bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-GDF11Treatment of β-Thalassemia Intermedia Mice Does Not Improve Erythropoiesis
Authors: Lob Heinrich E , Kravets Leah , Miloscio Lawrence , Mastaitis Jason , Economides Aris N , Hatsell Sarah J 
Published: November 2020

Beta-thalassemia is a hereditary iron-independent anemia, caused by a reduction of β-globin, affecting millions of people globally. Current treatments such as blood transfusions and iron chelation show significant toxicities and add to organ damage. Luspatercept (Acvr2b(L79D)-Fc) is a novel treatment for transfusion-dependent β-thalassemia patients that improves erythropoiesis independent of erythropoietin. The exact mechanism of action remains unknown, and it is controversially discussed if growth differentiation factor 11 (GDF11) is the main target of this drug. Genetic models raised doubts that GDF11 is the target of Acvr2b(L79D)-Fc. Here we tested if a GDF11 specific blocking antibody improves β-thalassemia intermedia in mice. Our findings support the genetic data that GDF11 does not play a role in the ineffective erythropoiesis in β-thalassemia. Anti-GDF11 treatment did not change hematocrit, hemoglobin and red blood cell number and it did not improve erythropoiesis. Ex vivo treatment of erythroblasts with recombinant GDF11 did not inhibit red blood cell maturation. Lastly, we identified that inhibiting GDF8 in β-thalassemia mice has a small effect on erythropoiesis and increased hemoglobin levels without being as effective as Acvr2b(L79D)-Fc. Of note, wild-type animals treated with anti-GDF8 did not show changes in any hematology parameters and therefore the small effect we observed might be due to the disease phenotype, but not due to a physiological mechanism involved in erythropoiesis. Taken together, GDF11 is not involved in erythropoiesis but GDF8 may have a minor role in the regulation of ineffective erythropoiesis. Given the small effect of anti-GDF8 on erythropoiesis compared to Acvr2b(L79D)-Fc, we conclude that either there is another target or several targets of Acvr2b(L79D)-Fc driving ineffective erythropoiesis, or that Acvr2b(L79D)-Fc efficacy is due to it altering the overall BMP/GDF/Activin ligand and receptor balance.

Disclosures
Lob: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kravets:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Miloscio:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mastaitis:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Economides:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hatsell:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.
The Effect of Macrophage Polarization on Cytokine Release in CAR-T Antitumor Response
Authors: Zmievskaya Ekaterina , Valiullina Aigul , Zhuravleva Margarita , Rakhmatullina Aigul R , Ganeeva Irina , Zaikova Ekaterina , Petukhov Alexey , Miftakhova Regina R , Rizvanov Albert A , Bulatov Emil 
Published: November 2020

Immunotherapy of cancer using T-lymphocytes with chimeric antigen receptor (CAR-T) is highly promising. CAR-T therapy is approved by FDA for the treatment of B-cell (CD19+) hemoblastoses, however it faced a number of major difficulties in application to solid tumors. One of the main problems of CAR-T therapy is the possibility of developing a serious complication - cytokine release syndrome (CRS), which in extreme cases becomes a life-threatening condition. CRS is often caused by the direct contact of tumor cell with T-lymphocyte and its subsequent activation. However, there is growing amount of evidence suggesting substantial participation of macrophages in this process.
We established the effect of macrophages of different phenotypes on secretion of cytokines during cocultivation with CAR-T cells. Initially, isolated monocytes were differentiation into M1 and M2 macrophages. After that M1, M2, and CAR-T cells were co-cultured with prostate adenocarcinoma PC-3M(Kat+CD19+) cells for 5 days. Supernatants were analyzed using multiplex assay.
Confocal microscopy revealed that co-cultivation of PC-3M(Kat+CD19+) cells with CAR-T cells decreases the number of tumor cells. Multiplex analysis revealed that macrophages of both populations did not affect the secretion levels of IFNγ and TNFα. However, M1 population promoted IL-1b, and M2 lowered IL-6 and IL-17F. Increase in sCD40L levels was also detected upon addition of both macrophage populations.
Results suggest that interaction of M1 and M2 macrophages with CAR-T cells leads to release of various pro-inflammatory cytokines and might be the cause of CRS in patients.
Work was funded by RSF 19-74-20026 and performed according to the Russian Government Program of Competitive Growth of Kazan Federal University. A.V. was supported by stipend of President of Russian Federation СП-227.2019.4.
References
Titov, et al. "Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment." Cancers 12, 1 (2020): 125. DOI: 10.3390/cancers12010125

