bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective Evaluation of plasma Levels of FVIII in Patients with venous Thromboembolism,
Authors: Bittar Luis Fernando , Fonseca Bruna Mazetto , Montalvão Silmara Lima , de Andrade Orsi Fernanda Loureiro , de Paula Erich V , Annichino-Bizzacchi Joyce M 
Published: October 2019

Abstract
Abstract 3348

Introduction:
Venous thromboembolism (VTE) is a multifactorial disease, and increased levels of coagulation factor VIII (FVIII) has been demonstrated as risk factor for first and recurrent episodes of VTE. Some authors reported that these high levels of FVIII were still persistent after 4 years of the episode, but median follow-up in these studies are relatively short. The aim of the study was investigate if after a long-term follow-up of 4–15 years (median of 10 years), patients with high levels of FVIII after anticoagulant treatment still showed this alteration.

Design and Methods:
Previously, we selected 174 adult patients with a first episode of acute VTE between January 1990 and September 2004. One hundred seventy four healthy adult individuals selected from blood donors were chosen as controls, from the same geographic area of origin. Of this group of VTE patients, 68 patients with plasma FVIII: C levels above the 90th percentile were selected. FVIII levels (FVIII:C) were measured by a one-stage clotting assay with FVIII-deficient plasma in duplicate in an automated coagulometer. Levels were measured twice, in 2004 and then in 2011. C-reactive protein (CRP) levels were determined in the same samples by a nephelometric method to evaluate the influence of inflammation on FVIII levels. For individuals with CRP values higher than 1mg/dL, an additional blood sample was analyzed. High FVIII levels were only considered for further analysis when in the presence of normal CRP levels. The presence of post-thrombotic syndrome (PTS) was evaluated and classified clinically by the Clinical-Etiologic-Anatomic-Pathophysiologic (CEAP) classification System.

Results:
68 patients with VTE and high levels of FVIII (19M:49F) with a median age of 47 years (range 20–70) were included in the study. The control group consisted of 59 subjects (42M:17F) with a median age of 35 years (range 21–56 years). VTE was spontaneous in 26 (38.2%) patients and secondary to an acquired risk factor in 61.8%. In the 1st evaluation, in 2004, patients with VTE had higher plasma levels of FVIII:C (median 235.8 IU/dL vs. 127.0 IU/dL; p<0.001) compared to controls. In 2011, seven years after the first evaluation and after a median follow-up of 10 years after the first VTE episode, this difference was still present (median 144.6 IU/dL vs. 96.4 IU/dL; p<0.001). Patients with severe PTS (167 IU/dL) showed higher plasma levels of FVIII when compared with patients without PTS (median 141.4 IU/dL), mild PTS patients (median 142.8 IU/dL), and moderate PTS patients (median 143.2); p=0.04.

Conclusions:
Our results show that even after a median of 10 years of VTE, patients still have increased levels of FVIII. Moreover, there seems to be a relationship between severe post-thrombotic syndrome and increased plasma levels of FVIII.

Disclosures:
No relevant conflicts of interest to declare.
MT1-MMP Regulates Hematopoiesis Through HIF-Mediated Chemo-/Cytokine Release From the Bone Marrow Niche,
Authors: Nishida Chiemi , Kusubata Kaori , Tashiro Yoshihiko , Gritli Ismael , Sato Aki , Ohki-Koizumi Makiko , Seiki Motoharu , Nakauchi Hiromitsu , Heissig Beate , Hattori Koichi 
Published: October 2019

