bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aberrant Subcellular Localization of Azurophil Granule Proteins in Myeloid Leukemia Favors Peptide Antigen Presentation on MHC-I and Susceptibility to Killing by Cytotoxic T Lymphocytes.
Authors: Alatrash Gheath , Ono Yoko , Lu Sijie , Sergeeva Anna , Wang Changqing , Wieder Eric , Molldrem Jeffrey J. 
Published: October 2019

Abstract
The recognition of leukemia-associated antigens (LAA) by immune cells is essential for generating anti-leukemia responses. Whether elicited by vaccine or hematopoietic stem cell transplantation (HSCT), anti-leukemia immunity requires that cytotoxic T lymphocytes (CTL) recognize and mount an effective response against leukemia cells. PR1 is a nonomeric HLA-A2-restricted peptide (VLQELNVTV) derived from the myeloid-restricted serine proteases neutrophil elastase (ELA2) and proteinase-3 (PRTN3), recognized azurophil granule proteins. PR1-specific cytotoxic T lymphocytes (PR1-CTL) have been shown to preferentially recognize and kill myeloid leukemia cells. We hypothesized that aberrant protein expression in target leukemia cells predisposes to CTL killing. To determine the subcellular localization of ELA2 and PRTN3 in leukemia and in healthy donor (HD) neutrophils, high-speed ultracentrifugation of leukapheresed cells from patients with AML and CML in blast crises yielded 4 fractions: cytoplasmic, nuclear, membrane and golgi/endoplasmic reticulum (ER). Western blot analyses identified higher levels of ELA2 and PRTN3 in cytoplasmic, nuclear, and golgi/ER fractions in leukemia, compared to HD granulocytes. Confocal microscopy of leukapheresed myeloid blasts and HD granulocytes confirmed these findings. We further hypothesized that cross-presentation of PR1 is necessary for priming anti-leukemia immunity. Confocal microscopy of the human B-cell line HMy.CIR-A2, co-incubated with either purified or recombinant ELA2 and PRTN3 demonstrated co-localization of both proteins with LAMP-2, a marker of lysosomes and early endosomes, and small distribution in cytoplasm after 2 hours. Uptake of ELA2 and PRTN3 by HMy.CIR-A2 cells was additionally confirmed by Western blots. Priming of naive PR1-CTL by co-culture of HD lymphocytes with PRTN3 or ELA2-transfected HMy.CIR-A2 cells was confirmed by cell proliferation assays using BrDU. This could be abrogated by addition of lactacystin and cyclohexamide to cell culture. Together, these results demonstrate that ELA2 and PRTN3 are aberrantly localized preferentially in gogli/ER and cytoplasmic fractions in leukemia, rather than azurophil granules, which are often absent or deficient in myeloid leukemia. Similar forced subcellular localization of these proteins in B cells leads to their susceptibility to PR1-CTL killing. Therefore, we conclude that the natural mistrafficking of PRTN3 and ELA2 in myeloid leukemia is necessary to render cells susceptible to CTL attack and that cross-presentation of ELA2 and PRTN3 contributes to priming of a PR1-CTL response.
Targeting Late Relapsed Acute Myeloid Leukemia Cells by Cytotoxic T Cells Generated from Late but Not Early Leukemic Antigen-Presenting Dendritic Cells.
