bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-Wide Association Study for Hb F Determinants in Sardinian Patients with Thalassemia Major and Intermedia.
Authors: Anni Franco , Galanello Renzo , Surrey Saul , Fortina Paolo M. , Bowser Mark , Devoto Marcella 
Published: October 2019

Abstract
Expression of fetal globin is silenced normally in adult life; however, determinants linked and/or unlinked to the globin-gene clusters could modify Hb F expression so it persists into adults. Increased expression in adults offers hope as a cure for sickle cell disease (SCD) and beta thalassemia, since formation of FS hybrids in SCD inhibits deoxy Hb S polymerization while increased fetal chain expression compensates partially for decreased adult beta-globin chains in beta thalassemia. Characterization and controlled manipulation of high Hb F determinants is critical to decreasing clinical severity of these life-threatening genetic diseases, which result in high morbidity and mortality worldwide. We report on analysis of a unique beta-thalassemia cohort from Sardinia who present with either
a mild, non-transfusion-dependent (NTD) form expressing high Hb F, or with a severe, transfusion-dependent (TD) form expressing low Hb F.
Both groups are homozygous for the beta39 chain-termination mutation and lack adult beta globin. Genome-wide DNA arrays were run on 42 TD and 33 NTD patients using the Affymetrix 500K (500,568 SNPs in a total of 23 individuals) or 6.0 (909,622 SNPs in a total of 52 individuals) SNP chip platforms. The average sample call rates were 96.3% for the 6.0 chip and 94.3% for the 500K chip. Data from the two chips were merged and a total of 482,243 SNPs that were present in both chips were considered for genetic association analysis using a case/control design (NTD versus TD). Quality control filters removed 42,166 SNPs (8.7%) with genotype call rates < 90%. An additional 54,683 SNPs (12.4%) were removed because they either failed a test of Hardy-Weinberg equilibrium at a p< 0.0001 or had a minor allele frequency (MAF) of < 0.01. The genotype call rate for the remaining 385,394 SNPs was 97.3%. Preliminary analysis of difference in allele frequency distributions in the two groups of patients did not reveal any signal of association that remained statistically significant when corrected for multiple tests. The smallest p-value observed was 2x10-6 for SNP rs8028098 on chromosome 15. However, several SNPs in two candidate regions on chromosomes 2p16 and 6q23 were nominally significant (p<0.05). The smallest p-values observed in these two regions were 0.004 for rs11886868 located in the BCL11A gene, and 0.002 for rs210950 in the MYB gene. These results confirm the likely involvement of these two genes in the regulation of Hb F expression, and show the usefulness of the association approach in the search for genetic modifiers of Mendelian disease phenotypes. Additional samples are being analyzed in an attempt to achieve sufficient power to reach genome-wide significance.
Salvage Allogeneic Hematopoietic Cell Transplantation with Fludarabine and Total Body Irradiation (3 or 4 Gy) after Failure of First Allografts.
Authors: Gyurkocza Boglarka , Cao Thai M. , Storb Rainer F. , Lange Thoralf , Leisenring Wendy , Franke Georg , Sorror Mohamed L. , Maloney David G. , Shizuru Judith , Sandmaier Brenda M. 
