bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of the Adition of Metformin on the expressión of Multidrug-Resistance Genes (ABCB1, ABCG2) in Acute Lymphoblastic Leukemia: In Vitro and In Vivo Study
Authors: Ramos Peñafiel Christian Omar , Olarte Carrillo Irma , Cerón Maldonado Rafael , Santoyo Sánchez Adrián , Castellanos Sinco Humberto Baldemar , Montaño Figueroa Efreen , Queipo García Gloria , Martínez Tovar Adolfo 
Published: October 2019

Abstract
INTRODUCTION. The over expresión of the multidrug resistance genes (MDR) specifficaly ABCB1 and ABCG2 correlate with a poor prognosis in patients with ALL. Different drugs specially the chomotherapeutic agents are they substrates. This genes encode a family of different membrane transports that Works with energy specifically the ATP. Metformin is a biguanide whose mechanism of action is the activiation of AMPK and depletes the levels of ATP.
PRIMARY OBJECTIVE: Evaluate the efficacy of the use of Metformin on the levels of expression of the MDR genes (ABCB1 y ABCG2) by RQ-PCR in ALL cell lines and patients with ALL during a preinduction treatment with prednisone.
RESULTS.
In vitro study . The ALL cell lines RS4, ReH, MOLT4 and SUB15 were elavluated. After the addition of Metformin (10uM) the expression level of ABCB1, ABCG2 started to decrease after the 24hrs of culture (mean expression level of 0.3823 ABCB1 and 0.4265 of ABCB2) with a máximum effect at 48 hours (0.2415 ABCB1 and 0.3452 ABCB2) The difference of levels were statystically significant (p= 0.0045).
In vivo study . About 108 patients were evaluated, 44 (40.7%) in the arm of prednisone and 64 (59.3%) in the arm of prednisone plus metformin. Fort eh subanalysis of the MDR genes by RQ-PCR we select 25 patients (14 in the prednisone arm and 11 in the metformin arm). The mean levels of the genes was 0.1906 for the ABCB1 gene and 0.3371 of the ABDG2. At the moment of diagnosis about 32% were considerer with high level of expression (n=8), 28% (n=7) of low expression and 40% (n=10) do not express any of the both genes. After the treatment with Metformin 4 patients with high expression at diagnosis change the patter for low expression. Although there is no difference in means of the expression of genes in both arms (p = 0.391 , p = 0. 828) in the group of metformin the prognosis in the high expression group was better than in the prednisone arm (p=0.043). Fort he entire cohort the complete remission rate was higher in the Metformin cohort comparing with prednisone (86.4% versus 67.2%) and the refractoriness was higher in the group of prednisone (n=16, 25%) p=0.002. About the relapse, the addition of Metformin reduce the relapse rate ( 6 vs 21 patients, p = 0.027).
Conclusion. The addition of metformin in a controlled enviroment reduce the expression of the MDR genes, but in vivo the impact is primarily on the refractory leukemias and the relapse rate

Disclosures
No relevant conflicts of interest to declare.
Phloridzin Docosahexaenoate (PZ-DHA) : A Novel Naturally Derived Drug Active in T-Cell Acute Lymphoblastic Leukemia (T-ALL)
Authors: Arumuggam Niroshaathevi , Melong Nicole , Too Catherine K.L. , Berman Jason N. , Rupasinghe H.P. Vasantha 
Published: October 2019