Authors: Liang Yin , Lien Lily , Han Shuhong , Tong Chun-Rong , Gao Zhi-Yong , Wu Tong , Tang Jih-Luh , Lu Dao-Pei , Chang Lung-Ji 
Published: October 2019

Abstract
Cancer-specific cytotoxic T lymphocytes (CTL) have great potential in cancer immunotherapy. We performed a longitudinal study of CTL primed with dendritic cells (DC) exposed to leukemic antigens or DC directly differentiated from leukemic cells in an acute myeloid leukemia (AML) patient. The patient received three HLA locus-mismatched allogeneic bone marrow transplantation, relapsed around day 43, and after a brief remission, suffered an ongoing multi-focal extramedullary relapse. CTL generated against AML cells early during the course of disease (early-AML) effectively targeted the early-AML cells as demonstrated by in vitro CTL assays. The patient received multiple infusions of immune cells specific to the early-AML cells in a pilot trial. While the patient established stable remission in the peripheral blood, extensive extramedullary relapse had occurred. The CTL prepared from DC exposed to the early-AML cells failed to target the late relapsed AML (late-AML) cells isolated from pleural effusion and peripheral blood. Further characterization of the late-AML cells showed complete and partial loss of class II and class I HLA expression, respectively. Interestingly, CTL prepared from the late-AML-derived DC were able to kill the late relapsed cancer cells. This result suggests that the late-AML cells, although escaped from the early-AML-derived CTL, expressed novel immunogenic leukemic antigens. It appeared that selective growth of AML cells resistant to the early-AML-specific immune cells had occurred in vivo. However, CTL primed with the late-AML-derived DC were able to kill the late relapsed cancer cells in vitro. Thus, AML could evolve in vivo under active immunotherapy, but this may be coped with preparation of cancer-specific immune cells using the late-AML cells.
Epidemiology of S pneumoniae Infection in Hematology Patients in Ile de France: Serotypes Covered by the Polysaccharide 23-Valent (PS23) and the Heltavalent Conjugate Vaccine.
Authors: Debbache Karima , Varon Emmanuelle , Hicheri Yosr , Legrand Patrick , Donay Jean-Luc , Ribaud Patricia , Cordonnier Catherine 
Published: October 2019

Abstract
Patients suffering from hematologic malignancies, mainly from lymphoproliferative diseases, and stem cell transplant recipients are at high risk of S pneumoniae invasive infections. The epidemiology of S pneumoniae in the community may vary from one country to an other. Few data are available for hematology patients on the clinical relevance of the two available, PS23 (Pneumo 23®), and heptavalent conjugate vaccine Prevnar® (PC7) according to the serotypes encountered in this population.
Objective: The aim of this retrospective study was to look at the serotype distribution of S pneumoniae infecting hematology patients in Ile de France, and their proportion covered by PS23 and/or PC7.
Methods: All the patients with S pneumoniae infections occurring between Jan 2004–Dec 2006 in 2 hematology departments of Ile de France (Henri Mondor and Saint-Louis hospitals) were identified from the laboratory registries. Only patient with invasive infections (blood cultures, CSF infection, pneumonia, pleural effusion) were included. Serotyping was performed at the CNRP in Paris. Among 40 consecutive cases, serotype was performed in 25 cases occurring in 22 patients. The remaining 15 strains were either not available or did not regrow.
Results: The 22 patients had acute leukemia (n=6), CML (n=1), myelodysplastic syndrome (n=1) or lymphoproliferative disease (n=14) (M/F: 1.4; median age: 54 y). Seventeen had received a stem cell transplant (SCT) (allo: 9; auto: 8) a median of 12 months before. The most frequent serotypes were 9V (n=7) and 19F (n=6). 19/25 (76%) of the strains were covered by PC7 and PS23, and 4/25 (16%) were covered only by PS23. Only 2 were not covered by any vaccine.
Conclusion: We found that most strains of S pneumoniae responsible for invasive infections in hematology patients from Ile de France, including SCT recipients, were covered by PS23 (92%), and PC7 (76%). Only 2/25 strains were covered neither by PS23 nor by PC7. These data make relevant the development of prospective studies and vaccination programs in the high risk hematology patients.
Herpes Simplex Virus Encephalitis (HSE) after Allogeneic Hematopoietic Stem Cell Transplatation (alloHSCT): Impact of Early Diagnosis and Treatment on Outcome.
Authors: Cavattoni Irene M. , Morello Enrico , Casini Marco , Decaminada Norma , Pagani Leonardo , Fabris Pietro , Cortelazzo Sergio 
Published: October 2019

Abstract
Introduction: HSE is a rare but very severe central nervous system (CNS) infection caused by Herpes simplex virus type 1 (HSV-1) in almost all cases, and characterized by a high morbidity and mortality rate (97 and 70% without therapy, respectively). Immunosuppression, is a known risk factor and both early diagnosis and treatment are critical points for a good outcome in this setting. Hereby we reported two cases of HSE after alloHSCT.
