bluuebunny/crossref_metadata_2025_split huggingface dataset:
Method for definition of CIS-TRANS status in double CEBPA mutations.
Authors: Mitne-Neto Miguel , Moreira Caroline Mônaco , Fraga Ana Maria 
Published: September 2018

e18511 Background: Acute myeloid leukemia (AML) is characterized by infiltration of blood and bone marrow by proliferative, clonal and abnormally differentiated hematopoietic cells, affecting 3 in 100.000 adults. CEBPA is a transcription factor and a biomarker for cytogenetically normal (CN) patients. Somatic CEBPA mutations occur in 10% of CN patients and recent studies have shown that a favorable outcome may only be obtained in those carrying CEBPA mutations in different alleles ( trans). The evaluation of double mutations and the definition of bi-allelic ( trans) versus mono-allelic ( cis) status applies long protocols, involving gene cloning and sequencing, which are challenging for the diagnostic routine and negatively impacts the turnaround time (TAT). The present study aimed the development of an alternate method for the identification of double mutations in CEBPA and its CIS- TRANScondition. Methods: A previously screened sample carrying double CEBPA mutations was selected and its DNA was extracted. This sample and a DNA control were quantified and diluted in order to obtain ½ DNA molecule per well for amplification, using digital PCR rationale. Samples were distributed in 40 wells of a 96 well plate. A pair of primers was used to amplify the entire CEBPA coding region in a Real-Time PCR using SYBR green-based detection in QuantStudio System. A subset of primers was used to amplify and to sequence the regions of interest. The entire process was repeated three times, in order to prove its reproducibility. Results: The above described dilution allowed an estimation that half of the wells had no DNA and half contained a single DNA molecule. An average of 18 wells presented amplification. Five of the positive wells were used as templates for a nested PCR followed by Sanger sequencing analysis. Since each mutation was identified as the result of distinct well amplification, we concluded that the mutations were in trans. Conclusions: Our results show that it is possible to determine the CIS- TRANS allelic configuration of CEBPA dual-mutation in a cost-effective process and with a short TAT, avoiding gene cloning systems. Additionally, the process is reproducible, can be easily implemented as a routine analysis and has a great impact for AML patients’ diagnosis.
CD19 targeted chimeric antigen receptor T (CAR-T) cell immunotherapy has demonstrated significant anti-leukemia activity in pediatric patients with relapsed/refractory acute lymphocytic leukemia: A multicentre study in China.
Authors: Xiao Lei , Tang Yongmin , Zhu Xiaofan , Chen Jing , Wu Zhao 
Published: September 2018

e18512 Background: Patients with relapsed/refractory B-ALL are difficult to be treated. Autologous CD19 CAR-T may overcome many limitations of conventional therapies and induce remission in patients with relapsed/refractory disease. We explored treatment of 11 pediatric cases (come from Multicenter) with r/r B-ALL and assessed the clinical safety and efficacy. Methods: We infused autologous CD19 CAR-T in patients at doses of 0.45 × 106 to 10.51 × 106cells per kilogram of body weight. Between Oct. 23 2015 and Jan. 12 2017, a total of 11 children from 3 clinical centers (in China) cases were treated with CAR-T cells (Table1). Patients were monitored for a response, toxic effects, and remission rate. Statistical analysis involving categorical or continuous covariates, univariates, or multivariates analyses. Results: 73% (8/11) of the patients achieved complete remission (CR) and MRD negative between Day7-14 after CD19 CART cell infusion. 4 patients received a repeat infusions following initial ones since they have endured the Cytokine release syndrome (CRS) and have no safety concerns. Cytokine release syndrome (CRS) was seen in 73% (8/11) of patients and severe CRS occurred in 18% (2/11) of patients. Severe CRS was relieved gradually when the anti-IL6R agent tocilizumab and Methylprednisolone were administrated. 1 patients performed bone marrow transplant after they achieved MRD negative. The median CR maintenance is 121 day. Conclusions: This effort provides the first large set of pediatrics data that describes the potential for CART19 therapy to benefit Chinese population. Autologous CD19 CAR-T was effective in treating relapsed/refractory B-ALL not only low leukemia burden, but also high-burden leukemia patients. The method also can associated with a high remission rate. Importantly, While the multicenter trial involves 3 clinical centers in China, the variable clinical settings do not seem to impact patient outcomes due to the highly standardized CAR T cell preparation protocol and manageable CRS in most. (NCT 02813837) Clinical trial information: NCT 02813837.
Clinical utilization of the Myeloid Malignancies Mutation Panel.
Authors: Arain Saad A , Hall Aric C. , Mattison Ryan J. 
Published: September 2018

