bluuebunny/crossref_metadata_2025 huggingface dataset:
HemoBase: A Multidisciplinary Registration Systeem in Hemato-Oncology.
Authors: Joosten Peter , Hoogendoorn Mels , Storm Huib , Kibbelaar Robby E.
Published: October 2019

HemoBase is a patient oriented prospective hemato-oncology database using three central concepts:

Report periods; Integrated Diagnosis; Multidisciplinary discussion of patient data.

The disease history of a patient is divided in report periods. Each containing an integrated diagnosis, a treatment plan and a therapy evaluation. The integrated diagnosis is composed of an overall diagnosis, the topography of the primary tumor and the prognostic factors. A new integrated diagnosis or new treatment strategy leads to a next report period. Relevant clinical and diagnostic data and conclusions leading to the integrated diagnosis are registered according to the (mandatory) international guidelines and coding systems (anamnesis, physical examination, clinical chemistry, blood and bonemarrow cytology, flowcytometry, histology, genetic analysis (i.e karyotyping, PCR, FISH), imaging studies (i.e. CT including perpendicular diameter calculation, MRI, PET). Microscopic or other images may be imported. Furthermore, it is possible to record general medication and make follow up notes during patient visits or hospital stay. HemoBase contains algorithms to determine prognostic factors and a diagnostic multiple myeloma algorithm. HemoBase registers chemo-, radio-, surgical- or transplantation therapy, including (inter)national trials and registration of toxicity and infections. Dose regimens and dose reduction are calculated automatically. Therapy evaluation includes response evaluation and registration of cause of death. Plenary discussion of patients is facilitated by providing on screen the list of patients to be discussed with a direct link to individual data. Essential items of patient status are shown in a nutshell on a visual time axis. Using the query module one can evaluate patient data for quality, research and management purposes, i.e. patient outcome for diagnosis X with therapy Y, or more complicated queries. The housekeeping part of the system contains a personal task list and an internal mail module. Using the management module fields, forms and thesauri may be configured by the user according to the latest standards, i.e. a new therapeutic trial, a new translocation, a new WHO diagnosis etc. Access to Hemobase and to the separate datasets is linked to hospital function (account name) and password protected.

HemoBase an application based on internet technology, currently implemented in the Dutch language and running on a central server. For access to the application Internet Explorer 6.0 is minimally required. At present, HemoBase is being used for a year in 6 different hospitals and laboratory locations in one region of the Netherlands (pop. 600.000) connected by secure intranet technology. This will be increased gradually and a HemoBase board will be developed for agreement and monitoring of registration protocols.
Burden of Visits for Treating Side Effects of Chemotherapy or Radiotherapy in Cancer Patients.
Authors: Henry David H. , Wade Shawn M. , Servin Mariana , Hershfield William
Published: October 2019

INTRODUCTION: The time incurred in seeking care for the treatment of side effects of chemotherapy (CT) or radiotherapy (RT) can result in lost productivity and resulting lost wages for cancer patients (pts) and their caregivers. The purpose of this study was to assess the amount of time spent by pts and caregivers to seek treatment for side effects of CT/RT and to examine productivity losses associated with such visits.

METHODS: A cross-sectional survey was conducted from April to May 2006 using a random sample of pts from a chronic illness panel of 550,233 pts. Inclusion criteria were being at least 18 years of age, diagnosed with cancer, and receiving CT and/or RT either currently or during the 12 months prior to participating in the study. Percentages and means were used to calculate descriptive statistics.

RESULTS: A total of 1,569 cancer pts were surveyed: 1,302 pts online and 267 pts by telephone. No significant differences were found between phone and online respondents. Of the pts currently receiving CT and/or RT (N=814), a total of 249 pts received treatment for side effects of CT/RT. The total time spent per visit to receive treatment for side-effects of CT/RT was approximately 5 hrs/visit including preparation time, travel time, and time spent at the clinic. Approximately one-half (54%) of the 249 patients currently receiving treatment for side effects of CT/RT were employed full-time (44%) or part-time (10%). Among employed patients currently receiving treatment for side effects of CT/RT, the mean number of work days missed as a result of visits for the treatment of CT/RT related side effects was 20 days per year. The primary reason for continuing to work during cancer treatment was financial need, reported by 59% of patients. Approximately 83% of all patients indicated that a caregiver generally accompanied them on their visits to the doctor’s office, clinic, or hospital to receive treatment for side effects of CT/RT. Seven out of ten caregivers (68%) were reported as being employed either full-time (62%) or part-time (6%).

CONCLUSIONS: Time related burden for patients receiving treatment for side effects of CT/RT and their caregivers is significant. Reduction in frequency of such visits is important from the standpoint of patients’ economic livelihood and can stand to benefit employers and society.

Table 1. Time Spent on Healthcare Provider Visits for Treatment of Side Effects Related to Chemotherapy and/or Radiation (N=249) Activity (per visit) Minutes Spent (mean) Standard Deviation Minutes Spent (median) Preparing to go to the doctor’s office, clinic or hospital 81 127 55 Travel to and from the doctor’s office, clinic, or hospital 102 188 58 Waiting at the doctor’s office, clinic, or hospital to see the doctor or another healthcare professional 64 72 39 Seeing the doctor or another healthcare professional 64 75 43 Total 311 380 210
Integrated Diagnosis Treatment Combinations To Improve Cure.
Authors: Van Hoef Marlies E.H.M.
Published: October 2019

A diagnosis treatment combination is defined as a combination of compounds or treatment modalities that is prescribed at diagnosis of a disease or disease condition. Combinations are administered when a synergistic or additive effect is known or a protection can be anticipated.

