bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in Immune Reconstitution and Cytokine Production in Children with Sibling Donor BMT Versus T-Cell Depleted PBSCT from Unrelated or Mismatched Family Donors.
Authors: Wiegering Verena A. , Eyrich Matthias , Schlegel Paul G. , Winkler Beate 
Published: October 2019

Abstract
Introduction: Transplantation of haematopoietic stem cell (HSCT) from human leucocyte antigen (HLA)-disparate parental donors presents an approach for the treatment of patients lacking an HLA-matched donor, but little is known about differences in immune reconstitution as compared to conventional BMT. We prospectively compared paediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated or HLA-mismatched donors vs. recipients of unmanipulated bone marrow from matched sibling donors.
Patients: Immune reconstitution was studied in 20 children (20 transplants [5 sibling, vs. 8 UD, 7 haplo]; median age was 9,6 years; range 7m-26y; 7 female, 13 male). Blood samples were drawn before allo-HSCT, on days 14 (take), 30, 60, 100, 200 and 365 and >15months after SCT.
Methods: We analyzed lymphocyte subpopulations using flow cytometry. Cytokines (IFNg, IL2, TNFa, IL4, IL5, IL10) were determined by FACS after in vitro stimulation with PMA, ionomycin and brefeldin for 24h. Additionally, we measured IL2, IL7, IL13, IL15, IFNg and TGFb in unstimulated sera by ELISA. Further more, we studied TREC values and did spectratype analysis by real time-PCR and gel electrophoresis.
Results: After allo-HSCT, NK-cells were the cells, which regenerated first. In T-cells, decreased absolute counts could be detected as well as an inverted CD4-CD8-ratio during the first year after SCT. In CD4+ T-cells, the memory phenotype (CD45RO+) predominated. Sibling recipients show a faster T-cell regeneration than recipients of UD or mismatched family donors (MM).
As to cytokine levels in unstimulated sera, IFNg levels remained stable, while we saw high level of IL4 shortly after allo-HSCT; IL4 levels decreased during the first year after SCT. TGFb showed increased levels post-transplantation for up to two years. In stimulated T-cells, we measured a rise in Th2-cytokines (IL4, IL5, IL10) until d60 and a decrease of IFNg/TNFa. Th2-cytokines returned to pre-transplantation levels until d200, whereas Th1-cytokines rise to higher level than before transplantation. We could find that IL2 was produced predominantly by CD4+ / IFNg+ cells and by CD8+cells. Patients who received T-cell depleted stem cell preparations show lower IFNg and TNFa values and higher Th2-cytokine levels than patients who received bone marrow.
TREC counts appear earlier in sib HSCT (median d60) than in MM-transplant (median d200). As to spectratype values, we found a distribution of the 24Vb gene families of 4,18% per Vb-family with clonal expansion, especially in the first months after HSCT, of BV6b>BV23>BV1>BV16.
Clinical and Pathological Differences between Nasal and Nasal-Type NK/T Cell Lymphomas: A Summary of 136 Cases from the International T Cell Lymphoma (ITCL) Project.
Authors: Au Wing , Intragumtornchai Tanin , Nakamura Shigeo , Armitage James Olen , Liang Raymond 
Published: October 2019

Background: Due to their lower incidence, pathological heterogeneity and varied geographical distribution, the clinicopathological features and prognostic factors in mature T/NK cell lymphomas have not been comprehensively studied in international studies.
Materials and methods: Consecutive adult new cases of mature T cell neoplasms from 1990–2002 from 21 clinical centers in 13 countries were reviewed. NK/T nasal/nasal type lymphoma was defined by standard WHO criteria after central review.
