bluuebunny/crossref_metadata_2025_split huggingface dataset:
CUDC-101 Overcomes Arsenic Trioxide Resistance Via Caspase-Dependent PML-Rarα Degradation in Acute Promyelocytic Leukemia
Authors: Zhang Tianzhuo , Wang Jishi 
Published: November 2019

While arsenic trioxide (ATO) treatment has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, many high-risk APL patients who fail to achieve a complete molecular remission or relapse become resistant to ATO. Studies have suggested that HDAC inhibitors (HDACi) have been targeted as promising agents for the treatment of several cancers. In this study, a novel pan-HDACi 7-(4-(3-Ethynylphenylamino)-7- methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) was used to tentatively to treat hematologic disease for the first time. The CCK-8 assay demonstrate that CUDC-101 exerts much stronger anti-proliferative effects than ATO in APL and ATO-resistant APL cell lines. Previous experiments on cell proliferation inhibition prompted investigation of whether CUDC-101 could induce apoptosis in APL and ATO-resistant APL cells. Then the results of apoptosis assay strongly support CUDC-101 as an effective apoptosis inducer that induced apoptotic cell death in both APL and ATO-resistant APL cell lines, more effectively than ATO. Our data also demonstrate that CUDC-101 is a novel drug that has a negligible cytotoxic effect on non-cancerous cell lines including normal CD34+ cells and BMSCs from APL patients. Mechanistically, we conclude that CUDC-101 directly induce hyperacetylation of histone 3, which subsequently lead to the activation of caspase 3, the activated-caspase 3 cleaves the PML-RARα fusion protein subsequently facilitates APL and ATO-resistant APL cells undergoing apoptosis. The precise mechanism of CUDC-101-induced degradation of PML-RARα remains unclear. Yet the apoptosis inducing effect of CUDC-101 offers a potent therapeutic advantage of CUDC-101 and its role in overcoming APL warrants further validation in patient-derived samples in future studies. Finally, using a NB4 xenograft mouse model, we demonstrated that CUDC-101 significantly represses leukemia development in vivo compared with ATO. These findings suggest that the CUDC-101 is efficient in inhibiting tumor growth in vivo and performs better than ATO. To the best of our knowledge, this is the first report that CUDC-101 functions as HDACi and has potential therapeutic value for the treatment of both APL and relapsed APL with ATO resistance in vitro and in vivo. In conclusion, these results suggested that CUDC-101 can serve as a potential candidate drug for APL, particularly for ATO-resistant APL.

Disclosures
No relevant conflicts of interest to declare.
Efficacy and Tolerance of Interferon-α in Hypereosinophilic Syndromes. a Retrospective Multicenter Study on 29 Patients
Authors: De Malglaive Pauline , Groh Matthieu , Lefèvre Guillaume , Morati Hafsaoui Chafika , Alexis Magda , Hunault Mathilde , Seneschal Julien , Charlanne Hilaire , Preudhomme Claude , Bonnotte Bernard , Kahn Jean Emmanuel 
Published: November 2019

Background: Corticosteroids and imatinib are the first line treatment in hypereosinophilic syndromes (HES) according FIP1L1-PDGFRA (F/P) positivity. In HES unrelated to F/P, second line available treatment are historically interferon alpha (IFN-α) and hydroxyurea, while anti-interleukin-5 antibodies are currently investigated. Data concerning efficacy of IFN-αin HES are limited to small case series and one large international study with a short-term follow-up.
Methods: We performed a multicenter, retrospective, descriptive study to evaluate the efficacy and safety of IFN-αin F/P-negative HES patients. Complete hematologic responses (CHR : eosinophils < 0,5 G/L) and partial hematologic responses (PHR: eosinophils between 0,5 to 1,5 G/L or a decrease of more than 50%), as well as tolerance and corticosteroid sparing-effect were analyzed at 1, 3, 6 and 12 months.
Results: Twenty-nine patients (9 women, with a mean [+/-SD]age at diagnosis of 38 [+/-13]years were included. Fifteen patients (52%) had idiopathic HES, 10 (34%) had a lymphocytic HES, and 4 (14%) had a clonal HES. The most common clinical manifestations were cutaneous (69%) and gastrointestinal involvement (31%). IFN-αwas used in pegylated form in 16 patients at an average dose of 113 [+/-45 μg]/week and in non-pegylated form in 13 patients at an average dose of 12 [+/-9]MIU / week. At one month, a CHR or PHR was observed in 24 patients (83%), including 16 in CHR. At 1 year, 16 patients were still treated with IFN-α, (9 in CHR and 7 in PHR). Treatment with IFN-αwas associated with a significant decrease in the mean daily prednisone dose from 20 [+/-16]mg/day at inclusion to 11 [+/-6]mg/day at 6 months and at 9 [+/-9]mg/j at 1 year. After a median of 15 months (range 1 to 161 months), 21 patients (72%) discontinued IFN-αmainly due to adverse events (27%) or loss of efficacy (31%). At the end of the follow-up, 8 patients were still on IFN-αwith a median duration of treatment of 21.5 months (3 to 161 months), including 6 in CHR and 2 in RHP. In these 8 patients, pegylated IFN-αwas used at the median maintenance dose of 50 μg/week with maintenance of a corticosteroid sparing-effect (median daily prednisone dose at 5.5 mg/day).
Conclusions: IFN-αappears to be an effective treatment for corticosteroid-resistant or corticosteroid-dependent F/P-negative HES. Its effectiveness can be maintained over long term and at low dose in nearly a quarter of patients, with good tolerance. However, a loss of efficacy or adverse effects justify discontinuation of IFN-αin the majority of cases, underlying the need of alternative therapies

