bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prior Therapy with Rituximab (R) in Patients with Follicular Lymphoma (FL) Does Not Affect Relapse-Free (RFS) or Overall Survival (OS) after High Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT).
Authors: Kang Tyler Y. , Sweetenham John William , Thakkar Snehal G. , Rybicki Lisa A. , Brown Stacey , Dean Robert , Sekeres Mikkael A. , Advani Anjali , Sobecks Ronald , Kalaycio Matt , Pohlman Brad , Bolwell Brian J. 
Published: October 2019

Abstract
ASCT has been used in FL to achieve durable remissions either as consolidation therapy in first remission or as salvage therapy in the relapsed or refractory setting. The recent addition of R to chemotherapy regimens for FL has been shown to improve RFS and, in some studies, OS. The effectiveness of HDT and ASCT in pts with FL who have received prior therapy with R is unknown, although there is speculation that R may adversely affect outcome.
We retrospectively reviewed 128 consecutive patients with FL who underwent HDT and ASCT from 1/1994 through 12/2004. The analysis included 106 patients who were divided into No R and R groups. We excluded 19 patients who received R only as salvage therapy and three patients who received bone marrow rather than stem cells as their auto-graft. Patients were analyzed according to whether or not they had received an R-containing regimen prior to transplantation.
71 patients with No R therapy and 35 patients with R therapy were included. Characteristics between No R and R group are similar, with major difference being age, CD34+ dose, and length of follow-up. The No R group had a median OS that was not reached during follow up, with a median RFS of 49.9 months. The R group had a median OS of 63.2 months and a median RFS of 24.6 months. The OS and RFS were not significantly different between the groups. To control for potentially confounding factors between cohorts, we used propensity analysis to identify 22 patients among the R group who were well-matched to 22 patients in the No R group. Analysis was done for this well-matched cohort (Table 1), and OS and PFS were also found to have no significant difference (Figures 1 and 2).
In conclusion, we did not observe a difference in outcome in the effectiveness of HDT and ASCT between FL patients who received R therapy and those who did not. Prospective studies are required to confirm these results.
Table 1. Matched Groups by Rituximab Use No Rituximab Rituximab N % N % Age (years) mean +/− SD 49 +/− 8 59 +/− 7 median (range) 51 (28–69) 59 (49–75) Stage I/II 4 8.2 3 23.1 III 8 16.3 2 15.4 IV 37 75.5 8 61.5 # of Prior Chemotherap mean +/− SD 2.4 +/− 1.0 3.1 +/− 1.7 median (range) 2 (1–5) 2 (1–7) IPI Low, Low-Int 29 59.2 13 100 High-Int, High 20 40.8 0 0.0 Follicular Lymphoma - Matched Groups Follicular Lymphoma - Matched Groups Follicular Lymphoma - Matched Groups Follicular Lymphoma - Matched Groups
Influence of GST Gene Polimorphisms in the Develovement of Liver Sinusoidal Obstructive Syndrome in Patients with Multiple Myeloma Undergoing Hematopoietic Stem Cell Transplantation.
Authors: Martinez-Lopez Joaquin , Garcia-Efroom Guillermo , Martinez-Sanchez Pilar , Garcia-Sanz Ramon , Blade Juan , Sanchez-Godoy Pedro , Arriba Felipe , Garcia-Larana Jose Maria , Terol Maria Jose , Albiza Enriqueta , Montejano Laura , Grande Silvia , Rapado Inmaculada , Hernandez Belen , Miguel Jesus San , Lahuerta Juan Jose 
Published: October 2019

Abstract
Introduction: Liver metabolism has two fundamental types of enzymes. Phase two enzymes include GlutathioneS-transferases (GST), with three main variants: GST-M1, GST-T1 and GST-P1. Individual differences in these enzymes could influence their detoxificating capacity.
Aim: To study the influence of several genetic GST liver enzymes variants in the development of liver Sinusoidal Obstruction Syndrome (SOS) in patients with multiple myeloma (MM) that received BUMEL as conditioning regimen for Autologous Stem Cell Transplantation (ASCT).