In hematological malignancies the highest probability of disease free survival can be obtained by a fast remission-induction and consolidation of complete response at diagnosis followed by an allogeneic transplant in first complete remission to eradicate residual malignant cells. Effects of treatment that induce side effects are to be controlled to reduce treatment risks. Therefore, ablative allogeneic transplants are more and more replaced by non-myeloablative reduced intensity conditioning transplants. In acute leukemia these transplants have a much more dramatic course than in more indolent hematological malignancies and solid tumors.

In the Netherlands reimbursement for treatment components such as remission induction chemotherapy, an autologous transplant and an allogeneic transplant are currently reimbursed as independent diagnosis treatment combinations. Review of epidemiological data of cancer incidence and death in the Netherlands reveal that treatment of hematological malignancies are poor compared to projections in the United States. In the period 1997 to 2003 treatment results in the Netherlands are more or less stable except for Hodgkin’s disease; allogeneic transplantation has mainly been reserved for hematological malignancies (figure 1). Epidemiological data show that no improvement was achieved. In particular leukemia’s do poor. American Cancer Society projections show that there is a trend towards improvement in the USA for leukemias, non-Hodgkin lymphoma and in myeloma in the period 1997–2005 (figure 2).

Non-myeloablative reduced intensity conditioning autologous and/or allogeneic transplants are the curative element for transplantable diseases not curable by standard or intensified cytotoxic cytoreductive therapy. Critical also is rapid remission induction. Delay of transplantation to later stage than first complete remission only increases costs and risk of treatment or disease related mortality. We will present our protocol full of treatment plans to support in improving cure internationally. (www.transplantcreations.com).

Death/incidence ratio per 100.000/annum Netherlands Death/incidence ratio per 100.000/annum Netherlands Death/incidence ratio per 100.000/annum USA Death/incidence ratio per 100.000/annum USA
Health Economic Review of Recombinant Activated Factor VII (Novoseven®) for Treatment of Bleeding Episodes in Hemophilia Patients with Inhibitors.
Authors: Stephens Jennifer M. , Botteman Marc F. , Joshi Ashish V. , Sumner Michael
Published: October 2019

OBJECTIVE: Severe hemophilia with inhibitors is a rare disease with substantial clinical, humanistic, and economic consequences. Within the past few years, a number of formal economic analyses have emerged which examined the cost of treating bleeding episodes with recombinant activated factor VII (rFVIIa) versus plasma-derived agents. Thus the objective was to review the recent health economic analyses of rFVIIa in the management of patients with hemophilia and inhibitors.

DATA SOURCES: Published, English-language medical literature on the economics of rFVIIa was searched from January 1996 through July 2006 using: the MEDLINE/PubMed database, PubMed related articles feature, company knowledge of published medical literature for rFVIIa that was not indexed by MEDLINE/PubMed, and a thorough review of retrieved article bibliographies.

STUDY SELECTION AND DATA ABSTRACTION: Abstracts selected for full article retrieval/review were those that specifically mentioned (or implied that the full article would address) cost impact, cost of treatment, or cost-effectiveness for rFVIIa in patients with hemophilia and inhibitors. Of 70 abstracts reviewed, 30 articles were selected for retrieval, and from those, thirteen economic analyses (6 burden of illness and 7 comparative studies) met inclusion criteria for data abstraction and synthesis. Seventeen articles were excluded for the following reasons: reports of basic drug acquisition costs without formal economic analysis, single case reports, studies without inhibitor patients, or studies of immune tolerance therapy.

DATA SYNTHESIS: The economic impact of rFVIIa on hospitals and treatment centers occurs primarily during hospitalization to manage major bleeding episodes and allow for elective orthopedic surgeries that would not have been attempted without availability of rFVIIa. Six out of seven comparative analyses for on-demand treatment suggest that total cost of treating a bleeding episode with rFVIIa may be lower than that of using plasma-based agents due to faster bleeding resolution, higher initial efficacy rates, and avoidance of second and third lines of treatment. Dosing assumptions for the various agents compared in the economic analyses were the most sensitive variables.

CONCLUSIONS: The currently available literature suggests that rFVIIa is a cost-effective treatment option and may ultimately lead to improvement in clinical outcomes for patients with hemophilia and inhibitors.
Once Weekly Subcutaneous Idraparinux Versus Placebo in the Extended Treatment of Deep-Vein Thrombosis or Pulmonary Embolism. The van Gogh Investigators.
Authors: Buller Harry R. ,   on Behalf of the Van Gogh Investigators
Published: October 2019

Background. Although vitamin K antagonists are effective for treatment of venous thrombo-embolism, in many patients their extended use is constrained by limitations of risk-benefit and inconvenience. We evaluated whether an extended six-month treatment with idraparinux would be effective and safe in patients with venous thrombo-embolism who had received an initial 6-month anticoagulant treatment.

Methods. We randomly assigned patients warranting consideration of extending anticoagulation, and who had completed 6-months of either idraparinux or vitamin K antagonist treatment, to once weekly injections of either 2.5 mg of idraparinux without monitoring or placebo for 6 months. Recurrent venous thrombo-embolism and major bleeding were assessed during this period as the primary efficacy and safety outcomes.