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant disease that accounts for about 15% of pediatric and 25% of adult ALL. Although risk stratification has provided more tailored therapy and improved the overall survival of T-ALL patients, clinical challenges such as suboptimal drug responses, morbidity from drug toxicities, and drug resistance still exist. Plant polyphenols have therapeutic efficacy as pharmacological adjuvants to help overcome these challenges. They can be acylated with fatty acids to overcome issues concerning bioavailability, such as poor intestinal absorption and low metabolic stability. Phloridzin (PZ), a flavonoid found in apple peels, was acylated with an omega-3 fatty acid, docosahexaenoic acid (DHA), to generate a novel ester called phloridzin docosahexaenoate (PZ-DHA). The cytotoxic effect of PZ-DHA was studied in the human Jurkat T-ALL cell line. PZ-DHA significantly reduced the viability and cellular ATP levels of treated cells. PZ-DHA was found to selectively induce apoptosis in Jurkat cells, while sparing normal murine T-cells. Apoptosis was further confirmed by demonstrating the ability of PZ-DHA to induce morphological alterations, DNA fragmentation, caspase activation, and the release of intracellular lactate dehydrogenase. PZ-DHA also significantly inhibited cell division in Jurkat cells. Furthermore, interferon-α-induced phosphorylation of the transcription factor, STAT3, was downregulated following PZ-DHA treatment. The in vitro efficacy of PZ-DHA was recapitulated in vivo in an established zebrafish xenograft model, where the proliferation of transplanted Jurkat cells was inhibited when PZ-DHA was added to the embryo water. Overall, these findings provide evidence for PZ-DHA as a novel therapeutic agent with activity in T-ALL. Studies examining the effect of PZ-DHA on patient-derived ALL cells engrafted in zebrafish are currently underway.

Disclosures
No relevant conflicts of interest to declare.
HLA Class I-Specific Effects in AML with Mutated Nucleophosmin
Authors: Kuželová Kateřina , Röllig Christoph , Racil Zdenek , Stickel Juliane S. , Brodská Barbora , Schetelig Johannes , Thiede Christian , Ehninger Gerhard , Helbig Grzegorz , Kyrcz-Krzemien Slawomira , Mayer Jiri , Cetkovsky Petr 
Published: October 2019

Abstract
Background
We have recently identified a skewed distribution of class I human leukocyte antigens (HLA) among patients with AML and mutated nucleophosmin gene (NPMc+ AML). A lower frequency of several HLA allelic groups in the NPMc+ AML patient cohort was in good correlation with the results of theoretical predictions for high-affinity immunopeptides derived from NPM1, suggesting that an anti-NPM1 immune response could prevent leukemia development in patients with a suitable HLA class I type.
Aim
We here present more detailed analysis of HLA-specific features, in a much larger cohort (N = 357) of AML patients with NPM1 mutation (type A/D) from several centers in the Czech Republic, Germany and Poland.
Results
Most importantly, we confirmed the lower incidence of B´40 and C´07 allelic groups in NPMc+ AML compared to the normal values. The moderate decrease of A´02 allelic group frequency became statistically significant in this larger patient cohort (see Table). On the other hand, no difference in HLA class II frequencies was found compared to the normal distribution.
Furthemore, patients with B´07 allelic group had a significantly better prognosis, but only in the absence of Flt-3-ITD mutations (p = 0.049, see Figure). HLA typing was performed by molecular methods in a subgroup of patients (N = 73), allowing for discrimination between C´07 alleles. In this subgroup, C*07:01, but not C*07:02/04 expression was associated with better overall survival (p = 0.036), in agreement with theoretical predictions.
Conclusion
Our results support the hypothesis that anti-NPM1 immune response reduces AML development and contributes to a better outcome of NPMc+ AML patients with suitable HLA class I type (including at least A´02, B´07, B´40 and C*07:01). Furthermore, NPMc+ immunogenicity is caused rather by its aberrant localization than by the generation of a unique aminoacid sequence.
Figure Figure.

Disclosures
Schetelig: Sanofi: Honoraria. Thiede:AgenDix: Employment, Other: Ownership.
FLT3-ITD As a Prognostic Factor for Chinese Patients with Acute Myeloid Leukemia
Authors: Sun Jie , He Jingsong , Wei Guoqing , Zheng Weiyan , Shi Jimin , Luo Yi , Huang He 
Published: October 2019