e18523 Background: The scientific community has made tremendous progress in discovering genetic changes that drive myeloid malignancies and elucidating the effect of these mutations on prognosis. Still, the links between mutational profiling and management decisions remain unclear. In an effort to determine its clinical utility, we evaluated the use of the Myeloid Malignancies Mutation Panel (MMMP) at our institution. Methods: The MMMP is an assay of 57 genes with possible diagnostic, prognostic, or therapeutic implications for myeloid malignancies run by ARUP Laboratories. The assay was run on 30 patients at the University of Wisconsin – Madison between 6/2015 and 8/2016: 18 with leukemia, 5 with myelodysplastic syndrome, and 7 with “other” diagnoses (unexplained cytopenias, myeloproliferative disorders, or myelodysplastic/myeloproliferative overlap syndromes). Separate questionnaires for hematologists and hematopathologists were created asking 1) if the results of the MMMP were expected and 2) if the results changed diagnosis or management for each patient. Results were coded in a binary “yes/no” system and further subdivided by disease risk and category of response. Results: Hematologists considered the MMMP results expected for 8 patients and unexpected for 22. Per hematologist assessment, test results affected management (changed risk assessment, monitoring parameters, or drug therapy) for 14 of the 30 patients. Per the hematopathologists, the MMMP results were expected for 17 patients and unexpected for 13. For 11 patients, the diagnosis was affected (confirmed a suspected diagnosis or reassured against malignancy), while for 19 patients, the diagnosis was unchanged. Notably, in half of this group for whom diagnosis was unchanged, the hematopathologists believed there were significant prognostic implications. Conclusions: This data suggests the MMMP had significant implications in the diagnosis and management of myeloid disorders for nearly half of our patients. Clarifying this utility further to determine optimal cost-effective application of this expensive testing will require additional evaluation.
A single center experience with two decades of follow-up on patients with hairy cell leukemia.
Authors: Ilhan Osman , Atilla Erden , Ataca Atilla Pinar , Civriz Bozdag Sinem , Kurt Yuksel Meltem , Toprak Selami Kocak , Topcuoglu Pervin , Demirer Taner , Arslan Onder , Ozcan Muhit , Akan Hamdi , Beksac Meral , Gurman Gunhan 
Published: September 2018

e18530 Background: HCL is a rare chronic lymphoid malignancy and frequency is 2% in all leukemia and diagnosed mostly in middle ages. Patients generally respond to purine analogues treatment. In this study our aim is to present our HCL patients with demographic features, treatment modalities and responses. Methods: 39 HCL patients who were diagnosed and treated at Ankara University Department of Hematology between 1984 and 2016 were retrospectively evaluated. Ki-square test and student t test were used in comparison. P < 0.05 was considered statistically significant. Results: Median age of patients were 51 (range, 31-79). 30 of patients (77%) were male. The average leucocyte, hemoglobin, platelet, lactate dehydrogenase (LDH) levels and the spleen size at diagnosis were as follows: 5,1 x 10^9/L (range, 1,5-20), 12,5 g/dl (range, 9-17,5), 116x10^9/L (range,15-300), 178 IU (range,107-394), 155 mm (range,110-290). BRAF mutation could be evaluated in two patients and revealed as positive. 9 patients (23%) underwent splenectomy prior to chemotherapy. All patients received cladribine (0.1mg/kg, 7 days) as a first line treatment; 8 patients (21%) had two courses for remission. 11 patients (30%) had treatment related febrile neutropenia, 2 patients (0.05%) had transient skin rash after infusion. 8 patients (21%) had a relapse and 1 patients received pentostatin (4mg/m2, 1 dose every 2 weeks, 6 months), 7 patients were retreated with the first line treatment and achieved complete response. The overall survival was 67 months, respectively. Leucocyte, hemoglobin, platelet levels were lower, LDH levels were higher and spleen size was increased in patients with relapse however no statistical difference were detected. The patients with splenectomy had improved survival compared to patients without splenectomy (144 vs 329 months, P = 0.024). Conclusions: We detected 18% relapse rate in our series and all patients were followed in remisson after second line purine analogue treatment. Splenectomy has improved overall survival and possibly still has a role to play in HCL therapy. Generally, HCL is a chronic disease with a favorable prognosis.
A prospective study to evaluate outcomes of AIDS-related lymphomas at a tertiary referral cancer centre.
Authors: Dhir Aruna Alahari , Sawant Sheela , Sengar Manju , Daddi Anuprita , Damania Blossom , Mishra Surya , Dittmer Dirk , Shet Tanuja 
Published: September 2018