Results. Of 1215 patients, 6 (1.0 percent) idraparinux and 23 (3.7 percent) placebo recipients had recurrent venous thrombo-embolism (p=0.002). Eleven (1.9 percent) idraparinux, but no placebo recipients, had major bleeding (p=0.0007), including 3 fatal intracranial bleeds. The patients previously treated with idraparinux (versus a vitamin K antagonist) had a lower incidence of recurrent thrombo-embolism among those randomized to placebo (0.7 versus 5.9 percent, respectively P=0.003), and a higher incidence of major bleeding among those randomized to idraparinux. (3.1 versus 0.9 percent, respectively, P=0.1647).

Conclusion: This placebo controlled trial demonstrated the effectiveness of idraparinux during a 6-month extended treatment, at the expense of an increased risk of bleeding. Previous administration of idraparinux was associated with extended anti thrombotic activity in the placebo recipients.
Potential Tolerizing Capacity of Human Dendritic Cells Featuring High Levels of Expression and Activity of the Tryptophan Metabolizing Enzyme Indoleamine 2,3 Dioxygenase.
Authors: Heitger Andreas , Juergens Birgit , Hainz Ursula , Fuchs Dietmar
Published: October 2019

An enhanced tryptophan metabolism mediated by the enzymatic activity of indoleamine 2,3 dioxygenase (IDO) has recently been demonstrated to profoundly affect T cell responses. By the present study we explored whether human dendritic cells (DCs) displaying high IDO expression and activity, down-regulate allogeneic T cell responses. A comparison of lipopolysaccaride (LPS), interferon-γ (IFN-γ), and CD40L as DC maturation agents showed that most abundant IDO expression and activity in DCs was observed when immature DCs were exposed to a combination of LPS and IFN-γ for 48 hours. This time period of maturation was associated with the development of a mature DC phenotype. In contrast, semi-mature DCs, i.e. DCs matured for 4 hours only, were IDO negative. In co-cultures with allogeneic T cells both types of DCs began to metabolize tryptophan, as determined by decreasing concentrations of tryptophan and increasing concentrations of kynurenines in cell culture supernatants, but mature IDO positive DCs did so at a faster rate (complete consumption of tryptophan within 16 hours of co-culture) than semi-mature DCs. A comparison of the allo-stimulatory capacity of semi-mature IDO negative DCs and mature IDO positive DCs showed that at a high DC/T cell ratio (1:1) IDO positive DCs had a significantly reduced capacity to stimulate allogeneic T cells (median 63% reduction, n=5). The reduction of the allogeneic T cell response induced by IDO positive DCs was reversed upon the addition of the IDO inhibitor methylhydantoin-tryptophan to the co-cultures, suggesting an IDO dependent mechanism. Furthermore, allogeneic T cells exposed to IDO positive DCs had

an increased rate of apoptosis in the activated cell fraction and after 8 days of co-culture contained a cell fraction (~30%) displaying a CD4+CD25+highFOXP3+ phenotype.

These latter cells, when enriched by fluorescent activated cell sorting (FACS), were able to suppress the proliferative response of naive T cells to anti-CD3 mediated stimulation, which indicates the generation of a regulatory T cell population by IDO positive DCs. Together, these findings suggest that the amount of IDO expression and activity by DCs is one feature to govern the type of response of stimulated T cells. Human DCs can be induced to display high levels of IDO expression and activity and, thereby, acquire the ability to effectivley modulate allogeneic T cell responses towards tolerance by

eliminating allo-reactive T cells through apoptosis and augmentation of their regulatory rather than their effector potential.

Our current approaches address whether this property can be employed to use DCs for the generation of allo-antigen specific tolerance in the setting of hematopoietic cell transplantation.
Bcr-Abl Tyrosine Kinase Domain Mutations Both Pre-Exist and Develop during Imatinib Treatment and Are Responsible for Resistance in Patients with Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ALL).
Authors: Pfeifer Heike , Wassmann Barbara , Pavlova Anna , Wunderle Lydia , Brueck Patrick , Hochhaus Andreas , Hoelzer Dieter , Ottmann Oliver
Published: October 2019

Background: Point mutations in the tyrosine kinase domain (TKD) of BCR-ABL are an important cause of resistance to imatinib (IM) in pts. with CML and Ph+ ALL. The significantly inferior response to IM in Ph+ALL pts. who failed prior chemotherapy compared to those with de novo Ph+ALL suggests that treatment with cytotoxic drugs may promote the development of TKD mutations. However, it is not known whether the frequency and pattern of TKD mutations at the time of treatment initiation with TK inhibitors are related to disease stage or prior anti-leukemic therapy. Moreover, the potential of combined treatment with IM and multi-agent chemotherapy to influence the development of mutational resistance, as compared to IM alone, has not been determined.

Patients and methods: 51 pts. with newly diagnosed Ph+ALL (>55 yrs.) enrolled in a GMALL study of combined IM and chemotherapy, and 68 Ph+ALL pts. who had failed prior chemotherapy and received single-agent IM as salvage therapy were analysed for the occurrence of point mutations within the TKD. Bone marrow samples collected pre-treatment, during therapy and at relapse were examined by denaturing high-performance liquid chromatography (D-HPLC) and cDNA sequencing.

Results: The frequency of TKD mutations pre-IM was 44% in newly diagnosed Ph+ALL and 53% (34/64) in pts. with advanced Ph+ALL. At relapse after combination therapy (n=19), the frequency of de novo ALL pts. harbouring a TKD mutation had increased to 89% (P-loop 47%, T315I 29%, A-loop 24%), 2 pts. (11%) showed wild-type BCR-ABL. The frequency of TKD mutations in pts. with advanced disease who relapsed after IM was 55% (P-loop 73%, T315I 23%, A-loop 4 %).

