bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Significance of WDR5 High Expression and Its Effect on Tumorigenesis in Adult Leukemia
Authors: Ge Zheng , Song Evelyn , Li Jianyong , Dovat Sinisa , Song Chunhua
Published: October 2019

Background: Mixed-lineage leukemia (MLL) functions within the context of a large multiprotein complex including MLL, WDR5, RbBP5, and ASH2L that is required for maximal enzymatic activity. Each component is required for full histone H3 trimethyl Lysine 4 (H3K4me3) methyltransferase activity of the complex. The structure-function analysis shows that WDR5 mediates interaction between the MLL catalytic unit and the core complex, as well as the histone H3 substrate. Recently it is found that blocking MLL1-WDR5 interaction by an inhibitor could result in the complex disassembly, inhibition methyltransferase activity and suppression of proliferation of leukemia cells. Despite our growing knowledge about MLL1 fusion proteins and leukemia, very little is known about the role of WDR5 in leukemia.

Methods: The WDR5 expression was determined by qPCR in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients. The genome-wide binding profiling of WDR5 and H3K4me3 was obtained by ChIP-seq. The effect of WDR5 on its target gene expression, cell proliferation and apoptosis was observed by qPCR, WST-1 cell proliferation assay and Annexin V-PE staining following the flow cytometry analysis, respectively, in leukemic cells with WDR5 shRNA knockdown

Results: WDR5 expression is significantly increased in adult ALL and AML compared to that of normal bone marrow control. WDR5 high expression is associated with high risk factors in the patients. Also, its high expression is associated with MLL1 high expression; particularly the patients with WDR5 high expression plus MLL1 high expression has poor complete remission (CR) rate. We further identified the global genomic binding of WDR5 in RS4:11 ALL and THP-1 AML cells by ChIP-seq and detected more than 2000 binding peaks in the two leukemia cell lines. We also examined global H3K4me3 peaks, analyzed the correlation of WDR5 peaks with H3K4me3 peaks and found the genomic co-localization of WDR5 binding with H3K4me3 enrichment. Moreover, WDR5 knockdown by shRNA suppressed the cell proliferation, induced apoptosis, inhibited the expression of WDR5 targets on oncogenesis and anti-apoptosis, blocked the H3K4me3 enrichment on the promoter of these targets. We also observed the positive correlation of WDR5 expression with its targets in B-ALL and AML cohort.

Conclusion: WDR5 has oncogenic effect and WDR5-mediated H3K4 methylation plays important role in the leukemogenesis

Disclosures

No relevant conflicts of interest to declare.
Genome-Wide Association Study Identifies PNPLA3 I148M Variant Associated with Elevated Transaminase Levels after Induction Therapy in Pediatric ALL Patients
Authors: Fernandez Christian A. , Smith Colton , Yang Wenjian , Liu Chengcheng , Ramsey Laura B. , Karol Seth E. , Pui Ching-Hon , Evans William E. , Jeha Sima , Relling Mary V.
Published: October 2019

Current regimens for remission induction therapy of pediatric acute lymphoblastic leukemia (ALL) include multiple potentially hepatotoxic drugs, including asparaginase. The objective of our genome-wide association study (GWAS) was to identify genetic loci associated with elevated alanine transaminase (ALT) levels immediately after remission induction in children with ALL. The patients included were enrolled on St. Jude Children's Research Hospital (SJCRH) protocols Total XV (n = 373) or Total XVI (n = 342); germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome Beadchip arrays. In multivariate analysis, risk factors associated with higher ALT included older age, higher body mass index, European (versus African) ancestry, treatment with PEGylated E. coli asparaginase (versus native E. coli asparaginase), and receiving additional doses of asparaginase during induction due to high level of minimal residual disease at day 15-19 of induction. GWAS identified an association between I148M PNPLA3 rs738409 (C>G) variant and post-induction ALT (Figure 1A; P = 7.9x10-9; median ALT of 34, 45, and 58 IU/L in CC, GC and GG genotypes, respectively), and the effect of the PNPLA3 variant was consistent for both protocols, both ALL risk groups, and among patients of European, African, and Hispanic ancestry. The PNPLA3 variant has previously been linked to elevated ALT and to the development of steatosis in adults;[PMID: 22001757; 18820647] in mice, this same variant led to a loss of catalytic function and to an increase of PNPLA3 accumulation in hepatic lipid droplets and to the development of steatosis.[PMID: 24917523] Within patients of African ancestry, we identified a variant near PIGV rs12748152 (C>T) associated with lower ALT levels at P = 1.7x10-8; median ALT of 28 and 6 IU/L in CC and TC genotypes, respectively (Figure 1B), consistent with lower ALT values observed in patients of African ancestry. The PIGV variant explained 7% of the variation in ALT for patients of African ancestry. The results of our study suggest that post-remission induction ALT levels may be related to treatment-related variables, such as increased asparaginase exposure, and to host genetic factors, at least some of which contribute to hepatic dysfunction in settings outside of ALL therapy.

Figure 1. Alanine transaminase (ALT) levels by PNPLA3 or PIGV genotype Figure 1. Alanine transaminase (ALT) levels by PNPLA3 or PIGV genotype

Disclosures

Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.
Preclinical Development of LNA Antimir-155 (MRG-106) in Acute Myeloid Leukemia
Authors: Zitzer Nina C. , Ranganathan Parvathi , Dickinson Brent A , Jackson Aimee L , Rodman David M , Croce Carlo M. , Marcucci Guido , Garzon Ramiro
Published: October 2019

Introduction

MicroRNAs (miRs) are deregulated in AML and play a key role in leukemogenesis. MiR-155 is one of the most frequently overexpressed miRs in AML. Higher expression of miR-155 is associated with FLT3 internal tandem duplication (FLT3-ITD) and is associated with worse outcome, independent of FLT3-ITD status. Preliminary data shows that silencing of miR-155 induces strong antileukemic effects in AML cell lines. Altogether these data support a therapeutic role for miR-155 antagonism in AML. Here, we show the in vitro and in vivo activity of MRG-106, a novel LNA antimiR-155 compound that we are developing as a potential treatment for hematological malignancies.