Results: Among 1159 cases of proven T cell lymphomas, 136 cases (11.7%) of NK/T lymphomas were registered (nasal 68%, nasal-type 26%, aggressive or unclassified 6%). Its incidence among T cell lymphoma was higher in Oriental (22%) than in Western countries (4%) and in Continental Asia (43%) than in Japan (11%, 19% excluding ATLL), where nasal-type subcategory is particularly uncommon (6% vs 42%). The median age was 49 years with male to female ratio of 2:1. The nasal-type cases had higher stage (p=0.0002) and LDH (p=0.01), more B symptoms (p=0.042), bulky disease (p=0.026) and poorer performance status (p<0.001) than nasal ones. Compared to nasal-type cases, more nasal patients received treatment (98% vs 80%, p=0.0009), including anthracycline (89% vs 76%, p=0.08) and radiotherapy (RT, 52% vs 24% p=0.018). The inclusion of RT to early stage nasal cases yielded survival benefit (p=0.045). The median overall survival (OS) was inferior in nasal-type than nasal cases for both early (0.36 vs 2.96 yr, p<0.001) and late stage diseases (0.28 vs 0.8 yrs, p=0.031). The event free and overall survival curves tend to overlap, signifying poor salvage efficacy for relapses. Among nasal disease, prognostic value for OS was confirmed for all three published indices: IPI (Schipp et al, p=0.0057), T-IPI (Went et al, p=0.044) and NK/T PI (Lee et al, p<0.001). In addition, Ki67 staining >50% (p=0.05), transformed T cell >40% (p=0.022), raised CRP (p=0.025), hemoglobin <11g/dl (p=0.0038), platelet count <150×109/l (p=0.0092), B symptoms (p=0.042) were associated with poorer OS on univariate analysis. Their prognostic values were retained on multivariate analysis, after controlling for factors used for the IPI, T-IPI and NK/T PI. However, none of the histological or clinical prognostic factors or prognostic indices was significant for nasal-type disease.
Conclusion: The prognosis of nasal/nasal-type lymphoma is distinctly worse than other categories of peripheral T cell lymphomas. The clinical feature, treatment response and epidemiology of nasal type lymphoma is different from that of nasal NK lymphoma and the poor response preclude the finding of any favorable prognostic factors. There are still grounds for developing a better prognostic model for nasal cases to triage patients to more aggressive or novel treatment.
Treatment of Adenovirus Infection by Adoptive Immunotherapy: Adenovirus Capsid Hexon Is the Main Target Protein of Adenovirus-Specific Cellular Immunity.
Authors: Arbach Olga , Frentsch Marco , Chmielewicz Barbara , Kaiser Marco , Ellerbrock Heinz , Lauster Roland , Arnold Renate , Radbruch Andreas , Voigt Sebastian , Ebell Wolfram , Thiel Andreas 
Published: October 2019

Abstract
Introduction: Adenovirus (AdV) infection is a severe complication after hematopoietic stem cell transplantation, particularly in paediatric patients. Control of AdV infection particularly seems to be dependent on CD4+ T-cells but their main AdV antigenic targets have remained unknown so far. In order to design protocols for targeted adoptive immunotherapy the identification of the main AdV antigenic targets is a fundamental prerequisite.
Methods: We here adapted a novel technique to directly assess the entire repertoire of CD4+ T-cells specific AdV antigens according to antigen-induced CD154 expression after short-term ex vivo stimulation. AdV-lysate-specific and AdV-hexon-specific CD4+ T-cells were isolated, expanded in vitro and further assessed for their fine specificities using recombinant AdV-proteins and AdV-lysates from various AdV-serogroups. The cytokine profile of AdV-lysate- and AdV-hexon-specific CD4+ T-cells were assessed by intracellular analysis of AdV-induced CD154+ CD4+ T-cells.
Results: AdV-lysate-specific CD4+ T-cells reacted predominantly with AdV-hexon capsid protein. Furthermore, AdV-hexon (serogroup B) specific CD4+ T-cells crossreacted with recombinant hexon protein derived from various other AdV-serotypes and were characterized by a Th1-like cytokine profile.
Conclusion: Our results prove the effectiveness of antigen-induced CD154-expression for assessment of the entire repertoire of CD4+ T-cells specific for pathogens, for the identification of immunodominant target antigen from pathogens. We demonstrate that adenovirus hexon protein is a suitable candidate antigen for the ex vivo generation of adenovirus-specific, serogroup cross-reactive CD4+ T-cells with a Th1-like cytokine profile for adoptive T-cell therapies.
