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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

Hodgkin's lymphoma is due to the clonal transformation of cells originating from B lymphocytes, generating the pathognomonic binucleate Reed-Sternberg cells. Hodgkin's lymphoma is a B cell disease with a bimodal distribution, with higher incidence in adolescence and the third decade of life, showing a second peak in people over 55 years of age. Classic Hodgkin lymphoma cells routinely undergo gene expression reprogramming, as they lose the expression of most of the typical B-cell genes and acquire the expression of multiple genes that are typical of other types of cells in the immune system. The treatment algorithm will depend on whether it is classic or predominantly lymphocytic HL, if it is early stage with unfavorable prognostic markers or not, the initial management regimen, and whether there is bulky disease, among the most relevant variables.El linfoma de Hodgkin (LH) se debe a la transformación clonal de células originadas en los linfocitos B, lo que genera las células binucleadas patognomónicas de Reed-Sternberg. El LH es una enfermedad de células B con una distribución bimodal, con mayor incidencia en la adolescencia y la tercera década de la vida y un segundo pico en personas mayores de 55 años. Las células del LH clásico habitualmente sufren una reprogramación de la expresión génica, ya que pierden la expresión de la mayoría de los genes típicos de las células B y han adquirido la expresión de múltiples genes que son típicos de otros tipos de células del sistema inmunitario. El algoritmo de tratamiento dependerá si se trata de LH clásico o de predominio linfocítico, si es un estadio temprano con marcadores de pronóstico desfavorables o no, el esquema inicial de manejo y si existe enfermedad voluminosa, entre las variables más relevantes.

Hemophilia is a hemorrhagic disorder with a sex-linked inherited pattern, characterized by an inability to amplify coagulation due to a deficiency in coagulation factor VIII (hemophilia A or classic) or factor IX (hemophilia B). Sequencing of the genes involved in hemophilia has provided a description and record of the main mutations, as well as a correlation with the various degrees of severity. Hemorrhagic manifestations are related to levels of circulating factor, mainly affecting the musculoskeletal system and specifically the large joints (knees, ankles, and elbows). This document is a review and consensus of the main genetic aspects of hemophilia, from the inheritance pattern to the concept of women carriers, physiopathology and classification of the disorder, the basic and confirmation studies when hemophilia is suspected, the various treatment regimens based on infusion of the deficient coagulation factor as well as innovative factor-free therapies and recommendations for the management of complications associated with treatment (development of inhibitors and/or transfusion-transmitted infections), or secondary to articular hemorrhagic events (hemophilic arthropathy). Finally, relevant reviews of clinical and treatment aspects of hemorrhagic pathology characterized by acquired deficiency of FVIII secondary to neutralized antibodies named acquired hemophilia.La hemofilia es un trastorno hemorrágico con patrón de herencia ligado al sexo, caracterizado por una incapacidad en la amplificación de la coagulación ocasionada por la deficiencia del factor VIII (hemofilia A o clásica) o del factor IX (hemofilia B). La secuenciación de los genes involucrados en la hemofilia ha permitido la descripción y registro de las principales mutaciones, así como la correlación con los diversos grados de severidad. Las manifestaciones hemorrágicas se relacionan con los niveles de factor deficiente circulante, afectando principalmente al sistema musculoesquelético y en particular a las grandes articulaciones (rodillas, tobillos y codos). El presente documento hace una revisión y consenso de los principales aspectos genéticos de la hemofilia, desde el patrón de herencia y el concepto de mujeres portadoras, la fisiopatología y clasificación de la enfermedad, los estudios básicos y de confirmación ante la sospecha de hemofilia, y de los diversos esquemas de tratamiento basados en la infusión del factor de coagulación deficiente hasta las terapias innovadoras libres de factor, así como de las recomendaciones para el manejo de las complicaciones asociadas al tratamiento (desarrollo de inhibidores y/o infecciones transmitidas por transfusión) o secundarias a los eventos hemorrágicos a nivel articular (artropatía hemofílica). La parte final del documento revisa los aspectos clínicos y de tratamiento relevantes de una patología hemorragica caracterizada por la deficiencia adquirida del FVIII mediada por anticuerpos neutralizantes denominada hemofilia adquirida.

Hemophilia is a hemorrhagic disorder with a sex-linked inherited pattern, characterized by an inability to amplify coagulation due to a deficiency in coagulation factor VIII (hemophilia A or classic) or factor IX (hemophilia B). Sequencing of the genes involved in hemophilia has provided a description and record of the main mutations, as well as a correlation with the various degrees of severity. Hemorrhagic manifestations are related to levels of circulating factor, mainly affecting the musculoskeletal system and specifically the large joints (knees, ankles, and elbows). This document is a review and consensus of the main genetic aspects of hemophilia, from the inheritance pattern to the concept of women carriers, physiopathology and classification of the disorder, the basic and confirmation studies when hemophilia is suspected, the various treatment regimens based on infusion of the deficient coagulation factor as well as innovative factor-free therapies and recommendations for the management of complications associated with treatment (development of inhibitors and/or transfusion-transmitted infections), or secondary to articular hemorrhagic events (hemophilic arthropathy). Finally, relevant reviews of clinical and treatment aspects of hemorrhagic pathology characterized by acquired deficiency of FVIII secondary to neutralized antibodies named acquired hemophilia.

Background: Cancer-associated venous thromboembolism (CAT) has detrimental impact on patients' clinical outcomes and quality of life. Data on CAT education, communication, and awareness among the general cancer population are scanty. Methods: We present the preliminary results of an ongoing patient-centered survey including 27 items covering major spheres of CAT. The survey, available in 14 languages, was promoted and disseminated online through social networks, email newsletters, websites, and media. Results: As of September 20, 2022, 749 participants from 27 countries completed the survey. Overall, 61.8% (n = 460) of responders were not aware of their risk of CAT. Among those who received information on CAT, 26.2% (n = 56) were informed only at the time of CAT diagnosis. Over two thirds (69.1%, n = 501) of participants received no education on signs and symptoms of venous thromboembolism (VTE); among those who were educated about the possible clinical manifestations, 58.9% (n = 119) were given instructions to seek consultation in case of VTE suspicion. Two hundred twenty-four respondents (30.9%) had a chance to discuss the potential use of primary thromboprophylaxis with health-care providers. Just over half (58.7%, n = 309) were unaware of the risks of bleeding associated with anticoagulation, despite being involved in anticoagulant-related discussions or exposed to anticoagulants. Most responders (85%, n = 612) valued receiving CAT education as highly relevant; however, 51.7% (n = 375) expressed concerns about insufficient time spent and clarity of education received. Conclusions: This ongoing survey involving cancer patients with diverse ethnic, cultural, and geographical backgrounds highlights important patient knowledge gaps. These findings warrant urgent interventions to improve education and awareness, and reduce CAT burden.

