bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary Cutaneous Marginal Zone B-Cell Lymphoma Treated with Intralesional Rituximab: Experience of a Single Center
Authors: Domingo-Domenech Eva , Salas Queralt , Climent Fina , Aguilera Carmen , Pomares Helena , González-Barca Eva , Mercadal Santiago , Lucas Anna , Fernandez de Sevilla Alberto , Sureda Anna , Servitje Octavio 
Published: October 2019

Abstract
BACKGROUND
Primary cutaneous marginal zone B-cell lymphomas (PCMZL) are low-grade lymphomas with an indolent course, but with a high rate of skin relapses. Surgical excision, local radiotherapy, or combinations of both are the first-line treatment in solitary or localized disease. Therapeutic options in cases of multifocal disease or relapse, include steroids or intravenous Rituximab in monotherapy or in combination with intravenous or oral chemotherapy. The effectiveness of intralesional Rituximab (ILR) in primary cutaneous B-cell lymphomas has been described in a small multicenter series of patients.
OBJECTIVE
To evaluate the effectiveness and safety of ILR in patients with PCMZL.
METHODS
In our center ILR is used since 2010 as fist-line treatment for patients with PCMZL with single facial lesions, multifocal disease that cannot be irradiated or in relapsed disease. The treatment regimen consist of a course of three injections of 10 mg ( days 1, 3 and 5) in a single week at monthly intervals. Oral paracetamol and dexclofeniramire were administrated 30 minutes before the procedure. Courses of ILR were monthly repeated until response or in cases of relapse. The primary outcome measure of the study was the rate of remissions (complete and partial remissions).
RESULTS
Eleven patients with PCMZL have been treated so far: 55% as first-line treatment and 45% in the relapse setting. The relapsed-group had previously received a median of 3 previous treatments (range, 1-6) including radiotherapy in 5 cases, surgery in 1 case, intravenous chemotherapy in 2 cases, and topic steroids in 2 cases. Clinical characteristics of the 11 patients are shown in the table below.
A total of 40 courses or ILR have been completed. All patients responded, with 73% complete responses, without evidence of progression or relapse in the site of ILR treatment.
Four patients experienced transitory mild perilesional erythema that did not require medication and resolved in less than 4 hours. No systemic toxicities or infections were observed; the tolerance was excellent in all cases.
CONCLUSIONS
In our preliminary experience, ILR is an effective and safe therapeutic approach for selected PCMZL patients with single facial lesion, multifocal disease than cannot be irradiated or in relapsed cases. Further controlled studies are needed to confirm these findings.

Disclosures
Sureda: Takeda: Consultancy, Speakers Bureau.
Downregulation of Glycosyltransferase a Expression By miRNA-331-3p Is Mediated By the Inhibition of the Transcription Factor SP1
Authors: Kronstein-Wiedemann Romy , Bugert Peter , Seifried Erhard , Tonn Torsten 
Published: October 2019

Abstract
More than 100 ABO subgroup-related variations were detected in the coding region of glycosyltransferases, which may be causative for a weak blood group antigen A or B expression. Most variation in expression is explained genetically by mutations that reduce transferase activity. However, a substantial number of weak variants have not yet been explained by current methods. We recently postulated a role of miRNA in the regulation of blood group A antigen expression levels. By using different approaches, including gene array analysis, luciferase reporter assay and overexpression of glycosyltransferase specific miRNAs in primary hematopoietic stem cells (HSCs), we found that miR-331-3p directly targets glycosyltransferase A and B mRNA. Now we have been further embarking on the underlying mechanisms of miRNA and glycosyltransferase interactions and show that the effects of miR-331-3p are mediated by inhibition of transcription factor SP1, which is a major regulator of the ABO gene, thereby resulting in downregulation of blood group A antigen expression in A2O individuals by up to 80% and in A1O individuals by up to 50%. Using microRNA target prediction tools we also identified Sp1 as a potential target gene for miR-331-3p. Western blot analyses of glycosyltransferase protein expression showed that overexpression of miR-331 led to a decreased glycosyltransferase and SP1 protein expression. Further approaches with the SP1 inhibitor, mithramycin A, revealed similar results. Analysis of Aw04/O1v genotypes revealed elevated miRNA levels, thus confirming microRNAs as regulators of blood group glycosyltransferase expression. Our findings extend our understanding of blood group regulation in carriers of weak blood group variants. Involvement of miRNAs in the downregulation of ABO blood group antigen expression may also provide an explanation for observed changes of ABO antigen expression in abnormal processes such as tumorigenesis, pregnancy and aging. Furthermore, this pathway may play a role in the regulation of other blood group variants (for instance Rhesus, KELL, amongst others).