Methods

Unconjugated, LNA-modified oligonucleotide against miR-155 (MRG-106) was developed by miRagen Therapeutics, Inc. MRG-106 was evaluated in FLT3-ITD+ AML cell lines and primary FLT3-ITD+ AML samples for impact on apoptosis and cellular proliferation using Annexin V and MTS assays. Predicted and validated targets of miR-155 were measured by qPCR and Western Blotting to assess the efficacy of miR-155 silencing. The in vivo antileukemic effect of MRG-106 was evaluated in NOD/SCID gamma mice engrafted with MV4-11 AML cells that have elevated miR-155 expression. One week after leukemic cell inoculation, the mice were separated in 3 cohorts and received either MRG-106 (n=12); LNA-scramble control (n=12); or saline (n=6).

Results

Inhibition of miR-155 decreased cell proliferation in MV-4-11 and MOLM-13 cells at 48hrs (Absorbance 450 nM (A450nM): 0.5 and 0.4 vs controls 2.4 and 2.5, respectively, p<0.01). These effects were associated with increased apoptosis (2-fold increase in Annexin staining) and re-expression of the validated miR-155 target WEE1 protein. MRG-106 produced a 4-6 fold increase in apoptosis in primary samples from 3 newly diagnosed AML patients with FLT3 -ITD cytogenetically normal AML (p<0.01). In addition, inhibition of miR-155 reduced the colony forming ability of the primary blasts (average # of colonies; controls=90 vs. MRG-106=55,p<0.01). In an MV4-11 xenograft model, MRG-106 significantly increased survival compared to controls (p<0.01). Biodistribution studies confirmed adequate MRG-106 distribution to bone marrow. GLP preclinical safety studies have been completed in rats and non-human primates, demonstrating an acceptable safety profile for MRG-106.

Conclusions

Inhibition of miR-155 in AML cell lines and primary AML samples in vitro and in vivo induces significant antileukemic effects. These studies validate miR-155 as a therapeutic target in AML and support the testing of MRG-106 in AML patients in the context of a phase 1 clinical trial.

Disclosures

Dickinson: miRagen Therapeutics: Employment, Equity Ownership. Jackson:miRagen Therapeutics: Employment, Equity Ownership. Rodman:miRagen Therapeutics: Employment, Equity Ownership.
Diffuse Large B-Cell Lymphoma Survivorship: Risk of Second Malignancies in Long Term Survivors
Authors: Gangavarapu Lakshmi Suryateja , Surapaneni Rakesh
Published: October 2019

Background: Survivors of Diffuse Large B-Cell Lymphoma (DLBCL) are at increased risk of subsequent malignancies secondary to their genetic makeup, environmental and treatment factors. Specific data on the long term risk of subsequent malignancies are underreported in the literature. Most oncologists release patients to be followed by their general physicians at five years. We studied the incidence rates of all second malignancies in survivors of DLBCL five years after their initial diagnosis.

Methods: We analyzed data from the Surveillance, Epidemiology and End Results 9 database, Nov 2014 Sub {1973-2012} to determine the risk of second malignancies in five year survivors of DLBCL. For our analysis we included only patients with initial diagnosis between 1992 and 2007 as there was a change in classification in 1992 and this will also give at least 5 year of follow up for all patients. With these criteria we had 10,905 patients and 58,192 patient years of follow up. The risk of subsequent malignancies is reported as a standardized incidence ratio (observed incidence [O]/expected incidence [E]).

Results: After five years from diagnosis of DLBCL, patients have the highest risk of a second cancer of Hodgkin's Lymphoma (O/E: 11.23; CI: 7.19-16.70; N=24). The risk of recurrence of Non-Hodgkin's Lymphoma also remains high after 5 years with an O/E ratio of 2.07 (CI: 1.63-2.59; N=76), with Extranodal NHL being at an especially high risk (O/E: 2.99; CI: 2.10-4.12; N=37). Survivors of DLBCL are also at high risk of Acute Non-Lymphocytic Leukemia (O/E: 4.38; CI: 3.03-6.12; N=34). There is also a high risk of Laryngeal cancer (O/E: 1.96; CI: 1.01-3.42; N=12). Furthermore, patients are also at a high risk of Cancer of the Colon excluding the Rectum (O/E: 1.28; CI: 1.01-1.58; N=82) and Anal Cancer (O/E: 3.26; CI: 1.41-6.42; N=8).

Conclusion: There are several second malignancies that long term survivors of DLBCL are at increased risk of, even after 5 years. This information may help physicians effectively monitor survivors of DLBCL for any second cancers.

Disclosures

No relevant conflicts of interest to declare.
Optimizing CD4+ T-Cells Transduction Protocol for Gene Therapy of HIV-1 Infected Patients
Authors: Ouedrani Amani , Djerroudi Lounes , Hmitou Isabelle , Cavazzana Marina , Touzot Fabien
Published: October 2019

Gene therapy represents an alternative and promising strategy that could provide a path to a curative therapy for HIV-1 infection. One approach involves the introduction of protective gene into a cell, thereby conferring protection against HIV.

