bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact Of Renal Insufficiency and Obesity On Safety and Outcomes Of BEAM Conditioning
Authors: Afifi Salma , Adel Nelly G. , Zhang Zhigang , Shi Weiji , Moskowitz Craig H. , Matasar Matthew J. 
Published: October 2019

Abstract

Introduction
BEAM (carmustine, etoposide, cytarabine and melphalan) is a standard conditioning regimen for patients with NHL undergoing autotransplant. Guidelines do not address whether patients with marginal renal function or obesity should undergo dose-adjustment to limit toxicity, and practices vary among centers.

Methods
We reviewed all patients who had BEAM autotransplant at MSKCC, 9/2003 - 12/2011; none received dose adjustment for chronic renal insufficiency [CRI, creatinine clearance (CrCl) 29-59 ml/min] or obesity (BMI>30). Outcomes included OS, relapse risk, transplant length of stay (LOS), and incidence of toxicities including mucositis, febrile neutropenia, and organ damage (acute renal failure by AKIN criteria; pulmonary toxicity requiring oxygen or corticosteroids; heart failure requiring inotropic support). Uni- and multivariate analysis evaluated association with baseline renal function and BMI, as well as age, histology, prior therapy, disease response, and comorbidity (hematopoietic stem cell transplant comorbidity index ≥4). Logistic regression was used for toxicity endpoints; linear regression and ANOVA were used for LOS; and Cox regression model and Gray’s competing risks were used for OS and relapse risk.

Results
343 patients received BEAM during the study period; median (range) age=56 (17-73), estimated CrCl=92 (29-208), and BMI=27.6 (16-47). 12% had CRI and 33% were obese (12% BMI≥35, 3% BMI≥40). Stepwise multivariate analysis showed CRI (OR 2.9, P<0.01) and obesity (OR 2.5, P<0.01) were associated with risk of organ damage independent of comorbidity and histology. Mucositis and febrile neutropenia were not associated with CRI or obesity. CRI (P=0.03), but not obesity, was associated with longer LOS. Relapse risk was associated with histology (PTCL vs. DLBCL, HR 2.3, P=0.01) and response at transplant (PR vs. CR, HR 2.3, P<0.01), but not CRI or obesity. Obesity was not clearly associated with overall survival (HR 0.62, P=0.10, NS), but CRI was associated with worse overall survival (HR 2.2, P<0.01) independent of disease status (for PR, HR=2.0, P=0.01), histology, prior therapy, or comorbidity (P=NS). However, 100d mortality was uncommon in patients with preserved (6/303, 2%) or impaired (2/40, 5%) renal function (P=NS).

Conclusions
Patients with CRI or obesity experience increased risks of acute organ damage, and those with CRI have inferior OS, but 100d mortality remains low in both groups. Our findings do not support routine dose-modification of BEAM for obesity or moderate renal insufficiency.

Disclosures:
No relevant conflicts of interest to declare.
CD34+ Selected Cells For The Treatment Of Poor Graft Function Following Allogeneic Stem Cell Transplantation
Authors: Stasia Alessandra , Ghiso Anna , Raiola Anna Maria , Galaverna Federica , Varaldo Riccardo , Gualandi Francesca , Dominietto Alida , Pozzi Sarah , Luchetti Silvia , Pogliani Enrico Maria , Bacigalupo Andrea 
Published: October 2019

Abstract

Background
We have previously defined poor graft function (PGF) as 2 or 3 cytopenic lines (Hb<10 g/dl, neutrophil count <1,0 x 10^9/L, platelet count <30 x 10^9/L), lasting for at least 2 consecutive weeks post-transplant, beyond day +14, with transfusion requirement, associated with hypoplastic-aplastic bone marrow, in the presence of complete donor chimerism and in the absence of severe GVHD and relapse (Larocca 2006). We have also shown that PGF can be treated with the infusion of donor CD34+ cells, selected from mobilized peripheral blood. (Larocca 2006) .

Aim of the Study
To update the 2006 study in 41 patients.

Methods
All 43 patients received a boost of CD34+ selected peripheral blood stem cells (PBSC) without prior conditioning and without GvHD prophylaxis. The median age of patients was 37 years (18-60y). The median number of CD34+ PBSC infused was 3.45 x106/Kg at median days of 140 days from 1st HSCT.
Complete response, or tri-lineage recovery was defined as achieving Hb >10 g/dl, ANC > 1000 x109/L, platelets > 100.000 x 109/L. A partial recovery was defined as transfusion independence, without a complete hematologic recovery. The median follow up was 1245 days.

