bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ten Years of Treating Chronic Myeloid Leukemia in Rural Rwanda: Feasible Approaches for Low-Resource Settings
Authors: Morgan Jennifer , Bigirimana Jean Bosco , Nguyen Cam , Deboer Rebecca , Shyirambere Cyprien , Paciorek Alan , Lehmann Leslie E. , Shulman Lawrence N. 
Published: November 2019

Objective: To describe the characteristics and outcomes of chronic myeloid leukemia (CML) patients treated through the Glivec Patient Assistance Program (GIPAP) in Rwanda.
Methods: We retrospectively reviewed all BCR-ABL positive CML patients treated with imatinib at two rural hospitals between 2009 and 2018. Clinical data were analyzed using descriptive statistics, Kaplan-Meier method, and proportional hazards regression.
Results: One hundred twenty-four patients were included; median age 35 (range: 9-81), 60% male, 88% without comorbidities. All patients presented with symptomatic disease, median duration 11 months (IQR: 4-24) and median WBC count 225.5 x 109/L (IQR: 117.7-308.5). At diagnosis, 71% were in chronic phase. On imatinib, 91% achieved complete hematologic remission (CHR); 67% within 90 days. Of those who achieved CHR, 51 (45%) lost it at some point and, of which, 36 (71%) regained CHR. At four years, overall survival was 79% (95% CI:69%-86%) for the entire cohort; 93% (95% CI: 79%-98%) for 53 patients who remained in CHR, 89% (95% CI: 69%-96%) for 34 patients who lost but regained CHR, 19% (95% CI: 1%-54%) for 12 patients who lost and never regained CHR. Never achieving CHR was associated with increased mortality (HR: 40.89; 95% CI: 9.88-169.32; p<0.001) as was losing CHR without regaining it (HR 15.73; 95% CI: 4.14-59.81; p<0.001) compared to never losing CHR.
Conclusions: Here we demonstrate the feasibility of coupling molecular diagnostics with chronic targeted therapy in a rural low-resource setting through health systems strengthening and international collaboration. Our CML patients are younger, slower to achieve CHR with imatinib, and have higher rates of primary and early hematologic resistance than historical cohorts, suggesting biological differences that warrant further investigation. It is uncertain what role non-adherence to medication influences these data. Without molecular response assessment, hematologic response is an accurate marker of disease control and survival. Our imatinib failure rates highlight the need for access to resistance testing and second generation tyrosine kinase inhibitors, as well as adherence rates.

Disclosures
No relevant conflicts of interest to declare.
Metabolomic Profile in Patients with Paroxysmal Nocturnal Hemoglobinuria
Authors: Yamakawa Patricia Eiko , Da Fonseca Ana Rita , Vescovi Matheus , Gomes Iara Baldim Rabelo , Guerreiro da Silva Ismael Dale Cotrim , Arrais-Rodrigues Celso 
Published: November 2019

