bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allo-Reactive NK Cells after HLA-Matched Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Hasenkamp Justin , Borgerding Andrea , Chapuy Bjoern , Wulf Gerald , Missal Inga , Jung Wolfram , Truemper Lorenz , Glass Bertram 
Published: October 2019

Abstract
Allo-reactive natural killer (NK) cells frequently occur early after haplo-mismatch hematopoietic stem cell transplantation (HSCT) with killer cell immunoglobuline-like receptor (KIR)-ligand mismatch in graft versus host (GvH) direction. Clinical data and experiments in mice indicate a beneficial influence on relapse rates, graft acceptance and Graft-versus-Host disease (GvHD). We determined the incidence of allo-reactive donor type NK cells after HLA A-, B-, DR-, DQ-matched allogeneic HSCT on a functional level. Clinical course, chimerism (PCR), immune-reconstitution (FACS) and frequencies of functional active and allo-reactive NK cells (ELISpot) were longitudinal determined in 19 patients so far. Patients (pts) suffered for high risk AML (7 pts), CML failing cytogenetic response to imatinib (3 pts), poor risk ALL (2 pts), relapse/refractory high-grade NHL (6 pts) and Multiple Myeloma (13q-) (1 pt). All patients received myeloablative conditioning regimens and GvHD-prophylaxis with cyclosporine A or tacrolimus and short course mycophenolat mofetil without in vivo or ex vivo T cell depletion. Chimerism analyses ensured hematopoietic reconstitution from donor type in 19/19 patients. In 3/19 patients NK cell activity was absent even against HLA class I negative control target cells. Absence of functional active NK cells correlates with severe acute GvHD accompanied by high doses of glucocorticosteroid medication. In all other patients we detected at least once functional active NK cells in peripheral blood. In 4/19 cases we detected allo-reactive NK cells after HSCT at days (d) +28, +68, +128 (case 19), d +56 (case 8), d +355 (case 1) and d +379 (case 13). Two cases were transplanted in KIR-ligand mismatch in GvH direction (donors HLA-CAsn80 and -CLys80, recipients missing HLA-CLys80). Allo-reactive NK cells were absent in all patients with known complete KIR-ligand match. Flow cytometry data on reconstitution of NK cell repertoire showed individual heterogeneous results. After median observation time post HSCT of 268 d (31–902) 3 patients died due to relapse. None of the patients with NK cell allo-reactivity experienced relapse. This is the first proof of circulating functionally active, allo-reactive NK cells after HLA-A, -B, -DR and -DQ matched HSCT. We detected NK cell allo-reactivity in all donor-recipient pairs with KIR-ligand (HLA-C) mismatch in GvH direction. After haplo-mismatch HSCT and T cell depletion NK cell allo-reactivity is restricted early after transplantation (within 3 months). In contrast, we detected late onset (>1 year) of NK cell allo-reactivity after one-locus (HLA-C) mismatch HSCT without T cell depletion of the grafts.
Prevention of Post Transplantation Lymphoproliferative Disorders by Adapted Management of EBV Reactivations. A Monocentric Prospective Study on 101 Patients.
Authors: Choquet Sylvain , Varnous Shaida , Deback Claire , Amiel Corinne , Golmar Jean Louis , Gandjbackhch Iradj , Raphael Martine , Leblond Veronique 
Published: October 2019

Abstract
Background:
Post-transplantation lymphoproliferative diseases (PTLD) represent a rare but aggressive graft complication. Patients who have received a solid organ transplantation have a 20 to 120 fold higher incidence of non-Hodgkin’s lymphoma. EBV reactivation represents a major predictive factor for PTLD, especially during the first year after transplantation, but there is no consensual attitude in this situation
Aim:
We conducted a monocentric prospective study in the Hospital of Pitie Salpêtriere, Paris, France, on all new heart or lung-heart transplanted patients. EBV viral load was systematically followed and confirmed reactivations were treated or surveyed, depending on viral load.
Methods:
101 patients were included between January 2004 and December 2006. Twelve to 15 blood samples per year were analysed. If the viral load was more than 50N, patients were treated by diminution of the immunosupression and one injection of rituximab (375 mg/m2), between 10N and 50N, only the immunosupression was modified, and rituximab was used in case of failure, and below 10N, a simple survey was decided. Correlation with CMV reactivation has been analysed.
