bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytotoxicity of the Recombinant Human Arginase (BCT-100) Against Acute Lymphoblastic Leukaemia (ALL)
Authors: Mussai Francis J , Booth Sarah , Vardon Ashley , Ng Margaret , Cheng Paul , De Santo Carmela
Published: October 2019

Acute Lymphoblastic Leukaemia (ALL) is the most common leukaemia of childhood. Despite improvements in overall survival, significant numbers of children die from relapsed/ refractory disease or suffer the morbidities of multi-agent chemotherapy regimens. A major challenge is to find new drugs which are active against ALL blasts or which make blasts more sensitive to existing chemotherapy, without adding to toxicity. Arginine, is a semi-essential amino acid, required for protein synthesis, and cell viability. Some cancers are dependent on arginine for proliferation and survival - 'arginine auxotrophism'. We have recently identified that arginine metabolism plays a key role in AML pathogenesis and can be therapeutically targeted. Therefore we investigated if Acute Lymphoblastic Leukaemia is also sensitive to therapeutic arginine depletion.

A clinical grade, FDA approved, pegylated-recombinant human arginase, PEG-rhArgI molecule BCT-100, has been developed by Bio-Cancer Treatment International (BCT, Hong Kong).A Phase I and II clinical trial has been successfully completed in adult hepatocellular carcinoma. The Phase I trial demonstrated that at 1600U/kg BCT-100 (Observed Biological Dose), plasma arginine falls below 8mM (Adequate Arginine Depletion - ADD) and is maintained for up to 166 hours, with no evidence for neutralising immunogenicity. Only grade 1 or 2 reversible transaminitis was seen and patients experienced significant improvements in overall survival.

Arginine is recycled by cells from ornithine, through the enzymes OTC and ASS. These enzymes have been identified as biomarkers of sensitivity to arginine depletion in solid tumours. ASS and OTC expression pattern was characterised in leukaemic blasts from 37 ALL patients (19 adult, 18 paediatric), revealing the majority of ALL cases are deficient in one or more of these enzymes (Adults: ASS-: 84% OTC: 53%; Paediatric: ASS- 44% OTC 27%). Thus the majority of ALL blasts are auxotrophic for arginine.

We tested the cytotoxicity of BCT-100 against ALL. We demonstrated that ALL cell lines (n=4) are dependent on arginine for proliferation and survival. In vitro, BCT-100 leads to a complete depletion of extracellular arginine and induction of autophagy. BCT-100 was tested against primary blasts from ALL patients - IC50S ranged from 17.5-2400ng/ml. Sensitivity to BCT-100 did not correlate with clinical or cytogenetic characteristics. The study is the first report on the arginine dependence of adult and paediatric ALL and provides the rationale for ongoing translation of BCT-100 for patients with relapsed ALL.

Disclosures

No relevant conflicts of interest to declare.
Correlation of PET Scan Negativity and Higher Absolute Lymphocytes: Monocytes (ALC:AMC) Ratio As Prognostic Markers in Classical Hodgkin Lymphoma Patients Treated with ABVD Chemothearapy at a Single Center in Saudi Arabia
Authors: Motabi Ibraheem H , Zaidi Syed Ziauddin A. , Iqbal Shahid , Gill Atta Munawar , Tailor Imran Khan , Alshehry Nawal Faiez , Elghazaly Assem A , Almudaibigh Samer Homoud S , AlGhamdi Mubarak S. , Murtaza Ghulam , Butt Ahmed
Published: October 2019

The International Prognostic Score (IPS) is the standard stratification system for survival in patients with classical Hodgkin's lymphoma (cHL). However, the IPS only applies to patients with advanced stage disease and it does not offer risk stratification for classical Hodgkin's lymphoma patients diagnosed with limited disease [i.e., stages I and IIA, without constitutional symptoms and no bulky disease. Furthermore, early interim positron emission tomography (PET) has been shown to have a prognostic value superior to that of the IPS in patients with advanced-stage cHL in an analysis (Gallamini et al).

Lymphopenia (<600/ul), monocytosis >750 per ul (Tadmore et al) and high tumor-associated macrophages (TAM) are reported to be negative prognostic factors for survival in classical Hodgkin's lymphoma (Koh et al). More recent studies suggested a prognostic role for the peripheral blood absolute lymphocyte count/absolute monocyte count (ALC/AMC) ratio at diagnosis in cHL patients treated with multitude of chemotherapies (Porrata et al, Tadmor et al). It is intriguing to investigate the significance of the ALC/AMC ratio in relation to PET negativity after treatment.

Out of 164 cases of cHL treated at our center with ABVD +/- radiation therapy, we identified 70 patients who were evaluated by PET Scan. Median age was 26 years (range 14-80), 33 (47%) were stage IV, Median IPS was 3 (range1-6). We tested correlation of a high ALC/AMC ratio (>2.1) with achievement of a negative PET scan after ABVD chemotherapy. We arbitrarily chose cut-off value of >2.1 (Tadmore et al) from the multiple values reported recently, as this multicenter study had the largest number of patients.

A total of 45 patients achieved a negative PET scan. Mean ALC/AMC ratio was 2.39 (range0.19-14.6). ALC/AMC ratio of >2.1 did show a trend for better OS in addition to a negative PET scan. A Spearman correlation test of a negative PET result showed a positive correlation with ALC/AMC ratio of >2.1 though it was weak.

This study suggests that the ALC/AMC ratio may be a simple, inexpensive, and independent prognostic factor in cHL outcome and may have a role in the stratification of cHL patients in addition to the International Prognostic Score, TAM content and acheivement of a negative PET scan early post chemotherapy. However we plan to define our own best cut off value for ALC/AMC ratio by ROC and AUC analysis as ALC/AMC Ratio of ≥2.1 did not discriminate survival advantage very well and it may be a reason for weaker correlation with likelihood of a negative PET.