Published: October 2019

Abstract
We analyzed data from 38 patients (median age = 56, range: 8 – 68 years) with acute leukemia (n=15), chronic idiopathic myelofibrosis (n=6), myelodysplastic syndrome with or without myeloproliferative disorder (n=5), chronic myeloid leukemia (n=4), non- Hodgkin lymphoma (n=4), aplastic anemia (n=2), multiple myeloma (n=1) and renal cell carcinoma (n=1), who underwent salvage allogeneic hematopoietic cell transplantation (HCT) for allograft failure. In 14 cases the original donors were used for second HCT, while in 24 cases different donors were identified (Table 1). Conditioning regimens for first HCTs included total body irradiation (TBI; 2 Gy) with or without fludarabine (Flu; n=28), myeloablative regimens (busulfan-cyclophosphamide, n=6; cyclophosphamide-TBI, n=2); and other, cyclophosphamide-anti-thymocyte globulin-based regimens (n=3). Conditioning for salvage HCT consisted of Flu 30 mg/m2/day on days -4 to -2 followed by TBI of 3 (n=24) or 4 (n=14) Gy on day 0. Cyclosporine and mycophenolate mofetil were used for postgrafting immunosuppression. The median time between first and salvage HCTs was 91 (range, 29 to 1004) days. Sustained second grafts were achieved in 34 patients (89%), while grafts failed in 4 patients (11%), all of whom had idiopathic myelofibrosis. With a median follow-up among surviving patients of 2.0 (range, 0.3 to 7.8) years, the 2 and 4 year Kaplan-Meier survival estimates were 49% (95% CI: 31%, 66%) and 42% (95% CI: 23%, 61%), respectively. The 2 year relapse-rate and non-relapse mortality were 36% (95% CI: 20%, 52%) and 25% (95% CI: 11%, 41%), respectively. The cumulative incidences of grades 2–4 acute and moderate-severe chronic graft-versus-host disease (GVHD) at 2 years were 42% and 41%, respectively. Four patients with chronic GVHD discontinued systemic immunosuppressive therapy at a median of 2.5 years. Within the limitations of the small patient numbers studied, TBI dose (3 vs. 4 Gy), same vs. different donors for salvage HCT, donor type (related, unrelated, HLA-haploidentical related vs. double umbilical cord), and HCT comorbidity scores did not appear to affect outcomes. Based on this retrospective multicenter analysis, we conclude that graft failure following allogeneic HCT can be effectively overcome by second transplantation using conditioning with Flu and low dose TBI (3 or 4 Gy), which should be further investigated in a prospective manner.
Table 1. Donors in 1st and 2nd HCTs. HLA-MURD: HLA-matched unrelated donor; HLA-MMURD: HLA-mismatched unrelated donor, UCB: umbilical cord blood.
2nd HCT Different Donor 1st HCT Same Donor HLA-MURD HLA-MMURD Double UCB HLA-haploidentical HLA-identical sibling 11 11 - - - - HLA-MURD 17 3 10 4 - - HLA-MMURD 8 - 1 7 - - Double UCB 2 - - - 1 1
Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloblastic Leukemia (AML) or Myelodysplastic Syndrome (MDS) in Patients (pts) Older Than 50 Years: a Retrospective Single Center Study
Authors: Robin Marie , Porcher Raphael , Ades Lionel , Raffoux Emmanuel , de Latour Régis Peffault , Petropoulou Anna , Boissel Nicolas , Ribaud Patricia , Devergie Agnès , Rocha Vanderson , Fenaux Pierre , Dombret Hervé , Socié Gérard 
Published: October 2019

Abstract
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment in MDS, and also in many cases of AML, 2 diseases where median age is higher than 50 years.
Aim: Analyse the outcome of patients older than 50 years who received an allogeneic hematopoietic stem cell transplantation (HSCT) for MDS or AML, in Saint-Louis Hospital from January 1997 to December 2007.
Method: 48 patients (pts) aged from 50 to 68 years (median: 56) received an HSCT for MDS (N=28) or AML (N=20) during this period. AML pts had intermediate (n=15) or high risk cytogenetics (n=3). 8 pts had failure to initial induction chemotherapy. FAB classification for MDS was: RAEB (n=8), RAEBt (n=6), secondary AML (n=2) or refractory anemia (n=2). Maximal IPSS score was high, intermediate-2 and intermediate-1 in 11, 14 and 4 pts. Ten pts with MDS received an “AML-like” chemotherapy and 5 received demethylating agents before transplant. 18 of the AML pts were in complete remission (CR) at time of transplant (CR1, n=15; CR2, n=3) and 2 were in relapse at time of HSCT. 10, 9 and 9 patients with MDS had < 5%, 5–10% and > 10% blasts in bone marrow at time of HSCT.