We plan to conduct an open label phase I/II gene therapy trial for HIV-1 infected patients presenting with lymphoma. The patients will received autologous hematopoietic stem cells transplantation with gene modified CD34+ cells and CD4+ T-cells. CD34+ and CD4+ will be ex vivo transduced by the LVsh5/C46 lentiviral vector (Cal-1, Calimmune, Inc. Tucson, USA). LVsh5/C46 is a SIN lentiviral vector that inhibits two crucial steps of CD4+ T cell infection by the HIV virus: (i) attachment of the virus to its target by downregulation of CCR5 via a short hairpin RNA, (ii) fusion of the virus to the target cell through expression of the C46 inhibitor.

We developed a transduction process for CD4+ T-cells using the TransAct™ reagent (Miltenyi Biotec, Bergisch Gladbach , Germany) for CD4+ T-cells activation. Compared to previously published T-cells transduction protocols, the use of Miltenyi TransAct™ permits an equivalent efficacy of transduction - evaluated by measurement of vector copy number through quantitative PCR - without major phenotypic modification. Indeed, CD4+ T-cells ex vivo transduced after activation with the TransAct™ reagent display very few changes in their surface marker with conservation of naive (CCR7+CD62L+CD45RA+), central memory (CCR7+CD62L+CD45RA-) and effector memory (CCR7-CD62L-CD45RA-) subsets in superimposable proportions as initially. Moreover, expression of CD25 remains below 15-25% of cells suggesting a more "gentle " activation of the transduced CD4+ T-cells.

Our transduction process had no significant impact in TCRβ repertoire diversity as evaluated by high-throughput sequencing and analyzis of diversity through the Gini-Simpson index or the Shannon index.

Finally, transduced CD4 + T-cells retained the ability to to be primed towards the TH1, TH2 and TH17 pathways suggesting that the transduction protocol used did not alter the functional properties of the target cells.

Disclosures

No relevant conflicts of interest to declare.
Prediction and Optimization of the Therapeutic Effect of mTOR Inhibitors in Aggressive B-Cell Lymphomas
Authors: Bi Chengfeng , Zhang Xiaoyan , Xuan Zhang , Chan Wing C , McKeithan Timothy , Fu Kai
Published: October 2019

Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in all eukaryotes. Rapamycin and its analogs (rapalogs) have been approved for the treatment of relapsed mantle cell lymphoma. A large proportion of aggressive B-cell lymphoma patients, however, respond poorly to rapalogs. The second generation of mTOR inhibitors function as ATP-competitive inhibitors (TORi), directly targeting the mTOR catalytic site. TORis have been proven to be more effective than rapalogs in cancer treatment. However, the mechanism underlying the cytotoxic effect of TORis in aggressive B-cell lymphomas remains unclear. In this study, we demonstrated that TORi-induced apoptosis is predominantly dependent on loss of mTORC1-mediated 4EBP phosphorylation. Knocking out Rictor, a key component of mTORC2, or inhibiting p70S6K has little effect on TORi-induced apoptosis. In contrast, increasing the EIF4E:4EBP ratio by either overexpressing EIF4E or knocking out 4EBP1/2 protected lymphoma cells from TORi-induced cytotoxicity. Furthermore, down-regulation of MCL1 and BCL-XL expression plays an important role in TORi-induced apoptosis whereas BCL-2, in cells with high expression, confers resistance to TORi treatment. Based on the mechanism study, we demonstrated that BH3 profiling, primarily NOXA and HRK stimulation, can effectively predict the cytotoxicity of the TORi in lymphoma cells. Also, in combination with pro-apoptotic drugs, especially BCL-2 inhibitors, the TORi exerted powerful anti-tumor effects both in vitro and in vivo. Taken together, this study provides mechanistic insight in TORi treatment in aggressive B-cell lymphoma and identified a mean to predict and improve its effectiveness clinically.

Disclosures

No relevant conflicts of interest to declare.
Iliopsoas Hemorrhage in Pediatric Patients with Hemophilia, Experience from One Centre
Authors: Türkkan Emine , Atay Didem Yalcin , Ocak Suheyla , Ozdemir Gul Nihal
Published: October 2019

Introduction: Iliopsoas hematoma is a serious, life threatening bleeding event in patients with hereditary clotting disorders and significantly associated with morbidity. It occurs most commonly in patients with severe hemophilia (Balkan et al Haemophilia 2005). In this review, we evaluated our patients with iliopsoas hematoma and compared with literature.

Methods: The eleven pediatric patients with hemophilia and iliopsoas hematoma treated in a research and training hospital in Istanbul, between 2005 and 2015 were enrolled. The clinical characteristics including symptoms, signs, complications, and treatment were analyzed retrospectively.

Results: We evaluated 14 episodes of iliopsoas hematoma from 11 patients (10 hemophilia A and 1 hemophilia B). All patients were male and the median age was 12 (8 -14) years old. Eight patients had one episode, three had two episodes. One patient had a high titer inhibitor against factor VIII. The hematoma was spontaneous and unilateral in all cases. The most common symptoms were hip pain and hip flexion contracture. Iliopsoas hematomas were confirmed by ultrasound, CT or MR scan. The treatment consisted of factor replacement and rehabilitation therapy. One patient needed erythrocytes transfusion. The mean duration of factor replacement therapy was 13.5 +/- 2.1 days. One severe hemophilia A patient with inhibitor treated with recombinant factor VIIa. Long term complications included paresthesia in 3 patients in the distribution of femoral nerve, quadriceps atrophy in 3 patients and permanent abnormal posture in one patient.