Results
Tri-lineage recovery was seen in 31/41 (76%) and 3/43 patients became transfusion independent, for an overall response of 83%). The median time for complete hematological recovery from CD34+ boost infusion was 183 days.
There was no influence on tri-lineage recovery of the following factors : dose of CD34 cells (</> 3.3) (78% vs 72%), nor patient age (</>35 years) 75% vs 76%, nor donor type (HLA id sib 83%, UD 79%, family mm 68%). All the patients who achieved tri-lineage recovery are alive and disease free (28/41 patients). In this cohort 13 patients died due to relapse 9/14 (64%) or GVHD 2/14 (14%) or other causes 2/14 (14%). The overall actuarial survival is 63% with a median follow up of 1245 days (94-4151 days).

Interpretations and Conclusions
We confirm that infusion of CD34+ selected PBSC is associated with a high rates of tri-lineage recovery, with low risk of acute or chronic GVHD in patients who develop poor graft function following an HSCT. Tri-lineage recovery or achieving transfusion independency have an interesting impact either on disease free and overall survival.

Disclosures:
No relevant conflicts of interest to declare.
Gene Polymorphism Profile May Predict Late Complications In Patients Undergoing Allogeneic Stem Cell Transplantation
Authors: Gil Lidia , Wojtaszewska Marzena , Mol Anna , Lewandowski Krzysztof , Styczynski Jan , Komarnicki Mieczyslaw 
Published: October 2019

Abstract
Gene polymorphism analysis may predict infection development, especially invasive fungal disease, in recipients of allogeneic stem cell transplantation (alloSCT), as previously reported (Gil et al., BMT 2013). It is also suggested that gene polymorphism may contribute to non-infectious complications occurrence.

Objective
Analysis of late complication after alloSCT with respect to gene polymorphism profile.

Material and Methods
Analysis for infectious or non-infectious complications was performed in a cohort of 126 adult patients (pts) with acute leukemias (94), chronic leukemias (10) or lymphoid malignancies (22) who underwent alloSCT and survived at least 100 days. All pts and their sibling (58) or unrelated (68) donors were previously screened for TLR4, IFNG, TNFR2 and DECT1 single nucleotide polymorphisms (SNP). The primer for TLR4 SNP was designed using Lasergene Primer Select. IFNG, TNFR2 and DECT1 polymorphisms were screened with published primers with PCR conditions common to all reactions. Patients were conditioned with myeloablative (58) or reduced intensity (68) regimen and grafted with 3.8 (0.8-5.2)x10^6/kg of CD34+ cells. Standard definitions for relapse, graft versus host disease (GVHD) and infections (neutropenic, bacterial, fungal and viral) were used.

Results
Infectious complications that occurred after 100 days posttransplant included bacterial infection in 28 (22%), CMV infection in 19 (15%) and invasive fungal infection in 12 (9%) pts. Late onset acute GVHD 2-4 grade was seen in 15 (12%), while chronic extensive GVHD in 18 (14%) pts. Relapse was diagnosed in 30 (24%) pts. Secondary malignancies were observed in 2 pts. Over a median follow-up of 34.5 (range; 6-85.5) months, 90 (71%) pts were alive with median survival 35.5 (95% CI=8-87) months. Among genetic factors by multivariate logistic regression analysis donor DECT1 SNP was significant for fungal infection development (p=0.016, HR 5.7); chronic GVHD development (p=0.038, HR=4.4) and death from chronic GVHD (p=0.028; HR=4.8). Additionally, donor INFG SNP was significant for CMV occurrence (p=0.019; HR=5.5). None of studied polymorphisms had impact on the outcome. Among transplant-related factors (age, sex, diagnosis, disease stage, dose and source of stem cells, type of transplant, intensity of conditioning, neutropenia duration) only alloSCT from unrelated donor was significant for late CMV infection (p=0.47; HR=3.9) and bacterial infection (p=0.036; HR=4.4) development.

Conclusion
Our results suggest that gene polymorphism profile may predict late infectious and non-infectious complications in patients undergoing alloSCT. It may influence stratification of pts to offer an individualized therapy.

