bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crosslineage T-Cell Receptor Genes Rearrangements and Active Receptor Editing in B-Cell Acute Lymphoblastic Leukemia.
Authors: Makuch-Lasica Hanna , Majewski Miroslaw , Nowak Grazyna , Lewandowska Monika , Solarska Iwona , Kania Iwona , Warzocha Krzysztof 
Published: October 2019

Abstract
B-cell acute lymphoblastic leukemia (B-ALL) results from clonal expansion of B-lymphocytes derived at different stage of differentiation. Immunoglobulin (Ig) heavy chain genes (IGH), light chain kappa (IGK) and lambda (IGL) genes rearrange during early B-lymphocyte differentiation. T-cell receptor (TCR) genes are postulated to rearrange exclusively in normal T lymphocytes, but malignant B lymphoblasts often contain crosslineage rearranged TCR genes. The clonal leukemic cell population, carrying identical copies of rearranged Ig and/or TCR genes, can be identified above 95% of B-ALL patients. In our study Ig/TCR genes rearrangements were detected by multiplex PCR with heteroduplex analysis according to BIOMED-2 protocol. DNA was isolated by column method from mononuclear cells isolated from the peripheral blood/bone marrow samples obtained at initial diagnosis from 28 B-ALL patients. Monoclonal rearrangements of Ig genes were detected in 96% (27/28) of patients. The most frequent rearrangements were observed in IGH genes (96%), including complete IGHV-IGHJ in 75% (21/28) and incomplete IGHD-IGHJ in 31% (8/28) of patients. Among complete IGH rearrangements 4 biallelic rearrangements in IGHV1-7 and IGHJ genes (FR3) were found. Ig light chain genes rearrangements were identified in 20 patients (71%) (including 25% of IGKV-IGKJ, 50% of IGKV/intron-Kde, and 25% of IGLV-IGLJ) indicating active receptor editing occurring during B lymphoblasts leukemogenesis. Cross-lineage TCR genes rearrangements were found in 77% (23/28) of patients. TCR beta genes rearrangements were detected in 46% (13/28) of patients (complete TRBV-TRBJ in 32% (9/28), TRBD-TRBJ in 5/28 patients - 18%). TRGV-TRGV were found in 46% (13/28), TRDV-TRDJ in 50% (14/28; 10 monoallelic and 4 biallelic). TCR beta genes rearrangements with presence of TCR gamma genes rearrangements were identified in 25% (7/28) of patients. The identified Ig and TCR rearrangements were stable in patients monitored for minimal residual disease (MRD) and patients with leukemia relapse. The inactivation of potentially functional IGKV-IGKJ by secondary rearrangements indicates active receptor editing. Our data describe IGK and IGL genes rearrangements incidence, present allelic exclusion and active receptor editing in B-ALL patients. B-ALL lymphoblasts undergo many rearrangements on the same IGK allele before they rearrange IGL genes. The data suggest the role of antigen in B-ALL immunopathogenesis. The results indicate also rearranged IGK, IGL and TCR genes as a possible molecular marker for monitoring MRD in B-ALL.
Experience of a Brazilian Institution with Treatment of Adult Acute Lymphoblastic Leukemia.
Authors: Pinheiro Edilson D. , Prachia Luiz F. , Velloso Elvira R.P. , Beitler Beatriz , Bucheri Valeria , Pereira Juliana , Dorlhiac-Laccer Pedro E. , Chamone Dalton A.F. 
Published: October 2019

Abstract
Adult Acute Lymphoblastic (ALL) is an aggressive bone marrow neoplasm, associated with a poor outcome in adult patients. The aim of this study is to compare different treatment protocols analyzing complete response after induction treatment (CR), overall survival (OS) and disease free survival (DFS). Statistical analysis was done by SPSS 10.0. The analysis of prognostic factors, protocols and response treatment was done by Pearson’s chi-square. OS and DFS curves were constructed by Kaplan-Meyer method and differences were analyzed by log-rank test.