Conclusion: The psoas muscles are located in the iliopsoas compartment posterior to the transversalis fascia, which is the posterior boundary of the retro peritoneum. Presentation of iliopsoas hematomas is often non-specific with abdominal, pelvic, back or groin pain or swelling. If they are large, iliopsoas hematomas can present with constipation, urinary frequency or fever. They can even compress the femoral nerve and cause a femoral neuropathy . A delay in treatment may result in permanent femoral nerve palsy (Mannucci N Engl J Med 2004). In this report, we present our experience and treatment modality in 14 episodes of iliopsoas hematoma in pediatric hemophilia patients. Rehabilitation treatment with factor replacement is safe and effective therapy for patients with small hematomas and little or no neurological symptoms. More aggressive recommendations have been made for patients with large hematomas and severe neurological symptoms or hemodynamic instability. An early diagnosis allows early factor replacement therapy, and decreases the risk of recurrence and morbidity.

Disclosures

No relevant conflicts of interest to declare.
Leukemia Cells Attenuate the Response of Leukemia-Associated Macrophages to LPS By Down Regulation of TLR4
Authors: Liao Jinfeng , Wang Rong , Yang Feifei , Feng Wenli , Yang Xiao , Wang Lina , Zheng Guoguang
Published: October 2019

Tumor-associated macrophages (TAMs) play important roles on tumor progress in solid tumors. Two therapeutic methods targeting TAMs, i.e. depleting TAMs and ¡°re-educating¡± TAMs to anti-tumoral M1 phenotype, have been proposed. LPS, which can stimulate macrophages to M1 phenotype, was suggested for anti-tumoral therapy. Recently, we reported leukemia-associated macrophages (LAMs), which showed leukemia-promoting effects, in leukemic microenvironment. In this study, we investigate whether LAMs can be re-educated by LPS in vitro.

THP-1 cells were treated with PMA for 48 hours for differentiation to macrophages. Then macrophages were treated with LPS for 24hrs directly (M¦Õ-LPS) or after cocultured with K562 or Jurkat cells for 48hrs (LAM-LPS). BrdU incorporation assay and TUNEL assay were used to detect the proliferation and apoptosis respectively. Significant decrease of BrdU positive rate was detected in M¦Õ-LPS while little change was detected in LAM-LPS. The TUNEL positive rates of both M¦Õ-LPS and LAM-LPS decreased. The expression of polarization related genes was studied by real time PCR. Increase of most M1 phenotype genes was detected and little difference of most M2 phenotype genes was detected in M¦Õ-LPS, whereas little difference of both M1 and M2 phenotype genes was detected in TAM-LPS. To further investigate the mechanism, Western blot was used to detect the M1 polarization determining transcription factor STAT1 among different groups. Drastic increase of p-STAT1 was detected in M¦Õ-LPS while little change was detected in LAM-LPS. These data suggested that LAMs had attenuated response to LPS. MAPK signal pathways were also examined by Western blot analysis. ERK, JNK and P38 pathway were significantly activated in M¦Õ-LPS, which was not observed in LAM-LPS. In order to further investigate the mechanism, real time PCR was used to detect the expression of LPS receptor complex: TLR4, CD14 and MD2. The results showed that TLR4 was decreased in LAM cocultured with both leukemia cells when macrophages without coculture or LPS treatment were set as control. Decrease of TLR4 was also observed in M¦Õ-LPS and LAM-LPS.

Our results suggested that leukemia cells attenuate the response of LAMs to LPS by down regulation of TLR4.

Disclosures

No relevant conflicts of interest to declare.
Presepsin (soluble CD14 subtype) Is Available in Febrile Neutropenic Patients with Hematological Malignancy As Diagnosis and Assesment Biomarker of Infections
Authors: Oyake Tatsuo , Masuda Takayuki , Sugawara Norifumi , Asahi Maki , Suzuki Yuzo , Okano Yoshiaki , Fujishima Yukiteru , Aoki Yusei , Kowata Shugo , Ito Shigeki , Ishida Yoji
Published: October 2019

BACKGROUND: Febrile neutropenia (FN) is often observed in hematological malignancy (HEM). Although most are considered to be due to bacterial infections, it is often difficult to specify the focuses and pathogens of infections in FN patients. Presepsin (Pre-SEP) is a subtype of soluble CD14, which is a receptor for lipopolysaccharide (LPS)/LPS-binding protein complexes and is expressed on the myeloid and monocytic cells' surface. Recently, Pre-SEP has been shown to be a useful biomarker for assessing the severity of sepsis. However, little is known about the biological characteristics of Pre-SEP in FN patients. Therefore, we compared the Per-CEP to the established infection markers including procalcitonin (PCT) and C-reactive protein (CRP) continually in FN patients.

METHODS: We measured Pre-SEP concentration in the plasma, PCT and CRP on Day 0, 2, 4, 7 and 14 after the onset of FN and compared them to those of non-febrile neutropenic patients. Furthermore we evaluated the impact of Pre-SEP, PCT and CRP on the diagnosis and assessment of active infection status in FN, using the cut-off value by setting to 314 pg/ml, 0.50 ng/ml and 0.30 mg/ml. Correlation analysis was performed using Peason's correlation coefficient test.

RESULTS: Sixty-two hospitalized FN patients with HEM (AML 14, ALL 9, MDS 14, NHL 13, MM 8, ATL 2, others 2 cases) were treated according to IDSA guideline. Figure 1 showed the each data in Pre-SEP, PCT and CRP value on day 0, 2, 4, 7 and 14. The frequency of less than the cut-off value at day 0 of FN onset were 33.8 %, 77.4 % and 37.1 % in Pre-SEP, PCT and CRP respectively, indicating that Pre-SEP showed the highest sensitivity. On day 0, a significant correlation was not observed between Pre-SEP and PCT (P=0.457, correlation coefficient: 0.096) but it was observed between Pre-SEP and CRP (P<0.01, correlation coefficient: 0.599). However, on day 2 and 4, significant correlations were observed between Pre-SEP and PCT (P<0.01, correlation coefficient: 0.650, p<0.01, correlation coefficient: 0.702 respectively) as well as between Pre-SEP and CRP (P<0.01, correlation coefficient: 0.542, p<0.01, correlation coefficient: 0.722 respectively). These data strongly suggested that Pre-SEP and CRP were available early in FN for a diagnosis and assessment of infection. On day 7, the negative frequencies were 43.5 %, 88.7 % and 45.1 % in Pre-SEP, PCT and CRP. These data strongly suggested that more sensitive assessment of infection would be possible using Pre-SEP.

