bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uniparental Disomy May Be Associated with NPM Mutations in AML with a Normal Karyotype.
Authors: Serrano Elena , Orantes Vanesa , Estivill Camino , Lasa Adriana , Brunet Salut , Aventin Anna M. , Sierra Jorge , Nomdedeu Josep F. 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders characterized by an abnormal proliferation of the myeloid precursors and a maturation block. A large proportion of AML cases have either a normal karyotype or non-recurrent chromosomal alterations. Underlying genetic lesions of some of these cases have been characterized with the discovery of MLL-internal tandem duplications, activating FLT3 mutations and NPM mutations. Loss of heterozygosity (LOH) derives from the loss of one of the two alleles at a given locus and can be a sign of inactivation of tumor-suppressor genes. We performed a high-resolution genotype analysis on DNA obtained from 19 AML patients with a normal karyotype, both at diagnosis and in samples obtained in complete remission(assessed by multiparametric flow cytometry) using the 10K SNP Array (Affymetrix). Both LOH and copy number analysis, as well as visualization of these analysis were performed by means of the dChip software (M. Lin et al., Bioinformatics (2004), 20:1233–40). A mean call rate of 96.8%. SNP array-based LOH analysis revealed that 4 patients presented large regions of homozygosity at diagnosis which were absent from samples in complete remission. In all four patients copy number analysis indicated no gross chromosomal losses or gains, as was confirmed by conventional cytogenetic analysis. Therefore, it can concluded that the LOH observed in these four patients was due to the presence of uniparental disomy.
Simultaneous analysis of FLT-3 internal tandem duplications (FLT-3/ITD), FLT3- D835 mutations, NPM mutations and MLL rearrangements was performed using conventional molecular methods. Two of these patients (UPN2 and UPN12) had FLT-3/ITD in association with NPM mutations. UPN4 had a mutated form of NPM whereas in patient UPN16 FLT-3 and NPM genes were in the germ line configuration. All four cases were negative for MLL rearrangements and FLT-3-D835 mutations. These results suggest that NPM and FLT3 mutations may be associated with acquired somatic recombinations. It remains to be investigated whether there are loci preferentially involved by these events.
Uniparental disomy and genetic lesions in normal karyotype AML Patient LOH FLT3 NPM D835 MLL UPN2 13q Mutated Mutated Germ line Germ line UPN4 6pter-p12.212q13.12-qter Germ line Mutated Germ line Germ line UPN12 2p Mutated Mutated Germ line Germ line UPN16 complex Germ line Germ line Germ line Germ line
Impact of Additional Cytogenetic Changes and FLT3 Mutations on the Outcome of Patients with Newly Diagnosed Acute Promyelocytic Leukaemia Treated with Single Agent Arsenic Trioxide.
Authors: Mathews Vikram , Thomas Maria , Srivastava Vivi M. , Chendamarai Ezhilarasi , George Biju , Lakshmi Kavitha M. , Viswabandya Auro , Sitaram Usha , Chandy Mammen , Srivastava Alok 
Published: October 2019

Abstract
The efficacy of single agent arsenic trioxide (ATO) in the management of relapsed and newly diagnosed patients with acute promyelocytic leukaemia (APL) has been established. The impact of FLT3 activating mutations and additional cytogenetic changes in newly diagnosed patients with APL treated with single agent ATO has never been reported. Between January 1998 and April 2005, 98 newly diagnosed cases of PML-RARα positive APL were treated with a regimen of single agent ATO at our centre. FLT3 activating mutations were seen in 33% (FLT3-ITD - 21.3%, D835V- 11.7%). Of the 69 patients evaluated for additional cytogenetic findings, 76.8% had an isolated t(15;17) while 23.2% had t(15;17) along with additional cytogenetic findings.
The presence of a FLT3 mutation was significantly associated with a higher mean white cell count (18.11±23.74 vs. 8.04±21.44, P=0.024) and a bcr3 PML-RARα isoform (48.4% vs. 20.6%, P=0.006). There was also a significant delay in achieving a molecular remission (MR) among patients with a FLT3 mutation as noted by the number of patients who were in MR prior to onset of consolidation therapy (60.9% vs. 85.7%, P=0.031). There was no significant difference in the hematological remission rate (CR), time to CR or early mortality between the group with and without a FLT3 mutation. At a median follow up of 20 months (range: 4 – 97), the 3 year Kaplan-Meier estimate of OS, EFS and DFS for patients with a FLT3 mutation was 82.51±7.24, 77.01±8.6, 88.82±7.48 percent while for those without a FLT3 mutation it was 92.06±3.4, 80.45±5.86, 89.02±5.31 percent. Statistical analysis of these survival curves by a log rank test did not reveal any significant difference between the two groups [Figure 1].