Disclosures:
No relevant conflicts of interest to declare.
Intracranial Hemorrhage and Mortality In 1461 Patients After Allogeneic Hematopoietic Stem Cell Transplantation For 6-Year Follow-Up: Study Of 44 Cases
Authors: Zhang Xiaohui , Han Wei , Chen Yuhong , Chen Huan , Liu Daihong , Xu Lanping , Liu Kaiyan , Huang Xiaojun 
Published: October 2019

Abstract

Although cerebral complications and causes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were well documented, assessment of incidence rates and risk factors of intracranial hemorrhage (ICH) following allo-HSCT are less discussed. The clinical data of 1461 consecutive patients undergoing allo-HSCT in Peking University Institute of Hematology from January 2005 to June 2011 were retrospectively analyzed. Among these patients, 44 developed intracranial hemorrhage (ICH) and matched 176 patients control subjects were accrued. ICH was verified by computed tomography (CT) scan in all patients. Among the 1461 patients, 44 patients (3.0 %) developed ICH, including 29 patients (65.9%) with multiple location hemorrhage, 4 patients (9.1 %) with subdural hematoma (SDH), 8 patients (18.2%) with subarachnoid hemorrhage (SAH), and 3 patients (6.8%) with other hemorrhage in the brain parenchyma. The median time of appearance for ICH was 129 days (1-450). Survival after 6 year was significantly reduced in patients who developed ICH complications compared with control (47.1% vs. 75.7%,p<0.001 ).Multivariate analysis showed that donor type, systemic infections, III-IV aGVHD, platelet count, fibrinogen level were the independent risk factors for ICH among allo-HSCT patients. The ROC curve analysis showed a cutoff value of 13.2×109/L for platelet count and 129.5 g/L for fibrinogen level in patients with ICH. The transplantation-related mortality rate in the ICH and control group were 50% and 22.2%, respectively(p<0.001).ICH is common cerebral complication after allo-HSCT which associated with high mortality and decreased overall survival rate. After allo-HSCT patients with severe thrombocytopenia plus low level of fibrinogen and/or III-IV aGVHD appeared to be at particularly high risk of ICH.

Disclosures:
No relevant conflicts of interest to declare.
Single Cord Blood Transplantation Combined With An HLA Mismatched Third Party Donor For High-Risk Hematological Patients With HIV Infection
Authors: Kwon Mi , Kuball Jurgen H , Ellerbroek Pauline , Balsalobre Pascual , Serrano David , Buno Ismael , Gayoso Jorge , van Besien Koen , Petz Lawrence D. , Diez-Martin Jose Luis , Wensing Annemarie 
Published: October 2019

Abstract

Background
The safety and usefulness of unrelated umbilical cord blood (CB) stem cell transplantation (SCT) in patients candidates for allogeneic SCT and HIV infection is unknown. Single CB with the co-infusion of CD34+ cells from a third party HLA-mismatched donor (TPD), or Haplo-cord SCT, has shown to reduce the period of post-transplant neutropenia and related early complications associated with single CB transplantation. This platform could potentially reduce the risk of early infections in this particular group of patients. On the other hand, the use of a cell source homozygous for the CCR5 delta32 allele mutation, which confers high resistance against HIV-1 acquisition, is of particular interest in HIV+ patients.

Methods and Results
We report here on the first two patients with HIV infection and high-risk haematological malignancies who underwent haplo-cord SCT in two different centers: (Case 1) a 53 year-old male patient with high-risk MDS; (Case 2) a 34 year-old male with Burkitt lymphoma in CR2. Both CB transplants were performed using the haplo-cord platform with the co-infusion of mobilized and selected CD34+ cells from a TPD. Conditioning regimen were myeloablative in both cases. Case 1 had the additional potential benefit from the use of a CB unit with the homozygous CCR5delta32 mutation. Both cases achieved neutrophil and platelet engraftment similarly to previous haplo-cord SCT performed in HIV negative patients, as well as full CB chimerism. However, case 1 developed beside a severe lung infection, relapse of the underlying malignancy 2 months after SCT and died consequently. Case 2 presented one episode of bacterial sepsis with good response to antibiotics, and one episode of CMV reactivation controlled with valgancyclovir. Thirteen months after SCT, this patient is alive and in CR. Extensive analyses of viral and immunological compartments were performed showing the early viral dynamics in both patients.

