bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toxicity Profile of Brentuximab Vedotin in Combination with Chemotherapy for Newly Diagnosed Patients with ALK+ ALCL: A Children's Oncology Group Study ANHL12P1
Authors: Lowe Eric J , Reilly Anne , Bollard Catherine M. , Barkauskas Donald A , Buxton Allen B , Hall David , Saguilig Lauren , Sandlund John T. 
Published: October 2019

Abstract
Background: Despite numerous treatment strategies, failure rates remain 25-30% for pediatric ALCL. Brentuximab vedotin is an antibody-drug conjugate containing an anti-CD30 monoclonal antibody linked to a tubulin inhibitor (monomethylauristatin E) which has significant activity as single agent in relapsed ALCL. The primary aim of ANHL12P1 (NCT01979536) is to determine the toxicity and efficacy of the addition of two novel agents (brentuximab vedotin or crizotinib) to standard chemotherapy (best arm of ALCL99) in children with newly diagnosed, non-localized, ALK+/CD30+ ALCL.
Methods: Patients on Arm BV received standard chemotherapy plus brentuximab vedotin. All patients initially received a 5 day prophase followed by 6 cycles of chemotherapy (dexamethasone, ifosfamide, cyclophosphamide, doxorubicin, etoposide, cytarabine, methotrexate) at 21 day intervals. Brentuximab vedotin was given on day 1 of each of the 6 cycles excluding prophase.
Results: From November 2013 to January 2017, 68 children with ALCL were enrolled on Arm BV. One patient was taken off protocol at the treating physician's discretion during prophase before receiving brentuximab vedotin leaving 67 eligible patients for toxicity evaluation. 66 of 67 patients completed all 6 cycles of chemotherapy resulting in 399 cycles evaluable. There were no toxic deaths, no cases of progressive multifocal leukoencephalopathy syndrome, and no cases of grade 3 or 4 neuropathy. Grade 3 or 4 toxicities which occurred in more than 5% of cycles included hematological toxicities, mucositis, and febrile neutropenia (see table). The mean/median interval between each cycle was: 22.7/22 days (cycle 1 to 2), 22.7/21 (2 to 3), 22.8/21 (3 to 4), 23/21 (4 to 5), and 22.8/21 (5 to 6). Interval between cycles was >28 days in only 3.6% of all cycles.
Conclusions: Arm BV of ANHL12P1 demonstrated that the addition of brentunixmab vedotin to standard chemotherapy does not cause significantly added toxicity. Brentuximab vedotin did not change the desired interval between cycles with the interval remaining similar from first to last cycle. It remains to be seen if the addition of brenutuximab vedotin improves overall or event-free survival compared to historical controls.
Table. Table.

Disclosures
Bollard: Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Torque: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neximmune: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Enhanced Zebrafish Xenograft Platform Improves Hematopoietic Stem Cell Engraftment and Leukemogenesis
Authors: Rajan Vinothkumar , Melong Nicole , King Benjamin , Campbell Clinton , Berman Jason 
Published: October 2019

Abstract
The hallmark of hematopoietic stem cells (HSCs) is their ability to self-renew and differentiate into multiple blood cell types. Transplantation of human HSCs into immunocompromised mice is the gold standard for evaluating functionality and has been adapted to study leukemia initiating cells (LICs). However, specific cellular subsets do not survive post-xenotransplantation, due to a dependence on factors that may be missing in a non-primate microenvironment.
We have been optimizing the zebrafish as a xenograft platform. We created novel zebrafish that express human stem cell factor (SCF/KITLG), granulocyte-macrophage colony stimulating factor (GM-CSF/CSF2) and stromal cell-derived factor 1 alpha (SDF1α/CXCL12) - factors essential for survival and expansion of HSCs.
CMK (Down Syndrome- acute myeloid leukemia (AML)) and Jurkat (T-cell acute lymphoblastic leukemia) cell lines injected into the yolk sac of these multi-cytokine zebrafish larvae exhibit increased proliferation and migration to hematopoietic niches, namely the caudal hematopoietic tissue (=fetal liver) at 7 days post-injection (dpi) and the kidney marrow at 11 dpi, compared to injections in control casper larvae.
Patient-derived AML bone marrow samples (n=3) injected into the circulation of these multi-cytokine fish similarly displayed enhanced proliferation and migration with associated larval mortality from increased disease burden. Historically, human HSCs do not survive beyond 24 hpi in zebrafish xenografts (Pruvot et al. 2011). Remarkably, human umbilical cord blood-derived HSCs injected into the circulation of zebrafish larvae survived past three days-post-injection in multi-cytokine fish but not in casper controls.
Transgenic zebrafish expressing human cytokines provide an enhanced model for studying human leukemia and HSC biology in a system that more closely recapitulates the human microenvironment. By employing these humanized zebrafish and exploiting the inherent capacity of this small organism for rapid chemical screening, we have created a new preclinical paradigm for testing anti-leukemic therapies and HSC enhancing agents.

