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The association between malignant neoplasms and venous thromboembolism (VTE) is well recognized, and anticoagulation therapy is commonly administered in the oncological setting. The treatment approach to cancer-associated VTE differs substantially compared to the general population, as chronic low-molecular-weight heparin (LMWH) has been shown to be more effective than vitamin K antagonist (VKA). There are also several challenges specific to the cancer patient. These include an increased risk of bleeding, higher rates of anticoagulation failure, drug interactions, decreased oral intake, chemotherapy-induced thrombocytopenia, and cerebral metastases.

Venous thromboembolism (VTE) is a common complication in cancer patients and anticoagulation (AC) remains the standard of care for treatment. Inferior vena cava (IVC) filters may also used to reduce the risk of pulmonary embolism, either alone or in addition to AC. Although widely used, data are limited on the safety and efficacy of IVC filters in cancer patients. We performed a retrospective review of outcomes after IVC filter insertion in a database of 1270 consecutive patients with cancer-associated pulmonary embolism (PE) at our institution between 2008 and 2009. Outcomes measured included rate of all recurrent VTE, recurrent PE, and overall survival within 12 months. 317 (25%) of the 1270 patients with PE had IVC filters placed within 30 days of the index PE event or prior to the index PE in the setting of prior DVT. Patients with IVC filters had markedly lower overall survival (7.3 months) than the non-IVC filter patients (13.2 months). Filter patients also had a lower rate of AC use at time of initial PE. There was a trend towards higher recurrent VTE in patients with IVC filters (11.9%) compared to non-filter patients (7.7%), but this was not significant (p = 0.086). The risk of recurrent PE was similar between the IVC filter cohort (3.5%) and non-filter group (3.5%, p = 0.99). Cancer patients receiving IVC filters had a similar risk of recurrent PE, but a trend towards more overall recurrent VTE. The filter patients had poorer overall survival, which may reflect a poorer cancer prognosis, and had greater contraindication to AC; therefore these patients likely had a higher inherent risk for recurrent VTE. A prospective study would be helpful for further clarification on the partial reduction in the recurrent PE risk by IVC filter placement in cancer patients.

BACKGROUND: The link between aging, cancer and atrial fibrillation is well known and the appropriate anticoagulation management of non-valvular atrial fibrillation (NVAF) in patients with active cancer is of growing clinical concern. Rivaroxaban has been broadly used for the primary prevention of stroke and systemic embolism in the general population of patients with NVAF. However, individuals with a serious concomitant illness associated with a life expectancy of less than 2 years were excluded from pivotal trials including the ROCKET-AF study, limiting the generalizability of results to patients with active cancer. There is little published evidence on the safety and efficacy of rivaroxaban for NVAF in this specific subgroup. OBJECTIVES: The aim of this study was to assess the safety and efficacy of rivaroxaban in patients with active cancer and NVAF. METHODS: The use of rivaroxaban in cancer patients at Memorial Sloan Kettering Cancer Center (MSKCC) was monitored in the setting of a Quality Assessment Initiative. Patients with active cancer and NVAF treated with rivaroxaban from 1/1/2014 through 3/31/2016 are included in this analysis. Endpoints of interest were defined a priori and include stroke, systemic embolism, major bleeding and clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days (CRNMB). Clinical events were assessed through text searches of medical records. The analysis was performed respecting different times on previous anticoagulation, considering the first 90 days as the acute phase of treatment and contrasting it with the subsequent chronic phase. RESULTS: A total of 163 evaluable patients were included in the analysis, with a median age of 72.0 years (interquartile range=67.0-77.5 years) and 56% of these individuals being men. The majority had a solid tumor (85%), with stage IV disease reported in 50% of cases. The mean CHA2DS2-Vasc score was 3.2 (standard deviation=1.5) and 64% of patients were already in the chronic phase of anticoagulation. Results for the acute, chronic and combined phases of anticoagulation are presented in the Table and plotted in the Figure. The estimated cumulative incidence of ischemic stroke, major bleeding, and CRNMB at 1 year were 1.4% (95% CI=0-3.4%), 1.2% (95% CI=0-2.9%) and 14.0% (95% CI=4.2-22.7%) respectively, after adjusting for competing risks. Interestingly, the cumulative incidence of major bleeding in our cohort is lower than the value reported for the ORBIT-AF registry of cancer patients on dabigatran or a vitamin K antagonist for NVAF, in which the estimated rate of this complication was 5.1/100 patient-years. Lastly, the 1-year cumulative incidence of mortality was 22.6% (95% CI=12.2-31.7%). This high risk of death was present throughout the observation period and reflects the cancer population. One patient died after developing an acute ischemic cerebrovascular insult and a myocardial infarction. There were no deaths related to bleeding and no recorded systemic embolism episodes. CONCLUSIONS: The safety and efficacy profile of rivaroxaban treatment for NVAF in patients with active cancer seems comparable to what was observed for the general population in the ROCKET-AF study, but ideally a prospective study would be required to confirm these findings. Table Cumulative Incidence of Competing risks for Patients in the Acute, Chronic and Combined Phases of Anticoagulation* *Cumulative incidence estimates for the chronic phase are conditional to reaching day 90 of anticoagulation without sustaining an event. The chronic phase was defined as lasting 275 days and the combined period encompasses 365 days. CRNMB: Clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days. *Clinically-relevant non-major bleeding leading to discontinuation of rivaroxabanfor at least7 days. Table. Cumulative Incidence of Competing risks for Patients in the Acute, Chronic and Combined Phases of Anticoagulation*. / *Cumulative incidence estimates for the chronic phase are conditional to reaching day 90 of anticoagulation without sustaining an event. The chronic phase was defined as lasting 275 days and the combined period encompasses 365 days. / CRNMB: Clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days. / *Clinically-relevant non-major bleeding leading to discontinuation of rivaroxabanfor at least7 days. Figure Figure. Disclosures Yu: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Soff:Janssen Scientific Affairs, LLC: Consultancy, Research Funding. Mantha:Janssen Scientific Affairs, LLC: Research Funding.

