bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Impact of FLT3-ITD and DNMT3A R882 Double Mutations in Patients with Acute Myeloid Leukemia
Authors: Tang Shanhao , Tang Xiaowen , Shen Hongjie , Xue Shengli , Wang Tingjing , Lu Jing , Yin Jia , Wu Depei 
Published: October 2019

Abstract
Background: FLT3-ITD and DNMT3A R882 mutations are both independent factors for poor prognosis of acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been confirmed to improve the outcome of AML with either of gene mutations. However, the clinical characteristics of AML with both of FLT3-ITD and DNMT3A R882 mutations and their outcome post allo-HSCT had been rarely evaluated.
Objective: To investigate the clinical characteristics and transplantation outcomes of AML patients with the double mutations.
Methods: A total of 241 patients were included in this retrospective analysis. Molecular genetic mutation sets in bone marrow (including FLT3-ITD, DNMT3A, C-kit, CEBPA, FLT3-TKD, and NMP1) of 241 AML patients were detected at diagnosis using direct sequencing method. And the clinical data of these patients were analyzed retrospectively.
Results: (1)According to the genetic mutation types, the 241 AML patients were divided into four groups: FLT3-ITD+DNMT3A R882+, FLT3-ITD+DNMT3A R882-, FLT3-ITD-DNMT3A R882+ and FLT3-ITD-DNMT3A R882- groups, which consisted of 19, 38, 21 and 163 patients, respectively. (2) Patients with FLT3-ITD+DNMT3A R882+ have high white blood cell count and a low complete remission rate after first induction chemotherapy (52.6%), which are common in M5、M2、M4 with normal chromosome karyotype, higher early cumulative incidence of relapse(6m-CIR 36.8±1.3%、12m-CIR 49.7±1.6%) and cumulative mortality rate (6m-CMR 26.3±10.1%、12m-CMR 48.5±11.8%) . (3) 2-year CIR of the FLT3-ITD+DNMT3A R882+ was (72.2±2.7%), which was significantly higher than that of the FLT3-ITD+DNMT3A R882- group (38.6±0.7%) and FLT3-ITD-DNMT3A R882+ group (36.8±1.6%). While the 2-year overall survival (OS) rate and 2-year leukemia-free survival (LFS) rate of double mutation group were (30.9±13.3% ) and (11.3±10.2%), respectively, which were considerably lower than those of the FLT3-ITD+DNMT3A R882- and FLT3-ITD-DNMT3A R882+ groups (2y-OS: 67.5±7.8%, 61.4±12.4%: 2y-LFS: 47.9±8.4%, 56.8±12.5%). Meanwhile, the 2-year CIR rates of the FLT3-ITD+DNMT3A R882- and FLT3-ITD-DNMT3A R882+ groups were significantly higher than that of the FLT3-ITD-DNMT3A R882- group (16.3±0.1%), while their 2-year OS rate and 2-year LFS rate were significantly lower than those of the FLT3-ITD-DNMT3A R882- group (2y-OS: 82.5±3.1%、2y-LFS: 80.9±3.2%). (3) Univariate and multivariate analyses revealed that disease status prior to transplantation, grade III-IV aGVHD, FLT3-ITD, DNMT3A R882 and FLT3-ITD+DNMT3A R882+ were independent factors for poor prognosis post transplantation.
Conclusion: AML patients with FLT3-ITD and DNMT3A R882 double mutations still present a very poor prognosis after transplantation with low OS and LFSas well as a high CIR rate. Therefore, it is necessary to explore prevention strategy for relapse post transplantation.

Disclosures
No relevant conflicts of interest to declare.
CD30 Expression and Its Correlation with Clinicopathologic Features in De Novo Diffuse Large B-Cell Lymphoma
Authors: Qian Shenxian , Zhao YiFei 
Published: October 2019