Conclusions
CB SCT is feasible in patients eligible for allogeneic SCT and HIV infection. The haplo-cord strategy with the co-infusion of auxiliary cells from a TPD seems to offer a fast neutrophil engraftment similarly to HIV negative patients. Therefore, this strategy should be considered in patients with HIV infection and indication for allogeneic SCT, whenever CB is the source of choice and especially if a CCR5 mutated unit is available.

Disclosures:
Kuball: Miltenyi: GMP product development Other.
Effect Of Genotype On Pulmonary Hypertension In Patients With Thalassemia
Authors: Teawtrakul Nattiya , Ungprasert Phuangpaka , Pussadhamma Burabha , Prayalaw Patcharawadee , Fucharoen Supan , Jetsrisuparb Arunee , Pongudom Saranya , Sirijerachai Chittima , Chansung Kanchana , Wanitpongpun Chinadol , Chuncharunee Suporn 
Published: October 2019

Abstract

Introduction
Pulmonary hypertension is one of the major complications in patients with thalassemia. The prevalence is higher among patients with non - transfusion dependent thalassemia (NTDT) than those patients with thalassemia major. Patients with NTDT have distinct genetic subgroups. Therefore, the effects of different genotype groups on pulmonary hypertension in patients with NTDT were assessed.

Methods
A cross-sectional study was conducted in patients with NTDT aged ≥ 10 years old at Srinagarind University Hospital and Udonthani Hospital. Pulmonary hypertension was defined as a tricuspid regurgitation velocity > 2.9 m/s by trans-thoracic echocardiography. All patients gave consent and the protocol was approved by the Ethics committee of Faculty of Medicine, KhonKaen University and Udonthani Hospital. Clinical characteristics and laboratory data that literature indicated as risk factors for pulmonary hypertension were collected. Genotypes were determined by hemoglobin typing and DNA analysis. The effect of genotype group on pulmonary hypertension was evaluated by using multivariate logistic regression analysis.

Results
Two hundred twenty two patients were recruited, 3 patients were excluded (1 patient with congenital heart disease and 2 patients with valvular heart disease). In a total of 219 patients, pulmonary hypertension was found in 24 patients (10.96%). All patients were categorized into 2 groups according to genetic data that included: 1) β-thalassemia (140, 63.93%) 2) α-thalassemia and combined α and β-thalassemia (79, 36.07%).Genotype groups were statistically and significantly associated with pulmonary hypertension based on the adjusted odds ratios after adjustment for other factors. Patients with β-thalassemia had a statistically significant higher risk for pulmonary hypertension compared to patients with α-thalassemia and patients with combined α and β-thalassemia had an odds ratio of 9.47 (p=0.036).

Conclusion
Genotype group is an independent risk factor for pulmonary hypertension in patients with NTDT. Echocardiography should be routinely recommended in patients with β-thalassemia. In patients with α-thalassemia and combined α and β-thalassemia, pulmonary hypertension is uncommon. Therefore, echocardiography should be only performed when these patients have a clinical indication.

Abbreviation
Hb CS = Hemoglobin Constant spring, Hb Pakse´= Hemoglobin Pakse´

Abbreviation
PHT= pulmonary hypertension, AOR= adjusted odds ratio, 95% CI= 95% confidence interval

Disclosures:
No relevant conflicts of interest to declare.
Platelets Impair NK Cell Immunosurveillance Of Metastasizing Tumor Cells By Altering Surface Expression and Shedding Of Ligands For The Activating Immunoreceptor NKG2D
Authors: Raab Stefanie , Kropp Korbinian Nepomuk , Steinle Alexander , Kanz Lothar , Kopp Hans-Georg , Salih Helmut R. 
Published: October 2019

