bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet Dense Granule Deficiency is Associated with Menorrhagia.
Authors: Sham Josh , Gunning William T. , Braggins Laura , Sham Ronald L. , Kouides Peter 
Published: October 2019

Abstract
Abstract 1327
Poster Board I-349
Outpatient evaluation of hemostasis for women with menorrhagia and/or other bleeding symptoms can be unrevealing. A candidate etiology in some of these patients may be platelet (PL) dense granule (DG) deficiency, a heterogeneous bleeding diathesis characterized by variable abnormalities in platelet aggregation and decreased DG number and/or decreased DG volume by electron microscopy (EM) and image analysis.

Objective
To determine the correlation between menorrhagia and the number and volume of platelet DGs in a cohort of women participating in a multi-center menorrhagia treatment study (British J Haem 145(2):212-220, 2009).

Patients and Methods
The diagnosis of menorrhagia was determined using a semi-objective pictorial blood assessment chart (PBAC) necessitating a score of >100. The menorrhagia patients were compared to control subjects, evaluated as paired subjects on the same day. A total of 29 pairs were studied. Patients were eligible only if gynecological exam was normal. All patients were tested for other underlying hemostatic defects. Hemostatic disorders included: a platelet function disorder in 7/29 (24%), a coagulation factor deficiency 2/29 (7%) and von Willebrand disease 1/29 (3%).

Results
The mean age of the menorrhagia group was 35 ± 6.07 years. These patients had an average PBAC score of 454 ± 302.6 Patients were found to have a mean of 2.910 ± 1.207 DG/PL compared to 4.617 ± 1.13 DG/PL for the control group (p-value <0.001 by t test). The mean difference between the two groups was found to be 1.707, and the 95% confidence interval on the difference was found to be [1.096, 2.318]. DG volume was also determined using image analysis. The mean volume for the menorrhagia group was found to be 5.93 ± 3.68 × 106 fL. The mean volume for the control group was 10.04 ± 3.31 × 106 fL (p-value <0.001 by t test). The difference between the two values was found to be 4.11 with a 95% confidence interval on the difference of [2.266, 5.947].

Conclusions
Patients with menorrhagia with and without other hemostatic defects, had fewer platelet DGs than the control group. In addition, the aggregate DG volume/PL was significantly reduced in menorrhagia patients compared to the control group. These findings suggest that the menorrhagia experienced by some women is associated with platelet DG deficiency. Further study is needed in determining the significance of these findings.

Disclosures
No relevant conflicts of interest to declare.
Diagnostic Delays and Survival for Medicare Patients with Chronic Myeloid Leukemia in the Pre-Imatinib Era.
Authors: Friese Christopher R , Magazu Lysa S , Neville Bridget A , Richardson Lisa C , Earle Craig C , Abel Gregory A 
Published: October 2019

Abstract
Abstract 1369
Poster Board I-391

Background:
Timeliness of diagnosis is a quality of care measure endorsed by the Institute of Medicine. Clinical outcomes for patients with chronic myelogenous leukemia (CML) are better when tyrosine kinase inhibitors, such as imatinib, are initiated in the early stages of disease. However, the patterns of care surrounding the CML diagnosis period, as well as the relationship between diagnosis delay and overall survival in the pre-imatinib era, are unknown.

Methods:
The Surveillance, Epidemiology and End Results (SEER)-Medicare linked database was used to identify traditional Medicare enrollees diagnosed with CML during 1991 through May 2001 (prior to the FDA approval of imatinib). Both inpatient and outpatient claims were analyzed from one year before, through six months following, the SEER diagnosis date. Signs, symptoms, and diagnostic studies commonly encountered in CML diagnoses were identified by CPT procedure and ICD-9 diagnosis and procedure codes. We calculated the time between the first visit for a sign or symptom and the SEER diagnosis date, and defined this time period as ‘diagnostic delay’ if it met or exceeded the median number of days for the sample. An accelerated failure time model examined variables associated with diagnostic delay. Overall survival was examined using a Cox proportional hazards model. Analyses were adjusted to account for a possible lag time in SEER cancer diagnosis dates, as well as year of diagnosis.