Abstract
Abstract 3409
Stem cells reside in a physical niche, a particular microenvironment. The organization of cellular niches has been shown to play a key role in regulating normal stem cell differentiation, stem cell maintenance and regeneration. Various stem cell niches have been shown to be hypoxic, thereby maintaining the stem cell phenotype, e.g. for hematopoietic stem cells (HSCs) or cancer stem cells. The bone marrow (BM) niche is a rich reservoir for tissue-specific pluripotent HSCs. Proteases, such as matrix metalloproteinases (MMPs) can modulate stem cell fate due to their proteolytic or non-proteolytic functions (abilities). We have investigated the role of membrane-type1 matrix metalloproteinase (MT1-MMP), known for its role in pericellular matrix remodeling and cell migration, in hematopoiesis. MT1-MMP is highly expressed in HSCs and stromal cells. In MT1-MMP−/− mice, release of kit ligand (KitL), stromal cell derived factor-1 (SDF-1/CXCL12), erythropoietin (Epo) and interleukin-7 were impaired resulting in erythroid, myeloid and T and B lymphoid differentiation. Addition of exogenous rec. KitL and rec. SDF-1 restored hematopoiesis in vivo and in vitro. Further mechanistic studies revealed that MT1-MMP in a non-proteolytic manner activates the HIF-1 pathway, thereby inducing the transcription of the HIF-responsive genes KitL, SDF-1 and Epo.
These results suggested MT1-MMP as a critical regulator of postnatal hematopoiesis, which as a modulator of the HIF pathway alters critical hematopoietic niche factors necessary for terminal differentiation and or migration. Thus, our results indicate that MT1-MMP as a key molecular link between hypoxia and the regulation of vital HSC niche factors.

Disclosures:
No relevant conflicts of interest to declare.
Hypoxic Hematopoietic Stem and Progenitor Cells Reside in Structurally Diverse Perivascular Niches in the Bone Marrow,
Authors: Nombela-Arrieta Cesar , Pivarnik Gregory , Winkel Beatrice , Harley Brendan , Mahoney John E , Lu Jiayun , Protopopov Alexei , Silberstein Leslie E 
Published: October 2019

Abstract
Abstract 3417
The identification of specific microenvironments, in which Hematopoietic Stem and Progenitor Cells (HSPCs), reside within the BM is a major challenge in stem cell biology. Yet the extreme rarity of HSCs, their dynamic nature, and the lack of unique specific markers to identify them, have precluded an accurate definition of HSC niches to date. Using Laser Scanning Cytometry, a powerful emerging quantitative imaging technology that enables analysis of whole femoral sections at the single cell level, we have mapped the global distribution of hematopoietic stem and progenitor cells within femoral bone marrow cavities, and analyzed their inmediate surrounding microenvironment.
Systematic mapping of the global distribution of endogenous HSPC-enriched populations in the BM, revealed an accumulation of these cells inside endosteal regions (ER <100μm from inner bone surface), but not necessarily in contact with endosteal surfaces. Interestingly, the vast majority of HSPCs were found in direct association with BM micrrovessels, further supporting previous work, which suggested bone marrow endothelium as a major component of HSPC niches. By employing a novel imaging approach, we provide a three-dimensional (3D) microscopic overview of the unique BM vascular network found in endosteal zones, which contain the transition of bone-lining arterioles and capillaries to the sinusoidal network. Of note, HSPC association to vascular structures is not restricted to sinusoids. A significant fraction of HSPCs lied adjacent to non-sinusoidal endothelium. Using five-color imaging cytometry and pimonidazole incorporation, we have assessed the hypoxic state of HSPCs in different BM microenvironments. Our in situ analysis reveals that intracellular hypoxia is a hallmark of HSPCs, independent of their distance to bone surfaces, and more importantly, regardless of their perivascular localization. These studies provide unequivocal anatomical evidence for the intrinsic rather than environmental regulation of intracellular hypoxia in HSPCs and challenge the hypothesis of a “super hypoxic” HSPC niche.