Further larger studies are needed to confirm our findings.

Disclosures

No relevant conflicts of interest to declare.
Extracorporeal Photopheresis for the Treatment of Mycosis Fungoides
Authors: Atilla Erden , Ataca Pinar , Civriz Bozdag Sinem , Toprak Selami Kocak , Yuksel Meltem Kurt , Akay Bengu Nisa , Sanli Hatice , Topcuoglu Pervin , Ozcan Muhit , Gurman Gunhan , Ilhan Osman
Published: October 2019

Backround: The treatment of mycosis fungoides (MF) is determined by disease extent, prognostic factors and patient characteristics. Extracorporeal Photopheresis (ECP) was approved by the US Food and Drug Administiration for the palliative treatment of mycosis fungoides since 1988. Herein, we present our MF patients who have received ECP.

Patients and Methods: We retrospectively included 50 MF patients who have diagnosed at our center. ECP was given empirically in cycles of 2 consecutive days in every 2 to 4 weeks at any time during their follow-up.

Results: The patient characteristics is shown in table. Previous lines of treatments were; topical retinoids (bexarotene), topical corticosteroids, phototherapy (PUVA), Narrowband ultraviolet B light (NBUVB), Interferons, Metotrexate (MTX), CHOP (cyclophosphamide, daunorubicin, vincristine, prednisolone). ECP is combined with gemcitabine, PUVA, MTX, Bexaroten, IFN or Vorinostat. The overall response rate (ORR) was 54% with 30% complete response rate (CRR). 10/15 complete responders (67%) had stage 3-4 disease at diagnosis and 7/15 (47%) had received ≥ 3 lines of treatment prior to ECP. 18 patients (36%) had progressive disease after ECP while 3 patients (6%) were refractory and underwent allogeneic stem cell transplantation. The few adverse events of ECP included in 8 patients (16%) as catheter-related infection, headache, fever, chills and nausea. The OS was 68 months.

Conclusion: ECP is a favorable treatment option for suitable patients in MF with high ORR and low risk of adverse events.

Presenter has relevant financial relationship(s) to disclose: No.

Disclosures

No relevant conflicts of interest to declare.
Clinical Features and Treatment Outcomes of Angioimmunoblastic T-Cell Lymphoma: An Analysis from a Nationwide Multicenter Registry, Thailand
Authors: Sirijerachai Chittima , Chansung Kanchana , Lekhakula Arnuparp , Julamanee Jakrawadee , Wudhikarn Kitsada , Bunworasate Udomsak , Norasetthada Lalita , Nawarawong Weerasak , Khuhapinant Archrob , Ekwattanakit Supachai , Numbenjapon Tontanai , Prayongratana Kannadit , Chuncharunee Suporn , Niparuck Pimjai , Suwanban Tawatchai , Kanitsap Nonglak , Wongkhantee Somchai , Wong Peerapon , Makruasi Nisa , Intragumtornchai Tanin
Published: October 2019

OBJECTIVES: To analyze clinical features, treatment outcomes in Thai patients with angioimmunoblastic T cell lymphoma (AITL).

PATIENTS AND METHODS: From a nationwide multicenter registry of 4,056 NHL patients in Thailand between 2007 and 2014, there were a total of 54 angioimmunoblastic T cell lymphoma (AITL) patients. The clinical features and treatment outcomes were analyzed.

RESULTS: There were a total of 54 cases accounted to the prevalence of 1.2 % of NHL and 12% of peripheral T cell lymphoma. The median age was 59 years (range 35-81). Male: female was 1.5:1. Seventy-eight percent of patients had advanced disease (stage III, IV), 69% had B symptoms, 28% had poor performance status (ECOG > 2) and 61% had elevated serum LDH level. Extranodal involvement was 56 %; the most common sites of which were bone marrow (30%) and liver (19 %). Thirty-five percent of the patients had IPI score > 2 and 7% had PIT >2. Eighty-one percent of patients were treated with chemotherapy of which CHOP/CHOP-like was the main regimen. Of the 43 evaluable patients receiving chemotherapy, complete remission was achieved in 41.9%. Forty-four percent of patients with complete remission had disease progression. With the median follow-up time of 65 months, the 5-year overall survival was comparable to peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), (28% vs. 37%, p=0.7). On multivariate analysis, response to treatment (at least PR) was associated with better outcome (HR 0.13, 95%CI 0.05-0.33, p= 0.000). Patients with PIT > 2 or B symptoms trended to have inferior survival outcome, although statistical significant was not achieve (HR 3.2, 95%CI 0.36-27.95, p=0.3; HR 2.3, 95%CI 0.78-7.31, p=0.13).

CONCLUSIONS: The prevalence of Thai patients with AITL was much less than data reported from the international T-cell lymphoma project (18% of T-NHLs) (Vose et al, JCO2008;26:4124-30). The long-term survival was not inferior to patients with PTCL, NOS.

Disclosures

Khuhapinant: Roche: Honoraria.
Mir-217 Reverses the TKI Drug-Resistance of K562 Cells By the Downregulation of Heme Oxygenase-1
Authors: Wang Jishi , Wang Chanjuan , Ma Dan , Fang Qin , Ren Mei
Published: October 2019

Upregulation of Heme oxygenase-1 (HO-1) strengthens drug-resistance to apoptotic death in the several kinds of cancer cells. Our recent study shows the higher levels of HO-1 expression in the thyrosine kinase inhibitors (TKI) resistance K562 cell line and cells from Imatinb-insensitive CML patients. The cause of HO-1 upregulating, though, is still unclear yet.