Background— Alternatively spliced tissue factor (asTF) is a novel isoform of full-length tissue factor, which exhibits angiogenic activity. Although asTF has been detected in human plaques, it is unknown whether its expression in atherosclerosis causes increased neovascularization and an advanced plaque phenotype. Methods and Results— Carotid (n=10) and coronary (n=8) specimens from patients with stable or unstable angina were classified as complicated or uncomplicated on the basis of plaque morphology. Analysis of asTF expression and cell type–specific expression revealed a strong expression and colocalization of asTF with macrophages and neovessels within complicated, but not uncomplicated, human plaques. Our results showed that the angiogenic activity of asTF is mediated via hypoxia-inducible factor-1α upregulation through integrins and activation of phosphatidylinositol-3-kinase/Akt and mitogen-activated protein kinase pathways. Hypoxia-inducible factor-1α upregulation by asTF also was associated with increased vascular endothelial growth factor expression in primary human endothelial cells, and vascular endothelial growth factor–Trap significantly reduced the angiogenic effect of asTF in vivo. Furthermore, asTF gene transfer significantly increased neointima formation and neovascularization after carotid wire injury in ApoE −/− mice. Conclusions— The results of this study provide strong evidence that asTF promotes neointima formation and angiogenesis in an experimental model of accelerated atherosclerosis. Here, we demonstrate that the angiogenic effect of asTF is mediated via the activation of the hypoxia-inducible factor-1/vascular endothelial growth factor signaling. This mechanism may be relevant to neovascularization and the progression and associated complications of human atherosclerosis as suggested by the increased expression of asTF in complicated versus uncomplicated human carotid and coronary plaques.

Our aim was to evaluate clinical management and outcomes in cancer patients who had an indeterminate Computed Tomographic Pulmonary Angiogram (CTPA) for the assessment of pulmonary embolus. We reviewed 1000 CTPA studies and identified 251 limited (indeterminate) CTPA. We examined follow-up imaging and reviewed clinical management decisions and any positive diagnosis of venous thromboembolic disease (VTE) within the subsequent 90 days. 60 patients (23.9%) had a follow-up imaging study within five days. 8 had a positive study for VTE disease within 5 days. 3 patients (1.2%) were placed on anticoagulation therapy based on the limited CT result.

Chemotherapy-induced thrombocytopenia (CIT) can cause delay or reduction in subsequent courses of chemotherapy. Here, we report on a series of 20 patients who had protracted CIT and were treated with romiplostim, a thrombopoietin receptor agonist.We performed a retrospective review of the use of romiplostim for dose-limiting CIT at Memorial Sloan-Kettering Cancer Center from 2010-2012. Romiplostim was initiated at 1-2 mcg/kg weekly, with dose escalation by 1 mcg/kg per week until recovery of platelets (≥ 100 × 10(9)/L). If patients resumed chemotherapy, weekly romiplostim was continued.Romiplostim improved platelet counts in all 20 patients. In 19 of 20 patients, platelet counts of ≥ 100 × 10(9)/L were achieved. The mean dose of romiplostim to achieve adequate platelet recovery was 2.9 mcg/kg (range 1.0-5.1). Sixteen patients achieved platelet recovery by 2 weeks. Fifteen patients resumed cytotoxic chemotherapy with continued romiplostim support and 14 tolerated at least two subsequent cycles of chemotherapy, on schedule, without recurrence of dose-limiting CIT. Sepsis prevented continued chemotherapy in one patient. No resistance to romiplostim was observed. Three deep vein thromboses (DVT) were observed; one of which was a recurrent DVT in a patient who had previously experienced a DVT and was off anticoagulation. Three DVTs within 20 patients is within the anticipated thrombosis rates of patients with active cancer on chemotherapy.Romiplostim resulted in improvement in platelet counts, allowing resumption of chemotherapy without recurrence of dose-limiting CIT. No treatment-related toxicity was observed, but this would need to be confirmed in a larger, prospective trial. Our series differs from prior studies in that we selected only those patients who had already demonstrated persistent thrombocytopenia, and we continued weekly romiplostim during chemotherapy. Romiplostim may be a safe and effective treatment for CIT.