Abstract
Internal tandem duplication of the FLT3 gene (FLT3-ITD) is one of most common genetic mutations found in patients with acute myeloid leukemia (AML). Although FLT3-ITD has been widely studied and used as an important prognostic indicator of AML in the western world, its association with disease features and prognosis in Chinese AML patients to date has rarely been investigated.In this study, 177 Chinese patients with AML were enrolled including a FLT3-ITD mutation positive group (n = 83) and a FLT3-ITD mutation negative group (n = 94).In FLT3-ITD-positive AML patients, the number of patients whose peripheral blood leucocyte count (≥ 100 × 109/L) before treatment was significantly higher than in FLT3-ITD negative patients (32.1% vs 7.6%), but comparing to FLT3-ITD mutation negative patients, 1 year and 2 year event free survival rates (EFSR) of FLT3-ITD-positive AML patients was lower ((37.0% vs 56.0%) and (14.8% vs 38.4%)), and also their 1 year and 2 year OS rates were significantly lower ( (50% vs 100%) and (18.0% vs 36.5%)). However, it was found that the rate of induced remissions in FLT3-ITD-positive AML patients was much lower than in negative patients (39.4% vs 56.0%). The median survival time of the FLT3-ITD+/NPM1- group (n = 39) was superior to the FLT3-ITD+/NPM1+ group (n = 27) (16.1 months vs 5.8 months). Lastly, after comparing chemotherapy regimes, we found that the allogeneic hematopoietic stem cell transplantation treatment method significantly improved the survival rate of FLT-ITD positive AML patients (not reached vs 14.5 months). Therefore, for FLT3-ITD-positive Chinese patients with AML, the relative rate of complication with leucocyte was increased; both the event free and overall survival rates were lower, these characteristics are the same as the FLT3-ITD-positive patients in western countries. The lower induced remission rate and shorter survival time suggested FLT3-ITD+/NPM1+ mutation is inferior to FLT3-ITD+/NPM1- mutation, which is not consistant with most reports. In addition, allogeneic hematopoietic stem cell transplantation was clearly an effective treatment for patients with FLT-ITD positive AML in China.

Disclosures
No relevant conflicts of interest to declare.
Exploratory Introduction of Cognitive Computing to Clinical Sequencing in Hematological Malignancies
Authors: Yokoyama Kazuaki , Yusa Nozomi , Itoh Mika , Suzuki Asako , Nakamura Sosuke , Ogawa Miho , Jimbo Koji , Kobayashi Masayuki , Kawamata Toyotaka , Konuma Takaaki , Kasajima Rika , Yui Hiroaki , Shimizu Eigo , Koyama Takahiko , Ohno Nobuhiro , Imai Yoichi , Takahashi Satoshi , Uchimaru Kaoru , Yamaguchi Rui , Imoto Seiya , Furukawa Yoichi , Miyano Satoru , Tojo Arinobu 
Published: October 2019

Abstract
Next-generation sequencing (NGS) is an attractive tool for prospective use in the field of clinical oncology. However, for this purpose, further innovations are necessary including medical informatics which links somatic mutations to clinical intervention. This process is currently labor-intensive, involving experienced curators who pick up the relevant evidence among a growing body of knowledge and translate it into medical practice. We organized a clinical sequencing team, called as IMSUT Tumor Board, and have been integrating clinical and genomic information in hematological malignancies with the aid of a cognitive computing (CC) system. Genomic DNA was prepared from malignant cell fractions and normal tissues in each patient, and subjected to comparative NGS, mainly targeted deep sequencing with ready-made panels and, on demand, whole exome sequencing. Sequence data was analyzed using a pipeline of in-house semi-automated medical informatics, namely YOKOMON-GO. CC was used to identify candidate driver mutations and pathways in each patient, from which pathogenic information as well as applicable drug information was deduced. A summary of NGS data was reported and discussed in IMSUT Tumor Board to deliberate upon potentially actionable findings. Up to date, we have performed NGS analysis on 90 patients with AML, MDS, MPN, et al., among which informative and actionable findings could be obtained in 50 and 18 patients, respectively. Six patients actually received treatments motivated in IMSUT Tumor Board. Our preliminary results indicate that CC can be well suited to clinical sequencing.