The presence of additional cytogenetic changes was not associated with any significant differences in the clinical or laboratory parameters at presentation. It also did not have an impact on the CR, MR, EFS, DFS or OS. Neither FLT3 activating mutations nor additional cytogenetic changes have a significant impact on the outcome of newly diagnosed patients with APL treated with single agent ATO in the short term. Whether either of these two parameters will affect long term outcome remains to be seen.
Figure 1: Kaplan-Meier product limit estimate of EFS based on FLT3 mutation status (n=94). Figure 1:. Kaplan-Meier product limit estimate of EFS based on FLT3 mutation status (n=94).
Bone Marrow Stroma (BMS) Prevents Apoptosis of Lymphoma Cells by Upregulation of BMS-Derived B-Cell Activating Factor (BAFF) and Activation of NF-kB.
Authors: Lwin Tint , Hazlehurst Lori A. , Moscinski Lynn C. , Dalton William S. , Tao Jianguo 
Published: October 2019

Abstract
Stromal cells are an essential component of the bone marrow microenvironment that regulate or supports tumor survival. The bone marrow stroma has long been recognized as a "sanctuary site" for lymphoma cells during traditional chemotherapy. In this study, we demonstrated that adhesion of the B-cell lymphoma cell lines SUDH-4 and 10 to bone marrow stroma inhibited mitoxantrone-induced apoptosis. This adhesion-dependent inhibition of mitoxantrone-induced apoptosis correlated with decreased activation of caspases- 8 and 9, and cleavage of caspase 3 and PARP. EMSA analysis demonstrated significantly increased NF-kB binding activity in cells adhered to stroma cells compared to lymphoma cells in suspension. This DNA binding activity could be attributed to cell adhesion-mediated proteolysis of p100 NF-kappaB2 resulted in generation of active p52, which translocates to the nucleus in complex with p65 and RelB. Furthermore, co-culture with stromal cells also induced expression of the NF-kB-regulated anti-apoptotic molecules, XIAP, cIAP1 and cIAP2. In addition, because of the knowledge that BAFF shown to be critical for maintenance of normal B cell homeostasis as well as the survival of malignant B cells, we characterized the functional significance of BAFF in BMS-mediated drug resistance and survival. BAFF was detected on BMS cell line HS-5 and BMS cells derived from lymphoma patients by flow cytometry. Concentrations of BAFF were 3- to 25-fold higher in bone marrow aspirate than in peripheral blood. Lymphoma cell adhesion to HS-5 cells significantly increased BAFF secretion evidenced by both ELISA and immunoblotting. Addition of BAFF counteracted mitoxantrone-induced apoptosis, and elicited a reduction in spontaneous apoptosis in primary lymphomas via activation of NF-kB activation. Finally neutralization of BAFF by TACI enhanced lymphoma cell response to chemotherapy and overcame cell-adhesion mediated drug resistance, suggesting that lymphoma cells utilize BAFF as survival factor. These data indicate that stromal cells prevent apoptosis of lymphoma cells by upregulation of BAFF and induction of NF-kB-regulated anti-apoptotic proteins. Bone marrow-derived BAFF plays a key role in lymphoma cell survival and drug resistance in bone marrow microenvironment.
Peroxisome Proliferator-Activated Receptor Gamma Promotes the Survival of Human T Lymphoma Cells through Its Regulation of Cellular Metabolism.
