bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Onset of Acute Graft-Versus-Host Disease Indicating a Worse Prognosis in Terms of Chronic Graft-Versus-Host Disease and Survival Compared to Late Onset.
Authors: Sohn Sang Kyun , Moon Joon Ho , Kim Jong Gwang , Chae Yee Soo , Cho Yoon Young , Ahn Byung Min , Kim Shi Nae , Lee Soo Jung , Kim Yun Jeong 
Published: October 2019

Abstract
Background: Acute graft-versus-host disease (GVHD) is an important risk factor for predicting chronic GVHD. The transplant outcome can be influenced by the onset time of acute GVHD in patients who received allogeneic stem cell transplantation (SCT)
Methods: The medical records of one hundred six patients with hematological malignancies who received allogeneic transplantation were retrospectively reviewed.
Results: Fifty four (39.7%) patients developed grade II to IV acute GVHD within D+30 after allogeneic SCT (<D+30 group) and 13 (9.6%) patients manifested acute GVHD after D+30 (≥D+30 group). The cumulative incidence of chronic GVHD was 81.5% and 53.8% in <D+30 group and ≥D+30 group, respectively.(p<0.001) On multivariate analysis, grade II to IV acute GVHD developed before D+30 and primary diagnosis of chronic myeloid leukemia were identified as independent variables predicting chronic GVHD. The overall survival rate was significantly lower in the <D+30 group than grade 0 or I group (p<0.001). But there was no statistical difference between the group with grade 0 or I and ≥D+30 group in terms of the incidence of chronic GVHD (p=0.295). Among the 54 patients with grade II to IV acute GVHD developed at before D+30, 26 (48.1%) patients developed into quiescent chronic GVHD and 20 (37%) patients progressive chronic GVHD. The quiescent chronic GVHD showed a better survival than progressive chronic GVHD (p=0.063).
Conclusion: Acute GVHD of early onset (within D+30) was regarded as a worse prognostic indicator in terms of chronic GVHD and survival.
Study on Early Diagnosis of Invasive Aspergillosis in Patients with Hematological Diseases.
Authors: Sun Ai-ning , Wang Jun , Wu De Pei , Chen Su-ning 
Published: October 2019

Abstract
Objective To evaluate the value of galactomannan(GM) detection and nest PCR for early diagnosis of invasive aspergillosis (IA) in patients with hematological disease.
Methods GM ELISA and nest PCR was performed to serially screen for circulating galactomannan(GM) and DNA of Aspergillus ssp. Respectively, 96 patients were grouped according to case definitions of the EORTC, including 5 proven IA and 28 probable IA cases. Samples of the patients included serum twice weekly(326) and bronchoalveolar lavage fluid(BALF 12). Sensitivity, specificity and predictive values were calculated respectively and compared.
Results
According to the receiver operator characteristic curve(ROC), using a reduced cutoff of 0.5 O.D.I of two-positive GM test result, we can achieved the most optimal results. The sensitivity, specificity, positive predictive value (PPV)and negative predictive value (NPV) of the ELISA test were 85.7%,91.6%,85.7%,91.6%respectively. While for the BALF samples, a increased cutoff 1.0 maybe improve the value of this diagnosis, with sensitivity 50% and specificity 100%.Quantitive results of the serum-based GM antigen can represent the status of IA and were correlated with the prognosis Of IA.Galactomannanemia preceded the development of characteristic findings on CT about 6 days. The nest PCR assay amplifies specifically a region of the 18S rRNA gene that is highly conserved in Aspergillus species and allows detection of down to 5.0 fg/ml of Aspergillus DNA. When two-positive results were used to define an episode as ‘PCR positive’, the sensitivity, specificity, PPV and NPV of the PCR test were 92.9%, 100%,100%,96.0% respectively. For the BALF samples, the sensitivity and specificity decreased to 75%and 60%. The frequency of the consecutively positive results of a patient was correlated with prognosis Of IA. The antifungal therapy usually causes a intermittent positive PCR results. Positve PCR results preceded the development of characteristic findings on CT about 9 days.
Conclusion
The cutoff 0.5 of two-positive serum-based GM ELISA test result is the most optimal cutoff value. GM ELISA test is a rapid,reliable method for early diagnosis and treatment of IA, with good sensitivity(85.7%)and specificity(91.6%). GM ELISA test is a good direction for preemptive antifungal therapy in patients with hematological disease at risk. Using two-positive results to define an episode as ‘PCR positive’, great sensitivity(92.9%)and specificity(100%) could be achieved. The serum-based PCR test is useful for screening for Aspergillus spp. in patients with hematological disease at risk but without antifungal treatment.
HHV-6 Reactivation after Hematopoietic Stem Cell Transplantation in Chinese Patients Is Associated with aGVHD.
Authors: Ye Xiu Jing , Liao Wei Wei , He Jing Song , Huang He 
Published: October 2019