Randomized Comparison of 4-Times-Daily Versus Once-Daily Intravenous Busulfan in a Conditioning Therapy for Hematopoietic Cell Transplantation (HCT).
Authors: Ryu Seong-Gil , Lee Je-Hwan , Choi Seong-Jun , Lee Jung-Hee , Lee Young-Shin , Seol Miee , Hur Eun-Hye , Lee Soo Han , Bae Kyun Seop , Noh Gyu Jeong , Lee Moo-Song , Yun SungCheol , Han Sang Beom , Lee Kyoo Hyung 
Published: October 2019

Abstract
Several single-arm studies have shown that once-daily or twice-daily intravenous busulfan (iBU) may be equally safe and effective compared to traditional 4-times-daily iBU. We performed a prospective randomized trial of 4-times-daily vs. once-daily dosing of iBU in a conditioning therapy for HCT, and compared pharmacokinetic (PK) characteristics of iBU and clinical outcomes in terms of engraftment, post-HCT toxicities, non-relapse mortality (NRM), and overall survival. All of 60 patients, who received iBU on the first day of conditioning therapy for HCT, were randomized to receive iBU either as 0.8 mg/kg over 2 hr 4 times a day (BU4 arm) or 3.2 mg/kg over 3 hr once a day (BU1 arm) between May 2004 and August 2005. Limited sampling strategy was used for PK studies, which were done for the first busulfan dosing. Baseline patient and donor characteristics were well balanced between 2 arms regarding sex, age, diagnosis of underlying disease, time from diagnosis to HCT, disease status at HCT, GVHD prophylaxis regimen, conditioning therapy regimen, ABO mismatch between donor and recipient, donor-recipient sex pair, donor age, type of graft, donor type, and cell doses of graft. The complete PK data were obtained from all 60 patients and those were comparable between 2 arms: elimination half-life (mean ± SD) was 2.75 ± 0.22 vs. 2.83 ± 0.21 hr in BU4 arm vs. BU1 arm, respectively (P=0.304), estimated AUC was 7933.43 ± 2177.71 vs. 8556.86 ± 2452.07 μM × min per day (P=0.367), and clearance was 2.05 ± 0.36 vs. 1.91 ± 0.31 ml/min/kg (P=0.133). Median times to engraftment of neutrophils (BU4 arm vs. BU1 arm, 14 vs. 14 days, P=872) and platelets (26.5 vs. 25.5 days, P=0.946) after HCT were similar between 2 arms. There were no significant differences in cumulative incidence of acute GVHD (BU4 arm vs. BU1 arm, 31.0% vs. 13.8%, P=0.145) and occurrence of CMV infection (40.0% vs. 23.3%, P=0.165) or hepatic veno-occlusive disease (10.0% vs. 16.7%, P=0.448). Other toxicities within 100 days after HCT were not significantly different between two arms. Cumulative incidence of NRM was 25.5% vs. 17.3% (P=0.488) and overall survival probability at 1 year was 69.0% vs. 70.0% (P=0.758). In conclusion, our randomized study demonstrates that once-daily iBU has similar PK profiles and results in at least not inferior clinical outcomes compared to traditional 4-times-daily iBU.
Voriconazole Therapeutic Drug Monitoring: Relationship between Drug Levels and Liver Function Tests.
Authors: Trifilio S. , Khalid M.K. , Pennick G. , Pi J. , Bainbridge N. , Zook J. , Mehta J. 