Disclosures
No relevant conflicts of interest to declare.
A Novel Enzyme Capture - ELISA for the Direct Determination of Factor XIII Activity
Authors: Durda Michael Andrew , Waller Amanda P. , Davis Kyle A , Kerlin Bryce A. 
Published: October 2019

Abstract
Background: Activated factor XIII (fXIII) mechanically stabilizes fibrin clots by catalyzing the formation of intramolecular crosslinks and retards plasmin-mediated fibrinolysis by incorporating intermolecular α2-antiplasmin (α2AP):fibrin crosslinks. High quality quantitative fXIII activity assays are required for the accurate and timely diagnosis of fXIII deficiency. Currently available high-throughput assays indirectly measure the transglutaminase activity of fXIII via detection of ammonia that is elaborated upon formation of ε-N-(γ-glutamyl)-lysyl crosslinking bonds. Unfortunately, these assays can be confounded by fXIII-independent ammonia producing and consuming reactions present in plasma. We thus set out to develop an assay which directly quantifies the transglutaminase activity. We hypothesized that fXIII could be captured in a microtiter plate with anti-fibrinogen antibodies and, following an activation step, its activity determined in a kinetic fashion via the rate of α2AP incorporation (measured in a subsequent ELISA step).
Methods: Co-immunoprecipitation and western blotting techniques were utilized to confirm fXIII/fibrinogen interactions and to determine the presence of basal interactions between fibrinogen and α2AP. Simultaneously, this approach enabled the determination of suitable antibody pairs for use in the enzyme capture-ELISA (EC-ELISA). In microtiter plates, fibrinogen-captured fXIII was activated with excess thrombin, physiologic calcium, and GPRP peptide (to block fibrin polymerization) in the presence of excess α2AP. FXIII activity was stopped with a potent fXIII-inhibitor (iodoacetamide) at predetermined time points. Subsequently, α2AP incorporation was determined with a primary anti-α2AP antibody and secondary HRP-conjugated antibody.
Results: Co-immunoprecipitation and western blotting experiments confirmed that both fXIII and α2AP circulate in complex with fibrinogen, as previously reported by others. However, α2AP incorporation significantly increased following incubation with activated factor XIII. Using the EC-ELISA method, we were able to demonstrate that α2AP is incorporated in a manner consistent with first order kinetics.
Discussion: These experiments demonstrate the feasibility of an EC-ELISA assay to directly measure fXIII activity. Further work will be required to determine the sensitivity of this assay in test plasmas with varying known quantities of fXIII and how its performance characteristics compare to currently available indirect activity assays. With further optimization, the EC-ELISA method may lead to an improved, high throughput diagnostic assay for clinical use.

Disclosures
No relevant conflicts of interest to declare.
Aspirin Use in Venous Thromboembolism Prophylaxis Following Hip or Knee Arthroplasty: A Network Meta-Analysis of Randomized Controlled Trials
Authors: Haykal Tarek , Kheiri Babikir , Barbarawi Mahmoud , Zayed Yazan , Shah Miran Muhammad , Chahine Adam , Abdalla Ahmed , Katato Khalil , Bachuwa Ghassan , Hadid Tarik , Kafri Zyad 
Published: October 2019