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
Interferon-Alpha is an off-label drug used in hypereosinophilic syndromes since more than 20 years.
Diagnostic Performance of Heparin-Platelet Factor 4 Antibodies in the Identification of Heparin-Induced Thrombocytopenia in Cancer Population
Authors: Oo Thein H. , Rojas Hernandez Cristhiam Mauricio 
Published: November 2019

Introduction: Cancer patients appear to have a higher risk of heparin induced thrombocytopenia (HIT) related complications than non-cancer patients; yet data on the performance of conventional diagnostic tools for HIT in cancer is limited.
Our aim was to determine among cancer patients with a 4T score ≥ 4, the performance of the conventional cut-off for HIT antibody testing (IgG anti PF4) to discriminate between serotonin release assay (SRA) positive and negative cases.
Methods: Retrospective and prospective analysis of cases (2002-2019) was performed of the electronic medical records of adult cancer patients at MD Anderson Cancer Center with suspected HIT. Cases were included in the analysis if the 4T score was ≥ 4 and investigated with IgG anti-PF4 optical density (HIT OD) and SRA.
Logistic regression model and the receiver operating characteristic curves were conducted to identify the sensitivity and specificity of different cut-off points for the HIT OD to discriminate HIT cases based on the SRA status.
Results: Among 50 cases, 18 were SRA positive. Median HIT OD was 1.03. At a cut-off point of 0.4, the HIT OD performed with a sensitivity of 0.89 and a specificity of 0.50 to discriminate the cases of SRA positive HIT. When the cut-off HIT OD was 1.0, the sensitivity was 0.78 with a specificity of 0.66.
Conclusions: Our findings suggest that in cancer patients the performance of IgG anti-PF4 is similar to that of non-cancer patients for the identification of HIT cases.

Disclosures
Oo: Janssen and Janssen: Other: Research: site co-investigator ; Medical Education Speakers Network: Honoraria.
Long Term Haematological Recovery of Children with Severe Malaria Anaemia in Uganda
Authors: Namazzi Ruth , Conroy Andrea L , Datta Dibyadyuti , John Chandy C. , Opoka Robert 
Published: November 2019

Long Term Haematological Recovery of Children with Severe Malaria Anaemia in Uganda
Ruth Namazzi, Andrea Conroy, Dibyadyuti Datta, Gloria Kyarisiima Chandy John, Robert Opoka
Background Children with severe malaria anaemia are at an increased risk of poor post discharge outcomes including frequent readmissions and clinic visits for malaria. How the post-discharge outcomes affect haematological recovery of children after severe malaria anaemia has not been evaluated.
Methods We enrolled and followed up for 12 months 248 children with severe malaria anaemia (SMA) and 120 age matched asymptomatic community controls (CC). Complete blood counts, reticulocyte percentages and erythropoietin levels were done at baseline, 1 month and 12 months after the malaria episode. Children were treated according to national guidelines, which included blood transfusion and anti malarial therapy. We evaluated the relationship between recovery of haematological indices and multiple readmissions in the post-discharge period in SMA children.
Results The mean age was 2.12 ± 0.9 and 2.2 ± 1.0 years (p=0.266) for SMA and CC respectively. The mean baseline haemoglobin (Hb), reticulocyte percentage and erythropoietin levels were 3.5 ± 0.9g/dL, 2.6±4.7% and 6843±5891 for SMA, compared to 10.8±1.5g/dL, 1.8±2.6% and 58.5 for CC, respectively. By 1-month, SMA children had made complete haematological recovery with mean Hb, reticulocyte percentage and erythropoietin levels of 11.2 ± 2.2g/dL, 1.8± 2.7% and 20.2 ± 58.3. The hematological recovery was sustained even by month12 follow up; mean Hb level was 10.7±2.1 and 11.6±2.1g/dL for SMA and CC, p =0.07. Reticulocyte percentages were comparable between SMA and CC, 2.5 ± 4.1vs 1.2±1.7,p=0.41. Amongst SMA group, more children who had multiple readmissions during the follow up period were still anemic at 12 months compared to those who did not have multiple readmissions, 7/64(10.9%) vs. 13/168(7.8%). The difference however was not statistically significant (p=0.438).
Conclusion Children with SMA achieve hematological recovery by 1 month post-discharge. The hematological recovery was maintained until 12 months post-discharge. Amongst SMA children, multiple readmissions in the post-discharge period did not appear to adversely affect hematological recovery by 12 months. The effect of repeated malaria episodes on long term haematological recovery needs further study.