Disclosures
No relevant conflicts of interest to declare.
Analysis of the Short-Term Efficacy of Decitabine Combined with Low-Dose Cytarabine in the Treatment of JMML
Authors: Cai Yuli , Liang Weiru , Yi Meihui , Zhang Xiaoyan , Liu Fang , Chang Lixian , Guo Ye , Chen Yumei , Zou Yao , Yang Wenyu , Zhu Xiaofan 
Published: November 2020

Objective: Juvenile myelomonocytic leukemia (JMML) has both the disease characteristics of myelodysplastic syndrome and myeloproliferative neoplasm. Currently, hematopoietic stem cell transplantation (HSCT) is the only possible cure. Most of the newly diagnosed pediatric patients with JMML have high tumor burden, rapid disease progression, and may not tolerate HSCT. This study explored the short-term efficacy of decitabine combined with low-dose chemotherapy in the treatment of JMML before transplantation.
Methods: A retrospective analysis of the patient files of 9 cases of JMML was performed from January 2019 to May 2020. All patients were given decitabine 20mg/m2× 5 days, supplemented with a small dose of cytarabine (50-100mg/m2×3~5 days), and/or etoposide (50mg/m2×3~5 days) chemotherapy. Each treatment interval is 3~4 weeks, bridging with HSCT after 3~4 treatment courses.
Results: The median age of onset of 9 cases of JMML was 2 years old (0.5~4 y), male to female ratio was 8:1, the median size of spleen was 6.4cm (2.9~9.8cm) under the costal arch, and WBC was 28.03×109/L (7.3~127.69×109/L), monocytes were 9.25×109/L (1.66~15.79×109/L) at diagnosis. There were 8 cases in the high-risk group and 1 case in the low-risk group. Second-generation sequencing results show that 7 cases carried PTPN11 somatic mutations. Five in 9 cases had two kinds of classic JMML mutations, and 1 case had only NRAS mutation. Seven patients had normal chromosomal karyotypes, and 3 patients had abnormal 8, 11, and 18 chromosomes, respectively. Median treatment courses with decitabine are 3 courses (1~5 courses), the response rate of one course is 77.8% (7/9), the response rate of three courses is 80% (4/5), one case from high-risk group achieved complete remission after treated with 4 courses of decitabine and low-dose chemotherapy. The five-month progression-free survival rate was 77.8% (7/9).
Conclusion: Treating JMML with decitabine combined with low-dose chemotherapy, can reduce patients' tumor burden, improve the general condition, and obtain approximately 80% clinical response rate. Decitabine combined with low-dose chemotherapy can be used as a treatment option for JMML before HSCT.

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
Safety and effecacy of decitabine applicated in JMML patients have not been confirmed.
Apixaban Anti-Xa Level Monitoring in Treatment of Provoked Acute Upper Extremity Deep Vein Thrombosis for Patient on Dialysis: A Case Report
Authors: Roberge Guillaume , Wells Philip S. 
Published: November 2020

Background. Patients with end stage renal disease on dialysis are at higher risk of major bleeding and recurrent thrombosis and as such, treatment of acute venous thromboembolism (VTE) is challenging. Ideally, treatment would avoid inpatient admission as for most other patients with acute VTE. DOACs represent the easiest option but there are concerns over bioaccumulation increasing bleeding risk. Despite the absence of a standardized therapeutic range, anti-Xa trough level is measured to monitor potential DOACs bioaccumulation and thus, used for safety surveillance.
Methods. We describe a case of a 51 yo female, 36 kg, on chronic hemodialysis with a provoked acute upper extremity deep vein thrombosis. Due to a lack of subcutaneous fat and calciphylaxis we were reluctant to use low molecular weight heparin and warfarin. She was treated with apixaban 2,5 mg twice daily for 6 weeks. Over 4 weeks, the apixaban anti-Xa trough levels were measured on dialysis days 12 hours after the morning dose.
Results. The anti-Xa trough levels ranged from 58 to 84 ng/mL, similar to what is expected in patients with normal kidney function. There were no adverse events in the 3 months after anticoagulation initiation.
Conclusion. We saw no evidence of bioaccumulation. This indicates a potential role for apixaban low doses in acute venous thromboembolism for patients on dialysis.

