bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of Second Malignancies after Non Hodgkin Lymphoma: A Cohort Study of 22,466 Survivors in Israel
Authors: Tadmor Tamar , Barbara Silverman , Liphshiz Irena , Polliack Aaron 
Published: October 2019

Abstract
Previous studies have shown an increase risk of second malignancies after non-Hodgkin's lymphoma (NHL). This is probably related to genetic predisposition, molecular and pathologic background, immunological status and type of therapy given for the lymphoma.
We evaluated the risk of second solid tumor and hematological malignancy among 24,666 survivors of NHL diagnosed in Israel during 1980-2011. Data was taken from the records of the Israeli National Cancer Registry (INCR), as all public and private medical facilities, and pathology laboratories engaged in diagnosing cancer patients in Israel, are obliged to send a copy of the medical summary, demographic data and details of diagnosis, to the registry. The INCR records all the available information on these cases, including the date of diagnosis and tumor location.
The cohort of 24,666 NHL-patients included Jews (22,601 cases) and Arabs (2065 cases). Median age at diagnosis of Jews was 61.3 years, and 48.2 for Arab patients. Of all Jews with NHL: 11,265 (50%) were of European-American descent, 5005 (22%) Asian African and 6114 (27%) were born in Israel. In both Jewish and Arabs sub-groups, there were more males (52%, 56% respectively). Second cancers were reported in 2010 patients; 1918 Jews (95.5 %), and 92 Arabs (4.5 %). Evaluation of the results was restricted to the cohort of Jews only, due to the small number of Arab patients.
Second malignancies in all recorded sites were significantly more common in males with standardized incidence ratio (SIR) of 1.28, and 1.25 for females. This was even more pronounced for secondary hematological malignancies, with SIR of 1.97 and 1.81 respectively, in a total of 283 cases. (Table)
Of the secondary hematological malignancies; the most frequent were leukemias (31%) and NHL (29%), followed by multiple myeloma (14%), Hodgkin lymphoma and mycosis fungoides (both 8%).
In conclusion; there is an increased risk of second malignancies after NHL in Israel, particularly leukemia and non- Hodgkin lymphoma. These clearly occur more frequently in Jews, suggesting that ethnicity and genetic susceptibility may be important risk factors. TableSecond cancer after NHL in Jews ( 1980 – 2011)All sitesObservedExpectedSIR 95% CImale1056822.181.281.211.36female862689.861.251.171.33HematologyObservedExpectedSIR 95% CImale16483.401.971.672.27female11965.611.811.492.14

Disclosures
No relevant conflicts of interest to declare.
The Expression of CD44v6 Predicts Poor Outcome in Patients with Diffuse Large B Cell Lymphoma Treated with R-CHOP
Authors: Wei Yongqiang , Xie Muchen , Huang Fen , Wei Xiaolei , Jing Hui , Hao Xiaoxiao , Zeng Hong , Zhou Qinjun , Xu Linwei , Feng Ru 
Published: October 2019

Abstract
Background:
CD44 variants have been implicated in metastasis and as an unfavorable prognosis factor in many types of cancers. Our previous study had showed that CD44v6 expression implied a poor clinical outcome in diffuse large B cell lymphoma (DLBCL) patients treated with CHOP. However, it is remains unknown the prognostic value in DLBCL patients treated with R-CHOP due to our sample sizes. Therefore, to examine the prognostic value of CD44v6 expression in DLBCL patients, we performed this retrospective study.
Methods: All 141 patients diagnosed as de novo DLBCL according to WHO classification were further confirmed. All patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The expression of CD44v6 was analyzed by immunohistochemistry (IHC). IHC was performed by an automated immunostainer complying with the instructions of the protocols.
Results: Among all the 141 patients, the expression of CD44v6 was observed in 41 cases (29.1%). CD44v6 is expressed predominantly in non-germinal center type DLBCL. There was no significant difference in gender, age, B symptoms, performance status, LDH, stage and IPI score between patients with and without CD44v6 expression. Patients with CD44v6 expression showed significant inferior overall survival, but not event-free survival compared with CD44v6-negative patients. (p=0.022 and p=0.142, respectively).Multivariate analysis showed that the expression of CD44v6, independent of the international prognostic index and cell of origin, implied a poor overall survival (HR=2.223; 95% CI= 1.007-4.906, p=0.048), but not event-free survival (HR=1.457; 95% CI=0.773-2.745, p=0.245).
Conclusions: These data suggest that the expression of CD44v6 implied poor outcome in DLBCL patients treated with R-CHOP.

Disclosures
No relevant conflicts of interest to declare.
The Hybrid Regimen of ABVD/BEACOPP May Overcome the High-Risk Features of the Advanced Stage Hodgkin Lymphoma
Authors: Alaskar Ahmed , Al Ameer Ahmad , Ahmed Gasmelseed , Alhejazi Ayman , Abuelgasim Khadega , Gmati Giamal , Rather Mushtaq , Al Zahrani Mohsen 
Published: October 2019

Abstract
Background: Hodgkin Lymphoma (HL) has improved markedly overtime. This study aims to assess our experience in treating advanced HL.
Method: In a retrospective cohort study, patients age >14 with advanced HL from 2007-2010 were included. Using IPI, patients were categorized into low and high risk. ABVD and Hybrid ABVD+BEACOPP regimens were used.
Result: 74 patients were included with the median age at diagnosis of 25.5 years. 50% presented with stage IV. Two different protocols were used (ABVD and Hybrid ABVD + BEACOPP). Median follow up was 30.3 months. Male gender and stage V were most often to receive hybrid regimen (odd ratio 3.74 and 6.58 respectively). When the two groups were compared, the higher risk group (mostly treated with hybrid regimen) showed similar survival rates to the lower risk group (treated mostly with ABVD) with p-values of 0.41 for OS and 0.42 for PFS.
Conclusion: This study shows quite similar results to the published studies in the OS and PFS with a tendency to overcome the high-risk features by the hybrid regimen in advanced HL. However, this needs to be confirmed in a prospective randomized study.

Disclosures
No relevant conflicts of interest to declare.
Haploidentical Hematopoietic Stem Cell Transplantation for Acquired Severe Aplastic Anemia
Authors: Miao Miao , Zhang Xiang , Xu Ting , Jin Song , Wang Hong , Yang Xiaofei , Pan Zhijuan , He Jun , Sun Aining , Depei Wu 
Published: October 2019

Abstract
Objective: To evaluate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in patients with acquired severe aplastic anemia (SAA), who lacked suitable related or unrelated HLA-matched donors.
Methods: 39 SAA patients underwent haplo-HSCT from Jul 2012 to Jun 2015 at our center. There were 23 males and 16 females at a median follow-up of 11 (range, from 0 to 36) months. The median time from diagnosis to transplantation was 1 (range, from 0.5 to 52) months. The median ages of SAA patients and related haploidentical donor were 23 years (range, 9 to 51years) and 45 (range, from 21 to 61) years, respectively. All patients were given BuCy plus ATG conditioning regimen. GVHD prophylaxis regimen consisted of cyclosporine A (CsA), mycophenolate motetil (MMF), and short-term methotrexate.
Results: Stem cells were collected from bone marrow in 23.08% (n=9) of patients, peripheral blood in 2.56% (n=1), bone marrow plus peripheral blood in 74.36% (n=29) patients. 36 patients received haplo-HSCT combined with the third part of cord blood transfusion 92.31%. The median stem cell dose transplanted was 9.76 (range, from 4.02 to 20.10)×108/kg for mononuclear cells, while 3.4 (range, from 1.05 to 8.60)×108/kg for CD34 cells. 36 patients achieved neutrophil engraftment at a median of 12 (range, from 9 to 28) , and 29 patients achieved platelet engraftment at a median of 29 (range, from 10 to 26) days. Cumulative incidence of III°~IV° acute graft versus host disease (aGVHD) was 8.9±4.9%. 6 patients died of transplant-related mortality (TRM), including 4 from severe infection, and 1 from TMA. The overal survival rate of all patients was 83.2%±6.4%
Conclusions: Haplo-HSCT is likely to be an option for SAA patients without suitable related or unrelated HLA-matched donors, in consideration of the acceptable TRM and severe GVHD incidences.

Disclosures
No relevant conflicts of interest to declare.
The RIG-I Agonist 3pRNA Synergizes with Checkpoint Blockade in Cancer Immunotherapy
Authors: Heidegger Simon , Kreppel Diana , Bscheider Michael , Wintges Alexander , Bek Sarah , Schmickl Martina , Ruland Jürgen , Peschel Christian , van den Brink Marcel , Haas Tobias , Poeck Hendrik 
Published: October 2019

Abstract
Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 has been shown to enhance anti-tumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches. Here we established a vaccination protocol that combines selective engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4-blockade. We found that vaccination together with RIG-I ligation strongly synergized with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8+ T cells and potent anti-tumor immunity. Cross-priming of cytotoxic T cells as well as anti-tumor immunity required the adapter protein MAVS and type I interferon (IFN) signaling and were mediated by dendritic cells. In addition, the benefit of the combined immunization with anti-CTLA-4 was reduced by systemic antibiotics pointing to the requisite of an intact commensal microbiota in this context. Together, our findings describe a novel combinatorial strategy that may form the basis for the design of new type I IFN-based regimens that enhance antigen-specific T cell reactivity against cancer.

Disclosures
No relevant conflicts of interest to declare.
Thrombomodulin Gene Mutations Associated with Thromboembolic Diseases
Authors: Wang Qingyun , Tang Liang , Hu Bei , Hu Yu , Liu Han 
Published: October 2019

Abstract
Background
Thrombomodulin (TM), encoded by the THBD gene, is an endothelial transmembrane glycoprotein that acts as a cofactor for thrombin in the activation of protein C (PC). It has been clearly demonstrated that the anticoagulant and profibrinolytic functions of the thrombin-TM-PC system play critical roles in the prevention of thromboembolic diseases.
Methods and Results
Using direct sequencing, six novel mutations were identified in THBD gene of eight patients with either arterial or venous thrombosis: c.376G>T (p.Asp126Tyr), c.569C>G (p.Ser190Trp), c.659T>G (p.Leu220X), c.1208G>A (p.Arg403Lys), c.1288G>A (p.Gly430Ser), c.*6_*23del and c.*23_*40del. Of the mutations, c.376G>T and c.*6_*23del were detected in a 10-year old child with venous thrombosis (VTE), who died one year later. The c.376G>T point mutation predicting p.Asp126Tyr in thrombomodulin protein was also detected in a 38-year old VTE patient. The nonsense mutation c.659T>G recurred in a 55-year old patient with coronary artery disease (CAD) and a 46-year old VTE patient, who died from repeated venous thrombosis two years later. The wild type and the mutant thrombomodulin were expressed in HEK-293t cells. Two mutations were found to have reduced TM protein expression compared to wild-type (100%), Ser190Trp (69.1% ±5%, P < .05), p.Leu220X (19.1% ± 7.6%, P < .001). Comparing to wild type, four point mutations diminished the cofactor activity of TM according to the reduced level of activation of PC in cultured cells. As for the two 18-bp deletions, a psiCHECKTM-2 vector containing wild type and mutant 3'UTR of TM was constructed. Compared with the wild-type, the deletions significantly reduced the reporter gene-expression level. The antigen level and activity in cultured cells with c.376G>T have no significant difference with the wild type, indicating that the mutant may cause a thrombophilic state through other unknown pathological mechanisms.
Conclusion
The results suggest that gene mutation of thrombomodulin may be important in the pathogenesis of thrombotic diseases. Further study on genetics of thrombosis should focus on resequencing of THBD gene in different populations.

Disclosures
No relevant conflicts of interest to declare.
Thyroid Hormone Receptor Beta and NCOA4 Regulate Terminal Erythrocyte Differentiation
Authors: Lee Hsiang-Ying , Lodish Harvey F. , Gao Xiaofei , Li Wenbo , Platt Randy , Barrasa Inmaculada , Elmes Russell , Rosenfeld Michael G. 
Published: October 2019

Abstract
An effect of thyroid hormone on erythropoiesis has been known for more than a century but the molecular mechanism(s) by which thyroid hormone affects red cell formation are still elusive. Our study demonstrates an essential role of thyroid hormone during terminal human erythroid cell differentiation; specific depletion of thyroid hormone from the culture medium completely blocked human erythroid differentiation. Genome wide analysis showed that thyroid hormone receptor β (TRβ) occupies many gene loci encoding transcripts abundant during terminal erythropoiesis, including globin genes, and cooperates with GATA-1 and RNA polymerase II (Pol II) to regulate their expression. Treatment with TRβ agonists enhanced erythroblast differentiation in vivo and alleviated anemic symptoms in a chronic anemia mouse model. To identify factors that cooperate with TRβ during human erythroid terminal differentiation, we conducted RNA-Seq in human reticulocytes and identified NCOA4 as a critical regulator of terminal differentiation. Furthermore, Ncoa4-/- mice are anemic in both the embryonic and perinatal periods and fail to respond to thyroid hormone by enhanced erythropoiesis. Genome wide analysis suggests that thyroid hormone promotes NCOA4 recruitment to chromatin regions that are in proximity to Pol II and are highly associated with transcripts abundant during terminal differentiation. Collectively, our results reveal the molecular mechanism of thyroid hormone function on red blood cell formation and are potentially useful to treat certain anemias.

Disclosures
No relevant conflicts of interest to declare.
A Novel Isoflavone, ME-344, Targets the Cytoskeleton in Acute Myeloid Leukemia
Authors: Jeyaraju Danny V , Hurren Rose , Wang Xiaoming , MacLean Neil , Gronda Marcela , Jordan Craig T , Minden Mark D. , Giaever Guri , Schimmer Aaron D. 
Published: October 2019

Abstract
The isoflavone ME-344 is a potent anti-cancer agent with preclinical efficacy in solid tumors in vitro and in vivo. In a recently completed phase I clinical trial in patients with refractory solid tumors, ME-344 was well tolerated and clinical responses in refractory patients were observed. ME-344 has been shown to reduce mitochondrial ATP generation in a tumor selective manner, though other potential activities have not been fully defined. In addition, the preclinical efficacy of ME-344 in leukemia has not been established. Therefore, we investigated the anti-leukemic properties and the mechanism of action of ME-344.
We treated a panel of 7 leukemia cell lines with increasing concentrations of ME-344, and measured cell growth and viability. ME-344 was cytotoxic to the 7 leukemia cell lines with an IC50 in the range of 70-260 nM. In addition, ME-344 induced preferential death in primary AML patient samples over normal hematopoietic cells. In an OCI-AML2 xenograft model, ME-344 reduced tumor growth by up to 95% of control without evidence of toxicity.
Mechanistically, as reported in studies in solid tumors, ME-344 increased mitochondrial ROS generation in leukemic cells. However, antioxidant treatment did not rescue cell death, suggesting that ME-344 has additional targets beyond the mitochondria. To identify additional targets of ME-344, we conducted haplo-insufficiency profiling in S.cerevisiae to identify genes whose heterozygous deletion confers increased sensitivity to ME-344. The top hits from the screen were genes involved in cytoskeletal organization. Therefore, we tested the effects of ME-344 on actin and tubulin polymerization in cell free assays. While ME-344 did not inhibit actin polymerization, it inhibited tubulin polymerization by interacting near the colchicine-binding site and at a site distinct from vinca alkaloids. Furthermore, cells resistant to tubulin inhibitors due to tubulin point mutations were also resistant to ME-344. Finally, we showed that ME-344 synergizes with vinblastine in leukemia cells. Thus, our study demonstrates that ME-344 displays preclinical efficacy in leukemia through a mechanism at least partly related to targeting tubulin polymerization.

Disclosures
No relevant conflicts of interest to declare.
SNPs in IL-10, TNF-Alfa, and NFkB1 Genes and Their Association with Prognostic Parameters in Patients with Hodgkin Lymphoma
Authors: Gaiolla Rafael Dezen , Moraes Marcelo Padovani de Toledo , de Oliveira Deilson Elgui 
Published: October 2019

Abstract
Hodgkin lymphoma (cHL) is a malignant lymphoid neoplasia that shows aberrant expression of cytokines, including IL-10 and TNF-a. Single nucleotide polymorphisms (SNPs) in genes encoding IL-10 and TNF-a or their regulatory proteins, such as NFkB, may impact cHL pathobiology. In this study, SNPs in the promoter regions of genes encoding for IL-10 (SNP/pIL-10 -592, rs1800872; and SNP/pIL-10 -1082, rs1800896), and TNF-a (SNP/pTNF-a -238, rs361525; and SNP/pTNF-a -862, rs1800630), as well as in the intronic region of the NFkB1 gene (SNP/iNFkB1, rs1585215) were genotyped in 73 patients with cHL and evaluated against clinical and laboratory prognostic parameters for the disease. SNPs/pIL-10 AA were significantly associated with higher leukocyte and lower lymphocyte counts at diagnosis. In case of TNF-a, SNP/pTNF-a -238 AG was associated with EBV infection while SNP/pTNF-a -862 CC presented more frequently with leukocytosis. SNP/iNFkB1 AA generally had stage IV and extranodal disease at diagnosis. Nonetheless, none of the studied SNPs had effect on treatment outcome. This study shows that some SNPs genotypes for IL-10 and TNF-a genes are associated with prognostic parameters in cHL; furthermore, this is the first time that the SNP/iNFkB1 (rs1585215) was implicated in clinical features of the disease.

Disclosures
No relevant conflicts of interest to declare.
ID3 Loss In Vivo Synergizes with MYC-Driven Oncogenesis in Burkitt Lymphoma
Authors: Love Cassandra , Remple Rachel , Li Guojie , Dave Sandeep 
Published: October 2019

Abstract
Burkitt lymphoma (BL) is an aggressive cancer, characterized by the deregulation of the c-myc (MYC) gene. BL is a major model disease for molecular studies in many other malignancies. Treatment of BL requires long courses of intensive chemotherapy which extracts a disproportionate toll on patients.
Previous studies using next generation sequencing have identified ID3 as a tumor suppressor gene, with silencing mutations in about 40% of BLs. However, relatively little is known regarding the biological role of ID3 in BLs.
In this study, we sought to elucidate the molecular mechanisms that are affected by ID3 loss in BL. We utilized two complementary strategies. First, we developed an in vivo approach through conditional knockout of Id3 in mice. Second, we utilized a CRISPR-based approach to genetically knockout ID3, to study the effects of ID3 loss in BL cell lines.
We have successfully knocked out exon 1, including the functional helix-loop-helix (HLH) domain of ID3 in 4 BL cell lines (Namalwa, Ramos, BJAB, and Jijoye) that do not harbor mutations in ID3. Deletion of exon 1 causes complete deletion at the protein level. Transcriptome sequencing from ID3 mutated BL cases identified increase in the expression of MYC target genes, as well as proliferation-related genes. Cell cycle analyses revealed faster cell cycle progression in the ID3 knockdown cells (P=0.02).
To study ID3 loss in vivo, we crossed Em-Myc+ mice with a standard Id3 knockout strain mice. We found that E m -Myc+;Id3-/+ mice demonstrated reduced latency to tumor development compared to Eµ-Myc+;Id3+/+ littermates (P<0.01). This decreased tumor latency noted in the E m -Myc+;Id3-/+ mice suggests a strong in vivo synergy between the oncogenic effects of MYC overexpression and ID3 loss. Many of these tumors displayed the classic "starry sky" pattern that is classic for human Burkitt lymphomas. We are continuing to use the AID -Cre positive strains to generate combined Id3 deletion and Myc over-expression specifically in germinal center B cell context. Additional characterization of the mouse tumors using mouse whole exome sequencing and transcriptome sequencing is in progress and will be presented in the meeting.
Our data reveal that ID3 greatly potentiates the oncogenic role of the MYC gene and understanding the role of ID3 enables new insights into the pathogenesis of BL, and potentially other MYC-driven malignancies.

Disclosures
No relevant conflicts of interest to declare.
Distrust and Conflict in Sickle Cell Disease: Intersecting Narratives of Patients and Physicians
Authors: Tsyvkin Elina , Riessman Catherine , Mathew Paul 
Published: October 2019

Abstract
A gap in trust between patients with sickle cell disease (SCD) and medical providers is well recognized, largely originating from repetitive requests for opioid analgesics. Although expert clinical care guidelines in sickle cell disease are available, they rarely address measures by which this endemic gap in trust may be narrowed to fulfill the goals of medicine. We hypothesized that an increased familiarity with the patient as an individual through exposure of physicians to first-person narratives of the life-world of SCD may allow reformulation of perceptions and narrow the gap between physicians and patients. In a pilot study, extended first-person narratives of the illness experience elicited from patients with SCD with a history of recurrent hospitalizations (n=10) point to the individualized impact of pain, illness and stigmatizing disruptions in life-building efforts imposed by SCD together with the recurrent conflicts with medical caregivers, particularly after transition from pediatric to adult medicine. Patient-elicited narrative fragments such as "You are constantly fighting with people who are supposed to be making us feel better", "You don't know me, I am a church boy!" and "Put down your microscopes and talk to us" reveal the yearning by patients for individual integrity to be acknowledged, absorbed and interpreted by physicians. Additional narrative fragments such as "I hate myself. I hate my life", "Why am I broken?", "you don't want to be the girl with jaundice", "I had to leave work for 2 months because I was hospitalized, it killed me, it killed me", "you never know when it's going to be the last day, the last moment", exhibit the woundedness and fragility of existence experienced by patients. Narratives elicited separately from physicians caring for SCD (n=5) reveal anxiety, fear and distrust of the reported pain experience and opioid requests, and point toward deeper schisms that disparities may define: "I was very scared when I took care of my first sickle cell patient", "I came in with a bias already", "a similar frequent flier who had the same kind of behavior", "you have to be careful with empathy, people can take advantage of it", "I am not an enabler", "My grandfather told me about these people". Yet when the same physicians were invited to read and reflect on transcripts of the life-world stories of patients, reshaped perceptions of the stigmatized patient are revealed; "without knowing the story, you can't put it all together", "this would change the way I view treating them", "I will have more patience now" as examples. However, "Why can't they listen to our story? It could help them to be better patients," suggests that additional studies of the mutual intersections of patient and physician narratives are warranted and that these can offer insights and pathways toward mitigating distrust and conflict between medical care providers and patients with SCD.

Disclosures
No relevant conflicts of interest to declare.