Disclosures
Koyama: IBM: Employment.
CD44 over Expression Caused Drug Resistance in Activated B Cell-like Diffuse Large B-Cell Lymphoma
Authors: Zhou Qinjun , Wei Yongqiang , Wei Xiaolei , Wei Qi , Feng Ru 
Published: October 2019

Abstract
CD44, a transmembrane glycocoptotein, involved in tumor cell survival, migration , invasion, metastasis and prognosis of many cancers. This study was performed to investigate the effects of CD44 over expression on the biological function and the chemotherapeutic sensitivity of ABC-DLBCL. The full length CD44 cDNA was cloned into pEASY-T vector and then transfected into activated B cell-like diffuse large B-cell lymphoma cell line OCI-ly3. QPCR and western blot confirmed that the CD44 expression was up-regulated in both mRNA and protein levels in CD44-transfected OCI-ly3 cells. The cell proliferation of OCI-ly3-CD44 cells was significantly faster than that in OCI-ly3-GFP cells and the OCI-ly3 cells (p<0.001). Annexin V-APC/PI staining results showed that the apoptosis ratio wasn't difference among three groups (p=0.676). OCI-ly3-CD44 cells showed significantly higher migration ratio than OCI-ly3-GFP cells and the OCI-ly3 cells(p=0.031). The IC50 of doxorubicin in OCI-ly3-CD44 cells (0.348±0.072uM) was higher than that in OCI-ly3-GFP (0.348±0.072uM ) and OCI-ly3cells(0.138±0.029uM ) ( P<0.001). After treatment with doxorubicin for 24h, the OCI-ly3-CD44 cells showed lower apoptotic ratio than OCI-ly3-GFP and OCI-ly3 cells ( (17.5±1.33)% VS. (41.7±9.91) %, (41.8±7.23)%), P<0.001). In conclusion, CD44 plays a key role in cell growth regulation and chemo-resistance and is a potential target to overcome drug resistance and improve prognosis in DLBCL.

Disclosures
No relevant conflicts of interest to declare.
Use of Ibrutinib Via Nasogastric (NG) Tube & Percutaneous Endoscopic Gastrostomy (PEG) Tube
Authors: Maddox Jamie M , Majid Mohammed 
Published: October 2019

Abstract
We describe the successful administration of ibrutinib via nasogastic (NG) tube & percutaneous endoscopic gastrostomy (PEG)tube. It was not previously known by the manufacturer if this route of administration was possible.
Our patient was a 71 year old man diagnosed with a leukaemic variant mantle cell lymphoma. He was commenced on R-CHOP (rituximab, cyclophospahmide, doxorubicin, vincristine, prednisolone) chemotherapy however after 3 cycles of chemotherapy there was no reduction in his lymphadenopathy or splenomegaly despite a reduction in the peripheral blood lymphocytosis.
During the R-CHOP chemotherapy, the patient suffered left-sided facial shingles causing Ramsay Hunt syndrome. He was left with a residual neurological swallowing deficit requiring nasogastric feeding. Due to the lack of response to R-CHOP chemotherapy, we felt that ibrutinib could be a useful second line treatment, however we were not sure if the capsule could be opened to allow administration via his nasogastric tube. We contacted the manufacturer who said that there was no data about this method of administration and therefore it was not recommended. Our own research identified one ongoing clinical trial comparing suspension and sprinkle formulations of ibrutinib to the capsule formulation (NCT02390609). This trial was unreported however we felt encouraged that this method of administration did seem feasible.
It was felt that ibrutinib represented the best chance of a useful disease response so full dose treatment was commenced via the nasogastric tube. This was later changed to a percutaneous endoscopic gastrostomy (PEG) tube. The patient opened the capsule and flushed the contents down the tube with water.
A follow up blood count 2 weeks later showed a marked lymphocytosis (baseline lymphocyte count 0.4 x109/L, risen to 40.8 x 109/L), as would be expected with ibrutinib therapy. This reduced to near normal values over the following 3 months, accompanied by an improvement in the haemoglobin and platelet counts. Imaging at 3 months confirmed compete resolution of all pre-existing lymphadenopathy and the previous 25.6 cm splenomegaly.
Our patients' dramatic response suggests that capsule formulation ibrutinib can be successfully administered by NG or PEG tubes.