Abstract
Background: Patients undergoing hip or knee arthroplasty are at high risk of developing venous thromboembolism (VTE), such as deep-vein thrombosis and/or pulmonary embolism. Various thromboprophylactic strategies have been studied for the prevention of VTE in this population with different outcomes. Therefore, we aimed to evaluate the efficacy and safety of aspirin prophylaxis when compared with a placebo or anticoagulants in reducing such risk.
Methods: A comprehensive electronic database search in PubMed, Embase, the Cochrane Collaboration Central Register of Controlled Trials, and conference proceedings, was conducted for all randomized clinical trials (RCTs) comparing the clinical outcomes of aspirin versus anticoagulants or placebo for the prevention of VTE after hip or knee arthroplasty. The primary outcome was VTE. Secondary outcomes were mortality, major bleeding, and any bleeding. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model at the longest follow-up.
Results: We included 13 RCTs with 20115 total patients, mean age of 67.15±9.54 and a male percentage of 24.39%. Aspirin was associated with a non-significantly reduced VTE risk compared with other thromboprophylactic strategies (RR 0.87; 95% CI: 0.61-1.23; P=0.43). Compared with a placebo, aspirin was associated with significant reduction of VTE (RR 0.65; 95% CI: 0.47-0.89; P=0.008). There were no significant differences in the clinical outcomes between all groups with regard to mortality (RR 0.98; 95% CI: 0.86-1.11; P=0.72), major bleeding (RR 0.96; 95% CI: 0.50-1.84; P=0.91), or any bleeding (RR: 1.09; 95% CI: 0.82-1.44; P=0.56).
Conclusion: Among patients who underwent hip or knee arthroplasty, aspirin prophylaxis was associated with similar efficacy and safety outcomes when compared with anticoagulants. Compared with a placebo, aspirin prophylaxis was associated with significantly reduced VTE risk and a similar safety profile.
Table Table.

Disclosures
No relevant conflicts of interest to declare.
Imatinib Mesylate Is Safe and Effective in Maintaining Cytogenetic and Molecular Response Achieved with 1 Year Nilotinib First Line in Newly Diagnosed Chronic Myeloid Leukemia: Preliminary Results of a Prospective Clinical Trial
Authors: Moukalled Nour , Massoud Radwan , Mahfouz Rami , Elcheikh Jean , Bazarbachi Ali 
Published: October 2019

Abstract
Background: Achieving complete cytogenetic response (CCyR) at 12 months for patients with chronic phase chronic myeloid leukemia (CML) treated with imatinib as first line, is associated with significantly improved progression-free survival. Nilotinib has shown a faster and higher rate of CCyR and molecular response as compared to imatinib. However, nilotinib use is associated with diet restriction, higher financial costs, and its long-term use is incriminated in cardiovascular and metabolic complications.
Methods: In this prospective single center trial, we evaluated the ability of imatinib to maintain a CCyR achieved after 12 months of first-line treatment with nilotinib. Inclusion criteria were adult patients with previously untreated Philadelphia -positive CML in chronic phase, with a WHO performance status ≤ 2. Patients received 1-year treatment with nilotinib (300mg twice daily) then were shifted to imatinib 400mg daily.
Results: Eleven patients (5 females) were so far enrolled in the study, with a median age at diagnosis of 50 years (range 31-83). Patients were started on Nilotinib at a median of 29 days (range 2-32) from diagnosis. One patient had to discontinue nilotinib after 6 months and start dasatinib due to recurrent pancreatitis that resolved upon interruption of nilotinib. Eight patients completed one year of nilotinib, and were switched to Imatinib. The remaining 2 patients are currently on nilotinib as per protocol (less than 12 months since inclusion). Three patients on imatinib had to be switched back to nilotinib, because of imatinib intolerance (n=2; elevated liver transaminases and myositis) or because of loss of MMR (n=1). Therefore, at last follow up (median 64 months), 5 patients are on imatinib, 5 on nilotinib and 1 on dasatinib. All patients (100%) achieved complete hematological response (CHR) and CCyR at 3 and 18 months respectively, and maintained them thereafter. At 12 months, 6 out of 8 eligible patients achieved complete molecular response (CMR; n=3) or major molecular response (MMR; n=3). At 36 months, all eligible patients (n=7) were either in CMR (n=2) or in MMR (n=5). All patients who reached 4 years (n=6), 5 years (n=5) or 6 years (n=3) of follow up remained in either MMR or CMR. No patient developed long-term serious adverse event including cardiovascular or metabolic complications.
Conclusion: These findings suggest that imatinib can maintain MMR achieved on short-term nilotinib therapy. This strategy is a potentially safe and effective long-term treatment approach, minimizing costs and cardiovascular and metabolic complications. This however, needs confirmation with a larger number of patients.
Table. Table.

