled with hematopoietic cells (of mouse origin) at various stages of erythroid, megakaryocytic and myeloid differentiation, creating an environment that strongly resembles the human bone marrow. A stricking finding was that this humanized environment in the mouse proved to be capable to not only support human GFP-luciferase gene-marked MM cell lines but also pMM cells. Intravenous or intracardial injection of MM cell lines or pMM cells showed homing to, engraftment and outgrowth of tumor cells in connection with the human bone layer in the ossicles. Hence, this novel humanized mouse model will provide the first opportunity to investigate patient derived MM plasma cells in their natural environment which may lead to better insights in the pathogenesis of this disease and serve as a model for preclinical testing of new therapeutic approaches for the treatment of Multiple Myeloma patients.

Disclosures:
de Weers: Genmab: Employment.
Stem Cell Transplant in Multiple Myeloma: Impact of Response Failure in the Era of Novel Therapies.
Authors: Gertz Morie A , Kumar Shaji , Lacy Martha Q. , Dispenzieri Angela , Dingli David , Hayman Suzanne R. , Buadi Francis , Hogan William 
Published: October 2019

Abstract
Abstract 1878
Poster Board I-900
Autologous stem cell transplant as a platform for multiple myeloma treatment is the standard of care for patients who can safely withstand the procedure. Before novel agents were introduced, one-third to one-half of patients did not achieve partial response at transplant. Previously published medical literature has showed that in this past era, absence of initial response to induction therapy had no impact on progression-free survival and overall survival after high-dose therapy. Lack of response to initial induction did not preclude a good response after stem cell transplant. With the introduction of novel agents—immunomodulatory drugs and proteasome inhibitors—response rates with initial therapy are now between 70% and 100%. This retrospective study analyzes progression-free survival and overall survival in patients who do not have a partial response after induction therapy with a regimen that contains a novel agent. Unlike patients in reports published previously—before novel agents—patients who do not achieve partial remission have a significantly shorter overall survival from transplant (74.0 vs 43.5 months) and a shorter progression-free survival (22.6 vs 13.1 months; P<.001). Absence of a response to induction therapy with a novel agent predicts a poorer outcome after high-dose therapy.{abstabft}.b CR+VGPR for plateau, P<.001 compared with other 3 categories.
Failure to respond to novel-agent induction leads to shorter posttransplant progression-free survival (PFS).
Failure to respond to novel-agent induction leads to shorter posttransplant overall survivalDisclosures: Gertz: celgene: Honoraria; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kumar: celgene: Honoraria; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lacy: celgene: Honoraria; millenium: Honoraria.TableMultivariable Analysis of Posttransplant Progression-Free SurvivalVariableP ValuePlateau vs relapsed-refractory.003Albumin.86Sex.94b2-Microglobulin.89Bone marrow plasma cells.18Age.75Abnormal cytogenetics.002CTX mobilization.51Labeling index.002
Effect of Phlebotomy Therapy On Hemoglobin Concentration and Tricuspid Regurgitation Velocity in Chuvash Polycythemia.
Authors: Miasnikova Galina Y , Niu Xiaomei , Nouraie Mehdi , Sergueeva Adelina I , Okhotin Daniel J , Ammosova Tatiana , Nekhai Sergei , Aliyu Zakari , Sable Craig , Dham Niti , Gordeuk Victor R. 
Published: October 2019

Abstract
Abstract 1897
Poster Board I-920

Background:
Chuvash polycythemia is caused by homozygosity for the VHL598C>T mutation, which leads to up-regulation of HIF-1a and HIF-2a in normoxia. As the result, circulating concentrations of erythropoietin are elevated. Chuvash polycythemia patients suffer from cardiovascular abnormalities that include pulmonary arterial hypertension, thrombosis and stroke. Phlebotomy is a common therapy for patients to decrease symptoms such as plethora and headache. However, the outcomes of phlebotomy have not been assessed for these patients. The objective of this analysis is to evaluate the effect of phlebotomy on hemoglobin concentration, serum concentrations of ferritin and erythropoietin, and echocardiographically-determined tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure.

Methods:
One hundred twenty patients homozygous for VHL598C>T and 38 controls of comparable age and gender from Chuvash Republic of the Russian Federation were studied. Clinical and demographic characteristics were determined and echocardiography was performed. Serum ferritin and erythropoietin concentrations were measured by ELISA.