Results:
45 (44%) patients presented an EBV reactivation. A simple survey has been sufficient in 29 cases, immunosupression decrease was the only treatment in 8 cases, 2 patients had to be treated in a second step by rituximab, because of stability or increase of the viral load beside the immnosupression modification, and 6 patients have been treated by rituximab as first treatment. All EBV reactivations have been controlled by this attitude, no PTLD has been diagnosed during this period and graft rejection rate did not change. From 1987 to December 2003, 24 PTLD have been treated in the same unit (18 EBV positive, 1 unknown), of which 13 were early PTLD (all EBV positive) with a diagnosis of less than one year after transplantation. We did not find any correlation between EBV and CMV reactivations.
Conclusion:
EBV reactivation after organ transplantation can be managed by diminution of immunosupression and/or rituximab, depending on viral load, without serious complication. A prolongation of this study and a longer follow-up are necessary to know if this attitude decreases the incidence of early EBV positive PTLD.
Bortezomib Added to the Standard Mobilization Regimen of G-CSF and High-Dose Cyclophosphamide Is a Safe and Effective Combination for a High Yield Stem Cell Collection While Promoting Further Tumor Mass Reduction in Myeloma.
Authors: Stern Jessica L. , Di Carlo Brian , Schuster Michael W. , Shore Tsiporah B. , Harpel John G. , Pearse Roger , Zafar Faiza , Dymek Joanne , Ryan Jessy , Jayabalan David , Chen-Kiang Selina , Ely Scott , Leonard John P. , Coleman Morton , Niesvizky Ruben 
Published: October 2019

Abstract
Standard stem cell mobilization regimens for multiple myeloma patients include G-CSF alone or in combination with high dose cyclophosphamide. Given the known in vitro and in vivo synergy between alkylating agents and proteosome inhibitors, we sought to optimize the potential for concurrent cytoreduction by adding bortezomib to the mobilization regimen. Five evaluable patients, whose prior therapy consisted of six cycles of a 21-day treatment with bortezomib/dexamethasone +/− pegylated liposomal doxorubicin, were mobilized. They received IV push bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 in combination with high-dose cyclophosphamide at 3mg/m2 and MESNA on day 8. G-CSF was given for 10 consecutive days starting on day 9. One patient began this regimen in nCR, two were in PR, and two were in CR by urine and serum immunofixation and bone marrow evaluation. Stem cells were easily harvested from each of the five patients. The number of CD34+ cells collected far exceeded the amount normally mobilized with cyclophosphamide and/or G-CSF alone, with four out of 5 patients collected in a single day.
The two patients who began the mobilization cycle in PR continued to respond positively. Their protein levels dropped an additional 8.9 and 14.6 percent respectively during the last cycle. The patient who began mobilization in nCR achieved a CR by the end of treatment. Some expected toxicities associated with high dose cyclophosphamide and G-CSF occurred. All patients experienced grade 3 and 4 cytopenias, however, they recovered and were able to continue on to transplant. Serious adverse events of grade 3 chest pain (non-cardiac), grade 4 pneumonia, and grade 4 febrile neutropenia also occurred. Bortezomib in addition to high dose cyclophosphamide followed by G-CSF is a novel, well-tolerated and efficacious combination for stem cell mobilization in patients with multiple myeloma. This regimen not only yields a high number of stem cells within a short collection time, but may further cytoreduce disease as well.
Stem Cell Collection Patients Days Required for Collection CD34+ Stem Cells (million/kg) 1 1 21.2 2 1 47.4 3 1 22 4 1 17.9 5 4 40.6
Adoptive Donor T-Cell Infusions Are Necessary and Efficient To Induce Lasting Molecular Remissions after Highly Purified CD34+ Sibling Donor Transplants for First Chronic Phase Chronic Myeloid Leukemia - Final Report and Long-Term Follow-Up of a Phase II Study.
Authors: Elmaagacli Ahmet , Peceny Rudolf , Koldehoff Michael , Ottinger Hellmut , Trenschel Rudolf , Steckel Nina K. , Beelen Dietrich W. 
