bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative Transfusion in Pediatric Patient with Sickle Cell Disease
Authors: Al Darwish Mohamed , Alabkary Sukainah , Al deabel Hajer , Alqatari Fatimah , AlDubaisy Wafa
Published: November 2019

Background: Sickle cell disease (SCD) is associated with perioperative complications. Red cell transfusion has been recommended in the management of SCD undergoing elective procedure to minimize perioperative complications. The aim of this study was to retrospectively review our experience in the management of children patients with SCD with the Arab-Indian (AI) haplotype undergoing elective and emergency surgery, and to determine blood transfusion requirement and surgery-related perioperative complications.

Patients and Methods: A total number of 173 SCD patients undergoing surgery at Qatif Central Hospital, Qatif, Eastern province, Saudi Arabia was conducted between February 2007 and June 2019. children less than 14 years and above one year were included (111 boys and 62 girls). Patients were divided into two groups: Group A did not receive transfusion and Group B had top-up transfusion. The medical records were reviewed to define the perioperative risks and the postoperative complications in relation to the type of transfusion modality selected.

Two surgical procedures were analyzed: a low and medium risk group including laparoscopic cholecystectomy, laparoscopic splenectomy, tonsillectomy, adenotonsillectomy, herniotomy and dental procedure.

Results: eighty-three (n:83) patients (Group A) did not received transfusions (Group B) while . There were 15 (17.2%) postoperative complications; seven (8.4%) occurred in group A patients who did not received transfusion and eight (8.8%) occurred in group B patients who received top-up transfusion. Sickle cell disease-related complications consisted of acute painful vaso-occlusive crises in three patients (3.5%). Six patients (3.9%) had acute chest syndrome, 4 (4.5%) had hepatic crises and one had subclinical pancreatitis. Only one (1.2%) patient in group B (top up) had a mild hemolytic transfusion reaction. Moreover, there was no significant difference in the complications between the transfusion and none transfusion subgroups.

Conclusion: Surgery in SCD patients is safe without a preoperative blood transfusion. Moreover, there was no significant difference in the complications between the transfusion and none transfusion subgroups. To conclude, blood transfusion or exchange blood transfusion should be individualized based on genotype, haplotype and type of surgery.

Disclosures

No relevant conflicts of interest to declare.
Stat3 Is Activated By ROS to Uniquely Regulate Primitive Erythropoiesis
Authors: Murphy Zachary C. , McGrath Kathleen E. , Palis James
Published: November 2019

The mammalian embryo requires the sequential circulation of primitive and definitive erythroid cells for survival and growth. The central cytokine regulator of primitive and definitive erythropoiesis is erythropoietin (EPO). We have previously determined that primitive erythroid progenitors, unlike their definitive (CFU-E) counterparts, do not require EPO for survival. However, the mechanisms regulating the EPO-independent emergence of primitive erythropoiesis in the yolk sac remains poorly understood. Interestingly, maturing primitive erythroblasts in the murine embryo, unlike definitive erythroblasts in the fetal liver and adult bone marrow, express not only STAT5 but also STAT3, which is tyrosine phosphorylated at baseline and in response to EPO. These initial findings led is to hypothesize that STATs 5 and 3 differentially regulate terminal differentiation of primitive erythroid cells. To analyze the function of these two STATs in primary erythroid cells, we developed an imaging flow cytometry-based methodology to quantitate total and phosphorylated levels of STAT proteins in small numbers of cells isolated from staged murine embryos. We found that STAT5 plays conserved roles in primitive and definitive erythroblast survival and surface CD71 expression. In contrast, STAT3 regulates cell cycle progression and mitochondrial polarization specifically in primitive erythroblasts. In addition, STAT3, unlike STAT5, was phosphorylated in the absence of cytokine stimulation. We asked if reactive oxygen species (ROS) may be activating STAT3, since primary primitive erythroblasts, unlike definitive erythroblasts, specifically express Aquaporins 3 and 8, which can transport hydrogen peroxide, as well as water. Indeed, hydrogen peroxide exposure increased endogenous ROS, as well as phosphorylated STAT3, levels both in wild-type and EPOR-null primitive erythroblasts. Consistent with these findings, inhibition of aquaporin channel transport prevented STAT3 phosphorylation by exogenous hydrogen peroxide, but not by EPO. Taken together, our data support the concept that the primitive erythroid lineage, emerging in the hypoxic and EPO-low environment of the yolk sac in the pre-circulation murine embryo, uniquely integrates ROS-mediated STAT3 activation to regulate key aspects of terminal erythroid maturation.

Disclosures

Palis: Rubies Therapeutics: Consultancy.
A Randomized Phase 3 Clinical Trial of the Combination of Plinabulin (plin) + Pegfilgrastim (peg) Versus (vs) Peg Alone for Tac (docetaxel, doxorubicin, cyclophosphamide) Induced Neutropenia (cin)
Authors: Blayney Douglas W. , Huang Lan , Mohanlal Ramon
Published: November 2019

Trial in Progress:

Granulocyte colony stimulating factors (G-CSFs) (including Peg) reduce, but do not completely ameliorate CIN. Plinabulin is a novel, small molecule, single-dose-per cycle therapy, with equal activity against docetaxel CIN vs. Peg, but with several advantages: Plin has 1. Less bone pain, 2. Anticancer effects, and 3. Dosing 30 min after chemotherapy (chemo). The CIN nadir with Plin occurs in week 2 and with Peg in week 1 of the chemo cycle. All these features suggest a mechanism of action (MoA) with Plin that is different from Peg (Blayney, ASCO 2018; IASLC 2018). Neutrophil demargination with Plin and a reduced neutrophil transit time consistent with IL-6 signaling, and reversal of a LSK block in bone marrow, suggest protective rather than a stimulatory MoA for Plin in CIN (Blayney, SLB 2018; Ghosh, AACR 2018, Suwa, Am J Physiol 2000). Due to their differences in MoA, there is a strong rationale to combine Plin and Peg, as this offers the potential of better protection against CIN in both week 1 and 2 in the chemo cycle. In the Phase II portion of study BPI2358-106 (Study 106., NCT03294577), we evaluated the effects of the Plin combined with Peg on CIN and Bone Pain. Study 106 treated breast cancer (BC) patients with TAC with 6 mg Peg alone (Peg6), or Peg6+Plin. Plin dose was 20 mg/m2. Grade (Gr) 3 and 4 neutropenia frequency, duration of Gr 3 and 4 neutropenia (DSMN), and neutrophil nadir was based on absolute neutrophil counts, obtained on days 0, 1, 3, 6, 7, 8, 9, 10, 11, 12, 13, 15. Bone pain was assessed by a validated questionnaire on days 1, 2, 3, 4, 6, 7, 8, 9, and expressed as % of patients reporting bone pain.

Phase II Results.

The confirmatory phase 3 portion of study 106 will test addition of Plin to Peg6, which may offer superior protection against TAC CIN vs Peg alone without bone pain. The Plin/Peg combination is a novel CIN approach with the potential to optimize chemotherapy, by minimizing chemotherapy dose modifications due to CIN or bone pain.*p<0.05; **p<0.001; ***P<0.01 Peg+Plin vs Peg 6mg

Table

Disclosures

Blayney: BeyondSpring Pharmaceuticals: Research Funding. Huang:BeyondSpring Pharmaceuticals: Employment. Mohanlal:BeyondSpring Pharmaceuticals: Employment.
Portal Vein Thrombosis: A Single Institution Experience
Authors: Pichardo Rayli , Katiyar Vatsala , Vohra Ishaan , Abu Omar Yazan , Patel Sanjay
Published: November 2019

Background: Portal vein thrombosis (PVT) is a common complication of liver cirrhosis but can also be seen in non-cirrhotic patients. In this context, we present a single institution experience of PVT in our patient population contrasting the difference of presentation between both groups of PVT.

Methods: We retrospectively analyzed electronic medical records of patients with PVT (confirmed with radiographic criteria) from 2009 to 2018. We collected data regarding the demographics, characteristics of PVT, liver cirrhosis, presence of malignancy, treatment and laboratory investigations done at the time of diagnosis. Clinical endpoints of 90-death mortality, admission to intensive care unit and length of stay were also collected.

Results: a total of 162 patients fulfilled inclusion criteria. 104 (64.2%) male patients, mean age of 56.4, predominantly African American patients 75 (46.3%). 81 (50.0%) patients had cirrhotic PVT and 85 (52.5%) had malignant PVT. Most patients presented with abdominal pain 102 (63%), with an acute onset 51 (31.5%). 111 (68.5%) patients were not treated with anticoagulation. 28 (17.3%) patients died within 90 days of diagnosis and 22 (13.6%) patients were admitted to intensive care unit during same admission. When comparing Malignant with non-malignant PVT, patients with malignancy had a higher death rate 22 (30.1%) vs 6 (8.8%), p value <0.05. When comparing cirrhotic vs non-cirrhotic PVT, patients with cirrhosis had a higher MICU admission, history of HCC and they were treated with anticoagulation more.

Conclusion: In terms of etiology, PVT patients with malignancy seem to be doing worse than patients without malignancy while patients with cirrhosis except for higher rates for MICU admission; they seem to be doing similarly. Reasons for this discrepancy could be attributed to the fact that malignancies associated with high rates of PVT seem to be more aggressive in terms of mortality. Other studies need to be conducted in order to further clarify what we know about malignant and cirrhotic PVT.

Table

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Safety of DAC Combined with CAG Regimen (decitabine in combined with aclacinomycin, cytarabine and G-CSF) As a Second Induction Regimen Compared with Non-DAC Regimen for Acute Myeloid Leukemia Who Failed the First Course of Standard Induction IA Chemotherapy
Authors: Chen Yili , Dai Min , Liu Qifa
Published: November 2019

BACKGROUND: Acute myeloid leukemia (AML) patients who failed the first course of standard induction chemotherapy remain a challenge owing to poor response to the second induction regimen. We retrospectively compared the efficacy and safety of DAC+CAG regimen with non-DAC regimen in AML patients who failed the first course of standard induction regimen.

MATERIALS AND METHODS: The three regimens consisted of (1) DAC combined with CAG regimen (decitabine, cytarabine, aclarubicin and granulocyte colony stimulating factor, n=25) ; (2) the repeated first course (IA 3+7, n=30); (3) Intermediate-dose AraC -based chemotherapy including IA 3+3 (idarubicin, Ara-C n=14) or CLAG (cladribine, aclarubicin and granulocyte colony stimulating factor, n=15).