In both patient groups, the D-HPLC pattern showed concordance between the mutation detected in pre-therapeutic specimens and the dominant mutation detected at relapse.

The CR rate in de novo pts. receiving IM induction was 90 % irrespective of detectable mutations pre-study. Bcr-abl transcripts became undetectable during the course of therapy in 40% of pts. with and 37% of pts. without a mutation. Median remission duration in pts. with a T315I mutation (n=4) was 130 d (range: 53–319d), in contrast to 526 d (range: 504–549d) with activation loop and 411 d (range: 106–745d) with P-loop mutations. To date, 7 pts. with an initially detected mutation remain in CR after median FU of 12.8 mo (range 2.4–24.5 mo.).

Conclusions: Bcr-abl TKD mutations are detectable prior to first imatinib exposure in approximately 50% of Ph+ALL patients. Clinical imatinib resistance is in most cases associated with the identical mutation detected pre-IM, which is not eradicated by the combination of chemotherapy and IM. Identification and elimination of TKD mutations during early stages of treatment is essential to improve treatment.
Long Acting Anticoagulant Effects of Idraparinux in Patients Treated for Prophylaxis of Recurrent Venous Thromboembolism.
Authors: Harenberg Job , Joerg Ingrid , Weiss Christel , Fenyvesi Tivadar
Published: October 2019

Prophylaxis of recurrent venous thromboembolism (VTE) has been investigated in patients with acute VTE participating in the VanGogh DVT, PE and Extension studies for a minimum of 6 months. These patients were given a fixed dose of Idraparinux once a week subcutaneously without coagulation monitoring. The VanGogh DVT/PE studies randomized patients to Idraparinux versus INR-adjusted Warfarin. Patients were then able to follow on to the double-blind VanGogh Extension study comparing Idraparinux versus placebo. Determination of the anticoagulant effects may still be necessary for patients in acute clinical settings. After termination of the studies, the anticoagulant effects of Idraparinux were followed-up in 23 patients using Heptest coagulation method, anti-factor Xa inhibition method (aXa, chromogenic substrate S2222) and prothrombin induced clotting time (PiCT) assay. The study was accepted by the local ethics board and patients gave written informed consent. Serial blood samples were taken for up to 15 months after termination. The Heptest and PiCT methods were prolonged in all patients’ blood for 9 to 15 months after therapy termination. The chromogenic assay method showed factor-Xa inhibition for the same period of follow-up. The elimination half-life of Idraparinux was calculated at 60.5 ± 23.3 days using the Heptest method and at 55.1±15.4 days using the aXa-assay method. There were no differences noted in the half-life between patients participating in the DVT/PE and Extension study. The half-lives were independent from patients’ body weight and creatinine clearance. The complete pharmacokinetic analysis of the results will be presented. The unexpectedly long half-life may be explained by the lipophilicity of methylated Idraparinux. Overall, the data suggests a benefit from the prolonged antithrombotic effect of Idraparinux as well as an increased risk of hemorrhage after therapy termination, possibly explaining some of the van Gogh studies results.
Identification of Specific TRAV6 and TRAV23 Genes in Peripheral Blood T Cells from Patients with Diffuse Large B-Cell Lymphoma.
Authors: Li Yangqiu , Yin Qingsong , Tan Huo , Chen Shaohua , Ye Jingmei , Yang Lijian , Li Bo
Published: October 2019

Antigen specific T cells were identified in peripheral blood from some malignancy, for example melanoma, as well as in B-ALL. The T cells proliferation in response to tumor antigen could be identified by analysis of T cell receptor repertoire, which can display the distribution of TRAV or TRBV subfamilies and the clonaltiy of different subfamily T cells, the clonal expanded T cells are thought to be relate to antigen specific T cells in non-T-cell malignancy. In order to identify the specific T cell clone which was expected to have a specific anti-DLBL (diffuse large B-cell lymphomas) effect and to use as immunotherapeutic cells to prevent minimal residual disease in patients with DLBL, TRAV subfamily genes from clonal expanded T cells were analyzed by using RT-PCR, genescan and DNA sequencing techniques. Peripheral blood mononuclear cells from 6 cases with DLBL were used in the study. By using RT-PCR with 29 specific TRAV subfamily primers, some of TRAV subfamilies could be detected in different samples, 4 monoclonal expanded TRAV subfamily T cells were identified by genescan analysis, in which PCR products direct sequencing was performed to identify the CDR3 sequence. Specific TRAV6 and TRAV23 sequences were obtained in 3 cases respectively, however the CDR3 sequence of TRAV6 or TRAV23 form different patients were not complete identical, suggesting that they recognized and bound specifically to different DLBL-associated antigens. And the CDR3 sequences of these 4 identified genes (two TRAV6 and two TRAV23) were not be reported in Genebank. The whole sequence of both TRAV6 and TRAV23 genes were obtained by RT-PCR amplification the global rearrangement TRAV6 or TRAV23 segments. There are being registered in NCBI Genebank. The sequences will be farther used in TCR gene transfer to T cells to establish the specific anti-DLBL T cell clone and to confirm its specific cytotoxicity.
IPI and R-IPI in Korean DLBCL Patients Treated with R-CHOP.
Authors: Bae Sung-Hwa , Ryoo Hun-Mo , Kim Min Kyoung , Lee Kyung Hee , Hyun Myung Soo , Kim Hawk , Park Jea-Hoo , Lee Won-Sik , Joo Young-Don
Published: October 2019

Background: The addition of rituximab to CHOP chemotherapy (R-CHOP) has resulted in a marked improvement in outcome for patients with diffuse large B cell lymphoma (DLBCL). The previously estimated risk factors needed to be re-evaluated in immunochemotherapy era. Shen et al. (Blood109:1857–61, 2007) reported that a revised (R) international prognostic index (IPI) provided a more clinically relevant prediction of outcome than IPI. To assess the applicability of IPI and R-IPI in unselected Korean DLBCL patients, we conducted this study.