Contains fulltext : 232751.pdf (Publisher’s version ) (Closed access) Clinical research in venous thromboembolism (VTE) is hindered by variability in the collection and reporting of data and outcomes. A consistent data language facilitates efficiencies, leads to higher quality data, and permits between-study comparisons and evidence synthesis. The International Society on Thrombosis and Haemostasis (ISTH) launched an international task force of more than 50 researchers to develop common data elements for clinical research in venous thromboembolism. The project was organized in seven working groups, each focusing on a topic area: General Core Data Elements; Anticoagulation and Other Therapies; Chronic VTE and Functional Outcomes; Diagnosis of VTE; Malignancy; Perioperative; and Predictors of VTE. The groups met via teleconference to collaboratively identify key data elements and develop definitions and data standards that were structured in a project-specific taxonomy. A Steering Committee met by teleconference and in-person to determine the overall scope of the project and resolve questions arising from the working groups. ISTH held an open public comment period to enable broader stakeholder involvement and feedback. The common data elements were then refined by the working groups to create a set of 512 unique data elements that are publicly available at http://isth.breakthrough.healthcare. The ISTH VTE Common Data Elements are intended to be a living project with ongoing curation, future expansion, and adaptation to meet the needs of the thrombosis and hemostasis research community.

The global annual incidence of venous thromboembolism (VTE) is estimated to be 0.75-2.69 per 1,000 population (1). Up to 60% of VTE events occur during or within three months after hospital admission: these are known as hospital-associated VTE and account for an estimated 10 million cases of VTE globally (2). Without preventive measures being used, hospital-associated VTE is the leading preventable cause of hospital death (2). The age-standardized pulmonary embolism (PE)-related mortality rate is similar in magnitude to respiratory infections and obstructive pulmonary disease. Although the impact of PE-related deaths is relatively high among young women (3), its global awareness by the public is low (4).

Introduction Venous thromboembolism (VTE) is a leading cause of cardiovascular morbidity and mortality. The majority of VTE events are hospital-associated. In 2008, the ENDORSE multinational survey reported that only around 40% of medical patients at risk of VTE received adequate thromboprophylaxis. Methods In our systematic review and meta-analysis, we aimed at providing updated figures concerning the use of thromboprophylaxsis globally. We focused on: (i) the frequency of patients with an indication to thromboprophylaxis according with individual models; (ii) the use of adequate thromboprophylaxis; (iii) reported contraindications to thromboprophylaxis. Observational non-randomized studies or surveys focusing on medically ill patients were considered eligible. Results After screening, we included 27 studies from 20 countries for a total of 137,288 patients. Overall, 50.5% (95%CI: 41.9%-59.1%, I2 99%) of patients had an indication to thromboprophylaxis: of these, 54.5% (95%CI: 46.2%-62.6%, I2 99%) received adequate thromboprophylaxis. The use of adequate thromboprophylaxis was 66.8% in Europe (95%CI: 50.7% to 81.1%; I2 98%), 44.9% in Africa (95%CI: 31.8% to 58.4% I2 96%), 37.6% in Asia (95%CI: 25.7%-50.3%, I2 97%), 58.3% in South America (95%CI 31.1%-83.1%, I2 99%), and 68.6% in North America (95%CI 64.9%-72.6%, I2 96%). No major differences in adequate thromboprophylaxis use were found across risk assessment models. Bleeding, thrombocytopenia, and renal/hepatic failure were the most frequently reported contraindications to thromboprophylaxis. Conclusions The use of anticoagulants for VTE prevention has been proven effective and safe, but thromboprophylaxis prescriptions are still unsatisfactory among hospitalized medically ill patients around the globe with marked geographical differences.

Coagulopathy and thrombosis associated with coronavirus disease 2019 (COVID-19) represent a major issue in the management of this disease. In the past months, clinical studies have demonstrated that COVID-19 patients present with a particular hypercoagulable state, in which a markedly increased D-dimer concomitant with increased levels of fibrinogen are observed. This hypercoagulable state leads to an increased risk of thrombosis, which seems to be higher among those patients with critical symptoms of COVID-19. The best therapeutic approach to prevent thrombotic events in COVID-19 has not been determined yet and several questions regarding thromboprophylaxis therapy, such as the time to initiate anticoagulation, type of anticoagulant and dose regimen, have emerged among physicians. To address these concerns, several medical societies have published position papers to provide the opinion of thrombosis experts on the management of coagulopathy and thrombosis associated with COVID-19. In line with this, the Latin America Cooperative Group of Hemostasis and Thrombosis (Grupo CLAHT) has constituted a panel of experts in thrombosis and hemostasis to discuss the available data on this topic. The aim of this review is to summarize the current evidence regarding hemostatic impairment and thrombotic risk in COVID-19 and to provide a carefully revised opinion of Latin American experts on the thromboprophylaxis and management of thrombotic events and coagulopathy in patients with suspected COVID-19.La coagulopatía y la trombosis asociadas a la enfermedad por coronavirus 2019 (COVID-19) representan un problema importante en el manejo de esta enfermedad. Los estudios clínicos de los últimos meses han demostrado que los pacientes con COVID-19 presentan un estado de hipercoagulabilidad particular, en el que se observa un aumento notable del dímero D concomitante con niveles elevados de fibrinógeno. El estado de hipercoagulabilidad conduce a un mayor riesgo de trombosis, que parece ser mayor entre aquellos pacientes con síntomas críticos de COVID-19. El mejor enfoque terapéutico para prevenir los eventos trombóticos en esta nueva enfermedad aún no se ha determinado y han surgido varias preguntas con respecto a la tromboprofilaxia, como el momento adecuado para iniciar la anticoagulación, el tipo de anticoagulante y el régimen de dosis. Para abordar estas preocupaciones, varias sociedades médicas han publicado artículos de posición para brindar la opinión de expertos en trombosis sobre el manejo de la coagulopatía y trombosis asociadas a COVID-19. Grupo Cooperativo Latinoamericano de Hemostasia y Trombosis (Grupo CLAHT) ha convocado a un panel de expertos en trombosis y hemostasia para discutir los datos disponibles sobre este tema. El objetivo de esta revisión es resumir la evidencia actual con respecto al deterioro hemostático y el riesgo trombótico en el COVID-19 y proporcionar una opinión cuidadosamente revisada de los expertos latinoamericanos sobre la tromboprofilaxis y el manejo de eventos trombóticos y coagulopatía en pacientes con sospecha de COVID-19.