In our institutional department, 102 patients with ALL diagnosed between 1990 and 2005 were treated with one of the follow protocols: BFM 86 modified (BFM 86M) (48/102), OPAL86 (6/102), OPAL87 (40/102) (Linker et cols; 1986Linker et cols; 1987) and CHOP (8/102). The results were analyzed retrospectively. The median follow up was 49 months. CR for BFM 86M, OPAL86, OPAL87 and CHOP was 76,7%, 100% 63,9% and 42,9%, respectively; with no statistically difference (p=0.08). OS was better with BFM 86M than with other protocols (p=0.001). BFM 86M was associated with 4-years DFS of 42,5% (median: 26,4 m) and OS of 49,5% (median: 35,4m). OPAL86, OPAL87 and CHOP had a median survival of 21, 12, and 5,5m respectively. Four-years OS of the patients treated with protocols other than BFM 86M was 16,8%.
The distribution of the clinical and laboratory data between the BFM 86M and the other protocols (OP) was compared. Age less than 18y (p=0.05) and L1 ALL (FAB) (p=0.01) were more prevalent in OP group. Myeloid expression antigens (p=0.05) and poor prognosis karyotype (e.g. Ph cromossome) (p=0.08) were more prevalent in BFM 86M group.
Age less than 35y (p=0.02), absent of fatigue at diagnosis (p=0.04), CNS not infiltrated (p=0.01) were associated to an early complete remission with OP but not with BFM 86M. Hepatomegaly, at diagnosis, was associated with poor complete remission when patients received BFM 86M protocol (p=0.02). Age less than 18y (p=0.002) and absent of hepatomegaly at diagnosis (p=0.01) were associated with a prolonged survival only in BFM 86M protocol. T-ALL (p=0.04) and infiltration of CNS (p=0.02) were related to worst survival in other protocols (OP) but not in BFM 86M. Bleeding at diagnosis for both BFM 86M and OP were related to short survival (p=0.03; p=0.01).
The Philadelphia-Chromosome Is Unmasked as the Secondary Genetic Change in Acute Myeloid Leukemia on Imatinib Treatment.
Authors: Yip Sze F. , Wan Thomas S.K. , Liu Herman S.Y. , Wong Michael L.G. , Chan Li C. 
Published: October 2019

Abstract
The Philadelphia chromosome (Ph) is present in less than 3% of the acute myeloid leukemia (AML) and associated with poor prognosis. There are only few reports on the use of imatinib in Ph+ AML. We describe an adult female patient presenting with AML (Hb 3.6 g/dl, Wbc 137×109/L, Plt 295,000/uL and marrow blast 74%, with no basophilia or splenomegaly). Cytogenetic studies showed 45,XX,inv(3)(q21q26),-7,t(9;22)(q34;q11.2) [12] and RT-PCR showed p190BCR-ABL transcripts. The leukemia failed to respond to 2 cycles of daunorubicin and ara-C and imatinib 600mg daily was then started. Fluorescence in-situ hybridization (FISH) analysis of 300 marrow cells using dual fusion BCR-ABL translocation probes (D-FISH, Vysis, Downers Grove, IL, USA) showed that before imatinib, 78% of the cells were positive for BCR-ABL (at diagnosis, it was 83%), which after 6 weeks of imatinib treatment, became BCR-ABL negative (sensitivity 0.3%). However, marrow biopsy still showed 15% blasts. Repeated cytogenetics showed poor growth, but one metaphase showed 45,XX,inv(3)(q21q26),-7. With FISH, 39% of the marrow cells, including neutrophils, were positive for monosomy 7. At 4 months of imatinib, when the marrow blasts count increased to 40%, BCR-ABL remained negative by FISH, whereas monosomy 7 positive cells had risen to 82%. However, by nested RT-PCR with sets of BIOMED primers (sensitivity of 10−5), the p190BCR-ABL transcript was still present, suggesting persistence of a small and quiescent population of BCR-ABL positive leukemic stem cells. In summary, our case study demonstrates the need for careful cytogenetic and molecular analysis in cases of acute leukaemia with Ph chromosome to exclude the possibility of Ph chromosome being a secondary event, in which case durable leukemia remission will be unlikely if treatment is by BCR-ABL inhibition alone.