MicroRNAs (miRNAs) play a significant role in the pathogenesis of cancer. They also are known as potential biomarkers and therapeutic targets. In the hematological neoplasm, miRNAs take part in not only cancer development, but also drug resistance. However, the problem has not been solved yet is how the microRNA involved in.

This study found that the expression level of microRNAs were much different depended on if it is Imatinb-insensitive or not. The phenomenon was observed both in the K562 and CML patients. The mir217 was one of these microRNAs that significantly deceased when the K562 had been induced to resist the Imatinb. Meanwhile,TKI-resistance K562 cells can be in association with an increase in levels of HO-1 and a decrease in levels of miR-217. In the TKI-resistant K562 cells, the decreased of miR-217 upregulated the expression of HO-1 through a 3'-untranslated region(UTR) of HO-1 and induced the resistance against TKI. Interestingly, TKI-resistant K562 cells exposed to miR-217 mimic can partially make the cells be sensitized to TKI again in association with upregulation of miR-217 and downregulation of HO-1 in vitro. The IC50 of the TKI-resistant K562 cells exposed in 7.5uM Imatinb for 48 hours also decreased after transfecting miR-217 mimic for 48 hours.

In our on-going experiment, the express level and interaction of HO-1 and miR-217 will be tested in K562 tumors growing in immune-deficient mice that were treated with the combination of mir-217 inhibitor, expression HO-1 virus and TKI. The express of HO-1 and miR-217 also will be examined in the TKI-insensitive CML patients and the mir217 and HO-1 regulated mechanism will be investigated in vivo.

According to our results, the reversibility of the mir-217 downregulating Heme oxygenase-1 in the K562 cells with TKI drug tolerance likely provides a potentially exciting miRNA therapeutic strategy.

MiRNAs therapy could be utilized as a powerful therapy which would focus to the drug-resistance patients. Drug-resistance cancer cells may be sensitized to former conventional or targeted chemotherapy.

Disclosures

No relevant conflicts of interest to declare.
High Prevalence of Peripheral Artery Occlusive Disease (PAOD) Among Patients with Chronic Myeloid Leukemia (CML) Receiving Tyrosine Kinase Inhibitors (TKIs): A Cross-Sectional Study
Authors: Rattanathammethee Thanawat , Tantiworawit Adisak , Rattarittamrong Ekarat , Chai-Adisaksopha Chatree , Hantrakool Sasinee , Phrommintikul Arintaya , Gunaparn Siriluck , Norasetthada Lalita
Published: October 2019

Background: Although TKIs become the standard of care in CML, the long-term complication has not been well recognized. There were reports of nilotinib associated metabolic derangements including diabetes and PAOD while these complications in other TKIs have not been well recognized.

Objectives: To compare the prevalence of PAOD among CML patients and matched-control population.

Methods: A cross-sectional case control study was conducted among CML patients receiving TKIs at Chiang Mai University Hospital between February to December 2014. The control group was matched by age, sex and diabetes. Screening PAOD using Fukuda VS-1500 to measure ankle-brachial index (ABI) and cardio-ankle vascular index (CAVI) for arterial stiffness were performed in both groups. The cutoff value of pathologic ABI and CAVI were less than 0.9 and higher than 8, respectively.

Results: Seventy-eight CML patients and 156 matched-control population(1:2 ratio) were included. For CML patients, the median age was 55 years (21-86). Atherosclerotic risks including hypertension(20.5%), diabetes(12.8%), dyslipidemia(26.9%), metabolic syndrome(19.2%) and smoking(2.6%). Sixty-one patients(78.2%) were on imatinib, all as first-line, 13 patients(16.7%) on nilotinib (7.7%first-line, 92.3%second-line) while 4 patients(5.2%) were on dasatinib(all third-line). Median duration of imatinib, nilotinib and dasatinib treatment were 89.6, 46.7 and 22.1 months, respectively. The prevalence of pathologic ABI and CAVI were 9.0% and 26.7%, respectively. Patients receiving nilotinib had highest prevalence of abnormal ABI of 30.7% while patients receiving imatinib and dasatinib had abnormal ABI of 5% and 0%, respectively (p=0.004). Abnormal arterial stiffness by CAVI in nilotinib users were 15.4% compared to 27.8% and 50% in imatinib and dasatinib (p=0.815). Patients with CML had higher prevalence of pathologic ABI than in control group with an odds ratio(OR) of 2.09(95%CI 0.71-6.21, p=0.181). The only factor independently associated with pathologic ABI was level of HbA1C over 7 g/dl [OR2.41(95%CI 1.11-5.25; p=0.026)]. Age over 60 years [OR 3.95(95%CI 1.22-12.73, p=0.022)] and fasting plasma glucose over 126 mg/dl [OR 7.96(95%CI 1.21-52.26, p=0.031)] were independently associated with pathologic CAVI.

Conclusions: The prevalence of PAOD by using ABI was higher among CML patients than in control population. CML patients receiving TKIs who have diabetes and older than 60 years old have a higher chance of developing PAOD and should be carefully monitored.

Disclosures

No relevant conflicts of interest to declare.
Oncoguide System- a Computerized Interactive Assistance System for the Diagnosis and Treatment of CML / MPN and MDS
Authors: Hempel Dirk
Published: October 2019

The project aims to develop and implement a computerized interactive assistance system for the diagnosis and treatment of CML / MPN and MDS. The system is based on modulated, established medical guidelines with reference to the individual patient information. The user is navigated through the complex recommendations of current guidelines and decision trees of the CML/MPN and MDS, similarly to a car navigation system.