Authors: Yang Chunyan , Song Zibo , Jo Seung-Hee , Csernus Balazs , Chadburn Amy , Hyjek Elizabeth , Wang Y. Lynn 
Published: October 2019

Abstract
Peroxisome proliferator-activated receptor gamma is a metabolic regulator involved in maintaining glucose and fatty acid homeostasis. Besides its metabolic functions, the receptor has also been implicated in tumorigenesis. Ligands of PPAR gamma have been found to induce apoptosis in a variety of tumor cell lines including lymphomas. However, apoptosis induction may not depend on the receptor since high doses of PPAR gamma agonists are required for this process. Using cells containing or lacking PPAR gamma, we reported previously that PPAR gamma attenuates apoptosis induced by growth factor withdrawal in a murine lymphocytic cell line via a receptor dependent mechanism. PPAR gamma exerts this effect by enhancing ability of cells to maintain their mitochondrial membrane potential during growth factor deprivation. In the current study, we demonstrate that PPAR gamma is expressed in human primary T lymphoma tissues and activation of PPAR gamma protects cells from serum starvation-induced apoptosis in human T lymphoma cell lines. Further, we show that the survival effect of PPAR gamma is mediated through its actions on cellular metabolic activities. In serum-deprived cells, PPAR gamma attenuates the decline in cellular ATP and suppresses accumulation of reactive oxygen species (ROS) in favor of cell survival. Moreover, PPAR gamma regulates ROS through its coordinated transcriptional control of proteins and enzymes involved in ROS production and scavenge. Introduction of PPAR gamma into a PPAR gamma-null T lymphoma cell line leads to increased cell survival. Meanwhile, knocking down the receptor in a PPAR gamma-positive lymphoma cell line reduces cell survival rate. Our studies identify cell survival promotion as a novel activity of PPAR gamma and suggest that high expression of PPAR gamma in lymphoma cells confers on them a survival advantage that renders cells resistant to growth factor and nutrient deprivation. These findings highlight the need for further investigation into the role of PPAR gamma in lymphoma and other types of cancer prior to widespread use of its agonists as anticancer therapeutics.
Constitutive Expression of SALL4B in Mice Confers Properties of Leukemic Stem Cells to Committed Hematopoietic Progenitors.
Authors: Chai Li , Cui Wei , Ma Yupo , Yang Jianchang , Kong Nikki , Kao Grace , Silberstein Leslie 
Published: October 2019

Abstract
The homeotic gene SALL4 is a transcription factor involved in multi-organ developments. Recently, our group and others have shown that murine Sall4 plays an important role in maintaining the properties of embryonic stem (ES) cells by interacting with Oct4 and Nonag. Knock down of Sall4 expression in mouse ES cells led to their spontaneous differentiation and loss of self-renewal ability. Parallel to these findings, using quantitative RT-PCR approach, we found that human SALL4 was preferentially expressed in the CD34+CD38− hematopoietic stem cell (HSC) population, and was dramatically down regulated in the CD34+CD38+ progenitor (HPC) population, suggesting that SALL4 functions similarly at the HSC level as it does in ES cells. In contrast to normal hematopoiesis, we found that SALL4 was constitutively expressed in the leukemia initiation stem cell (CD34+CD38− and CD34+CD38+), and its expression in human acute myeloid leukemia (AML) was deregulated. To investigate the effect of constitutive expression of SALL4, we have generated a transgenic mouse model with constitutive expression of SALL4B, one of the SALL4 isoforms. The SALL4B transgenic mice developed myelodysplastic syndrome (MDS)-like features and subsequent AML that was transplantable. Further analysis on the pre-leukemic and leukemic SALL4B transgenic mice showed constitutive expression of SALL4B in the HSC and HPC subpopulations (GMP), which resulted in the expansion of the GMP population and eventually led to myeloid leukemia development. Activation of Wnt/beta catenin pathway and up-regulation of Bmi-1, the two key elements that are known to be involved in the self-renewal of HSC and leukemia stem cell (LSC), were found in the SALL4B transgenic mice. Taken together, our data suggests that constitutive expression of SALL4B contributes to leukemogenesis by conferring leukemia stem cell properties to committed murine hematopoietic progenitors. To our best knowledge, SALL4 is one the few genes, if not the only gene, that play an important role in the self-renewal properties of ES cell, HSC and LSC.
Blinded Mid-Treatment FDG-PET in Newly Diagnosed Aggressive Non-Hodgkin Lymphoma (NHL): First Results of a Prospective Multicenter Study.