Patients: A 35-year-old female with relapsed multiple myeloma, underwent alloHSCT from a matched unrelated donor (MUD). On day +120, she developed an acute onset of fever, drowsiness, and generalized seizures. After 48 hours, a rapid deterioration of neurological symtoms was observed and the brain MRI showed acute encephalitis with high signal intensity in the temporal lobe and insula cortex (fig. 1). The HSV-PCR from cerebrospinal fluid (CSF) was positive for HSV-1, and a treatment with acyclovir 30 mg/Kg/d was initiated, 72 hours after the hospital admission. A 66 year-old male with high risk AML underwent MUD alloHSCT. Thirteen months after transplant, an acute sialoadenitis and HSV-1 gengivostomatitis occurred, followed by fever and focal seizures. Since typical lesions of HSE were demonstrated by brain MRI, antiviral therapy with aciclovir was promptly administrated, within 24 hours from the symptoms onset. HSV-PCR on CSF was performed two days later, and proved negative, probably due to ongoing antiviral therapy and delay to CSF analysis. After 21 days of antiviral treatment, both patients recovered from the acute phase, but in the first case we observed serious neurological sequelae that required prolonged unsuccessful cognitive rehabilitation. The second patient didn’t experienced significant residual neurological impairment, and didn’t require any other supportive measure. Both pts have had chronic GVHD and received prolonged courses of immunosuppressive therapy; they experienced recurrent CMV infections thereafter, and were under high dose foscarnet therapy at the diagnosis of HSE, but without HSV prophylaxis.
Conclusion: the time from diagnosis-to-antiviral therapy, and the level of consciousness at the onset of symptoms are two major risk factors impairing morbidity and mortality of HSE. In heavily immunosuppressed alloHSCT pts with initial focal neurological signs, an early and aggressive diagnostic approach should be performed as emergency, even if they are under anti-CMV therapy; prompt acyclovir administration is therefore warranted in these settings, in order to prevent severe disability or mortality.
Figure Figure
Similar Background of Graft-Versus-Host Disease (GVHD) Following Allogeneic Blood and Marrow Transplantation (Tx) in Korean and Japanese Populations Allows a Uniform Foundation To Perform Large-Scale Clinical Studies in the Region.
Authors: Kim Sung-Won , Lee Jong-Wook , Kim Hyeoung-Joon , Fukuda Takahiro , Kanda Yoshinobu , Kim Hee-Je , Min Woo-Sung , Mori Shin-ichiro , Tanosaki Ryuji , Lee Je-Hwan , Lee Kyoo-Hyung , Yamashita Takuya , Sakamaki Hisashi , Sohn Sang-Kyun , Chae Yee-Soo , Ohshima Kumi , Ichinohe Tatsuo , Kanda Junya , Kasai Masaharu , Kobayashi Naoki , Ando Kiyoshi , Onizuka Masahito , Taniguchi Shuichi , Seo Sachiko , Yang Deok-Hwan , Kim Yeo-Kyeoung , Shin Ho-Jin , Takaue Yoichi , Kim Chun-Choo 
Published: October 2019

Abstract
Background: Although it has been reported that the incidence of acute GVHD (aGVHD) and early non-relapse mortality (NRM) after HLA-identical sibling BMT are different between Japanese and other ethnicities, including white American, African American and Irish populations (Oh, Blood.2005), there has been no previous comparison among Asian countries.
Patients and Methods: We retrospectively surveyed the data of 1933 patients (pts) (996 Korean and 937 Japanese) who underwent allo-Tx for leukemia or MDS between Jan, 2000 and Dec, 2005. The median age of the pts was 37 yrs (range, 16–70; 34 yrs vs 43 yrs, respectively) and the median follow-up of surviving pts was 1046 days (11–2435). Unexpectedly, the pts’ backgrounds, including age, underlying disease, disease status at Tx, stem cell source, donor type, No. of HLA-mismatched (MM) antigen/allele, conditioning regimen, in vivo T-cell depletion with ATG or Campath-1H and GVHD prophylaxis were significantly different between the two groups.
