bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Features and Outcomes of Iron Deficiency Anemia in Patients with Gastrectomy
Authors: Ryu Hyewon , Jo Deog-Yeon , Lee Kyu-Seop , Song Ik Chan , Choi Yoon Seok , Moon Ji-Young , Lee Myung-won 
Published: October 2019

Abstract

Background: Iron deficiency anemia (IDA) is common in patients with partial or total gastrectomy; however, clinical features and appropriate therapy in these patients have not been well described. We compared clinical features and outcomes in IDA patients with and without gastrectomy.
Methods: We retrospectively analyzed clinical features at the time of diagnosis and response to iron therapy in IDA patients with partial or total gastrectomy (gastrectomy group) and in age- and gender-matched IDA patients without gastrectomy (control group) who were diagnosed between 2002 and 2010 at Chungnam National University Hospital.
Results: A total of 2,072 patients were diagnosed with IDA during the study period. Thirty-seven and 40 patients were enrolled in the gastrectomy and control groups, respectively. The median ages were 58.8 years (range, 19–84 years) and 52.7 years (range, 25–84 years), respectively. At initial presentation, the hemoglobin levels, mean corpuscular volume (MCV), mean corpuscular hemoglobin levels, mean corpuscular hemoglobin concentration, serum iron levels, total iron binding capacity, ferritin levels as well as endoscopic findings did not differ between the two groups. After 2 weeks, 6 weeks, and 3 months of oral iron therapy, hemoglobin levels were significantly lower in the gastrectomy group than in the control group (8.3 vs. 9.6 g/dL, P=0.012; 9.7 vs. 12.0 g/dL, P=0.000; 11.9 vs. 13.3 g/dL, P=0.016, respectively). After 2 weeks and 6 weeks of treatment, the increase in the hemoglobin level and that in the MCV were significantly slower in the gastrectomy group than in the control group (hemoglobin: 0.6 vs. 2.3 g/dL, P=0.000; 2.1 vs. 4.7 g/dL, P=0.000, respectively) (MCV: 2.6 vs. 6.2 fL, P=0.005; 7.2 vs. 12.7 fL, P=0.008). Parenteral iron was required in nine (23.4%) patients in the gastrectomy group, but not in the control group. The follow-up duration was much longer in the gastrectomy group (23.2 vs. 5.2 months, P=0.008), and 11 (29.7%) patients in this group needed long-term maintenance iron therapy. To normalize hemoglobin levels, longer treatment was required in the gastrectomy group (0.8 vs. 2.8 months, respectively; P=0.013).
Conclusion: The response to oral iron therapy in IDA patients with gastrectomy is slower than in those without gastrectomy. Parenteral iron therapy is needed in one-fourth of these patients to normalize hemoglobin levels.

Disclosures
No relevant conflicts of interest to declare.
ASPP2 Attenuation Is an Early Step in Leukemogenesis Facilitating Acquisition of Mutations
Authors: Kampa-Schittenhelm Kerstin M , Akmut Figen , Illing Barbara , Lopez Charles , Schittenhelm Marcus M 
Published: October 2019

Abstract
Inactivation of the p53 pathway is an universal event in human cancers. As p53 mutations are rare in de novo acute leukemias, the p53-pathway must be inactivated by other mechanisms instead. The Apoptosis stimulating Protein of p53-2 (ASPP2) is a haploinsufficient tumor suppressor, which we have shown to be attenuated in acute leukemia. We now provide evidence that ASPP2 regulates pathways involved in early hematopoiesis, and attenuated expression perturbs malignant transformation.
Gene-chip microarrays were performed on ASPP2+/+ versus +/- mouse embryonic fibroblasts (MEFs) (-/- knockouts are not viable) and pathway analysis was performed using Affimetrix software. ASPP2 expression was silenced in IL3-dependent Ba/F3 pro-B cells and leukemia cell lines using standard siRNA protocols. Cellular proliferation was assessed using XTT-based assays. To evaluate for malignant transformation, long term cell cultures with stably retrovirally silenced Ba/F3 cells (+/- stress inforcement using gamma irradiation, 4x 5Gy) were employed. IL3 weaning was performed as an indicator of autoactivated cellular proliferation, and analysis of chromosomal defects or gene mutations were performed.
Microarray mRNA analysis revealed that attenuated ASPP2 expression resulted in significant alterations of pathways involved in mediating cellular growth, proliferation and tissue differentiation. Subanalysis proofed involvement of genes playing a major role in embryogenesis, the development of the hematopoietic system and leukemogenesis (homeobox (HOX) family members, NOTCH, BCL, IRF7 and EGR1). Population doubling times were significantly increased in ASPP2+/- MEFs compared to the parental cells. Modeling ASPP2 attenuation via specific siRNA knockdown in leukemia cell lines (K562 and Kasumi1) resulted in significantly increased cellular proliferation. Similarly, ASPP2-interference in pro-B Ba/F3 cells lead to perturbed proliferation and an increase of polyploid cells with a dramatic change in morphology with megaloid cells, indicating mitotic failure. This effect was even more pronounced after stress induction with daunorubicin. Lentiviral shRNA-ASPP2 stable knock-out was performed in Ba/F3 cells to follow cells in long term cultures for malignant transformation. Again, we confirmed signs of mitotic failure as observed in the siRNA approach. Even more, gamma irradiated ASPP2-lacking strains were successfully IL3 weaned, which indicates autoactivated cellular proliferation. A screen for acquired oncogenic mutations was performed and analyses are ongoing.
In summary, we provide evidence that ASPP2 has a pivotal role in early hematopoiesis, and loss of ASPP2 is a driver mechanism to fuel leukemogenesis.