Background: Cancer-associated thrombosis (CAT) is a leading cause of death in cancer patients after cancer itself. Risk factors for CAT include tumor type/stage, body mass index (BMI), blood cell counts and chemotherapy exposure. These factors form the basis of prediction algorithms for CAT risk, including most notably the Khorana Risk Score. However, significant limitations exist with these currently-available risk prediction models. Emerging data suggest that a tumor's molecular profile can impact venous thromboembolism (VTE) risk. Mutations of ALK, EGFR, IDH1, ROS1, and KRAS for example have been shown to modulate the risk of CAT; however, these studies were limited by the number of mutations and specific tumor types analyzed. We hypothesized that extended molecular testing in a large patient cohort would allow for improved detection of molecular signatures associated with CAT. We analyzed deep-coverage targeted sequencing data (up to 341 genes) of tumor samples from 11,776 cancer patients to identify gene mutations associated with VTE. Methods: Adult patients with any solid tumor diagnosis who had their tumors sequenced using MSK-IMPACT from 1/2014 to 12/2016 were retrospectively assessed for CAT events using redundant algorithmic methods and individual chart reviews. The endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis (DVT). An episode of upper extremity DVT was considered a competing event. The observation period was limited to 365 days after IMPACT blood control sampling. Cause-specific Cox proportional hazards regression was used to test for an association between gene and CAT risk, adjusting for clinical covariates including age, cancer type, cytotoxic chemotherapy (time-dependent), anticoagulant use, stage (metastatic/non-metastatic) and prior history of VTE. Separate multivariate models evaluated the association for the 60 most frequently-mutated genes identified, along with ALK, MET, ROS1 which were included based on existing literature suggesting an effect on VTE risk. Final p-values were adjusted for false discovery using the Benjamini-Hochberg procedure, and the threshold for statistical significance was set at 0.10. Patients with multiple cancer diagnoses were excluded. Results: Out of 11,776 individuals we observed 727 CAT events (6.2% of cohort). The most commonly represented tumor types were lung (18%), breast (15%) and colorectal cancer (10%); see Figure for a breakdown of CAT incidence by tumor type. Most (72%) of patients were metastatic at time of IMPACT testing and 4% were on anticoagulation therapy. Statistically significant predictors of CAT included cytotoxic chemotherapy (HR 1.61 [1.37-1.9]; p Conclusions: This work is the first large-scale analysis to elucidate cancer-specific genomic determinants of CAT. Using a large patient cohort, we found that somatic tumor mutations in STK11, KRAS, IDH1, KEAP1, and MET modulate the risk of venous thromboembolism in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types. We hope these findings will ultimately translate into improved risk stratification for patients at risk of CAT. Disclosures Mones: Janssen: Research Funding. Iyengar:Puma Biotechnology: Consultancy; Novartis: Consultancy. Hyman:AstraZeneca: Consultancy, Research Funding; Fount: Consultancy, Equity Ownership; Pfizer: Consultancy; Chugai Pharma: Consultancy; Loxo Oncology: Research Funding; Boehringer Ingelheim: Consultancy; Bayer Pharmaceuticals: Consultancy, Research Funding; Genentech / Roche: Consultancy; PUMA Biotechnology: Research Funding; CytomX Therapeutics: Consultancy. Park:Merck: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Astellas: Research Funding; Ipsen: Consultancy. Khorana:Bayer: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy. Soff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Mantha:Medical Case Management Group: Consultancy; MJH Live Events: Other: Give CME talk; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; Daboia Consulting LLC: Equity Ownership; Janssen: Research Funding.

1555 Background: Thrombocytopenia is a common toxicity of chemotherapy, yet there are limited data on its occurrence in routine clinical practice. Methods: Using structured patient-level data from the Flatiron Health EHR-derived database, we assessed risk (3-month cumulative incidence) of chemotherapy-induced thrombocytopenia (CIT) in adult patients (2012-2017) based on platelet counts, overall and by each grade of CIT, cancer type, and chemotherapy regimen (Table); and the co-occurrence of other hematologic abnormalities. Results: Of 15,521 solid tumor patients who initiated chemotherapy, 13% had evidence of CIT within 3 months (platelet count 9/L), 4% had grade 3 (25 to 9/L) and 2% had grade 4 (9/L) CIT. Of the solid tumors examined, incidence was highest in melanoma patients. In hematologic malignancies (N = 2,537), 3-month risk was even higher with nearly 30%, 16%, and 12% having any grade, grade 3 and 4 CIT, respectively; and the greatest risk being in multiple myeloma patients. Anthracycline-based regimens were associated with the highest risk of CIT (7% grade 3; 4% grade 4), followed by gemcitabine- and platinum-based regimens. Anemia often accompanied first evidence of CIT (49%); isolated thrombocytopenia occurred in 15%. Conclusions: This study provides a current snapshot of CIT risk in a large sample of adult patients undergoing chemotherapy in routine clinical practice, highlighting patients at highest risk for CIT and underscoring the complexity of managing cancer treatment. [Table: see text]