A Case of Relapsed Variant Acute Promyelcytic Leukemia with t(11;17)(q23q21), PLZF/RARa Fusion Gene, with Durable Molecular Remission Following an Induction and Consolidation Regimen That Included ATRA with Low Dose G-CSF and Valproic Acid as a Histone Deacetylase Inhibitor.
Authors: Efiom-Ekaha Daniel N. , Sanmugarajah Jasotha , Solomon William B. 
Published: October 2019

Abstract
Background:
Acute promyelocytic leukemia (APL) accounts for 10% of acute myeloid leukemias. Greater than 95% of cases are associated with the t(15;17)(q22;q21) translocation with the PML-RARa fusion product which is associated with increased affinity for nuclear co-repressor protein complex and recruitment of histone deacetylase. This leads to an alteration in chromatin conformation and inhibition of transcription and differentiation in promyelocytes in the presence of physiologic levels of retinoic acid. Pharmacologic doses of retinoic acid however are usually required to overcome this repression of transcription and leads to promyelocyte differentiaton and improvement in clinical outcomes in classic APL. A variant translocation in APL, t(11;17) (q23;q21) where the 3′ end of the RARa gene is fused to the 5′ end of a gene called PLZF (promyelocytic leukemia zinc finger), accounts for about 1% of cases. This disease phenotype is associated with refractoriness to pharmacologic doses of retinoic acid.
Case Report;
52 year-old male presented with fever and rapidly progressive leukocytosis. His HCT was 24%, WBC count was 75,000/mcl and platelet count was 109,000/mcl. He required endotracheal intubation and mechanical ventilation with leukapharesis on his second day of admission due to leukostasis. He had been diagnosed with APL variant with t(11;17) (q23;q21) two years prior to this admission and had induction with Ara-c + daunorubicin (7+3), with an additional cycle for consolidation. He was then placed on maintenance with 6-MP + MTX for 24 months. Bone marrow and peripheral blood analysis confirmed disease relapse. Flow cytometric analysis revealed immature myeloid population CD34−, CD15−, CD13+, CD56+, HLA-DR-, with partial expression of CD33. FISH analyses on peripheral blood was negative for t(15;17) and positive for the variant t(11;17)(q23q21). He was started on induction therapy with Idarubicin 12mg/m2/day for three consecutive days with ATRA 45mg/m2/day (via NGT) + G-CSF 5mcg/kg/day. His Day 21 bone marrow examination revealed complete hematologic response. Consolidation/ maintanance with sodium valproate 500mg po BID (to maintain serum levels of 50–100mcg/ml), ATRA 45mg/m2/day (via NGT) + G-CSF 5mcg/kg/day (with G-CSF dose reductions for leukocytosis with a final stable dose of 30mcg/day). He subsequently achieved a complete cytogenetic remission and relapsed after 18 months on this regimen.
Conclusion:
Induction of promyelocyte differentiation and reversal of retinoic acid refractoriness in variant APL with t(11;17) (q23;q21) can be achieved with G-CSF priming and the addition of valproic acid s a HDAC inhibitor.
Endoplasmic Reticulum Stress Is a Target for Therapy in Waldenstrom’s Macroglobulinemia (WM).
Authors: Leleu Xavier , Xu Lian , Hunter Zachary R. , Jia Xiaoying , Moreau Anne-Sophie , Ho Allen W. , Hatjiharissi Evdoxia , N’Go Hai , Santos Daniel D. , O’Connor Kelly , Manning Robert , Soumerai Jacob , Patterson Christopher , Ghobrial Irene M. , Treon Steven P. 