Disclosures
No relevant conflicts of interest to declare.
Impaired DNA Damage Repair in Severe Congenital Neutropenia Patients
Authors: Mir Perihan , Klimiankou Maksim , Dannenmann Benjamin , Zeidler Cornelia , Schulze-Osthoff Klaus , Kanz Lothar , Welte Karl , Skokowa Julia 
Published: October 2019

Abstract
Severe congenital neutropenia (CN) is a pre-malignant bone marrow failure syndrome with maturation arrest of granulopoiesis at the level of promyelocytes in the bone marrow. We hypothesized that increased genetic instability in hematopoietic stem and progenitor cells (HSPC) of CN patients caused by inherited mutations in ELANE (neutrophil elastase) or HAX1(mitochondrial HCLS1-associated protein X-1) may lead to high risk of malignant transformation. Treatment of CN patients with granulocyte-colony stimulating factor (G-CSF) overcomes maturation arrest by forcing unfit HSPC to proliferate and differentiate despite the presence of inherited mutations and thus increasing the risk of leukemogenic transformation.
We first investigated differences in DNA damage susceptibility of CD34+ and CD33+ bone marrow cells from CN-ELANE (n = 3) and CN-HAX1 (n = 3) patients, as compared to healthy donors using short-term treatment (5 minutes) with bleomycin to induce DNA double-strand breaks. To detect DNA lesions we used the LORD-Q method, a high-sensitivity long-run real-time PCR-based technique for DNA damage quantification (Lehle S. et al., Nucleic Acids Research, 2014). We found no differences in DNA damage induction between both groups of CN patients and healthy donors. Therefore, we hypothesized that not DNA damage but DNA repair mechanisms may be affected in these patients. Indeed, Gene Set Enrichment Analysis (GSEA) of microarray data revealed a marked inhibition of gene expression in pathways associated with DNA double-strand break (DSB) repair, mismatch repair as well as cell cycle regulation in HSPC from CN patients as compared to cells from healthy individuals. Validation by qRT-PCR confirmed severe downregulation of genes related to DSB repair (BRCA1 and RAD51), mismatch repair (MSH2 and PCNA) as well ascell cycle regulation (CHEK2 and CDKN2C) in CD33+ of both CN groups as compared to healthy individuals. Interestingly, CN-ELANE and CN-HAX1 groups behaved similarly with some exceptions showing decreased expression of CDC25B, RAD50 and ATR expression in the CN-HAX1 group only and of MRE11A in the CN-ELANEgroup only.
Taken together, disrupted DNA repair and impaired expression of cell cycle regulating genes resulting from inherited mutations in ELANE and HAX1 indicate that HSPC of CN patients are more susceptible to malignant transformation.

Disclosures
No relevant conflicts of interest to declare.
Engineered Exosomes Expressing HLA and Co-Stimulatory Molecules to Generate Antigen-Specific CD8+ T Cells for Adoptive Cell Therapy
Authors: Kim Sueon , Sohn Hyun-Jung , Lee Hyun-Joo , Sohn Dae-Hee , Hyun Seung-Joo , Cho Hyun-Il , Oh Il-Hoan , Kim Tai-Gyu 
Published: October 2019