Abstract
Recent reports indicate that human herpesvirus (HHV)-6 reactivation occurs in 40–65% of patients undergoing hematopoietic stem cell transplantation (HSCT).But the complication after HSCT that predispose to HHV-6 viremia are not well characterized. The aim of our research is to study the potential relationship between HHV-6 activation and acute graft-versus-host disease (aGVHD) after hematopoietic cell transplantation (HSCT) in chinese patients. Peripheral blood samples were collected before and weekly after HSCT from 40 consecutive recipients who underwent HSCT between March 2005 and Joungry 2007 (2 autologous and 38 allogeneic transplants) .HHV-6 DNAemia was monitored by real-time PCR. The genotypes of HHV-6 were identified by Hind III restriction assay. Of the 40 patients, HHV-6 DNAemia were detected in only 1 patient (2.5%) before HSCT, and the viral load was 420 copies/ml.After HSCT there were 18(45%) patients detected HHV-6 DNA on a median of day 14.5 (range, 0– 23 days), and the median HHV-6 viral load of 4884.4±374.4 copies/ml (range, 282 – 43400 copies/ml). Respectively, HHV-6B was identified as the predominant variant.Grade I – IV aGHVD occurred in 18 (45%) on a median of day 20 (range, 8–40 days). The median onset time of HHV-6 DNAemia was significantly earlier than that of aGHVD (P <0.05). Compared with that in HHV-6 DNAemia positive [HHV-6(+)] patients, the cumulative incidence of grade I – IV aGHVD was higher (72.2% vs. 27.7%, P <0.05) than in negative [HHV-6(−)] patients. Cumulative incidence of grade I – IV aGVHD was higher in patients with both HHV-6 and CMV positive (CMV+/HHV-6+) than in those with either CMV (CMV+/HHV-6−) or HHV-6 positive (CMV−/HHV-6+) and neither of them positive (CMV−/HHV-6−) [66.7% (10/15),26.7% (4/15) ,66.7% (2/3) and 28.6% (2/7), respectively, P<0.05]. Our data suggest that patients who undergo HSCT are at significant risk for HHV-6 reactivation. HHV-6 viremia occurs early during the post-transplant course, most often within the first 2 weeks. Patients with HHV-6 activation or HHV-6/CMV co-infection maybe involved in the occurrence of aGVHD after HSCT.
A Novel Strategy for the Treatment of Acute Graft-Versus-Host Disease Using the Adsorbent To Remove Excessive Inflammatory Cytokines.
Authors: Takami Akiyoshi , Teshima Takanori , Ushizaki Koshin , Taniguchi Takumi , Endo Tohru , Sakurai Hiroshi , Kondo Yukio , Yamazaki Hirohito , Shimadoi Shigeru , Okumura Hirokazu , Nakao Shinji 
Published: October 2019

Abstract
Acute graft-versus-host disease (aGVHD) remains the major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). Previous studies show that inflammatory cytokines such as tumor necrosis factor alfa (TNFα), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-18 (IL-18) are involved in the pathogenesis of aGVHD, and that the excess of these cytokines is associated with severity and mortality of aGVHD. We hypothesized that removal of these excessive cytokines from patients’ blood at the onset of aGVHD might improve the treatment outcome. A novel absorbent CTR can effectively adsorb small- to middle-sized proteins like cytokines and enterotoxins in vitro. In view of future exploitation of extracorporeal treatment using CTR column, we tested whether CTR could remove these inflammatory cytokines from blood. When the serum containing a mix of recombinant cytokines was incubated with a CTR adsorbent for 2 hrs, 55% of TNFα, 81% of IL-6, 83% of IL-8, and 22% of IL-18 were successfully removed. Next, we measured TNFα, soluble TNFα receptor 1 (TNFR1), IL-6, IL-8, and IL-18 levels in serum samples obtained from 5 patients (median age 38y, range 26–63y) who underwent myeloablative SCT in 4 and non-myeloablative SCT in 1. AGVHD developed in 2 with grade 3 and in 3 with grade 2. When cytokine levels in patients were expressed as a ratio to the mean cytokine level in control serum samples obtained from three healthy individuals, the mean ratios of TNFα, TNFR1, IL-6, IL-8, and IL-18 at the onset of aGVHD were 6.0 (range, 1.2–12.0), 6.5 (2.5–9.0), 274 (3.5–651), 48.3 (11.3–75.2), and 6.7 (3.2–10.8). The CTR adsorption considerably reduced the concentrations of these cytokines except for IL-18 (Figure 1). The adsorption rates of these cytokines were 64% for TNFα, 48% for TNFR1, 59% for IL-6, more than 94% for IL-8, and 0% for IL-18. The efficient removal of inflammatory cytokines suggests that extracorporeal blood purification with CTR column may be effective in the treatment of aGVHD. This treatment strategy may be promising because it essentially has no deleterious effects on immune functions of SCT recipients unlike other GVHD treatments.
Figure Figure
Antifungal Prophylaxis in Allogeneic Stem Cell Transplantation: Results of a Retrospective Cohort Study.
Authors: Wolschke Christine , Lellek Heinrich , Heinzelmann Marion , Kroeger Nicolaus , Zander Axel 
Published: October 2019