Disclosures:
No relevant conflicts of interest to declare.
Telomere Elongation In Vivo and Clinical Response Upon Androgen Treatment in a Patient with Aplastic Anemia and a Heterozygous hTERT Gene Mutation,
Authors: Brümmendorf Tim H , Ziegler Patrick , Akkad Jamil , Brassat Ute , Vankann Lucia , Panse Jens , Wilop Stefan , Balabanov Stefan , Schwarz Klaus , Martens Uwe M. , Schrezenmeier Hubert 
Published: October 2019

Abstract
Abstract 3427
Telomere length both reflects and limits the replicative life-span of normal somatic cells and critically shortened telomeres are associated with a variety of disease states. In patients with aplastic anemia telomere lengths in granulocytes and lymphocytes can be found to be significantly shorter as compared to age-adjusted controls. Telomere shortening in peripheral blood cells therby mirrors telomere shortening in the underlying hematopoietic stem cell reserve, which can be severely diminished in acquired bone marrow failure syndromes. Genetic aberrations such as mutations in the gene for dyskerin or in subunits of the telomerase-complex such as the RNA subunit hTERC or mutations in the human telomerase gene (hTERT) have been described and linked to critically short telomeres found in blood cells.
We report here on a 51 year old male patient with moderate aplastic anemia (AA) and a non-synonymous variation of codon 1062 of the hTERT gene (pAla1062Thr). Cells with deficient expression of glycosylphosphatidylinositol-anchored proteins (GPI-AP), i.e. cells with a PNH phenotype, were detected (1.2% of erythrocytes, 8% of reticulocytes and 15% of neutrophils). The patient was found to have dramatically shortened telomere length below 1% percentile of normal individuals both in lymphocytes (4.28 +/− 0.02 kbp) and granulocytes (4.14 +/−0.1 kbp). Based on the clinical presentation (i.e. predominance of red blood cell transfusion dependence and thrombocytopenia, but absence of immediate risk e.g. of infections or bleeding) we decided to initiate androgen treatment rather than to initiate standard immunosuppression.
The initially red blood cell transfusion dependent and thrombocytopenic patient became completely red blood cell transfusion independent after twelve months of ongoing androgen treatment. A significant proportion of GPI-AP deficient red cells and reticulocytes could no longer be detected and only a very small proportion of GPI-AP deficient granulocytes (<1%) persisted.
The clinical and hematological improvement during androgen therapy was mirrored by a continuous and persistent lengthening of telomere length in total peripheral blood mononuclear cells (MNCs) measured by qPCR as well as in both leukocyte subpopulations measured by Flow-FISH.
To our knowledge, this represents the first case of sustained telomere elongation in hematopoietic stem cells induced by a pharmacological approach in vivo.

Disclosures:
No relevant conflicts of interest to declare.
Safety and Efficacy of the Novel Combination of Panobinostat (LBH589) and Everolimus (RAD001) in Relapsed/Refractory Hodgkin and Non-Hodgkin Lymphoma,
Authors: Younes Anas , Copeland Amanda , Fanale Michelle A. , Fayad Luis , Romaguera Jorge E , Kwak Larry W , Neelapu Sattva S. , Hagemeister Fredrick , Pro Barbara , de Castro Faria Silvana , Ji Yuan , Berry Donald , Buglio Daniela , Medeiros L. Jeffrey 
Published: October 2019