Authors: Schot Bart W. , Zijlstra Josée , Hoekstra Otto S. , Pruim Jan , van Imhoff Gustaaf W. , Sluiter Wim , Raemaekers John M.M. , Oyen Wim , Van Gelder Michel , Eriks Olga , Huijgens P.C. , Vellenga Edo 
Published: October 2019

Abstract
In aggressive B-cell NHL, determination of early response to induction therapy by FDG-PET may improve risk stratification. In a multicenter prospective trial in patients with aggressive NHL (stage II–IV) treated with 2 or 3 weekly (R)CHOP chemotherapy, FDG-PET was performed after the third cycle of chemotherapy. Both clinicians and nuclear medicine physicians were blinded for PET and clinical outcome, respectively. Clinical decisions were based on conventional diagnostic methods (CDM) only. In total 114 patients were included of which 95 were evaluable. 19 patients were excluded because of patient refusal (n=7), early progression (n=7) or logistical reasons (n=5). Median age was 55 yrs (range 20–82), 72% had DLBC-NHL, 76% IPI&lt;3. The majority (85%) of patients completed chemotherapy according to protocol. 14(15%) went off protocol because of less than PR after 3 cycles of (R)CHOP or progression on treatment based on CDM or excess toxicity. CR(u) was reached in 60% of the patients. 34 (36%) patients relapsed and 2 patients died of NHL after a median follow-up of 26 months. PET was scored qualitatively using a Likert scale. PET after 3 courses was negative in 45 patients and positive in 50. 24/50 (48%) PET positive patients progressed or relapsed as compared to 10/45 (22%) PET negative patients. Median progression free survival (PFS) for PET positive versus PET negative patients was 19.8 months versus not yet reached (p=.0087). In a multivariate analysis, IPI and PET were independent predictors for PFS.
These results corroborate and extend the evidence that mid-treatment FDG-PET is highly predictive for PFS and may be a useful tool for risk-adapted management of aggressive NHL.
Intensifying Methotrexate (MTX) Dosage Reduces Treatment Failure in Adults with Burkitt or Burkitt-Like Leukaemia/Lymphoma (BL) Treated with an Adapted BFM Protocol.
Authors: Tauro Sudhir , Begum Gulnaz , Lauritzsen Grete Fossum , Delabie Jan , Roberts Claudia , Mahendra Premini , Holte Harald 
Published: October 2019

Abstract
The use of short-duration intensive combination chemotherapy protocols has improved survival in adults with Burkitt/Burkitt-like leukaemia and lymphoma (BL). Systemic methotrexate (MTX) is an integral component of these regimens, but the dosage varies between treatment schedules, and the precise dose required to optimise tumour-kill without causing severe toxicity is not known. In this study of 66 adults with sporadic BL, we have investigated whether the dosing intensity of MTX can influence treatment failure (defined as disease relapse or resistance to treatment, or death due to therapy). There were 49 males and 17 females in the cohort (median age 36 years, range 16–69y), including 9 with HIV disease and 2 organ-transplant recipients. Majority of patients (66%) had St Jude stage III/IV disease. The median increase in serum LDH level relative to normal (adjusted LDH) was 1.4 (range 1–65). Patients were treated with a combination of CNS-directed and systemic chemotherapy comprising of a pre-phase [fractionated (Fr) cyclophosphamide and prednisolone], followed by a possible total of 6 cycles of alternating Fr ifosfamide, dexamethasone, vincristine, cytarabine and etoposide [Cycle A], with Fr cyclophosphamide, dexamethasone, vincristine and adriamycin [Cycle B] as outlined by the German BFM paediatric protocols. Patients received a 24h intravenous infusion of MTX on d1 of each cycle of treatment. Based on the mean MTX dose administered per cycle, patients were stratified into three dosage groups: low (<1gm/m2, n=4), intermediate (1–1.5g/m2, n=24) or high (>1.5–3g/m2, n=34). There were 3 toxic deaths, disease was refractory in 8 patients and 9 experienced disease relapse. Durable complete responses following BFM were observed in 46/66 (70%) patients. A significantly lower proportion of patients receiving high-dose MTX (17%) experienced treatment failure compared to 45% and 50% in the intermediate and low-dose groups respectively (Fisher’s Exact p=0.01). Risk stratification on the basis of pre-treatment stage and bulk of disease, adjusted LDH and ECOG score was however unable to identify patients who may benefit from intensifying MTX dosage. These data thus uniquely highlight the impact of MTX dose in influencing outcomes in adult BL as well as the need for novel biological markers to identify patients requiring additional therapeutic strategies.
Enteropathy-Type T-Cell Lymphoma: Clinical Features of a Series of 62 Cases. Jan Delabie, Harald Holte, Andrew Lister and Julie Vose for the International T-Cell Lymphoma Project.
Authors: Delabie Jan , Holte Harald , Lister Thomas A. , Vose Julie M. 