Results:
We studied 768 patients who met eligibility criteria. The most frequent signs and symptoms prior to CML diagnosis were infection (29.4%), anemia (22.4%), leukocytosis (13.4%) and fatigue (11.9%). The median time between any sign or symptom and CML diagnosis date in SEER was 90 days (interquartile range = 270). The median survival time was 3.5 years. The time between sign or symptom and CML diagnosis was increased for patients with at least one comorbidity (β=0.83, p < .001), and for those diagnosed at age 75 or greater (β=0.30, p < .05). Males had shortened times to diagnosis (β=-0.41, p < .01). Diagnostic delay was not a significant predictor of overall survival (HR = 1.04, 95% CI = 0.88-1.23).

Conclusions:
The most common signs and symptoms older patients experience prior to CML diagnosis are nonspecific, which may impair diagnostic efforts. Prior to the approval and general availability of imatinib, differences in timeliness of diagnosis were observed by age, gender, and presence of comorbidities. Examination of patient-provider interactions stratified by these variables may aid efforts to standardize the diagnostic process, although diagnostic delay was not significantly associated with overall survival in the pre-imatinib era.

Disclosures:
No relevant conflicts of interest to declare.
Results of First-in-Man Phage Idiotype Vaccine Study in Patients with Multiple Myeloma.
Authors: Roehnisch Tim , Nagel Wolfgang , Boehm Thomas , Donceau Mariel , Bourquin Carole , Roehnisch Dilda A. , Rutz Beata , Straka Christian , Emmerich Bertold , Oduncu Fuat S. 
Published: October 2019

Abstract
Abstract 1858
Poster Board I-883

Objective:
Idiotypes (Id) expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and may therefore be used as a target for vaccine immunotherapy. In this phase I/II study we have evaluated the feasibility, safety and response of phage idiotype vaccination in patients with relapsed multiple myeloma (MM) using phage displayed Id-specific proteins as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) as immunoadjuvants.

Study Design:
Patients received a total of 6 intradermal/subcutanous (i.d./s.c) immunizations of phage idiotype vaccines at day 1, 7, 14 and at week 4, 8 and 12. The vaccine dose started from 0.25 mg for the first 5 patients and was escalated to 1.25 mg (patient 6-10) and 2.5 mg (patient 11-15) if no dose-limiting toxicity was observed. Each vaccine contained 0.2 mg GM-CSF (Leukomax®) as adjuvant and 0.2 mg KLH (Immucothel®) as control antigen. They received all subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting.

Patient Characteristics:
15 patients who had previously been treated with high-dose chemotherapy (HDT) followed by peripheral blood progenitor cell (PBPC) transplantation entered this study. All patients were in a beginning relapse after high dose therapy at the time of vaccination. Patients with fulminant relapse or patients with active infection and hematopoetic insufficiency after HDT were excluded.

Results:
The results of this first-in-man phase I/II trial for phage-based idiotype vaccination clearly demonstrated the feasibility, safety and excellent tolerability of the phage vaccination whereas local skin reactions were the most frequent side effects. Furthermore, we were able to gather precious data regarding the immunology of phage vaccines in man. We could confirm our preclinical data, that phages are good immunogens, capable of inducing a strong immune response mainly of IgG1-type and therefore enabling ADCC and CDC immune response. Altogether these data suggest, that phage idiotype vaccines has the potential to exert a beneficial effect especially in patients with minimal residual disease. Strikingly, the immune response of phages compared to the well-known KLH particles showed > 10 time higher antibody titer than KLH, which emphasize the prominent immunogenicity of the phages. Overall these data pinpoint to a promising role of phage vaccination for the immunotherapy of cancer but further studies are necessary to evaluate the full potential of phage vaccines.

Disclosures:
Roehnisch: Apalexo Biotechnologie GmbH: Research Funding. Nagel:Apalexo Biotechnologie GmbH: Research Funding. Donceau:Apalexo Biotechnologie GmbH: Research Funding. Bourquin:Apalexo Biotechnologie GmbH: Research Funding.
Oral Cyclic Melphalan and Dexamethasone in the Treatment of Patients with AL Amyloidosis; Ineligible for High-Dose Melphalan and Stem Cell Transplantation.
Authors: Sanchorawala Vaishali , Seldin David C. , Sloan John Mark , Berk John L. , Skinner Martha 
Published: October 2019