Abstract
Abstract 3718
Based on preclinical experiments that demonstrated in vitro synergism between pan-deacetylase (DAC) inhibitor Panobinostat (LBH589) with mTOR inhibitor Everolimus (RAD001) in Hodgkin and non-Hodgkin lymphoma cell lines, we conducted a phase I/II study to determine the safety and efficacy of this novel regimen. Patients were eligible if they had relapsed or refractory Hodgkin or non-Hodgkin lymphoma regardless of the number of prior regimens, including autologous and allogeneic transplantation. Everolimus was self administered orally daily and Panobinostat three times weekly on 4 dose escalation levels [Table 1]. To date, a total of 30 patients have been treated. The histologic subtypes include small lymphocytic (n=1), follicular (n=2), mantle cell (n=3), hodgkin (n=12), diffuse large B-cell (n=7), T-cell (n=3), one discordant Hodgkin/marginal zone lymphoma and one discordant Hodgkin/large cell lymphoma. The median number of prior therapies is 3 with 11 patients receiving prior autologous transplantation. 30 patients received at least 1 dose and are evaluable for safety and 28 are evaluable for response. The DLT was thrombocytopenia observed in the 4th cohort with a dose of 30mg Panobinostat and 10mg of Everolimus. Therefore, 6 patients were treated at the lower dose level of 20mg Panobinostat and 10mg Everolimus which was determined to be the maximum tolerated dose (MTD) and starting dose in the phase II portion of the study. To date, 16 patients have been treated in the phase II portion of the study. Treatment side effects are manageable with the following grade 3/4 adverse events most commonly observed: thrombocytopenia 48%, neutropenia 48% and anemia 20%. One death occurred on study, possibly related to pulmonary embolus. 20 out of 28 evaluable patients (71%) had tumor reduction ranging from -12% to -72% of whom 50% had PR or CR. Our data demonstrate safety and promising clinical activity of this novel combination in a variety of lymphomas. The phase II portion continues to enroll patients to determine the efficacy of this novel regimen.
Dose Level Everolimus Panobinostat N 1 5mg 10mg 3 2 5mg 20mg 3 3 (MTD) 10mg 20mg 6 4 10mg 30mg 2 Phase II 10mg 20mg 16

Disclosures:
Neelapu: celgene: Research Funding. Pro:Celgene: Consultancy, Honoraria.
IPSS Independent Prognostic Value of Plasma CXCL10, IL-7 and IL-6 Levels in De Novo Myelodysplastic Syndromes,
Authors: Pardanani Animesh , Finke Christy , Lasho Terra L , Al-Kali Aref , Begna Kebede , Hanson Curtis A. , Tefferi Ayalew 
Published: October 2019

Abstract
Abstract 3795
Recent studies suggest a powerful prognostic value for plasma cytokine levels in primary myelofibrosis (IL-2R, IL-8, IL-12, IL-15 and CXCL10) and large cell lymphoma (IL-2R, IL-8, IL-10, IL-12, CXCL9 and CXCL10). In order to examine the possibility of a similar phenomenon in myelodysplastic syndromes (MDS), we used multiplex ELISA to measure 30 plasma cytokines in 78 patients with primary MDS. Compared to normal controls (n =35), the levels of 19 cytokines were significantly altered. Multivariable analysis identified increased levels of CXCL10 (p<0.01), IL-7 (p=0.02) and IL-6 (p=0.07) as predictors of shortened survival; the survival association remained significant when the Cox model was adjusted for the international prognostic scoring system (IPSS), age, transfusion-need or thrombocytopenia. MDS patients with normal plasma levels of CXCL10, IL-7 and IL-6 lived significantly longer (median survival 76 months) than those with elevated levels of at least one of the three cytokines (median survival 25 months) (p<0.01). Increased levels of IL-6 were associated with inferior leukemia-free survival, independent of other prognostic factors (p=0.01). Comparison of plasma cytokines between MDS (n =78) and primary myelofibrosis (n =127) revealed a significantly different pattern of abnormalities. These observations reinforce the concept of distinct and prognostically-relevant plasma cytokine signatures in hematologic malignancies.Figure:Survival data for 78 patients with de novo myelodysplastic syndrome (MDS) stratified based on plasma levels of CXCL10, IL-7 and IL-6: (i) normal levels of all 3 cytokines (top curve), or (ii) increased (> 3 standard deviations of the normal mean level) level(s) of one or more of the aforementioned cytokines (bottom curve) (p=0.002).Figure:. Survival data for 78 patients with de novo myelodysplastic syndrome (MDS) stratified based on plasma levels of CXCL10, IL-7 and IL-6: (i) normal levels of all 3 cytokines (top curve), or (ii) increased (> 3 standard deviations of the normal mean level) level(s) of one or more of the aforementioned cytokines (bottom curve) (p=0.002).