Results: 19 patients with AML (95%) and 16 patients with MDS (57%) received a HSCT from an HLA-identical sibling donor. Other pts received a matched unrelated donor. Thirty-two pts, including 9/20 and 23/28 had at least one co-morbidity according to Sorror score. The conditioning regimen was myeloablative (MAC) in 14 pts (29%). Reduced intensity (RIC) was fludarabine based in 34 pts, associated with either 2 Gy TBI (n=25) or chemotherapy (n=9). All pts engrafted. 35 pts had acute graft-versus-host disease (GVHD): grade I in 11, grade II in 18 and grade III in 6. GVHD incidence did not differ between pts who received a MAC or a RIC regimen. Two-year overall survival (OS) was 41% (95% CI: 26–57). OS and relapse-free-survival (RFS) were similar after MAC or RIC regimen (OS: 29% vs 35% and RFS: 29% vs 30%). Short-term non-relapse mortality (NRM) was lower in patients who received a RIC as compared to patients who received a MAC regimen but was similar at long-term (6-month NRM = 21% vs 9% and 12-month NRM = 21 vs 19 %). Patients with AML or MDS had similar OS and RFS (OS: 42 vs 41%; RFS: 37 vs 26% at 2 years for AML and MDS, respectively). NRM was not significantly higher in pts with MDS (26 vs 10% at one year) whereas relapse rate was not significantly higher in pts with AML (13 vs 6%).
Conclusion: HSCT for AML or MDS after 50 years is a curative option for pts with related or unrelated HLA-identical donor regardless kind of conditioning regimen and co-morbidity at time of transplantation.
Incorporating Marrow Plasma Cell Infiltration at Diagnosis and Cytogenetic Features into Prognostic Scoring at Point of Autologous Stem Cell Transplantation for Multiple Myeloma
Authors: Klammer Matthias , Giles Chrissy , Reid Alistair G , Ross Fiona M , Szydlo Richard M. , Pavlu Jiri , Apperley Jane F. , Rahemtulla Amin 
Published: October 2019

Abstract
240 patients (152 male, 88 female) with a median age of 59 years (27ys–73ys), referred to Hammersmith Hospital, London, for high dose therapy (HDT) and autologous stem cell transplantation (ASCT) between 1994 and 2007 were treated in a uniform fashion with myeloablative doses of Melfalan. The median OS post HDT/ASCT of all patients was 53 months with a median time to disease progression (TTP) of 20 months. In univariate analysis (194 pts) a > 60% plasmacell infiltration of trephine biopsy at presentation was associated with a significantly shorter median TTP (15 months) following HDT/ASCT compared to patients with a lesser degree of marrow plasmocytosis, whose median TTP was 20 months (p=0.003). Studies of chromosomal aberrations were undertaken by metaphase cytogenetics and interphase FISH in 142 pts at the time of ASCT and yielded interpretable results in 96 (67%) pts. Failure of conventional G –banding and FISH was universally due to low plasma cell content of the marrow aspirate below 5% of nucleated cells. 59 pts (42%) did not show any chromosomal abnormalities at point of transplantation; 37 pts (26%) had chromosomal aberrations, involving the IgH gene locus on chromosome 14q32 and/or deletions of the long arm of chromosome 13 (del 13q) in 33 cases. Deletion of the short arm of Chromosome 17 (del 17p) was only seen in one patient. In multivariate analysis (92 pts), independent risk factors for early relapse post ASCT were progressive disease/minimal treatment response at time of transplantation (RR 5.95, 95%CI 2.86–12.57), a plasma cell infiltrate of more than 60% on marrow trephine at diagnosis (RR 3.4, 95% CI 1.68–6.88) and presence of cytogenetic abnormalities other than sole t(11;14) or del 13q (RR 2.04, 95% CI 1.0–4.17) at time of ASCT. An additive scoring model based on these predictive factors (Table 1) identifies a low risk group of 49 pts (score 0) with a median progression free survival (PFS) of 33 months, an intermediate risk group of 34 pts (scores 1–2) with a median PFS of 15.7 months and a high risk group of 9 pts (scores 3–4), whose median PFS is 4.6 months (p<0.0001).