Testing for polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene is still a standard part of thrombophilia testing in many laboratories. However, it is clear that these polymorphisms are not risk factors for arterial or venous thrombosis and therefore should not be part of thrombophilia testing. Eliminating MTHFR from thrombophilia testing will reduce patient concerns and health care costs.

The treatment of Hodgkin's lymphoma has been characterized by a story of success with the use tried-and-true protocols. During the second half of 2019 to the first-half of the 2021 the Mexican health system experienced a shortage of drugs, which compromised the possibility of using in most of the common protocols for this cancer: ABVD, BEACOPP, IGEV, ESHAP, DHAP, GEMOX. Clinician had option of using a common protocol with incomplete doses or applying an alternative complete CHOEP protocol, which has been used with some success in exploratory studies [1,2]. For 12 months, we treated a total of 58 patients of which we compared the base characteristics and response rates to 10-year compiled data from pre-shortage patients (PS) (total 475). The baseline characteristics of the PS vs shortage (S) group showed a statistical similar gender distribution (males 55.2% vs 63.8%, P 0.21), histologic subtype (P 0.24), international prognostic score (IPS ≥3 57.7% vs 58.6%, P 0.89) and clinical stage (advanced 78.1% vs 84.5%, P 0.26). The S patients did show higher frequency of B symptoms (P 0.002), extranodal disease (P 0.0001), while the PS group had a higher frequency of bulky disease (P 0.001), ABVD protocol (96% vs 63.8%, P 0.0001) and radiotherapy use. In the S group a total of 37 ABVD (29 incomplete), 7 BEACOPP (5 incomplete) and 14 CHOEP protocols (1 incomplete) were infused, it means only 10 (17.7%) were able to receive a standard complete treatment, while the rest received an incomplete or alternative treatment. Complete response for the PS and S group were 71.4% vs 56.9% with the corresponding therapeutic failure 28.6% vs 43.1% (p 0.023) respectively. Analyzing the response rate of each chemotherapy protocol in the S group, the complete ABVD vs incomplete ABVD demonstrated an 87.5% vs 69% (p 0.28) respectively. The complete BEACOPP vs incomplete showed 50% vs 40% (p 0.7) and CHOEP exhibited an unexceptional complete response rate of 21.4%. The median follow up was 48 months (1-148) for all cohort. One year OS were 98% vs 82% on PS vs S group respectively (log rank 0.0001). One year-PFS for the PS and S group were 96% and 61% respectively (log rank 0.003). The risk factors associated with lower PFS were B symptoms (OR 1.7, 1.1-2.6), advanced disease (OR 1.66, 1-0-2.7) and IPS≥3 (OR 2.1, 1.4-3.3); as favorable factors we observed radiotherapy (OR 0.07, 0.6-0.8) and the PS group (OR 0.5, 0.3-1.0); however, in the Cox regression, only the IPS≥3 remained as an independent unfavorable factor (HR 1.8, 1.2-2.6), as did radiotherapy (HR 0.4, 0.3-0.6) as favorable. For the OS the drug shortage were an independent risk factor (HR 2.2, 1.1-4.3) like IPS ≥3 (HR 2.8, 1.5-5.1). Analyzing the 1-year PFS in the S group according to which chemotherapy protocol they received, those with ABVD or BEACOPP (regardless of the complete dose status) was of 72%, compared to 20% (P 0.001) in the CHOEP regimen. CHOEP regimen in LH patients is ineffective treatment. In times of shortages, continuing with incomplete standard schemes offers better response rates than alternative schemes. Despite Hodgkin's lymphoma is considered a neoplasm with high cure rates when an economic recession followed by an international event (for example a global pandemic) limited our availability for the use of standard treatments, an area of opportunity for considering alternative protocols has risen for resource-limited countries and institutions. [1] Walewski J,et al. CHOP-21 for unfavorable Hodgkin's lymphoma. An exploratory study. Med Oncol. 2010;27(2):262-7 [2] Kolstad A, et al. Standard CHOP-21 as first line therapy for elderly patients with Hodgkin's lymphoma. Leuk Lymphoma. 2007;48(3):570-6 Disclosures No relevant conflicts of interest to declare.

International audience; Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at a high risk of VTE recurrence and bleeding during anticoagulant therapy. The International Initiative on Thrombosis and Cancer is an independent academic working group aimed at establishing a global consensus for the treatment and prophylaxis of VTE in patients with cancer. The International Initiative on Thrombosis and Cancer last updated its evidence-based clinical practice guidelines in 2016 with a free, web-based mobile phone application, which was subsequently endorsed by the International Society on Thrombosis and Haemostasis. The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods, with the support of the French National Cancer Institute. These guidelines were reviewed by an expanded international advisory committee and endorsed by the International Society on Thrombosis and Haemostasis. Results from head-to-head clinical trials that compared direct oral anticoagulant with low-molecular-weight heparin are also summarised, along with new evidence for the treatment and prophylaxis of VTE in patients with cancer.