Abstract
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease disease with 40% of patients presenting as refractory/relapsing disease following R-CHOP treatment. Recently, CD30 was reported as a useful predictor with favorable clinical outcome. However, CD30 expression patterns and the clinicopathologic features of CD30 positive DLBCL are not well described thus far, Here, we studied149 patients with de novo DLBCL to investigate clinicopathologic features of CD30-positive DLBCL by immunohistochemistry. useing a >0% cut-off,CD30 was expressed in approximately 13% (19)patients with DLBCL, showing a lower frequency of MYC/BCL2 co-expression. The clinic features were very similar between the CD30+ and CD30- groups,such as age, sex, B symptoms, staging, ECOG PS, LDH level, extranodal site involvement, IPI, GCB or non GCB type, bone marrow involvement. By univariate analysis Patients with CD30-positive DLBCLs showed better progression-free survival and overall survival compared with patients with CD30-negative DLBCLs, although the superior outcome of CD30 positivity had minimal effects on DLBCL with MYC/BCL2 co-expression. Epstein-Barr virus (EBV) was identified in 8(5.3%) cases, all of which were almost exclusively positive for CD30 expression (8/8) (P < 0·001). We conclude CD30 is expressed in a substantial proportion of DLBCL and CD30 immunohistochemistry may be a useful prognostic marker in R-CHOP treated GCB-DLBCL. The significant association of CD30 with EBV-positive DLBCL suggests a distinct pathobiology for these cases. We concluded that CD30 may be useful as a prognostic marker in rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treated DLBCLs, indicating favorable outcomes

Disclosures
No relevant conflicts of interest to declare.
Co-Expression of MYC, BCL2 and PD-L1 in Primary Central Nervous System Diffuse Large B Cell Lymphomas ( PCNSL)
Authors: Saad Nibal , Anand Ankit , Naous Rana , Neerja Vajpayee , Zhang Shengle , Gentile Teresa 
Published: October 2019

Abstract
Background
Increased protein expression and gene translocations of MYC and BCL2/BCL6promote increased cell growth and inhibit apoptosis. They are associated with inferior prognosis in systemic diffuse large B cell lymphomas (DLBCLs). Their role in primary PCNSLs however is less clear. The immune checkpoint molecules, programmed death 1 (PD1) and its ligand PD-L1 are involved in inhibitory pathways to maintain immune tolerance and it is now clear that tumor cells interfere with these pathways to promote escape from immune surveillance. Antibody blockade of these immune checkpoints has been shown to enhance antitumor immunity and is emerging as an important target for cancer immunotherapy. We examined the co expression of these proteins on tumor samples from patients with PCNSL .
Methods
Immunohistochemistry (IHC) for MYC, BCL2 and PDL-1 and florescence in situ hybridization ( FISH) for MYC (8q24), BCL2 ( 18q21) and BCL6 (3q27) were performed on tumor samples from 14 patients with PCNSL.
Results
Eleven patients were positive for PDL-1 (79%) by IHC. Of these eleven patients, six (55%) were also positive for both MYC and BCL2 by IHC and negative by FISH. Eight patients (57%) were positive for MYC and BCL2 by IHC but negative for PD-L1. One patient was positive by FISH for MYC, BCL2, and BCL6 but negative for PDL-1.
Conclusions
Our results, although in a small number of patients, demonstrate that a large percentage of patients with PCNSL who express MYC and BCL2 also express PD-L1.It has been suggested that the frequent over expression of MYC, BCL2, and BCL6 noted in PCNSL may underlie the inferior prognosis as compared to systemic DLBCL. We suggest that the co-expression of MYC/ BCL2 with PD-L1 may contribute to this poor prognosis by engaging the complimentary mechanisms of increasing cell growth, inhibiting apoptosis and evading immune surveillance. The use of PD-L1 inhibitors in hematologic malignancies is limited but has demonstrated clinical responses in relapsed/refractory disease following multiple lines of therapy and warrants further investigation in PCNSLs.
Table Table.

Disclosures
No relevant conflicts of interest to declare.
Molecular Predictors of Treatment Failure in ALK-Negative Anaplastic Large T-Cell Lymphoma
Authors: Gorenkova Liliya , Kravchenko Sergey Kirillovich , Mkrtchyan Asmik , Musyirin Vsevolod , Misyurina Anna Evgenevna , Savchenko Valeriy G. 
Published: October 2019