Acute promyelocytic leukemia (APL) is associated with a complex coagulopathy. In spite of substantial recent improvements in treatment regimens, hemorrhagic death remains the main cause of induction failure. In this review, we delineate recent understanding of the pathophysiology and management of the hemorrhagic diathesis of APL.Laboratory and clinical data suggest that the malignant leukocytes mediate the hemorrhagic diathesis associated with APL through multiple mechanisms which lead to a combination of consumptive coagulopathy and primary hyperfibrinolysis. Exposure of tissue factor and Annexin II by the leukemic blasts is the main determinants of these processes. Promyelocyte-derived microparticles have recently been implicated in the coagulopathy as well. Total white cell count and platelet count have emerged as good general predictors of hemorrhagic death, along with the different routine hemostatic parameters. Prompt treatment with all-trans retinoic acid, with or without arsenic trioxide, is the most important step in preventing bleeding complications. Repletion of coagulation factors and platelets with blood products remains the mainstay of supportive treatment, whereas the role of recombinant soluble thrombomodulin is currently being investigated.The coagulopathy of APL is multifactorial, with both disseminated intravascular coagulation and primary hyperfibrinolysis mediated largely by the malignant leukocytes.

Sodium salicylate is an inexpensive, readily available anti-inflammatory agent which inhibits NF-κB in in vitro models. We examined whether it was possible to safely achieve and maintain salicylate levels known to inhibit NF-κB in vitro in 11 patients with MDS or AML taking sodium salicylate. Most patients achieved the target blood salicylate level (20-30mg/dL) with acceptable toxicity, including reversible grade 1/2 elevations of hepatic transaminases (n=4) and ototoxicity (n=4). One patient had grade 3/4 elevations in AST/ALT. This study suggests that sodium salicylate may be safely combined with conventional chemotherapy regimens which are not associated with significant ototoxicity or hepatotoxicity.

After more than 50 years of thrombosis treatment and prophylaxis being based on heparin and vitamin K antagonists, a new generation of oral, direct anticoagulants is now available. The past 5 years have brought a strikingly large number of trials that evaluated these new oral anticoagulants in a range of clinical trials, particularly nonvalvular atrial fibrillation, thrombosis prophylaxis after major joint replacement surgery, treatment of venous thromboembolic events, and, most recently, acute coronary syndrome. These studies have been notably similar in design between the drugs for specific indication. This review focuses on the 3 drugs that either have recently been approved by the US Food and Drug Administration (dabigatran and rivaroxaban) or have the most mature phase III clinical data (apixaban).

BACKGROUND: Pancreatic adenocarcinoma is among the most common malignancies associated with thromboembolic events (TEs); however, reported incidence figures vary significantly and contain small patient cohorts. Pancreatic cancer-specific thrombosis studies examining the correlation between clinical variables, including thrombosis timing and the impact of thrombosis on survival, have not been reported. METHODS: Survival analyses were performed relating to the development and timing of a TE in 1915 patients administered chemotherapy at Memorial Sloan-Kettering Cancer Center with invasive exocrine pancreatic cancer from January 1, 2000 to December 31, 2009. TE timing, relative to clinical parameters including laboratory data, erythropoietin-stimulating agent use, and body mass index (BMI), were also analyzed. RESULTS: A thrombosis was identified in 690 (36%) patients. After adjusting for patients with pancreatic surgery and thrombosis (n = 127), developing a TE significantly increased the risk of death (hazard ratio [HR], 2.6; 95% confidence interval [CI], 2.3-2.8; P < .01). Patients with an early TE (within 1.5 months from pancreatic cancer diagnosis) had a significantly higher risk of death (HR, 2.1; 95% CI, 1.7-2.5; P < .01) compared with patients with late TE or no TE. Erythropoietin-stimulating agent use and an elevated international normalized ratio were associated with significantly shorter time to thrombosis. Low BMI was associated with significantly longer time to thrombosis. CONCLUSIONS: TEs are common in exocrine pancreatic cancer, with coagulopathy, erythropoietin-stimulating agent use, and underweight BMI influencing thrombosis timing. TEs, particularly early ones, confer a significantly worse prognosis, suggesting a biological significance, underscoring the relevance of ongoing prophylaxis trials, and raising the question of whether early TEs should be considered a stratification factor for clinical trials. Cancer 2012;118: 3053–61. © 2011 American Cancer Society.