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
The use of Apixaban for treatment of acute venous thromboembolism in patient on dialysis has not been approved.
A Rare Aggressive Case of Follicular Dendritic Cell Sarcoma
Authors: Fang Yi , Xiao Fei , Fang Jianchen , Hou Jian , Huang Honghui 
Published: November 2020

Follicular dendritic cell sarcoma (FDCS) is a rare lymphoid neoplasm with indolent clinical process. However, we presented here a rare case of FDCS in aggressive pace.
The case was a 48-year-old female complaining of dysphagia for half a year. She was found gastric fundus bulge under gastroscopy and diagnosed as low-differentiated gastric adenocarcinoma in the local hospital. After three courses of chemotherapy with paclitaxel combined with oxaliplatin and 5-fluorouracil, PET-CT showed progressive disease (PD) with not only gastric bulk but also invasion to the liver and multiple lymph nodes in the abdomen. The patient was admitted to the Department of Surgery of our hospital. Total gastrectomy and liver tumor resection were performed and postoperative pathology demonstrated FDCS. The patient was transferred to our department for chemotherapy. After three courses of CHOP, PET-CT showed tumor in the anastomotic site, partial liver resection margin and left adrenal gland. The patient was sent for radiotherapy. After radiation, PET-CT demonstrated PD and the puncture of left supraclavicular lymph node confirmed FDCs. Thalidomide and prednisone were given orally. At the same time, the whole exome sequencing (WES) was performed, based on which therapy response index (TRI) was analyzed by Cellworks software. According to TRI, the regimen of etoposide, carboplatin, bendamustine and chidamide was chosen for the patient. After the chemotherapy, the patient developed repeated vomiting and diarrhea. Abdominal CT showed intussusception and intestinal obstruction. She was sent for gastrointestinal surgery to relieve obstruction and postoperative pathology again confirmed FDCS. However, her abdominal pain and diarrhea occurred again one month after operation. The patient was discharged voluntarily and went to local hospital for supportive care.
During a year from the onset to abandon of tumor therapy, the case was administered operation, radiotherapy and chemotherapy. The regimens of chemotherapy included paclitaxel-based chemotherapy for solid tumors, CHOP for lymphoma, and formulated regimen according to the analysis of WES. However, all of these therapeutic strategies were unable to control the progress of her disease. Hitherto, there is no guideline or consensus to guide the treatment of FDCS. The diagnosis and treatment process of this relapsed and refractory case can provide reference for clinicians to manage FDCS.

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
FDCS of this case was in the aggressive manner. Routine therapeutic strategies, including operation, radiotherapy and chemotherapy based on paclitaxel or CHOP, were not able to control the progress. Therefore, the whole exome sequencing (WES) was performed, based on which therapy response index (TRI) was analyzed by Cellworks software. According to TRI, the regimen of etoposide, carboplatin, bendamustine and chidamide was chosen for the patient under the consent of her and her family for off-label use.
Combining the mTOR Inhibitor Everolimus and Gemcitabine in Relapsed/Refractory Peripheral T-Cell Lymphomas
Authors: Huang Ling , Jiang Xinmiao , Li Wenyu , Guo Hanguo , Wei Xiaojuan , Liu Sichu , Chen Feili , Liang Zhanli 
Published: November 2020

Background: Relapsed/refractory Peripheral T-cell lymphomas (PTCL) is an aggressive and heterogeneous Non-Hodgkin's T cell lymphoma, which is resistant to conventional chemotherapy with poor prognosis. Therefore, there is an urgent need to exploit potential therapeutics and novel treatment for R/R PTCL. Targeting PI3K/AKT/mTOR pathway is an effective therapy for PTCL. However, recent research demonstrated that the mTOR inhibitor everolimus monotherapy has low response rate and short duration time in treating with R/R PTCL.
Methods:We retrospectively reviewed 18 patients with pathologically diagnosed T cell lymphoma who received the mTOR inhibitor everolimus combined with gemcitabine for six cycles (everolimus 10mg qd, gemcitabine 1000mg/m2 d1, every 21 days a cycle) and sequential autologous stem cell transplantation, at Guangdong Provincial People's Hospital from November 2015 through October 2019. We evaluated the objective response rate (ORR), progressive free survival (PFS) and safety.
Results:Of the 18 patients, 33.3% (n=6) had PTCL-not otherwise specified (PTCL-NOS), 27.8% (n=5) had angioimmunoblastic T-cell lymphoma(AITL), 27.8% (n=5) had anaplastic large cell lymphoma(ALCL) (anaplastic lymphoma kinase positive ALCL: 20.0%, n=1; anaplastic lymphoma kinase negative ALCL: 80.0%, n=4), and 11.1%(n=2) had other subtypes. The median age was 46.5 years (range 26-64) old and most patients were males (66.7%) with advanced stage disease (III/IV, 73.7%). The ORR was 55.6% (n=10), with complete response rate of 50% and partial response rate of 5.6%. One patient was stable disease (5.6%), and seven patients were progressive disease (33.8%). For subtypes, the ORR was 80% in ALCL, 66.7% in PTCL-NOS and 20% in AITL, respectively. With a median follow-up time of 18.9 months (range 3.1-99.6), the median PFS was 4.5 months and overall survival(OS) was 18.9 months, respectively. The most frequent hematological adverse events were thrombocytopenia (27.8%), anemia (22.2%), leukopenia (11.1%). The non-hematological adverse events were inappetence (22.2%), diarrhea (11.1%), rash(11.1%), fatigue (11.1%).
Conclusions:Our pilot studies have shown that combined everolimus with gemcitabine have better efficacy than monotherapy reported previously for R/R PTCL patients, but the mechanism is still unclear. It suggests that further investigation for mechanisms and predictive biomarker is needed.
Figure