RESULTS: Our data indicate that after the second course, the overall response (OR, complete remission [CR]+partial remission [PR]) rates in DAC+CAG group was higher than the Intermediate-dose AraC -based group (80% vs 48.3%, P= 0.049), whereas the CR rates among 3 groups were not statistically different (P = 0.09). The overall survival (OS) of DAC+CAG group is longer than IA 3+7 group and Intermediate-dose AraC -based group with significance (21 months VS 18.5 months, P=0.038 and 21 months VS 10 months, P=0.023, respectively), the relapse-free survival (RFS) of DAC+CAG group is longer than Intermediate-dose AraC-based group (16 months VS 8.5 months, P=0.016), though there was no significant difference in overall survival (OS) of the transplanted patients among the 3 groups (P = 0.064). The median duration of thrombocytopenia in the DAC+CAG group is shorter than IA 3+7 group and Intermediate-dose AraC-based group (10 days vs 12 days, P<0.001 and 10 days vs 14 days P=0.023, respectively). Fewer incidence of lung infection and febrile neutropenia in the DAC+CAG group than other two groups (P=0.018 and P=0.025, respectively) were observed, no patients died within 4 weeks after initiating the second induction course in the DAC+CAG group whereas 2 patients died in the Intermediate-dose AraC -based group.

CONCLUSION: Our data indicate that DAC combined with CAG regimen may represent a better alternative option with good response and safety for AML patients who failed the first course of standard induction chemotherapy.

Disclosures

No relevant conflicts of interest to declare.
Anaemia in Labour: A Prospective Assessment of Women in Rivers State University Teaching Hospital, Nigeria
Authors: Kua Paul L , Omunakwe Hannah E , Okafor Afam C , Williams George Monima
Published: November 2019

Background: Anemia in any phase of pregnancy is associated with much morbidity and risk of mortality to the mother and the fetus, it is a global health concern and is quite prevalent in Africa. About 58% of pregnant women in Nigeria are said to be anemic and earlier reports from this study site showed that 69.6% of women initiating antenatal care were anemic, it was commoner in women of teen-age and the hematocrit was lower as the gestational age at booking increased.

Methods: We assessed 464 consenting consecutive pregnant women who presented to our labour ward between November 2017 and July 2018 to know their age, booking status, haematocrit at late pregnancy and followed on to know the mode of delivery as well as the occurrence of postpartum bleeding. The data were analysed using IBM Statistical Package for Social Sciences version 23.

Results: A total of 462 consenting women were included in the study, majority of study participants were between the age of 26-35 years 299 (64.7%) with a minimum age of 15 years and maximum age of 47 years and mean age was 31.2 ± 5.2 years. The majority had moderate to severe anemia 335 (70.3%) and were booked for antenatal care with trained personnel 402 (87.2%) and 47 (10.2%) of them developed post-partum haemorrhage.

A significantly higher proportion of the study participants who were un-booked presented with severe anemia (χ2 =14.3; p=0.001); developed PPH (χ2 =13.9; p<0.001) Table 1. The highest proportion of persons who developed postpartum hemorrhage was found in persons with severe anaemia. This difference was significant. (χ2 =87.1; p<0.001).

Hematocrit was found to be the strongest determinant of the occurrence of postpartum hemorrhage among the study participants. The adjusted regression analysis showed that for every one-unit increase in hematocrit of study participants, there was a 16% reduction in the probability of occurrence of PPH and this probability was statistically significant (p<0.001). Booking status was also found to be a predictor of PPH such that un-booked women were 2.3 times more likely to experience PPH than booked women in the study population. This was found to be significant (p=0.04). Table 2

This data supports earlier findings that anaemia worsens the outcome of pregnancy. Unbooked mothers are more at risk of dire outcomes such as postpartum haemorrhage which is the leading cause of maternal mortality. There is a need for guidelines and enforcement of such at all levels of healthcare delivery especially in unorthodox centres where women go for care, as is common in developing countries. The need for health education and active prevention and management of anaemia in the early stages of pregnancy is advocated.

Disclosures

No relevant conflicts of interest to declare.
Splanchnic Venous Thrombosis (SVT) Case Series at a Tertiary Care Hospital: Exploring Clinical Presentation, Diagnosis, Etiology, Thrombophilia, Treatment, and Outcome
Authors: Alsheef Mohammed Abdullah , Alomar Mukhtar , Kullab Ghaydaa Juma , AlTwaijri Abdurahman , Maymani Hassan , Zaidi Abdul Rehman Z.
Published: November 2019

Background

Splanchnic vein thrombosis (SVT) is an uncommon, but potentially life-threatening disease.

Aims

The aim was to gather more information on most common clinical presentations, risk factors, and treatment outcomes with anticoagulant therapy of SVT patients.

Methods

A retrospective study for 100 patients diagnosed with SVT confirmed by radiological imaging. Variables about demographics and history, signs and symptoms, risk factors, and treatment were collected from patients medical charts.

Results

The age group and the age of diagnosis of the patients was mainly 26-40 (40% and 46% respectively). 19% of patients had positive family history. The most affected veins were multiple veins (42%), followed by portal vein (34%), and then the superior mesenteric vein (11%). Recurrence was seen in 12% of patients. SVT was unprovoked in 48% of our patients and provoked in 52% commonly associated with significant trauma (29%), surgery (18%) in which bariatric surgery was the main culprit (11%) followed by colon/small intestine surgery (9%). 56% of the patients presented with abdominal pain, and 21% had abdominal distension, 9% had melena and 9% had splenomegaly. Thrombophilia was seen in 19% of the patients. Maintenance of anticoagulation was mostly by Warfarin (89%) and Rivaroxaban (9%). Duration of anticoagulation was extended (more than one year) in 72% of patients. 12% of patients had mesenteric ischemia and required bowel resection.

Conclusions

Anticoagulant therapy, in addition to surgery, showed excellent outcome in most patients with SVT. The most common provoking factors were trauma and bariatric surgery. Rivaroxiban demonstrated good safety and efficacy profile and can offer an alternative to traditional therapy in SVT patients.