Published: October 2019

Abstract
Voriconazole is increasingly being used after HSCT. The hepatic cytochrome P450 isoenzyme 2C19 plays a significant role in voriconazole metabolism. As CYP2C19 exhibits significant genetic polymorphism, some patients metabolize voriconazole poorly resulting in increased plasma drug levels. However, the clinical significance of this is unknown. There is some evidence that toxicity rates are higher in patients with higher voriconazole levels (Boyd et al. Clin Infect Dis2004;39:1241–1244). In a preliminary study of 41 voriconazole levels in 25 patients, we had found that voriconazole levels correlated with aspartate aminotransferase (AST) and alkaline phosphatase (AP) levels (Trifilio et al. Bone Marrow Transplant2005;35:509–513). It was unclear if the abnormal liver function was the cause or the result of higher voriconazole levels. To further elucidate this relationship, we analyzed data on 171 steady-state plasma trough levels performed after at least 5 days of voriconazole therapy in 87 patients with hematologic malignancies. There were 1–5 levels per patient (median 2). Most patients had undergone allogeneic hematopoietic stem cell transplantation. Drug levels were monitored using HPLC (Pennick et al. Antimicrob Agents Chemother2003;47:2348–2350). Of the 201 samples assayed, 30 were below the detection limit of the assay (0.2 μg/mL), and were excluded. The daily voriconazole dose (divided into 2) was 200 mg (n=3), 400 mg (n=129), 500 mg (n=18), 600 mg (n=15), or 800 mg (n=6); corresponding to 2.0–13.3 mg/kg (median 5.3). The voriconazole levels were 0.2–12.5 μg/mL (median 1.7). The table shows the correlation between voriconazole levels, and weight, dose and biochemical parameters individually.
However, in multivariate regression analysis, the parameters found to correlate significantly with voriconazole levels were ALT (P=0.0005), AST (P=0.003), and AP (P=0.027). The relationship with albumin was of borderline significance (P=0.062). Importantly, the daily dose of voriconazole in mg or in mg/kg was not predictive of drug levels. This larger data set confirms our previous observation that there is a significant relationship between elevated liver function tests and higher voriconazole levels. However, because of the relatively high frequency of abnormal liver function tests in such groups of patients, the cause-effect relationship still remains uncertain. These data suggest that pending further clarification, voriconazole levels may need to be monitored in patients with significantly abnormal liver function tests.
Parameter Median (range) r P Dose (mg) 400 (200–800) 0.19 0.013 Weight (kg) 80 (39–135) 0.18 0.018 Dose (mg/kg) 5.3 (2.0–13.3) 0.23 0.002 ALT (IU/L) 25 (4–608) 0.10 0.25 AST (IU/L) 25 (6–524) 0.14 0.11 AP (IU/L) 95 (27–920) 0.27 0.002 Bilirubin (mg/dL) 1.1 (0.1–17.3) 0.01 0.89 Albumin (g/dL) 2.4 (0.8–3.9) 0.28 0.001 Creatinine (mg/dL) 1.1 (0.2–10.1) 0.01 0.92
Influence of Killer Immunoglobulin-Like Receptor (KIR) Matching on Achieving T Cell (CD3+) Complete Donor Chimerism (CDC) in Related Donor Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation (NMHSCT).
Authors: Sobecks Ronald , Ball Edward J. , Askar Medhat , Theil Karl , Rybicki Lisa , Thomas Dawn , Bates Jennifer , Kalaycio Matt , Andresen Steven , Pohlman Brad , Dean Robert M. , Sweetenham John William , Bernhard Laura , Cherni Kelly , Maciejewski Jaroslaw P. , Bolwell Brian J. 
Published: October 2019

Abstract
The reactivity of NK cells and some T cell populations is regulated by KIR interactions with HLA class I molecules. Such interactions have been suggested to influence outcomes after myeloablative allogeneic HSCT. However, in NMHSCT the effect of KIR interactions on outcomes including the development of CDC has not been well described. We analyzed 51 pts who received related donor NMHSCT at our institution from 1/10/00–10/25/05. All pts received fludarabine 30 mg/m2/d x 3 days followed by total body irradiation 200 cGy (n=35) or 400 cGy (n=16) for conditioning. The median age was 54 (range, 21–64). Short tandem repeat analysis for T cell (CD3+) chimerism was performed on peripheral blood and CDC was defined as achievement of >95% DNA of donor origin in the CD3+ T cells. 37 (73%) of patients achieved CDC at a median time of 3.3 mos (range, 0.4–11.2). KIR genotypes were determined for recipients by PCR-rSSOP analysis. Donor HLA KIR ligands were categorized as:
HLA-Cw groups C1 (+ or −); C2 (+ or −); HLA-Bw4 (+ or −); and HLA-A3 or -A11 (+ or −) [as reviewed by Farag et al. Blood2002; 100:1935–47].