Results: (Table) In a multivariate analysis, Tx from a serologically HLA-1-antigen MM donor, Tx from an unrelated donor (URD), pts with high-risk disease at Tx, no in vivo T-cell depletion and a conditioning regimen that included TBI ≥ 10 Gy were associated with an increased risk of grade II–IV aGVHD. Overall, race was not a risk factor for grade II–IV (P=0.19) or III–IV (P=0.98) aGVHD. The incidence of chronic GVHD (cGVHD) in Japanese was significantly lower than that in Korean (P=0.016). In a multivariate analysis, Tx from a genetically HLA-allele MM donor, Tx from an URD, pts with performance status 2–4 at Tx, pts with high-risk disease at Tx, pts with ALL, female to male Tx and pts’ age ≥ 40 yrs were associated with poor OS. Race was not a risk factor for OS. The incidence of relapse adjusted for the underlying disease status was associated with grade II–IV aGVHD (RR 0.75, 95% CI 0.61–0.94, P=0.010), but not cGVHD (P=0.63).
Conclusions: Despite their different medical backgrounds, our data confirmed that the biology of GVHD is very similar between these two Asian populations, and this provides a uniform foundation for large-scale clinical studies in the region.
Korean (n=996) Japanese (n=937) Grade II–IV/III–IV aGVHD 37%/15% 44%/19% Median onset of aGVHD day 28 day 21 cGVHD 60% 47% 3-yr OS in standard/high risk 70%/42% 65%/41% NRM 25% 30% Relapse 25% 24%
Refractory Autoimmune Hemolytic Anemia Following Unrelated Cord Blood Transplantation for Acute Lymphoblastic Leukaemia: A Case Report and Review of the Literature.
Authors: Liu Huilan , Geng Liangquan , Tong Juan , Wang Zuyi , Sun Zimin , Yao Wen , Yuan Xiao , Chen Jie 
Published: October 2019

Abstract
Autoimmune haemolytic anaemia (AIHA) after hematopoietic stem cell transplantation(HSCT) is a rare severe complication particularly in the paediatric population who underwent umbilical cord blood transplantation(UCBT).The pathogenesis of the post-HSCT AIHA is poorly understood, which frequently difficult to treat and overall prognosis is often poor. We present a case of a 13-year-old boy who developed AIHA 6 months after UCBT with a minor ABO blood group incompatiblity, 5/6 HLA matching umbilical cord blood unit from an unrelated donor was used for high risk acute lymphocyte leukemia in third remmision. Following conditioning with busulfan, cyclophosphamide, and antithymocyte globulin (ATG), the patient underwent transplantation and attained sustained hemopoietic reconstitution without severe graft-versus-host disease. At 6 months following UCBT,he developed severe acute autoimmune hemolytic anemia associated with a “warm” IgG antibody. He was being treated with packed RBC transfusions, cyclosporine, steroids and immunoglobulins, His AIHA was partly resolved. Hemolysis recurred after steroid tapering and partially responded to rituximab (375 mg/m(2) once weekly ×4 and plasma exchange.Despite a range of complex treatment regimen, the unstable hemolytic anemia was present and repeated severe infectious episodes occurred.We reduced suppression,strengthened antibiotic therapy,Pulmonary infection and hemolysis could not be controlled, the patient died of respiratory failure and circulatory collapse finally. This case report highlights the difficulty in managing posttransplant AIHA,Further studies about the pathogenesis of AIHA associated in HSCT recipients are needed.
Low-Dose Azacitidine for Relapse of MDS/AML after Unrelated Donor Peripheral Blood Stem Cell Transplantation.