Disclosures
No relevant conflicts of interest to declare.
Efficacy of Newer Combinations and Fibril-Targeting for AL Amyloidosis: A Systematic Review of Transplant and Innovative Non-Transplant Therapies
Authors: Pandya Shaunak , Nunes Cavalcante Parr Nadia Carenina , Sardar Muhammad , Chiu Christine , Serafini Maria , Anwer Faiz 
Published: October 2019

Abstract
Background
Light-chain (AL) amyloidosis is a multi-organ amyloid deposition disease caused by misfolded protein aggregation. Current treatments have improved overall (OS) and progression-free survival (PFS) but challenges remain in improving therapy with newer agents and targeting amyloid protein deposits with novel immunotherapy. We review the literature regarding efficacy of existing chemotherapy in AL amyloidosis and summarize non-FDA approved novel drugs and monoclonal antibodies (mAbs) in early phase clinical development.
Methods
We searched databases including Cochrane library, PubMed and ClinicalTrials.gov for all prospective and retrospective studies (As of 4/15/2018) with measured hematologic response rate (HR) in patients with AL amyloidosis since 2000. Inclusion criteria included all prospective and retrospective studies with melphalan-based treatments, bortezomib combinations including bortezomib, cyclophosphamide and dexamethasone (VCD), bortezomib and dexamethasone (VD) and immunotherapies. We included all studies with at least 5 or more patients and reported HR.
Results
From 918 studies, we selected 57 studies (2640 patients) evaluating HR with melphalan-based stem cell transplant (SCT) treatments and non-stem cell transplant treatments including melphalan and bortezomib combinations. Other agents included daratumumab (anti-CD38 mAb), and ixazomib (proteasome inhibitor). Mean aggregate HR reported from studies with melphalan-based SCT treatment (17 studies, n=587) was 67%. Mean aggregate HR from all non-transplant treatments (40 studies, n=2053) was 64%. Of the non-transplant treatments, HR for melphalan-based treatments (21 studies, n=1148) was 59% and varied as follows: melphalan + lenalidomide + dexamethasone (57%) and melphalan + dexamethasone (52%). Mean aggregated HR for non-transplant bortezomib-based treatment (17 studies, n=859) was 72% consisting of VD (69%) and VCD (76%). HR with Ixazomib (1 study) and Daratumumab (1 study) was 52% and 76% respectively. Other novel drugs currently being studied include 11-1F4 (chimeric fibril-reactive mAb), GSK2398852 and GSK2315698 (anti-serum amyloid protein mAbs), and NEOD001 (anti-circulating soluble and deposited aggregated amyloid mAb).
Conclusion
For AL amyloidosis, melphalan-based SCT has shown effectiveness while VD and VCD demonstrate effectiveness in non-transplant patients. Further studies are warranted to evaluate novel proteasome inhibitors (Ixazomib) and emerging immunotherapy with daratumumab. Current trials including amyloid protein and fibril targeting (circulating and tissue-fixed) with novel immunotherapy are innovative and may have higher clinical efficacy, but need further testing.

Disclosures
No relevant conflicts of interest to declare.
Optimal Hemoglobin Level for Pediatric Sickle Cell Patients Who Undergo Adenotonsillectomy
Authors: Hu Zhongbo , Chang Simone Megan , Younis Ramzi , Alvarez Ofelia A. 
Published: October 2019

Abstract
Background:The prevalence of obstructive sleep apnea syndrome (OSA) in children with sickle cell disease (SCD) is higher than in the general pediatric population. Adenotonsillectomy involves significantly increased risks in patients with SCD because of the need for general anesthesia,which could induce a vaso-occlusive event. Various preoperative regimens have been suggested to reduce peri-operative risks for SCD patients.
Objective: We retrospectively reviewed the perioperative management for pediatric SCD patients undergoing adenotonsillectomy. We sought to identify the optimal preoperative hemoglobin (Hb) level for patients to have lowest risk of post-operative complications.
Methods: Children between 1 and 18 years old with SCD including HbSS, HbSC, HbS beta thalassemia (Sβ0 and Sβ+) who underwent adenotonsillectomy from 2007 to 2017 were identified at Holtz Children's Hospital. Patients without these diseases who underwent the procedures were collected as a control. The study was approved by the University of Miami Institutional Review Board (IRB). De-identified data were exported to GraphPad Prism version 5.02 to perform the statistical analyses. Means were analyzed by student t test, rates by Chi-squared test. p < 0.05 is considered statistically significant.
Results: Thirty-four patients with SCD (mean 7.1 yrs) and 145 controls (mean 7.0 yrs) were identified with adenotonsillectomy (see Table 1). SCD patients had significant longer hospital stay (2.6 versus 0.9 days, p< 0.001), and higher postoperative complication rates than the control group (20.6% vs 4.0%, p= 0.02). Most of the sickle cell patients' complications were hypoxemia (5 out of 7), except one supraventricular tachycardia and one headache. Four out of 7 patients with pretransfusion (pretrx) Hb level above 10 g/dL received manual exchange transfusion to keep Hb over 10 g/dL. None had complication or PICU stay. When patients' pretrx Hb levels was 9-10 g/dL, 5/8 received transfusion without significant complications, with the goal of not increasing post transfusion Hb over 11.5 g/dL. Most patients with pretrx Hb level 7-9 g/dL received simple blood transfusion. For patients with preoperative Hb level 9-11.5 g/dL, the PICU transfer rate was significantly lower than ones with Hb <9 or >= 11.5 g/dL (11.5% vs 60%, p=0.04; see Figure 1). Complication rates were also lower in the Hb 9-11.5 g/dL group, but without statistical difference (19.2% vs 40%, p=0.3). Data is limited by small sample size in the SCD group.
Conclusion(s): We concluded that for pediatric SCD patients planning for adenotonsillectomy, it is better to keep the posttransfusion Hb level at least above 9 mg/dL but less than 11.5 g/dL before procedure to avoid significant post operational complications. If pretransfusion Hb level is above 9 mg/dL, exchange transfusion by partial phlebotomy or simple transfusion (not to exceed 11.5 g/dL) may be considered.