The system was developed in cooperation between the Steinbeis Institute for Clinical haematooncology and the Fraunhofer IOSB in Karlsruhe. In addition to the guidelines, recommendations on current evidence-based research results will be incorporated into the expert system. The medical user is hereby offered a systematic decision support. In addition, the decisions are documented and visualized in an intuitive user interface. The expert system is also able to point to currently recruiting therapy studies. The future system is planned to be self-learning by weighing the decision criteria. It will adjust the decision criteria by increasing usage and possibly readjusted criteria.

Technical implementation and advantages of this solution:

From a technical perspective, the knowledge-based system should be implemented as a client-server architecture. The server acts as a central data storage, for example, in the form of a database. As a client, for example, Internet browsers can be used. So it is possible to centrally reproach the accumulated knowledge and to present the current results to each user. The advantage of such a technical solution compared to guidelines-books is rapidly adaptable knowledge on new research results, as well as the implementation of a self-learning system. The system design has to pay particular attention to an intuitive user interface. On the server's side, the knowledge of guidelines and interviews with experts have to be formalized in an appropriate manner. There are approaches based on an ontological or logic-based modeling.

On the client's, side the system suggests the user appropriate decision for the diagnosis and further treatment of diseases. The underlying methodology is based on approaches from artificial intelligence, such as the Bayesian inference or machine learning methods.

Disclosures

Hempel: Novartis and Celgene: Research Funding.
Bortezomib-High Dose Melphalan Conditioning for the Treatment of MM Patients Undergoing ASCT
Authors: Jimenez-Zepeda Victor , Duggan Peter , Neri Paola , Chaudhry Ahsan , Tay Jason , Luider Joanne , Bahlis Nizar J.
Published: October 2019

Introduction Recent data suggests that bortezomib, a proteasome inhibitor, in combination with high-dose melphalan (Bor-HDM) provides with a synergistic effect able to improve the level of response for MM patients undergoing auto-SCT. In the present study, patients receiving induction followed by ASCT with Bor-HDM and HDM alone were evaluated. Methods All consecutive patients undergoing ASCT from 01/2004 to 03/2016 were evaluated. All patients received induction chemotherapy before undergoing auto-SCT. Patients received conditioning with either HDM at 200 mg/m2 (or adjusted as per renal failure) or HDM with Bortezomib (Bor-HDM). Most of patients received Bortezomib conditioning at 1.3 mg/m2. As per physician discretion, the dose of 1 mg/m2 was also employed in 30% of cases. Definitions of response and progression were used according to the EBMT modified criteria. MRD negativity was assessed by flow cytometry at day-100 post-ASCT. Results Clinical characteristics are shown in Table 1. Among 301 cases, 129 were treated with Bor-HDM while 172 patients went onto receive HDM alone as part of the conditioning regimen. Induction regimens are shown in Table 1. At the time of analysis, 83% and 58% of patients in the Bor-HDM and HDM group are still alive and 34% and 69.1% of patients have already progressed, respectively. At day-100 post ASCT, ORR of 97%, with CR/VGPR rate of 84.2% was seen in the Bor-HDM group compared to 94.2% and 68.6% in the HDM group (p=0.001). MRD negativity was higher in the Bor-HDM group (33.3%) compared to HDM (12.2%) (p=0.001). Median OS was similar for Bor-HDM and HDM (p=0.864) (Fig 1a). In addition, median PFS did not differ among patients receiving HDM or Bor-HDM (37.7months vs 29.3 months, p=0.2) (Fig1b) In conclusion,Bor-HDMis a conditioning regimen able to provide higher rates ofnCR/CR, as well as MRD negativity compared to HDM alone. Further studies are warranted to explore this regimen, especially when other upfront therapies are employed.

Overall Survival according to the conditioning regimen employed for patients with MM undergoing ASCT Overall Survival according to the conditioning regimen employed for patients with MM undergoing ASCT Figure 1 Progression-Free Survival according to the conditioning regimen employed for patients with MM undergoing ASCT Figure 1. Progression-Free Survival according to the conditioning regimen employed for patients with MM undergoing ASCT

Disclosures

Jimenez-Zepeda: Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene, Janssen, Amgen, Onyx: Honoraria. Neri:Celgene and Jannsen: Consultancy, Honoraria. Bahlis:Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; BMS: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau.
Immunohistochemical Analyses on Angiogenesis in a Porcine Von Willebrand Disease Model
Authors: Von Depka Mario , Allerkamp Hanna , Ekhlasi-Hundrieser Mahnaz , Pfarrer Christiane , Detering Carsten , Lehner Stefanie
Published: October 2019

Objectives: Women with von Willebrand Disease (VWD) type 3 may develop miscarriage during pregnancy. There is evidence that besides its role in coagulation von Willebrand Factor (VWF) is also involved in angiogenesis and defects of this pathway could play a role in miscarriage. For this reason, VWF as well as proteins with known functions in angiogenesis were analysed by immunohistochemistry of several tissues in a pig model comprising all VWD type 3 genotypes (VWD, heterozygous carriers, wildtype).

Methods: Uterus tissue samples including the endometrium were collected from a total of 6 pigs. Of these, two were affected by VWD type 3, two were heterozygous carriers, and the remaining two were wildtype individuals, which served as controls. Hematoxylin-eosin-staining was implemented for morphological evaluation of the tissues, especially with regard to possible differences in structure and pattern of blood vessels. In a second step immunohistochemical analyses comparing the expression of angiogenic factors including VWF were performed in VWD-animals, genetic carriers and wildtype pigs.