Disclosures
No relevant conflicts of interest to declare.
A Novel SAHA-Bendamustine Hybrid Induces Apoptosis of Leukemia Cells
Authors: Yu Jing , Qiu Shaowei , Ge Qiufu , Wang Ying , Wei Hui , Guo Dianwu , Chen Shuying , Liu Shuang , Rao Qing , Wang Jianxiang , Wang Min 
Published: October 2019

Abstract
Introduction Hybrid anticancer drugs are of great therapeutic interests as they can potentially overcome the flaws of conventional chemotherapy drugs and improve their efficacy. Histone deacetylase inhibitors (HDACi) and DNA damaging agents have showed synergistic effects in recent studies. In this study, we reported a novel hybrid NL-101 that combines chemo-active groups from suberoylanilide hydroxamic acid (SAHA) and bendamustine, the typical HDACi and alkylating agent respectively.The anticancer effect of NL-101 and its possible mechanisms were investigated in human leukemia cell lines and primary leukemia cells.
Methods MTT assay was performed to determine the proliferation of Kasumi-1 and NB4 cells treated with NL-101. Cell cycle distribution and apoptosis rate were detected by flow cytometry. Western-blot analysis was used to analyze the level of acetylated H3 as well as apoptotic-related proteins including γ-H2AX, PARP, caspase-3, Bax, Bcl-2 and Bcl-xL. Bone marrow mononuclear cells of AML patients were isolated by density gradient centrifugation. Wright staining and Western blot were performed to determine the inducing apoptosis effect.
Results NL-101 inhibited the proliferation of leukemia cell lines Kasumi-1 and NB4 cells with similar IC50 to that of SAHA. Cell cycle analysis indicated that NL-101 induced S phase arrest. As expected, apoptotic cell death was observed in response to NL-101 treatment. After treatment with 2 µmol/L NL-101 for 48 hours, the apoptosis rate of Kasumi-1 and NB4 cells were (60.19±12.01)% and (49.43±11.61)%, respectively. Western blot analysis showed that NL-101 exposure could induce the accumulation of acetylated Histone H3 and γ-H2AX as the biomarker of DNA double-strand breaks. Anti-apoptotic protein Bcl-xL involved in mitochondrial death pathway was also decreased. Moreover, NL-101 induced apoptosis with a low micromolar IC50 in various leukemia cell lines but not in nonmalignant cell line HEK293. The efficacy of NL-101 was also tested in human primary leukemia cells and all the treated samples exhibited apoptosis confirmed by the morphological examination and expression of apoptotic markers.
Conclusions The novel SAHA-bendamustine hybrid NL-101 inhibited the proliferation and induced apoptotic cell death of leukemia cell lines and primary leukemia cells. It presented the properties of both HDAC inhibition and DNA damaging. Down-regulation of Bcl-xL was also involved in the apoptosis induction. These results indicated that NL-101 might be a potential compound for the treatment of leukemia.