Veterinaria Mexico OA ISSN: 2448-6760 Cite this as: Sanchez D, Sanchez-Verin R, Corona H, Gutierrez A, Nunez-Ochoa L, Paredes J, Cesarman-Maus G. Canine lymphoma: Pathological and clinical characteristics of patients treated at a referral hospital. Veterinaria Mexico OA. 2019;(2). doi: 10.22201/fmvz.24486760e.2019.2.495. Non-Hodgkin’s lymphomas are common canine cancers with variable demographic and clinical presentations. Their pathological characterization and treatment lag far behind those of humans. We describe consecutive lymphoma patients detected over a one-year period at the National Autonomous University of Mexico (UNAM). Of 4,512 dogs: 220 (4.9%) had a cancer diagnosis, of which 27 (0.6%) had lymphoma (12% of cancer patients). We found an association with Miniature Schnauzers, which represented 18.5% (5/27) of lymphoma patients, but it was only 6.4% (288/4,512) of the dogs studied in this time period ( p

Risk factors for venous thromboembolism in cancer vary between tumours. Leucocytosis, thrombocytosis, tumour histology and vascular compression may drive thrombosis in ovarian cancer. Thrombosis developed in 13.4% of our patients. Higher median leucocyte, neutrophil and monocyte counts were related to thrombosis. Thrombocytosis >350 × 109 /L was frequent (63.8%), but not predictive of thrombosis. Identification of prothrombotic biomarkers may help personalise preventive treatments.

Oncolytic virotherapy has been investigated for several decades and is emerging as a plausible biological therapy with several ongoing clinical trials and two viruses are now approved for cancer treatment in humans. The direct cytotoxicity and immune-stimulatory effects make oncolytic viruses an interesting strategy for cancer treatment. In this review, we summarize the results of in vitro and in vivo published studies of oncolytic viruses in different phases of evaluation in dogs, using PubMed and Google scholar as search platforms, without time restrictions (to date). Natural and genetically modified oncolytic viruses were evaluated with some encouraging results. The most studied viruses to date are the reovirus, myxoma virus, and vaccinia, tested mostly in solid tumors such as osteosarcomas, mammary gland tumors, soft tissue sarcomas, and mastocytomas. Although the results are promising, there are issues that need addressing such as ensuring tumor specificity, developing optimal dosing, circumventing preexisting antibodies from previous exposure or the development of antibodies during treatment, and assuring a reasonable safety profile, all of which are required in order to make this approach a successful therapy in dogs.

Summary Background Venous thromboembolism is a common complication of cancer, but the risk of developing venous thromboembolism varies greatly among individuals and depends on numerous factors, including type of cancer. We aimed to develop and externally validate a clinical prediction model for cancer-associated venous thromboembolism. Methods We used data from the prospective Vienna Cancer and Thrombosis Study (CATS) cohort (n=1423) to select prognostic variables for inclusion in the model. We then validated the model in the prospective Multinational Cohort Study to Identify Cancer Patients at High Risk of Venous Thromboembolism (MICA) cohort (n=832). We calculated c-indices to show how the predicted incidence of objectively confirmed venous thromboembolism at 6 months compared with the cumulative 6-month incidences observed in both cohorts. Findings Two variables were selected for inclusion in the final clinical prediction model: tumour-site risk category (low or intermediate vs high vs very high) and continuous D-dimer concentrations. The multivariable subdistribution hazard ratios were 1·96 (95% CI 1·41–2·72; p=0·0001) for high or very high versus low or intermediate and 1·32 (95% CI 1·12–1·56; p=0·001) per doubling of D-dimer concentration. The cross-validated c-indices of the final model were 0·66 (95% CI 0·63–0·67) in CATS and 0·68 (0·62–0·74) in MICA. The clinical prediction model was adequately calibrated in both cohorts. Interpretation An externally validated clinical prediction model incorporating only one clinical factor (tumour-site category) and one biomarker (D-dimer) predicted the risk of venous thromboembolism in ambulatory patients with solid cancers. This simple model is a considerable improvement on previous models for predicting cancer-associated venous thromboembolism, and could aid physicians in selection of patients who will likely benefit from thromboprophylaxis. Funding Austrian Science Fund, Austrian National Bank Memorial Fund, and participating hospitals.

Background To determine the activity of antithrombin (AT), protein C (PC), and protein S (PS), as well as the frequency of deficiencies of these proteins in a population of healthy Mexican mestizo blood donors. Methods AT, PC, and PS were determined from 1,502 plasma samples of healthy blood donors by using commercial kits in a coagulometer 4 STA (Diagnostica Stago, Asnieres, France). Results A total of 741 women and 761 men were under study. They were divided into age range groups (18–24, 25–34, 35–44, 45–54, and 55–64 years). Activity of AT, PC, and PS was determined. For AT, activity values were specific for each age group according to gender when it had to do with PS, as well as when PC was determined. Frequencies of AT, PC, PS, and activated PC resistance activity deficiencies were obtained from reference levels (RLs) and average levels of this study. Differences were found between both frequencies for AT, PC, and PS, and the average levels obtained were used in this study. The frequencies of the activity deficiencies obtained through the values gotten in this population were: AT, 0.6%; PC, 1.06% (which is higher than the one obtained using the RLs described by commercial kits 0.33% and 0.66%, respectively); and PS, 1% (which is less than 4.5%). Conclusions It is necessary to know the characteristics and biological behavior of the coagulation proteins in the Mexican population because the RLs used have been established for populations that are genetically different.

Thrombosis is a marker of poor prognosis in individuals with solid tumors. The expression of tissue factor (TF) on the cell surface membrane of malignant cells is a pivotal molecular link between activation of coagulation, angiogenesis, metastasis, aggressive tumor behavior and poor survival. Interestingly, thrombosis is associated with shortened survival in solid, but not in lymphoid neoplasias.We sought to study whether the lack of impact of thrombosis on survival in lymphoid neoplasias could be due to a lack of tumor-derived TF expression.We analyzed TF gene (F3) expression in lymphoid (N=114), myeloid (N=49) and solid tumor (N=856) cell lines using the publicly available dataset from the Broad-Novartis Cancer Cell Line Encyclopedia (http://www.broadinstitute.org/ccle/home), and in 90 patient-derived lymphoma samples. TF protein expression was studied by immunohistochemistry (IHC).In sharp contrast to wide F3 expression in solid tumors (74.2%), F3 was absent in all low and high grade T- and B-cell lymphomas, and in most myeloid tumors, except for select acute myeloid leukemias with monocytic component. IHC confirmed the absence of TF protein in all indolent and high-grade B-cell (0/90) and T-cell (0/20) lymphomas, and acute leukemias (0/11).We show that TF in lymphomas does not derive from the malignant cells, since these do not express either F3 or TF protein. Therefore, it is unlikely that thrombosis in patients with lymphoid neoplasms is secondary to tumor-derived tissue factor.