Patients: 91 patients with MM - included in Spanish protocol Myeloma 2000 that had received BUMEL as conditioning schedule for ASCT - have been studied; 12 of them had developed SOS. 62 healthy individuals as well as 12 patients with monoclonal gammapathy of uncertain significance (MGUS) were also studied.
Methods: Three genotype variants of GST enzymes were studied: presence or absence of GST-M1, GST-T1 and GST-P1 polymorphism Ile105Val by real time PCR in light cycler v2 or ABI PRISM 7900HT thermocyclers. Associations between variables were studied by X2 and exact Fisher test. Logistic regression analysis was performed to calculate Odds ratios and relative risk of SOS development.
Results: Significant differences (p>0.0001) were found in the prevalence of homozygous genotype GST-P1 Ile105Val comparing the group of patients with MM and SOS (5 of 12, 41%) and the rest of MM patients without SOS (5 of 79, 6%). This genotype was present in 17% of healthy individuals and MGUS. The genotype absence of GST-M1 was observed in 33% (4/ 12) of MM patients with SOS, 46% (37/79) of MM patients without SOS (p=0.38), 56% of controls and 71% of MGUS. The genotype absence of GST-T1 was observed in 50% (6/ 12) of MM patients with SOS, 27% (22/79) without SOS (p=012), 19% (16/62) of healthy individuals and 21% of MGUS. 33% (4/12) of MM patients with SOS presented the absence of GST-T1 genotype and the presence of homozygous GST-P1 Ile105Val and none of the patients with MM without SOS (p=0,000) presented these genotypes. The only factor associated to development of SOS in regression study was the presence of genotype GST-P1 Ile105Val in homozygosis (OR 10.57 CI 2.45–45.6 p=0.002).
Conclusions: The genotype absence of GST-T1 together with the homozygous GST-P1 Ile105Val polymorphism, especially the latter, should be considered as new risk factors in the development of SOS in MM undergoing ASCT conditioning regimen with BUMEL.
Early Recovery of Thymus-Derived Naïve T Cells in Pediatric Patients (pts) Treated with Non-Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation (NMSCT) for Cancer.
Authors: Fry Terry J. , Rager Alison R. , Hakim Frances , Love Cynthia , Layton Paula , Fowler Daniel , Bishop Michael R. , Gress Ronald , Mackall Crystal L. , Wayne Alan S. 
Published: October 2019

Abstract
Background: Current SCT approaches consistently achieve rapid donor myeloid engraftment, but delayed immune recovery remains a significant obstacle and results in increased risk of infection and relapse. T cells are regenerated via 2 pathways, thymus-derived and peripheral expansion, processes for which IL-7 is critical. We postulated that non-myeloablative pre-transplant conditioning might preserve thymic function in pediatric SCT recipients thus enhancing thymus-derived naïve T cell regeneration.
Methods: We analyzed T cell subsets, T cell receptor excision circles (TREC), and IL-7 levels in peripheral blood after SCT in 21 pediatric pts with high-risk malignancies (median age 14, range 4–21). Fludarabine-based induction chemotherapy was administered for disease control and targeted CD4 count reduction. Pre-transplant conditioning consisted of cyclophosphamide (1,200 mg/m2/day) and fludarabine (30 mg/m2/day) × 4 days plus melphalan (100 mg/m2 × 1 dose in sarcoma pts). Grafts consisted of G-CSF mobilized unmodified peripheral blood stem cells from 5–6/6 HLA-matched first-degree relatives (median CD34 dose 11.7 × 10E6/kg, range 4.4–19.1; median CD3 dose 416 × 10E6/kg, range 228–815). Cyclosporine was used for GVHD prophylaxis.