Results: Hematoxylin-eosin-staining of histological sections of the porcine uteri comprising the different genotypes revealed differences in the vascular architecture within the lamina propria. Compared to non pregnant wild type pigs where blood vessels in the lamina propria of the endometrium usually are of smaller caliber (mostly categorized as arterioles, venules and capillaries), the lamina propria of VWD type 3 animals contained multiple large arteries and veins (of the type usually found in the uterine wall). The immunohistochemical analysis for VWF showed almost no VWF expression in the pigs affected by VWD. In wildtype and heterozygous pigs, expression was obvious in the endothelium. A narrow band of VWF expression apically on the epithel cells as well as partial expression in glands was seen only in wildtype pigs, but not in heterozygous pigs. For some, but not all further angiogenic factors analysed, expression differences were present among the porcine VWD genotypes.

Conclusion: The results of our study confirm effects of VWF on the uterine vascular architecture and on the expression of specific angiogenic factors. Pigs affected by VWD showed almost no expression of VWF and the blood vessels within the uterine lamina propria had a surprisingly high percentage of large arteries and veins indicating a crucial role of vWF for uterine angiogenesis. Expression differences among the genotypes were obvious for specific angiogenic factors.

Disclosures

Von Depka: Octapharma: Other: Study Investigator, Speakers Bureau.
A MRI Prospective Survey on Heart and Liver Iron and Cardiac Function in Thalassemia Major Patients Treated with Deferasirox Versus Deferiprone and Desferrioxamine in Monotherapy
Authors: Pepe Alessia , Pistoia Laura , Cuccia Liana , Fortini Monica , Caruso Vincenzo , Rosso Rosamaria , Campisi Saveria , Peluso Angelo , Sorrentino Francesco , Maggio Aurelio , Positano Vincenzo , Peritore Giuseppe , Meloni Antonella
Published: October 2019

Background: No prospective data are available about the efficacy of deferasirox versus deferiprone and desferrioxamine in monotherapy. Our study aimed to prospectively assess the efficacy of deferasirox versus deferiprone and desferrioxamine in monotherapy in a large cohort of thalassemia major (TM) patients by quantitative Magnetic Resonance (MR).

Methods: Among the 2551 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we selected those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans. We identified three groups of patients: 235 treated with DFX, 142 with DFP and 162 with DFO. Iron overload was measured by T2* multiecho technique. Liver T2* values were converted into liver iron concentration (LIC) values. Biventricular function parameters were quantitatively evaluated by cine images.

Results: Excellent/good levels of compliance were similar in the DFX (98.7%) vs DFP (96.3%) and DFO (97.5%) groups.

Among the patients with myocardial iron overload at baseline, in all three groups there was a significant improvement in the global heart T2* value (DFX: +4.58±5.91ms P<0.0001, DFP: 8.53±6.97ms P<0.0001 and DFO: +3.93±5.21 ms P<0.0001) and a reduction in the number of pathological segments (DFX: -4.49±4.55 P<0.0001, DFP: -8.08±5.5.84 ms P=0.001 and DFO: -3.65±3.81 ms P<0.0001). In DFP and in DFO groups there was a significant improvement in left ventricular ejection function (LVEF) (+4.86±6.99% P=0.044 and +3.87±7.48% P=0.004, respectively). Only in the DFP group there was a significant improvement in right ventricular ejection function (RVEF) (6.69±4.61% P=0.001). The improvement in the global heart T2* was significantly lower in the DFX versus the DFP group , but it was not significantly different in the DFX versus the DFO group (Figure 1). The improvement in the LVEF was significantly higher in both DFP and DFO groups than in the DFX group while the improvement in the RVEF was significantly higher in the DFP than in DFX group (Figure 2).

Among the patients with hepatic iron at baseline (LIC≥3mg/g dw) the changes were not significantly different in DFX versus the other groups.

Conclusions: Prospectively in a large clinical setting of TM patients, DFX monotherapy was significantly less effective than DFP in improving myocardial siderosis and biventricular function and it was significantly less effective than DFO in improving the LVEF.

Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures

Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..
Overlapping Onset and Sequential Progression of Vasculopathy in Multiple Organs in Sickle Cell Disease
Authors: Chaturvedi Shruti , Ghafuri Djamila , Kassim Adetola A. , DeBaun Michael
Published: October 2019

Background: Sickle cell disease (SCD) is associated with vasculopathy in multiple vital organs, which ultimately leads to complications such as stroke, proliferative retinopathy, chronic kidney disease and pulmonary hypertension. Existing studies focus on single organ specific vasculopathy without an emphasis on shared mechanisms and simultaneous progression of vasculopathy in multiple organs. We conducted this retrospective cohort study to determine the onset and progression, as well as sequence of involvement of vasculopathy in the central nervous system (CNS), eye, kidney and lungs of adults with SCD.

Methods: Our institutional practice is to perform annual magnetic resonance imaging with magnetic resonance angiography (MRI/MRA, for CNS vasculopathy and silent cerebral infarcts), echocardiography (for tricuspidregurgitant jet velocity > 2.5 m/sec, a surrogate of pulmonary hypertension), retinal examination, and measurement of urinaryalbumin:creatinine ratio, and serum creatinine in all adults with SCD. All patients were followed until death or last clinical encounter. Data were summarized as counts and proportions. Multivariable logistic regression was used to identify associations of number of organs affected with mortality.