Methods: We performed a retrospective analysis of patients with newly diagnosed DLBCL treated with R-CHOP to assess the value of the IPI and R-IPI.

Results: From January 2004 to July 2006, 113 newly diagnosed DLBCL patients from four Korean institutes were included. Patients characteristics were: median age 54 y (range: 14–83), male 62.8%, extranodal disease 54.9%, age greater than 60y 40.7%, ECOG PS greater than 2 10.6%, elevated LDH 46.9%, more than 1 extranodal sites 17.7%, stage III/IV 40.7%. The 3 year EFS rate was 60.2% and the 3 year OS rate was 66.7%. Estimated 3 year EFS and OS according to IPI were described in the table.

Conclusions: The IPI score as well as R-IPI was an important prognostic parameter in unselected Korean DLBCL patients treated with R-CHOP.

No of Pt 3 year EFS (%) p-value 3 year OS (%) p-value No of IPI <0.001 0.001 0 22 78.6 83.3 1 40 71.8 81.9 2 28 59.3 61.8 3 16 36.5 42.4 4 6 16.7 22.8 5 1 0 0 IPI <0.001 <0.001 Low 62 74.7 82.8 Low intermediate 28 79.3 61.8 High intermediate 16 36.5 42.4 High 7 14.3 16.7 R-IPI <0.001 0.008 Very good 22 78.6 83.3 Good 68 65.8 71.6 Poor 23 28.1 34.9
The PPARß Activation Mechanism Which Suppresses the Constitutive NF-kB Activity in Human Myeloma Cell Lines.
Authors: Otsuyama Ken-ichiro , Amin Jakia , Abroun Saeid , Islam Abul , Shamsasenjan Karim , Iqbal Shamim Mohd , Kawano Michio M.
Published: October 2019

[Purpose] It is considered that human myeloma cells have the constitutively high NF-kB activity involved in survival and proliferation. PPAR (Peroxisome proliferator-activated receptor) ß is ubiquitously expressed in all cells and considered to be involved in the lipid metabolism and regulating the inflammatory response and cell proliferation. We already have found that adrenal cortex hormones (DHEA and DHEA-S etc), dexamethasone (Dex) and baicalein augmented the expression of reporter gene. However, it remain to be clarified the role of PPARß in human myeloma cells. We focus on the mechanism of PPARß suppressed NF-kB activity.

[Method]

To know NF-kB activity of human myeloma cells, we performed EMSA with NF-kB consensus oligo. To investigate NF-kB and PPARß after stimulation of PPAR agonist, we did EMSA with NF-kB and PPAR consensus oligo. To confirm whether it is repression according the NF-kB activity suppression accompanying PPARß activation to the interaction of PPARß and NF-kB, we conducted immunoprecipitation - western blot analysis. To check whether the expression of NF-kB target genes (cIAP1, Bcl-xL, etc) were suppressed after stimulation of PPAR agonist, we performed RT-PCR analysis.

[Result and discussion] It was suggested that human myeloma cell lines have constitutive NF-kB activity, and its activity mainly regulated p50. NF-kB activity and its target genes were repressed by stimulation of PPAR agonist. From the above, it was suggested that the activated PPARß interacted NF-kB and then its activity was suppressed.
Comprehensive Mapping of Transposon Insertions in Human Hematopoietic Neoplasias.
Authors: Burns Kathleen H.
Published: October 2019

Abstract 1103

Poster Board I-125

Our genomes are replete with mobile DNAs, many of which are retrotransposons that have accumulated over time by “copy-and-paste” mechanisms involving reverse transcription of RNA intermediates. Subsets of human transposable elements have been recently active or remain active today, resulting in many insertional polymorphisms in modern populations. In vitro studies in human tumor cell lines have unequivocally shown that expressed retrotransposons can generate new insertions and potentiate large scale genomic rearrangements. Though normally transposon sequences are highly methylated and thus stably suppressed in somatic cells, loss of methylation has been described in some malignant states, including chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and ‘blast crisis’ phase chronic myeloid leukemia (CML). This has led to speculation that derepressed transposons contribute to clonal evolution of these pathologies, though experimental evidence for this has been lacking due to an inability to detect new genomic insertions. In collaboration with Jef Boeke's laboratory, I have developed an array-based transposon insertion profiling method (TIP-chip) for mapping mobile retrotransposons in the human genome. Early application of this technology in leukemia patients and leukemia cell lines shows numerous novel insertions of L1 LINEs, AluYb SINEs, and HERV-K transposons, including several insertions in genes known to be involved in leukemogenesis. We expect the technology will add a new dimension to our understanding of the human genome, including genetic predispositions to cancer development, and will enable tests of the hypothesis that insertional mutagenesis by endogenous transposons is a driving force in hematopoietic malignancies.