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant clonal disease of hematopoietic cells with a complex pathophysiology and variable clinical spectrum, characterized by signs and symptoms related to intravascular hemolysis, hypercoagulability, and cytopenias. Metaboloma is the end product of an organism's genetic configuration plus the influence of all factors to which it is exposed. Metabolomic profile is able to provide a more accurate functional measure of a phenotype formed by the result of genomic, transcriptomic and proteomic changes.
Aims: To compare a metabolomic profile in the PNH hemolytic group with healthy controls, and to compare a metabolomic profile before and after the administration of eculizumab in PNH patients.
Methods: To perform metabolomic profile, we used mass spectrometry in 23 patients with hemolytic PNH and in 166 healthy adults, as control group. Twelve PNH patients samples were also collected before and 24 hours after receiving eculizumab. Liquid chromatography with mass spectrometry was performed using the AbsoluteIDQ P180 Biocrates kit (Biocrates, Life Science AG, Innsbruck, Austria): 186 metabolites from 7 different classes were identified and quantified. The data were imported to the analytical site MetaboAnalyst 4.0 and ROCCET: ROC Curve Explorer & Tester for the generation of Univariate and Multivariate Operational Characteristic curves of the Receiver (ROC).
Results: In the patients with hemolytic PNH, of the 186 metabolites analyzed, 92 of them showed significant differences between patients and controls, with positive or negative correlation. The major metabolites increased in the PNH group were long-chain acylcarnitines, while the major metabolites reduced in the PNH group were histidine, taurine, glutamate, glutamine, aspartate and phosphatidylcholines. The C14:1/C16:1 ratio lower than 1.4 was shown to be a reliable marker in patients with PNH, suggesting a disorder in lipid elongation. Besides, PNH patients had a significant increase in C6:1 levels and C14:1/C6 and C4/C6 ratios. After receiving eculizumab, patients reached levels comparable to those of normal subject.
Conclusion: We observed differences in the metabolome of PNH patients as compared to healthy controls, suggesting a unique metabolomic profile of these patients, characterized by an altered acylcarnitine balance, reduction in aminoacids participating in the glycogenesis pathway and an impaired glutaminolysis. Acylcarnitines levels seem to significantly reduce with the use of eculizumab, demonstrating that the use of the antibody has action in reducing hemolysis and possibly in mitochondrial function of these patients.

Disclosures
No relevant conflicts of interest to declare.
Diagnosing Mds; Do We Really Need to FISH?
Authors: Jamshed Saad , Fricke William , Ogunsesan Yetunde 
Published: November 2019

Objectives
Making a definitive diagnosis of myelodysplastic syndrome (MDS) currently entails review of morphology on peripheral blood and bone marrow as well as cytogenetics by standard karyotyping. Fluorescence in situ hybridization (FISH) panel is performed to identify specific abnormalities in addition to karyotyping.
Methods
We reviewed 186 patients who had undergone bone marrow biopsy for suspected MDS from 2016 to 2018 across our health system and subsequently had karyotyping and FISH testing performed.
Results
We identified 186 patients in our study cohort, 164 of these patients had karyotype and FISH testing available. There was excellent concordance rate of 93% (152 of 164) between karyotype and FISH.
Among the 164 bone marrow biopsy samples reviewed, 40(24.4%) eventually had a confirmed diagnosis of MDS. Concordance rate of karyotyping and FISH results in the confirmed cases of MDS was 75% (30 of 40). Overall, 9 of the 40 cases (22.5%) had discordant findings, of these 20% (8 of 40) demonstrated abnormal karyotype analysis with normal FISH while only 1 of 40 (2.5%) had normal karyotype with abnormal FISH diagnostic of MDS. The abnormal FISH finding was a cryptic RUN X1 deletion.
Conclusion
Our study indicated excellent concordance between karyotype and MDS-FISH. FISH rarely added additional value to karyotype.

Disclosures
Jamshed: Takeda Pharmaceutical: Honoraria.
Alterations of Bone Marrow Microenvironment in Acute Graft-Versus-Host Disease
Authors: Lin Yan , Gu Quan , Cheng Hui , Zheng Zhaofeng , Guohuan Sun , Xie Xiaobao , Cheng Tao , Gu Weiying 
Published: November 2019

Severe acute graft-versus-host disease (aGVHD) indicates a poor prognosis after allogeneic hematopoietic stem cell transplantation. In our previous study, we found that hematopoiesis was progressively suppressed during aGVHD, while the hematopoietic regenerative potential of donor-derived hematopoietic stem cells remains intact. It prompts us to investigate whether bone marrow niche is a major target of GVHD. We addressed this issue by studying the critical components in bone marrow microenvironment, including mesenchymal stem cell (MSC), osteoblasts and adipocytes in haplo-MHC-matched murine bone marrow transplantation model. By comparing confocal images of femurs from control and aGVHD SCF-GFP mice or Col2.3-GFP mice, we found that both MSCs and osteoblasts were significantly reduced during aGVHD development. In addition, anti-perilipin staining showed that adipocytes were also decreased in aGVHD mice. We found a defect in the differentiation potential of MSCs from aGVHD niche by in vitro culture of both murine and human bone marrow niche cells. qRT-PCR showed decreased gene expressions of PPAR-gamma, Adipoq, Runx1 and Col2a1, suggesting the potential of MSCs differentiation into adipocytes and osteoblasts was blocked. These data provide new insights into the pathogenesis of aGVHD and may improve the clinical management of aGVHD.