CONCLUSION: (1) Pre-SEP is available even in neutropenia. (2) Pre-SEP is a useful biomarker for infection on the onset of FN as well as CRP. (3) Pre-SEP can help more sensitive assessment of infection.

Figure 1. Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Safety of Micafungin As Salvage Treatment for Invasive Fungal Disease in Patients with Hematologic Malignancies
Authors: Gao Li , Lin Ren , Dai Min , Sun Jing , Fan Zhiping , Zhang Yu , Zhou Hongsheng , Liu Qifa
Published: October 2019

Objective To explore the efficacy and safety of micafungin as salvage treatment for invasive fungal disease(IFD) in patients with hematologic malignancies.

Methods A retrospective, observational, sequential cohort study was performed between Feb 2012 and June 2015 at southern medical university nanfang Hospital. We selected a group of 51 patients who either refractory or intolerant to first-line antifungal therapies, received micafungin as salvage therapy. Of the 51 patients, IFD was proven in 5 and probable in 46 patients. The predominant cause for treatment switch to micafungin was refractory therapy in 33 patients, followed by intolerance in 15 patients or both in 3 patients. For their first-line antifungal therapies of IFD, 34 patients received voriconazole, 7 patients received itraconazole, 2 patients received amphotericin B,1 patients received caspofungin,1 patients received posaconazole and 6 patients received voriconazole combined amphotericin B. The median duration of antifungal treatment before salvage therapy was 26 days (range, 4 to 57 days). The successful resolution rates、the median time of micafungin treatment, the drug related adverse events and overall survival were assessed.

Results All of the patients were treated with 150 mg/d micafungin. The median time of micafungin treatment was 23 days (range,12-72 days). The success rate was 64.7%, including 16 achieved complete response, 17 achieved partial response and 18 patients had no overall response (failure in 9 patients, 2 patient with stable disease and 7 patients died). Only one patient experienced an adverse event. No patient discontinued micafungin therapy due to an adverse event.

Conclusions This study demonstrated that micafungin was efficacy and safety as salvage treatment IFD in patients with hematologic malignancies.

Disclosures

No relevant conflicts of interest to declare.
Thymic Hyperplasia after Chemotherapy: Combined Experience of Two Centers
Authors: Dominguez-Perez Pamela , Maxey Nicole , Mohammadi Zeinab , Cortes Erasto , Antony Nishaal , Gupta Anuradha , Landeros Mark M , Campos-Gines Angel , Reiter Ethan , Arango Carmen , Gutierrez Javier , Morales Elena , Gonzalez Matilde , Herrada Juan
Published: October 2019

Background: Lymphoid tissue hyperplasia has been described in oncologic patients after receiving chemotherapy at different sites including: adenoids, tonsils, nasopharynx and thymus. Thymic hyperplasia has been reported more frequently in the pediatric age, associated most commonly with lymphomas. Biopsies of the thymic tissue show benign growth most likely due to a rebound effect after the chemotherapy treatments. Thymic hyperplasia occurring during cancer remission after chemotherapy treatment poses a diagnostic dilemma to clinicians. Our aim is to describe our experience with eight patients (pts) who were treated with chemotherapy and subsequently developed benign thymic hyperplasia.

Methods: Retrospective analysis.

Results: We reviewed the medical records of 8 consecutive pts seen in our two institutions between 2004 and 2015 who were referred with the diagnosis of breast cancer (7 pts) or lymphoma (1 pt). All pts were female; median age was 41 years, with an age range from 35 to 44. Each pt presented with benign thymic hyperplasia following the completion of chemotherapy treatments. The median time for diagnosis of thymic hyperplasia (demonstration of a new anterior mediastinal mass on follow-up CT scan) was 7 months following completion of chemotherapy, with a range of 1 to 11 months. In the first patient, the diagnosis was confirmed after thymic removal by thoracotomy and the remaining pts were followed up with serial computed tomography (CT) scans. All eight pts remain in complete remission from their primary cancers.

Conclusion: Thymic hyperplasia following chemotherapy treatment is an unusual benign phenomenon that merits awareness by clinicians in order to prevent unnecessary invasive and risky procedures.

Disclosures

No relevant conflicts of interest to declare.
Characterization of Phenotypic Expression of Inherited Fibrinogen Coagulopathy in Pakistani Index Patients
Authors: Naz Arshi , Khan Tehmina nafees sonia , Malik Noman A , Tariq Shahla , Saqlain Nazish , Shamsi Tahir
Published: October 2019

Background: Congenital afibrinogenemia is inherited as an autosomal recessive trait and consanguinity is common among affected families. Phenotypic expression of this particular factor deficiency is still not unanimously established in research literature globally as the disease manifests with variability in symptoms which may ranges from minimal bleeding to catastrophic hemorrhage.

Aim: To characterize the clinical manifestations of patients to set a standard parameter of bleeding severity in our local population.