Disclosures:
No relevant conflicts of interest to declare.
Cladribine Alone and in Combination with Cyclophosphamide or Cyclophosphamide and Mitoxantrone in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL): Long-Term Follow-up of the the Polish Adult Leukemia Group (PALG CLL2) Study,
Authors: Robak Tadeusz , Blonski Jerzy , Jamroziak Krzysztof , Calbecka Malgorzata , Dwilewicz-Trojaczek Jadwiga , Boguradzki Piotr , Dmoszynska Anna , Kowal Malgorzata , Kloczko Janusz , Piszcz Jaroslaw , Stella-Holowiecka Beata , Sulek Kazimierz , Kuliczkowski Kazimierz , Potoczek Stanislaw , Warzocha Krzysztof , Lech-Maranda Ewa , Skotnicki Aleksander , Magdalena Piotrowska , Moskwa Andrzej , Zawilska Krystyna M , Gora-Tybor Joanna 
Published: October 2019

Abstract
Abstract 3915

Purpose.
In 2006 we have published an early report of the prospective, randomized, multicenter study (PALG CLL2) comparing the efficacy and toxicity of cladribine alone and in combination with cyclophosphamide (CC) or cyclophosphamide plus mitoxantrone (CMC) in 508 previously untreated patients with progressive and advanced CLL (Blood. 2006;108:473–9). In this early analysis we found that CMC induced higher CR rate than CC (36% vs. 21%, p=0.004), but no differences in overall response (OR), progression-free survival (PFS) and overall survival (OS) among treatment groups were observed. The aim of the present study was to verify whether long-term follow-up might change originally published data on PFS or/and OS as well as to compare the rate of late complications including secondary neoplasms and Richter's syndrome. Methods. In PALG CLL2 study PFS was defined as the time from the end of first–line therapy to disease progression or death from any cause. OS was measured from the time of randomization to death or last contact. OS and PFS were calculated according to the method of Kaplan and Meier and compared between groups by the log-rank test. Only patients with pathologically-proven tumours diagnosed after chemotherapy initiation were considered as having secondary neoplasms or Richter's syndrome. Frequencies of secondary tumours were compared by chi2 test. Results. The median time of follow-up as of Januar y 2011 was 45.6 months (95% CI: 39.9–51.4). The results of comparison of survival times and late complications in different study arms are shown in Table 1 and Figure 1. Conclusions. Long term results for 508 r andomized patients confirm that cladribine alone, CC and CMC regimens produce comparable PFS and OS in previously untreated progressive CLL. The risk of secondary tumours does not differ in the investigated treatment groups.

Disclosures:
No relevant conflicts of interest to declare.
Pomalidomide (Pom) in Relapsed and Refractory Multiple Myeloma (RRMM) - theUARK Compassionate Use Protocol,
Authors: Usmani Saad , Waheed Sarah , Szymonifka Jackie , Panozzo Susan , Petty Nathan M , Steward Doug , Nair Bijay , Alsayed Yazan , Hoering Antje , Crowley John , Barlogie Bart 
Published: October 2019