Disclosures
No relevant conflicts of interest to declare.
Addiction of B Cell Lymphomas to microRNA-17-92 Is Mediated By a Single Target Gene
Authors: Schoeler Katia , Mittermeier Teresa , Villunger Andreas , Rajewsky Klaus , Labi Verena 
Published: November 2019

Mature microRNAs (miRNA) are short non-coding RNAs that regulate gene expression by binding to messenger RNAs (mRNA) in a sequence-specific manner, causing translational repression and/or mRNA decay. The mammalian genome harbors thousands of miRNA genes, many of which are organized into transcriptionally co-regulated clusters such as miR-17-92.
Knockout of the miR-17-92 cluster gene in mice blocked B lymphopoiesis, and ectopic miR-17-92 expression sufficed to initiate B cell lymphomas and autoimmunity. In humans, the miR-17-92 gene is commonly amplified or overexpressed via MYC-driven transcription in diffuse large B cell and Burkitt's lymphomas.
A computationally predicted shared target of the miR-17-92 miRNAs is the pro-apoptotic BCL-2 family protein BIM, central to life-death decisions in mammalian cells. To clarify the contribution of miR-17-92:Bim interactions to the miR-17-92 knockout and overexpression phenotypes, we engineered a unique in vivo system of conditional mutagenesis of the nine Bim 3'UTR miR-17-92 binding sites. Instead of causing the predicted B cell developmental block, interruption of miR-17-92:Bim interactions produced a selective inability of B cells to resist cellular stress; and prevented lymphocyte hyperplasia caused by Bim haploinsufficiency.
Surprisingly, partial genetic disruption of miR-17-92:Bim interactions was sufficient to fully prevent B cell lymphoma formation in two out of three mice using two independent pre-clinical MYC-driven cancer models. This protective effect could be attributed to an increased activity of the mitochondrial apoptosis pathway in pre-malignant B cells, as apoptosis was abolished by concomitant overexpression of an anti-apoptotic BCL-2 protein. MYC-driven B lymphoma cells are addicted to miR-17-92 function. Our data build on these results and strongly suggest that miR-17-92:Bim interactions are vital in this context as acute ablation of miR-17-92:Bim interactions effectively promoted lymphoma cell apoptosis, both in vitro and in vivo.
In conclusion, among hundreds of putative miR-17-92 target mRNAs a single direct binding partner is vital for lymphoma development and maintenance, a discovery whose therapeutic exploitation is of major relevance.

Disclosures
No relevant conflicts of interest to declare.
Dual Targeting of ALDH1 and ALDH3: A Promising Therapeutic Approach in Acute Myeloid Leukemia
Authors: Perez-Alea Mileidys , Colle Julien , Yazir Muhube , Baier Céline , Labiad Yasmine , Arnoux Isabelle , Venton Geoffroy , Guillaume Guillaume , Ceylan Ismail , Costello Regis T. 
Published: November 2019