Materials and Methods: This descriptive and cross sectional study was conducted at NIBD Karachi in collaboration with Chugtai's Lab and CHL Lahore in conformance with the Helsinki declaration. Consent was signed from all participants. Inclusion criteria for index patients specifically encompass the diagnosed cases of congenital afibrinogenemia excluding all acquired causes of this condition. Initially all the samples were processed at collection centers and platelet poor plasma and serum was separated and collected in labeled aliquots. Samples were transported to NIBD Karachi by maintaining cold chain. First line investigations including prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen levels by clauss method were performed to reconfirm the results. Grading of every individual's signs and symptoms depends upon severity of the disease and define here as per bleeding score [Tossetto et al]

Results: Total 18 patients were evaluated with mean age group10±2 yrs and 11 were males. Two patients were sibling. PT was >120s, APTT >180s and fibrinogen levels were (<0.2g/l).The most common symptom is umbilical bleeding (95%) followed by circumcision hemorrhage (90%) in males, cutaneous manifestations (85%) and epistaxis (68%). Grading of bleeding was done by WHO bleeding scale criteria and very well correlated with bleeding score and haemorrhagic manifestations exhibiting by patients. Severe bleeding patients were shown to have high bleeding scores along with II and III grades of bleeding .

Conclusion:The clinical manifestations of congenital afibrinogenemia in our local population are more or less same as reported in global literature. Due to the low prevalence rate of RBDs and the variability of bleeding manifestations are not well characterized clinically so far. Few exceptions do exists as we didn't find most of the rare complications in our set of patients.

Disclosures

No relevant conflicts of interest to declare.
Platelet-Derived Microparticles May Influence Phenotypic Heterogeneity in Patients with Severe Hemophilia
Authors: Zhou Xuan , Qin Fangmei , Li Han , Li Zhitao , Liu Yang , Yi Zhengshan , Sun Jing
Published: October 2019

Large heterogeneity in bleeding phenotype is observed among patients with severe hemophilia A. Some severe patients do not require regular replacement therapy, so to address the factors influencing phenotypic Heterogeneity in Patients with Severe Hemophilia A seems particularly important. We first initiate a cohort study 0f 274 patients with severe hemophilia A who were treated at the hemophilia treatment centre at Nanfang hospital, then 209 patients were enrolled and their bleedings were recorded, finally 12.9% (12/209) of the patients were found to be mild phenotypes, which annual bleeding rate(ABR)were less than 6 times. We then use Flow-cytometric analysis to detect the platelet-derived microparticles (PMPs) among patients with mild phenotypes, patients with severe phenotypes (ABR more than 24) and the normal control group, megamix beads (0.5μm; BioCytex, Marseille, France), CD42a-PE, CD42b-PE, CD41b-PE (GPIX, platelet MPs [PMPs], BD, NJ, USA) were involved, then the results showed that there was no difference in the level of PMPs between hemophliac patients and the normal control group (P=0.317), however, the level of PMPs in patients with mild phenotypes were significantly higher than patients with severe phenotypes (3.65±1.38 vs 1.13±0.64, P<0.05).These findings indicated that 12.9% were mild phenotypes in 209 patients with severe hemophilia A, moreover, the platelet-derived microparticles which may influence phenotypic heterogeneity in patients with severe haemophilia A will be further study for individual treatment.

Disclosures

No relevant conflicts of interest to declare.
Quality of Life in Children with Rare Bleeding Disorders
Authors: Karimi Mehran , Mohtadi Hassan , Haghpanah Sezaneh , Akbari Mahboobeh
Published: October 2019

Background: Patients with rare bleeding disorders (RBDs) face with several problems due to the chronic feature of the disease. So their physical and mental health is affected. Objective: The aim of this study is to evaluate quality of life (QOL) in patients with RBDs using haemo-QOL questionnaire.

Methods: In this cross-sectional study, 52 consecutive children aged between4-18 years old with RBDs registered at the Haemophila center of Fars province in Southern Iran were investigated from January to April 2015. Quality of life was evaluated by expert nurses using haemo-QOL questionnaire in different age groups including 4-7, 8-12, and 13-16/18 years old. Final score range is defined between 0-100 and higher score of QOL shows worse condition. Disease severity was determined based on coagulation factor levels: mild >5%, moderate 1-5% and severe <1%. P value less than 0.05 was considered statistically significant.

Results: Mean age of the patients was 13.9 ± 4.5 ranged from 4 to 18 years old including 28 males and 24 females. The distribution of frequency of RBDs was as follow: Factor I deficiency 9; Factor V deficiency 2; Factor VII deficiency 15; Factor X deficiency7; Factor XI deficiency 8; Factor XIII deficiency 8; and combined Factor V&VIII deficiency 3 patients. Overall QOL of the patients was 41.15 ± 14.72. In Univariate analysis, from all evaluated variables only bleeding severity based on bleeding score showed a statistically significant correlation with QOL of the patients (r =0.298, P=0.032). In multiple linear regression models only degree of being bothered by the disease was determined as an independent influencing factor on QOL.

Conclusion: Based on our results, QOL of children with RBDs was correlated significantly with bleeding severity but not correlated with disease severity based on factor level. Due to chronicity and feature of bleeding disorders, more attention to different aspects of the disease is necessary to improve QOL of the patients with RBDs.

Disclosures

Karimi: Octapharma: Other: Investigator.
Massive Pulmonary and Coronary Artery Thromboembolism in the Setting of Undetected Patent Foramen Ovale
Authors: Thomas Sarah , Braswell Diana , Stephenson Corinne
Published: October 2019

Invasive surgery brings with it a unique set of post-surgical risks that are directly dependent on various factors including the specific surgical approach used, pre-existing comorbidities and features such as gender and age. Pulmonary thromboembolism is one of the most feared complications following surgery, and diagnosis and treatment of this entity is a challenging task for the clinician. Here we describe a case of massive pulmonary thromboembolism and associated coronary artery thromboemboli status post spinal fusion surgery in a 68 year-old man with an undetected patent foramen ovale (PFO). Although the decedent was managed clinically with proper deep venous thrombosis prophylaxis protocols and physical rehabilitation, he went into cardiorespiratory arrest after experiencing acute oxygen desaturation and newly detected right bundle branch block. PFO can be incidentally found in 25% of the adult population. Several clinical syndromes including stroke, migraine headaches and obstructive sleep apnea have been associated in patients with PFO, the last two from which the decedent suffered. The pathology of this unique case of massive pulmonary thromboembolism resulting in coronary artery thromboemboli in the setting of an undetected PFO is discussed. The discovery of PFO in patients prior to surgery, if detected early, may improve post-surgical outcomes.