Disclosures
Maddox: Janssen: Other: Funding to attend ASH 2016 (travel, accommodation, registration); Boehringer-Ingelheim: Other: Funding to attend ASH 2014 (travel, accommodation, registration).
Primary Testicular Lymphoma:a Single Center Experience and Literature Review
Authors: Li Ling , Zhang Fangwen , Young Ken H. , Duan Wenjing , Li Zhaoming , Yan Jiaqin , Fu Xiaorui , Zhang Lei , Li Xin , Sun Zhenchang , Zhang Xudong , Chang Yu , Nan Feifei , Zhang Mingzhi 
Published: October 2019

Abstract
Background: Primary testicular lymphoma (PTL), a rare and aggressive lymphoma mainly affecting the elderly, makes up 1-2% of Non-Hodgkin's lymphomas (NHL). Diffuse large B cell lymphoma (DLBCL) is the most common histological type of PTL. At present, comprehensive management is used for the treatment of PTL, such as operation, chemotherapy and radiotherapy. Although there are multiple treatment methods for PTL, its prognosis is very poor.
Materials and Methods: We retrospectively studied clinical data of 28 patients who were 10 to 82 years old and were diagnosed with PTL between March 2006 and November 2014.The clinical data included clinical characteristic, staging, treatment and outcomes. All of the patients received therapy [rituximab, CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), intrathecal prophylaxis, or irradiation for the contralateral testis] after orchiectomy. The therapeutic effects were evaluated as complete response (CR), partial response (PR), progressive disease (PD) and stable disease (SD). The prognostic evaluation was based on age, lactic dehydrogenase (LDH), Eastern Cooperative Oncology Group Performance Status (ECOG PS) and staging.
Results: The main clinical features of the 28 patients were shown in Table 1. All patients had testicular mass. Nine patients achieved complete response (CR), 8 patients had partial response (PR), and progressive disease (PD) occurred in 3 patients after 13, 12 and 20 months after treatment, respectively(Table 2). Eight patients died. The median overall survival (OS) was 19.6 months and the median progression-free survival (PFS) was 19.4months(Figure 1,2).
Conclusion: PTL is a highly aggressive disease. Although there are multiple treatment methods for PTL, it readily recurs and its prognosis is very poor. From this study, we can see that age, LDH, ECOG PS and staging are the main factors to affect PFS and OS of the patients with PTL(Table 3).

Disclosures
No relevant conflicts of interest to declare.
Prognostic Impact of p190 and p210 Co-Expression in Early Molecular Response in Chronic Myeloid Leukemia (CML) Patients Treated with Tyrosin Kinase Inibitors
Authors: Catania Gioacchino , Trincheri Nicol , Gottardi Enrico Marco , Limberti Giulia , Ladetto Marco , Monaco Federico , Pini Massimo , Giai Valentina 
Published: October 2019