Published: October 2019

Abstract
In an international retrospective clinical study of 1159 adult, non-cutaneous mature T-cell lymphomas, verified by an expert pathology panel, 62 cases of enteropathy-type T-cell lymphoma (ETTCL) were identified, representing 5.3%. Patients in this study were diagnosed at one of the participating centers in North America, Europe, and Asia between 1990 and 2002. ETTCL represented the 6th most common T-cell lymphoma, affecting predominantly the small bowel. Of interest, about a third of the cases of ETTCL were obtained from Norway, as the only participating center from Scandinavia. Twenty out of 52 cases (38%) were associated with celiac disease. As expected, abdominal pain was the most frequently recorded symptom, followed by general symptoms such as fatigue, weakness and anorexia. Overall as well as failure-free 5-year survival were poor, 20% and 4%, respectively. Univariate statistical analysis revealed that high T-IPI score (Gallamini, et al: Blood 103: 2474–2479, 2004) but not high IPI score, high CRP and LDH levels, and tumor size >5cm were adverse prognostic factors at p values <0.05. Most patients (51/60) were treated with anthracycline-containing chemotherapy regimens, whereas 9 received other or no treatment and showed a worse survival, probably due to a negative patient selection. Multivariate analysis controlling for T-IPI score, revealed that only high CRP levels and tumor size >5cm were independent prognostic factors. In conclusion, ETTCL is a clinically aggressive and fatal disease for which, currently, no effective treatment exists. T-IPI score, CRP levels and tumor size can be used as prognostic factors.
Hodgkin Lymphoma in Very Young Children Can Be Treated Successfully without Radiation Therapy.
Authors: Belgaumi Asim F. , Al-Kofide Amani A. , Joseph Nicey , Khafaga Yasser , Malik Rubina J. , Mourad Walid , Mohamed Gamal-Eldin H. , Sabbah Rajih S. 
Published: October 2019

Abstract
Hodgkin Lymphoma (HL) is rarely seen in <5-year olds in developed nations. Even in developing countries, where a tendency towards younger age of presentation has been shown, this represents a minority of cases. Little is known about the biology and behavior of these very young patients with HL as compared to older children.
Methods: We retrospectively reviewed HL cases diagnosed and treated at our institution between 1975 and 2003. HL was diagnosed histopathologically and staged clinically. The pediatric age group ranged from 0–14 years. Treatment strategy for these very young children was focused on the elimination of radiation therapy (XRT).
Results: 69/368 (18.75%) patients were less than 5 years at diagnosis. When compared to older patients, there was a trend towards male predominance (M:F 4.31 v. 2.65; p=0.2), but no difference in the incidence of B-symptoms (26.1% v. 32.9%; p=1.0) and stage distribution (p=1.0). There was less mediastinal involvement (p=0.025) or bulky disease (p=0.01) in the younger patients. These patients had more mixed cellularity and less nodular sclerosis subtype (p=0.025). Fifty-five were treated with chemotherapy (CTX) alone, 12 with combined modality therapy (CMT) and 2 with XRT only. 35/55 CTX patients were treated with ABVD (20 per standard schedule, 13 modified and 2 unknown), 12 MOPP and 8 with hybrid or combination CTX (4 MOPP/ABVD, 3 COPP/ABVD and 1 unspecified). All CMT patients received ABVD (9 standard and 3 modified) and XRT (1500cGy/IF for 5, 1500cGy/EF for 4 and 2400cGy/EF, 2720cGy/IF and 3060cGy/IF for one each). The two XRT alone patients had stage I cervical disease and received 3900cGy and 3250cGy IFXRT. At ten years the EFS and OS for these patients under 5-years of age was 81.5% and 90.4%, respectively, compared to 75.5% and 90.5% for the children between 5 and 14 years of age (p>0.5 for both comparisons). OS (86.4% v. 100%; p=0.3, Log Rank test) and EFS (81.0% v. 90.9%; p=0.4, Log Rank test) for CTX v. CMT groups were not statistically significantly different. The CTX group had more B-symptoms (29.1% v. 16.1%) and higher stage disease (stage III/IV 47.3% v. 25%; stage IV 12.73% v. 0%).
Conclusions: HL patients <5years old do not present with higher risk disease than older children. They can successfully be treated without XRT using CTX alone. XRT can be reserved for treating the few who relapse. This may result in reduction in XRT related toxicity, which can be significant in these very young children.