Published: October 2019

Abstract
Background: WM is an incurable low-grade lymphoplasmacytic lymphoma with limited options of therapy. Proteasome inhibition has been shown to induce components of the proapoptotic/terminal unfolded protein response (UPR), a signaling pathway activated by accumulation of misfolded proteins within the endoplasmic reticulum (ER). We previously found that UPR gene expression is related to disease activity in WM with a particular role for GRP78/Bip as a prognostic factor. We therefore examined tunicamycin (Sigma, St Louis, MO), a potent inducer of ER stress, for potential anti-tumor effects in WM.
Methods: WM cell lines (BCWM.1 and WSU-WM), IgM secreting low-grade lymphoma cell lines (MEC1, RL) and primary CD19+ selected LPC cells from WM patients were incubated with tunicamycin (0.01–10 uM) for 24–72 hours and evaluated by MTT, thymidine uptake, and Apo2.7/PI staining for effects on proliferation and survival. Since bone marrow stromal cells (BMSC) confer growth and resistance to conventional treatments, we also tested the effect of tunicamycin on WM cells co-cultured with BMSC. Immunoblotting for caspases was also performed and expression of UPR genes determined using relative quantitative RT-PCR reaction following (0.5–16 hrs) culture with tunicamycin.
Results: WM cells inherently expressed the ER chaperones GRP78/Bip and GRP94/gp96. Tunicamycin rapidly induced components of the proapoptotic/terminal UPR, including PERK, the ER stress-specific eIF-2alpha kinase; ATF6, an ER stress-induced transcription factor; and its proapoptotic target, CHOP/GADD153. Tunicamycin also induced significant cytotoxicity, and inhibited DNA synthesis with an IC50 of 0.5–1 ug/mL in all cell lines, as well as primary LPC from 3/3 WM patients. Furthermore, tunicamycin induced apoptosis in WM cells, with an increase in the sub-G1 population notable at 12 hrs. Tunicamycin induced apoptosis was preceded by caspase-12 cleavage, followed then by caspase-8, -9 and PARP cleavage. Importantly, co-culture of WM cells with the survival factors IL-6, IGF-1 as well as BMSC did not inhibit tunicamycin induced cytotoxicity. Lastly, tunicamycin did not induce cytotoxicity in healthy donor peripheral blood mononuclear or hematopoietic stem cells.
Conclusion: These pre-clinical studies provide a framework for further evaluation of ER stress inducing agents as therapeutic agents in WM.
Standard CHOP-21 as First Line Treatment for Elderly Patients with Hodgkin’s Lymphoma.
Authors: Kolstad Arne , Holte Harald , Nome Ole 
Published: October 2019

Abstract
Background: Outcome for elderly patients with Hodgkin’s lymphoma is not as good as for younger patients, partly due to inferior capability to tolerate appropriate chemotherapy. There is no consensus on standard treatment. In 2000 we introduced CHOP-21 as standard chemotherapy for elderly Hodgkin’s lymphoma patients at our institution with the aim to improve treatment results. CHOP-21 is known to be well tolerated in older patients with non-Hodgkin’s lymphoma and contains active drugs for Hodgkin’s disease.
Patients and methods: Twenty-nine consequtive patients admitted to our institution from 2000–2004, 60 years and older with Hodgkin’s lymphoma were included in this retrospective survey. Stage I/IIA patients received 2–4 cycles of CHOP-21 followed by 30–35 Gy involved field radiotherapy. Stage IIB-IV patients were treated with 6–8 cycles of CHOP-21. Selected cases received 30–35 Gy involved field radiotherapy against residual tumors.