Disclosures

No relevant conflicts of interest to declare.
Extended Half-Life of the Double-Chain Recombinant Factor VIII-Fc Fusion Protein (FRSW107) in Hemophilia a Patients
Authors: Xue Feng , Sun Jing , Chen Yun , Zhang Xinsheng , Sun Haiyan , Wang Yali , Yang Renchi
Published: November 2019

Objective:To determine pharmacokinetics (PK), safety and tolerability of a double-chain recombinant human factor VIII-Fc fusion protein (FRSW107) in previously treated patients (PTPs) in clinical trial which was registered at www.clinicaltrials.gov as NCT03747653 and scheduled to finish at end of July, 2019. Methods:At least 12 PTPs (12 to 60 years old) with FVIII:C<2% and without history of FVIII inhibitors received a single dose of rFVIII (Advate) at 25 or 65 IU/kg followed by an equal dose of FRSW107. Results: Up-on the data from 7 subjects received 25 IU/kg , the geometric mean t1/2 of FRSW107 was 26.23 hours. This represents a 1.98-fold improvement over that of rFVIII (13.34 hours) at equivalent doses. All adverse events were unrelated to study drug. None of the study subjects developed FVIII inhibitors. Conclusion:According to the preliminary data from this phase 1 clinical trial, FRSW107 shows a significantly extended half- life compared to control FVIII while no safety issue identified.

Disclosures

No relevant conflicts of interest to declare.
Clinical Outcome of Pediatric Acquired Aplastic Anemia Underwent Immunosuppressive Therapy and Transplantation: A 13-Year Experience in Two Tertiary Care Centers , Southern China
Authors: Huang Junbin , Huang Lifeng , Liu Su , Cheng Yucai , Xue Hongman , Chen Chun , Lin Shaofen
Published: November 2019

Objective To evaluate efficacy, complications and contributing factors for response of immunosuppressive therapy(IST) and allogenic hematopoietic stem cell transplantation(allo-HSCT) in children with acquired aplastic anemia; to explore optimal therapy for different clinical types of aplastic anemia.

Methods 230 children diagnosed with aplastic anemia accepted immunosuppressive therapy from January 1, 2006 to July 15, 2019 in Department of pediatrics, Sun Yat-sen memorial hospital and Department of pediatrics, The seventh affiliated hospital, Sun Yat-sen University, the response rate for 3, 6, 9, 12months for IST, complications,predictors of response and overall survival were analyzed and response rates were compared according to clinical types.

Results 230 children were followed with median time 47.3 months. Among all AA patients, there are 67 NSAA patients, 95 SAA patients and 68 VSAA patients. 214 patients had received IST initially, due to economic, medical insurance related factors or lack of well-matched donors at the time, and 16 patients had undergone allo-HSCT initially. And 21 patients , who had failed to had a CR/PR responds to IST, received allo-HSCT as a salvage regimen. The overall survival(OS) rate of all patients was 79.6±2.9% with a 46.2 months median follow-up.

For those who had received IST therapy overall CR rate was 27.1%(58/214), PR rate 37.4%(80/214), therefore overall response (CR+PR)rate was 64.5%(138/214). CR rate at 3,6,9,12 months were 7.9%, 15.9%, 16.4%, 27.1%, respectively; meanwhile PR rate 3,6,9,12 monthsatwere 28.0%, 34.1%, 34.1%, 37.4%, respectively. When we termed"transplantation and death"as an even, the transplantation-free survival(TFS) for NSAA was 90.7±4.0%, significantly superior to SAA(59.7±6.5%) and VSAA(50.5±7.5%). As for complications, serum sickness and infection are most commonly seen.

Among 37 patients who had recieved allo-HSCT, 33 patients had long term CR, while 2 died of infection, 1 of extensive aGVHD, 1 of thrombotic microangiopathy. 21 patients who underwent HSCT as a salvage regimen had 85.4±7.8% OS with a 55.6 months median follow-up, and 16 patients who recieved HSCT as initial treatment had 93.8±6.1% OS with a 69.1 months median follow-up.

Conclusions In children with AA, overall response rate to IST goes higher over time with a highest response rate 64.5% at 12 month. TFS for NSAA IST-group is significantly superior to SAA and VSAA IST-group. However, well-matched allo-HSCT still achieve nearly 90% OS as both initial or salvage treatment. Hence, we agure that IST is a pratical treatment for pediatric AA, especially NSAA, in conditions of economic status and poor medical insurance, and HSCT is still a cure for those who failed IST.

Figure

Disclosures

No relevant conflicts of interest to declare.
Automation in Hemopoietic Stem Cell Gene Therapy: Results of a Head-to-Head Comparison of a Manual Vs an Automated Procedure
Authors: Papanikolaou Eleni , Bissels Ute , Johnston Ian , Reinartz Sarah , Brams Dominik , Aivazidou Faidra , Krenz Dariusz , Bomhard Inga von , Knöbel Sebastian , Bosio Andreas
Published: November 2019

The recent successes in gene therapy for the treatment of rare blood disorders such as primary immunodeficiencies and hemoglobinopathies have highlighted the need to generate robust and scalable manufacturing processes. Here we compare large scale lentiviral transductions of hemopoietic stem cells performed on the CliniMACS Prodigy® to manual processes in terms of efficacy and viability of the end product. In our first series of experiments, we used a low, non-saturating MOI of 30 and the results showed that transduction efficiency on the CliniMACS Prodigy® was significantly increased from an average of 23.3% (manual) to 50.5% (CliniMACS Prodigy®). These results were further confirmed when we employed an MOI of 100 and showed that the average transduction efficiency was 74% from the CliniMACS Prodigy® compared to 54.1% from the manual steps. Moreover, the total viability of the cells cultured on the CliniMACS Prodigy® remained unaffected after two days of cultivation with an average recovery of 105% but with significantly less variability (SD: 15.4) compared to the manual steps (SD: 35.7). Finally there was no difference to the average VCN which was 2.2 from the manual steps and 2.4 from the CliniMACS Prodigy®. Overall, our results indicate that the CliniMACS Prodigy® generates higher transduction rates, combined with high viability compared to the manual process, but most importantly, with significantly lower variability, suggesting that it represents a closed system able to automatically perform complex processes as successfully as when manual handling steps are performed, but with higher predictability, efficiency and with minimal user interaction.