Results:
The median (interquartile) age for Chuvash polycythemia cases was 36 (22–48) years. They included 68 females (56%). Chuvash polycythemia patients had higher serum erythropoietin concentration (medians of 46 versus 8 mIU/ml, P = 0.0001) and lower serum ferritin concentration (medians of 12 versus 48 ng/ml, P = 0.0001) compared to controls. Tricuspid regurgitation velocity was higher in cases than controls (medians of 2.5 vs. 2.3 m/sec, P = 0.007). Among the cases, 87 (71%) had a history of phlebotomy and 54 of these had phlebotomy within the last year. Phlebotomy was associated with higher erythropoietin concentration (P = 0.033) and lower ferritin concentration (P = 0.024) but no significant difference in hemoglobin concentration (P = 0.9) (Table 1). After adjusting for the effect of age, phlebotomy was associated with significantly higher odds of tricuspid regurgitation velocity ≥2.5 (m/sec) (odds ratio: 3.3; 95% CI: 1.1–9.9).

Conclusion:
Patients with Chuvash polycythemia tend to mobilize iron stores and increase erythropoietin production to maintain a constant, elevated hemoglobin concentration despite phlebotomy therapy. In this process, estimated pulmonary systolic blood pressure appears to increase. Therefore, phlebotomy therapy might be a risk factor for pulmonary hypertension in the context of Chuvash polycythemia.

Disclosures:
No relevant conflicts of interest to declare.
JAK2V617F Mutation Selectively Exerts the STAT3 Pathway for Enhancing a Neutrophil Activation Marker.
Authors: Oku Seido , Takenaka Katsuto , Shide Kotaro , Kumano Takashi , Yoshikane Kikushige , Kuriyama Takuro , Urata Shingo , Iwamoto Chika , Yamauchi Takuji , Shimoda Haruko , Miyamoto Toshihiro , Shimoda Kazuya , Akashi Koichi 
Published: October 2019

Abstract
Abstract 1901
Poster Board I-924
Leukocyte alkaline phosphatase (LAP) is considered as a neutrophil activation marker. The level of LAP is quantitated as the LAP score. It is well known that patients with chronic myelogenous leukemia (CML) usually have low LAP scores, whereas those with BCR-ABL negative chronic myeloproliferative disorders (MPD) have elevated LAP scores. In CML patients, the premature release of granulocytes from the bone marrow into the peripheral blood is considered as the cause of low LAP scores. However, the reason for elevated LAP scores in BCR-ABL negative MPD patients has been unclear. An acquired JAK2V617F mutation is observed in most patients with BCR-ABL negative MPD. It has been shown that the JAK2V617F mutation induces constitutive activation of its downstream signaling pathways such as STAT3/STAT5, Ras/MAPK and PI3K pathways. We speculated that an elevated LAP score might be due to the activation of Jak2 downstream pathways through the JAK2V617F mutation.
We analyzed LAP expression in BCR-ABL negative MPD patients. JAK2V617F homozygous patients had higher LAP expression than JAK2V617F heterozygous or negative patients. AG490, the Jak2 inhibitor, was shown to significantly decrease the LAP expression in neutrophils of JAK2V617F positive patients.
The myeloid cell line NB4 was transfected with the JAK2V617F mutation and a wild-type Jak2 using lentivirus vectors. It was observed that the JAK2V617F mutation, but not wild-type Jak2, enhanced cell proliferation. Then the LAP expression in NB4 cells was evaluated after these cells were differentiated by all-trans retinoic acid and granulocyte colony-stimulating factor. It was observed that the JAK2V617F mutation, but not wild-type Jak2, increased LAP expression. Next, we examined which of the Jak2 downstream pathways played a major role in increasing LAP expression and prompting cell proliferation. By using MEK1/2 inhibitor U0126, PI3K inhibitor LY294002, STAT3 siRNA and STAT5 siRNA, we demonstrated that the JAK2V617F mutation primarily used the STAT3 pathway to increase LAP expression. On the other hand, the JAK2V617F mutation used the STAT5, the Ras/MAPK and the PI3K pathways, but not the STAT3 pathway, to prompt proliferation of NB4 cells.
In conclusion, we obtained direct evidence that the JAK2V617F mutation induced elevation of LAP scores via the STAT3 pathway, and prompted proliferation of NB4 cells via the STAT5, the Ras/MAPK and the PI3K pathways. Our findings showed the possibility that the JAK2V617F mutation might use specific downstream pathways depending on various phenotypic manifestations of BCR-ABL negative MPD.

Disclosures:
No relevant conflicts of interest to declare.