Results: The median age was 71 years (range 60–91). Sixty-two percent presented in stage IIB-IV and 38% in stage I-IIA. Forty-five percent of the early stage patients had bulky disease and/or elevated SR. For the advanced stage patients IPS score of 2–3 was the most common category (72%). B-symptoms occurred in 52% of the total population. Nodular sclerosis was the most frequent histology subgroup (38%), followed by mixed cellularity (17%). Fifty-five percent had co-morbidity prior to treatment, cardiac conditions were most common. Two cases of treatment-related deaths were seen (7%). The most common toxicity during therapy was febrile neutropenia (31%). Treatment modifications were necessary in 38% of cases. The complete response rate after CHOP +/− radiotherapy was as high as 93%. Median follow-up for the whole population is now three years. Five patients have relapsed, and four have died from Hodgkin’s lymphoma. Total overall survival (OS) at three year was 80%, and better for the stage I-IIA subgroup (90% versus 60%). Total Hodgkin-specific survival (HSS) at three years was 73%, and 80% versus 60% for early and advanced stages, respectively. No relapses have occurred after 2 years.
Outcome with CHOP +/− radiotherapy for Hodgkin’s lymphoma patients 60 years and older Response 29 pts (%) NE = not evaluable, patients died after one cycle of CHOP. CR 27 (93) PR 1 (3) ORR 28 (97) NE 1 (3) Relapsed 5 (18) Cause of death Hodgkin’s lymphoma 4 (14) Toxicity 2 (7) Other 1 (3)
Conclusion: The data shows that CHOP-21 is a well tolerated and highly effective first line treatment for elderly patients with Hodgkin’s lymphoma. Of particular interest were the findings that advanced stage patients did so well and that no relapses have been seen after two years.
Addition of Rituximab to CHOP Regimen Improves Clinical Outcome in Non-Germinal Center Type Diffuse Large B-Cell Lymphoma.
Authors: Yokoyama Masahiro , Ennishi Daisuke , Ueda Kyoko , Kodaira Makoto , Yamada Shuhei , Myojo Tomohiro , Sakajiri Sakura , Mishima Yuko , Takeuchi Kengo , Saotome Takashi , Terui Yasuhito , Takahashi Shunji , Ito Yoshinori , Hatake Kiyohiko 
Published: October 2019

Abstract
Background: In recent years, diffuse large B-cell lymphoma (DLBCL) has been classified into the germinal center B-cell (GC) type, the activated B-cell (ABC) type, and the type 3 using global gene expression profiling or immunohistochemical staining. It has been reported that the GC type DLBCL showed significantly longer survival than the non-GC (ABC and the type 3) type DLBCL treated with CHOP or CHOP like regimen not using rituximab.
Methods: We analyzed retrospectively the prognosis between the GC and non-GC types of DLBCL treated with R-CHOP regimen. All 50 patients with DLBCL, diagnosed between July 2003 and July 2005 were included in this study. The pathology was reviewed by hematopathologist and confirmed to be de novo DLBCL according to the WHO classification. Patients with primary CNS- and post-transplant lymphomas were excluded. GC type or non-GC type DLBCL was determined by immunohistochemistry such as the expression patterns of CD10, BCL-6, and IRF-4 (MUM1). All patients were initially treated with six cycles of R-CHOP regimen consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. If we evaluated partial response after six cycles of R-CHOP, the patients have added radiation therapy.
Results: The patients consisted of 30 GC type and 20 non-GC type DLBCL with a median age of 61.0 yr (range 31–83 yr). The median follow up of surviving patients was 24 months. CR rate between GC and non-GC types were 57.0% vs. 75.0%, p=0.186, and overall response rate were 87.0% vs. 90.0%, p=0.929, respectively. The median of progression free survival was 17.3 months vs. 19.6 months, p=0.80. There is no statistical significance difference between two groups.
Conclusion: These results suggest that addition of rituximab to CHOP regimen improves clinical outcome of non-GC type DLBCL as well as GC type DLBCL.
Cyclin-Dependent Kinase Inhibitor Seliciclib Shows In Vitro Activity in Diffuse Large B Cell Lymphomas.
Authors: Bertoni Francesco , Lacrima Katia , Rinaldi Andrea , Vignati Sara , Martin Vittoria , Tibiletti Maria Grazia , Gaidano Gianluca , Catapano Carlo C. , MacCallum David E. 