Results: We identified 280 adults with SCD followed for a median period of 66 months (interquartile range [IQR] 15.7 to 112 months). Median age was 31.1 (IQR 25.4 to 39.7) years and 49.6% were female. Over half (51.8%) were on hydroxyurea therapy. The prevalence of vasculopathy in different organs was: CNS, 37.8%; retinopathy 26.1%, proteinuria, 20.7% (nephropathy 5.71%); and pulmonary hypertension, 15.36%. There was no evidence of vasculopathy in 103 (36.8%) individuals. Of the remaining 177 (63.2%) adults, vasculopathy was present in one, two, three and all four end organs in100, 55, 18, and 4 individuals respectively. Median age of onset was earliest for CNS vasculopathy [25.42 (IQR 19.31, 38.85)] years followed by retinopathy [28.41 (IQR 23.04, 35.79)] years, proteinuria [31.25 (IQR 25.6, 46.0)] years, and pulmonary hypertension [33.08 (IQR 23.83, 47.17)] years (Figure 1). Mortality rate was 1.69 per 100 patient-years. Patients with vasculopathy affecting 3 or 4 organs had a significantly higher mortality rate than those with 0-2 organs affected by vasculopathy [odds ratio 5.50 (95%CI 4.49-20.35), p=0.007], adjusted for phenotype, age, sex, hydroxyurea therapy, and smoking status.

Conclusion: Vasculopathy in SCD occurs in multiple organs simultaneously, with a predisposition to affectthe CNS first. These data strongly support that multiple vasculopathy is common, and when present in at least three organs, is associated with earlier mortality.

Disclosures

No relevant conflicts of interest to declare.
Allosteric Regulation of V(D)J Recombination By Active Chromatin
Authors: Bettridge John T , Na Chan-Hyun , Pandey Akhilesh , Desiderio Stephen
Published: October 2019

V(D)J recombination, the process by which antigen receptor genes are assembled, is implicated in the pathogenesis of lymphoid malignancies. Rearrangement is initiated by the RAG recombinase, a heterotetrameric complex consisting of two subunits each of RAG-1 and RAG-2, which cleaves participating DNA segments at conserved signal sequences. The susceptibility of gene segments to undergo recombination is positively correlated with active chromatin marks, such as tri-methylation of histone H3 at lysine 4 (H3K4me3). RAG-2 interacts directly with H3K4me3 through a plant homeodomain (PHD), and this interaction is required for efficient V(D)J recombination in vivo. Genetic and biochemical evidence suggest that H3K4me3 stimulates substrate binding and DNA cleavage by RAG through an allosteric mechanism. This predicted that H3K4me3 binding induces conformational changes in RAG-2 that are transmitted to RAG-1. To determine whether the conformation of the RAG complex is altered by H3K4me3, we mapped changes in solvent accessibility of cysteine thiols using pulse-alkylation mass spectrometry. Binding of H3K4me3 to the RAG-2 PHD induces conformational changes in RAG-1 within the DNA-binding domains and in the ZnH2 domain, which comprises part of the scaffold for the catalytic center. Our results demonstrate that engagement of the RAG-2 PHD induces dynamic conformational changes in the RAG-1 catalytic subunit, consistent with a model of allosteric control of RAG by active chromatin.

Disclosures

No relevant conflicts of interest to declare.
Yin Yang 1 (YY1) Acting Primarily As an Oncogene and Rarely As a Tumor Suppressor in Distinct Hematological Malignancies: Prognostic and Therapeutic Implications
Authors: Kaufhold Samantha , Wottrich Stephanie , Garban Hermes , Libra Massimo , Bonavida Benjamin
Published: October 2019

Yin Yang 1 (YY1) is a transcription factor that is ubiquitously expressed in many normal and cancerous tissues. This transcription factor was reported to have contradictory functions, consistent with its name, and it was shown to either activate and/or repress several gene products. The role of YY1 in cancer was initially reported to be overexpressed in a large number of solid cancers, and its overexpression was suggested to be of prognostic significance (Shi et al, Curr Cancer Drug Targets 2015;15:145-57). In addition, YY1 was also shown to be a pivotal factor in both drug and immune resistance, as well as it plays an important role in invasion and metastasis (Bonavida and Baritaki, Critical Reviews in Oncogenesis 2011;16:211-226). The reported protein expression and mRNA expressions derived from Oncomine datasets were examined to assess the functions of YY1 in a large number of hematological malignancies (Bonavida and Kaufhold, Pharmacol Ther 2015;150:149-68). However, YY1 expression was not reported in all cancer types. Our preliminary findings suggested that YY1 may act either as an oncogene or as a tumor suppressor in distinct types of hematological malignancies. In multiple myeloma (MM), YY1 protein overexpression was reported and shown to be complexed with the NF-κB subunit RelA. In addition, computational analysis revealed that increased YY1 transcript levels were observed in MM. These findings suggested that YY1 may act as an oncogene in MM, and the supporting data demonstrated that knockdown of YY1 resulted in cell death of MM cell lines. Further bioinformatic analyses showed that YY1 was overexpressed in AML patient-derived tumor tissues. In contrast to AML, bioinformatics analysis revealed that YY1 mRNA was not upregulated in chronic lymphocytic leukemia (CLL) and no significant differences were observed when compared to normal tissues. Clearly, these findings suggested that YY1 may be acting as an oncogene in AML but as a tumor suppressor in CLL. In B-cell non-Hodgkin lymphoma (NHL), the overexpression of YY1 at both mRNA and protein levels suggests its involvement in the malignant transformation. Overall, these data strongly support the notion of the oncogenic role played by the transcription factor YY1 in the majority of hematological malignancies. Accordingly, we suggest that YY1 may have important implications as a therapeutic target and as a prognostic biomarker in hematological malignancies.