Abstract
S.K and H.-J.S. contributed equally for this works
Dendritic cell-derived exosome (DEX) has been known as an efficient stimulator of T cells. However, the production of sufficient DEX remains a barrier to broad utility for immunotherapy. In this study, we engineered K562 cells expressing triple-co-stimulatory signals (CD80, 4-1BBL, and CD83) with HLA-A2 as an AAPC. Specifically, CD137L (4-1BBL) is an ideal signaling molecule for long-term propagation of CD8+ T cells, and the addition of other co-stimulatory molecules, such as CD80 and CD83, is used to support the expansion of naive T cell subsets. DC-derived exosomes display immunologically important molecules such as HLA and co-stimulatory molecules. Likewise, CoEX-A2 expressed high levels of HLA-A2, CD80, CD83, and CD137L (41BBL) and mediate strong, antigen-specific CD8+ T lymphocyte activation. The stimulation of freshly isolated peripheral CD8+ T cells with the appropriate antigen specificity observed here was likely made possible by the use of the sensitive ELISPOT assay. Viral or tumor protein-pulsed exosomes can directly stimulate CD8+ T cell proliferation and differentiation into CTLs in vitro. In addition, exosomes can be taken up by both CD8+ T cells and K562 cells. Meanwhile, K562 cells that have taken up exosomes can also stimulate CD8+ T cells, which may be due to the higher levels of HLA-A2, CD80, CD83, and 41BBL expression observed on exosomes. Therefore, the CD8+ T cell antigen-specific expansion observed in our cultures is likely the result of coated CoEX-A2s working directly or in a cross-dressed manner. The results suggest that these novel exosomes may provide a crucial source to generate antigen-specific CD8+ T cells for adoptive cell therapy against viral infection and tumors.

Disclosures
No relevant conflicts of interest to declare.
A Large-Scale Prospective Cohort Study on Factor XIII Deficiency in Southeast of Iran
Authors: Naderi Majid , Dorgalaleh Akbar , Peyman Eshghi , Malek Fatemeh , Karimi Mehran 
Published: October 2019

Abstract
Background: Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder with an estimated incidence of 1 per 2 million which has the highest global incidence in the southeast of Iran. Hence, this cohort study was designed to assess the prevalence of FXIIID, its molecular basis and clinical manifestations of FXIII deficiency (FXIIID) in Sistan and Baluchestan Province, southeast Iran.
Methods: All data about the prevalence of this disorder, its genotype and phenotype were collected prospectively from 2010 to 2016.
Results: In total , 410 patients were identified within the study period, a prevalence of 1 per ~ 7,000 in this area. The mean age of patients was 12 years (range, 1 month to 55 years), of which 51% (n: 209) were female. The main clinical presentation leading to the diagnosis of FXIIID was umbilical cord bleeding (82%). Three hundred and eighty patients were receiving regular prophylaxis of 10 IU/Kg of FXIII concentrate (Fibrogammin) every 28 days. This therapeutic dose was successful in the management of major and minor bleeding and the prevention of life-threatening bleeding in this cohort. But despite receiving prophylaxis, 63 minor bleeding episodes were recorded: 70% lower extremity ecchymoses, 25% oral cavity bleeding and 5% of menorrhagia. The prophylaxis interval for 5 patients was reduced to 21 days due to these bleeding events. Molecular analysis showed that 407 of the patients had a unique Trp187Arg mutation in exon 4 of the FXIII-A subunit gene, while the three remaining patients did not have a detectable underlying mutation.. During the study period, 70 patients underwent minor and major surgeries that were managed by 10-50 IU/Kg Fibrogammin without any significant bleeding. Furthermore, 32 successful deliveries were reported, consisting of 17 normal deliveries and 14 cases of Caesarian section, with a dose of 10-25 IU/Kg. No blood-borne disease was detected in patients receiving Fibrogammin.
Discussion: FXIIID has the highest global incidence in the southeast of Iran. The Trp187Arg mutation im the FXIII-A gene is the sole underlying mutation in this area due to the founder effect. Fibrogammin is a safe and suitable therapeutic choice for prophylaxis and management of major and minor bleeding.

Disclosures
No relevant conflicts of interest to declare.
Ribavirin Treatment for Respiratory Syncytial Virus in Immunocompromised Hosts
Authors: Nouvini Rosa , Kiner Bonnie , Yarovikova Margarita , Strachan Paul 
Published: October 2019