Abstract
Abstract 1883
Poster Board I-906
AL amyloidosis is caused by a clonal plasma cell dyscrasia and is characterized by widespread, progressive amyloid deposition leading to multisystem organ failure and death. In this disease, amyloid protein deposits are derived from monoclonal immunoglobulin light chains. Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. However, only selected patients with AL amyloidosis are eligible for HDM/SCT due to amyloid-associated organ dysfunction. Recently, several investigators have demonstrated the efficacy of treatment with oral cyclic melphalan and dexamethasone (Mel/Dex) in inducing hematologic responses and improving survival for patients with AL amyloidosis. We report on 70 patients with AL amyloidosis who were treated with oral Mel/Dex. Oral melphalan was administered at 0.22 mg/kg/day for D1-4 and dexamethasone at 20-40 mg one day per week and repeated every month. The median age was 65 years (range, 46-84) and the median number of organ system involvement was 3 (range, 1–6). Majority of the patients (n=31) had predominant cardiac involvement. The reasons to select this regimen of Mel/Dex rather than HDM/SCT included severe cardiac involvement (n=23), age > 75 years (n=6), patient choice (n=6), severe autonomic neuropathy (n=6), poor functional status (n=5), treatment started by local physicians (n=9), complications of stem cell mobilization and collection precluding HDM (n=5) and others (n=11). Patients received a median of 4 cycles of Mel/Dex, (range 1-13). Hematologic responses were not evaluable in 22 patients due to early death, toxicity or patients failing to return for follow-up. Of 48 evaluable patients, 7 patients (15%) achieved a complete hematologic response. Median survival for these 70 patients has not yet been reached with a median follow-up of 17 months. Overall survival is 60% at 3 years. Thirteen of these patients received additional treatment for their disease. In conclusion, oral cyclic melphalan and dexamethasone can lead to hematologic complete responses in 15% of patients and to improvement in survival for patients with AL amyloidosis, who are not eligible for HDM/SCT.

Disclosures:
relevant conflicts of interest to declare.
Mechanism of Transfusion-Related Acute Lung Injury Induced by HLA Class II Antibodies.
Authors: Sachs Ulrich J , Wasel Wiebke , Reil Angelika , Bux Juergen , Bein Gregor , Santoso Sentot , Weissmann Norbert 
Published: October 2019

Abstract
Abstract 19

Introduction:
Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated fatalities in developed countries. It has been demonstrated that antibodies to human neutrophil antigens (HNA) present in a blood product can precipitate a TRALI reaction in the blood recipient. In the majority of TRALI cases, however, HLA class II antibodies rather than HNA antibodies are detected in the implicated donor. HLA class II antigens are not present on neutrophils or endothelial cells, the cellular key players in TRALI pathophysiology. Whether or not HLA class II antibodies are capable of inducing TRALI is thus under discussion. Here, we investigated a possible mechanism of HLA class II antibody-induced TRALI via monocytes. Methods and Results: Plasma from blood donors containing HLA class II antibodies (H2+plasma) is capable of activating monocytes expressing cognate antigen(s) as demonstrated by the release of IL-8, GRO-alpha, and TNF-alpha in culture supernatants. H2+plasma does not activate monocytes that do not express the cognate HLA class II antigen(s). Culture supernatants from matched pairs, but not H2+plasma itself, induce a respiratory burst reaction in neutrophils. In Boyden chamber experiments, FITC-albumin transendothelial flux is significantly increased in the presence of H2+plasma, matched monocytes, and neutrophils, but unchanged in the presence of non-matched monocytes. Diphenyleneiodonium chloride inhibits this barrier breakdown. In the ex vivo rat lung model, supernatants from matched pairs, but not from non-matched pairs, are capable of inducing TRALI in the presence, but not in the absence, of neutrophils. H2+plasma precipitates a TRALI in this model if neutrophils and matched, but not non-matched, monocytes are present. IgG-depletion of H2+plasma abolishes this effect. Conclusions: HLA class II antibodies present in donor plasma can induce TRALI in a transfusion recipient via monocyte activation. Once activated, monocytes stimulate neutrophils to produce reactive oxygen species, which lead to an increase in endothelial permeability and subsequent lung edema. This cascade depends on a match between the donor's antibodies and the recipient's HLA class II antigens and can be reproduced in a rat lung model. Our findings have important impact on current strategies that aim to prevent TRALI by donor testing and/or exclusion.