Disclosures

No relevant conflicts of interest to declare.
Correlations Between Host Cellular Immune Responses and Adenovirus (AdV) Associated Complications in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Guérin Valérie , Dalle Jean-Hugues , Pedron Béatrice , Yakouben Karima , Cordeiro Debora Jorge , Peltier Lucas , Ouachée-Chardin Marie , Baruchel Andre , Sterkers Ghislaine
Published: October 2019

Abstract 1145

Poster Board I-167

Rational

Correlations between host AdV-specific immunity and the risk of AdV-associated complications remain to be clarified for improving patients care in allogeneic hematopoietic-stem cell transplantation (HSCT) setting, particularly for pediatric patients. In immunocompromised individuals, high number of AdV-specific IFNg secreting T-cells appears to be associated with AdV control. Infusion of IFNg-secreting AdV-specific T-cells has been shown to cure patients with severe AdV infection. We realized an in vitro study to correlate host cellular immune response and AdV associated complications.

Material and Methods

In this study, CD4+ T-cell AdV-specific immune-recovery was relied to AdV-infection in 40 pediatric patients (median age: 7.60 years) who underwent allogeneic HSCT after either Bu-based or TBI-based fully myelo-ablative conditioning regimen. HSCT were performed for haematological malignancies. Patients received CSA +/- short course MTX as GvHD prophylaxis. Monitoring for AdV infection in transplanted patients consisted of weekly PCR during at least the first 3 months following HSCT. Antiviral chemotherapy was initiated if AdV-DNA levels were over 2000 copies/ml. Blood samples from 34 healthy children (median age: 5.4 years) and 31 healthy adults were analyzed as reference. Proliferative-responses were assessed by 3HT incorporation and cytokine-responses by intracytoplasmic flow-cytometry assay.

Results

In conclusion,

Disclosures

No relevant conflicts of interest to declare.
Clinical Significance of EBV-Associated LPD After Cord Blood Transplantation.
Authors: Satou Maho , Kimoto Tomiko , Yamada Kayo , Kondou Osamu , Tokimasa Sadao , Yasui Masahiro , Ohta Hideaki , Inoue Masami , Kawa Keisei
Published: October 2019

Abstract 1161

Poster Board I-183

Introduction

The number of cord blood transplantation (CBT) is rapidly increasing. In this setting, development of Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD) appears to be at high risk. To clarify this issue, we retrospectively analyzed EBV serology and clinical course of 57 patients who received CBT during the past 12 years.

Patients and methods

We underwent 79 CBT until 2008. Fifty-seven patients were available for assessing EBV serology. The mean age of patients was 63 months (range, 6m-28y5m). The underlying disease was hematologic malignancy (n=27), hematologic non-malignancy (n=10), autoimmune disease (n=2), solid tumor (n=7), and EBV-associated T/NK-LPD (n=11).

Results

Forty-six (80.7%) of the 57 recipients were EBV seropositive before CBT (sero+/). Nineteen (41.3%) of 46 EBV seropositive recipients before CBT became EBV seronegative after CBT (sero+/sero-). Five patients (8.8%) developed EBV-associated post-transplantation LPD. Three of the 5 LPD patients arose from 27 patients of sero+/sero+ group, and the time of onset of LPD was 2-6 months after CBT. Two of them died of LPD. The remaining 2 patients arose from 19 patients of sero+/sero- group, and the time of onset of LPD was 6-9 months. These 2 patients were successfully treated. None of the 11 patients (6 in sero-/sero- group and 5 in sero-/sero+ group) developed LPD.

Discussion

Among EBV seropositive patients, about 60% of them remained seropositive (endogenous infection group), and 40% of them became seronegative after CBT. The latter group is likely to experience exogenous infection (secondary primary infection). In both instances, incidence of LPD seems to be quite high. Therefore regular monitoring of EBV serology and EBV-DNA load after CBT should be essentially required for all CBT patients.

Disclosures

No relevant conflicts of interest to declare.
Clinical Characteristics and GVL Effect of Chronic Graft-Versus-Host disease Following Reduced-Intensity Umbilical Cord Blood Transplantation (RICBT).
Authors: Wake Atsushi , Uchida Naoyuki , Ishiwata Kazuya , Araoka Hideki , Tsuji Masanori , Nakano Nobuaki , Yamamoto Hisashi , Takagi Shinsuke , Kato Daisuke , Matsuno Naofumi , Seo Sachiko , Asano-Mori Yuki , Masuoka Kazuhiro , Makino Shigeyoshi , Yoneyama Akiko , Taniguchi Shuichi
Published: October 2019

Abstract 1162

Poster Board I-184

Backgrounds

Umbilical cord blood can be an alternative stem cell source for the patients of hematological diseases. However, little is known about chronic GVHD (cGVHD) and graft versus leukemia/lymphoma (GVL) effect in reduced-intensity cord blood transplantation (RICBT). We had been demonstrated that cGVHD in CBT is tolerable compared with that in BMT and that the occurrence of cGVHD could result in good prognosis. Here, we analyzed the clinical picture of chronic GVHD following RICBT and the GVL effect.

Methods

We reviewed medical records of 192 patients with hematological diseases who had received CBT between Jan. 2004 and Dec. 2008 who had been free from disease progression for more than 100 days after RICBT at Toranomon Hospital, Tokyo, Japan. Median age was 54 years (17-82). Most of them had diseases in advanced status (n=168). Most of the pre-transplant conditioning were reduced intensity consisted of fludarabine, melphalan and TBI 4Gy (n=157). GVHD prophylaxis were tacrolimus (Tac) alone (n=99) and Tac plus mycophenolate mofetil (MMF) (n=93). HLA disparities were as follows; 6/6 (n=9), 5/6 (n=38), 4/6 (n=142), and 3/6 (n=3). Underlying diseases were AML (n=58), myelodysplastic syndrome (n=36), ALL (n=23), lymphoma (n=64) and others (n=11).