Disclosures
Conroy: ALC: Patents & Royalties: angiopoietin-1, angiopoietin-2.
Effect of CXCL14 on Migration of Mds Via CXCL12/CXCR4 Axis in Vitro
Authors: Ying Wang 
Published: November 2019

Objective:To detect the expression level of chemokine CXCL-14 in patients with MDS, and to explore how it is regulated and what clinical effects may occour . For the further step ,to find new target in MDS therapy.Method:45 patients with MDS and 28 donors' peripheral blood samples were included. The expression of chemokine CXCL14, CXCL12 / CXCR4 and CXCR7 were detected by ELISA and FCM. Logistic regression analysis confirmed the association between chemokine expression level and disease progression. Kaplan-meier survival analysis ,introducing time factors, show how CXCL14 works on median survival time and cumulative survival. Methylation specific PCR detected the promoter methylation level in CXCL14.To affirm the clinical significaonce of CXCL14 in MDS, the group conduct experiment with cell line SKM-1 and rebuild the cell in the way of CXCL14 and CXCR7 overexpression .CCK-8 cell proliferation experiment tested cell vigor, Flow Cytometry detected cell apoptosis, transwell chemotactic experiment evaluated cell migration and invasion.Result:With the progression of MDS, the expression of receptors, CXCR4 and CXCR7, on tumor cell membrane increases .Statistical analysis showed that CXCL14 expression of stem cell mobilized donors was significantly high. Logistic regression analysis showed that increased expression of cxcl14 might hinder MDS progression, and overexpression of CXCL12 / CXCR4 axis was beneficial to disease progression. Kaplan-meier survival analysis showed that the median survival time and cumulative survival rate of patients with high CXCL14 expression were both better than the low CXCL14 expression group's. In the CXCL14 low-expression group, the gene promoter was hypermethylated.The expression of CXCR4 and CXCR7 on the surface of cell SKM-1 was down-regulated after Descitabine treatment, similarly in CXCL14 overexpression. In vitro, the high expression of CXCL14 could inhibit cell SKM-1 proliferation and promote cell apoptosis, and weak the cell migration and invasion induced by CXCL12/CXCR4 axis.Conclusion: In MDS, up-regulating CXCL14 expression might is one of the key factors to prevent the excessive activation of CXCL12 /CXCR4 axis, to maintain the stem cells in dynamic balance and limit the migration of tumor cells. To stimulate CXCL14 in vivo and infusion CXCL14 analogues are expected to be a new way in MDS treatment.

Disclosures
No relevant conflicts of interest to declare.
Tumor Lysis Syndrome Management in Community Oncology Settings
Authors: Howard Scott 
Published: November 2019