Disclosures:
No relevant conflicts of interest to declare.
Trends in Human T-Cell Leukemia Virus Type-1 (HTLV-1) Prevalence and the Incidence of Adult T-Cell Leukemia/Lymphoma (ATL) in Nagasaki, Japan: A Hospital-Based and Population-Based Study.
Authors: Iwanaga Masako , Koga Yoshito , Soda Midori , Inokuchi Naoko , Sasaki Daisuke , Hasegawa Hiroo , Yanagihara Katsunori , Yamaguchi Kazunari , Kamihira Shimeru , Yamada Yasuaki 
Published: October 2019

Abstract
Abstract 1920
Poster Board I-943

Introduction:
The prevalence of HTLV-1 is mostly evaluated by the age-specific seroprevalence in blood donors, and the results have been conventionally used to estimate the age-specific incidence of ATL in Japan. However, the results may be underestimated due to an age limit (16-69 yr) for donation, a healthy donor effect, and a birth cohort effect. Data concerning the birth-year specific incidence of ATL among HTLV-1 carriers other than blood donors are scarce.

Methods:
The study evaluated data of the anti-HTLV-1 antibody testing of 10,261 patients (males: 5,523, females: 4,737) who visited the Nagasaki University Hospital during 2000-2007 and data of 360 ATL cases (males: 188, females: 172) who were diagnosed in Nagasaki City (an endemic area in Japan) in a population-based Nagasaki Prefectural Cancer Registry (NPCR). To estimate birth-year specific incidence rates of ATL in population-based HTLV-1 carriers, we used the 2006 census population for Nagasaki City by applying the hospital-based seroprevalence data.

Results:
Of 10,261 patients, 1,392 (males: 653, females: 739) were HTLV-1 antibody positive. The overall HTLV-1 seroprevalence was 13.57% (95%CI: 12.90-14.23%). The seroprevalence was significantly higher in females than in males (15.60% vs. 11.82%, P<0.0001). The birth-year specific seroprevalence was 18.69% (before 1926), 17.83% (1927-1936), 15.91% (1937-1946), 13.80% (1947-1956), 9.19% (1957-1966), 4.07% (1967-1976), 2.07% (1977-1986), and 0% (after 1987) (a significantly declining trend: P <0.0001). The estimated annual number of HTLV-1 carriers by birth-year in Nagasaki city was 5257, 8093, 8151, 8083, 4434, 2180, 785, and 0, respectively. Finally, we estimated the annual incidence rate of ATLL per 100,000 HTLV-1 carriers by birth-year; 171 (before 1926), 86 (1927-1936), 41 (1937-1946), 32 (1947-1956), 11 (1957-1966), and 0 (after 1967). The crude lifetime risk of developing ATLL in HTLV-1 carriers was estimated to be 7.29% for males and 3.78% for females.

Conclusions:
The birth-year specific HTLV-1 seroprevalnces in the present study were approximately 50% higher than those previously reported in blood donors1 (for example: 6.22% in those born before 1950). Although it is possible that our results are over-estimated2, the present study suggests that there is still a large pool of elderly HTLV-1 carriers in this endemic area. Further studies are needed to investigate the mechanism of the development of ATL among HTLV-1 carriers for preventing the development. Reference: 1) Iwanaga M et al. Int J Hematol, 2009. 2) Arisawa K et al. Int J Cancer, 2000.

Disclosures:
No relevant conflicts of interest to declare.
Predictors of Early Response to Single Agent Rituximab in Patients with Indolent Lymphoma.
Authors: Cornec Divi , Tempescul Adrian , Querellou Solène , Mankai Amani , Hutin Pascal , Cymbalista Florence , Berthou Christian , Renaudineau Yves , Youinou Pierre 
Published: October 2019

Abstract
Abstract 1946
Poster Board I-969

STATEMENT OF PURPOSE:
Rituximab (RTX) is a chimeric antibody targeting CD20, a membranous B-cell specific protein, currently used in the treatment of B-cell malignancies and various autoimmune diseases. Despite its clear efficacy in non-Hodgkin's lymphoma, clinical and biological responses are highly variable between patients. Therefore, predictive factors are necessary to adapt therapy to each individual as early as possible.