Abstract
Background: Expression of p190 BCR-ABL mRNA is generally considered to be confined to patients with acute lymphoid or more rarely myeloid leukemias, whereas p210 BCR-ABL mRNA is the hallmark of CML. In reality it is not uncommon the presence of p190 m-RNA in p210 CML in chronic phase, due to alternative or missplicing. Its presence seems to have no impact on prognosis in the pre-TKI era, although it may be expression of genomic instability.
Aim: Primary object of this study was to investigate if the co-expression might influence the rate of early outcome surrogate endpoints such as such as optimal molecular response (EMR; BCR-ABL < 10% (IS) at 3 month and BCR-ABL < 1% or 6 month). in patients treated with TKI.
Methods: Were evaluated patients with CML in chronic phase treated with TKI at our institution. We excluded cases with less than one year of treatment or treated with conventional chemotherapy. The fusion transcripts BCR-ABL were evaluated at diagnosis in peripheral blood by NESTED-PCR and the molecular response were evaluated in peripheral blood with Real-Time PCR. The patients were divided into two groups, "double transcripts" (DT) and "single transcript" (ST).
Results: A total of 34 patients were analyzed. The median age was 61 years (range 22-80) and 26 (68%) were male. Ten patients (29%) were DT and twenty-fouru(71%) ST. The distribution according to Sokal score was: 2 (10%), 5 (50%) 3(30%) patients for low, intermediate and high risk in the DT, whereas 13 (54%), 10 (41%) 1 (5%) low, intermediate and high risk in ST, respectively. The optimal response at 3 month was achieved in 3 patients with DT and 20 patients with ST ( 10% vs 83), at 6-month optimal response was achieved in 3 patients with DT and 20 patients with ST (10% vs 83). No patients with BCR-ABL > 10 % at 3 months, achieved molecular response at 6 months.
Summary/Conclusion: In our study the co-expression of p190 and p210 BCR-ABL transcripts influences the early molecular response to TKI and suggesting the need for a larger validation study

Disclosures
No relevant conflicts of interest to declare.
Aberrant Let7a/HMGA2 Signaling Axis with Unique Clinical Phenotype in JAK2-Mutated Myeloproliferative Neoplasms
Authors: Hsu Chia-Chen , Chen Chih-Cheng , Gau Jyh-Pyng , Huang Cih-En , You Jie-Yu , Lung Jrhau , Chen YI-Yang , Ho Hsing-Ying , Li Chian-Pei , Lu Chang-Hsien , Lee Kuan-Der 
Published: October 2019

Abstract
High mobility group AT-hook 2 (HMGA2) is an architectural transcriptional factor that is negatively regulated by Let-7 microRNA. Dysregulated HMGA2 has been shown to exhibit a myeloproliferative phenotype in engineered mice. To decipher the Let-7-HMGA2 axis in myeloproliferative neoplasms (MPN), we studied a cohort of 151 MPN patients. Overexpressed HMGA2 was detected in about one-fifth of the cases, and it was more commonly seen in ET (26.9%, vs. 12.7% in PV, p=0.044). Compared to their counterparts, HMGA2-overexpressing patients had higher platelet counts, increased thromboembolic risk, and inferior thrombosis-free survival. Fluorescence in situ hybridizationanalysis showed that chromosomal translocation was not a major cause of HMGA2 overexpression in MPN patients, yet there was an inverse correlation between the expression levels of let-7a and HMGA2. Furthermore, up-regulation of HMGA2 was significantly associated with MPN patients carrying JAK2V617F mutation. In vitro studies showed that Ba/F3 cells carried JAK2V617F (Ba/F3-JAK2V617F) had decreased let-7a and up-regulated HMGA2. Silencing of HMGA2 in Ba/F3-JAK2V617F cells resulted in growth inhibition coupled with a significant increase in apoptosis. Our findings suggest that, in a subset of JAK2-mutated MPN patients, Let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.

Disclosures
Hsu: Ministry of Science and Technology (Taiwan): Research Funding; Chang-Gung Memorial Hospital: Employment, Research Funding. Chen:Ministry of Science and Technology (Taiwan): Research Funding; Chang Gung Memorial Hospital, Chiayi branch: Research Funding. Gau:Taipei Veterans General Hospital, Taipei, Taiwan: Employment. Huang:Chang-Gung Memorial Hospital: Employment, Research Funding. You:Lotung Poh-Ai Hospital, Yilan, Taiwan: Employment. Lung:Chang-Gung Memorial Hospital: Employment, Research Funding. Chen:Chang-Gung Memorial Hospital: Employment. Ho:Chang-Gung Memorial Hospital: Employment, Research Funding. Li:Chang-Gung Memorial Hospital: Employment, Research Funding. Lu:Chang Gung Memorial Hospital, Chiayi, Taiwan: Employment. Lee:Chang-Gung Memorial Hospital: Employment, Research Funding.