e19012 Background: AIDS related non Hodgkin’s Lymphoma (ARL) remains a major cause of morbidity and mortality .There are limited prospective studies on ARLs in Indian population. We studied the clinical profile and outcome of patients with ARL . Methods: Consecutive patients diagnosed with ARL in the period February 2014-march 2016 who were treatment naïve were included in the study. Details of HIV and ARL, treatment details , complications and outcome were recorded. The primary objective was overall survival(OS), secondary objectives were response rates correlation of overall survival with CD4 count, IPI, duration of HIV, histopathology and stage of NHL. Survival was described with the Kaplan-Meier method, and effect of predictor variables was tested with the log-rank test. Results: 42 patients(28 males) with a median age 45.5 years were included in the study . The commonest types of NHL were DLBCL 22 (52.38 %) and plasmablastic lymphoma 14 (33.33%). HIV infection was detected at the time of lymphoma diagnosis in 21 (50%). The median CD4+ T cell count was 137 cells/mm3 . 32 (76.19%) had stage III/IV disease and and 35(83.3%) had extranodal involvement. IPI score was >2 in 20/40(50%). 30/42 patients received chemotherapy of these 21 received atleast 4 cycles. 19 patients received CVEP regimen , 8 REPOCH and 3 others . NNRTI plus 2 NRTI combination was the HAART regimen in 26/30(86.6%) patients. Grade 3-5 febrile neutropenia was seen in 17/30 (56.6%) . Response was assessed using PET-CT scan in 22 patients ,16 (72.7%) had complete response .16/30 patients expired , 8 of these were due to infections . Median survival was 10 months (0.0-20.4 months). The estimated 2 year overall survival is 43.6 % . Patients with early stage disease had better overall mean survival (p=0.01). Type of NHL, IPI, CD 4+ T cell count, HAART prior to NHL treatment did not affect overall survival . Conclusions: Patients of ARL present at a younger age ,with higher grade and advanced disease. Higher proportion of plasmablastic lymphomas were seen in our study as compared to western data. Though most patients achieve complete response the overall survival is low . Myelosuppression and associated infections continues to be a challenge in the management of ARL.
A cost-effectiveness analysis of DA-EPOCH-R versus R-CHOP for the treatment of diffuse large B-cell lymphoma.
Authors: Gokul Ashni , Boyce Maria , O'Mahony Deirdre , Bird Brian Richard 
Published: September 2018

e19018 Background: Clinical trials have indicated that dose adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) may improve clinical outcomes when compared to standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) treatment in diffuse large B-cell lymphoma (DLBCL). The cost-effectiveness of the newer regimen, DA-EPOCH-R when compared to R-CHOP has not been assessed. Methods: Patients who received either DA-EPOCH-R or R-CHOP treatment at the Bon Secours Hospital from 2008-2016 for DLBCL were identified. The overall survival (OS), progression free survival (PFS) and event free survival (EFS) was determined for each treatment group using Kaplan-Meier survival estimation curves. Direct costs per treatment for each regimen were obtained from public hospital sources. Results: 71 patients were identified, 40 received DA-EPOCH-R, 31 received R-CHOP therapy. The DA-EPOCH-R group had a mean age at diagnosis of 62 years and a higher overall proportion under 70 years old (70%). The mean age for R-CHOP patients was 66 years and the patient age was largely equal for above and below 70 years at diagnosis. The majority of DA-EPOCH-R patients (77.5%) were stage III or higher at diagnosis compared to approximately half of R-CHOP patients (48.4%). Using a 6-year time horizon, there was no significant difference in Kaplan-Meier survival estimates between the two treatment groups for OS (p=0.58), PFS (p=0.48) or EFS (p=0.23). DA-EPOCH-R was found to be a more expensive treatment option in terms of total drug costs and hospital stay costs. Conclusions: DA-EPOCH-R was shown to have no significant difference in OS, PFS and EFS when compared to standard R-CHOP treatment overall in this population yet it is a significantly more expensive treatment option. The results of this study have not shown an economic or clinical advantage to the use of DA-EPOCH-R. It would be of interest to investigate this question in other high grade lymphomas.
Role of neutrophil to lymphocyte ratio in addition to revised international prognostic index (R-IPI) in patients with extranodal diffuse large B-cell lymphoma of head and neck.
Authors: Cisak Kamila Izabela , Gill Amitoj , Faber Erin , Redman Rebecca A. , Dunlap Neal E , Rai Shesh , Wu Xiaoyong , Perez Cesar Augusto 
Published: September 2018