Results: Donor-derived engraftment was rapid (absolute neutrophil count > 500/uL median day 9, range 8–11). Complete donor lymphoid chimerism (>95% by VNTR-PCR on CD3 sorted peripheral blood) was achieved in all by day 28. Immune recovery was brisk and sustained. Substantial numbers of naïve (CD45RA+/CD62L+) CD4+ and CD8+ T-cells were detected at day 28 (Fig 1). There was a steady increase in TREC from 3 to 12 months consistent with early, robust thymic-dependant T cell generation (Fig 2). This was not seen in adult pts treated on a parallel trial (data not shown). IL-7 levels were elevated and inversely correlated with T cell counts (r=−0.56, p<0.0001).
Conclusions: Targeted immune depletion and NMSCT results in rapid, sustained immune reconstitution in pediatric pts with malignancy. Preserved thymic function appears to contribute to naïve T cell recovery in this setting. We postulate that non-myeloablative conditioning is thymus sparing and that this, in combination with immune depletion-induced IL-7 elevation, promotes early thymic-derived lymphoid recovery. This approach may serve as a strategy to overcome the prolonged immunodeficiency commonly encountered after allogeneic SCT in pediatrics and might be used as a platform to direct allogeneic anti-tumor immune responses in high-risk childhood cancers.
Figure 1 Figure 1. Figure 2 Figure 2.
Outcomes of c Hematopoietic Stem Cell Transplantation (HCT) after Non-Myeloablative Conditioning in Relapsed, Refractory, or Transformed Indolent Non-Hodgkin Lymphoma (NHL).
Authors: Rezvani Andrew R. , Sandmaier Brenda M. , Storer Barry , Maris Michael , Agura Edward , Maziarz Richard , Wade James C. , Chauncey Thomas , Forman Stephen J. , Niederwieser Dietger W. , Shizuru Judith , Langston Amelia , Pulsipher Michael , Storb Rainer F. , Maloney David G. 
Published: October 2019

Abstract
Sixty-two patients (pts) with chemotherapy-refractory indolent or transformed NHL were treated at 10 centers with allogeneic HCT from related (n=34) and unrelated (n=28) donors after 2 Gy total body irradiation with or without fludarabine. Diagnoses included follicular lymphoma (FL) (n=54, including 10 with grade 3 FL), small lymphocytic lymphoma (n=6), and marginal zone lymphoma (n=2). Median age was 54 years (range 33–66 years), and median time from diagnosis to HCT was 4.4 years (range 0.5–18.5 years). Sixteen pts had histologically documented transformation to diffuse aggressive lymphoma prior to HCT. Twenty-seven pts (44%) had failed autologous HCT. Disease status at the time of HCT was complete response (CR, n=16), partial response (PR, n=22), refractory (n=13), untested relapse (n=9), or unknown (n=2). Eleven of the 28 unrelated donor/recipient pairs (39%) had HLA mismatches: 2 at a single allele, 7 at a single antigen, and 2 at an antigen and an allele. One pt had non-fatal graft rejection from a 1-antigen-mismatched unrelated donor. Median follow-up of survivors after HCT was 36.6 months (range 2.3–60 months). Responses (CR [n=18] and PR [n=7]) were seen in 25 of 44 (57%) pts with evaluable disease prior to HCT, while 5 had stable disease, 9 progressed, and 5 were not evaluable due to early non-relapse mortality (NRM) on d27–d108. Two of 16 pts (13%) transplanted in CR relapsed; one was treated with donor lymphocyte infusion and achieved a persistent CR. The incidences of acute GVHD grades II–IV, III–IV, and chronic GVHD were 63%, 19%, and 53%, respectively. At 3 years, the risks of relapse/progression and NRM were 19% and 42%, respectively. There was a trend toward increased mortality with unrelated donors (HR 1.87 [0.9–3.7, p=0.08]). Progression-free and overall survival (PFS and OS) were significantly better in the non-transformed group (see tables 1 and 2).