Background. The aldehyde dehydrogenasesfamily(ALDHs) play a major cytoprotective role in cells via detoxification of a wide range of aldehydes. Their functional activity also extends to modulation of cell proliferation, differentiation and survival of cancer cells. Nevertheless, the identity of the specific isoforms contributing to this in acute myeloid leukemia (AML), the underlying mechanisms and the therapeutic value of ALDH inhibitors remain elusive.
Methods. We conducted a meta-analysis to investigate the impact of ALDHs on clinicopathological parameters and survival in AML patients. The expression of ALDHs and their corresponding enzymatic activities were monitored in AML patient-derived cells (n=83) and pharmacologically inhibited with DIMATE, an irreversible suicide inhibitor of ALDH1 and ALDH3. Targeting of ALDH was evaluated both, in vitro and in orthotopic xenograft tumor models and the molecular mechanisms associated were studied in loss-of-function experiments, luciferase reporter assays and combination-index for DIMATE-drug interactions.
Results. We detected gene amplification or mRNA upregulation of ALDH1 and ALDH3 subfamilies in about 45% of AML (n = 200). The expression of these isoenzymes revealed shorter survival times in patients and strong impact on chemotherapy resistance. Lower enzymatic activity of ALDH was noted in AML patients in the favorable cytogenetic risk group. Consistently, the ALDH activity was significantly higher in patients with refractory AML (>5% blasts after first line treatment) compared to non-refractory patients (p<0,005). Simultaneous inhibition of ALDH1 and 3 activates JNK signaling, compromises glutathione homeostasis and induces a redox state imbalance that is amplified by the accumulation of malondialdehyde and 4-hydroxynonenal-protein adducts. This condition ultimately results in severe oxidative damage and cell death. In AML xenografts with high to moderate resistance to cytarabine, combination with DIMATE promoted strong synergistic responses.
Conclusion. These results provide a proof of concept that AML with increased expression of ALDH1 and 3 may benefit from strategies including inhibitors of these isoenzymes, as single agents or in combination with chemotherapy to overcome patient-specific drug resistance. For these patients, who often have poor responses and no alternative therapeutic plan, DIMATE could be a promising option.

Disclosures
Perez-Alea: Advanced Biodesign: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: MPA reports patent WO/2017/064247. Guillaume:Advanced Biodesign: Patents & Royalties: GM reports patent WO/2017/064247. Ceylan:Advanced Biodesign: Patents & Royalties: IC reports patent WO/2017/064247.
A Systematic Review and Meta- Analysis of Randomized Controlled Trials on Primary Ambulatory Thromboprophylaxis (PATP) in Patients with Gastrointestinal Cancers Receiving Chemotherapy
Authors: Thein Kyaw Zin , Quick Donald P. , Oo Thein Hlaing 
Published: November 2019

Introduction: PATP in solid cancer patients remains uncertain and is not routinely recommended although thrombosis is shown to be the second leading cause of death in cancer patients. Many studies failed to demonstrate in solid cancer outpatients improvement in overall survival despite decreasing venous thromboembolism (VTE) rates by PATP. We conducted a systematic review and meta-analysis of RCTs to determine the benefit and risk of PATP with low-molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in patients with gastrointestinal cancers receiving chemotherapy.
Methods: We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2019. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic.
Results: A total of 1,932 patients with gastric, gastroesophageal junctional (GEJ) and colorectal cancers from a subgroup of three RCTs were included in our meta-analysis. The prophylactic doses of LMWHs and DOAC (rivaroxaban) were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I2 statistic for heterogeneity was 0, suggesting homogeneity among RCTs. The VTE incidence was 13 (1.26%) in PATP group and 23 (2.55%) in control group with a RR of 0.49 (95% CI: 0.25 to 0.96, P = 0.04). The absolute RD in VTE was -0.01 (95% CI: -0.03 to -0.00, P 0.04) with an estimate of the number needed to treat (NNT) of 78 to prevent one VTE event. In a subset of patients with gastric and GEJ cancers (n=587), the VTE incidence was 4 (1.37%) in PATP group and 10 (3.40%) in control group with a RR of 0.40 (95% CI: 0.13 to 1.24, P = 0.11).
Conclusions: In our study, the relative risk reduction is 48% with a NNT of 78 to prevent one VTE in ambulatory patients with gastrointestinal cancers. Nevertheless, there is no statistically significant reduction in VTE events in a subset of gastric and GEJ cancers which are considered high risk in Khorana score. Based on the findings, PATP is not recommended in patients with gastrointestinal cancers on chemotherapy at this time. Further studies are necessary to define high risk subsets of gastrointestinal cancer patients receiving chemotherapy who may benefit from PATP.