MATERIAL AND METHODS:
We studied a set of biomarkers in a cohort of 39 patients with indolent non-Hodgkin's B-cell lymphoma (low grade follicular lymphoma or marginal zone lymphoma) and a low tumour burden, treated with single agent RTX as follows: 4 weekly 375 mg/m2 infusions, associated with short-course oral steroids. All patients benefited from FDG-PET analysis before treatment and 10 weeks later, allowing their classification into 3 early response groups: complete isotopic remission, partial response and no response. Dosage of rituximabemia, BAFF and Human Anti-Chimeric Antibodies (HACA) was performed with in-house ELISAs before each infusion and 2 months later. Polymorphisms of FcγRIIIa[158], FcγRIIa[131] and C1qA[276] genes were determined using allele-specific PCR or direct sequencing. Results were compared using Student's t-Test or two-tailed Fischer's exact test when appropriated.

RESULTS:
Referring to PET analysis, 18 patients were classified as complete isotopic remission, and 21 as partial or no response. Mean age was significantly lower in the first group (54 y+/-19 vs 66+/-13, p=0.022), as well as initial SUVmax (6.3+/-3.4 vs 10.8+/-6.8, p=0.024). Serum levels of RTX were highly variable between patients at each timepoint, but were not statistically different between the different response groups. Basal levels of BAFF were not statistically different between lymphoma patients and a control population, and did not vary after RTX-induced B cell depletion. No patient developed a HACA response during the study. Homozygous FcγRIIIa158V/V genotype was significantly associated with a complete response (p=0.037). Conversely, FcγRIIa[131] and C1qA[276] polymorphisms were not associated with the response. Genetic polymorphisms seemed to modify RTX pharmacokinetics, since homozygous FcγRIIa[131]H/H, FcγRIIIa[158]V/V and C1qA[276]G/G subjects displayed lower levels of RTX than others, without reaching statistical significance.

CONCLUSIONS:
Younger age, lower initial SUVmax and FcγRIIIa[158]V/V genotype are associated with a better early response to RTX in indolent lymphoma patients, as assessed by PET analysis. FcγR polymorphisms affect RTX kinetics probably through a modification of the efficacy of antibody dependant cell cytotoxicity. Determination of these factors could help in adapting individually therapeutic protocols.

Disclosures:
No relevant conflicts of interest to declare.
MiR-29 MicroRNAs Regulate IGF-1R Expression and Contribute Mantle Cell Lymphoma Growth and Survival.
Authors: Lin Jianhong , Zhao Jianjun , Lwin Tint , Luis Crespo , Guan Fangxia , Dessureault Sophie , Moscinski Lynn C. , Dalton William S. , Sotomayor Eduardo M. , Cheng Jin , Tao Jianguo 
Published: October 2019

Abstract
Abstract 1957
Poster Board I-980
Mantle cell lymphoma (MCL) is now recognized as a distinct clinicopathologic subtype of B-cell lymphomas and carries the poorest prognosis among NHL subtypes with a median survival is 3 to 4 years. Clearly better understanding of MCL oncogenesis and novel therapeutic approaches to treating MCL are needed. Mounting evidence now shows that small noncoding microRNAs (miRNAs) can play roles as oncogenes or tumor suppressor genes, suggesting their contribution to cancer development and progression. Here, we for the first time, demonstrated that that miR-29a-c is frequently deleted or down-regulated and IGF-1R is often over-expressed in primary mantle cell lymphoma cells. Expression of miR-29 inversely correlates with the expression of IGF-1R. Consistent with these results, 1) overexpression of miR-29-c down-regulated IGF-R1, 2) overexpression of miR-29c inhibited cell growth, colony formation and induced cell cycle arrest in MCL cells, 3) depletion of miR-29-c by anti-miR29-c increased the threshold for apoptosis, 4) enforced expression of miR-29c suppressed MCL growth and tumor progression in NOD/SCID mouse xenograft models, 5) miR-29 directly regulates IGF-1R expression . Furthermore cell cycle arrest induced by these miRNAs depends on the expression of IGF-1R. Our results indicate that miR-29a-c are implicated in MCL cell cycle control, survival and likely contribute to the tumorigenesis of MCL.

Disclosures:
No relevant conflicts of interest to declare.