Background The 10th edition of the CHEST Guideline and Expert Panel Report for the treatment of venous thromboembolism (VTE) was recently updated with recommendations on both the choice of anticoagulants and the duration of treatment in diverse clinical scenarios. Method In this paper, we focus on news in the use of direct oral anticoagulants (DOACS), a group of synthetic low molecular weight drugs capable of directly and specifically inhibiting either activated factor X or both free and fibrin- bound thrombin. Results New to the guidelines is the recommendation of the use of DOACS over vitamin K-antagonists (VKA´s) in individuals without cancer who develop VTE. The choice and intensity of anticoagulants is the same for lower and upper extremity thrombosis or for pulmonary embolism. For cancer-related thrombosis low molecular weight heparin is still recommended over the use of VKA´s or DOACS, though high quality evidence for this choice is lacking. If therapy is given beyond three months, remaining on the same anticoagulant is suggested. Re-thrombosis while on regular use of DOACs requires switching to low molecular weight heparins at least for one month. Conclusion Ultimately the choice of anticoagulant will depend on patient-specific factors such as comorbidities, compliance, patient preferences, availability and costs. We address the news in DOAC use in VTE from the perspective of an upper-middle income economy.

Since its discovery as a src kinase substrate more than three decades ago, appreciation for the physiologic functions of annexin A2 and its associated proteins has increased dramatically. With its binding partner S100A10 (p11), A2 forms a cell surface complex that regulates generation of the primary fibrinolytic protease, plasmin, and is dynamically regulated in settings of hemostasis and thrombosis. In addition, the complex is transcriptionally upregulated in hypoxia and promotes pathologic neoangiogenesis in the tissues such as the retina. Dysregulation of both A2 and p11 has been reported in examples of rodent and human cancer. Intracellularly, A2 plays a critical role in endosomal repair in postarthroplastic osteolysis, and intracellular p11 regulates serotonin receptor activity in psychiatric mood disorders. In human studies, the A2 system contributes to the coagulopathy of acute promyelocytic leukemia, and is a target of high-titer autoantibodies in patients with antiphospholipid syndrome, cerebral thrombosis, and possibly preeclampsia. Polymorphisms in the humanANXA2gene have been associated with stroke and avascular osteonecrosis of bone, two severe complications of sickle cell disease. Together, these new findings suggest that manipulation of the annexin A2/S100A10 system may offer promising new avenues for treatment of a spectrum of human disorders.

Venous thromboembolism (VTE) occurs at a higher rate in cancer patients and is frequently associated with well-known prothrombotic risk factors such as prolonged bed rest, central venous catheters, diverse oncological treatments and invasive procedures. Patients may share one or more risk factors. In addition, there seem to be tumor-driven prothrombotic pathways. Thus different tumors may promote activation of coagulation either directly through the expression of procoagulant molecules such as tissue factor or indirectly through the secretion of factors that in turn induce thrombocytosis or leukocytosis. Certain pathways may be more characteristic of a particular cancer cell type. Figuring out what these pathways are in different tumors may help better understand how these risk factors may be targeted. Regarding ovarian cancer, it has been suggested that tumor-driven elevated platelet counts may be the pathway promoting thrombosis (Hisada Y and Mackman N. Blood 2017 :blood-2017-03-743211). Indeed platelet counts above 450,000/ul are reported in close to a third of women with ovarian cancer at diagnosis and murine models show aberrant IL-6/IL-6R expression by malignant cells which induce hepatic thrombopoietin secretion driving thrombocytosis (Stone RL et al N Engl J Med. 2012, 16;366(7):610-8) In fact, high IL-6 levels have been documented in woman with ovarian cancer. Another pathway is tumor-induced leucocytosis through expression of granulocyte colony stimulating factor (G-CSF) by ovarian cancer cells. Broad G-CSF and GCSF receptor expression has been reported across all ovarian cancer primary cell lines. Despite these observations, to our knowledge there are no reports showing that high platelet and/or leukocyte counts indeed correlate with VTE. We sought to evaluate the incidence and prognostic impact of VTE in women with an initial diagnosis of ovarian cancer as well as the prevalence and impact of thrombocytosis or leukocytosis on the incidence of VTE and on survival. We retrospectively looked at a cohort of women with epithelial ovarian cancer admitted at the NCI in Mexico between Jan-Nov 2017. Baseline pretreatment complete blood counts were obtained in 118 consecutive women (mean age 53; 19 - 82 years). We obtained pathological staging data, doppler US and CT images were reviewed for corroboration of extent of VTE. Standard statistical analysis was carried out using SPSS software version 20 (SPSS Inc., Chicago, IL). With a median follow up of 6.5 months (range: 0.5 - 13.7) the incidence of VTE was 13.4% (n=16). Consistent with other reports, patients often developed VTE at diagnosis 44% (n=7/16) associated with tumor activity before having been subjected to treatment. Six women developed VTE in association with surgery (mean of 24.6 days post-operatively; range 4- 58). The other 3 developed VTE in association with neoadjuvant chemotherapy (without surgery). As compared to patients with serous carcinoma, those with endometrioid carcinoma had a higher risk of VTE (8/91: 8.8%; 4/9: 44.4%, respectively, p Despite a high prevalence of thrombocytosis 37.8% (n=45) using cutoff values of >350x 103/□l or 450 x 103/□l. this was not a risk factor for symptomatic thrombosis in our patients. The median platelet counts for all patients were 379 x 103/□l (range 31 - 914 x 103/□l), with no differences in patients with or without VTE: 407x 103/□l (107 - 914 x103/□l) and 378 103/□l (31 - 792 x103/□l) p=0.779, respectively. Notably, pretreatment leukocytosis, neutrophilia and monocytosis were all found to be associated with VTE. Women with VTE had higher median leukocyte counts (8.9 [4.5 - 27.3] vs 7.3 [3.1 - 29.3] 103/□l, p=0.051). Median neutrophyl counts were higher in VTE patients (6.5[3.2 - 23.6] vs. 5.1[1.8 vs.27.4] 103/mm3, p=0.036). Likewise, median monocyte count was higher among VTE patients (0.7 [0.3 - 1.7] vs. 0.5[0.3 - 1.2], p=0.042). Although mortality data is still premature, VTE was associated with a higher mortality rate at both six (27% vs 7%), and at 12 months (40% vs 13.4%; p:0.003) Fig 1. Thrombocytosis did not correlate with survival Fig 2. Thus leukocytosis, but not thrombocytosis, may constitute a prothrombotic pathway in women with ovarian cancer. Disclosures No relevant conflicts of interest to declare.