Abstract
Intro: Respiratory syncytial virus (RSV) is a common virus that can cause infection in the immunocompromised population.. In patients with hematologic malignancies, mortality rates have ranged from 7% to 83%. Most studies have focused on allogeneic stem cell transplant patients; however, those that have studied hematologic malignancies have shown equivalent RSV related mortality rates. Mortality is seen in the setting of lower respiratory tract infections (LRTI) and RSV progresses to lower respiratory tract infection in 40-50% of infected patients. In this study, we reviewed the charts of 35 immunocompromised, hospitalized patients diagnosed with RSV and treated with oral Ribavirin +/- IVIG to evaluate clinical outcome.
Methods: A retrospective chart review was conducted on 35 patients who tested positive for RSV via polymerase chain reaction (PCR). Data was collected between January 2010 and July 2016. These patients were treated with oral Ribavirin 10mg/kg loading dose on day 1, 400mg q8h on day 2 followed by 600mg q8h for the duration of the therapy from day 3 forward with or without IVIG 500mg/kg weekly as per treating physician.
Results: The cohort consisted of 20 males and 15 females. There were13 allogeneic stem cell transplant patients, 1 autologous stem cell transplant patient, and 21 patients with hematologic malignancies actively undergoing chemotherapy. Thirty-three patients were tested via nasopharyngeal swab and two were tested via BAL. Twenty were diagnosed with LRTI and 15 diagnosed with upper respiratory tract infection (URTI). Twenty one patients developed worsening hypoxemia with increased oxygen requirement. Two patients were intubated. Thirty patients were treated with Ribavirin and IVIG and 5 patients with Ribavirin alone. Sixteen patients started treatment within 2-3 days of positive RSV PCR and the rest began treatment after 3 days. All patients showed clinical improvement within 14 days of treatment. No patients died during the treatment period.
Conclusion: In our cohort,oral ribavirin with or without IVIG was an effective treatment for RSV infection in immunocompromised patients with hematologic malignancies. Further studies are needed to confirm this result.

Disclosures
No relevant conflicts of interest to declare.
Rabbit ATG Plus Cyclophosphamide with or without Fludarabine Is Superior Conditioning Regimen for Patients with Severe Aplastic Anemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Ahmed Parvez , Satti Tariq Mahmood , Chaudhry Qamar Un Nisa , Mehmood Kamran , Shahbaz Nighat , Khan Mehreen Ali , Ghafoor Tariq , Iftikhar Raheel , Satti Humayoon , Hanif Andleeb 
Published: October 2019

Abstract
Objective: To compare rabbit antithymocyte globulin (ATG) containing conditioning regimen (group A) with horse antilymphocyte globulin (ALG)-based regimen (group B) for sibling allogeneic hematopoietic stem cell transplant (HSCT) outcome, disease free survival, rejection and complications in severe aplastic anemia patients.
Methods: We analysed 205 aplastic anemia patients undergoing allogeneic HSCT from HLA matched sibling donors from July 2001 to April 2016. Group A (n=169) received conditioning with ATG plus Cyclophosphamide (CY) 200 mg/Kg with Fludarabine (Flu) 120mg/m2 (n=100) or without Flu (n=69), whereas group B comprised of CY plus ALG (n=36). The stem cell source was bone marrow (43.9%); PBSC (8.3%) and bone marrow plus PBSC (47.8%). Cyclosporin (CsA) was given as GVHD prophylaxis in 129 patients, while methotrexate (MTX) was added to CsA in 76 cases. Chi-square test was used to compare categorical variables. Kaplan Meier survival curves with log rank test was applied to compare the groups for survival analysis.
Results: Overall survival was 78.7% in Group A compared to 69.4% in group B (p=0.23). Patients in group A had significantly better disease free survival (DFS) (75.1%) than group B (55.6%) (p=0.018). The incidence of acute GVHD was 18.3% in Group A compared to 22.2% in Group 2 (p=0.64), while chronic GVHD was significantly higher in Group 2 (22.2%) as compared to Group A (9.5%) (p= 0.04). Likewise frequency of Mucositis was high in Group B (30.5%) compared to Group A (10.7%) (p = 0.006). Moreover, patients receiving ALG-based conditioning had more frequent infections (86%) compared to ATG-based group (67.4%) (p=0.03). There was no significant difference within group A with respect to use of fludarabine as part of conditioning.
Conclusion: Rabbit ATG containing conditioning regimen is associated with less complications and better survival in patients with severe aplastic anemia undergoing allogeneic HSCT.