Abstract
NK cells play an important role in the immunosurveillance of tumor cells. The mechanisms leading to NK cell activation are described by the ‘missing-self’ and “induced-self’ hypotheses, implying that cells with low or absent expression of MHC class I and stress-induced expression of ligands for activating receptors like e.g. NKG2D (NKG2DL) are preferentially recognized and eliminated by NK cells. Besides the direct interaction with their target cells, NK activity is further influenced by various other hematopoietic cells. In mouse models, thrombocytopenia impairs metastasis, and this is reversed by additional depletion of NK cells. However, the knowledge regarding the molecular mechanisms by which platelets influence NK cells is still fragmentary. We recently reported that release of TGF-β by platelets upon their interaction with (metastasizing) tumor cells downmodulates NKG2D on NK cells (Kopp et al., Cancer Res. 2009; Placke et al., J Innate Immun. 2011). Moreover, platelets transfer “healthy” MHC class I to the tumor cell surface. Thus, platelets may facilitate metastasis by interfering with both, “induced and missing self’ NK cell recognition. Here we provide evidence for a yet unknown mechanism by which platelets further impair NKG2D-mediated immunosurveillance. Tumor cells were incubated with platelets from healthy donors resulting in coating of tumor cells and activation of the platelets, or treated with platelet-derived soluble factors (releasate) obtained either by tumor cell-induced platelet activation (TCIPA) or the platelet agonist thrombin. Presence of platelet derived factors derived either from coating of tumor cells or contained in platelet releasate substantially reduced NKG2DL surface expression on tumor cells. This was paralleled by enhanced levels of soluble NKG2DL in culture supernatants, indicating that platelet-derived factors mediate NKG2DL shedding from the tumor cell surface. Diminished NKG2DL surface expression resulted in decreased NKG2D-dependent cytotoxicity of NK cells as revealed by blocking experiments using NKG2D antibody and NKG2DL-specific F(ab)2 fragments targeting the specific modulated NKG2DL. Our data thus identify induction of NKG2DL shedding as novel mechanism by which interaction of platelets with metastasizing tumor cells impairs NK cell immunosurveillance.

Disclosures:
No relevant conflicts of interest to declare.
Histone Deacteylase Inhibitors (HDACi) Suppress Toll-Like Receptor-Induced Dendritic Cell Maturation and Alter Secretion But Not Gene Expression Of Polarising Cytokines By Dendritic Cells
Authors: Dickinson Michael J. , Davenport Alexander , Petrone Pasquale , Prince H Miles , Ritchie David , Neeson Paul 
Published: October 2019

Abstract

Aim/Background
HDACi induce cancer cell apoptosis and are in use for T-cell lymphoma. Prior studies have indicated that HDACi are immune-suppressive. In this study, we address this issue by examining the effects of two different HDACi on human monocyte derived dendritic cell (hmDC) biology.

Methods
hmDC were activated by TLR stimuli (LPS or poly:IC). HDACi effect on TLR-induced hmDC activation was assessed by up regulation of co-stimulatory molecules CD80, CD86 and CD83 along with secretion of IL-12p70, IL-10 and IL1β. To address the mechanism for drug-induced altered cytokine secretion mRNA for IL-12p70, IL-10 and IL1β were assessed followed by mir-155 mRNA and SOCS-1 protein. The functional outcome was assessed in an allogeneic MLR.

Results
At doses sub-optimal to induce myeloma cell death, both drugs significantly inhibited TLR-induced hmDC increase in CD80 and CD83, but not CD86. TLR-induced secretion of IL-10 and IL12p70 was reduced while IL-1β secretion was increased. This occurred regardless of drug sequencing. HDACi did not significantly alter expression of IL-12p70, IL-10 or IL-1β mRNA despite changes in protein levels. To reveal the mechanism for the HDACi-induced hmDC IL-12p70 defect, the upstream molecules miR-155 and SOCS-1 were examined. Interestingly, panobinostat but not romidepsin induced mir-155 down-regulation and SOCS-1 protein increase. Subsequently, allogeneic T-cells co-cultured with HDACi/TLR-ligand-treated hmDC secreted lower levels of cytokines (decreased secretion of IFN-γ, IL-2, TNF, IL-4 and IL-17) compared to those allogeneic T cells co-cultured with control hmDC.

Conclusion
In this study, we show that whilst HDACi impair DC maturation and modulate subsequent T cell responses. Our findings suggest that panobinostat induces the IL-12p70 effect via the mir-155/SOCS-1 pathway, whereas romidepsin induces the effect via a mir-155 independent pathway. This data suggests that HDACi affect the hmDC maturation response to pathogen, and that these drugs may alter the ability of treated patients to raise an effective immune response to pathogens or, indeed, tumour antigens.

Disclosures:
No relevant conflicts of interest to declare.