Abstract
ALK-negative anaplastic large T-cell lymphoma (ALK-negative ALTCL) is a rare aggressive disease, constituting 12% of all T-cell lymphomas of adults. When using CHOP/CHOEP chemotherapy overall and event-free survival is less than 50%. Factors of poor prognosis include IPI (3-5), CNS and skin involvement as well as molecular predictors.
The aim of current study was to detect rearrangements (R) of DUSP22 gene, t(6;7)(p25.3;q32.3), inv(3)(q26q28), involving TP63 gene using fluorescence in situ hybridization and ТР63 mutation by Sanger sequencing.
23 patients with ALK-negative ALTCL were involved in current study: 14 males, 9 females. Advanced stage of disease was diagnosed in 70 % of patients. All patients were treated with high-dose chemotherapy.
In 20% of patients were revealed DUSP22-R, 13% - TP63 abnormalities, 67% of patients were triple-negative (without ALK-R, DUSP22-R, TP63-R).
There weren't detected any mutations in DNA-binding domain of TP63 gene.
Comparing data of molecular studies and clinical data it was revealed that presence or absence of above-mentioned gene rearrangements did not affect disease stage: III stage was diagnosed in 30% of cases with DUSP22-R and in 33% of triple-negative cases, IV stage in 100% cases with TP63-R, in 67% with DUSP22-R, in 40% with triple-negative variant. Majority of patients had IPI (3-5) in all three cytogenetic groups. In 100% of cases with DUSP22-Rwere revealed more than 2 extranodal site of involvement.
Overall (OS) and progression-free survival (PFS) depending on molecular profile were 100% and 100%, respectively, in case with DUSP22-R. In case of TP63-R OS and PFS were 8% and 10%, respectively, in triple-negative cases - 60% and 39%, respectively.
Thus, detection of DUSP22, TP63 gene rearrangements has great practical value in ALK-negative ALTCL. Statistical significance should be confirmed by further study.

Disclosures
No relevant conflicts of interest to declare.
Nivolumab Induces Impressive Complete Responses in Heavily Pretreated Classical Hodgkin Lymphoma (cHL): Immune System Reloaded in Case Series
Authors: Dada Reyad , Malas Al-Beirouti Bassim T. 
Published: October 2019

Abstract
Background: cHL is a histopathologically distinguish cancer type with an interesting microenvironment. The number of malignant cells is small in relation to the dominant T lymphocytes that have lost their antitumor activity through different mechanisms. Therefore, reactivation of host antitumoral immune response is promising approach to convert cHL in amenable disease for the immune system. Nivolumab is a novel antibody that binds to program death receptor-1 (PD-1) and prevents immune tolerance. Recently, several published clinical trials confirmed the clinical efficacy of single agent nivolumab in patients with few cancer types. Publications on nivolumab in cHL are very scarce. The available literature is limited to only one phase 1 (Ansell et al., N Engl J Med 2015;372:311-9) and another non-randomized phase 2 (Younes et al., Clin Oncol 34, 2016 (suppl; abstr 7535) clinical study that included 23 and 80 patients with relapsed/refractory cHL respectively.
Case series: We report on three patients with heavily pretreatedcHL who failed several lines (mean 6.3, range: 3-9) of chemotherapy. Table 1 illustrates the patients' characteristics. All patients had stage IV disease at initiation of nivolumab. Two patients had very poor performance status (ECOG 3 and 4) attributed to progressivecHL and were oxygen dependent. One patient was wheelchair bound and the other was bedridden.
The patients were started on single agent nivolumab 3 mg/kg every two weeks. Impressive clinical responses were observed in all patients after just one dose of nivolumab. In particular, significant rapid clinical improvement was obtained in both patients with the worst performance status. Both patients became mobile and self-dependent within 2-4 days after the first dose. This pattern of clinical response resembles that seen on the 1stday of immune response mediated recovery from viral respiratory infection.
All patients reached complete metabolic response after 4 doses with continuous improvement of clinical condition. Both oxygen dependent patients became oxygen independent. No treatment related significant side effects were observed.
Conclusion: Pre-treatedcHL is amenable to novel immunotherapy. Nivolumab induces impressive clinical and radiological responses with excellent tolerance. The drug enriches our treatments options by reloading the immune system response against cancer. Further clinical studies are needed to determine the effectiveness on large patients' cohort.

Disclosures
No relevant conflicts of interest to declare.
Synergistic Lethality with Gemcitabine and Arsenic Trioxide Against Human T Cell Lymphoma Jurkat Cells
Authors: Zhang Mingwan , Xu Xiaojun , Ye Yongbin , Liu Qifa 
Published: October 2019