Results

The Median observation period after the transplantation was 924 days (range, 109–1944). Chronic GVHD was admitted in 114 patients (59.4%) consisted of limited type 88 (45.8%) and extensive type 26 (13.5%) in classical criteria, and mild type 96 (50.0%), moderate type 15 (7.8%), and severe type 3 (1.6%) in NIH consensus criteria of cGVHD. The target organs of cGVHD were skin 87.5%, liver 40.6%, and mouth mucous membranes 32.8 %, eye 23.4%, and the lungs only 7.8% (COP3 and BOS2). Except 21 cases ( 10.9%) required systemic steroid or MMF therapy. The median of Karnofsky score of cGVHD was 90%(40-100). During observation period, no patients except one patient caused by heart failure were died of cGVHD. In multivariate analysis, high-risk disease (p=0.019) and preceding acute GVHD (p=0.026) are related to the occurrence of cGVHD, and cGVHD increased overall survival (p<0.01) and suppressed recurrence of the disease (p<0.01).

Conclusion

Although the frequency of cGVHD was not low, the severity was mild, and the death related to cGVHD is rare in RICBT. NIH consensus criteria is useful for the evaluation of cGVHD severity. Some effect of GVL may play a role on better survival and lower relapse rate in RICBT.

Disclosures

No relevant conflicts of interest to declare.
Impact of Missing KIR Ligands in HLA-Matched Unrelated Donor HSCT.
Authors: Sun Aining , Li Weiyang , Depei Wu , He Jun , Bao Xiaojing , Zhou Lina
Published: October 2019

Abstract 1185

Poster Board I-207

Objective:

To analyze the prognostic impact of missing ligands for inhibitory killer-immunoglobulin receptor(KIR) in HLA-matched hematopoietic stem cell transplantation(HSCT) using unrelated donor.

Methods:

HLA genotype of 51 patients (ALL 22 cases, AML 13 cases, CML 14 cases, MDS 1 cases and HAL 1 cases) and their matched unrelated donors was determined by polymerase chain reaction sequence oligonucleotide probes(PCR-SSOP) and sequence specific primers (PCR-SSP). The KIR genotype was determined by PCR-SSP.

Results:

Patients were divided into those with(n=37) and those without(n=14) missing 1 or more HLA class I ligands for donor inhibitory KIR. The period of platelet reconstruction was shorter in patients [ 13 d(10d∼27d)] with missing KIR ligands than those[14d(12d∼21d)] without missing KIR ligands(P=0.046). There was no significant difference in neutrophil recovery, ≥II° acute GVHD(13.5% vs 35.7%, P>0.05) and extensive chronic GVHD (16.2% vs 28.6%, P>0.05) between the two groups. The 3-year continuous complete remission(CCR) rate for patients with and without missing KIR ligands was 73.6% and 37.4%, respectively(P=0.183). The 3-year overall survival(OS) rate for the two groups was 77.5% and 52.4%, respectively(P=0.533).

Conclusions:

In HLA-matched unrelated donor HSCT, missing KIR ligands may be associated with enhanced engraftment, decreased severe GVHD, improved CCR and OS.

Disclosures:

No relevant conflicts of interest to declare.
Clinical Relevance of Circulating Poly-Ubiquitin as a Prognostic Indicator in Chronic Lymphocytic Leukemia.
Authors: Ma Wanlong , Kantarjian Hagop M. , Wang Xiuqiang , O'Brien Susan , Yeh Chen-Hsiung , Zhang XI , Estrov Zeev , Sferruzza Anthony , Weirda William , Keating Michael , Albitar Maher
Published: October 2019

Abstract 1240

Poster Board I-262

The ubiquitin-proteasome pathway is implicated in the pathogenesis of many hematological malignancies. We have reported that proteasome activities in plasma samples can be detected in patients with chronic lymphocytic leukaemia (CLL). Here we examined the correlation of plasma ubiquitin protein levels with clinical behavior in CLL patients. Using the Meso Scale Discovery (MSD) platform, we quantified poly-ubiquitin levels in plasma samples from 138 patients with CLL and 101 healthy control subjects, and examined the associations of ubiquitin levels with various clinical and laboratory variables and overall survival. Patients with CLL had significantly higher levels of poly-ubiquitin proteins (median=158.2; range=35.0-281.2) than did normal control subjects (median=57.3; range=22.0-160.2) (P<0.001). Poly-ubiquitin levels showed no correlation with Rai stage, performance status, beta-2 microglobulin (B2M), or the mutation status of IgVH. However, when considered as a continuous variable, poly-ubiquitin levels correlated negatively with survival. Higher levels of poly-ubiquitin were associated with longer survival (P=0.04). In a multivariate model incorporating poly-ubiquitin, B2M, and IgVH mutation status only B2M (P=0.00004) and poly-ubiquitin P=0.04) levels, but not IgVH mutation status (P=0.12), were independent predictors of survival. When a cut- point corresponding to the upper quartile was used, patients with poly-ubiquitin levels >193 ng/mL had significantly better survival than did those with lower levels. Using B2M and poly-ubiquitin in combination allowed us to stratify patients into 3 different groups : survival was greatest in patients with high poly-ubiquitin and low B2M levels, lowest in those with low poly-ubiquitin and high B2M levels, and intermediate in those with high levels of B2M and ubiquitin or low levels of both (P<0.00001). In conclusion, these findings confirm the importance of the proteasome-ubiquitin system in the pathophysiology of CLL. Moreover, our data also suggest that plasma levels of poly-ubiquitin, along with B2M, should be explored as a prognostic factor in CLL.