Table 1. Outcomes Non-transformed Transformed Relapse 6/46 (13%) 6/16 (38%) NRM 20/46 (43%) 6/16 (38%) 3-year OS 24/46 (52%) 4/16 (25%) 3-year PFS 20/46 (43%) 4/16 (25%) Table 2. Hazard Ratios (HR) for Transformed vs. Non-Transformed Pts HR (95% CI) p All-cause Mortality 2.39 (1.2–4.9) 0.02 Relapse/progression 4.75 (1.5–15) 0.01 Grade 3+ acute GVHD 1.84 (0.5–6.3) 0.35 Extensive chronic GVHD 1.96 (0.8–5.0) 0.18 Figure Figure
Allogeneic HCT after non-myeloablative conditioning can produce durable responses and prolonged survival in pts with refractory indolent or transformed NHL. Pts transplanted before histologic transformation had significantly better outcomes. Future efforts will focus on reducing NRM and identifying optimal timing of HCT.
Serum Amyloid A (SAA) as a Molecular Marker for Pre-Engraftment Immune Reactions (PIR) after Cord Blood Transplantation.
Authors: Morita-Hoshi Yuriko , Heike Yuji , Ohsaki Yuka , Shiwa Mieko , Masuoka Kazuhiro , Wake Atsushi , Taniguchi Shuichi , Tobinai Kensei , Takaue Yoichi 
Published: October 2019

Abstract
〈Background and Methods〉: High-grade fever prior to engraftment without any apparent signs of infection, mimicking hyperacute GVHD or engraftment syndrome, is often observed in patients who undergo cord blood transplantation (CBT). This “pre-engraftment immune reaction (PIR)” peaks at around day 9 of CBT, and is often accompanied by high-grade fever, skin rash and weight gain. Although PIR responds well to corticosteroid therapy, the prolonged use of steroid often causes an increased incidence of infectious complications, leading to significant treatment-related mortality, particularly in the elderly. It has been speculated that cytokines induced by the initial immune/inflammation reaction are the primary cause of PIR, but no confirming data are available. To clarify this point, we evaluated the protein expression profile of serum in CBT recipients using a surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy (SELDI-TOF MS) system and found marker candidates in PIR after CBT.
〈Results〉: Thirty-eight blood samples were taken from 13 CBT recipients at 3 different occasions, i.e.
afebrile period prior to PIR onset, onset of fever and resolution of fever, to compare the relative protein expression levels.
Samples were analyzed in 56 spectra by changing the elution conditions with 4 kinds of chips (IMAC30, CM10, H50, Q10), 5 different rinse conditions and 3 kinds of energy absorption molecules. Six candidate protein peaks that commonly increase at the time of PIR with molecular masses of 8611Da, 8642Da, 11452Da, 11512Da, 11539Da and 11669Da were identified. The 11kDa protein peaks that bind to a Q10-anion exchange chip were selected for further analysis. Two 11kDa protein peaks were eluted at pH9 and pH4, but since the proteins eluted at pH4 included albumin which overlapped the candidate protein peak, the elution fraction at pH9 was used for purification and identification. Proteins eluted at pH9 were separated by SDS-PAGE. After in-gel digestion of the 11kDa band by trypsin, the digested peaks were analyzed by PCI Qstar MSMS and the protein was determined using the ProFound database. The results revealed that the 11kDa protein was an N-terminal portion of serum amyloid A (SAA). The SAA level was measured by ELISA in the same sample that was assessed by SELDI-TOF MS. The mean SAA level prior to fever onset was 14 (3–51) μg/mL, and this increased to 883 (40–2470) μg/mL at the time of PIR and decreased to 45 (8–126) μg/mL after resolution of the fever.
〈Conclusion〉: A specific marker for PIR after CBT was identified by an SELDI-TOF MS system. SAA increased by 10- to 100-fold at the time of PIR, and thus may become a useful tool for the diagnosis of PIR.
Figure Figure
Unrelated Donor Hematopoietic Cell Transplantation after Non-Myeloablative Conditioning for Patients with High Risk Multiple Myeloma.