Authors: Rossetti James M. , Shadduck Richard K. , Thatikonda Chandana , Sahovic Entezam , Lister John 
Published: October 2019

Abstract
Background: Post-transplant relapse in patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) is difficult to manage. Cytogenetic relapse and decreasing donor chimerism often precedes morphological relapse. Weaning of immunosuppressive agents and donor lymphocyte infusion (DLI) may induce graft versus tumor effect (GVT), but is of limited value for patients with existing GVHD. In addition, the degree of GVT in high-risk myeloid disease is suboptimal. We present our experience using low-dose azacitidine (AZA) for cytogenetic relapse post-transplantation.
Methods: Six patients with high-risk myeloid malignancy with cytogenetic relapse after matched unrelated donor peripheral blood stem cell transplantation were treated with low-dose AZA at 25 mg/m2 SC or IV for 5 days. An average of 2 cycles of AZA were given (range = 1 to 3). There were 3 females and 3 males with a mean age of 48 years (range = 31 to 59 years). Four had high-grade MDS (including 2 with treatment related disease) and 2 had high-risk AML. Conditioning consisted of fludarabine and ablative doses of busulfan in all patients. Cytogenetic relapse was seen by FISH testing within 187 days post-transplant (range = 30 to 730 days). AZA was given after an initial attempt to wean immunosuppression, which was not possible in 3 patients due to existing GVHD. All patients tolerated AZA well, without major toxicity. DLI was possible in 3 patients following AZA. A reduction in cytogenetic abnormalities (by FISH) and increase in donor chimerism (by FISH or STR) was observed in 5 out of 6 patients (83%) within 21 days post-AZA (range = 7 to 71 days). Three of the 5 responders demonstrated improvement after 1 cycle. The other 2 responders improved after 2 cycles given 28 and 60 days apart, respectively. One of these patients responded to a second AZA cycle after failing DLI. AZA did not appear to induce or worsen GVHD in any patient. One patient remains in CR 4 months after 1 cycle of AZA. Another patient demonstrated ongoing improvement in chimerism until her death from previously existing GVHD 20 days after a third cycle of AZA. The remaining 3 responders relapsed within 30 days from time of first response (range = 17 to 43 days).
Conclusions: Low-dose AZA appears to have activity in post-transplant relapse of MDS and AML. This low-dose regimen appears to be well tolerated, however, response to AZA is short-lived in the majority of patients. Further investigation is planned to improve the durability of response by giving AZA at regular intervals from the time of early relapse. The utility of AZA as a preparatory regimen pre-DLI should also be explored.
Allogeneic Stem Cell Transplantation for Relapsed Follicular Non-Hodgkin’s Lymphoma: Single Centre Experience.
Authors: Peyman Amir , Couban Stephen , Thompson Kara , Fernandez Louis , Forrest Donna L. , Nevill Thomas J. , White Darrell J. 
Published: October 2019

Abstract
Between 1993 and 2005, 57 patients with follicular lymphoma underwent high-dose chemo/radiotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), 49 Allogeneic, (16 Bone Marrow and 33 Peripheral Blood), 6 MIN, 2 MUD. Median age was 47 years. Median days to neutrophil and platelet engraftment after HSCT were 18 and 13 days respectively. Twenty-five patients experienced Acute GVHD and thirty-four had Chronic GVHD (12 mild and 22 extensive). Thirty-three patients were in grade 1, 17 in grade 2, 4 in grade 3 and 3 grade 4. As of their FLIPI score, 4, 14, 21 and 18 patients were calculated to have score of 0, 1, 2 and 3 respectively. Forty-one patients are alive. Two patients have relapsed, one a year and the other two years after HSCT. The 5 year survival was 71.9% (95% CI 57.5–82.2%) and 5 year survival was 67.2% (95% CI 52.3–78.5%). Transplant related mortality rate (TRM) in 5 year was 22.4% (95% CI 63.6–86.8%). No significant differences was found among FLIPI groups 0,1,2 and 3 in terms of overall, relapse-free survival, TRM Allogeneic HSCT for patients with progressive follicular lymphoma is feasible and may result in prolonged disease-free survival.
Haploidentical Hematopoietic Stem Cell Transplantation without In Vitro T Cell Depletion for Treatment of Hematological Malignancies in Children.