Table 1: Prognostic scoring model
Risk Factor Score Plasmacells >60% on diagnosis trephine biopsy 1 Plasmacells <60% 0 Progressive disease/minimal response at time of ASCT 2 Complete response/partial response 0 Normal Cytogenetics or t (11.14)/del 13q as sole abnormalities at time of ASCT 0 All other chromosomal aberrations 1
FIG.1: Progression free survival in low risk (score 0), intermediate risk (1–2) and high risk (3–4) patients FIG.1:. Progression free survival in low risk (score 0), intermediate risk (1–2) and high risk (3–4) patients
Outcome of African-American (AA) Multiple Myeloma (MM) Patients after Autologous Stem Cell Transplantation (ASCT): A Single-Center Experience.
Authors: Wu Yin , Goloubeva Olga , Ruehle Kathleen , Yanovich Saul , Rapoport Aaron P. , Akpek Gorgun , Badros Ashraf Z. 
Published: October 2019

Abstract
The incidence of MM in African-Americans is more than double that in Caucasians. Historically AAs have had a higher mortality rate than Caucasians; but over the past 10 yrs, the age-adjusted mortality rate has been on the decline for AAs while it has been stable for Caucasians as a result of ASCT and novel agents. Previous studies (n=74 AA patients) suggested that response to ASCT is similar, if not better, for AA patients (Verma et al 2008, Saraf et al 2006). We retrospectively analyzed the clinical presentation of a large cohort of AA patients (n=103) who underwent ASCT at our center between 1998 and 2008 and compared their outcome to that of Caucasians patients (n=183) transplanted in the same time period. AA patients were significantly younger than Caucasian patients at diagnosis with median age 53 (range: 32–75) vs 59 (range: 27–80), respectively (p<0.0001). The distribution of isotype and stage of MM at diagnosis were similar between the two groups. Approximately 20% patients in each group presented with renal insufficiency. Among the AA patients, 45% had albumin < 3.5 g/dL; 14% and 18% had beta2-microglobulin > 3.5 mg/L and > 5.5 mg/L, respectively. Initial cytogenetic data were not available for the majority of patients. Median time from diagnosis to ASCT was significantly longer for AA than for Caucasian patients at 0.8 yrs (range: 0.23–9.2) vs 0.5 yrs (range: 0.1– 7.0), respectively (p<0.0001). There was no difference in incidence of transplant-related complications, as reflected by similar lengths of hospital stay, with a median of 15 days for both groups. No significant difference in response to ASCT was found between the two groups. Median EFS was 1.7 yrs (range: 1.5–2.7) for AAs and 1.8 yrs (range: 1.5–2.4) for Caucasians (p=NS). At a median follow up of 5 yrs, 74% of AA and 70% of Caucasian patients were alive. Median OS was also not significantly different at 9 yrs (range: 6.7- not reached) for AAs and 8 yrs (range: 5.9-not reached) for Caucasians (p=NS). Cox regression model for prognostic markers: albumin, calcium, creatinine, hemoglobin, and platelet count were significant for OS in AA patients (p range 0.004–0.0001). The current study is the largest one of AA patients undergoing SCT at a single institution. AA patients with MM present at a younger age, but undergo ASCT at a significantly later time from diagnosis than Caucasian patients. This delay may reflect a disparity in referral pattern and access to health care. AA patients have similar EFS and OS after ASCT. It is likely that better responses to the newer anti-myeloma agents, as well as favorable impact of ASCT, even if delayed, may explain the improvement of AA patients with MM over the past decade. Further studies of responses of AA patients to novel myeloma agents are needed.
Sequential VAD (Vincristine, Adriamycin, Dexamethasone) and VTD (Bortezomib, Thalidomide, Dexamethasone) Induction Followed by High-Dose Therapy with Autologous Stem Cell Transplantation and Maintenance Treatment with Bortezomib for Newly Diagnosed Multiple Myeloma: Final Analysis of Phase II Trial.