Disclosures
Wang: Bristol Myers Squibb: Consultancy; Novartis: Consultancy.
Aggravated Bone Density Decline after Symptomatic Osteonecrosis in Children with Acute Lymphoblastic Leukemia
Authors: den Hoed Marissa , Pluijm S.M.F. , Te Winkel Mariël L. , de Groot-Kruseman Hester A. , Fiocco Marta , Hoogerbrugge Peter M. , Leeuw J.a. , Bruin Marrie , van der Sluis Inge M. , Bresters Dorine , Lequin Maarten H. , Roos Jan C. , Veerman A. , Pieters Rob , van den Heuvel-Eibrink Marry M. 
Published: October 2019

Abstract
Background: Osteonecrosis (ON) and decline of bone mineral density (BMD) are serious side effects during and after treatment of childhood acute lymphoblastic leukemia (ALL). It is unknown whether ON and low BMD co-occur in the same patients, and whether these two osteogenic side effects can influence each other’s development during pediatric ALL treatment.
Methods: BMD and the incidence of symptomatic ON were prospectively assessed in 466 patients with ALL (4-18 years of age) treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Symptomatic ON was defined as persistent pain in arms or legs not caused by vincristine administration, and confirmed by magnetic resonance imaging. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) were measured by dual X-ray absorptiometry at ALL diagnosis, after 32 weeks of treatment, at cessation of treatment (109 weeks) and 1 year after cessation of treatment. BMD was expressed as age-matched and gender-matched standard deviation scores (SDS; Z-score). Multivariate linear mixed models were adjusted for age at diagnosis.
Results: Thirty patients (6.4%) suffered from ON. At cessation of treatment, mean BMDLS was -1.28 SDS (SD: 1.27, n=332; p<0.01) and BMDTB was -0.74 SDS (SD: 1.29, n=65; p<0.01) lower in ALL patients compared to their healthy peers. At baseline, BMDLS and BMDTB did not differ between patients who developed or who did not develop ON (mean BMDLS ON+: -0.90 vs. ON-: -1.14, p=0.36; mean BMDTB ON+: 0.07 vs. ON-: 0.25 p=0.65). At cessation of treatment, patients with ON seem to have a trend for a lower mean BMDLS (ON+: -1.68 vs. ON-: -1.31, p=0.18) and they have a lower mean BMDTB (ON+: -1.91 vs. ON-: -0.59, p=0.01) than patients without ON. Multivariate analyses showed that BMDTB change during follow-up was significantly different for patients with ON than without ON (interaction group time, p=0.04). Between BMD measurements before and after the diagnosis, patients with ON seemed to have a more rapid decline of BMDTB than in patients of the same age without ON (mean BMDTB difference -1.13 vs. -0.62, p=0.10).
Conclusion: We conclude that symptomatic ON and low BMD during antileukemic treatment co-occur in pediatric ALL patients. BMD status at ALL diagnosis does not seem to precede ON. However, the development of ON seems to aggravate BMD decline during antileukemic treatment, most likely due to bone destruction and the advised physical immobilization.

Disclosures
No relevant conflicts of interest to declare.
The Negative Impact of Underweight and Weight Loss on Survival of Children with Acute Lymphoblastic Leukemia
Authors: den Hoed Marissa , Pluijm S.M.F. , de Groot-Kruseman Hester A. , Te Winkel Mariël L. , van den Akker Erica L.T. , Hoogerbrugge Peter M. , van den Berg Henk , Leeuw J.a. , Bruin Marrie , Bresters Dorine , Veerman A.J.P. , Fiocco Marta , Pieters Rob , van den Heuvel-Eibrink Marry M. 
Published: October 2019

Abstract
Background: Body mass index (BMI: kg/m2) and change in BMI during treatment might influence treatment outcome of pediatric patients with acute lymphoblastic leukemia (ALL). However, previous studies in pediatric acute lymphoblastic leukemia reported contradictory results. Therefore, we studiedthe influence of (change in) BMI on treatment outcome in pediatric ALL patients who were treated according to a dexamethasone-based protocol (Dutch Childhood Oncology Group [DCOG] ALL-9).
Patients and Methods: Data on body composition were prospectively collected from a cohort of newly diagnosed Dutch pediatric ALL patients (N=762, age 2-17 years), treated from 1997-2004. BMI at diagnosis was expressed as standard deviation scores (SDS) and categorized into underweight (≤–1.8SDS), or normal weight and overweight (>–1.8SDS). BMI loss was defined after 32 weeks of treatment. Dual X-ray absorptiometry scans were performed in a nested single center cohort (n=106) to assess the contribution of %fat and lean body mass to BMI. Multivariate analyses were corrected for age at diagnosis and risk treatment grpup.
Results: Multivariate analyses showed that patients with underweight (8%) had an increased risk of relapse (Hazard Ratio (HR) 1.79, 95% CI: [1.04-3.10], and a similar overall survival (HR 1.10 [0.57-2.10]). BMI loss during the first 32 weeks of treatment was associated with a decreased overall survival (HR 2.10 [1.14-3.87]), and a similar risk of relapse (HR 1.27 [0.70-2.30]) compared to patients without BMI loss. Dual X-ray absorptiometry revealed that BMI loss mainly consisted of a loss of lean body mass and gain in %fat.
Conclusion: Underweight at diagnosis is associated with an increased risk of relapse and a BMI loss early during treatment is associated with an increased mortality. This suggests that these patients might benefit from exercise interventions and a high-quality nutrient diet during therapy.