Authors: Liu Daihong , Huang Xiao Jun , Liu Kaiyan , Xu Lanping , Chen Huan , Han Wei , Chen Yuhong , Jiang Qian 
Published: October 2019

Abstract
Objective: To evaluate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (HCT) for children with donors from family members.
Patients and methods: Forty-two children under fourteen years old with hematologic malignancies underwent haploidentical HCT. The outcome was analyzed.
Results: Four (9.5%) of the forty-two patients/donor pairs mismatched in one HLA locus, fifteen (35.7%) pairs in two loci and twenty three (54.8%) in three loci. They were followed up for a median of 612 (40–1779) days. All patients achieved stable engraftment. The cumulative incidence of acute graft-versus-host disease (GVHD) grade 2–4 was 57.2%, and that of grade 3–4 was 13.8%. The cumulative incidence of total and extensive chronic GVHD was 56.7% and 29.5%, respectively. The probability of leukemia-free survival was 65.1% in standard-risk group and 49.6% in high-risk group. Fourteen patients died, four from infection, six from relapse of leukemia, two from heart failure, one from severe acute GVHD, and one from lymphoproliferative disorders. The probability of relapse was 13.8% at 1 year and 27.9% at 2 year after transplantation.
Conclusion: The results in this study encourage extending the haploidentical HCT without T-cell depletion to children with an indication for transplantation.
Risk Factor Analysis of Outcomes after Unrelated Cord Blood Transplantation for Children with Hurler’s Syndrome. An Eurocord-Duke University Collaborative Study.
Authors: Boelens Jaap Jan , Rocha Vanderson , Aldenhoven Mieke , Wynn Robert , O’Meara Anne , Cavazzana-Calvo Marina , Ionescu Irina , Parikh Suhag , Prasad Vinod , Escolar Maria , Gluckman Eliane , Kurtzberg Joanne 
Published: October 2019

Abstract
Hurler’s syndrome (HS), the most severe form of mucopolysaccharidosis type-I causes progressive deterioration of the central nervous system and death in childhood. Allogeneic-stem cell transplantation (SCT) before the age of two years halts disease progression and prolongs life. Graft-failure and mixed-chimerism (40–50%) limit the success of SCT for HS. Unrelated-cord blood transplants (UCBT) are suggested to be a good alternative option for bone marrow, however, little is known about risk factors for outcomes after UCBT for this disease. We have analyzed 93 HS children that received an UCBT from 1995 to 2007 and were reported to EUROCORD or transplanted at Duke University. Median age at UCBT was 1, 3 (0, 2–4) yrs, and median follow up was 24 (3–140) mths. The donor was HLA-identical (HLA-A and -B by low resolution and HLA-DRB1 by high-resolution) in 13 cases (16%) and incompatible in 67 cases (84%: most with 1 (54%) and 2(26%) HLA disparities). The median nucleated cell dose/kg and CD34+/kg at infusion were respectively 7.2 (2–22) x 107 and 2, 3 (0, 5–17) x 105. With the exception of 5 patients, all received a Busulfan/Cyclophosphamide (+Fludarabine: 6) regimen. All patients received ATG or Campath (4).
Results: Median days to neutrophil and platelet recovery were 22 (10–46) and 35 (13–82) days, respectively. Mixed-chimerism was found in only 6%. All patients had normal enzyme levels after engraftment. In multivariate analyses for neutrophil recovery, a CD34+-dose of >2.3x105/kg (HR=2.0; p= 0.015) was associated with increased probability of recovery. Acute-GvHD (grade II-IV) was observed in 27%, while chronic-GvHD was seen in 10% at 2 years. Two years overall survival (OS) and disease free survival were 78% and 70%, respectively. For 2 years OS, time from diagnosis to UCBT more than 6 months was associated with increased risk of death (6% for those children transplanted earlier and 30% for those transplanted later: p=0,04). Transplantation improved somatic features of HS. In conclusion, outcomes following UCBT for Hurler’s syndrome are encouraging. UCB appears to be a good alternative allogeneic stem cell source to transplant children with HS. Earlier transplantation and higher cell dose are associated with better outcomes after UCBT for HS patients.