Authors: Sorasio Roberto , Giaccone Luisa , Patriarca Francesca , Montefusco Vittorio , Guidi Stefano , Busca Alessandro , Scime’ Rosanna , Console Giuseppe , Milone Giuseppe , Marotta Giuseppe , Dominietto Alida , Rotta Marcello , Falda Michele , Bacigalupo Andrea , Bosi Alberto , Corradini Paolo , Fanin Renato , Pollichieni Simona , Bruno Benedetto , Boccadoro Mario 
Published: October 2019

Abstract
Allografting can induce long-term molecular remissions and possibly cure in myeloma patients. The recent development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) typically associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pre-treated patients. Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at disease relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning regimen consisted of fludarabine 90 mg/m2 and 2 Gy total body irradiation. GVHD prophylaxis included oral cyclosporine (CyA) and mycophenolate mofetil (MMF). CyA was administered at 6.25 mg/Kg every 12 hours from day -3; levels were targeted to the upper therapeutic range (450–500 ng/ml, Abbott TDX, Abbott Park, IL) for the first month post-transplant. In the absence of GVHD, CyA was tapered from day +100 and discontinued on day +177. MMF was administered from day 0 after PBSC infusion to day +40 at 15 mg/Kg every 8 hours, and then tapered till day +96. Twenty/22 (91%) patients readily engrafted. Two patients experienced graft failure and eventually recovered autologous hematopoiesis. After a median follow up of 11 months (3–27), TRM was 18% and 16/22 patients (73%) are alive. Deaths occurred in 10% of patients transplanted upfront and in 42% of those transplanted at relapse: 3 patients died from infections, 1 from hemolytic uremic/ thrombotic thrombocytopenic purpura syndrome, and 2 from disease progression (both were transplanted at relapse). Ten/20 engrafted patients (50%) had grade II–IV acute GVHD (10% grade III–IV), and 59% had extensive chronic GVHD. Overall response rate was 60% (including 20% CR): 78% in patients transplanted upfront (no disease progression observed) and 45% in those transplanted at relapse. In the two groups, progression-free and one year event-free survival were 100% and 44% (p<0.025), and 90% and 28% respectively (p<0.005).
Unrelated donor non-myeloablative allografting is feasible with relatively low TRM and high response rate. Graft-versus-myeloma effect appears to be more efficient when patients are treated soon after diagnosis. Longer follow-up is needed to assess response duration.
Factors Influencing Short Term In Vivo Biodistribution of Human Bone Marrow Derived Mesenchymal Stem Cells (hMSCs) in a Xenogeneic Animal Model.
Authors: Kyriakou Charalampia , Rabin Neil , Nathwani Amit , Pizzey Arnold , Linch David C. , Yong Kwee 
Published: October 2019

Abstract
Human MSCs are potential agents for tissue regeneration, enhancing haemopoietic stem cell transplantation and delivering genes of therapeutic interest. To successfully implement any of these therapeutic strategies, we need a better understanding of the tissue localisation of systemically administered hMSCs and of the factors that critically influence their biodistribution. Bone marrow (BM) derived hMSCs were isolated from normal donors, cultured using previously described protocols and characterised by phenotype and multi-lineage differentiation. HMSCs were labelled with PKH-26 and injected by tail vein into b2m/NOD/SCID animals (2x106 cells /animal). Analysis of murine tissue mononuclear cells by flow cytometry 24 hours later consistently detected a proportion of transplanted cells in the BM (327 ± 31), spleen (645 ± 147) and lungs (1485 ± 138) in all experiments. This was also confirmed by flow cytometry using human-specific HLA-Class I mAb and FISH analysis. Homing of infused hMSCs to the BM and spleen of b2m/NOD/SCID animals was significantly higher in younger (<10 weeks) when compared with older (>10 weeks) animals (p<0.0001). [BM (424 ± 24 vs 209 ± 20), spleen (1175 ± 154 vs 292 ± 30), lungs (2760 ± 321 vs 1225 ± 269) respectively]. Prolonged ex vivo expansion of hMSCs also impaired their homing. Homing to the BM and spleen was significantly lower (p<0.022, and p<0.015 respectively) for late passage (> P14) when compared with earlier passage hMSCs (< P10). Lentiviral transduction of hMSCs with eGFP did not alter homing when compared to unmanipulated cells.