Figure 1. Massive pulmonary artery thromboembolism in situ, gross examination. Figure 1. Massive pulmonary artery thromboembolism in situ, gross examination. Figure 2. Histology, hematoxylin and eosin. A. Pulmonary thromboembolus at the bifurcation of the pulmonary arteries and pulmonary trunk. B. Hemorrhagic infarct and thromboemboli in varying stages of organization, right lower lobe, lung. C. Cross section of the proximal left anterior descending coronary artery with thromboembolus. D. Cross section of the posterior descending coronary artery with thromboembolus. Figure 2. Histology, hematoxylin and eosin. A. Pulmonary thromboembolus at the bifurcation of the pulmonary arteries and pulmonary trunk. B. Hemorrhagic infarct and thromboemboli in varying stages of organization, right lower lobe, lung. C. Cross section of the proximal left anterior descending coronary artery with thromboembolus. D. Cross section of the posterior descending coronary artery with thromboembolus. Figure 3. Patent foramen ovale, gross examination. Figure 3. Patent foramen ovale, gross examination.

Disclosures

No relevant conflicts of interest to declare.
Inpatient Thrombophilia Workup in Patients with Acute Venous Thromboembolism
Authors: Mehta Vivek Rashmikant , Khan Uzma , Basu Aparna , Jan Asif , Gbadamosi Bolanie , Chowdhury Junad , Parashar Kamesh , Khawaja Muznay , Kufile Oluwatoyin , Bhattarai Rajiv , Thobani Sanya , Korman Michael
Published: October 2019

Background

Any inherited or acquired condition that increases the risk of developing deep venous thrombosis or pulmonary embolism is considered a thrombophilic disorder. Some examples of inherited causes of thromboembolic disorders are Factor V Leiden mutation (FVL), Prothrombin gene mutation, Protein C deficiency (low or dysfunctional), Protein S deficiency (low or dysfunctional), Anti-thrombin (AT) deficiency (low or dysfunctional). Use of these studies in clinical practice has been questioned. We attempted to identify if there are populations of patients that undergo more inpatient screening for inherited causes of venous thromboembolism (VTE).

Methods

Retrospective chart review of patients admitted with PE or DVT in a community teaching hospital between May 2012 and December 2014. Only patients who had DVT confirmed with ultrasound or PE confirmed with CT angiogram or had high probability of PE on V/Q scan were included in the study. Individual charts were reviewed to see if thrombophilia workup was ordered.

Results

A total of 704 patients with acute venous thromboembolism were identified who met our inclusion criteria for the study. Of this 111 patients (15.76%) had one or more thrombophilia screening studies ordered. Risk factors related to venous thromboembolism were evaluated for all of the 704 patients. In our patient population, patients who were smokers (31% vs 20%), had history of sleep apnea (9% vs 3%), a past medical history (PMH) of VTE (37% vs 25%) or who had a family history (FH) of VTE (11% vs 4%) were more likely to have a thrombophilia workup ordered. Table 2 shows the frequency of individual thrombophilia studies ordered among the 111 patients who had testing performed and table 3 shows distribution of positive results.

Table. Test Result Abnormal Test Results ANA 1 Decreased AT III 10 Decreased Protein C 10 Decreased Protein S 7 Increased Homocysteine 6 Factor V Leiden 4 PT Gene Mutation 1 APLA 1

Conclusion

The largest numbers of positive test results were noted for Protein C, Protein S and Antithrombin III and these are known to be affected by acute thrombosis and therefore could be false positives. Our study shows that those patients with PMH or FH of VTE were more likely to have thrombophilia studies. There is no consensus opinion as to whether to perform thrombophilia screenings in acute care settings. Given this and the fact that personal or family history of VTE do not usually modify future treatment decisions and that there may be significant number of false positives we do not recommend routine screening in these patient populations.

Figure 1. Figure 1. Figure 2. Figure 2.

Disclosures

No relevant conflicts of interest to declare.
Early Outcomes Following Endoluminal Deep Venous Reconstruction Using Dedicated Venous Stents
Authors: Saha Prakash , Black Stephen A , Cohen Ander , Karunanithy Narayan , Hunt Beverley J , Breen Karen
Published: October 2019

Objectives

Evaluate early outcomes following endoluminal stenting using first-generation dedicated venous stents.

Methods

Patients undergoing deep venous reconstruction using venous stents between 2012-2015 were identified. Duplex ultrasonography was used to assess sent patency at 1d, 2wks, 3mths, 6mths and yearly following intervention. Venous Disability Scores (VDS) and Villalta Scores (VS) taken before and after intervention (6wks, 6mths, yearly) were calculated.

Results

347stents were inserted in 140pts (median age 39yrs, 80 female) with median follow-up 16mths (1-38mths). Overall 1yr primary, primary-assisted and secondary patency rates were 67%, 80% and 82% respectively. The 1yr re-intervention rate was 30% with 16% occurring within two-weeks.

57pts had stenting of residual stenoses after catheter-directed-thrombolysis for acute iliofemoral DVT. Median post-operative VDS and VS were 0 (P<0.001). 1pt developed an ulcer at 6mths.