Disclosures

No relevant conflicts of interest to declare.
LPL Is the Strongest Prognostic Factor in a Comparative Study of RNA-Based Markers in Chronic Lymphocytic Leukemia.
Authors: Kaderi Mohd Arifin , Kanduri Meena , Mansouri Mahmoud , Buhl Anne Mette , Sevov Marie , Cahill Nicola , Gunnarsson Rebeqa , Jansson Mattias , Smedby Karin Ekström , Hjalgrim Henrik , Juliusson Gunnar , Jurlander Jesper , Rosenquist Richard
Published: October 2019

Abstract 1254

Poster Board I-276

Introduction

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with varying clinical outcome, where many patients have an indolent course for many years, whereas others show a more aggressive disease despite treatment. This has prompted the search for biomarkers that can predict outcome in this disease. Recent studies have proposed the RNA expression levels of certain genes, i.e. LPL, CLLU1, TCL1, MCL1 and ZAP70 to be novel predictors of clinical outcome in CLL. However, a comprehensive assessment of these RNA-based markers is still lacking. The current study aimed to investigate the potential of these markers in CLL prognostication, either as single markers or in combination with established markers.

Patients and Methods

By applying real-time quantitative PCR, we measured the RNA expression levels of LPL, CLLU1, TCL1, MCL1 and ZAP70 in 256 newly diagnosed CLL samples from a Scandinavian population-based cohort collected from 1999 to 2002 (median follow-up, 89 months) and correlated with clinical outcome. The expression cut-offs for each RNA marker was determined by constructing ROC curves. Additionally, Binet stage, IGHV mutation status, CD38 expression (cut-off 7%) and the presence of recurrent genomic aberrations (i.e. 11q-, 17p-, 13q- and +12) were evaluated for all cases.

Results

High expression of all RNA-based markers except MCL1 predicted significantly shorter overall survival (OS) and time to treatment (TTT), with LPL being the most significant prognostic marker in both log-rank (Table 1) and Cox univariate regression analyses. In multivariate analysis including the RNA markers, LPL expression was the only independent prognostic factor for OS, whereas both LPL and CLLU1 could predict TTT. When including all established markers, LPL lost its significance in the model, due to its close association to the IGHV mutation status. Once the mutation status was excluded from the analysis, LPL regained its prognostic power in addition to genomic aberrations and CD38. Interestingly, all of the RNA-based markers added further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results. Notably, high LPL expression predicted a worse outcome in favorable prognostic subgroups such as patients with Binet stage A, CD38 negativity or favorable genomic aberrations (Table 2).

Conclusions

Altogether, we conclude that LPL expression appear to be the strongest among the RNA-based markers for prediction of clinical outcome in CLL and thus could potentially be applied in the clinical laboratory to predict outcome, particularly in combination with established markers.

Disclosures

No relevant conflicts of interest to declare.
Neutrophil CD64 Is a Good Indicator of Infection and Sepsis.
Authors: Jou Josep M , Navalón Fulgencio , García Rosario , Brugues Rosa , Nicolás José , Escolar Gines , Diaz-Ricart Maribel
Published: October 2019

Abstract 1347

Poster Board I-369

Introduction

Sepsis is among the top 10 causes of death, but improvements in the diagnostic tests for detecting and monitoring sepsis and infection have been limited in the last years. Neutrophil CD64 expression increases rapidly in the presence of inflammation mediators and in response to infection and tissue damage. We have evaluated changes in the expression of neutrophil CD64 in infected patients in comparison with other markers of infection and sepsis.

Methods

Prospective analysis of 56 blood samples from patients from the intensive care unit at our institution was performed for neutrophil CD64 expression, C-reactive protein (CRP), automated absolute neuthophil count (ANC), and complete manual leucocyte formula including % of bands (BANDS), and % of metamyelocytes and myelocytes (IG). Neutrophil CD64 expression was measured by flow cytometry using a quantitative method (Leuko64TM, Trillium Diagnostics, LLC). Patients were categorized into 5 groups (CLINIC) based on the clinical history and the degree of a systemic inflammatory response, from 1 (no inflammation) to 5 (septic shock). Statistics were performed using linear regression, correlation coefficient, and Passing-Bablock (P-B) regression. Sensitivity (S), specificity (SP), efficiency (E), and positive and negative predictive values (PPV and NPV respectively) were analyzed for all the parameters measured.

Results

Our results showed a correlation with CLINIC of 0.417, 0.552, 0.268, and 0.136 for CD64, CRP, BANDS, and ANC, respectively. P-B regression was only good for CD64, with a slope of 1.03 (0.6-1.4). Percentages (%) of S, SP, E, PPV, and NPV for CD64 were of 81%, 72%, 71%, 46% and 92%, respectively for groups 4 and 5. For CRP, S was of 93% with SP of 20%, E of 38%, PPV of 27%, and NPV of 91%. The remaining parameters showed deficient correlation with CLINIC. Correlations between CD64 and CRP, BANDS, and ANC were of 0.435, 0.342, and 0.01, respectively.

Conclusions

Neutrophil CD64 expression quantitation provides improved diagnostic detection of infection/sepsis compared with the standard diagnostic tests used in current medical practice. CD64 expression showed a better PPV than CRP, and an acceptable NPV. CRP showed deficient SP and E. BANDS, GI, and ANC showed no correlation with CLINIC. CD64 is a new indicator of infection that deserves consideration to be introduced in the daily hematology laboratory analysis.

Disclosures

No relevant conflicts of interest to declare.