Background: Folate deficiency is classically taught as a cause of anemia; with the advent of widespread dietary fortification, the prevalence of folate deficiency in the general population has decreased significantly. Recent studies have examined the yield of testing for folate deficiency and questioned its value, demonstrating negligible clinical yield across multiple care settings. However, patients with cancer are at increased high risk of folate deficiency. To our knowledge, no studies have specifically examined patterns and yield of folate testing among inpatients at a cancer institution. We sought to determine the yield of folate testing in this setting, and to characterize the patients found to have folate deficiency. Methods: We used our institutional clinical database to identify all inpatient folate and red blood cell folate (RBCF) tests done at our institution in calendar-year 2017. We included testing done in our Urgent Care Center in patients who were subsequently admitted to the hospital. We defined folate deficiency as < 4.0 ng/mL according to our lab reference. Among patients with folate deficiency, we performed manual chart review to evaluate the presence of known risk factors for folate deficiency: alcohol abuse, gastrointestinal malabsorption, pancreatic insufficiency, culprit medications, end-stage renal disease requiring hemodialysis, malnutrition (defined as BMI Results: A total of 1013 serum folate level tests were performed in 960 patients; one patient underwent RBCF testing alone. A majority of tests were done on medical rather than surgical patients (85% vs 13%). Overall, 69 (6.8%) of patients were found to have folate deficiency. Almost all patients with folate deficiency were anemic. Surprisingly, macrocytosis was infrequent in patients with folate deficiency in cancer; over 90% of patients had normal or even low MCV. Among 69 patients with folate deficiency, less than half the patients (N=28, 41%) had an identifiable risk factor for folate deficiency, most commonly medications. Identified malabsorption/ malnutrition, hemolysis, and hemodialysis collectively accounted for 7.2%, and no case was attributed to alcoholism. The degree of anemia was not significantly different between the patients with folate deficient and those with adequate folate levels. The mean MCV values were normal in both the folate deficient and folate replete patients. Co-testing of vitamin B12 levels was performed in 859 (85%) of testing instances; 23 (2.7%) had isolated B12 deficiency and 3 (0.3%) had concurrent folate and B12 deficiency. Conclusions: In our cohort of hospitalized cancer patients, folate testing identified deficiency in 6.8%, notably higher than in other studies of general populations. A higher rate of folate deficiency may have been present in this study due to the comorbidities associated with advanced malignancies and their treatments. Surprisingly, folate deficiency did not correlate with macrocytosis, which is characteristic of the folate deficiency-associated anemia in non-cancer patients. This may reflect more acute development of deficiency, or the presence of multiple factors affecting red cell production, thus "masking" the macrocytosis. Neither the degree of anemia nor the MCV provided guidance as to the presence of folate deficiency and a minority of deficient patients had identifiable risk factors. Folate deficiency, while not common in hospitalized cancer patients, needs to be considered in the presence of anemia, even in the absence of macrocytosis. Disclosures Soff: Amgen: Research Funding; Janssen: Research Funding.

Introduction: Cancer associated thrombosis (CAT) is a common complication of cancer, associated with significant morbidity and mortality. While incidence varies with cancer type, stage, chemotherapy, and other factors, estimates are that up to 20% of cancer patients will experience at least one venous thromboembolic (VTE) episode. VTE consist of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and there is a spectrum of vascular involvement. DVTs are classified as proximal (popliteal vein or above) and PE may be subsegmental, segmental, lobar, main, or saddle embolism. Our standard approach has been to treat all DVTs and all PEs in cancer patients, regardless of the size of the involved vessel. However, it is not clear if the risk of recurrent VTE in a patient with a "small" subsegmental PE, or a calf vein DVT, is comparable to that of an individual with a larger vascular involvement. In this study, we characterized the largest vessel involved in the initial VTE episode, and the relationship with recurrent VTE. Methods: All patients at MSKCC with CAT are monitored within an existing Quality Assessment initiative. From 1/1/2014 through 10/31/2016, 1072 patients with CAT were treated with rivaroxaban (Riva). (The overall outcomes of this cohort are the subject of a separate abstract.) In this study we compared the rate of recurrent VTE in patients with a distal (calf) DVT with proximal DVT, and PE. We designated the most proximal, or largest thrombosed vessel. As patients with a PE do not routinely undergo Doppler leg ultrasound, we are unable to differentiate PE with a DVT from those without. We also analyzed if the PE was unilateral or bilateral. We used competing risk endpoints for the purpose of this analysis, including recurrent VTE, major bleeding, clinically relevant non-major bleeding leading to discontinuation of Riva, and death. Results: In the Table, we present the data on the relationship of the initial VTE and the risk of recurrence. The majority of CAT events (55%) were PE. There were no significant differences in the rates of recurrent VTE between patients with a PE, a distal DVT or proximal DVT. Within patients with a PE as the index VTE event, there was no significant association between the risk of recurrent VTE and the size of the PE. A subsegmental PE as an index event was associated with a comparable rate of recurrent VTE when compared with segmental and more proximal vessel involvement. The only meaningful trend towards a higher rate of recurrent VTE was in patients whose index event was a bilateral PE, compared with unilateral, although this association did not reach statistical significance. Conclusions: The goal of this Quality Assessment initiative was to evaluate the risk of recurrent VTE in cancer patients to determine if distal DVT's or subsegmental PEs had a significantly lower rate of recurrence than other VTE episodes. Our analysis indicated that the risk of recurrent VTE is not related to the size of the index thrombosed vessel. Within PE, from large, proximal index events through to subsegmental PE, the risk of recurrent VTE is comparable. Similarly, there was only a trend towards lower risk of recurrent VTE in patients with an index distal DVT, versus proximal DVT. But this association was not statistically significant, with overlapping 95% confidence intervals. The one parameter that appeared to have the strongest prediction of recurrent VTE was patients with bilateral PE, versus unilateral. However, this too was only a trend, not statistically significant, and was not one of the parameters within our initial hypotheses. We were unable to identify any subgroup of index VTE, based on vessels involved, that had a significantly lower rate of recurrent VTE while on anticoagulation. Within cancer patients, a subsegmental PE or a distal, calf vein DVT are associated with a risk of recurrent VTE comparable to thrombosis of larger vessels. Table Table. Disclosures Soff: Janssen: Research Funding; Amgen: Research Funding. Mantha:Janssen: Research Funding; GLG: Consultancy; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy.