Tissue homing was markedly enhanced by prior irradiation of animals (325Gy). Numbers of PKH positive cells detected by flow cytometry were significantly higher in the BM of irradiated recipients (425.3 ± 42 vs 110 ± 20 for unirradiated mice, p=0.001). Irradiation also increased homing to the lungs (4722 ± 1220 vs 495 ± 70, p=0.0327). Overexpression of CXCR4 by lentiviral gene transfer in hMSCs significantly enhanced their migration to SDF-1 in vitro. CXCR4 overexpression did not influence short term homing to the BM and other tissues of unconditioned b2 m NOD/SCID. In contrast, CXCR4 transduced hMSCs demonstrated significantly higher levels of homing (compared with eGFP-control transduced hMSCs) when transplanted into irradiated b2 m NOD/SCID. This was particularly marked in the lungs (p=0.007).
Conclusion: In vivo homing of hMSCs is critically influenced by animal age, length of ex vivo cell manipulation and is enhanced in the irradiated-stressed animal model. Overexpression of CXCR4 does not significantly alter hMSCs homing in the unconditioned animal model but does so in the irradiated recipients. Identifying these factors and strategies to improve tissue homing is of great importance for the successful application of hMSCs in cell and gene therapy.
Fibrinogen Enhances Homing-Related Responses of CD34+ by Incorporating Membrane Type1-Matrix Metalloproteinase into Membrane Lipid Rafts.
Authors: Shirvaikar Neeta , Turner A. Robert , Ratajczak Mariusz Z. , Janowska-Wieczorek Anna 
Published: October 2019

Abstract
Clinical studies have shown that transplanted mobilized peripheral blood (mPB) hematopoietic stem/progenitor cells (HSPC) home faster to the bone marrow (BM) than harvested BM or cord blood cells. We previously showed that fibrinogen has a priming effect on HSPC homing by enhancing the chemotactic responses of CD34+ cells towards a low SDF-1 gradient by incorporating CXCR4 into membrane lipid rafts (Blood2005; 105:40). In this study we further investigated the mechanism of priming by determining the effect of fibrinogen on matrix metalloproteinases (MMPs) expressed by CD34+ cells, particularly MT1-MMP which is localized on the leading edge of migrating cells and not only activates latent MMPs but by itself degrades several extracellular matrix (ECM) components such as collagens, laminin, fibrin and fibronectin.
We found that fibrinogen
highly upregulated MT1-MMP protein expression (Western blot) in CD34+ cells as well as proMMP-2 and proMMP-9 secretion (zymography); primed trans-Matrigel chemoinvasion of CD34+ cells towards a low SDF-1 gradient (20 ng/mL), which was inhibited by epigallocatechin-3-gallate, a potent inhibitor of MT1-MMP; and stimulated MMP-2 activation in co-cultures of stromal cells (BM fibroblasts and HUVEC) with CD34+ cells.
Moreover, we demonstrate by confocal microscopy, for the first time, that in CD34+ cells MT1-MMP is localized in the GM1-fraction of lipid rafts where it co-localizes with CXCR4; this co-localization is enhanced when CD34+ cells are stimulated with fibrinogen. Furthermore, disruption of lipid raft formation by the cholesterol-depleting agent methyl-b-cyclodextrin inhibited MT1-MMP incorporation into membrane lipid rafts and also trans-Matrigel chemoinvasion of CD34+ cells towards an SDF-1 gradient. Thus we conclude that fibrinogen enhances homing-related responses of CD34+ cells towards SDF-1 by increased incorporation and co-localization of CXCR4 and MT1-MMP in membrane lipid rafts. Further, we postulate that while the presence of CXCR4 in lipid rafts allows the cells to better sense the SDF-1 chemokine gradient, the upregulated MT1-MMP in the lipid rafts facilitates their migration through the ECM and possibly towards the BM niches.