Abstract
Abstract 3995

Background:
Pom is a third generation immunomodulatory drug (IMiD) which has demonstrated safety and efficacy in RRMM with prior exposure/resistant to other IMiDs and bortezomib. This is the first report on the UARK Pom compassionate use experience in RRMM. Methods: First cycle Pom was given at 4mg orally Days 1–21 every 28 days; dexamethasone (DEX) was given to 9/23 patients at doses varying from 12 to 40 mg on schedules ranging from Days 1–4, weekly, twice a week, or three times a week. In the absence of at least PR, Pom dose was escalated to 5mg. 1patient also received bortezomib and 1 patient received bortezomib and cytoxan. Cox regression modeling was employed for univariate and multivariate analyses, whereas Kaplan-Meier curves were used for overall survival (OS) and progression free survival (PFS). Results: 23 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 43%, ISS stage >=II was seen in 78% of patients, cytogenetic abnormalities (CA) within 6 months in 80%, and GEP-defined high risk in 41% of patients. 22/23 patients (96%) had prior autologous stem cell transplant. 19/23 patients (83%) had at least 2 transplants. All 23 patients had disease progression after having received regimens containing bortezomib, thalidomide, lenalidomide, melphalan and steroids. At least 1 cycle of treatment was administered to all 23 patients enrolled, 52% of patients received >1 cycle of treatment and only 13% received =>5 cycles. 10 patients (43%) discontinued therapy primarily due to progression or death. 5/23 (22%) patients achieved PR, 57% had stable disease. A trend towards PFS benefit was observed in patients receiving cycle 2 (HR=0.30, p=0.215) on univariate analysis and multivariate analysis (HR=0.40, p=0.48) after adjusting for GEP-defined risk status (HR=2.69, p=0.16). Most common toxicities, counting all toxicities (>=grade 3) were: thrombocytopenia (70%), leukopenia (61%), anemia (43%), hypophosphatemia (35%) and hypokalemia (26%). Overall and progression- free survival at 12 months were 52% and 30%, respectively. Conclusions: Pom demonstrates anti-myeloma activity in this advanced RRM population, especially in a sub-population with GEP-defined low-risk disease.

Disclosures:
Barlogie: Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.
Incidence Rates of the Leukemias in the United States Are Significantly Associated with Birth Cohort,
Authors: Rosenberg Philip S , Anderson William F. 
Published: October 2019

Abstract 4203

BACKGROUND:
Leukemia (all types) is a common cancer in the United States (US) with 44,600 new cases expected in 2011. There are currently only a few established risk factors for any major type. If leukemia risks are substantially modulated by known or unknown environmental and lifestyle exposures, then incidence rates in the population should vary significantly by birth cohort. However, prior studies have not examined birth cohort effects using contemporary data and methods.

METHODS:
We used nationally representative data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program for 1992 – 2008 (68,481 leukemias and 6.6×108 person-years of follow-up). For each major type in male and female pediatric (ages 0 – 17) and adult (ages 18 – 85) populations, we estimated the average annual percentage change in incidence attributable to calendar period and/or birth cohort (net drift), and the significance of unique (non-linear) birth cohort effects, using age-period-cohort statistical models and Poisson regression.

RESULTS:
In adults, birth cohort effects for AML were significant in men (P = 0.002) and borderline significant in women (P = 0.053). Compared to men born during 1947 – 1951, men born in the 1920s–1930s were 1.4-fold more likely to develop AML; AML rates were stable in men born after 1951. Birth cohort patterns for AML were qualitatively similar in women compared to men. For CLL, birth cohort effects were highly significant in men (P=5.7×10−6), peaking among men born circa 1939 and falling by 38% among men born circa 1963. In contrast, birth cohort effects for CLL were almost completely absent in women. For CML, incidence declined steadily by 1.3%/year among men (P = 0.0003) and by 1.5%/year among women (P = 0.0008). For ALL, incidence increased steadily by 2.0%/year among women (P = 0.001); birth cohort patterns were similar in men but not statistically significant (P = 0.36). In the pediatric population, AML rates were stable over time. In contrast, ALL rates increased by 1.4%/year among males (P = 0.001) and by 1.1%/year among females (P=0.04).

CONCLUSIONS:
In the US, leukemia risks increase or decrease substantially by birth cohort for each major leukemia type except adult female CLL and pediatric AML, on the order of 1–2%/year or 20–40% per generation. These results are consistent with the hypothesis that leukemia risks are substantially affected by known (i.e. smoking, certain chemicals) or suspected (i.e. obesity) environmental and lifestyle exposures, a number of which are potentially modifiable.

Disclosures:
No relevant conflicts of interest to declare.