Disclosures
No relevant conflicts of interest to declare.
Acute Megakaryocytic Leukemia (AMegL) Is Associated with Inferior Outcomes Relative to Other Acute Myeloid Leukemia (AML) Morphologies
Authors: Giri Smith , Martin Michael G , Pathak Ranjan , Li Bojia , Prouet Philippe E 
Published: October 2019

Abstract
Introduction: Acute Megakaryocytic Leukemia (AMegL) is a rare subtype of Acute Myeloid Leukemia (AML) resulting from uncontrolled proliferation of megakaryoblasts. Due to its rarity it is unclear if AMegL morphology is independently associated with outcomes in AML.
Methods: We used the Surveillance, Epidemiology and End Results (SEER) 18 database to identify adult patients with AML diagnosed between 1991-2011 using the appropriate International Classification of Disease (ICD-O-3) histology codes. Cases of APL (M3) were excluded. Kaplan Meier Survival curves were generated to compare survival statistics between AMegL subtype and the rest of AML types. Multivariate analysis was done using Cox Linear Proportional Hazard Regression model. Statistical analysis was done using Statistical Package of Social Sciences (SPSS) version 21.0 (IBM Corporation, Armonk, NY).
Results: Of 45,564 cases of AML identified, 304 (0.7%) belonged to the AMegL subtype. The median ages were 69 (range 18-111), and 67.5 (range 18-92) years, respectively (p value 0.08); the proportion of males were 54.3% and 59.2% respectively (p value 0.09), the median year of diagnosis was 2004 in AMegL versus 2002 in other AML. Whites comprised 82.6% and 84.7% respectively. The 5 year overall survival rates were 17.5% and 10.6% respectively. Kaplan Meier Survival curves showed significantly inferior survival for AMegL relative to other AML cases (p value of log rank test 0.01). On multivariate analysis AMegL was as an independent predictor of increased mortality (adjusted RR 1.23, 95% CI 1.09-1.38, p value <0.01), after adjusting for age of diagnosis, sex, race and year of diagnosis. This remained significant after removing core binding factor leukemia cases from the analysis (RR 1.21; 95% CI 1.07-1.36, p value <0.01)
Conclusion: AMegL is a rare subtype of AML which is associated with significantly worse survival in comparison to other AML subtypes. We recommend that the National Comprehensive Cancer Network (NCCN) consider adding AMegL morphology to the list of adverse prognostic factors and as a reason to consider allogeneic stem cell transplantation.
Table 1: Multivariate Analysis showing the independent predictors of survival in the study population. Variable RR 95% CI of RR P value Lower Upper AML M7 type 1.229 1.092 1.383 0.001 Race - White - American Indian/Alaska Native - Asian or Pacific Islander - Black 1.0 1.166 0.957 1.112 0.994 0.919 1.070 1.366 0.996 1.156 0.06 0.03 <0.01 Age at diagnosis 1.035 1.034 1.036 <0.01 Year of Diagnosis 0.985 0.983 0.987 <0.01 Male Sex 1.040 1.019 1.061 <0.01

Disclosures
No relevant conflicts of interest to declare.
Allogeneic but Not Autologous Stem Cell Transplant Attenuates the Negative Prognostic Impact Dictated By Pretransplant MRD Positivity
Authors: Buccisano Francesco , Maurillo Luca , Del Principe Maria Ilaria , De Angelis Gottardo , Cerretti Raffaella , Ditto Concetta , Di Veroli Ambra , Picardi Alessandra , Cudillo Laura , Cefalo Mariagiovanna , Sarlo Chiara , Fedele Giorgia , Refrigeri Marco , Lo Coco Francesco , Arcese William , Amadori Sergio , Venditti Adriano 
Published: October 2019