Disclosures
No relevant conflicts of interest to declare.
Stat3 Regulates Alloreactive T Cell Susceptibility Towards PD-L1-Mediated Tolerance Signaling, Gvhd and GVL Activity
Authors: Yang Shijie , Wang Xiaoqi , Zhang Yuankun , Zeng Deye , Song Qingxiao , Martin Paul J , Zhang Xi , Zeng Defu 
Published: October 2019

Abstract
Prevention of graft versus host disease (GVHD) while preserving graft-versus-leukemia/lymphoma (GVL) activity of alloreactive donor T cells remains an elusive and long-sought goal. We and others reported that Stat3 deficiency in donor T cells results in expansion of Foxp3+ Treg cells and reduction of pathogenic Th17 cells, leading to prevention of chronic GVHD. We have now tested whether Stat3 deficiency in donor T cells can prevent acute GVHD while preserving GVL activity.
We transplanted wild-type (WT) or Stat3-/- T cells from C57BL/6 (H-2b) donors into irradiated WT BALB/c recipients bearing B cell lymphoma line BCL1 or aggressive acute lymphocytic leukemia (ALL) cells. WT donor T cells caused acute GVHD, as expected. Stat3-/- donor T cells did not cause acute GVHD but still had strong GVL activity. This separation of GVL activity from GVHD was associated with augmented expansion and impaired tolerance by Stat3-/- T cells in lymphoid tissues such as the spleen. In contrast, tolerance by Stat3-/- T cells was enhanced in GVHD target tissues by different mechanisms. The yield of Stat3-/- T cells in gut tissues was lower than the yield of WT T cells due to the markedly higher apoptosis of Stat3-/- T cells compared to WT T cells. The yield of Stat3-/- T cells in the lung and liver was not lower than the yield of WT T cells, but expression of anergy/exhaustion markers such as PD-1 and KLRG1 was markedly higher in Stat3-/- T cells than in WT T cells.
We recently reported that GVHD tissue expression of PD-L1 can tolerize donor CD8+ T cells in the absence of donor CD4+ T cells, but not when CD4+ and CD8+ T cells were given together. In contrast, PD-L1 expression in recipient GVHD target tissues tolerized Stat3-/- donor T cells when both CD4+ T cells and CD8+ T cells were given together. The induction of tolerance in Stat3-/- T cells by GVHD target tissue expression of PD-L1 depended on PD-L1/PD-1 interaction, which led to marked reduction of glycolysis in Stat3-/- T cells but not in WT T cells. These observations fit with previous findings that enhanced glycolysis was associated with enhanced GVHD activity of alloreactive T cells, as reported by Xue-zhong Yu's group. Our results indicate that Stat3 deficiency in donor T cells can augment their susceptibility to tissue PD-L1-mediated tolerance mechanisms such as down-regulation of glycolysis. Current experiments are testing whether Stat3 knockdown in mature T cells in the graft can prevent GVHD while preserving GVL activity. (Grant support: R01AI066008 to Zeng)

Disclosures
No relevant conflicts of interest to declare.