Disclosures
No relevant conflicts of interest to declare.
Immunoglobulin Recovery after ASCT for Patients with Multiple Myeloma: Impact on Overall Survival and Progression-Free Survival
Authors: Jimenez-Zepeda Victor , Duggan Peter , Neri Paola , Chaudhry Ahsan , Tay Jason , Bahlis Nizar J. 
Published: October 2019

Abstract

Introduction Immunoparesis, defined as suppression of uninvolved immunoglobulins (Igs), has been described as one of the most common indicators of immune dysfunction in patients with multiple myeloma (MM). The role of immunoglobulin recovery, however, has not been properly evaluated, in particular in the setting of immunomodulatory therapy. In the present study, we aimed to assess the impact of immunoparesis and Igs recovery after ASCT on Overall and Progression-Free survival (OS and PFS).
Methods All consecutive patients undergoing ASCT at our center from 01/2004 to 03/2016 were evaluated. All patients received induction chemotherapy before undergoing auto-SCT. Patients received conditioning with either HDM at 200 mg/m2 (or adjusted as per renal failure) or HDM with Bortezomib (Bor-HDM). Definitions of response and progression were used according to the EBMT modified criteria. Immunoglobulin recovery was assessed at 12 months post-ASCT in those cases where immunoparesis was noted at diagnosis.
Results Clinical characteristics are shown in Table 1. Decrease of uninvolved Ig's was noted in 94% of cases. At the time of analysis, 69.2% of patients are alive and 54.9% have already progressed, respectively. Median OS did not differ between patients with or without immunoparesis (p=0.851). With regards to Ig recovery at 12 months post-ASCT, median OS was longer for those patients with complete or partial normalization of Ig's compared to those with no recovery at all (Estimate median OS of 97, 77 and 69 months, respectively, p=0.008) (Fig1a). In addition, median PFS was longer for those patients with normalization or partial recovery of Ig's at 12 months post-ASCT (median of 40.3 and 38 months, compared to 24.6 months for those without Ig recovery, p=0.002) (Fig1b). Furthermore, 121 patients receiving lenalidomide maintenance were evaluated, 49% of cases exhibited complete or partial recovery of Ig's at 12 months post-ASCT, compared to 40% for those cases that were not treated with any maintenance strategy (p=0.6).
In conclusion, Immunoglobulin recovery at 12 months post-ASCT is an important factor to predict for better progression-free and overall survival. The use of lenalidomide as a maintenance strategy did not seem to affect the process of Ig recovery. Based on our observations, the use of immune enhancement strategies in the post-transplant setting seem appealing and requires further investigation.

Disclosures
Jimenez-Zepeda: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene, Janssen, Amgen, Onyx: Honoraria. Neri:Celgene and Jannsen: Consultancy, Honoraria. Bahlis:Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau.
CD34+ Selected Cells "Boost" for Poor Graft Function Post Allogeneic Stem Cell Transplantation
Authors: Mohty Razan , Ruggeri Annalisa , Battipaglia Giorgia , Malard Florent , Brissot Eolia , Belhocine Ramdane , Eder Sandra , Giannotti Federica , Dulery Remy , Mohty Mohamad 
Published: October 2019

Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of a variety of hematologic diseases. However, allo-HSCT can be associated with many complications, including poor graft function early after transplant requiring long-lasting supportive care. In the literature, the incidence of poor graft function post allo-HSCT has been reported to range from 4 to 27%.
Here, we retrospectively studied 10 patients (male/female: 4/6, median age: 45 years, range 19 to 67) who received a boost of CD34+ selected cells for poor graft function after allo-HSCT (of whom 4 cases of haplo-identical allo-HSCT with post-Cy prophylaxis), between January 2014 and January 2016. Patients' disease and transplant characteristics are summarized in the below table.
Patients were selected for the CD34+ cells "boost" therapy after eliminating other causes that could explain a poor graft function (eg. drug toxicity, infections, disease relapse, etc.) The same original allo-HSCT donor was used to collect the CD34+ cells after mobilization with G-CSF and positive selection. The patients did not receive any prior conditioning therapy prior to CD34+ cells boost infusion. At time of the boost, all patients were in full donor chimerism. The number of infused CD34+ cells differed from one patient to another ranging from 2.91 to 7.99 x106 cells/kg recipient body weight. The median day of infusion post- allo-HSCT was 120 (range, 76-352). Among these 10 patients, 7 patients had full counts recovery at a median of 15 days (range, 7-30) post-infusion, while 3 patients had an incomplete response with persistent anemia and/or thrombocytopenia. None of the patients experienced clinically significant GVHD symptoms after the boost. At last follow-up, 7 patients were alive whereas 3 patients died of severe infections after 1, 6 and 13 months post-boost.
Based on these results, we concluded that boost therapy can be used in the treatment of poor graft function post-allogeneic HSCT, including in those patients who received a haplo-transplant.

Disclosures
No relevant conflicts of interest to declare.