Disclosures
No relevant conflicts of interest to declare.
Isavuconazonium Sulfate Use in Multi-Modal Management of Invasive Zygomycosis in Four Pediatric Allogeneic Hematopoietic Cell Transplant Patients
Authors: Ferdjallah Asmaa , Nelson Kristina M , Meyer Kailey , Jennissen Cathryn A , Ebens Christen L. 
Published: November 2020

Prolonged neutropenia increases risk for lethal invasive fungal infection (IFI) such as Rhizopus. Isavuconazonium sulfate is a new triazole that lacks pediatric dosing recommendations. Clinical courses of 4 pediatric patients with IFI in the peri-allogeneic hematopoietic cell transplantation (alloHCT) period between 2015 and 2017 were reviewed, including previously unreported pharmacokinetic and safety data. IFI included Rhizopus and presumed fungal meningitis. Isavuconazonium sulfate was initiated with a loading dose followed by daily dosing, adjusted to a goal trough &gt;3 ug/mL based on adult literature. This target was achieved at a median of 7 days, demonstrating varying rates of metabolism. Renal insufficiency, electrolyte disturbances, and transaminitis were noted, though attribution was confounded by other alloHCT complications. 1 patient survived infection-free to hospital discharge and 1 of 3 deceased patients had evidence of unresolved IFI (Case 2). Case 2 was subtherapeutic for 39% of the duration of treatment, compared to others at an average of 29%, suggesting this target trough to be clinically relevant. We recommend initiation of isavuconazonium sulfate at 10 mg/kg with a max dose of 372 mg. A loading dose of 10 mg/kg is utilized every 8 hours for 6 doses followed by 10 mg/kg dosing every 24 hours. Monitoring must continue beyond steady state. If early monitoring is not possible, we recommend a first drug level at week 3. If dose increases are required, a partial reload has been more successful instead of increasing daily doses. Further larger studies are needed to demonstrate optimum dosing in pediatric patients.
Figure 1

Disclosures
No relevant conflicts of interest to declare.
Defining the Super Massive Transfusion in Pediatric Casualties during Combat Operations in Afghanistan and Iraq
Authors: Schauer Steven Gremel , Fisher Andrew , Borgman Matthew , Cap Andrew P. , Bynum James 
Published: November 2020

Introduction: Hemorrhage is the leading cause of potentially preventable death on the battlefield. We previously published data defining the pediatric massive transfusion at 40mL/kg of total blood products. However, there is a subset of casualties that require large volumes of blood products - super massive transfusions - which remains unclear. We seek to determine what defines a super massive transfusion within the pediatric population as understanding this unique group would help mobilize resources early in their clinical course.
Methods: This is a secondary analysis of a previously described dataset from the Department of Defense Trauma Registry. In this analysis, we sought all casualties within our dataset that met inclusion for MT. To describe the super MT, we sought the top quartile of total products administered within the first 24 hours on a volume per weight basis.
Results: Within our original dataset of 3439 pediatric casualties, we identified 543 that met inclusion for massive transfusion, with the 75th percentile at 120.6 mL/kg - we rounded this to 120mL/kg for simplicity which left 137 for analysis. Most of the casualties were in the 5-9 and 10-14 age groups (24% and 39%, respectively) and were most frequently injured by explosive (71%). Those in the super MT group had lower survival (75% versus 84%, p=0.015), longer ventilator courses (median 3 days versus 2 days, p=0.029) despite similar median injury severity scores (17 versus 17, p=0.100). However, they more frequently had serious injuries to the extremities (62% versus 35%, p&lt;0.001). Super MT casualties more frequently had age-adjusted hypotension (45% versus 26%, p&lt;0.001) but no difference in age-adjusted tachycardia (88% versus 86%, p=0.514). Super MT casualties had worse international normalized ratios (2.06 versus 1.65, p=0.006), and worse base deficits (-11.3 versus -8.5, p&lt;0.001).
Conclusions: In our analysis, we found that 120 mL/kg of total blood products administered within the first 24 hours was the threshold for the top 25th percentile of pediatric blood product consumers. More data is needed to define this unique population that requires mobilization of extensive resources.