Abstract
Background: Patients with haematogical diseases and undergoing stem cell or bone marrow transplantation are at high risk for an invasive fungal infection. The appearance and course of this is a significant threat to the overall success of transplantation. The optimal antifungal prophylaxis for stem cell transplanted patients has not yet been clearly etablished. Whereas oral medication seems to be convenient it is often hampered in the course of administration by mucositis or/and unclear absorption. We analysed the impact of antimycotic prophylaxis in our unit. We started with Voriconazol (tbl.) or Itraconazol (solution) followed by an early switch to liposomal amphotericin B with a dose 1 mg/kgBW, if the patients didn’t tolerate oral medications.
Patients and methods: 48 patients (18f/30m) with a history of possible (n=4), probable (n=1) or proven (n=3) invasive fungal infection according to EORTC-MSG criteria or no (n=40) fungal infection underwent allogeneic stem cell transplantation in our centre between 08/2005 and 05/2006. Mean age was 47 (6–67) and underlying disease was acute leukaemia (18 AML, 5 ALL, 3 NHL, 4 MM, 4 CML, 14 other). Transplants were unrelated in 38 and related in10 cases.
Results: Prophylaxis started on average 6 days prior to transplant (mean 6, range 0–19) with ITZ (n=24), VOR (n=8) or LAMB (n=8). 8 pts. developed early signs of fungal infection precluding analysis within the prophylaxis population. 15/24 pts. on ITZ and 3/8 pts. on VOR needed a switch to i.v.-medication with LAMB. 3/24 pts. starting with ITZ developed a fungal infection (2 possible, 1 probable). Pts. starting with VOR or LAMB required empiric therapy in 1 and 4 cases, respectively. 12 pts. after switching to LAMB required no further antifungal-therapy.
Conclusions: In our experience antifungal prophylaxis with oral medication being switched to LAMB in case of mucositis or side effects is an effective and tolerated option to prevent invasive fungal infection in patients during allogeneic stem cell or bone marrow transplantation.
Should Patients with Myelodysplasia and/or Acute Myeloid Leukemia (MDS/AML) Be Screened for Inherited RUNX1 Mutations Prior to Sibling Donor Allografting?.
Authors: Owen Carolyn J. , Yin John A.L. , Toze Cynthia J. , Forrest Donna L. , Macheta Anthony , Smith Clayton A. , Barnett Michael J. , Andrew T. , Fitzgibbon Jude 
Published: October 2019