Background: Patients on systemic therapy for cancer are at varying risk for venous thromboembolism (VTE) and its consequences. Thromboprophylaxis is recommended in hospitalized medical and surgical cancer patients, but most VTE occurs in ambulatory cancer patients where risk can be estimated with a validated score. However, the benefit of extended outpatient thromboprophylaxis is uncertain with heparins and has not been tested with direct oral anticoagulants. Methods: We conducted a double-blind, randomized, placebo-controlled, parallel-group, multicenter study in adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE (defined as Khorana score ≥ 2). Enrolled subjects were screened for deep-vein thrombosis (DVT) and if none found randomized 1:1 to rivaroxaban 10 mg once daily or placebo up to day 180. Subjects were screened with lower extremity ultrasounds every 8 weeks on study. Primary efficacy endpoint was a composite of objectively confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper- or lower-extremity distal DVT, symptomatic or incidental pulmonary embolism and VTE-related death. ISTH-defined major bleeding was the primary safety endpoint. All endpoints were adjudicated by blinded independent committees. Analyses for efficacy endpoints were conducted for intent-to-treat (ITT) population (all randomized patients) for the up-to-day 180 observation period (primary) and the on-treatment period (supportive). Safety analyses were conducted for on-treatment period only for patients who received at least one dose of study drug. Results: Of 1,080 patients who provided consent, 49 (4.53%) had DVT on baseline screening and another 190 screen-failed due to other reasons. Of 841 randomized patients, 274 (32.6%) had pancreatic cancer; 698 (83%) were white and 428 (50.9%) were male. The primary efficacy endpoint occurred in 25 of 420 patients (5.95%) and 37 of 421 patients (8.79%) (HR, 0.66; 95% CI, 0.40 to 1.09; p=0.101) in the rivaroxaban and placebo groups respectively (number needed to treat, NNT=35) in the up-to-day 180 observation period (Figure 1A). Of all patients with VTE, 38.70% experienced events after discontinuing study drug. In a pre-specified analysis of all randomized patients during the on-treatment period, the primary endpoint occurred in 11 of 420 patients (2.62%) and 27 of 421 (6.41%) in rivaroxaban and placebo groups respectively (HR 0.40, 95% CI 0.20 to 0.80, p=0.007) (NNT=26) (Figure 1B). Major bleeding occurred in 8 of 405 (1.98%) in the rivaroxaban group and in 4 of 404 (0.99%) patients in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49; p=0.265) (number needed to harm, NNH=101). Clinically relevant non-major bleeding occurred in 2.72% and 1.98% of rivaroxaban and placebo groups, respectively (HR, 1.34; 95% CI, 0.54 to 3.32; p=0.53) (NNH=135). Adverse events were comparable between groups. For secondary efficacy endpoints, a pre-specified analysis of the composite of primary endpoint with addition of arterial and visceral thromboembolic events in the up-to-day 180 observation period showed significantly fewer events in rivaroxaban versus placebo group (6.90% versus 10.70% respectively; HR, 0.62; 95% CI: 0.39, 0.99; p=0.04). All-cause mortality occurred in 20.0% of patients in rivaroxaban group and 23.8% in placebo group (HR=0.83, 95% CI 0.62, 1.11; p=0.213). A pre-specified composite of the primary endpoint with all-cause mortality occurred in 23.1% of patients in rivaroxaban group and 29.5% in placebo group (HR 0.75; 95% CI 0.57 to 0.97; p=0.03) (Figure 1C). Conclusions: Rivaroxaban significantly reduced VTE and VTE-related death during the on-treatment period but not during the full study period; over one-third of events occurred post discontinuation of study drug. The incidence of major bleeding was low. The Khorana risk score cut-off of ≥2 identified cancer patients at high risk of thrombotic events both at baseline (4.53%) and during study (8.79% with additional 1.66% arterial events in placebo group). These results should inform future recommendations regarding thromboprophylaxis in at-risk ambulatory cancer patients. (Funded by Janssen; ClinicalTrials.gov number, NCT02555878) Figure 1 Figure 1. Disclosures Khorana: Parexel: Other: Personal fees and non-financial support for travel; Sanofi: Consultancy, Other: Personal fees and non-financial support for travel; Pfizer: Consultancy, Other: Personal fees and non-financial support for travel; Janssen: Consultancy, Other: Personal fees, Research Funding; TriSalus: Other: Personal fees; Halozyme: Other: Personal fees and non-financial support for travel; Seattle Genetics: Other: Personal fees and non-financial support for travel; AngioDynamics: Other: Personal fees and non-financial support for travel; LEO Pharma: Other: Personal fees and non-financial support for travel; Medscape/WebMD: Other: Personal fees and non-financial support for travel; Pharmacyclics: Other: Personal fees; PharmaCyte: Other: Personal fees; Bayer: Consultancy, Other: Personal fees and non-financial support for travel. Soff:Janssen: Research Funding; Amgen: Research Funding. Kakkar:Bayer AG: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Daiichi Sankyo Europe: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sanofi S.A.: Consultancy; Verseon: Consultancy. Vadhan-Raj:AMAG Pharmaceuticals, Inc: Other: received funding from Amag to support clinical trial; Janssen: Consultancy, Research Funding. Riess:Janssen Scientific Affairs: Other: Travel reimbursement; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Wun:Eli Lilly, Inc.: Research Funding; Emmaus, Inc.: Membership on an entity's Board of Directors or advisory committees; Glycomimetics, Inc.: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees. Streiff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Other: outcome adjudication committee; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Roche: Research Funding; Portola: Consultancy, Research Funding. Garcia:Shingoi: Consultancy; Portola: Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Bristol Meyers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Retham Technologies LLC: Consultancy; Genzyme Corporation: Consultancy; Alexion: Consultancy. Liebman:Janssen (Johnson & Johnson): Other: steering committee of the CASSINI trial during the conduct of the study. Belani:Janssen: Consultancy. O'Reilly:3DMed, Agios, AlignMed, Amgen, Antengene, Aptus, ASLAN, Astellas, AstraZeneca, Bayer, BeiGene, Bioline, BMS, Boston Scientific, Bridgebio, CARsgen, Celgene, CASI, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis, Genoscience, Gilead, Halozyme: Consultancy; Hengrui, Incyte, Inovio, Ipsen, Jazz, Janssen, Kyowa Kirin, LAM, Lilly, Loxo, Merck, Mina, NewLink Genetics, Novella, Onxeo, PCI Biotech, Pfizer, PharmaCyte, Pharmacyclics, Pieris, QED, RedHill, Sanofi, Servier, Silenseed, Sillajen, Sobi, Targovax: Consultancy; Janssen: Research Funding; Acta Biologica, Agios, Array, AstraZeneca, Bayer, BeiGene, BMS, CASI, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, MabVax, Novartis, OncoQuest, Polaris Puma, QED, and Roche: Research Funding; Tekmira, twoXAR, Vicus, Yakult, and Yiviva: Consultancy. Patel:Janssen Pharmaceuticals: Research Funding. Yimer:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Epizyme: Equity Ownership; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership. Wildgoose:Janssen Scientific Affairs: Employment; Johnson & Johnson: Equity Ownership. Burton:Janssen Pharmaceuticals: Employment; Johnson & Johnson: Equity Ownership. Vijapurkar:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Kaul:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Eikelboom:AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, GlaxoSmithKline, Janssen, sanofi-aventis, and Eli Lilly: Honoraria, Research Funding; Heart and Stroke Foundation: Other: Personnel award. Bauer:Janssen: Consultancy. Kuderer:Celldex: Consultancy; Mylan: Consultancy, Other: Travel, Accommodations, Expenses; Myriad Genetics: Consultancy; Halozyme: Consultancy; Coherus Biosciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen Scientific Affairs, LLC: Consultancy, Other: Travel, Accommodations, Expenses; Pfizer: Consultancy; Bayer: Consultancy. Lyman:Halozyme; G1 Therapeutics; Coherus Biosciences: Consultancy; Generex Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Research support.