Background
Tumor lysis syndrome (TLS) can complicate the management of patients with bulky chemosensitive cancers. TLS incidence and severity are increasing with new highly effective agents for hematologic cancers. However, prophylaxis and management vary widely, even within the same center.
Methods
We examined TLS management and outcomes from records of 14383 newly-diagnosed adults with lymphoma treated from 2010- 2019 at 110 member hospitals of the Guardian Research Network (GRN, www.GuardianResearch.org), a non-profit community oncology consortium with a database containing patients' entire medical, including all demographics, diagnoses, labs, medications, procedures, encounters, and notes of all kinds (clinical, radiology reports). Anonymized, de-identified data about demographics, diagnosis, treatment, supportive care, and outcomes was analyzed to determine patterns of TLS management in the community setting. Natural language processing was used to identify clinicians' references to tumor lysis syndrome, risk assessment, and cancer bulk.
Results
Of 529784 cancer patients in the Guardian Research Network database, there were 14383 newly-diagnosed adults with lymphoma, of whom 81% received no uric acid lowering therapy, 17% received allopurinol or febuxostat, and only 2% received Rasburicase. TLS management varied by region: 11% of patients in Virginia received uric acid lowering therapy vs 26% in South Carolina (p<0.001) and lymphoma subtype: 11% Hodgkin lymphoma, 26% B-cell non-Hodgkin lymphomas, p<0.001). Acute kidney injury (AKI) occurred in 4.3% of patients and logistic regression confirmed NHL (versus Hodgkin), black race (versus white), and older age as risk factors (p<0.01 for each). 216 patients (1.5%) died within 30 days. Of special note, bone marrow infiltration in acute leukemia patients was not noted as a site of bulky disease, despite the fact that a marrow with 50% infiltration of leukemic cells typically contains 700 grams of cancer, and represents bulky disease that places the patient at significant risk for TLS if treated with highly active agents.
Conclusions
Early acute kidney injury is common in patients with B-cell lymphomas. Assessment of TLS risk and prophylaxis is warranted, especially when using new, highly effective chemotherapy agents in patients with bulky disease. Assessment of tumor bulk was rarely documented in the medical records.
Table

Disclosures
Howard: BTG: Consultancy, Research Funding; EUSA Pharma: Consultancy; Sanofi: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Amgen: Honoraria.
Hospital mortality in acute coronary syndrome: adjustment of GRACE score by D-dimer enables a more accurate prediction in a prospective cohort study
Authors: Yu Tongtong , Jiao Yundi , Song Jia , He Dongxu , Wu Jiake , Sun Zhijun , Sun Zhaoqing 
Published: November 2019

Abstract

Backgroud
To assess the value of D-dimer and its combination with The Global Registry of Acute Coronary Events (GRACE) score in predicting in-hospital mortality in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).

Methods
In 5923 ACS patients undergoing PCI, the role of D-dimer and the added value of D-dimer to GRACE score for predicting in-hospital mortality were tested.

Results
After multivariable adjustment, D-dimer could significantly predict in-hospital mortality. Also, it could significantly improve the prognostic performance of GRACE score (C-statistic: z = 2.269, p = 0.023; IDI: 0.016, p = 0.032; NRI: 0.291, p = 0.035).

Conclusion
In patients with ACS undergoing PCI, D-dimer was an independent predictor of in-hospital death. It could also improve the prognostic performance of GRACE score.
Cross-sectional associations between personality traits and device-based measures of step count and sedentary behaviour in older age: the Lothian Birth Cohort 1936
Authors:   on behalf of the Seniors USP Team, Čukić Iva , Gale Catharine R. , Chastin Sebastien F. M. , Dall Philippa M. , Dontje Manon L. , Skelton Dawn A. , Deary Ian J. 
Published: November 2019

Abstract

Background
While the associations between personality traits and self-reported physical activity are well replicated, few studies have examined the associations between personality and device-based measures of both physical activity and sedentary behaviour. Low levels of physical activity and high levels of sedentary behaviour are known risk factors for poorer health outcomes in older age.

Methods
We used device-based measures of physical activity and sedentary behaviour recorded over 7 days in 271 79-year-old participants of the Lothian Birth Cohort 1936. Linear regression models were used to assess whether personality traits were cross-sectionally associated with step count, sedentary time, and the number of sit-to-stand transitions. Personality traits were entered one at a time, and all-together, controlling for age and sex in Model 1 and additionally for BMI and limiting long-term illness in Model 2.

Results
None of the associations between personality traits and measures of physical activity and sedentary behaviours remained significant after controlling for multiple-comparisons using the False Discovery Rate test (all ps > .07).