Abstract
Background Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant disease characterised by platelet abnormalities and risk of MDS/AML. FPD/AML results from germline mutations in RUNX1. The phenotype is heterogeneous with ∼35% of affected individuals developing MDS/AML. This clinical variability may obscure the diagnosis and prevent appropriate screening. We describe 2 families with novel C-terminal RUNX1 mutations and FPD/AML phenotypes, in which potentially affected siblings were used as haematopoietic stem cell transplant (HSCT) donors prior to identification of the inherited mutation.
Methods DNA was collected from members of two families with histories of thrombocytopenia and MDS/AML. Direct PCR sequencing was performed on exons 1 and 3–8 of the RUNX1 gene. Results Pedigree 1 has 4 affected members from 2 generations. The proband (I-1) had a history of chronic thrombocytopenia and developed MDS at age 63 and died of AML at age 64. Her daughter (II-1) presented with MDS at age 37 and underwent 2 HSCTs from II-2, relapsing 8 months after the first and remaining well 6 years after the second HSCT. Individuals II-2 and II-3 were recently noted to have mild thrombocytopenia with normal bone marrow morphologies. DNA from blood and bone marrow of II-2 and II-3 revealed an out-of-frame 7 base pair (bp) deletion in exon 8 (1007_1013del) of RUNX1 at amino acid 336 (Gly336fsTer564). Pedigree 2 has 2 affected individuals from 2 generations. The proband (I-1) had a history of chronic thrombocytopenia since childhood. She developed MDS at age 52 and received an HSCT from her brother (I-2) in 2007 with normal engraftment and no early transplant complications. Her son (II-2) had presented with AML at age 8 and received an HSCT from his sister (II-1) at that time. He remains well 26 years later. DNA from blood and saliva of I-1 revealed a substitution of C for T in exon 7 (877C>T) of [italic[RUNX1, resulting in a stop codon and an early-truncated protein at position 292 (Arg292Ter).
Conclusions Two novel, C-terminal RUNX1 mutations are described in families with FPD/AML phenotypes. Both families were investigated after affected individuals received HSCT from siblings (who were also at risk of having inherited the mutation). The sibling donors exhibited normal or near-normal platelet counts prior to HSCT, obscuring a FPD/AML diagnosis. Therefore, all patients with MDS/AML should be screened for a family history of thrombocytopenia and/or MDS/AML and considered for investigation of RUNX1 mutations prior to HSCT.
Figure Figure Figure Figure
Phase I/II Gene Therapy Study for Chronic Granulomatous Disease: Results, Lessons and Perspectives.
Authors: Ott Marion G. , Stein Stefan , Schultze-Strasser Stephan , Jauch Anna , Burwinkel Barbara , Schlegelberger Brigitte , Goehring Gudrun , Preiss Carolin , Kramer Rolf , Schwarzwaelder Kerstin , Koehl Ulrike , Kunkel Hanna , Kuehlcke Klaus , Schilz Andrea , Schmidt Manfred , von Kalle Christof , Trasher Adrian , Hoelzer Dieter , Seger Reinhard , Grez Manuel 
Published: October 2019

Abstract
Gene transfer into hematopoietic stem cells has been envisaged as an alternative to stem cell transplantation for the treatment of many genetic diseases of the blood system. In 2004 we initiated a gene therapy trial aimed at the correction of Chronic Granulomatous Disease (CGD), a rare inherited immunodeficiency caused by a functional defect in the microbial killing activity of phagocytes. Gene marking and functional correction of phagocytes were high shortly after transplantation of gene modified cells, leading to the eradication of therapy resistant infections from which patients had suffered for many years. However, one of our patients died 27 months after treatment due to a severe sepsis with multiorgan dysfunction. Although gene marking was still high at this time point, expression of the therapeutic gene, gp91phox, was minimal. This down regulation of transgene expression was due to CpG methylation within the viral LTR. Similar effects were observed in a second patient treated more than 3 years ago. In both patients CpG methylation was restricted to the promoter region of the viral LTR, while CpG dinucleotides within the enhancer region of the viral LTRs were not methylated. As a consequence, gp91phox gene expression was suppressed but the capacity of the viral LTRs to transactivate nearby sequences is still intact. Indeed we were able to detect cellular transcripts at predominant retroviral integration sites leading to an unbalanced clonal distribution of gene marked cells in peripheral blood and bone marrow. A third patient, a 5 years old child was treated in a similar way in Zurich. In this case only low levels of engraftment and gene correction were achieved. Although the treatment has been beneficial for all treated patients, the side effects observed in the two adults demand modifications in vector design for sustained gene expression and long term correction of the disease without side effects.
Allogeneic Hematopoietic Stem Cell Transplantation as Consolidation Therapy for Adult T Cell Leukemia/Lymphoma Patients: A Single-Center Experience in 35 Patients.
Authors: Takemoto Shigeki , Hidaka Michihiro , Nagakura Shoichi , Sakai Tatsunori , Matsui Takahiro , Kawakita Toshiro , Inoue Yoshiko , Tsukamoto Atsuko , Kiyokawa Tetsuyuki , Kawano Fumio 
Published: October 2019