Published: October 2019

Abstract
Since September 1998, we prospectively studied the feasibility of transplantation using purified peripheral blood CD34+ cells from HLA-identical sibling donors in first chronic phase chronic myeloid leukemia (CML). A total of 60 patients (pts) with a median pretransplant risk score of 2 (range 1–4) has been included in this study. One patient received an unmanipulated graft due to poor CD34+ donor cell mobilization, while three pts (5%) were successfully retransplanted with an unmanipulated graft from the primary donor after secondary graft failure (n=2) or from an unrelated donor after hematologic relapse (n=1). As part of the study protocol, all pts were closely monitored for BCR-ABL transcripts using real-time RT-PCR analysis of peripheral blood cells as well as BCR-ABL-interphase FISH and metaphase karyotyping of marrow cells. Of the 60 pts, 56 were eligible for the application of donor lymphocyte infusions (DLI), but 7 pts did not receive DLI due to sustained molecular remission and complete chimerism. Thirty-one pts (52%) received DLI because of increasing BCR-ABL transcript levels or hematologic relapse, and 18 pts (30%) as programmed T-cell add-back. The median starting dose was 0.33 (0.01 – 10) x 106 CD3+ cells per kg with a median maximum dose 3.3 (0.17 – 100) x 106 CD3+ cells per kg. DLI induced a lasting reduction of median BCR-ABL transcript levels (BCR-ABL/GAPDH ratio) of more than 3 log10 and the estimate of being in a complete molecular remission at 7 years is 83% ± 5%. Six pts. (10%) did not respond to DLI, but 4 of these pts. attained a cytogenetic and molecular response by imatinib and/or interferon treatment. The cumulative risk of grades II-IV acute GvHD is 15% ± 5% for all study pts, and the risk of chronic GvHD is 25% ± 6%, respectively. After a median follow-up period of 46 (range 6 – 86) months for all pts, the cumulative 7-year survival estimate is 91% ± 4% (survival rate 92%). Causes of death were disease progression, secondary malignancy, liver failure, septicemia, and systemic capillary leak syndrome in one patient each. In conclusion, the concept of highly purified peripheral blood CD34+ cell transplantation in conjunction with adoptive DLI is associated with a particularly low risk of non-relapse mortality and allows induction of lasting molecular disease control in the majority of first chronic phase CML patients.
Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myelogenous Leukemia.
Authors: Shapira Michael Y. , Panagiotis Tsirigotis D. , Or Reuven , Resnick Igor B. , Gesundheit Benjamin , Slavin Shimon 
Published: October 2019

Abstract
Despite increases in CR rates, most patients with AML will relapse following successful induction treatment. Allogeneic stem cell transplantation (SCT) remains the most effective post-induction relapse preventing treatment. Similarly, for patients with relapsed/chemorefractory disease, SCT represents the only possible curative treatment modality. However, because of the significant morbidity and mortality of myeloablative conditioning regimens, SCT has been mainly restricted to young patients without co-morbidities. Because of these limitations, currently most transplant centers limit the application of SCT to patients younger than 50–55 years old.
This study included 73 patients (M=37, F=46, median age 39-years, range (17–65)) with AML treated with a single nonmyeloablative (NST) regimen in the BMT department of Hadassah University Hospital. The majority of patients had advanced AML pre-transplant (CR1 n=27; CR2 n=14; CR3 n=1; relapse n=31; chemorefractory disease n=24). All patients were prepared by the NST protocol that included IV fludarabine 30mg/m2/day (on days -10 to -5) and oral busulfan 4mg/kg/d or IV busulfex at a dose of 3.2 mg\kg\d (on days -6 and -5), with IV ATG (on days -4 and -1).
Results: Engraftment of neutrophils was achieved in 70/73 (96%) patients within a median of 15 (range 9–31) days, while engraftment of platelets was achieved in 69/73 patients (95%) within a median of 12 (range 0–86) days. Chimerism analysis data were available for 68 patients. Complete donor chimerism in the peripheral blood was achieved in 58/68 (85%) patients. 42/68 patients (62%) who survived at least one month and had a sustained engraftment, developed aGVHD. The cumulative incidence of severe aGVHD grade III-IV was 27% (18/68 patients). 35/65 (54%) patients who survived more than 100 days developed cGVHD, which was extensive in 22 (34%) cases. The cumulative incidence of NRM at 100d and 1y was 12% and 28% respectively. With a median follow up of 38m (range 10 – 118), 24/73 patients survived. Twenty-one patients survive in continuous CR, while 3 patients who relapsed post-transplant survive in CR after a second allo-SCT. The estimated long-term OS for the whole group is 30% (figure 1). 27/73 patients underwent transplantation while in CR1. Two out of these 27 patients relapsed and died, while another 8 patients died due to transplant associated complications. The estimated long-term OS for this subgroup is 63% (17/27 patients surviving in continuous CR) (figure 2).