81pts had stenting for chronic outflow obstruction after failed medical management. 77pts (95%) had occluded vessels prior to treatment. The median pre-operative VS was 14 (4-23) and 9pts had an ulcer. Following intervention, the median VS was 4 (0-22, P<0.001) and ulcer healing was achieved in 67% (n=6/9).

Conclusions

First-generation dedicated venous stents show promise at providing symptom relief in the short-term. Close surveillance is, however, required to maintain stent patency and factors that influence occlusion warrant further investigation. Long-term evaluation of these stents is required to investigate whether these encouraging early results can be maintained.

Disclosures

Saha: Bayer: Honoraria. Black:Veniti: Consultancy. Cohen:Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Johnson and Johnson: Consultancy, Honoraria, Research Funding; Mitsubishi Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding. Karunanithy:Cook: Honoraria.
Cost-Effectiveness Evaluation for the US of Fondaparinux Compared to Argatroban in the Management of Suspected HIT
Authors: Aljabri Ahmed , Gharaibeh Mahdi , Huckleberry Yvonne , Kutbi Hussam , Raz Yuval , Yun Seongseok , Abraham Ivo , Erstad Brian
Published: October 2019

Introduction. The relative efficacy and safety of fondaparinux and argatroban in the management of suspected heparin-induced thrombocytopenia (HIT) have been documented. We conducted a cost-effectiveness analysis of both agents in terms of cost and adverse events averted.

Methods. We developed a two-armed decision tree model to simulate a cohort of patients with suspected or confirmed HIT managed with argatroban or fondaparinux, using published efficacy data and probabilities of developing HIT-related VTE or major bleeding. The primary base case analysis considered our institutional cost while the secondary analysis used the Average Wholesale Price. Probabilistic sensitivity analysis (PSA) was performed to confirm findings and one-way sensitivity analysis to evaluate additional scenarios.

Results. In the primary base case analysis, fondaparinux dominated argatroban treatment as it was less expensive in managing suspected HIT ($154 vs. $2,064) and more effective in terms of adverse events averted (0.998878 vs. 0.995739). This was confirmed in PSA in terms of both cost ($154 vs. $1,999) and adverse events averted (0.9988711 vs. 0.9957212). Sensitivity analysis showed that the total costs of argatroban would never be less than fondaparinux based on our assumptions. In the secondary analysis, fondaparinux was less expensive ($362 vs. $3722) and more effective in terms of adverse event averted (0.998878 vs. 0.995739). The PSA confirmed these findings both in terms of cost ($343 vs. $3477) adverse events averted. (0.9988711 vs. 0.9957212).

Conclusions. The cost savings from a once-daily SC fondaparinux injection with limited laboratory monitoring are more advantageous than IV argatroban infusion that requires continuous titration.

Disclosures

Off Label Use: Fondaparinux is used as "off-label" for the management of patients with suspected or confirmed HIT.
Influence of Gender and Coagulation Factors on Efficacy and Safety of Rivaroxaban in Adolescents & Young Adults with Venous Thromboembolism
Authors: Krause Manuela , Limperger Verena , Henningsen Anna , Clausnizer Hartmut , Kenet Gili , Kowalski Dorothee , Nowak-Gottl Ulrike
Published: October 2019

Background: Venous thromboembolism [TE] is a multifactorial disease and antithrombotic therapy with Rivaroxaban [RIVA] is increasingly being administered for TE treatment in adults.

Aim: The objective of the present study was to evaluate efficacy and safety of standard RIVA administered as routine medication in an outpatient cohort of patients with TE.

Methods: In 212 consecutively admitted outpatients (14-<55 years; male:female ratio 1.5:1) with TE on standard RIVA medication (2x 15 mg followed by 20 mg) recruited between January 2013 and December 2014, monitoring of RIVA through (24h) and peak levels (Xa-based chromogenic substrate S-2732; Haemochrom Diagnostica) along with anti-factor-Xa-activities [Xa; Xa-based assay, Haemochrom Diagnostica], selected coagulation factors and biomarkers (factors II, V, VIII, Ristocetin-cofactor [RICO] was performed. Efficacy endpoints were defined i) as any TE or thrombus progression during treatment [TP], safety endpoints were defined as ii) significant bleeding [B] requiring any medical intervention, such as dose reduction, withdrawal of RIVA or death related to therapy. Descriptive analysis non-parametric statistics, Chi-square test and logistic regression were performed.

Results: Patients were followed over a median of 12 months. The median daily RIVA dose of 0.25 mg (0.1-0.52) in females was significantly higher compared to males with 0.21 mg (0.09-0.4; p<0.000). RIVA dose was clearly correlated to Xa (p<0.0001; rho=0.945). During the study period two out of 212 patients developed TP [0.94%] and a total of 46 clinical relevant B episodes [21.7%] were diagnosed in 38 females (hypermenorrhagia n=21: necessitating hysterectomy in 2 cases) and 8 males. In bleeders compared to non-bleeders median (min-max) RIVA dose per kgbw was significantly higher (0.26 mg [0.16-0.52] vs. 0.22 mg [0.09-0.52]; p=0.008). Multivariate analysis adjusted for gender, body mass index, RIVA dose, through levels and coagulation factors revealed and increased odds [95% CI] of 3.9 [1.5-9.6] in women to develop B. In addition, a gradual decrease of RICO per IU/ml was significantly associated with clinical relevant B (p=0.04).

Conclusion: Along with good efficacy results our data demonstrate a high bleeding rate of 36.9% in women on standard RIVA. Lower RISTO activities in fertile/premenopausal women contributed significantly to B.

Disclosures

Kenet: Bayer, LFB, NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Nowak-Gottl:Bayer, LFB: Membership on an entity's Board of Directors or advisory committees.