Abstract
Abstract There is still lack suitable agent that significantly changes the poor prognoses of T-cell non-Hodgkin's lymphoma (NHL), so that part of the patients who are far beyond the standard of first-line could not received effective treatment, therefore, it is urgent that seeking for a salvage treatment for patients with refractory malignant lymphoma, our destination is combination strategy aimed to higher anti-tumor activity with lower toxicity.
GEM is a deoxycytidine analog with anti-metabolite activity in tumors through destroying the replication of cells and inhibiting ribonucleotide reductase as a prodrug. Recently, many clinical trials show that gemcitabine alone or in combination with other chemotherapy drugs can improve overall response rate and survival outcomes in malignant lymphoma patients compared with other chemotherapy regimens, such as vinorelbine and liposomal doxorubicin, busulfan and melphalan, which are active agents in all types of malignant lymphoma.
ATO as a traditional medicine has been evaluated its good efficacy in a variety of hematologic malignancies, including myeloproliferative diseases, multiple myeloma, lymphoma. Currently, many clinical trials represented that the addition of ATO to standard treatment regimens can improve survival outcomes and may allow a reduction in cytotoxic chemotherapy exposure in other malignancies. The basis of related research found that ATO play killing effect on the cancer cells through multiple apoptotic pathways and many mechanisms. ATO was shown to bear relevant cytotoxic activity on lymphoma cell lines. The safety profile of ATO for the effective treatment and its toxicity is easily under control, which make it a preferred solution for combined chemotherapy scheme.
Thus, in this study we found that the combination of ATO and GEM can lead to synergistic the cytotoxic effect, exert an enhanced effect on inhibiting Akt signaling and Bcl-2, up-regulating cleaved caspase-3, and inhibit the cell proliferation and self-renewal ability, and induce G0/G1 cell cycle arrest and apotosis in Jurkat cells, which provide preclinical evidence and a theoretical basis for combination therapy with ATO and GEM as a salvage therapy in treating relapsed or refractory aggressive non-Hodgkin's lymphoma.

Disclosures
No relevant conflicts of interest to declare.
Prx II(Peroxiredoxin II) Activity Has Important Roles As a New Mechanism to Control ABL Tyrosine Kinase Activity in STIs(Signal Transduction Inhibitor) Treated CML Patients
Authors: Yoo Eun-Sun , Mun Yeung-Chul , Ahn Jee-Young , Huh Jung-Won , Seong Chu-Myong 
Published: October 2019

Abstract
Purpose: In this study, we investigated the roles of PRX II, one of 3 critical peroxidases besides catalase and GPXs, in CML primary cells at diagnosis and remission while patients were treated with STI(Signal Transduction Inhibitor) and tested the same roles in Imatinib(IM) sensitive Ph+ cell lines and resistant cell lines as well.
Methods: Newly diagnosed CML cells, IM resistant K562 cells and parental K562 cells were treated STIs and analyzed western blot assay to detect BCR-ABL, phosphorylated BCR-ABL and PRX2 protein expression level. We added N-Acetylcysteine (0-5mM, 6hr) to K562 cells to show antioxidant effect of imatinib and analyzed DCF-DA detection for intracellular ROS level and western blot for PRX2 protein level. MTT assay was performed to detect cell death by NAC time-dependent treatment of 5mM NAC(0, 24, 40, 48hr). Imatinib resistant K562 cells were established by treatment of gradual increment of imatinib. We also repeatedly investigated the effects of IM therapy using PRXII overexpressed K562 cells by transfection.
Results: At diagnosis of CML, ROS level was elevated and PRX II was either absent or significantly suppressed. As Ph chromosomes were decreased with STIs, suppressed or absent PRXs levels were restored to the level of normal individuals. These findings were also inversely correlated with the level of Ph chromosomes in the cases of disease progression and re-remission with further treatment. When STI were treated in Ph positive cell line, we found deceased cell survival and ROS level by MTT assay and DCF-DA methods respectively, but elevated PRX II by western blot. By the treatment of NAC into Ph+ cell lines, the level of DCF-DA was decreased and MTT level was down, but PRX II level was elevated. Interestingly, the level of BCR-ABL oncogene were decreased in PRX II tranfected cells. Meanwhile, we observed that PRX II restoration was mild or weak in Imatinib resistant K-562, which we established in our lab.
Conclusions: The importance of the roles of ROS and its PRX II, antioxydant enzymes in CML is further extablished by our work. Our finding may contribute to find a new pathway on which TKIs are working besides the mechanisms of ATP binding competitively, blocking the binding of ABL-BCR kinase and substract resulting apoptosis of Ph+ cells. Furthermore, our finding may be useful to overcome the STIs resistant CML in the clinics.