Disclosures
Oo: Medical Education Speakers Network: Honoraria; Janssen and Janssen: Other: site co-investigator.
Non-Hematologic Therapy Toxicities Correlated with Survival, Drug Discontinuation and Response in Multiple Myeloma Patients: A Retrospective Study
Authors: Huang Weimin , Wei Yongqiang , Zheng Jingxia , Wei Xiaolei , Feng Ru 
Published: November 2019

Background
The age distribution character makes Multiple myeloma (MM) a geriatric disease. Several geriatric assessment models have built for the identification of the unfit patients and making individual treatments. However, their prediction value on treatment-related toxicities is limited or lacking. It is time to identify the significance of treatment-related toxicities.
Methods
A total of 119 patients consecutively diagnosed as active MM with previous untreated between 2010 and 2018 in Nanfang Hospital were reviewed.
Results
Among all 119 patients analyzed, 30 patients exhibited grad 3-4 non-hematologic adverse events (non-HAEs). The MM patients with non-HAEs showed more likely to present geriatric features, such as poor physical status (PS) and renal function, lower hemoglobin (HGB) and albumin (Alb), higher N-terminal B-type natriuretic peptide (NT-proBNP) (P<0.01). Patients with non-HAEs presented poor overall survival (OS), higher drugs discontinuation rate and poor overall response rate (ORR) at 4 months (P<0.01). The multivariate analysis showed that non-HAEs is an independent unfavorable factor for OS, drug discontinuation and response at 4 months.
Conclusions
Non-hematologic therapy toxicities are correlated with geriatric features, poor survival, high drug discontinuation rate and poor response at 4 months.

Disclosures
No relevant conflicts of interest to declare.
Plasmablastic Lymphoma - Experience with Infusional EPOCH Chemotherapy from India
Authors: PK Jayachandran , Rajan Arun Kumar , Mehra Nikita , Selvarajan Gangothri , Girishchandra Joshi Archit , Karunakaran Parathan , Dhanushkodi Manikandan , Radhakrishnan Venkatraman , Kannan Krishnarathinam , Ganesan Trivadi S , Sagar Tenali Gnana 
Published: November 2019

Background: Plasmablastic lymphoma (PBL) is a rare type of aggressive large B - cell Non Hodgkin Lymphoma (NHL) which was initially described in HIV positive individuals and later was also described in immune competent individuals. It constitutes about 2-3% of HIV associated malignancies. It was included as a distinct entity in WHO lymphoma classification in 2008.
Methods: The clinical features, HIV status, treatment details and outcomes of patients diagnosed with plasmablastic lymphoma during the period of January 2012 to December 2018 were retrospectively collected from the patient records and analyzed. The survival analysis was done by Kaplan Meier analysis and the comparison was done by Log Rank test.
Results: Median age of 25 patients, included in the study was 41 years (Range 13 - 71 years). Males constituted 76% (n=19). HIV positivity was 72% (n=18). Stage 4 disease was present in 76% (n=19). Extra nodal involvement was seen in 96% (n=24), of which the common sites were gastrointestinal tract and bone. Out of 25 patients, 7 did not receive any treatment and 3 received metronomic oral chemotherapy due to poor performance status at presentation. Fifteen patients received chemotherapy on a curative intent. Infusional EPOCH chemotherapy was given in 13 patients. CHOP and CHOPE chemotherapy was given in one patient each. The median number of cycles was 6 (Range: 3 - 8). The overall response rate of patients treated on a curative intent was 80% (Complete response and partial response in 8 and 4 respectively). Three patients underwent high dose chemotherapy with autologous stem cell rescue at first remission (2 HIV patients and 1 Non HIV patient). The median overall survival (OS) of the whole study population was 12.4 months with a median follow of 15.9 months. The Medial OS was not reached in the curative intent group and the 2 year OS of the curative group was 55% with a median follow up of 22.8 months. The factors adversely influencing the OS were Age > 40 years and High IPI (International prognostic index).
Conclusion: Plasmablastic lymphoma commonly presents as stage 4 disease with extra nodal involvement. It is more common in immunodeficient individuals especially HIV positive patients. Infusional EPOCH chemotherapy is a promising option which induces long term remission in fit patients.
Figure

Disclosures
No relevant conflicts of interest to declare.