Disclosures
No relevant conflicts of interest to declare.
Hemorrhagic Cerebral Vascular Accident with Breakdown of Salt-Wasting Cerebral Syndrome in Acute Lymphoblastic Leukemia: Case Report
Authors: Ferreira Hugo Henrique de Freitas , Silva Alessandra Suelen Jardim , Júnior Lenilton Silva DA Silva , Oliveira Gustavo Henrique de Medeiros , Araujo Maria das Graças Pereira , Soares Victor lima , Bahia Frank , Oliveira Taissa Moura , Silva Dany GKC , Sales Valéria SF , Paiva Aldair Sousa , Cavalcanti Geraldo Barroso 
Published: November 2020

Introduction:Cerebral Salt Losing Syndrome (SCLS) is defined as a renal loss of sodium during intracranial disease, leading to hyponatremia and decreased volume of extravascular fluid. Studies show the existence of an association with hemorrhagic stroke (HCV) and SCLS as a complication that significantly contributes to the morbidity and mortality of patients with acute lymphoid leukemia (ALL).Objective:To report a case of a patient with ALL who presented HCV with neurological lesion, showing repercussions in the nervous system through SCPS.Case Description:A 33-year-old female patient was referred to the specialized hematology service, complaining of petechiae spread in the trunk and limbs, high fever, progressive asthenia, generalized pain in addition to nausea and vomiting. Laboratory data showed pancytopenia and IgM and IgG serology reagent for dengue. Cytomorphological examination of peripheral blood showed the presence of 68% of lymphoid blast cells, later confirming by bone marrow aspirate immunophenotyping as a CD10 negative pre-B ALL (pro-B ALL). After the start of chemotherapy treatment, the patient presented episodes of generalized tonic-clonic seizure crisis that were repeated in the two days that followed, in addition to referring to intense paresthesia in the upper limbs and headache and referred to the Intensive Care Unit (ICU). Imaging exams showed heterogeneous right frontal hemorrhage compatible with HCV, and sagittal sinus thrombosis, with an increase in frontal hematoma with deviation of centro medial structures. Subsequently, he presented high urinary output (6,500 mL / 24 hours) with severe polydipsia, in addition to hyponatremia (129), hypouricemia (20) and decreased creatinine (0.3), urinary sodium concentration and urinary osmolarity, evolving with dehydration (+++ / 4+) and hemodynamic instability, establishing the diagnosis of SCPS. After intervention with flourcortisone and hydroelectrolytic replacement, the patient presented an improvement in the condition of SCLS and, with significant clinical improvement, the patient continues on specific cancer treatment, and without neurological sequelae.Conclusion:The correct clinical and laboratory diagnosis allows an early and safe intervention. Knowledge of this clinical entity enables specific treatment and a favorable outcome for the patient.

Disclosures
No relevant conflicts of interest to declare.
The Mechanism of Activated TGF-β1 Inhibiting GVL Effects of Bone Marrow NK Cells Leading to Early Relapse after Transplantation
Authors: Wang Dongyao , Zhu Xiaoyu , Sun Zimin 
Published: November 2020

Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is one of the best ways to cure acute myeloid leukemia (AML). However, patients with AML undergoing allo-HSCT are at risk of relapse, the mechanism remains poorly understood. Here, we demonstrated the significant decrease of nature killer (NK) cells, and the declined proportion of multi-functional effector NK cells in bone marrow from patients who had a relapse in 3 months after allo-HSCT. Furthermore, we verified the levels of activated Transforming growth factor-β1 (TGF-β1), not the total TGF-β1, increased in bone marrow of these patients. This high level activated TGF-β1 was correlated with reduced cytotoxicity of NK cell, and contributed to immune escape of tumor cells. Moreover, the expression of glycoprotein A repetitions predominant (GARP), which is critical to TGF-β1 activation, high expressed in CD4+ T cells of patients who had a relapse. These data reveal a mechanism of immune escape and proposes approaches for therapeutic administration of NK cells in order to reverse suppression of activated TGF-β1 during early allo-HSCT.

Disclosures
No relevant conflicts of interest to declare.