e19032 Background: Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma (NHL). One third of DLBCLs cases have a primary extranodal origin and head and neck localization is second most common localization after gastrointestinal tract. The Revised-International Prognostic Index (r-IPI) is commonly used as prognostic tool, but there is growing evidence that neutrophil to lymphocyte ratio (NLR) also has prognostic significance in DLBCL. Methods: We retrospectively reviewed all cases of extranodal DLBCLs diagnosed between 2006 and 2016 at a single academic institution. Collected data included race, gender, primary site, baseline laboratory data, IPI score, pathology, treatment and survival. Results: A total of 33 patient were included, with 18 (54.5%) being females. Median age at diagnosis was 68 (range 28-92). 15% of patients had a r-IPI of 0, 30% a r-IPI of 1-2, 12% a rIPI of 3-5 and 36% a not evaluable (NE) r-IPI. Twelve (36%) patients had germinal center B cell subtype (GCB) and 17 (51%) patients had activated B cell subtype (ABC) by immunohistochemistry. Among all patients, 13 (39%) had pretreatment NLR equal or more than 3.5 and 11 (33%) patients had NLR less than 3.5 and 9 patients had a NE NLR. . Among deceased patients, 5 (56%) of them had NLR of more that 3.5 (p =0.011). Nine (27%) patients had pretreatment monocyte count less than 700/mm3 and 14 (42%) patients had monocyte count at least 700/mm3 (p=0.611). The 2-year overall survival was 77% (95% CI 0.61 - 0.93). Conclusions: (R-IPI) is the most common tool to predict outcome in DLBCL and our study showed that pretreatment NLR can be used as additional poor prognosis marker for patients with extranodal DLBCL of the head and neck. [Table: see text]
Impact of FDA approval of lenalidomide maintenance therapy in the first-line treatment of multiple myeloma after autologous stem cell transplant on total healthcare costs.
Authors: Xie Jipan , Parikh Kejal , Chen Christina , Yang Chelsey , Farrukh Adina , Cockrum Paul , Agarwal Amit Balkrishna , Abouzaid Safiya 
Published: September 2018

e19509 Background: Lenalidomide maintenance therapy after autologous stem cell transplant (ASCT) in the first-line treatment has been shown to improve progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM) patients (pts). This study assessed the impact of FDA approval of lenalidomide maintenance therapy on total healthcare costs of a US health plan. Methods: A model was developed to estimate the incremental (additional) total plan costs (in 2016 USD) for maintenance therapy in each year for the first 3 years after lenalidomide monotherapy (R) maintenance therapy approval. The number of post-ASCT adult MM pts eligible for initiating maintenance therapy was estimated from published epidemiological data and an analysis of Connect MM Registry data. Clinical endpoints for R-maintenance, including time on treatment, PFS and OS, were obtained from a meta-analysis of published clinical trials (CALGB, IFM, and GIMEMA). The use of common off-label maintenance therapies was considered. Types of costs included in the model were drug, drug administration, adverse events (AE), AE monitoring, one-time progression and terminal care costs. Results: In a hypothetical health plan with 1 million members, the number of adult MM pts eligible to initiate post-ASCT maintenance therapy was estimated to be 28. Among them, 14.8 pts initiated R-maintenance in Year 1, 15.2 in Year 2, and 15.3 in Year 3, representing an incremental increase of 2.9%, 4.2% and 4.4% after R-maintenance therapy approval, respectively. After considering additional costs of maintenance, as well as potential offsets resulting from delayed progression the incremental total healthcare costs by year are listed in the table. Conclusions: Approval of lenalidomide monotherapy for maintenance after ASCT in the first-line treatment of MM has minimal impact on total plan costs, primarily due to the small incident population and the already common use of lenalidomide in post-ASCT maintenance. [Table: see text]
Differential response to carfilzomib based on initial therapy with bortezomib in multiple myeloma.
Authors: Yellapragada Sarvari , Ifeorah Chizoba , Fletcher Luke , Rivero Gustavo , Yasin Zahida , Krieger Jordan , Mulchandani Alka , Catic Andre , Mims Martha P. 
Published: September 2018