Disclosures

Papanikolaou: Miltenyi Biotec: Employment. Bissels:Miltenyi Biotec: Employment. Johnston:Miltenyi Biotec: Employment. Reinartz:Miltenyi Biotec: Employment. Brams:Miltenyi Biotec: Employment. Aivazidou:Miltenyi Biotec: Employment. Krenz:Miltenyi Biotec: Employment. Bomhard:Miltenyi Biotec: Employment. Knöbel:Miltenyi Biotec: Employment. Bosio:Miltenyi Biotec: Employment.
Endogenous Retinoid X Receptor Ligands Act As Tumor Suppressors in MLL-AF9 Mouse Leukemia
Authors: Di Martino Orsola , Ferris Margaret Y , Gayla Hadwiger , Niu Haixia , Welch John S.
Published: November 2019

Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are ligand-activated transcription factors that influence hematopoietic stem cell self-renewal and differentiation. In normal hematopoiesis, RARA and RXRA are dynamically regulated during myeloid maturation, with highest expression in mature neutrophils. In acute myeloid leukemia (AML) RARA and RXRA have parallel expression among AML subtypes, with the highest expression in M4/M5 myelomonocytic and monocytic subtypes. Using a murine reporter assay, we found that natural RXRA ligands, but not RARA ligands, were present in vivo in primary mouse myelomonocytic leukemia cells (derived with an MLL-AF9 retrovirus) and acted as tumor suppressors. RXR ligands were absent in erythroleukemia (derived with TLS-ERG) or T-cell leukemia (derived with activated Notch1), suggesting the presence of natural RXRA ligands specifically in myelomonocytic leukemia. Moreover, we found that deletion of Rxra and Rxrb was naturally selected in MLL-AF9, but not in Notch1 or TLS-ERG leukemias, and that loss of Rxra and Rxrb accelerated leukemic growth. This suggests that Rxrs act as tumor suppressors, but only when exposed to natural ligands. In MLL-AF9 derived leukemia cells, pharmacologic treatment with single-agent retinoid led to modest growth inhibition due to non-permissive activity of the RARA:RXR heterodimer, whereas concurrent activation of both RARA, with all-trans retinoic acid (a pan-RAR ligand), and RXR, by bexarotene (a pan-RXR ligand), enabled efficient co-repressor release and synergistic leukemic apoptosis. We observed that co-repressors release (SMRT/NCoR) from the RARA:RXRA heterodimer was specifically associated with RARA activation, whereas growth inhibition required RXR binding, and this occurred through apoptosis rather than maturation. Generating a series of RXRA mutant proteins we demonstrated the active contribution of RXRA to the activity of the RARA:RXRA heterodimer, specifically requiring the activation domains (AF1 and AF2) and the ability to recruit co-activator to the RXRA element. Finally, we observed a significant dose-dependent effect of combination ATRA and bexarotene treatment in in vivo in MLL-AF9 leukemic mice with a striking reduction in the tumor burden of treated mice compared to the control cohort. These data provide a strategy for clinical retinoid therapies in leukemias beyond acute promyelocytic leukemia and provide a mechanism for integrating retinoid therapy into future clinical trials.

Disclosures

No relevant conflicts of interest to declare.
The Platelet Millionaire: A Rare Cause of Thrombocytosis in an Adolescent
Authors: Walia Ritika , Sepulveda Theresa , Wretzel Sharon , Brandt Philip H
Published: November 2019

Objectives: Primary myelofibrosis is rare in pediatrics, often manifesting as persistent idiopathic thrombocytosis.Transitions from pediatric to adult medical care can be complicated by workup requiring invasive procedures.

J.M., an 18-year-old healthy male, presented for excessive gingival bleeding after wisdom tooth extraction. Workup revealed persistent thrombocytosis to 1,165K, prompting a referral to hematology-oncology. A peripheral smear was notable for many platelets but normal RBC morphology. He had splenomegaly on abdominal ultrasound and a decreased von-Willebrand's activity to antigen ratio, suggesting acquired vWD. A bone marrow biopsy was advised; however, J.M. became lost to follow up for over 9 months owing to self-reported anxiety about the procedure. He remained asymptomatic in this interim until he re-presented to clinic for easy bruising, with no other evidence of bleeding at the time. The biopsy was pursued, revealing hypercellular marrow for age with left shifted granulocytic and erythroid maturation, abnormal megakaryocytes, and 3% blasts. This was consistent with primary early myelofibrosis (PMF), positive for MF-1, CALR, and TP53 mutations and negative for JAK2 and BCR-ABL. He was transitioned to adult hematology, maintained on baby aspirin, and referred for potential allogeneic hematopoietic stem cell transplant (HSCT).