Conclusions
We found no evidence that personality traits are associated with device-based measures of physical activity or sedentary behaviour in older age. More studies are needed to replicate and examine the nature of these relationships.
Native aortic valve endocarditis with Morganella morganii in a patient with multiple myeloma and valvular amyloidosis: a case report
Authors: van Bentum Renée , Nieken Judith , de Waal Esther , Hoogendoorn Mels 
Published: November 2019

AbstractBackgroundPatients with multiple myeloma (MM) are known to be immune incompetent and experience higher incidences of infectious diseases. However, infective endocarditis (IE) is rarely observed in patients with MM andMorganella morganii (M. morganii) has rarely been associated with IE.Case presentationA 72-year-old female receiving 4th line treatment for MM presented with fever and concomitant confusion. Urinary culture revealed growth ofEscherichia coli, wherefore broadspectrum penicillin and high-dose corticosteroids were initiated. However, blood cultures showed growth ofM. morganii. Fluoroquinolone was added due to penicillin-resistance of theMorganellaspecies. Two days after admission, the patient acutely deteriorated with hemodynamic instability. Gentamicin and high dose corticosteroids were added. Echocardiography showed marked aortic valve vegetation with severe aortic valve regurgitation, leading to the diagnosis of bacterial endocarditis of the native aortic valve. Shortly after diagnosis, the patient died. At autopsy, vegetation with gram-negative rods in the native aortic valve was observed, confirming the diagnosis ofM. morganii-endocarditis. Additional staining for amyloid confirmed advanced light-chain (AL) amyloidosis with extensive amyloid depositions of the aortic valve and valvular damage as complications of her MM.ConclusionsOur case suggests that IE withM. morganiiwas facilitated by the combination of the cardiac amyloidosis with valvular impairment and the profound immune deficiency caused by the several chemo-immunomodulatory treatment lines and the MM itself. This case further illustrates that awareness for rare opportunistic infections in an era with growing potential of combined chemoimmunotherapy is warranted.
Ruxolitinib shows activity against Hodgkin lymphoma but not primary mediastinal large B-cell lymphoma
Authors: Kim Seok Jin , Yoon Dok Hyun , Kang Hye Jin , Hong Jung Yong , Lee Ho Sup , Oh Sung Yong , Shin Ho-Jin , Kong Jee Hyun , Yi Jun Ho , Sakamoto Kana , Ko Young Hyeh , Huh Jooryung , Lee Seung-Sook , Takeuchi Kengo , Shin Dong-Yeop , Suh Cheolwon , Kim Won Seog 
Published: November 2019

Abstract

Background
The upregulated expression of the JAK/STAT pathway promotes tumor growth in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL). Based on the hypothesis that JAK2 is a therapeutic target, we performed a prospective pilot study using ruxolitinib.

Methods
Relapsed or refractory patients with HL or PMBCL were eligible for this study, and JAK2 amplification was assessed by fluorescence in situ hybridization. Ruxolitinib was administered orally at a dose of 20 mg twice daily for a 28-day cycle. Treatment was continued for up to 16 cycles or until progressive disease or intolerability. The primary objective was to assess the overall disease control rate comprising complete response (CR), partial response (PR), or stable disease (SD).

Results
We analyzed 13 HL patients and six PMBCL patients. All responders (one CR, five PR, and one SD) had HL whereas all cases of PMBCL progressed after first or second cycle. The disease control rate for HL was 54% (7/13) with median response duration of 5.6 months. JAK2 amplification was present in six of nine patients tested (four HL, two PMBCL), and three of these HL patients showed PR (n = 2) or SD (n = 1). None of the three HL patients shown to not have JAK2 amplification responded to ruxolitinib. Most treatment-related adverse events were grade 1 or 2 and manageable.

Conclusions
Ruxolitinib has single-agent activity against HL but does not act against PMBCL with or without JAK2 amplification.

Trial registration
The study population was patients who had relapsed or refractory HL or PMBCL, and patients were registered for our pilot study after providing written informed consent between November 2013 and November 2015 (CilinicalTrials.gov: NCT01965119).
A rare content of congenital inguinal hernia: a case report of splenogonadal fusion
Authors: Xiang Xi , Jiang Yong , Liu Ju-xian , Qiu Li 
Published: November 2019

AbstractBackgroundSplenogonadal fusion (SGF) is a rare congenital malformation that occurs during embryonic development. SGF typically presents as a left-sided scrotal swelling, left inguinal hernia, scrotal mass, or cryptorchidism. Therefore, it is easily misdiagnosed, and unnecessary orchiectomy may occur. This study aimed to report a rare case of SGF.Case presentationA 5-month-old male child presented with a history of obvious left scrotal swelling for 1 month, which progressively worsened 10 h before the hospital visit. The ultrasound examination exhibited a solid mass in the left scrotum, with echo quite similar to that in the testicle and went up into the abdominal cavity through an identical echogenic band structure. After surgical resection, the pathological examination confirmed that the submitted tissue was spleen tissue with extensive bleeding.ConclusionUltrasound can provide important information regarding the diagnosis of SGF. The possibility of SGF should be considered for further differential diagnosis in the case of similar patients.