In conclusion, the results of our study showed that our NST approach is associated with a potent anti-leukemic efficacy. The results of our study look comparable to those obtained after standard myeloablative conditioning even when stratified into disease status subgroups. Prospective randomized trial comparing myeloablative vs nonmyeloablative regimens low-risk patients is warranted.
Figure Figure Figure Figure
Four-Year Follow-Up after High-Dose Immunosuppressive Therapy (HDIT) for Severe Systemic Sclerosis (SSc).
Authors: Nash Richard A. , McSweeney Peter , Crofford Leslie , McDonagh Kevin T. , Mayes Maureen , Nelson J. Lee , Gooley Ted , Holmberg Leona , Shulman Howard , Wener Mark , McLaughlin Bernadette , Henstorf Gretchen , Molitor Jerry , Seibold James , Sullivan Keith , Furst Daniel 
Published: October 2019

Abstract
To determine if sustained responses could be achieved after HDIT and rescue with autologous CD34-selected hematopoietic cells, we assessed the 4-yr outcome in patients (pts) with severe SSc. Thirty-four early (≤4 years), diffuse [mod. Rodnan skin score (mRSS) ≥16] SSc pts with predefined visceral organ dysfunction (primarily lung) were included. G-CSF was used for mobilization of peripheral blood stem cells and the autologous graft was CD34-selected. HDIT included cyclophosphamide (120 mg/kg), antithymocyte globulin (90 mg/kg) and total body irradiation (800 Gy) (with lung shielding of the last 26 pts). Neutrophil and platelet counts recovered by 9 (7–13) and 11 (7–25) days, respectively. There was a significant improvement in skin (−73%, p<0.0001) and in overall function (HAQ-DI: −56%, p<0.0001) at 4 (1–8) years in evaluable pts compared to baseline (Table). Lung, heart and kidney function, in general, remained clinically stable. Importantly, biopsies confirmed a response in skin associated with resolution or a significant decrease of dermal fibrosis. Seventeen (63%) of 27 evaluable patients surviving at least 1 year after HDIT continued to have sustained responses at 4 (1–8) yrs and required no DMARD (drug-modifying antirheumatic drug) treatment. Twelve patients died (transplant-related=8 [23%]; SSc-related=4 [12%]). Two transplant-related deaths were secondary to renal crisis events that occurred within 3 months of HDIT. The other 6 transplant-related deaths were cardiac or pulmonary toxicities (n=4), EBV-PTLD (n=1) and a myelodysplastic syndrome (n=1). The estimated overall survival was 64% at 5 yrs. In conclusion, sustained responses were observed in 63% of evaluable patients after HDIT (median: 4 yrs) and marked improvement in skin and overall function was observed in high-risk SSc pts. A decrease in skin score was associated with skin remodeling.
Assess-ments Mean Baseline (BL) (n=34) Year 1–2 Difference from BL* Year 3–4 Difference from BL* Year 5–8 Difference from BL* Difference at 4 (1–8) Yrs from BL* * Difference between last measurement in that time period from baseline. mRSS (skin score) 30.12 −17.56, p<0.0001 (n=25) −21.24, p<0.0001 (n=21) −21.82, p<0.0001 (n=11) −22.08, p<0.0001 (n=25) mHAQ (disability score) 1.85 −1.26, p<0.0001 (n=23) −1.08, p<0.0001 (n=20) −1.50, p<0.0001 (n=11) −1.03, p<0.0001 (n=26) FVC (%) 71.53 4.48, p=0.06 (n=27) 2.09, p=0.56 (n=23) 10.36, p=0.007 (n=11) 2.11, p=0.50 (n=27) DLCO (%) 60.09 −1.37, p=0.60 (n=27) −3.70, p=0.31 (n=23) −2.27, p=0.51 (n=11) −7.07, p=0.02 (n=27) Creatinine (mg/dL) 0.78 0.26, p=0.02 (n=26) 0.25, p=0.009 (n=23) 0.13, p=0.008 (n=11) 0.25, p=0.003 (n=27) Ejection Fraction (%) 63.24 −0.21, p=0.90 (n=24) −2.84, p=0.06 (n=19) −3.85, p=0.03 (n=11) −2.37, p=0.06 (n=27)
Genetic Polymorphisms Correlated with Outcome in Multiple Myeloma Patients Receiving High Dose Melphalan.