Introduction: Venous thromboembolism (VTE) is a common complication of cancer, associated with significant morbidity and mortality. Low-molecular weight heparin (LMWH), the most widely used anticoagulant in this setting, is expensive and burdensome. Rivaroxaban (Riva) was approved for treatment of VTE in 2012, but there is limited experience in cancer-associated thrombosis (CAT). In 2014, we established a Clinical Pathway (CP) to guide use of rivaroxaban (Riva) for CAT at Memorial Sloan Kettering Cancer Center. We were concerned that a direct oral anticoagulant (DOAC) would be more likely than LMWH to cause upper gastrointestinal (GI) bleeding in the presence of abnormal mucosa. DOACs have partial renal clearance and are active in the urine, in contrast to LMWH, and we also anticipated increased genitourinary (GU) tract bleeding in the presence of GU lesions. Therefore, the key to our CP has been to recommend against use of Riva or other DOAC in the setting of active (GI) or (GU) tract lesions. As the elderly are known to be at higher risk of bleeding from anticoagulation, the CP recommended reduced dose Riva in patients≥75 year old (yo), (10 mg bid X 3 wks., followed by 15 mg daily). Otherwise, we adhere to the standard FDA approved guidelines. We published a 200-patient cohort in 2016 demonstrating rates of recurrent VTE and bleeding that were at least as low as historical controls with LMWH. This past year, two randomized clinical trials were published comparing a DOAC with dalteparin ("Hokusai VTE Cancer" of edoxaban, Raskob G.E. et al, NEJM, 2017, and "Select-D" of Riva, Young A.M. et al, JCO 2018). Both studies showed a trend towards better efficacy with the DOAC, but with increased GI/GU bleeding. However, those studies did not exclude patients with known GI/GU lesions. We now report our expanded experience with Riva treatment of CAT, confirming the safety and efficacy of Riva treatment of CAT when guided by our CP. Methods: From 1/1/2014 through 10/31/2016, 2000 patients at MSKCC received Riva. 1072 had CAT, defined as a lower extremity DVT and/or PE in a patient with active cancer or receiving cancer therapy. (The other 928 patients did not have active cancer, or received Riva for other indication). All patients treated with Riva for CAT are included in this analysis, even in the presence of active GI/GU lesions. Recurrent VTE, major bleeding (MB), clinically relevant non-major bleeding (CRNMB) leading to discontinuation of Riva, and death were competing risk endpoints for the purpose of the analysis. We also evaluated the outcomes of the subgroup of patients ≥75 yo. Results: At 6 months, the cumulative incidence for the various endpoints estimated within a competing risks framework were; recurrent VTE (4.2%), MB (2.2%), CRNMB (5.5%). Overall, the 6-month incidence of death was 22.2%. In the elderly patients, the risks of recurrent VTE and bleeding were similar to the Conclusions: In our expanded experience of Riva therapy for CAT, applying our CP, we continue to maintain low rates of recurrent VTE and bleeding. Allowing for differences in methodology between a cohort study and randomized clinical trials, the rate of recurrent VTE was as low as the DOAC arm in Hokusai VTE Cancer and Select-D studies. Further, by applying the exclusion criteria in our CP, and not treating patients with known GI/GU lesions, we achieved a low rate of bleeding compared with the DOAC treatment arms in the two recent randomized clinical trials. Those two trials demonstrated bleeding rates greater than LMWH, particularly GI/GU bleeds. We saw no increased rates of recurrent VTE or bleeding in the elderly, which is reassuring, but we cannot conclude if reduced dose is of benefit. These new expanded observations further support the validity of our CP. The key to anticoagulation choice for CAT is not which anticoagulant is "better," but rather which anticoagulant to choose for a specific patient. In the absence of GI/GU contraindications, Riva provides effective and safe anticoagulation, at substantially lower cost and burden to the patient than LMWH. In contrast, we propose that LMWH is preferable in patients with GI/GU lesions. (We are now obtaining specific data for that subgroup). Disclosures Soff: Amgen: Research Funding; Janssen: Research Funding. Mantha:Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; GLG: Consultancy; Janssen: Research Funding.