PMF is characterized by marrow fibrosis due to secretion of fibroblast growth factor by clonally proliferative megakaryocytes. It is a disease of adulthood, with 67 years being the median age at diagnosis. Only 100 cases have been reported in children, most of which are secondary to AML, ALL or other malignancies.1 Most patients present with complications of extramedullary hematopoiesis or bleeding.2 Diagnosis is suggested by a leukoerythroblastic picture on peripheral smear and confirmed with a bone marrow biopsy "dry tap" revealing marrow fibrosis.3 Prognosis in pediatric PMF is difficult to predict but outcomes tend to be worse;4 TP53 mutation is rare and based on limited adult studies may portend a poorer prognosis.5 Our young patient with this rare mutation was therefore referred for HSCT evaluation. Further complicating this case was J.M.'s anxiety, which delayed definitive diagnosis by biopsy. He only agreed to it when, at the med-peds clinic, the concept of local pain management was discussed. Anticipation of upcoming procedures by primary care physicians and close follow-up is especially important for patients transitioning from pediatric to adult providers.

Disclosures

No relevant conflicts of interest to declare.
A Comparison of the Effect of Granulocyte-Colony Stimulating Factor (G-CSF) in Chemotherapy Versus Plerixafor for Hematopoietic Stem Sell Transplantation (HSCT) and Mobilization
Authors: Piazera Flavia zattar , Nonino Alexandre , Vasconcelos Rafael De Sá , Cunha Andre Luiz Soares , Pinto Jorge Vaz , Profiro Mariana
Published: November 2019

INTRODUCTION: Peripheral Hematopoietic Stem Cells have been widely used as a source for Autologous Hematopoietic Stem Cell Transplantation (HSCT). The use of G-CSF associated with chemotherapy increases the number of circulating Hematopoietic Progenitor Cells; however, there is no harmony about the best medical strategy for the use of G-CSF associated with the mobilization conduct. The use of plerixafor for poorly mobilized patients has provided a safe and effective option for optimizing apheresis procedures despite the high cost. Thus, the evaluation of efficacy becomes essential for the incorporation of plerixafor into the HSCT routine. OBJECTIVE: To evaluate the mobilization of autologous HSCT in chemotherapy associated with G-CSF and cyclophosphamide (QT) versus plerixafor. METHODS: Retrospective evaluation of 66 patients mobilized for autologous HSCT with G-CSF associated with chemotherapy versus plerixafor (plerixafor was used in the first mobilization), also to evaluate the number of apheresis procedures, CD34-positive cells, cell viability and for the bone marrow engraftment date. Statistical analyses were performed with GraphPad Prism 5.0 (GraphPad Software, Inc., San Diego, CA), using the Mann-Whitney test for nonparametric data (p <0.05). RESULTS: A mobilization protocol was performed in 83 patients (60% male), with a median age of 55 years (17 to 68 years). Multiple myeloma (55.7%), Hodgkin's lymphoma (14.7%), Non-Hodgkin's lymphoma (16.39%), primary amyloidosis (4.9%) were the most common hematologic malignancies. There was no statistical difference between G-CSF and QT group versus plerixafor groups regarding age, sex, type of disease and previous QT. The plerixafor group had better CD34 positive cell counts compared to G-CSF and QT (median 6.2 versus 3.8 x106, p<0.004), shorter sessions of apheresis procedure (median 2 versus 4, p < 0.0002) and a better cell viability rate (98 versus 95%, p <0.0034). The bone marrow engraftment rate was 10 days for plerixafor group versus 15.05 days for G-CSF and QT group, p <0.0055 (Figure 1).CONCLUSION: Our results showed the mobilization group using plerixafor had superior data and statistical significance regarding the number of apheresis procedures, cell viability, number of CD34 positive stem cells and earlier bone marrow engraftment rates when compared to the G-CSF + QT. These findings suggest and encourage the use of plerixafor in the first mobilization, as well as it should be incorporated into the standard routine. In addition, the number of apheresis procedures will be reduced, cell viability and CD34-positive cells rate will be increased. As a result, there will be a better medullary recovery and the reducing of both hospital costs and infectious complication rates.

Disclosures

No relevant conflicts of interest to declare.
Clinical Characteristic and Survival Outcome of Peripheral T Cell Lymphoma in a Chinese Population
Authors: Li Wenyu , Huang Ling , Jiang Xinmiao , Wei Xiaojuan , Guo Hanguo , Sichu Liu , Feili Chen , Liang Zhanli
Published: November 2019

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group comprising about 10-15% of non-Hodgkin lymphomas in Western populations. Only a minority (~30%) of patients with the most common PTCL subtypes achieve a durable remission and long-term survival. Data on the clinical features of PTCL in a Chinese population are limited.

Methods: We retrospectively reviewed 342 patients with pathologically diagnosed T cell lymphoma at Guangdong Provincial People's Hospital from June 2007 through March 2019. We evaluated the incidence of PTCL subtypes, clinical characteristics and survival status.

Results: Of the 342 patients, 17.3% (n=59) had PTCL-not otherwise specified(NOS), 9.4% (n=32) had angioimmunoblastic T-cell lymphoma(AITL), 19.6% (n=67) had anaplastic large cell lymphoma(ALCL) (anaplastic lymphoma kinase positive ALCL:12.0%, n=41; anaplastic lymphoma kinase negative ALCL: 9.6%, n=26), 36.2%(N=124) had NK/T cell lymphoma, 12.9% (n=44)had lymphoblastic lymphoma(LBL), and 4.6%(n=16) had other subtypes. For next data analysis, NK/T cell lymphoma and LBL were excluded. Finally, a total of 164 patients with integrally follow-up information were analyzed. The median age was 49.5 years (range 15-87) old and the median follow-up time was 15.8 months (range 0.5-124.3). Most patients were males (62.0%) with advanced stage disease (III/IV, 74.5%), and 51.0% of patients presented with B symptoms and 83.0% with no bulky disease. For the total population, the median progression-free survival(PFS) and overall survival(OS) was 6.5 months and 13.5 months, respectively. ALCL patients had better PFS and OS than PTCL-NOS and AITL (PFS: 51.2 vs. 5.8 vs.4.7 months, P = 0. 000; OS: not reached vs. 13.4 vs. 8.8 months, P = 0.000). There were no difference of PFS and OS between PTCL-NOS and AITL(P = 0. 550 and P = 0. 333, respectively).

