bluuebunny/crossref_metadata_2025_split huggingface dataset:
Follicular Non-Hodgkin Lymphoma Grade 3a and 3b Subtypes Exhibit Similar Clinical Behaviour and Treatment Outcome
Authors: Shustik Jesse , Quinn Michael , Connors Joseph M , Gascoyne Randy D , Skinnider Brian , Sehn Laurie H 
Published: October 2019

Abstract
The clinical usefulness of separating follicular lymphoma (FL) grade 3 into FL grade 3A (FL3a) and 3B (FL3b) subtypes remains controversial. The relative aggressiveness of these two subtypes and their potential curability with anthracycline-based therapy continues to be debated. Discrepancies in the literature may be related to the relatively small number of patients in most series and to the variable inclusion of patients with a diffuse histologic component on biopsy, likely representing early transformation. We present a retrospective review of clinical characteristics and outcome in a large cohort of patients with FL3a and FL3b, as strictly defined by WHO diagnostic criteria.
Patients Patients diagnosed with FL grade 3 in the province of British Columbia (BC) between the years 1982 and 2008 were identified through the BC Cancer Agency Lymphoid Cancer Database. A total of 161 patients with pathology available for central review were included for analysis, and were categorized as FL3a (n=139) or FL3b (n=22) using current WHO criteria. Cases containing a diffuse component on biopsy were excluded.
Results Median age of the entire cohort was 63 years (range, 18–88). There were no significant differences in age, sex, stage, serum LDH levels, or number of extranodal sites between the subgroups. However, there was a trend toward worse performance status in patients with FL3b compared with FL3a (PS 2–4 27% vs. 12%, respectively; p=0.054). Overall, more patients in the FL3b subgroup had a high-intermediate or high-risk IPI score compared with patients in the FL3a subgroup (36% vs. 17%, p=0.028). A significantly higher number of patients with FL3b received an anthracycline-based regimen as front-line therapy (82% vs. 36%, p <0.001) and approximately one third of the entire cohort received rituximab. With a median follow-up of 38 months (range, 1–224), no difference in overall survival (OS) (p=0.79) or disease-specific survival (DSS) (p=0.38) was observed between FL3a and FL3b patients (see Figure below) (5-year OS, 72% vs. 70% and 5-year DSS, 77% vs. 70%, respectively). Analysis limited to the FL3a subgroup showed no OS advantage for patients who received an anthracycline-containing regimen as initial therapy compared with those who did not (p=0.24).
Conclusions Overall no significant differences in clinical outcome were noted between patients with FL3a and FL3b. No plateau in the survival curves was seen, suggesting that neither subtype is curable even with the use of anthracycline-based therapy. This large retrospective analysis, which expands on an earlier cohort from the province of British Columbia, calls into question the clinical relevance of this histological grading designation.
Figure Figure
High-Throughput Sequencing for Diagnosis, Prognosis and Monitoring of Lymphoid Malignancies
Authors: Boyd Scott D , Merker Jason D. , Zehnder James L. , Fire Andrew Z 
Published: October 2019

Abstract
New high-throughput DNA sequencing methods have many advantages for the analysis of rearranged immunoglobulin (Ig) and T cell receptor (TCR) loci in suspected lymphoid malignancies. Instead of primarily analyzing the size distribution of rearranged immune receptors using gel or capillary electrophoresis, sequencing complex nucleic acid pools provides much more complete characterization of the receptor sequences present. Currently, separate assays are used to evaluate Ig and TCR clonality, Ig hypermutation status, and to test for residual malignant cells after treatment. We used multiplexed PCR amplification of immunoglobulin heavy chain loci for high-throughput pyrosequencing with the Roche 454 platform to evaluate the detection of clonal IgH sequences, determination of hypermutation status, and sensitivity of detection of low levels of a known clonal receptor. Our method also evaluated the feasibility of physical “bar-coding” of DNA molecules derived from different samples to enable cost-effective sequencing of sample pools. 23 pooled specimens were sequenced including: known lymphoma specimens (4); peripheral blood leukocytes from normal individuals (4); specimens with indeterminate or discordant results by conventional clonality assays (7); and a dilution series of a clonal CLL/SLL specimen into normal peripheral blood leukocytes. Our initial experiment characterized 522,099 IgH sequences from these specimens, with a mean read length of 242 base pairs. We have employed IgBlast (NCBI) for initial alignment of rearranged IgH sequences to germline V, D and J gene segments. Our data demonstrate that clonal IgH populations can be readily detected and characterized as to their germline or hypermutated status and unique V-D and D-J junctions with this approach. In our dilution series experiment, the clonal receptor sequence could be reliably observed after 1000-fold dilution. Normal patient specimens show expected extensive sequence diversity, and we are exploring methods for optimally summarizing and representing these data. Some PCR artifacts, as well as non-immunoglobulin sequences commonly amplified by current IgH primer sets were also detected, and suggest avenues for further improvement of the methods used for detection and characterization of clonal immune receptors. More broadly, these methods also offer a novel approach to monitoring normal immune responses such as the response of patients to vaccination, and of characterizing the immune system in patients with autoimmune diseases.
LEF1 Is a Tumor Suppressor in T Cell Acute Lymphoblastic Leukemia
Authors: Gutierrez Alejandro , Sanda Takaomi , Winter Stuart , Larson Richard S. , Silverman Lewis B. , Hunger Stephen P. , Sallan Stephen E. , Look A. Thomas 
Published: October 2019

Abstract
In an effort to further unravel the molecular pathogenesis of T cell acute lymphoblastic leukemia (T-ALL), we performed array CGH on diagnostic specimens from 47 pediatric patients with T-ALL. The LEF1 transcription factor is best known as a positive mediator of oncogenic β-catenin signaling, and it is required for the expression of MYC, Cyclin D1 and Survivin in some contexts, including some normal hematopoietic progenitors. Additionally, Lef1 has been shown to be required for the survival of murine Notch-dependent T cell lymphoma cells. We were thus surprised to find highly focal deletions of LEF1 in 10.6 % (n = 5 of 47) of primary T-ALL patient samples, with 3 cases harboring homozygous deletions and 2 harboring heterozygous deletions of this locus. These deletions involved no other known genes. We then sequenced this gene in 45 of these cases and found heterozygous mutations in 3 additional T-ALL samples, including 2 cases with frameshift mutations predicted to truncate the protein prior to its context-dependent activation and HMG box domains, and one case with an Asp85Asn substitution. Seven of the eight samples harboring LEF1 abnormalities also had mutations in the heterodimerization or PEST domains of NOTCH1. In an effort to characterize the biologic consequences of LEF1 loss in T-ALL, we took advantage of expression microarrays that were previously performed on most of these samples. LEF1 loss defines a novel T-ALL subtype characterized by arrest at the CD1-positive early cortical stage, and whose gene expression profile resembles that of HOX11-positive cases, although expression of HOX11 was generally low in these samples. Loss of LEF1 was mutually exclusive to overexpression of TAL1 and of the HOXA/MEIS1 cluster. Interestingly, LEF1-negative T-ALL cases were associated with increased expression of MYC, and gene set enrichment analysis identified a significant association between LEF1 loss and upregulation of MYC target genes. In addition to its role as a transcriptional activator in the setting of active WNT/β-catenin signaling, LEF1 can also act as a transcriptional repressor in some cellular contexts. Experiments are currently underway to establish the mechanism mediating the tumor suppressor activity of LEF1 in T-ALL.
Incidence of Cancer-Associated Venous Thromboembolism (VTE): A Population-Based Cohort Study
Authors: Ashrani Aneel A. , Heit John A. , Crusan Daniel J. , Petterson Tanya M. , Bailey Kent R. , Melton L. Joseph 
Published: October 2019

Abstract
Background: Active cancer without or with chemotherapy is associated with a 4- to 6.5-fold increased risk for VTE 1. However, cancer-associated VTE incidence may be under- or overestimated by reports that linked cancer registry data to an anticoagulation clinic database or to hospital discharge diagnosis codes 2–5.
Objective: To estimate the incidence of VTE in active cancer in a well-defined geographic population that includes the full spectrum of VTE events (including rapidly fatal events) occurring in the community.
Methods: Using the longitudinal resources of the Rochester Epidemiology Project and Mayo Clinic Tumor Registry, we identified all Olmsted County, MN residents with incident VTE by review of their complete medical records in the community 6, and all residents with active cancer (by cancer site), over the 28-year period, 1973–2000. Using residents with active cancer within the three months prior or subsequent to incident VTE as the numerator, and all residents with active cancer as the denominator, we estimated the incidence of VTE in active cancer, both overall and for the subsets of pancreatic cancer, brain cancer and lymphoma.
Results: Over 78,236 active-cancer person-years, 595 Olmsted County residents developed incident VTE. The overall active cancer-associated VTE incidence was 760 per 100,000 person-years (95% CI: 701, 824), about 6.5-fold higher than the general population 7. Over 473, 983 and 4,258 pancreatic cancer, brain cancer and lymphoma person-years, respectively, 51, 18 and 46 residents developed incident VTE. The pancreatic cancer-, brain cancer- and lymphoma-associated VTE incidence rates were 10,784 (95% CI: 8029, 14,179), 1,831 (95% CI: 1085, 2,893) and 1,080 (95% CI: 791, 1,441) per 100,000, respectively. Overall, cancer-associated VTE incidence increased with age, and for all ages, men had a higher VTE rate than women. We observed a much higher pancreatic cancer-associated VTE incidence than previously reported.
Conclusions: The incidence of VTE in individuals with active cancer (especially pancreatic cancer) is higher than the general population. The incidence of VTE in patients with pancreatic cancer is higher than previously estimated.
Assessment of Clinical Risk Factors for Symptomatic Venous Thromboembolism in Common Cancers: A VERITY Registry Study
Authors: Paneesha Shankaranarayana , McManus Aidan , Arya Roopen , Scriven Nicholas , Nokes Tim , Farren Timothy , Bacon Sue , Nieland Anthea , O’Shaughnessy Denise , Rose Peter 
Published: October 2019

Abstract
The association between venous thromboembolism (VTE) and cancer is well-recognised, but the thrombosis risk factor profile of patients with cancer-associated VTE is poorly characterised; it is unclear if additional risk factors contribute to the risk of thrombosis beyond the cancer itself, or if the risk factor profile is tumour-specific. Our aim was to compare the thrombosis risk factor profiles of cancer patients with or without symptomatic VTE enrolled in VERITY, an ongoing UK prospective VTE registry. The VERITY registry records data on patients with VTE and those in whom the diagnosis of VTE is excluded. Between Jun 05 and Mar 08, 49044 patient entries were made. Individual case data for patients with cancer were extracted. Using available risk factor data, univariate analysis of 9 established risk factors for VTE (medical in-patient history/immobilisation >3 days within last 4 weeks; major surgery in the last 4 weeks; hormonal risk factor; previous history of VTE; family history of VTE; known thrombophilia; intravenous drug abuse; current smoking; and leg paralysis), comparing VTE and non-VTE cancer cases, was performed for the 4 most common cancers using SPSS. To account for the potential impact of age and sex on VTE risk, age-adjusted values were calculated for breast and prostate cancer, and age- and sex-adjusted values for colorectal and lung. A nominal level of 5% statistical significance was assumed. Of 2825 cancer cases, 1382 had an objectively confirmed diagnosis of VTE and in 1443 the diagnosis of VTE was excluded. Breast (n=498), prostate (n=374), colorectal (n=343) and lung cancer (n=275) accounted for 53% of cancer cases. Univariate associations between risk factors and symptomatic VTE were found only for prostate cancer: history of VTE (odds ratio [OR] = 3.48; 95% CI, 2.01, 6.02; p < 0.00001), family history of VTE (OR = 2.56; 95% CI, 1.02, 6.44; p = 0.046), hormonal risk factor (OR = 2.22; 95% CI, 1.00, 4.92; p = 0.049). In colorectal cancer, smoking was less likely in VTE cases (OR = 0.54; 95% CI, 0.34, 0.87; p = 0.012). Adjusting for age (and sex), univariate associations between risk factors and symptomatic VTE were again found only for prostate cancer: history of VTE (OR = 3.23; 95% CI, 1.56, 6.68; p = 0.002), with smoking less likely in age-adjusted VTE cases (OR = 0.50; 95% CI, 0.28, 0.91; p = 0.022). Our analysis of a registry population found few associations between known thrombosis risk factors and symptomatic VTE in patients with common cancers, suggesting these factors impact little on thromboembolic risk in these cancers.
Changes of Platelet and Endothelial Microparticles in Patients with Venous Thromboembolism
Authors: Oh Doyeun , Jang Mun Ju , Lee Sun Joo , Bang Soo-Mee , Park Seonyang , Yun-Choi HS 
Published: October 2019

Abstract
Background: Microparticles (MP) are small membrane vesicles released from a variety of cells including platelet, leukocyte, endothelial cell which mediate intravascular coagulation. In this study, the plasma levels of total microparticle (TMP), platelet microparticle (PMP) and endothelial microparticle (EMP) in patients with venous thromboembolism (VTE) were investigated to test their clinical utilities.
Methods: Subjects were divided to 3 groups consisted of 119 patients with VTE, 72 cancer without VTE and 93 healthy controls. MP were assayed by flow-cytometry using non-washed, frozen platelet-poor plasma samples. TMP, PMP and EMP were identified using antibodies against Annexin V, CD41a, and CD144 respectively.
Results: The mean levels of plasma TMP, PMP, but not EMP in VTE without caner group (n=77) were significantly increased compared with those in healthy controls (n=93); 1972.9/μl vs 917.0/μl, p=0.001; 1496.6/μl, 586.5/μl, p=0.001; 108.0/μl vs 97.8/μl, p=0.321). In the VTE without cancer group, the mean levels of plasma TMP, PMP, but not EMP in newly diagnosed VTE group (n=59) were significantly increased compared with previously diagnosed VTE group (n=18); 2242.5/μl vs 1089.1/μl, p=0.008; 1728.6/μl vs 735.9/μl, p=0.005; 101.8/μl vs 84.6/μl, p=0.885). Mean peak thrombin generations in VTE samples (n=9) were increased in platelet poor plasma (385.2 nM vs 163.1 nM, p=0.002) but not in microparticle free plasma (MFP) (86.2 nM vs 22.6 nM, p=NS) as compared with those of controls (n=10) suggesting the thombin generation is originated from MP of plasma. But, the mean levels of plasma TMP, PMP, but not EMP in VTE with caner group (n=42) were not increased compared with those in cancer controls without VTE (n=72); 2158.1/μl vs 1644.2/μl, p=0.094; 1637.2/μl vs 1246.8/μl, p=0.168; 86.0/μl vs86.0/μl, p=0.996). The plasma levels of B-TG were well correlated with those of PMP. The levels of plasma TMP, PMP, and EMP did not show any correlation with the level of D-dimer.
Conclusion: The plasma levels of TMP and PMP are significantly increased in VTE patients and the levels are normalized after anticoagulation, suggesting MP may be used as surrogate markers for monitoring of VTE.
IL-3 Coordination of the Myeloblast Transcriptome by Modulating mRNA Stability
Authors: Ernst Jason , Bar-Joseph Ziv , Ghanem Louis , Steinman Richard A. 
Published: October 2019

Abstract
The growth factor interleukin-3 (IL-3) promotes the survival and growth of multipotent hematopoietic progenitors and stimulates myelopoiesis. It has also been reported to oppose terminal granulopoiesis and to support leukemic cell growth through autocrine or paracrine mechanisms. While most investigations of the action of hematopoietic cytokines such as IL-3 have focused on cytokine signal transduction leading to transcriptional activation, IL3 has been reported to downregulate proapoptotic Bim in factor-dependent lymphocytes (Matsui et. al., Mol. Cell, 2007). We hypothesized that IL-3 could support the myeloblast phenotype and oppose differentiation by stabilizing transcripts involved in proliferation or differentiation blockade. Kinetic microarray analysis of actinomycin chase experiments in IL-3-dependent 32Dcl3 myeloblasts demonstrated that IL-3 caused stabilization of hundreds of transcripts in pathways relevant to myeloblast function. Control of transcript decay by IL-3 did not require new transcription. Among the most IL-3 stabilized transcripts, 8 out of the top 22 gene ontology categories at a corrected significance level <0.001 were related to cell cycling, and 5 were related to RNA processing. Northern Blotting validated stabilization of transcripts by IL-3, including transcripts associated with proliferation and leukemic transformation (pik3cd, myb, pim-1), hematopoietic development (cited2), differentiation control (cdkn1a) and RNA processing (BRF1, BRF2). A domain was localized in the 3′-utr of IL-6 that mediated IL-3 responsiveness. Proteins known to modulate mRNA stability bound to this domain and to other IL-3 controlled transcripts. The v-Abl oncoprotein (that can support cytokine-independent proliferation of 32Dcl3 myeloblasts) was also shown to stabilize several of the IL-3 targeted transcripts. These findings support a new model of IL-3 action through coordinated mRNA stability control and suggest that leukemic oncoproteins can hijack the ability of IL3 to regulate the decay rate of critical transcripts in myeloblasts.
Evidence for the Interaction Between VWF Carboxyl-Terminal Domains and ADAMTS13 Domains Distal to Its Spacer Domain
Authors: Zanardelli Sara , Chion Chan Kwo , Laffan Michael , Lenting Peter J , Groot Evelyn , Lane David 
Published: October 2019

Abstract
ADAMTS13 plasma metalloprotease regulates the multimeric size of von Willebrand factor (VWF) by cleaving the Y1605-M1606 bond in the A2 domain. Several studies have characterised high affinity binding sites in the A2 domain, probably interacting with the ADAMTS13 spacer and proximal domains. We have previously provided preliminary evidence for an additional ADAMTS13 binding site distal to the A domains, by measuring a ~7-fold increase in affinity for ADAMTS13 of plate-immobilised VWFA1CK (residues 1260-2813) (KD 11 nM) compared with VWFA1A2A3 (residues 1260-1874) (KD 78 nM) (Zanardelli et al, JTH, volume 5 Supplement I, XXI ISTH congress 2007, abstract number O-W-018). We subsequently expressed a series of VWF carboxyl-terminal fragments, VWFD4CK (residues 1874-2813), VWFA3CK (residues 1671-2813), VWFD4 (residues 1874-2299) and VWFB1CK (residues 2296-2813). Using an equilibrium binding assay, we assessed their binding to full-length ADAMTS13 and truncated ADAMTS13 proteins MDTCS (residues 34-685) and del(TSP5-CUB) (residues 34-894). KD values calculated for VWFD4CK and VWFA3CK binding to full-length ADAMTS13 were 134 and 108 nM, respectively. This confirmed the presence of an ADAMTS13 binding site outside VWF A2 domain, in the region D4CK. It also excluded a major role in the interaction for the VWF A3 domain. However, isolated VWFD4 and VWFB1CK did not bind significantly, suggesting that integrity of the VWF C-terminal region is also required for the binding. Furthermore, MDTCS bound to VWFA1CK and VWFA1A2A3 with similar affinity (KD 120 and 82 nM, respectively) and no significant interaction occurred with VWFD4CK. Similar results were found for the binding of del(TSP5-CUB) to the VWF fragments (VWFA1CK KD 85 nM, VWFA1A2A3 KD 65 nM and VWFD4CK no binding). Together these results suggested a multiple interaction between the carboxyl-terminal region of VWF (within D4CK) and the distal domains of ADAMTS13 (TSP5–8 and CUB domains). The VWF carboxyl-terminal binding site may be important for initial anchoring of ADAMTS13, allowing the subsequent binding between the spacer domain and VWF A2 domain.
Evaluation of Moyamoya Disease in Sickle Cell Anemia Patients After Encephaloduroarteriosynangiosis
Authors: Earl Janice , Sun Peter , Martin Kenneth , Quirolo Keith C. , Vichinsky Elliott , Hoppe Carolyn 
Published: October 2019

Abstract
Abstract 1059

Background:
Moyamoya disease is a progressive cerebrovascular complication of sickle cell anemia characterized by collateral arterial formation in response to progressive stenosis of the large intracranial arteries. Despite chronic transfusions, moyamoya is associated with a high risk of stroke recurrence. Encephaloduroarteriosynangiosis (EDAS) is a surgical technique used to reestablish or augment cerebral perfusion in patients with moyamoya disease. However, evidence for its efficacy in SCA patients is limited. We initiated a prospective study to determine whether EDAS is safe and increases blood flow to ischemic areas of brain in SCA patients with moyamoya.

Methods/Results:
SCA patients who had complete or partial obstruction of the dICA with progression to moyamoya disease were eligible for EDAS. Progressive cognitive decline, dystonia and persistent seizures were also factors influencing eligibility. Seven SCA patients (age: median 16yrs, range 4–23yrs; sex: 5F/2M ) with moyamoya disease underwent encephaloduroarteriosynangiosis (EDAS) procedures between 3/2007 and 9/2010. All 7 patients were regularly transfused for a history of stroke or MRA-documented ICA stenosis. Complete or partial obstruction of the dICA with moyamoya changes was detected on MRA scans and confirmed by cerebral angiography. Bilateral (n = 2) or unilateral (n = 5) encephaloduroarteriosynangiosis procedures in which the superficial temporal artery is transplanted through a small craniotomy with dural and arachnoid opening and sutured to the pia were performed. Perfusion MR-weighted imaging was performed pre- and post-operatively to evaluate changes in relative cerebral blood volume and time to peak enhancement.

Results:
All patients have remained free of neurovascular complications and have had no new ischemic changes on MRI with an average follow-up of 26 months. All patients subjectively reported improvement in overall well-being. A decrease in the frequency of headaches (n=1), resolution of seizures (n=2) and improved gait (n=1) were also observed. Collateral anastomoses between external and internal carotid arteries were established by MRA in all patients. All 4 patients who had pre and post-procedure MRA perfusion imaging showed a reduction in the delay of time to peak enhancement in the affected territory after EDAS.

Conclusion:
Our results indicate that EDAS is a safe and effective surgical procedure to re-establish blood flow to ischemic brain tissue in patients with SCA who develop moyamoya disease. MRA perfusion imaging may be a useful tool to evaluate improved perfusion status after EDAS. Further examination of neuropsychologic correlates, such as executive function, with EDAS procedures in these patients is presently underway.

Disclosures:
Vichinsky: Novartis: Research Funding; Apotex: Research Funding.