© 2015, The Author(s). Recent advances in basic cardiovascular research as well as their translation into the clinical situation were the focus at the last “New Frontiers in Cardiovascular Research meeting”. Major topics included the characterization of new targets and procedures in cardioprotection, deciphering new players and inflammatory mechanisms in ischemic heart disease as well as uncovering microRNAs and other biomarkers as versatile and possibly causal factors in cardiovascular pathogenesis. Although a number of pathological situations such as ischemia–reperfusion injury or atherosclerosis can be simulated and manipulated in diverse animal models, also to challenge new drugs for intervention, patient studies are the ultimate litmus test to obtain unequivocal information about the validity of biomedical concepts and their application in the clinics. Thus, the open and bidirectional exchange between bench and bedside is crucial to advance the field of ischemic heart disease with a particular emphasis of understanding long-lasting approaches in cardioprotection.

Research on oncolytic viruses has mostly been directed towards the treatment of solid tumors, which has yielded limited information regarding their activity in hematological cancer. It has also been directed towards the treatment of humans, yet veterinary medicine may also benefit. Several strains of the Newcastle disease virus (NDV) have been used as oncolytics in vitro and in a number of in vivo experiments. We studied the cytolytic effect of NDV-MLS, a low virulence attenuated lentogenic strain, on a human large B-cell lymphoma cell line (SU-DHL-4), as well as on primary canine-derived B-cell lymphoma cells, and compared them to healthy peripheral blood mononuclear cells (PBMC) from both humans and dogs. NDV-MLS reduced cell survival in both human (42% ± 5%) and dog (34% ± 12%) lymphoma cells as compared to untreated controls. No significant effect on PBMC was seen. Cell death involved apoptosis as documented by flow-cytometry. NDV-MLS infections of malignant lymphoma tumors in vivo in dogs were confirmed by electron microscopy. Early (24 h) biodistribution of intravenous injection of 1 × 10(12) TCID50 (tissue culture infective dose) in a dog with T-cell lymphoma showed viral localization only in the kidney, the salivary gland, the lung and the stomach by immunohistochemistry and/or endpoint PCR. We conclude that NDV-MLS may be a promising agent for the treatment of lymphomas. Future research is needed to elucidate the optimal therapeutic regimen and establish appropriate biosafety measures.

Individuals with cancer are at increased risk of developing thrombosis. The prevalence of thrombosis depends on tumor-related factors such as histological type, stage, the use of central venous catheters, or treatment with surgery, chemotherapy or radiotherapy, as well as general prothrombotic factors including advanced age, immobility, obesity, hereditary thrombophilias and comorbidities. Prophylactic or therapeutic treatment of thrombosis should be individualized and will depend on both the risk of thrombosis and bleeding. In this review we intend to update concepts that have changed substantially such as green food-free diet, or the indication of absolute bed rest in patients with recent thrombosis. We propose evidence-based therapeutic strategies regarding the most prevalent clinical problems encountered in patients with cancer and thrombosis.

Thrombosis portends a poor prognosis in individuals with solid tumors. Constitutive expression of tissue factor (TF) by cancer cells is a key in triggering activation of coagulation and promoting aggressive tumor behavior. Though multiple myeloma (MM) is associated with a high frequency of thrombosis in the context of thalidomide and lenalidomide therapy, prognosis is not affected by its occurrence. We sought to determine the expression of TF in MM. F3 (TF gene) expression profiling was analyzed in 55 human MM cell lines (HMCL) and in 223 solid tumor cell lines obtained from GlaxoSmithKline (GSK) Cancer Cell Line Genomic Profiling Dataset. TF was not expressed in any of the 55 HMCLs studied, in sharp contrast to solid tumors, 90% of which showed TF expression. F3 expression was also absent in tumor samples from 239 MM patients. Immunohistochemistry for TF was negative, with either no or focal (1+) staining in 70/73 MM patients. Only three marrow biopsies were moderately (2+) positive either focally or diffusely, suggesting that in rare cases bone marrow microenvironment may support TF expression. General lack of TF expression by neoplastic plasma cells may explain why thrombosis is not predictive of poor outcome, and why aspirin prophylaxis is often effective in MM.

Background and Purpose— Cerebral venous thrombosis (CVT) may be a manifestation of underlying autoimmune disease. Antibodies against annexin A2 (anti-A2Ab) coincide with antiphospholipid syndrome, in which antiphospholipid antibodies (aPLA) are associated with thrombosis in any vascular bed. Annexin A2, a profibrinolytic receptor and binding site for β2-glycoprotein-I, the main target for aPLA, is highly expressed on cerebral endothelium. Here we evaluate the prevalence of anti-A2Ab in CVT. Methods— Forty individuals with objectively documented CVT (33 women and 7 men) and 145 healthy controls were prospectively studied for hereditary and acquired prothrombotic risk factors, classical aPLA, and anti-A2Ab. Results— One or more prothrombotic risk factors were found in 85% of CVT subjects, (pregnancy/puerperium in 57.5%, classical aPLA in 22.5%, and hereditary procoagulant risk factors in 17.5%). Anti-A2Ab (titer >3 SD) were significantly more prevalent in patients with CVT (12.5%) than in healthy individuals (2.1%, P Conclusions— Anti-A2Ab are significantly associated with CVT and may define a subset of individuals with immune-mediated cerebral thrombosis.