Disclosures
No relevant conflicts of interest to declare.
Factors Related to the Development of Acquired Von Willebrand Syndrome in Patients with Essential Thrombocythemia and Polycythemia Vera
Authors: Rottenstreich Amihai , Kleinstern Geffen , Krichevsky Svetlana , Varon David , Lavie David , Kalish Yosef 
Published: October 2019

Abstract

Objective: We characterized acquired von Willebrand syndrome (AVWS) among essential thrombocythemia (ET) and polycythemia vera (PV) patients.
Methods: A review of patients with ET or PV evaluated for AVWS.
Results: Of 116 patients with ET, 64 (55%) developed AVWS; of 57 with PV, 28 (49%) developed AVWS. Median platelet counts of ET and PV patients who developed AVWS were 920 X 109/L and 679 X 109/L, respectively (P=0.01). Of patients who developed AVWS, 69.5% had platelet counts below 1000 X 109/L. Bleeding was more common in patients with AVWS, among both ET and PV patients (P<0.001). VWF:RCo levels and VWF:RCo/VWF:Ag ratio were lower among JAK2 V617F positive- vs. JAK2 V617F negative- ET patients (P=0.02 and P=0.002, respectively); whereas VWF:Ag levels were comparable (P=0.96). ET patients harboring the JAK2 V617F mutation were more likely to develop AVWS than were calreticulin-positive patients (70.3% vs. 45.7%, P=0.02), despite lower platelet counts (median 773 vs. 920 X 109/l, P=0.05). In multivariable analysis, age (β=0.26, P=0.002), platelet count (β=-0.38, P<0.001), hemoglobin level (β=-0.22, P=0.01) and JAK2 V617F mutation (β=-0.23, P=0.01) independently predicted VWF:RCo, among ET patients; whereas only platelet count predicted VWF:RCo among PV patients (β=-0.49, P<0.001).
Conclusion: Among ET and PV patients, AVWS was common and associated with higher bleeding rates and higher platelet count; nonetheless, most AVWS patients had platelet counts under 1000 X 109/L. Thus, AVWS screening should be included in routine assessment of ET and PV patients. Among ET patients, JAK2 V617F was a main driver for the development of AVWS.

Disclosures
No relevant conflicts of interest to declare.
Influence of JAK2V617F Allele Burden on Hematological Response in the Treatment of Polycythemia Vera
Authors: Shikhbabaeva Dzhariyat , Shuvaev Vasily , Golovchenko Regina , Udaleva Vera , Fominykh Mikhail , Zotova Irina I , Polushkina Lyubov , Martynkevich Irina , Abdulkadyrov Kudrat 
Published: October 2019

Abstract
Background. The presence of the JAK2V617F mutation is a major criterion in diagnostic of Polycythemia Vera (PV). The role of JAK2V617F allele burden in the progression of PV is not completely understood. The significance of this variable for the progression of the disease, complications development and response to therapy are still a big question mark.
Aim. To estimate the significance of the level of JAK2V617F allele burden in the treatment of PV.
Methods. Seventy-nine patients (pts), 48 females and 31 males, were included in the study. PV was diagnosed from 1980 to 2016. Median age was 61 years (range, 28 - 85), median of the observation period was 4.9 year (0,2 - 35 years). JAK2V617F allele burden was studied in all pts. Patients received therapy with phlebotomy (erythrocytapheresis), hydroxyurea, interferon-alpha or combined therapy. Hematological response to the therapy was evaluated according to ELN criteria[1]. Differences between the groups were assessed with the Mann-Whitney U test.
Results. Out of the 79 patients, complete hematological response (CHR) was achieved in 8 (10%) pts, partial response (PHR) in 48 (60.8%) pts, and no response was achieved (no response - NR) in 23 (29,2%) pts. The mean level of allele burden in the group of patients with PHR was 68%(CI 57%-79%), in that without response - 65%(CI 43%-86%), and in the group with CHR was 35% (CI 19%-50%). The JAK2V617F allele burden was significantly different between the groups with CHR and PHR (p<0,03). We also observed statistical trends (p<0,09) regarding differences between the groups with CHR and NR. The JAK2V617F allele burden by groups is shown in Figure 1. Consequently, patients who achieved CHR on treatment, had lower JAK2V617F allele burden compared to patients with PHR or NR to the therapy.
Conclusion. The level of JAK2V617F allele burden can be a predictive marker of a response to treatment of PV. An individual approach to each patient, including a detailed study of molecular factors, is the key to successful prevention of complications and ensuring positive outcomes.
[1] Barosi G, Birgegard G, Finazzi G, et al. Response Criteria for Essential
Thrombocythemia and Polycythemia Vera: Result of a European LeukemiaNet
(ELN) Consensus Conference. Blood. 2009 Mar 10
Figure The JAK2V617F allele burden levels in patients groups by treatment response. Figure. The JAK2V617F allele burden levels in patients groups by treatment response.

Disclosures
Shuvaev: Novartis pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Fominykh:Novartis Pharma: Honoraria; BMS: Honoraria.