Published: October 2019

Abstract
Background. Despite recent improvements in treatment, a significant fraction of patients with diffuse large B cell lymphoma (DLBCL) still fail therapy. Therefore, new therapeutic modalities are needed to advance the cure rate. Seliciclib (CYC202, R-roscovitine) is a purine analogue developed as an inhibitor of CDK2/cyclin E CDK7/cyclin H and CDK9/cyclin T. Seliciclib has been shown to be active in B cell neoplasms, such as mantle cell lymphoma, chronic lymphocytic leukemia and in multiple myeloma in vitro. The aim of this study was to assess the in vitro activity of seliciclib in DLBCL.
Materials and methods. The anti-proliferative activity of seliciclib was tested in nine human DLBCL cell lines and six DLBCL primary cell cultures. The effects of seliciclib on the cell cycle and on apoptosis, as well as on transcription-related proteins were assessed.
Results. The cell viability of all DLBCL cell lines and primary cells was reduced by seliciclib treatment. The IC50 for the cell lines ranged from 13 to 36 μM. The effect of seliciclib was independent of the genetic aberrations characterizing the cell lines. After seliciclib exposure cells accumulated in G2/M or in G1 phase, with most of the cells showing signs of apoptosis. Despite the clear cytotoxic effect and induction of apoptosis, we could not identify a unique mechanism of action.
Conclusions. Our in vitro data suggest that seliciclib is an active agent in DLBCL. Its efficacy is apparently independent of the underlying chromosomal translocations characteristic of DLBCL. The drug might represent a new therapeutic agent in this lymphoma subtype.
Recombinant Protein A Activity in SCID Mouse Models of Human B Cell Tumors.
Authors: Cooper Andrew , Stein Rhona , Hall Katherine , Boismenu Richard , Chen Susan , Rusche James 
Published: October 2019

Abstract
Protein A from Staphylococcus Aureus acts as a potent B cell superantigen through specific interaction with B cell receptors displaying variable heavy chain sequences from the VH3 clan. In humans, 30–50% of all B cells are VH3-positive, so protein A activity may serve to interfere with host immune responses to S. Aureus through deletion of normal B cell subsets. Indeed, protein A-mediated B cell deletion has been demonstrated in transgenic mice with nearly all B cells expressing VH3-positive surface Ig [Goodyear, J. Immunol176(4), 2262, 2006]. However, it is conceivable that this activity may be usurped to target clonal B cell diseases with a VH3-positive cell origin. In the current study, the superantigen function of a recombinant therapeutic form of protein A (TpA) was exploited to investigate potential anti-tumor activity of protein A in in vitro and in vivo models of B cell neoplastic disease. TpA initiated apoptotic cell death of VH3-positive B cell tumor lines in culture within 24–48 of exposure as evidenced by alteration in mitochondrial membrane potential, activation of caspases, and external exposure of phosphatidylserine in the cell membrane. By 72–96 hours, cell viability was reduced by >50%. Addition of human IgG was essential for cell killing and optimal activity was observed at a 2:1 molar ratio of IgG to TpA. In SCID mice engrafted with the non-Hodgkin’s lymphoma cell line 2F7, TpA administered along with human IgG resulted in modest but statistically significant extension of median survival. In two independent studies employing a SCID mouse KMS-12-BM tumor model, TpA along with 40mg/kg human IgG produced a dose-dependent, reproducible therapeutic effect. At the highest dose studied (30mg/kg), median survival was 45 days compared to median survival of 27 days for control animals. Increased frequency of TpA administration also positively impacted median survival. While human IgG was required for optimal response, a five-fold increase in IgG diminished TpA anti-tumor activity, further underscoring the importance of the ratio of TpA to IgG in cell killing. These results demonstrate that the capacity of protein A to act as a B cell superantigen is not limited to normal cells but can be manifest on transformed cells as well. Since the VH3 clan is highly represented in the human B cell repertoire and is over-represented in some B cell neoplastic diseases, protein A may have utility as a therapeutic agent in cases of B cell malignancy where a VH3 origin is identified.