The association of thrombosis and gestational morbidity with antiphospholipid antibodies is termed antiphospholipid syndrome (APS). Annexin 2 (A2) is a profibrinolytic endothelial cell surface receptor that binds plasminogen, its tissue activator (tPA), and β2-glycoprotein I (β2GPI), the main antigen for antiphospholipid antibodies. Here, we evaluate A2 as a target antigen in APS. Serum samples from 434 individuals (206 patients with systemic lupus erythematosus without thrombosis, 62 with APS, 21 with nonautoimmune thrombosis, and 145 healthy individuals) were analyzed by enzyme-linked immunosorbent assay (ELISA) and immunoblot for antiphospholipid and A2 antibodies. Anti-A2 antibodies (titer > 3 SDs) were significantly more prevalent in patients with APS (22.6%; venous, 17.5%; arterial, 34.3%; and mixed thrombosis, 40.4%) than in healthy individuals (2.1%, P < .001), patients with nonautoimmune thrombosis (0%, P = .017), or patients with lupus without thrombosis (6.3%, P < .001). Anti–A2 IgG enhanced the expression of tissue factor on endothelial cells (6.4-fold ± 0.13-fold SE), blocked A2-supported plasmin generation in a tPAdependent generation assay (19%-71%) independently of β2GPI, and inhibited cell surface plasmin generation on human umbilical vein endothelial cells (HUVECs) by 34% to 83%. We propose that anti-A2 antibodies contribute to the prothrombotic diathesis in antiphospholipid syndrome.

The molecular mechanisms that finely co-ordinate fibrin formation and fibrinolysis are now well defined. The structure and function of all major fibrinolytic proteins, which include serine proteases, their inhibitors, activators and receptors, have been characterized. Measurements of real time, dynamic molecular interactions during fibrinolysis of whole blood clots can now be carried out in vitro. The development of gene-targeted mice deficient in one or more fibrinolytic protein(s) has demonstrated expected and unexpected roles for these proteins in both intravascular and extravascular settings. In addition, genetic analysis of human deficiency syndromes has revealed specific mutations that result in human disorders that are reflective of either fibrinolytic deficiency or excess. Elucidation of the fine control of fibrinolysis under different physiological and pathological haemostatic states will undoubtedly lead to novel therapeutic interventions. Here, we review the fundamental features of intravascular plasmin generation, and consider the major clinical syndromes resulting from abnormalities in fibrinolysis.

Thrombophilia or prothrombotic state appears when activation of blood hemostatic mechanisms overcomes the physiological anticoagulant capacity allowing a thrombotic event. Thrombosis is the leading worldwide mortality cause and due to its high associated morbidity and mortality, it should be insisted in the opportune identification of a thrombophilic state. The study of thrombophilia identifies individuals at high risk for thrombosis. This meeting was conceived first to analyze the current status of the diagnosis of thrombophilia in Mexico and second to create the base for a national consensus for thrombophilia screening and for the establishment of a national center for laboratory reference and quality control for thrombophilia. Since searching of activated protein C resistance (APCR) and FV Leiden seem to have priority either in the clinical setting and in public health services, it was decided to start with these two abnormalities as a model to analyze the current status of thrombophilia diagnosis in the clinical laboratory. At this time, several thrombophilic abnormalities have been described however, APCR remains the most important cause of thrombophilia, accounting for as much as 20% to 60% of all venous thrombosis. APCR is a consequence of the resistance of activated FV to be inactivated by activated protein C. Procoagulant activity of activated FV increases the risk of thrombosis. Hereditary APCR is almost always due to a point mutation at the nucleotide 1691 of the FV gen inducing an Arg506Glu substitution in FV molecule. This mutation is better known as FV Leiden. Heterocygous carriers of FV Leiden have a thrombotic risk 5 to 10 times higher than general population while the risk for the homocygote state is increased 50 to 100-fold. When activated PC is added to plasma from patients with FV Leiden, this last resists the anticoagulant effect of activated PC. Therefore, thrombin production is not inhibited. This phenomenon is called APCR. The functional test evaluates the partially activated thromboplastin time (aPTT) in a plasma sample before and after adding activated PC. The result is reported as a standardized sensibility index: aPTT post-activated PC/aPTT pre-activated PC. The conclusions of this national reunion pretend to optimize the available resources in our country in order to allow a wide and less-expensive diagnosis of patients with thrombosis.

Oncolytic viruses, either naturally or genetically modified, possess the ability to kill cancer cells. Newcastle Disease Virus (NDV), a type I avian paramyxovirus, has demonstrated a selective ability to kill cancer cells directly as well as through immunostimulation. NDV is able to infect more than 250 species of birds, particularly poultry and is considered a zoonosis, primarily causing conjunctivitis. Importantly, no infections have been reported in mammalian species nor is there evidence of human to human transmission. We use the LaSota strain which is lentogenic (less pathogenic). We seek to study the in vitro oncolytic (lympholytic) potential of NDV on healthy mononuclear and malignant lymphocytes and the in vivo oncolytic therapeutic potential in dogs with lymphoma. LaSota vaccine strain (LSV) was propagated in pathogen –free 9 day old chicken embrios. Viral titers were reported as mean infective dose. Healthy human and canine mononuclear cells as well as a human diffuse large B cell lymphoma cell line (DHL4 cell line) were exposed to medium alone, LSV at a multiplicity of infection (MOI) of 0.1, 10 and 100 or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. Apoptosis was assessed by flow cytometry using annexin V/FITC/IT. Cell counts were carried out at 48 and 72 hs. Data was analyzed by FlowJo 9 and Prisma 6 Softwares. Interestingly, cells at the highest MOI (100) had the same rate of apoptosis as those exposed to chemotherapy, both significantly higher than negative controls. The in vivo response and toxicity to intravenous and intratumoral inyection of LSV in a dog with naturally occurring aggressive, multicentric cutaneous T-cell lymphoma is reported. The patient had a 4 week history of paraplegia due to lymphomatous infiltration of the spinal canal and a 3 week history of rapid development of multiple elevated cutaneous lesions ranging from (from 0.5 by 0.5 cm to 15 cm in diameter and 2 cm in thickness). After informed consent, LSV was given in a single occasion with 1x106 mean (50%) infective dose in tissue culture (TCDI 50) in only one lesion, as well as intravenously with a TCDI 50 of 1x1012 in order to assess response of distant non-virally infiltrated lesions. At four weeks of follow up, no new lesions have appeared. All tumors are responding with complete flattening of the lesions and decrease in diamenter of all lesions. Spontaneous bleeding from the lesions was seen from days 4 through 7 after treatment. All laboratory work up is within normal limits except for indirect hiperbilirrubinemia (2x above normal) in the 4th week (Coombs results are pending). Consecutive samples for histology, electron microscopy and viral load are being evaluated. The patient has had an excellent performance status with no evident clinical toxicity and has begun to wag his tail and show slow movement of the posterior limbs with gain in sensitivity. We have demonstrated the specific in vitro, oncolytic/lympholytic activity of NCV (LaSota) on human lymphoma- derived cells with minimal tropism towards healthy cells. Response to treatment of the first patient (dog) is encouraging. Longer follow up as well as histologic evaluation and viral shedding are being evaluated. Disclosures No relevant conflicts of interest to declare.