Disclosures

No relevant conflicts of interest to declare.
Early Different Downstream Target of Glucocorticoid Receptor Contributing to Glucocorticoids Sensitivity in Kasumi-1 Cells
Authors: Gu Wenbin , Li Meng , Liang Liang , Zhang Jian , Guo Chongye , Xing Zhikai , Lan Yongqing , Li Sha , Li Yangyang , Gao Ran , Mi Shuangli
Published: October 2019

The t(8;21) chromosome translocation frequently occurs in acute myeloid leukemia (AML), resulting in an in-frame fusion between the DNA-binding domain of AML1 and almost the entire of ETO gene. The fusion AML1-ETO protein is thought to play a critical role in the abnormal proliferation and differentiation of myeloid leukemia cells, such as Kasumi-1 and SKNO-1 cells. Glucocorticoids (GC) can induce apoptosis in these cells at low concentrations, whereas most other myeloid leukemia cell lines are resistant to glucocorticoid-induced apoptosis. To experimentally address possible sensitive mechanisms in leukemia cells with AML1-ETO translocation, we generated aGC-resistant Kasumi-1 cell line by induction of 10-6 M dexamethasone (Dex) for three weeks. The IC50 of Dex to cells is increased from 2.5×10-8 M for original GC-sensitive Kasumi-1 cell line ( K-S cell line) to more than 1×10-5 M for induced GC-resistant Kasumi-1 cell line (K-R cell line). Since GC resistance often results from mutations in the glucocorticoid receptor (GR), all the exons of GR gene were sequenced and no mutation was found in K-R cells. Comparing to those in K-S cells, the GR protein level didn't decrease in K-R cells after 2h, 4h, 8h, 12h and 24h exposure to dexamethasone. Given that the difference of direct GR downstream genes between K-S and K-R cells may play a key role in the GC sensitivity, we systematically analyzed the changes of gene expression induced by Dex versus ethanol vehicle for 8h in K-S and K-R cells by high throughput RNA sequencing. The time point of 8h was selected according to the expression peaks of several foregone GR target genes after Dex induction. There were found 32 genes conversely regulated in K-S and K-R cells, including 14 mRNAs and 18 long non-coding RNAs. Pathway analysis indicated that the upregulated genes in K-S cells might promote the AML1-ETO fusion protein degradation by proteasomes, while the component genes of this pathway were downregulated in K-R cells. Further validation and function studies of these mRNAs and long non-coding RNAs are ongoing. Our data suggested that the downstream targets of GR among GC-sensitive and -resistant Kasumi-1 cells were significant different and they may contribute to the GC sensitivity and resistance by degradation or reservation of AML-ETO fusion protein and the regulation of apoptosis in t(8;21) leukemia cell subtype.

Disclosures

No relevant conflicts of interest to declare.
Expression of DDIT4 Is Correlated with NOTCH1 and High Molecular Risk in Acute Myeloid Leukemias
Authors: Pinto Joseph A , Bravo Leny , Chirinos Luis A. , Vigil Carlos E
Published: October 2019

In a meta-analysis, our team identified previously that DDIT4 expression is related with a worse outcome of several cancer types, including acute myeloid leukemia (AML). DDIT4 gene product is a repressor of mTOR activity and recent findings in the triple negative breast cancer model suggest that mTOR pathway inhibition lead to the enrichment of cancer stem cells, explaining indirectly the relationship between DDIT4 and the outcome and suggesting that a high DDIT4 expression could be related with expression of stem-cells markers, such as NOTCH1.

We evaluated 200 AML patients from the TCGA dataset. Clinical features and level 2 data of gene expression were retrieved from the website cbioportal.org for mTOR pathway and stem cell markers including ALDH genes. Gene Set Enrichment Analysis (GSEA) for biological processes was done comparing patients with high risk vs low risk determined by molecular abnormalities.

GSEA analysis found not differences in the mTOR pathway. DDIT4 is not included in none gene ontology datasets. NOTCH1 and DDIT4 expression was enriched in patients with high molecular risk and statistical differences were found mainly between good and poor prognostic groups (score -0.45 and -0.46, respectively). We next compared the correlation between DDIT4 and NOTCH1 in the entire cohort. The correlation was significant (R2=0.121; P<0.0001). NOTCH1 was over expressed in the M0 FAB subtype while the lowest expression was found in M3, M4, M5 and M7 subtypes.

This work shows the relevance of DDIT4 and NOTCH1 in the biology of AML and his association with most undifferentiated subtypes. Association between DDIT4 with NOTCH1 should be evaluated with the intention of explore therapeutic opportunities.

Disclosures

No relevant conflicts of interest to declare.
The Investigation of Hepatitis Virus Infection in Different Subtypes of B-Cell Non Hodgkin Lymphoma in China: High Infection of Both HBV and HCV in Splenic Marginal Lymphoma
Authors: Xiong Wenjie , Yi Shuhua , Li Heng , Li Zengjun , Lv Rui , Liu Wei , Xu Yan , Zou Dehui , Qiu Lugui
Published: October 2019

Background: The hepatitis virus infection is considered as one of the important pathogens in the pathogenesis of lymphomas. But the divergence of hepatitis infection between aggressive and indolent B cell Non-Hodgkin Lymphoma (B-NHL) has rare been investigated and dates for the subtypes of different lymphomas are limited too.

Methods: 733 new diagnosed indolent B-NHL patients and 148 aggressive B-NHL patients from January 1994 to January 2014 at institute of Hematology&Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College were retrospectively investigated. The data of general population were from large scale of national epidemiological survey in China.