Recipient KIR genotype and donor HLA KIR ligands were used to generate an inhibitory KIR score for pts from 1 to 4 corresponding to the potential number of inhibitory KIRs engaged. 7 pts had a score of 1, 27 had a score of 2, 14 had a score of 3 and 3 had a score of 4.
Figure Figure
The Kaplan-Meier method was used to estimate the achievement of CDC by inhibitory KIR score (figure, p=0.09). Pts with a score of 1 were less likely to achieve CDC compared to those with a score of 2 (p=0.02), while those with a score of 2 tended to be less likely to develop CDC than those with a score of 4 (p=0.07). There were no differences in CD34+ or CD3+ cell doses between any of the groups. When combined with the inhibitory KIR score data the presence of single or multiple activating KIR’s was not found to influence the development of CDC. Thus, pts with lower inhibitory KIR scores may have more active anti-donor effector cells (NK cells and T cell subsets) that may reduce donor cell chimerism. Conversely, those with higher inhibitory KIR scores may have less active populations and be more likely to achieve CDC. Given the genotypic potential to inhibit all NK cells KIR expression may be variable among different clones, and may affect the development of CDC. Further investigation of KIR expression at the cellular level rather than by genotyping alone should be pursued.
Severe Alterations of Bone Mass and Bone Structure after Allogeneic Stem Cell Transplantation: An Osteopathologic Analysis.
Authors: Massenkeil Gero , Fiene Cornelia , Rosen Oliver , Doerken Bernd , Arnold Renate , Delling Guenther 
Published: October 2019

Abstract
Prolonged survival after allogeneic SCT has led to an increased awareness of late complications in these patients. Loss of bone density after SCT has been reported in radiologic analyses (Ebeling 1999, Schulte 2000, Massenkeil 2001). We have studied bone mass and structure alterations in bone marrow biopsies after SCT.
Patients and Methods: 67 patients after allogeneic SCT were included in this analysis. Median age was 36 years (range 17–56), 35 male, 32 female. Diagnoses were: ALL 27 patients, AML 14, MDS 6, CML 20. 38 patients were in 1. CR or 1. cP, 29 were transplanted with advanced disease. 64 received standard high-dose conditioning and 3 were transplanted after reduced intensity conditioning. 42 received bone marrow and 25 mobilized peripheral blood as stem cell source.40 patients were transplanted from HLA-identical related and 27 from unrelated donors.
31 bone marrow biopsies underwent Micro-CT (Scanco, Zürich, CH) and were analysed after 3-D reconstruction. Usual parameters of trabecular structure were investigated.
Results: Median bone volume/tissue volume (BV/TV), which serves as a parameter of histopathologic bone mass was 13.7% before SCT (range 8.6–44.4%), well below 18%, which are considered the osteopathologic threshold for osteoporosis. At first follow-up 6–9 months after SCT, BV/TV had dropped to 10.1% (5.9–24.6%) and at 1–2 years after SCT BV/TV was still below the pre-SCT values at 12.2% (6.1–19.3%).
Number of trabecules (Tb.N.) dropped from 1.63/mm (range 0.93–2.32/mm) to 1.34 (1.01–5.61/mm) after 6–9 months and slightly increased to 1.54 (1.26–1.88/mm) after 1–2 years.
Trabecular thickness (Tb. Th.) fell from 0.20 mm before SCT (normal Tb. Th. 0.20–0.30 mm) (range 0.16–0.49 mm) to a minimum of 0.16 mm (0.14–0.25 mm).
As a consequence, intertrabecular space (Tb.Sp., normal appx. 0.60 mm) increased from 0.60 mm (0.36–1.11 mm) to 0.73 mm (0.23–1.04 mm) after SCT.
Discussion: Independently from underlying diagnosis trabecular parameters changed within the first 6 months after SCT, indicating early loss of bone mass and structure. Afterwards, they showed some tendency to normalization, however, none of the parameters went back to baseline values. Number of patients analysed over time was to small to find out causative clinical parameters like chronic GvHD. Radiologic bone density was available for these patients and showed synchronous variations over time.