Abstract 1139 Background: Central venous catheters (CVC) are cornerstone for the management of cancer patients on chemotherapy, however their use may be associated with venous thrombosis (VTE). The incidence of symptomatic thrombosis varies widely depending on the threshold for ordering diagnostic tests and the population under study. As opposed to lower extremity thrombosis, which is a marker of underlying tumor aggressiveness portending a poor prognosis in cancer patients, it is not clear if CVC-related thrombosis leads to a detriment in patient survival. Objectives: In this retrospective study we address the prognostic implications of symptomatic CVC-and non CVC-related thrombosis. We also evaluate the relevance of thrombotic risk factors reported for cancer-related VTE. Methods: We included 1088 consecutive patients with cancer and CVC followed in the Catheter Clinic at the NCI-Mexico. Of these, only the 506 with breast cancer diagnosis were included in this report. Clinical criteria that prompted the request for a diagnostic doppler ultrasound were dysesthesia, pain, collateral venous circulation and or edema of any extent or duration, affecting the upper extremity, shoulder, or neck. Results: The prevalence of symptomatic CVC-related VTE was 26.1% (132/506), with 61% and 86.7% detected by 60 and 120 days of CVC placement, respectively. The side of catheter placement was not relevant for the development of thrombosis (Right:64/132, Left:68/132). Non-CVC-related upper extremity VTE (33/6.5%) and lower extremity VTE (20/3.9%) were confirmed by doppler ultrasound. Only leucocytosis (>11,000/mm3) prior to thrombosis (but not hemoglobin or platelet count) was more prevalent in individuals with CVC-related VTE, as compared to those without VTE (11.4% vs 4.3%, p=0.006). It is noteworthy that CVC-related upper extremity DVT did not impact overall survival (OS) when compared by bivariate analysis to patients without thrombosis (HR: 0.96, CI 9.75–1.2, p 0.760), with a median survival not reached in either group (18.7% and 18.3% deaths respectively). Non-CVC-related upper extremity VTE may also lack impact on survival (HR:1.16, CI 0.9–1.48, p 0.254), though the number of patients is small. In contrast, the detrimental effect of lower extremity DVT as compared to individuals without thrombosis was significant (HR: 4.6 CI 2.3–9.1 p Conclusions: CVC-associated VTE was detected in a fourth of patients primarily during initial treatment. The site of catheter placement did not affect the risk of VTE. Except for leucocytosis prior to thrombosis, other thrombosis risk score parameters useful for lower extremity VTE may not be applicable to CVC-related thrombosis. Importantly, CVC-related thrombosis was not associated with underlying enhanced aggressive tumor behavior as evidenced by a lack of impact on survival. Disclosures: No relevant conflicts of interest to declare.

Abstract 5132 There is a well- recognized correlation between cancer and aberrant hemostasis. Venous thromboembolism (VTE) in individuals with solid epithelial tumors has been associated with a poor prognosis, with more than three-fold higher risk of early death as compared to cancer patients without thrombosis. The expression of tissue factor (TF), a cell-surface membrane glycoprotein that triggers the activation of coagulation by cancer cells, is one of the main underlying mechanisms linking thrombosis and aggressive tumor behavior. TF is expressed in a variety of solid tumors in association with genetic events affecting oncogenes and tumor suppressor genes. However, the mechanisms of thrombosis in individuals with hematological malignancies may differ from those with solid tumors. We have previously shown that despite the high rate of thrombosis in multiple myeloma, malignant plasma cells only rarely express TF. We sought to determine TF gene (F3) and protein expression in hematological neoplasias. F3 expression profiling was studied on a variety of cell lines established from lymphoid and myeloid neoplasias available at Glaxo Smith Kline (GSK) Cancer Cell Line Genomic Profiling Dataset (https://array.nci.nih.gov/caarray/project/woost-00041). Interestingly, F3 expression was absent in all lymphoid neoplasias studied, in sharp contrast to acute myeloid leukemias (AML) and solid tumors, of which 30 and 90% expressed F3, respectively. Immunohistochemistry (IHC) confirmed the absence of TF protein expression in all indolent and high-grade B-cell lymphomas (99 patients, including germinal center and activated B-cell phenotype diffuse large B-cell lymphomas) and in all T-cell lymphomas/leukemias (20 patients) studied. IHC for TF was also negative in AML (11 patients) but positive in representative solid tumors (breast, pancreas, prostate), except for renal cell carcinoma which has been previously shown to lack TF. We propose that the pathogenesis of VTE associated with hematological neoplasias differs from that of solid tumors. Though TF from non-neoplastic cell sources may still be important for the prothrombotic state often seen in these patients, we show there is no evidence for a role of tumor-derived TF in the development of DVT, nor in neoplastic behavior. Thus, treatments directed against TF may not impact on prognosis in lymphoid, and non TF-expressing myeloid neoplasias. Disclosures: No relevant conflicts of interest to declare.