Abstract
Adult T cell leukemia/lymphoma (ATL) has a high incident in Japanese. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) against ATL made the patients’ survival longer than chemotherapy alone. Actually, some of them became long survivors (LS). The efficacy of allo-SCT for ATL was examined and the prognostic factors were discussed. We retrospectively surveyed the data of ATL patients who underwent allo-HSCT at our hospital between June 1997 and June 2007. The results of allo-HSCT in ATL patients (n=35) including acute type (n=18) and lymphoma-type (n=17) were analyzed retrospectively. Donors were HLA-related relation in 24 patients (69%) or unrelated volunteers in 11 patients (31%). Twelve patients (34%) were in complete remission (CR) before conditioning regimen. Twenty-one (60%) received a conventional stem cell transplantation (CST) and 14 (40%) received a reduced intensity stem cell transplantation (RIST). Because transplant related mortality (TRM) and relapse are mainly observed within day 100, we divided the patients into short survivors (SS) who died within day 100 and LS who were alive more than one year after allo-HSCT. The median survival time (MST) of SS and LS were 55.6 (10–99) days and 1241.3 (503–2492) days. Most of LS (8 of 10) showed CR as status of ATL before allo-HSCT and all LS were received CST but not RIST. Response of induction chemotherapy and following CST are important factors for the success of allo-HSCT for ATL as a promising consolidation therapy.
Characteristics of patients ATL subtype Acute type Lymphoma-type 18 17 Gender Male Female 21 14 Age (range) 51.1 yo (41–61) ATL status CR PR PD Relapse 13 16 4 2 Conditioning regimen CST RIST 21 14 Stem cell source PB BM CB  Related 22 2 0  Unrelated 0 9 2 Short survivors TRM PD or Relapse  Related 8 5  Unrelated 5 1 Long survivors Alive Died  Related 6 2  Unrelated 2 0
Successful Hematopoietic Stem Cell Transplantation in a Patient with a Novel DNA Ligase IV Mutation.
Authors: Unal Sule , Cerosaletti Karen , Tekin Mustafa , Cetin Mualla , Uckan-Cetinkaya Duygu , Gumruk Fatma 
Published: October 2019

Abstract
DNA Ligase IV deficiency syndrome (LIG4 syndrome) is a rare autosomal recessive disorder caused by mutations in the DNA ligase IV gene (LIG4), which is essential for the repair of DNA double-strand breaks in mamalian cells by non-homologous end joining (O’Driscoll et al, 2001; Critchlow et al, 1998). LIG4-deficient patients are characterized by microcephaly, growth retardation, developmental delay, low birth weight, dysmorphic facial findings called bird-like face, immunodeficiency, pancytopenia, and pronounced clinical and cellular radiosensitivity (O’Driscoll et al, 2001). Herein, we report two siblings with a novel DNA ligase IV mutation, one of whom underwent hematopoietic stem cell transplantation (HSCT). Case 1, was a 10 year-old girl, whose pancytopenia started at 4 years of age. History revealed a birth weight of 2400 g. There was a first-degree consanguinity between parents. Body weight, height, and head circumference were below the third percentile. Low anterior hairline, prominent nasal bridge and bilateral epicanthus were present. Recurrent upper respiratory infection (URI) history was striking. Serum IgM was low for age. Pancytopenia deepened progressively and HSCT was performed from 6/6 HLA matched father after non-myeloablative conditioning; however autologous reconstruction developed and a 2nd HSCT was performed after busulfan, cyclophosphamide and ATG conditioning. Engraftment was achieved by +12 day. Case 2 was a 6 year-old boy, presented with widespread echymoses at three years of age. Microcephaly, body weight and height below the third percentile, inguinal hernia, prominent nasal bridge and bilateral epicanthi were positive findings. History revealed recurrent URI. Serum IgG and IgM were low for age. DEB and mitomycin-C induced chromosomal analyses were within normal limits, whereas spontaneous breakage was found to be increased. Bone marrow examination revealed hypercellularity in both siblings. Alpha-fetoprotein levels were within normal limits. Mutation analysis for Nijmegen breakage syndrome was negative, however sequencing revealed a novel mutation in the LIG4 gene. A homozygous sequence variant, 1762delAAG, which results in the amino acid deletion 588delK, was identified in case 2. Both parents were heterozygous for the alteration. This novel mutation is located in a highly conserved peptide in the ligase IV protein, adjacent to the ligase domain, with previously unknown function (Wei et al, 1995). Our results demonstrate that non-myeloablative conditioning may not be adequate for LIG4 syndrome patients with hypercellular bone marrow. However, successful treatment of LIG4 syndrome can be achieved by HSCT after more potent conditioning.