Authors: Yoon Sung-Soo , Kim Hye Jin , Chung Joo Seop , Eom HyeonSeok , Jang Jun-Ho , Kang Hye Jin , Kim Cheol Soo , Kim Kihyun , Lee Dongsoon , Lee Jae Hoon , Lee Junglim , Lee Sang Jae , Min Yoo Hong , Seong Chu-Myong , Sohn Sang-Kyun , Suh Cheolwon , Won Jong-Ho 
Published: October 2019

Abstract
Background: Incorporation of novel agents has resulted in improved response rate and reduced side effects in multiple myeloma. Especially in newly diagnosed multiple myeloma, novel agents are very promising as induction chemotherapy.
Methods: Patients are planned to receive 2 cycles of VAD (vincristine 0.4mg D1–4, adriamycin 9mg/m2 D1– 4, dexamethasone 40mg D1–4, 9–12 every 3 weeks), and VTD (bortezomib 1.3mg/m2 D1, 4, 8, 11, thalidomide 100mg daily, dexamethasone 40mg D1–4, 9–12 every 3 weeks). High dose melphalan (200mg/m2) is used as a conditioning regimen for ASCT. Bortezomib (1.3mg/m2) as a maintenance treatment is administered weekly x 4 times every 6 weeks for 4 cycles after ASCT. Response was assessed by EBMT criteria, with additional category of nCR. Adverse events were graded by the NCI-CTCAE, Version 3.0.
Results: Total 71 patients were enrolled, and efficacy could be assessed in 62 patients. After 2 cycles of VAD, response rate was 71% (95% CI, 59.7–82.3). After VTD, overall response rate was more increased to 96% (95% CI, 90.8–100, rate of CR and nCR 27%). Especially, nine patients with poor prognostic cytogenetics all showed response after VTD. So far, autologous stem cells were successfully collected in 42 patients with a median CD34+ count of 6.49 x 106/kg (range, 0.6–44.7 x 106/kg) except one patient. After autologous stem cell transplantation, twenty five patients completed bortezomib maintenance, and the rate of CR + nCR was 68%. The median follow-up duration was 16.4 months, and median time to response was 1.6 months. Median time to progression was not reached, and 1 year survival rate was 98%. In total, 127 cycles of VAD and 115 cycles of VTD were given and grade 3,4 hematologic toxicity was more frequently observed after VAD than VTD (anemia 18.1% vs 8.7%, neutropenia 12.6% vs 4.3%), and incidence of grade 3 peripheral neuropathy after VAD was lower (1.5%) than VTD (7%). All patients received low-dose aspirin prophylaxis. Deep vein thrombosis was observed in two patients, but this was not related with thalidomide.
Conclusions: Sequential VAD and VTD induction therapy in newly diagnosed multiple myeloma was very effective, even in patients with poor prognostic cytogenetics, and did not prejudice stem cell collection. VTD as induction therapy has contributed to increased response rate and decreased side effects. *Protocol Number : KMM51-NCT00378755
Defect in DNA Double Strand Break Response in Paediatric ALL Is Caused by Upregulation of Multiple Pro-Survival Pathways That Can Serve as Therapeutic Targets.
Authors: Stankovic Tatjana , Marston Eliot , Weston Victoria , Agathanggelou Angelo , Mapp Katie , Kearns Pamela , Falciani Francesco , Moss Paul , Taylor Malcolm 
Published: October 2019

Abstract
The molecular basis of clinical heterogeneity in paediatric ALL is poorly understood. Defects in cellular responses to DNA double strand breaks (DSBs) have been associated with resistance to DNA damaging agents and poor clinical response in patients with leukaemia. We have previously shown that one third of paediatric ALL tumours exhibit in vitro defect in ionising radiation (IR)-induced apoptosis, despite retained integrity of p53 pathway. In this study we addressed molecular basis of defective (DSB) response in paediatric ALL with the view of identifying novel therapeutic targets.