Abstract
Multiparametric flow cytometry (MPFC) detection of minimal residual disease (MRD) represents a robust surrogate for the quality of complete remission (CR) and reliably predicts clinical outcome. In our experience, MRD detection provides prognostically relevant information when assessed at the post-consolidation time point. Ten years ago we demonstrated that the amount of MRD before autologous stem cell transplant (AuSCT) affected outcome. More recently, other authors have extended this observation to allogeneic stem cell transplant (ASCT) showing that pre-transplant MRD is a major determinant of prognosis regardless of graft-versus-leukemia (GVL) effect. The aim of our study was to evaluate, in an extended series of patients submitted to AuSCT or ASCT, the impact of a pre-transplantation MRD positive (MRDpos) or negative (MRDneg) status on overall survival (OS) and disease free survival (DFS). We analyzed 173 MRDpos and 53 MRDneg patients of whom 67 were submitted to AuSCT and 51 to ASCT. Eighty-two patients received no transplant because of age, poor performance status or insufficient stem cell harvest whereas 26, all in the MRDpos group, relapsed before transplant delivery. In the AuSCT group, before transplant, 32/67 (48%) were MRDneg and 35/67 (52%) MRDpos, with MRDneg group showing a superior OS (55% vs 20%, p=0.007). In the ASCT group, before transplant, 45/51 (88%) were MRDpos and 6/51 (12%) MRDneg. For 21 out of 51 (41%) sources of stem cells were matched unrelated donors (12) or haploidentical donors (9). In this subgroup, MRDpos and MRDneg patients shared a comparable 5-years OS (60% vs 56%, p=NS), with a 36% survival gain for those MRDpos who received ASCT as compared to AuSCT. Among MRDneg patients, no survival differences were demonstrated between those submitted to AuSCT or ASCT (55% vs 60%, p=NS). Such a lack of difference is likely due to the higher treatment related mortality (ASCT 3/6, 50% vs AuSCT 2/32, 6%, p=0.003) which counterbalanced the lower relapse rate in the ASCT group (ASCT 0/6, 0% vs AuSCT 11/32, 34%, p=NS). In conclusion, ASCT confers a significant survival advantage to MRDpos patients, attenuating the negative prognostic impact of pre-transplant MRD positivity. ASCT may expose MRDneg patients to an excess of toxicity suggesting that in these patients the allogeneic option should be postponed after a second remission. In MRDpos patients, AuSCT does not represent a valid therapeutic choice and ASCT, which should be timely delivered, also considering alternative sources of stem cells.

Disclosures
No relevant conflicts of interest to declare.
Defining the Primate T Cell Transcriptome during Graft Versus Host Disease: New Data Implicating the Hedgehog and Aurora Kinase Pathways in Pathogenesis and Prevention
Authors: Furlan Scott N. , Watkins Benjamin , Flynn Ryan P , Ramakrishnan Swetha , Singh Karnail , Giver Cynthia R. , Hanby Kelly , Stempora Linda , Garrett Aneesah P. , Ziegler Carly GK , Tharp Gregory , Bosinger Steven , Blazar Bruce R. , Waller Edmund K. , Kean Leslie S. 
Published: October 2019

Abstract
Graft versus host disease (GvHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate targeted strategies for prevention and treatment. To address this, we determined the gene expression profile of non-human primate (NHP) T cells during active and partially controlled acute GvHD (aGvHD), in order to accomplish two goals: 1) uncover important genetic drivers of aGvHD and 2) identify novel, targetable pathways for optimal aGvHD prevention.
Utilizing microarray technology, we measured the gene expression profiles of flow cytometrically purified CD3+ T cells from NHP recipients of MHC partially-matched HCT in three treatment cohorts resulting in increasing degrees of survival: 1) no immunoprophylaxis (No Rx, MST = 7.5); 2) sirolimus monotherapy (MST = 17) tacrolimus-methotrexate (Tac-Mtx) dual prophylaxis (MST = 49). Arrays were performed on T cells purified on Day +14 post-transplant (unless terminal analysis occurred earlier due to severe disease). This comparison allowed us to determine the impact of both mTOR and calcineurin inhibition on the molecular pathways dysregulated during GvHD, and to determine which genes and pathways remained dysregulated despite prophylaxis.
Pathways identified by this strategy may contain new therapeutic targets unaffected by current immunoprophylactic approaches. We found that the transcriptional profile of donor T cells from HCT recipients with unprophylaxed GvHD was characterized by significant perturbation of pathways regulating T cell proliferation, effector function and cytokine synthesis (Figure 1a). By identifying pathways unaffected by sirolimus or tac-mtx therapy (Figure 1b), we discovered multiple potentially druggable targets not previously implicated in the pathophysiology of aGvHD. These targets prominently included the hedgehog and the aurora kinase A pathways. Utilizing a murine aGvHD model, we demonstrated that pharmacologic inhibition of these pathways could mitigate disease and improve survival (Figure 2a,b).
These data provide the first identification of the T cell transcriptome of primate acute GvHD and the hedgehog and aurora kinase A pathways as novel potential targets for prevention of this disease.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.