Conclusions: ALCL has better outcome than other PTCL subtypes. However, no efficacy therapy has emerged for patients with relapsed/refractory PTCL and outcomes in this setting are still poor. Novel potential targets for PTCL, with particular focus on identifying markers of response and resistance need further investigation.

Disclosures

Li: Guangdong Province Hospital: Employment.
The Role of M2 Macrophage in Primary Immune Thrombocytopenia
Authors: Shao Xia , Wu Boting , Chen Pu , Zhan Yanxia , Li Feng , Hua Fanli , Sun Lihua , Cheng Yunfeng
Published: November 2019

Background: Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disorder, characterized by immune-mediated platelet destruction and impaired megakaryocyte maturation. Although impaired T cells have been implicated to participate in the pathogenesis of ITP, another immune cell signified as M2 macrophages has not been investigated properly in ITP patients. This study aimed to investigate the role of M2 macrophage subsets in primary immune thrombocytopenia (ITP).

Methods: Peripheral blood mononuclear cells (PBMC) from newly diagnosed ITP patients and healthy controls (HC) were isolated. M2-like macrophages (CD68+CD163+) and M2 macrophages (CX3CR1+CD163+) were measured by flow cytometry. The correlation between CD68+CD163+ cells and CX3CR1+CD163+ cells was also analyzed. The CX3CR1+cells were sorted by magnetic bead, CD68+CD163+ in PBMC of ITP patients and healthy controls were then isolated, and the proportion of m2-like macrophages before and after the sorting was analyzed. The PPAR gamma and arg-1 levels of mRNAs and proteins of CX3CR1+ M2 macrophages were examined by Real-time PCR and Western Blot, respectively.

Results: CX3CR1+CD163+M2 macrophages were positively correlated with CD68+ CD163+ M2-like macrophages in ITP patients (r = 0.54, p < 0.01). After magnetic bead separation, the proportion of CD68+CD163+ cells in CX3CR1+ cells was significantly increased (p = 0.02). Compared with HC, both the mRNA and protein levels of arg-1 of CX3CR1+ M2 macrophages were significantly increased in patients with ITP. The expression level of PPAR gamma protein was significantly increased in ITP than that of HC. However no statistical difference was detected at mRNA expression level, although it was numerically higher in ITP patients than in HC ( p = 0.19).

Conclusion: The peripheral CX3CR1+ M2 macrophage exercises similar phenotypes and functions of M2 macrophage. The remarkably increased expression of arg-1 at both transcription and protein levels and PPAR gamma at protein level of CX3CR1+M2 macrophages in ITP patients suggests potential immunomodulatory functions of these macrophage subsets during ITP pathogenesis. However, no significant change at mRNA level of PPAR gamma indicating that the increased PPAR gamma protein level might be caused by other mechanisms, such as after transcription abnormalities, which warrants further investigation.

Disclosures

No relevant conflicts of interest to declare.
Tumor Microenvironment Differs between Germinal Centre B-Cell and Non-Germinal Centre B-Cell like Diffuse Large B-Cell Lymphomas and Has Subtype-Specific Prognostic Impact on Survival
Authors: Autio Matias , Leivonen Suvi-Katri , Karjalainen-Lindsberg Marja-Liisa , Pellinen Teijo , Leppa Sirpa
Published: November 2019

Introduction

Based on the cell of origin, diffuse large B-cell lymphoma (DLBCL) is divided into germinal center B-cell (GCB) and activated B-cell (ABC) like subtypes, which differ in their gene expression profiles and clinical presentation with the ABC DLBCLs showing a worse outcome in response to R-CHOP immunochemotherapy. However, composition of the tumor microenvironment (TME) of these molecular subtypes has not been characterized.

Methods

We used Hans algorithm to determine the molecular subtypes (GCB vs non-GCB) and multiplexed immunohistochemistry (mIHC) to characterize tumor infiltrating T-cell phenotypes, including cytotoxic T-cells (CTLs; CD8, Granzyme B, OX40, Ki67), T regulatory cells (Tregs; CD3, CD4, FoxP3), Th1 effector cells (CD3, CD4, TBET) and T-cell immune checkpoint (CD3, CD4, CD8, PD1, TIM3, LAG3) in 165 primary DLBCLs. The findings were correlated with the expression of human leukocyte antigens (HLA) I and II (beta-2 microglobulin (B2M), HLA-ABC and HLA-DR), and outcome of the patients treated with R-CHOP-like immunochemotherapy.

Results

In the whole cohort, 82 (50%) cases were classified as GCB and 83 (50%) as non-GCB DLBCLs. In the GCB subtype, cytotoxic T-cells were more often PD1+, and T-cells FoxP3+than in the non-GCB subtype (Figure 1A-B). Furthermore, GCB DLBCLs tended to be more commonly HLA-DR+(p=0.102). In the non-GCB DLBCLs in turn, HLA I positivity was more frequent (B2M, P=0.007; HLA-ABC, p=0.108), cytotoxic T-cells more often granzyme B+(Figure 1C), T-cells TBET+(p=0.018) and LAG3+TIM3+(p=0.033). A high proportion of granzyme B+cells (p=0.002), PD1+cells (p=0.02) and TIM3+CD4+T-cells (p=0.006) from all cells translated to adverse overall survival (OS) in the patients with non-GCB DLBCL, all independent of the IPI. In contrast, a high proportion of TIM3+cells (p=0.015), and FOXP3+TBET+T-cells (p=0.005) from all cells were associated with poor OS in the patients with GCB DLBCL, also independent of the IPI.