Conclusions: Structural changes of trabecular bone develop early after allogeneic SCT and underscore the severeness of bone loss observed in these patients. Even after prolonged follow-up, structural changes and diminished bone mass persist and indicate a long-term cause of morbidity in these patients.
Myeloablative Allogeneic Stem Cell Transplantation for Relapsed Composite Low and Intermediate Grade Lymphoma Is Not Superior to Autologous Stem Cell Transplantation - Reduced Relapse Risk Is Offset by Higher Treatment Related Mortality.
Authors: Ramadan Khaled M. , Connors Joseph M. , Al-Tourah Abdulwahab J. , Gascoyne Randy D. , Song Kevin , Barnett Michael J. , Nantel Stephen H. , Nevill Thomas J. , Shepherd John D. , Sutherland Heather J. , Lavoie Julye , Forrest Donna L. , Hogge Donna E. , Voss Nicholas J. , Smith Clayton A. , Toze Cynthia L. 
Published: October 2019

Abstract
No reports compare autologous and allogeneic stem cell transplantation (auto-SCT vs allo-SCT) for patients (pts) with relapsed (REL) composite low and intermediate grade non-Hodgkin lymphoma (L/I-NHL). Fifty four pts with composite L/I-NHL (30 transformed, 16 composite(same site), 8 discordant(different sites)) who underwent allo (n=40) or auto-SCT (n=14) from Jan ‘89 to June ‘05 were evaluated (Table 1) to compare long-term results.
Twenty pts (37%) (11/40 allo and 9/14 auto) are alive with median follow-up of 32 months (range 10–87). The 2 and 5-y OS for the whole group were 43% [95% confidence interval: 28–56%] and 29% [14–46%] respectively; the 2 and 5-y EFS 40% [26–53%] and 24% [11–39 %]. 5-y OS for the auto and allo-SCT were 51% and 23% respectively (p=.09)(Fig. 1). The 2 and 5-y EFS for the allo vs auto-SCT groups were 36% [24–55%] vs 54% [33–89%] and 27% vs 23% (p=0.4).
Thirty four pts (63%) died; 18 (33%) with REL NHL and 16 (30%) with TRM. TRM was due to GVHD (n=7), infection (n=6), cerebral edema (n=1) and veno-occlusive disease (n=1). All but one (cerebral edema) TRM deaths occurred post allo-SCT. The cumulative incidence (CI) of TRM and REL for the whole group were 37% [17–57%] and 47% [30–64%]. The CI of TRM for allo and auto-SCT were 47% [20–74] and 8% [0–23%] respectively (p=.009)(Fig. 2).
Twenty pts (37%) relapsed post SCT (14/40, 35% allo and 6/14, 43% auto). CI of REL NHL for allo and auto-SCT were 42% [23–61%] and 65% (p=.008)(Fig. 2).
In conclusion EFS for composite L/I-NHL is low post auto-SCT due to a high relapse rate despite acceptable TRM. While relapse risk is significantly lower post allo-SCT, this advantage is offset by a higher TRM in these pts. Future attempts to reduce TRM while preserving the allogeneic graft vs lymphoma effect may be beneficial.
Table 1. The clinicopathological characteristics of 54 patients treated with auto and allo-SCT for relapsed composite L/I-NHL Parameter Allo-SCT n=40(%) Auto-SCT n=14(%) * at diagnosis Age: Range (Median) 28–57(44) 25–59(49) M:F 2:1 1.3:1 Diagnosis Transformed lymph. 25(63) 5(36) Discordant lymph. 7(17) 1(7) Composite lymph. 8(20) 8(57) Initial Stage I/II 4(10) 6(42) III/IV 36(90) 8(58) B symptoms* 11(28) 6(43) BM involvement* 29(73) 3(21) IPI* 0–1 18(45) 11(79) 2–3 21(53) 3(21) 4–5 1(2) 0 Prior treatment CHOP 33(83) 14(100) Purine analogue 17(43) 2(14) Rituximab 12(30) 6(43) Fig 1: OS for auto/alle groups Fig 1:. OS for auto/alle groups Figure Figure