e19515 Background: Proteasome inhibitors (PIs) are efficacious in multiple myeloma (MM). In randomized phase 3 studies Carfilzomib doubled the progression free survival (PFS) compared to Bortezomib from 9.4 mo to 18.7 mo (ENDEAVOR study) in relapsed and refractory MM. However concern for suboptimal Carfilzomib based therapy (CBT) response in patients (pt) progressing on Bortezomib based therapy (BBT) suggests “cross-resistance”. Methods: AfterIRB approval, all pt with symptomatic MM over the last 10 years at the Michael E. DeBakey VA Medical Center with initial BBT followed by salvage CBT at progression were included. The primary aim was to evaluate ORR (PR + VGPR+CR) and and PFS by the IMWG criteria, among relapsed/refractory pt treated with salvage CBT whether or not they had an initial BBT response (i.e., primary refractory+stable vs CR+PR+VGPR). Results: In this cohort, the median overall survival was 45 mo. Pt initially treated with BBT had an ORR of 17/19 (89.4%) and median PFS of 7.7 mo. For 12 pt attaining PR, PFS was 4.3 mo, whereas for those achieving CR/VGPR was 9.1 mo, p= 0.03. Two pt were primary refractory to BBT and also to CBT. For initially treated BBT responders the ORR with CBT was 68.4% (13/19), median PFS was 5.26 mo. 6/19 pt (32%) were CBT refractory. PFS during BBT for CBT responders versus CBT refractory patients was not statistically different. Among those who responded to both CBT and BBT there was no significant correlation between the PFS or depth of response (CR vs VGPR vs PR) with initial BBT and PFS with CBT. Conclusions: In our retrospective analysis, pt who exhibited primary resistance to initial BBT did not benefit from salvage therapy with CBT, raising the possibility that hard-wired PI-resistance mechanisms exist. Among BBT responders, CBT ORR was 68%. However the PFS with CBT was significantly shorter than the published literature of CBT in RRMM naïve to PI leading us to hypothesize that uncharacterized resistance mechanisms from “priming” bortezomib leads to inferior outcome with salvage CBT. We conclude that CBT can be attempted in those who respond to BBT independent of depth of response or PFS duration. However, alternative therapies should be considered in pt with primary refractoriness to BBT.
Blocking the formation of induced multiple myeloma stem-like cells through PI3K/AKT/mTOR pathway.
Authors: Liu Bingshan , Wang Danyang , Song Yongping 
Published: September 2018

e19518 Background: Multiple myeloma (MM) is still an incurable disease. There are many different treatment options and most patients in the early treatment will have a good effect, but some patients will relapse due to acquired drug resistance. The purpose of this study is to investigate the existence of MM stem cells and its relationship with drug resistence. Methods: A total of 53 patients were recruited who underwent MM between 2010 and 2012. We analysed the expression of stem cell markers (Nanog, Oct4 and Sox2) and their relationship with clinical characteristics and 3– year disease free survival (DFS) or overall survival (OS). Then we chose MM cell line RPMI 8226 for the study, explored the possible mechanism of chemotherapy tolerance. Results: We found that that expression levels of Nanog, Oct4 and Sox2 were 11.3% (6/53), 17.0% (9/53) and 20.8% (11/53), respectively. Only positive expression of Sox2 had relationship with ISS stage ( p= 0.049). Furthermore, positive expression of Sox2 ( p= 0.039) was significantly associated with poor DFS. And after induced treatments, RPMI 8226 cells changed, including cell morphology, cell cycle, apoptosis, stem cell markers and changes in signal transduction pathways. Inhibiting PI3K/AKT/mTOR pathway can improve sensitivity to chemotherapy and radiotherapy. Conclusions: These findings demonstated stem cells markers had significant meanings in MM patients’ prognosis. There may be stem-like cells in MM, which is insensitivity to radiotherapy or chemotherapy, and blocking PI3K/AKT/mTOR pathway can reverse it.