Conclusions

TME differs significantly between GCB and non-GCB DLBCLs and has subtype-specific prognostic impact on survival.

Figure 1

Disclosures

Leppa: Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees.
Evaluation of Newborns Screening Laboratory Tests for Sickle Cell Disease and Other Haemoglobinopathies in Tanzania
Authors: Christopher Heavenlight Hebron , Burns Adam , Josephat Emmanuel , Saul Sephord , Mgaya Josephine , Makani Julie , Nkya Siana Watoky , Schuh Anna
Published: November 2019

Affiliation

1Muhimbili University of Health and Allied Sciences, Dar es salaam, Tanzania.

2Department of Oncology, University of Oxford, Oxford UK.

3Dar es salaam University College of Education, Dar es salaam, Tanzania.

ABSTRACT.

Background; SCD constitutes to be a major public health problem in Tanzania. NBS for SCD identify infants with SCD at birth and subsequently enroll them into SCD comprehensive care program and it has been reported to reduce early childhood mortality and morbidity due to SCD and increase life expectancy. There are different methods for Newborn screening for SCD such as HPLC, IEF, DNA analysis, sickle scan and hemotype SC that helps in early detection of SCD and other haemoglobinopathies but we are lacking sufficient information on alternative screening methods that can be used for NBS in Tanzania so this study is aiming at investigating the effectiveness and feasibility of NBS laboratory tests.

Aim of the study; To evaluate newborn screening Laboratory assays for sickle cell disease and other haemoglobinopathies in Tanzania.

Methodology; This will be a retrospective and prospective study which will be conducted in Dar es Salaam and Mwanza.1000 newborns and 100 children with SCD under five years old will be enrolled. DBS samples will be collected and analyzed by DNA Analysis, sickle scan, Hemotype SC, HPLC, and IEF. SPSS version 16.0 will be used to analyze data. Statistically, significant tests will be declared at a level of p-value < 0.05.

Progress: Initially we have conducted a pilot of 12 individuals who were screened for SCD and turned out to be carriers ( Hb AS). However these individuals continuously reported to experience painful events. Initial analysis has include Hb subtyping and quantification by HPLC,Sickle scan and HemotypeSC to ascertain indicator for thalassaemia syndrome. Definitive analysis involved sequencing of thalassaemia and SCD associated regions by using Oxford Nanopore Technology and NGS

Expected outcomes; The findings of this study will inform Newborn screening stakeholders on the best point of care screening test and definitive test, in terms of turnaround time and cost. Such findings will assist in planning and scaling up of newborn screening services across the country.

Corresponding Author; HChristopher, Email; hchristopher@blood.ac.tz, Tel; +255762175732.

Disclosures

Schuh: AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Verastem: Speakers Bureau.
Preliminary Results of a Prospective Observational Study to Assess the Prevalence of Gaucher Disease in an Adult Population Affected By MGUS
Authors: Giuffrida Gaetano , Conticello Concetta , Nicolosi Daniela , Calafiore Valeria , Romano Alessandra , Consoli Ugo , Musolino Caterina , Innao Vanessa , Fiorenza Flavia , Maugeri Cinzia , Longo Giuseppe , Cingari Maria Rocca , Di Raimondo Francesco
Published: November 2019

INTRODUCTION: Gaucher disease (GD) is a rare, autosomal recessive genetic disorder. It is due to a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in tissue macrophage with damage to hematological, visceral, and skeletal organ systems.

Although GD has a continuous spectrum of severity, it is traditionally classified into three forms: type 1 (chronic; lacking early onset neuronopathy), type 2 (acute; with early onset neuronopathy),and type 3 (chronic; with early onsetneuronopathy).

Type 1GD accounts for more than 90% all GD patients. Its prevalence world-wide is 1 in 50,000-100,000 but it is as high as ~1 in 850 in individuals of Ashkenazi heritage.

Type 1 GD is frequently associated to monoclonal gammopathies; despite the emergence of theories advanced to explain these observations, the cause remains unknown.

OBJECTIVE: Aim of the ongoing observational study is to determine the prevalence of unrecognized type I GD in a selected Italian population with MGUS.

MATERIALS AND METHODS: From January 2018, dried blood spots (DBS) sample from patients with laboratory evidence of MGUS coming from five hematology units of Sicily and Calabria were collected and tested for the acid β-glucosidase enzyme activity.

The study was approved by the local institutional review board. All patients provided informed consent for the prospective collection of their data.

In case of DBS positive result, a confirmatory test was carried over and, if GD was confirmed, the patient was referred to one of the Regional Reference Centers for Metabolic Disease, as for current clinical practice in Italy.

RESULTS: To date, 308 patients with MGUS were enrolled; acid β-glucosidase enzyme activity was low in 22 patients (7%). Sequence analysis of GBA gene was performed in these selected patients, but we have found only 4 patients with heterozygous mutation in the GBA1 gene, 1 homozygous(c.1226A>G -N370S) and 1 compound heterozygous (c.1226A>G -N370S and c.1448T>C -L444P); the last 2 patients had signs of GD (hepato-splenomegaly and mild thrombocytopenia).

CONCLUSIONS: Type 1 GD remains a rare lysosomal storage disorder but preliminary results of our observational study show that it should be considered in the diagnostic framework of patients with MGUS, particularly when other GD symptoms are present.

Disclosures

Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Di Raimondo:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding.