bluuebunny/crossref_metadata_2025_split huggingface dataset:
Derivation and Validation of a Prediction Tool for Venous Thromboembolism: A VERITY Registry Study.
Authors: Arya Roopen , Paneesha Shankaranarayana , McManus Aidan , Parsons Nick , Scriven Nicholas , Farren Tim , Nokes Tim , O’Shaughnessy Denise , Rose Peter 
Published: November 2019

Abstract
Accurate estimation of risk for venous thromboembolism (VTE) may help clinicians assess prophylaxis needs. Only empirical algorithms and risk scores have been described; an empirical risk score (‘Kucher’) based on 8 VTE risk factors (cancer, prior VTE, hypercoagulability, surgery, age>75 yrs, BMI>29, bed rest, hormonal factor) using electronic alerts improved hospitalized patient outcome (NEJM2005;352:969–77). We wished to develop a multivariate regression model for VTE risk, based on Kucher, and validate its performance. The initial derivation cohort consisted of patients enrolled in ‘VERITY’, a multicentre VTE treatment registry for whom the endpoint of VTE and all 8 risk factors were known. Initial univariate analysis (n=5928; 32.4% with diagnosis of VTE) suggested VTE risk was not accounted for by the 8 factors; an additional 3 were added (leg paralysis, smoking, IV drug use [IVD]). The final derivation cohort was 5241 patients (32.0% with VTE) with complete risk data. The validation cohort (n=915) was derived from a database of 928 consecutively enrolled patients at a single DVT clinic. Model parameters were estimated using the statistical package ‘R’ using a stepwise selection procedure to choose the optimal number of main effects and pair-wise interactions. This showed that advanced age (estimated odds ratio [OR]=2.8, p<0.001); inpatient (OR=3.0, p<0.001); surgery (OR=3.1, p<0.001); prior VTE (OR=2.9, p<0.001); leg paralysis (OR=3.8, p<0.001); cancer (OR=5.3, p<0.001); IVD (OR=14.3, p<0.001); smoking (OR=1.2, p=0.009); and thrombophilia (OR=2.8; p<0.001) increased the risk of VTE. Obesity (OR=0.7; p<0.001) increased the VTE risk only in patients with a hormonal factor (OR=2.0, p=0.007). Backward stepwise regression showed prior VTE as the most important factor followed by cancer, IVD, surgery, inpatient, age, leg paralysis, hormonal factor, obesity, thrombophilia and smoking. Expressing the parameter estimates in terms of probabilities defines a risk score model for VTE. Using the model, the receiver operating characteristic (ROC) curve (see figure) area under the curve (AUC) was estimated as 0.720 (95% CI, 0.705–0.735) for the model (dashed line), indicating a good diagnostic test significantly better (p<0.001) than Kucher (AUC=0.617, 95% CI, 0.599–0.634)(solid line). For the validation cohort, AUC was estimated as 0.678 (95% CI, 0.635–0.721) for the model, which was not significantly different from AUC for the full dataset used for model development, and was 0.587 (95% CI, 0.542–0.632) for Kucher. This model to predict individual patient risk of VTE may contribute to decision making regarding prophylaxis in clinical practice.
Figure Figure
A Negative D-dimer Excludes Recurrent Deep Vein Thrombosis: Results of a Multicentre Management Study.
Authors: Bates Shannon , Kearon Clive , Kahn Susan , Julian Jim A. , Crowther Mark A. , Gerdes Victor , Geerts William , Kovacs Michael J. , Weise-Kelly Lorraine , Ginsberg Jeffrey S. 
Published: November 2019

Abstract
The high frequency of residual radiologic abnormalities after initial deep vein thrombosis (DVT) makes management of patients with suspected recurrence difficult. D-dimer (DD) and serial compression ultrasonography (CUS) of the proximal veins have a high sensitivity and negative predictive value (NPV) in suspected first DVT. We hypothesized that it would be safe to withhold anticoagulation in patients with suspected recurrence who had a negative sensitive DD or negative serial CUS when DD testing was positive. In a multicentre prospective cohort study, patients underwent DD testing with an immunoturbidometric assay (MDA DD). If the DD was negative (<0.5 ug fibrinogen equivalent units [FEU]/mL), patients had no further testing. If the DD was positive, CUS was performed and, if normal, repeated after 1–3 and 7–10 days. Patients with a positive DD and abnormal CUS at presentation were managed as per their treating physician. Patients were followed for 3 months to detect venous thromboembolism (VTE) and suspected VTE were adjudicated centrally. Of the 504 patients enrolled in this study, 14 were subsequently deemed ineligible and 2 patients were lost to follow-up. The overall prevalence of confirmed recurrent DVT at presentation or during follow-up was 17%. 230 patients had a negative DD at presentation and, of the 227 evaluable patients, 4 had definite confirmed VTE (NPV of DD = 98%; 95% Confidence Interval [CI], 96–99%). Of the 135 patients with a positive DD and normal initial CUS, serial CUS was negative in 129 cases. Of these patients, 3 had definite VTE during follow-up (NPV of serial CUS in patients with positive DD = 98%; 95% CI, 93–99%). These results suggest that a negative MDA DD result excludes clinically significant recurrent DVT and that anticoagulants can also be safely withheld in patients with negative serial CUS, even if their DD is positive. This simple diagnostic approach can be used to safely manage approximately 70% of patients with suspected recurrent DVT.
High Plasma Levels of Soluble P-Selectin Are Predictive for Venous Thromboembolism in Cancer Patients - Results from the Vienna Cancer and Thrombosis Study (CATS).
Authors: Ay Cihan , Simanek Ralph , Vormittag Rainer , Dunkler Daniela , Alguel Guelay , Koder Silvia , Wagner Oswald , Zielinski Christoph , Pabinger Ingrid 
Published: November 2019

Abstract
Cancer patients are at high risk for venous thromboembolism (VTE), which represents an additional burden and a frequent cause of increased mortality. Laboratory parameters with a predictive value for VTE could help to assign a patient to a high or low risk group. In recent studies the cell adhesion molecule P-selectin was identified to be a strong risk factor for VTE. However, the role of soluble P-selectin (sP-selectin) in cancer-associated VTE is not known because up to now clinical data are not available. Therefore, we assessed sP-selectin plasma levels in cancer patients as a risk predictor for VTE and provide a report from the ongoing prospective observational CATS. Patients with newly diagnosed cancer or progression of disease who had no chemotherapy within the last three months were enrolled from October 2003 to October 2006 and followed prospectively via phone and mail. Occurrence of VTE and information on the patientś anti-cancer-treatment within the follow up period were recorded. VTE has always been confirmed by imaging. sP-selectin levels were measured with a highly sensitive ELISA. Kaplan Meier and Cox regression analysis were applied for statistical calculation. We included 687 patients (319 female/368 male, median age [IQR]: 62 [54–68] yrs) with malignant disease and followed them for a median observation period of 415 days. Main tumour entities were malignancies of the breast (n=125), lung (n=86), upper (n=30) and lower gastrointestinal tract (n=100), pancreas (n=42), kidney (n=19) and prostate (n=72). Furthermore, 80 patients had high-grade glioma, 73 lymphomas, 18 multiple myeloma and 42 other tumour types. Distant metastases were found in 268 patients at the time of recruitment. During the observation period VTE occurred in 45 patients (21 female/24 male, median age [IQR]: 62 [48–66] yrs). Elevated plasma levels of sP-selectin (cut-off level 53.1 ng/mL representing the 75th percentile of the total study population, 173 patients) [hazard ratio (HR): 2.5, 95% CI 1.4 – 4.6], surgery [HR: 3.9, 95% CI 1.8 – 8.5] and radiotherapy [HR: 3.2, 95% CI 1.6 – 6.4] were statistically significant risk factors for VTE in multivariable analysis including sP-selectin, age, sex, surgery, chemotherapy and radiotherapy. The cumulative probability of VTE after 6 months was 11.9% in patients with sP-selectin plasma levels above and 3.7% in those below the 75th percentile. In conclusion, high plasma levels of sP-selectin independently predict VTE in cancer patients. Measurement of sP-selectin at diagnosis of cancer would help to identify patients at increased risk for VTE.
Efficacy of Dasatinib in Patients with Chronic-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2-Year Follow-Up Data from START-C (CA180-013).
Authors: Stone Richard M. , Kantarjian Hagop M. , Baccarani Michele , Lipton Jeffrey H. , Hughes Timothy , Ezzeddine Rana , Bleickardt Eric , Hochhaus Andreas 
Published: November 2019

Abstract
Dasatinib (SPRYCEL®) is 325-fold more potent than imatinib against BCR-ABL in vitro and binds to BCR-ABL in both the inactive and active, oncogenic conformations. Dasatinib has been shown to be an effective treatment option for patients with imatinib-resistant or -intolerant chronic-phase chronic myelogenous leukemia (CP-CML). Here we report the extended follow-up of START-C, a 75-center, international study of dasatinib in 387 patients with CP-CML with resistance (n=288) or intolerance (n=99) to imatinib. Recruitment took place from February to July 2005. Dasatinib was administered on a 70-mg BID regimen; dose escalation (90 mg BID) or reduction (50 or 40 mg BID) were allowed for lack of response or toxicity, respectively. Median time from diagnosis of CML was 61 mo (range 32–50). Prior therapy included interferon-α in 65% of patients and stem-cell transplantation in 10%; 55% had received prior imatinib doses >600 mg and 53% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 82%, and complete (CCyR) and partial cytogenetic response (PCyR) in 19% and 18%, respectively. With a median follow-up of 15.2 mo, CHR was attained in 91% of patients (95% CI 87–93%), major cytogenetic response (MCyR) in 59% (95% CI 54–64%) (52% imatinib-resistant, 80% imatinib-intolerant), and CCyR in 49% (40% imatinib-resistant; 75% imatinib-intolerant). For patients with no prior MCyR to imatinib, 42% achieved a MCyR with dasatinib. A MCyR rate of 59% was recorded for patients with baseline BCR-ABL mutations; responses were seen across all mutations with the exception of T315I. MCyRs were durable, with only 7 of the 230 patients who had achieved a MCyR with dasatinib losing this response. Major molecular response rate (ie, a BCR-ABL/ABL ratio of <0.1% according to the international scale by RQ-PCR) at 12 mo was 25%. Progression-free survival at 15 mo was 90% while overall survival was 96%. Dose interruptions were required for 87% of patients and dose reduction for 73%; the average daily dose administered was 101 mg (range 11–171). Reports of grade 3–4 thrombocytopenia and neutropenia were documented for 48% and 49% of patients, respectively. Non-hematologic toxicity consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), and dyspnea (30%). Pleural effusion was experienced by 27% of patients; this was categorised as grade 1–2 in 21% and grade 3–4 in 6%. Dasatinib-induced cytogenetic responses remain durable in patients with CP-CML resistant or intolerant to imatinib. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.
B-CLL Antibodies Encoded by Stereotypic VH1-69, D3-16, and JH3 Rearrangements Immunoprecipitate Non-Muscle Myosin Heavy Chain IIA.
Authors: Chu Charles C. , Zhang Lu , Hatzi Katerina , Catera Rosa , Allen Steven L. , Rai Kanti R. , Chiorazzi Nicholas 
Published: November 2019

Abstract
B-cell chronic lymphocytic leukemia (B-CLL) patient clinical outcomes can be segregated based on the degree of mutation of immunoglobulin (Ig) variable region genes. This observation suggests a functional role for antigen binding by the Ig B-cell receptor in B-CLL. Furthermore, over 20% of B-CLL patients share antibodies with very similar Ig heavy chain (H) variable region CDR3 sequences, suggesting common antigen reactivity. For example, sixteen unrelated B-CLL patients have been reported to express an unmutated Ig heavy chain encoded by VH1-69, D3-16, and JH3 with nearly identical HCDR3 sequences. The probability that these patients developed B-CLL with identical IgH variable regions by random chance is extremely small. This stereotypic set of antibodies strongly bind cytoplasmic structures in HEp-2 cells as observed by immunofluorescence. Therefore, HEp-2 cell extracts were used as the source of material to isolate the cellular antigen recognized by these antibodies. These B-CLL antibodies were recombinantly overexpressed and purified as human IgG1 molecules. Recombinant antibody was bound to protein G agarose beads and incubated with cell extracts overnight. Bound cellular antigen was immunoprecipitated, washed, eluted, run on SDS-PAGE, and stained with Coomassie Blue. B-CLL antibodies from this stereotypic set immunoprecipitated protein bands at approximately 45 and 225 kDa in size. These bands were isolated and identified by mass spectrometry analysis of trypsin-digested peptides. The 45 kDa and 225 kDa proteins are cytoplasmic actin and non-muscle myosin heavy chain IIA (MYHIIA), respectively. The VH1-69, D3-16, and JH3 encoded stereotypic set of antibodies has been reported to be polyreactive against multiple autoantigens, such as DNA, Ig, and actin. However, MYHIIA has not been previously reported as an antigen recognized by this stereotypic set of antibodies. Therefore, we confirmed that MYHIIA was recognized by this stereotypic antibody set by probing B-CLL antibody immunoprecipitates by Western blot with anti-MYHIIA antibody. Furthermore, anti-MYHIIA antibody immunofluorescent staining of HEp-2 cells co-localized with this B-CLL stereotypic antibody immunofluorescent staining. Thus, stereotypic VH1-69, D3-16, and JH3 encoded B-CLL antibodies are polyreactive with common cellular proteins, including the newly identified autoantigen MYHIIA. The cellular antigens recognized by these stereotypic antibodies may be important in the pathogenesis, diagnosis, and treatment of B-CLL.
Does Imatinib Change the Outcome in Philapdelphia Chromosome Positive Acute Lymphoblastic Leukaemia in Adults? Data from the UKALLXII/ECOG2993 Study.
Authors: Fielding Adele K. , Richards Susan M. , Lazarus Hillard M. , Litzow Mark R. , Luger Selina M. , Marks David I. , McMillan Andrew K. , Rowe Jacob M. , Tallman Martin S. , Goldstone Anthony H. 
Published: November 2019

Abstract
The UKALLXII/ECOG2993 international study for adults with acute lymphoblastic leukeamia (ALL) included a separate, single-arm study (still open) to evaluate the role of etoposide/TBI conditioned allogeneic bone marrow transplantation (BMT) in patients with Philadelphia chromosome positive (Ph pos) disease. Patients received 2 phases of induction, intensification with high dose methotrexate and BMT using unrelated donor stem cells where a matched sibling was not available. 267 patients with Ph pos ALL were treated from 1993 onwards, in the pre-imatinib era. The study was amended in 2003 to add imatinib 600mg per day following induction and after BMT for 2 years or until relapse. A subsequent amendment at the end of 2005, added imatinib 600mg per day also to phase 2 of induction. 153 patients have now been treated on the imatinib-containing protocol − 89 received imatinib following induction and 64 started imatinib with phase 2 induction.
Complete remission (CR) rate at the end of 2 phases of induction was 91% with imatinib started in induction, 81% with imatinib started in consolidation only & 83% in the pre imatinib era. 128 of the 153 patients treated with any imatinib were eligible for BMT. Of the 98 patients with over 6 months follow-up, 57 (58%) actually received BMT. This transplant rate does not differ from the 62% in the pre-imatinib era although the data pertain mostly to those whose imatinib started later during therapy. Overall survival of the imatinib-treated group as a whole is 23% at 3 years, which does not differ from the 26% pre-imatinib rate as shown in the figure. Hence, imatinib started post-induction does not appear to improve survival. Imatinib given with induction may improve the CR rate, but there is insufficient follow up to assess transplant or survival rates. Earlier imatinib may be optimal but overall, our study does not provide evidence yet that imatinib alters the outcome of this disease.
Figure Figure Patient characteristics Pre-imatinib (N=267) Post-imatinib (N=153) Gender: Male 150 (56%) 96 (63%) WBC (x 10 ^9/l) (2 unknown): <30 141(53%) 86 (56%) ≥ 30 124 (47%) 67 (44%) Median (range) 26.8 (1.5–438) 21.0 (0.5–491) Age: median (range) 40 (15–60) 42 (16–64) CNS disease (82 unknown) 14 (8%) 4 (3%)
Identification of Novel, Non-Synonymous Sequence Changes in the Tyrosine Kinase Genes of Patients with Acute Myeloid Leukemia.
Authors: Xiang Zhifu , Zhao Yu , Mitaksov Vesselin , Fremont Daved H. , Kasai Yumi , Molitoris AnnaLynn , Ries Rhonda E. , Miner Tracie , McLellan Michael D. , DiPersio John F. , Link Daniel C. , Payton Jacqueline E. , Graubert Timothy A. , Watson Mark , Shannon William , Heath Sharon , Mardis Elaine R. , Wilson Richard K. , Ley Timothy J. , Tomasson Michael H. 
Published: November 2019

Abstract
Activating mutations in receptor tyrosine kinase (RTK) genes (including FLT3 and KIT) occur in more than 30% of newly diagnosed patients with acute myeloid leukemia (AML); we and others have speculated that mutations in other TK genes may be present in the remaining 70%. We therefore examined the expression of all annotated RTK and cytoplasmic tyrosine kinase (CTK) genes to prioritize these genes for sequencing. We performed high-throughput re-sequencing of the kinase domains of 24 TK genes (9 RTK and 15 CTK) using amplified genomic DNA from the bone marrow (tumor) and matched skin biopsy samples (“germline”) from 94 patients with de novo AML, and validated positive findings in an additional 94 AML tumor samples (14.4 million base pairs of double-stranded coverage). In addition to previously reported somatic mutations in FLT3, KIT, and JAK2 (which occurred at expected frequencies), we found novel somatic mutations in four patients in JAK1, NTRK1 and DDR1. Unexpectedly, we also identified novel non-synonymous germline sequence changes in 14 genes, including TYK2. We examined frequencies of known polymorphisms in our patients versus controls. We determined that the previously reported JAK3P132T allele is a germline variant that occurs in 19% of normal African Americans. Even when controlling for race, the TYK2G363S allele was found significantly less frequently in AML samples (12/376 alleles, 3.2%) compared to 147 normal controls (27/294 alleles, 9.2%, p=0.0013). Notably, there was loss of heterozygosity (LOH) at TYK2 in 2 patients. Additional population based studies and biologic validation will be required to define the significance of these sequence changes for AML pathogenesis. Lastly, we compared the expression of RTK and CTK genes in AML samples (n=92) to highly enriched normal human CD34+, promyelocyte, or polymorphonuclear neutrophil populations (n=5 each). We found several RTKs (FLT3, KIT, LTK) and CTKs (FYN, LCK, ITK, HCK and FGR) were tightly regulated in normal hematopoietic development but were dysregulated in many AML samples. Taken together, our data suggest that RTK or CTK mutations are not required for AML development but may be disease modifying events. Our data also suggest that germline variants and dysregulated expression of RTK and CTK genes may play significant roles AML pathogenesis.
Bimodal Degradation of MLL Protein by the Cell Cycle SCFSkp2 and APCCdc20 E3 Lilgases Assures Cell Cycle Execution: A Critical Regulatory Circuit Lost in Leukemogenic MLL-Fusions.
Authors: Liu Han , Chen David , Westergard Todd , Takeda Shugaku , Sasagawa Satoru , Cheng Emily H.-Y. , Hsieh James J.-D. 
Published: November 2019

Abstract
The MLL (mixed lineage leukemia) gene encodes a highly conserved 3,969 aa histone H3 K4 methyl transferase, of which chromosome translocations result in poor prognostic infant and therapy-related leukemias. Mysteriously, the pathognomonic MLL leukemia fusions consist of a common amino(N)-terminal ∼1400 aa of MLL fused in frame with more than 60 different partners with no shared characteristics. The most well known genetic function of MLL is to antagonize polycomb group of proteins for proper Hox gene expression. Consequently deregulated Hox genes caused by MLL translocations contribute to the MLL leukemogenesis. Besides Hox genes, it remains largely undetermined whether MLL participates in other biological processes. The 500kD MLL precursor undergoes evolutionarily conserved proteolytic maturation mediated by Taspase1 (Hsieh et al. 2003, MCB, 23, 186–194; Hsieh et al. 2003, Cell, 115, 293–303). Our recent studies on Taspase1 knockout cells established an MLL-E2F axis in orchestrating core cell cycle gene expression including Cyclins and possibly Cdk inhibitors (Takeda et al. 2006, Genes & Development, 20, 2397–2409). As MLL actively participates in the cell cycle regulation, we investigated the regulation of MLL through cell cycle transition. We uncovered a unique biphasic expression of MLL conferred by defined windows of degradation mediated by specialized cell cycle E3 ligases. Specifically, SCFSkp2 and APCCdc20 mark MLL for degradation at S phase and late M phase, respectively. Abolished peak expression of MLL incurs corresponding defects in G1/S transition and M phase progression. Conversely, over-expression of MLL blocks S phase progression. Remarkably, MLL degradation initiates at its N-terminal ∼1400 aa that is retained in all MLL leukemia fusions. We examined prevalent MLL-fusions, including MLL-AF4, MLL-AF9, MLL-ELL and MLL-ELL, and observed their increased resistance to degradation. Furthermore, the same resistance was observed with the leukemogenic MLL-lacZ but not the non-leukemogenic MLL-Myc tag fusion. Thus, non-oscillating expression of MLL-fusions through the cell cycle, resulted from impaired degradation, likely constitutes the universal mechanism underlying all MLL leukemias. Our data conclude an essential post-translational regulation of MLL by the cell cycle ubiquitin/proteasome system (UPS) to assure the temporal necessity of MLL in coordinating cell cycle progression. Future studies aim at providing a comprehensive analysis on the cell cycle consequences associated with MLL-fusions using genetically modified cells derived from mice carrying various MLL-fusion knockin alleles, including MLL-AF4, MLL-AF9, and MLL-CBP.