We analysed differences in transcriptional and posttranscriptional in vitro responses to IR in 22 ALL patients, stratified as either apoptotic resistant or apoptosis sensitive. Analysis of coordinate IR induced expression of functionally related genes, by two independent methods (gene set enrichment analysis, GSEA, and functional module analysis) revealed in resistant cases differential upregulation of multiple pro-survival pathways involved in EGF, PDGF, IGF, PI3 and MAPK signalling. In response to IR resistant ALLs also showed differentially induced phosphorylation of Akt and S6, downstream targets in PI-3 pathway. Array analysis of 42 receptor tyrosine kinases (TRKs), revealed differential phosphorylation of TRKs that act upstream of the PI3 including ErbB3,4, FGF R4,2a, VEGF R1,2 as well as IGF-I R. Furthermore, we were able to demonstrate that in apoptotic resistant leukaemias PI3/Akt upregulation during IR response lead to differential phosphorylation of DNA-PK catalytic subunit, a protein involved in non homologous end joining (NHEJ) repair of DNA DSBs. Consequently, increased repair of DSBs was observed in apoptosis resistant ALL cases and this was documented by faster resolution of IR induced intranuclear foci of γH2AX, a marker of DNA DSBs. Finally, pharmacological inhibition of pro-survival pathways PI3-Akt, IGF and MAPK in resistant leukaemias restored sensitivity to IR.
We suggest that abnormal activation of pro-survival pathways during DSB response may represent one of the mechanisms of resistance to DNA damaging agents in paediatric ALLs and that targeting these pathways should be considered as therapeutic approach in aggressive form of disease.
Evolution of Gene Expression Signatures in Relapsed Childhood Acute Lymphoblastic Leukemia Differs Based on Timing of Relapse.
Authors: Bhojwani Deepa , Wang Jinhua , Yang Jun J , Morrison Debra , Devidas Meenakshi , Raetz Elizabeth , Hunger Stephen P. , Relling Mary V. , Carroll William L. 
Published: October 2019

Abstract
The outcome for childhood acute lymphoblastic leukemia (ALL) following marrow relapse remains bleak in spite of numerous approaches to further intensify therapy. Understanding the biological basis of relapse and chemoresistance, as well as identifying and validating potential new targets, are the goals of our study. Previously we determined global gene expression patterns of matched diagnosis and relapse leukemic blasts in 32 patients (64 samples) with childhood B-precursor ALL using Affymetrix U133A arrays (Blood2006;108(2):711–7). We now have extended this analysis to 60 patients (120 samples). Thirty-six patients relapsed early (within 36 months of initial diagnosis), while 24 patients relapsed late. Within the TEL/AML1 subset (n=12 patients), time to relapse was inversely proportional to the correlation co-efficient of expression profiles of the diagnosis and relapse matched pair samples, suggesting that the later the relapse, the more distinct the relapse clone is from the diagnostic clone. A supervised pairwise analysis in all 60 patients identified 292 probesets that were differentially expressed between diagnosis and relapse (FDR < 10%). In a relative enrichment analysis, multiple genes mediating cell death were down-regulated at relapse (p=0.00003), suggesting that the leukemia cells had evolved mechanisms to enhance survival. These included p21, TNFPAI3, RIPK2, BCLAF1, STK17B. In concert, DNA replication genes were up-regulated at relapse (p=0.00002). Differences in pathways leading to early vs. late relapse were evident. Early relapse was characterized by an over-expression of cell cycle genes reflecting a proliferative state. At the time of relapse, a marked over-representation of genes involved in the progression through the M phase of the cell cycle was observed in early relapse compared to late relapse (p=1.3E-08). Late relapse was characterized by the over-expression of genes involved in nucleoside biosynthesis, particularly targets of antifolates (DHFR, MTHFD1, TYMS). A small number of gene expression patterns were common to both early and late relapse, including up-regulation at relapse of BIRC5 (survivin): an attractive target for therapeutic intervention. In conclusion, analysis of an expanded cohort of matched diagnosis/relapse pairs has validated and extended our previous findings that early relapse is associated with a proliferative gene expression signature. In addition we have now identified pathways operative in late relapse. Targeting these individual genes and pathways may lead to innovative strategies to treat or prevent relapsed ALL.