Results: Compared with general population, the HCV positive rate was significantly higher in the whole B-NHL group and the indolent group (1.8% vs 0.4%, 1.9% vs 0.4% respectively, both p=0.000). While it had no significant difference in the aggressive group (1.35% vs 0.4%, p=0.068). The HCV-positive patients was similar in the indolent group and the aggressive one (1.9% vs 1.35%, P=0.639). In different indolent subtypes , the HCV-Ab positive rate of CLL、WM、SMZL、HCL, NMZL group was significantly higher than the general population. The HBs-Ag positive rate in the whole B-NHL group and the aggressive group was 9.0% and 14.2% respectively, which was significantly higher than the general population (9.0% vs 7.2%, p=0.044; 14.2% vs 7.2%, p=0.001). While it had no significantly difference between the indolent group and the general population (7.9% vs 7.2%, p=0.548).However, in the indolent B-NHL subtypes, the SMZL group had the highest HBs-Ag positive rate, which was significantly higher than the general population (18.8% vs 7.2%,p=0.002).

Conclusion: The hepatitis virus infection rate varied from different subtypes of lymphoma. In different indolent B-NHL subtypes, SMZL had the highest HBs-Ag and anti-HCV positive rate, which were significantly higher than the general population and other B-NHL. This result may suggest that the infection of hepatitis virus may play an etiologic role in SMZL.

Disclosures

No relevant conflicts of interest to declare.
A Prospective Study of Thyomosin α1 and Intravenous Immunoglobulin Role to Prevent the Infectious Pneumonia Related to Rituximab Based Immuno-Chemotherapy for B Cell Lymphoma
Authors: Lin Tongyu , Prem Raj Shrestha , Huang He , Li Xueying , Hong Huangming , Zhang Mengping , Fang Xiaojie , Wang Zhao , Guo Chengcheng , Xia Zhongjun
Published: October 2019

Background: Rituximab (Rtx) with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) regimen could improve the survivalship in treatment of B cell lymphoma, however, also increases the possibilities of infectious disease including pulmonary pneumonia.

Methods and materials: A prospective study was conducted in Sun Yat-sen University Cancer Center from Feb 2008 to Oct 2015 to analyze the addition of thyomosin (Th α1) and intravenous immunoglobulin (IVIG) supportive therapy impact in preventive role of pulmonary adverse effect (PAE) incidence rate related to Rtx based immuno-chemotherapy.

Results: Out of 379 cases, 215 in Th α1 and IVIG (study) group and 164 in non Th α1 and IVIG (control) group compared; 80 (21.1%) of them developed PAE: 39 Rtx immuno-chemotherapy induced interstitial pulmonary disease (IPD) and 41 infectious pneumonia (IP) cases were developed after the 4rth median cycles (2.8 months) of R-CHOP regimen from the first exposure until prior to induced PAE and 11 cases of IP were isolated with etiology. In comparing the role of Th α1 and IVIG vs. control group; out of 41 R-CHOP induced pneumonia cases: 9 (2.4%) vs. 32 (8.4%) with p <0.001, respectively found. In multivariate analysis, Th α1 and IVIG (p <0.001) was the independent highly significant factors related to decrease infectious pneumonia prevalence rate. Furthermore chemotherapy disruption rate due to pneumonia was 4.2% vs. 38.5%, in study and control group (p = 0.005), respectively. Incidence of pneumonia was found significantly lower in study group than control group in account of high risk advanced stages (Fisher's Exact Test, p <0.001) and age≥60 (Fisher's Exact Test, p = 0.002) group. 6 years of event free survival (EFS) was found higher in study group 73.2% in compare to control group 52.6% with p<0.001.

Conclusions: The B cell lymphoma patients with high risk factors along with the risk of developing infectious pneumonia may be substantially decreased by the regular implication of Th α1 and IVIG along the Rtx based chemotherapy that may result effective in improving EFS too.

Disclosures

No relevant conflicts of interest to declare.
Can Body Mass Index Predict the Outcome of Diffuse Large B-Cell Lymphoma? - a Single-Center Retrospective Study in China
Authors: Li Tong , Liu Zhuo-Gang , Liang Pei-Qi , Wang Hong-Tao
Published: October 2019

Body mass index (BMI), as a rough indicator of obesity, has been increasing over the years, along with a high incidence of cardiovascular disease and many malignancies, including diffuse large B-cell lymphoma (DLBCL). However, the predictive prognostic value of BMI at diagnosis for the outcome of DLBCL is controversial. So far, the reported study population has rarely been Chinese. We aimed to assess whether BMI can predict the outcome of Chinese DLBCL patients.

We carried out a single-center retrospective study to assess the predictive value of BMI in the outcome of Chinese patients with DLBCL. Among a total of 207 patients who were newly diagnosed with DLBCL in our center between January 2008 and May 2015, 143 eligible patients were enrolled. These patients were stratified into two groups, 74 patients in the low BMI group (BMI<23.0kg/m2)and 69 patients in the high BMI group (BMI≥23.0kg/m2). We compared the baseline characteristics in the low and high BMI groups, and complete remission (CR), partial remission (PR) and progressive disease (PD) as primary response criteria in the two groups. Univariate and multivariate analyses were used to evaluate whether low or high BMI had an impact on progression-free survival (PFS) and overall survival (OS).

Well-known influence factors including age, Ca125, B2-microglobulin, international prognostic index, B symptoms, Ann Arbor stage and the use of rituximab were similar between the two groups, while gender was not (P<0.023) but did not act as a risk factor. Besides, drug dose did not vary by BMI. No association between BMI and primary response was observed. Patients in the higher BMI group were inclined to have better OS (p=0.008), but we did not find an association between BMI and PFS (p=0.069).

Higher BMI at diagnosis may predict a longer OS, especially for female patients but may not affect the outcome of primary response and PFS. Multi-center and prospective studies are warranted to see if this holds true for the general Chinese DLBCL population, and mechanistic investigations may lead to new treatment options.

Disclosures

No relevant conflicts of interest to declare.