Authors: Dumontet Charles , Landi Stefano , Reiman Tony , Plesa Adriana , Bellini Ilaria , Barale Roberto , Pilarski Linda , Tavtigian Sean , Gemignani Federica 
Published: October 2019

Abstract
High dose melphalan is an essential component in the treatment of patients with advanced multiple myeloma. However little is known regarding genetic polymorphisms possibly correlated with patient outcome in this setting. To identify polymorphisms predictive of survival and/or toxicity we performed a SNP analysis in 83 patients having received high dose melphalan for multiple myeloma. All patients had received one or two courses of high dose melphalan with stem cell reinfusion. DNA was obtained from peripheral blood mononuclear cells and analyzed for 230 SNPs in genes selected for their role in drug metabolism, DNA repair, cell cycling or apoptosis. There were 48 males and 35 females and the median age was 58 years. The average number of VAD courses received before high dose melphalan was 4 (3–6). 49 patients received two high dose melphalan courses. The best response to melphalan was CR in 22 pts, very good response in 14 pts, partial response in 37 patients and stable or progressive disease in 10 patients. 37 patients had experienced disease progression and 8 patients had died at last follow-up. 29 patients experienced high grade (III-IV) mucositis after high dose melphalan. The median freedom from progression was 40 months. CYP2E1 polymorphism 7632 was correlated with freedom from progression (FFP) after high dose melphalan (p=0.02). SULT1A2 704 polymorphism was correlated both with FFP (p=0.002) and with overall survival (p=0.001). Occurrence of severe mucositis after high dose melphalan therapy was correlated with XRCC1 polymorphism 1198 (24% vs 51% of high grade mucositis) as well as ATM polymorphisms. These results suggest that SNPs of genes involved in drug metabolism or repair could be used to distinguish patients subgroups with different toxicity/efficacy profiles after high dose melphalan.
OS according to SULT1A2 N235T OS according to SULT1A2 N235T
Increased Calreticulin Expression in Clonal Plasma Cells Is Associated with Complete Response to Melphalan and Autologous Stem Cell Transplant in Systemic Light-Chain Amyloidosis.
Authors: Zhou Ping , Olshen Adam B. , Teruya-Feldstein Julie , Comenzo Raymond 
Published: October 2019

Abstract
Systemic light-chain amyloidosis (AL) is a protein deposition disorder and a monoclonal plasma cell disease. Treatment of AL has focused on the reduction or elimination of the clonal plasma cells that make amyloid-forming light chains. High-dose melphalan and stem cell transplant (MEL SCT) is an effective therapy for selected AL patients. At 3 months post-SCT, response of the clonal plasma cell disease can be reliably scored; the achievement of a complete response (CR= immunofixation negative) is usually associated with extended survival while no response (NR= < 50% reduction) is not. Many factors likely contribute to this distribution of responses. In order to identify factors specific to clonal plasma cells, gene expression profiles (GEP; Affymetrix U133 PLUS 2.0) were obtained using FACS-sorted CD138+/DAPI- plasma cells (>95% pure) from untreated AL patients before SCT. Supervised analyses were then performed based on responses at 3 months post-SCT, comparing the CR (n=4) and NR (n=5) groups. The basic analysis was a t-test, filtering genes for differential expression at p<0.01, and those that passed were subject to EASE analysis in order to identify gene ontology families over-represented on the gene list. A secondary filtering selected only genes with two-fold difference in expression between CR and NR, average expression of at least 1000, and inclusion in an EASE group that had a p<0.05. Five genes were identified as over-expressed in the CR group: WARS, SHMT2, IARS, CALR, and PSMB4. Our initial validation studies, using purified baseline clonal plasma cells from 11 patients and baseline marrow biopsy specimens from 25 patients, have focused on calreticulin (CALR) and tryptophanyl tRNA synthetase (WARS). By real-time polymerase chain reaction studies with GAPDH and normal plasma cell controls, the expression levels of CALR were significantly lower in NR patients (p=0.02) while differences in WARS expression did not achieve significance (p=0.25). By immunohistochemical (IHC) staining for CALR in marrow biopsies, a CALR IHC index was developed, with scoring of the fraction of plasma cells expressing CALR (over total CD138 positivity) and intensity of CALR staining (both scored 0, 1, 2 or 3; the scores were multiplied to compute the index, range 0–9). CALR-stained marrows were scored blindly. Patients with CALR index of 9 had an 88% likelihood of achieving CR while those with scores of 0–6 had a 39% chance (Fisher’s exact test, p=0.046). In sum, calreticulin expression in clonal plasma cells from AL patients is associated with the response to MEL SCT. Further studies are on-going to determine the basis for this association.