BACKGROUND: To define the clinicopathologic and prognostic features of patients with human T-cell lymphotropic virus type-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATLL) in North America, standard criteria were used to identify patients with ATLL. METHODS: Statistical analyses used included descriptive statistics, Kaplan-Meir survival analysis, and recursive partitioning. RESULTS: Eighty-nine patients were identified between August 1992 and May 2007, including 37 (41.6%) males and 52 (58.4%) females with a median age of 50 years (range, 22-82 years). All but 6 patients had immigrated to the United States from the Caribbean, Latin America, or Africa. The acute subtype predominated (68.5%). The majority of patients received a combination-alkylator-based chemotherapy regimen in the front-line setting (72.6%). The most common regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone at standard doses or attenuated and/or with methotrexate (CHOP-like), which produced an overall response rate of 64.1%. Despite initial responses to therapy, the median overall survival for all subtypes was 24 weeks (range, 0.9-315 weeks). Although the International Prognostic Index and Prognostic Index for peripheral T-cell lymphoma unspecified identified subsets of patients, these models were not completely predictive. A recursive partitioning analysis was performed on the data, which successfully identified 3 prognostic categories based on Eastern Cooperative Oncology Group performance status, stage, age, and calcium level at diagnosis. CONCLUSIONS: This series proposed a new prognostic model for patients with HTLV-1-associated ATLL and confirmed a poor outcome for these patients in North America.

Increased tissue factor (TF) expression is observed in many types of cancer, associated with more aggressive disease, and in thrombosis. The mechanism by which TF promotes tumor growth remains unclear. Anticoagulation has been shown to result in a trend toward improved survival; no direct antitumor effect has been shown in cancer patients. Alternatively spliced tissue factor (asTF) was recently described, in which exon 5 is deleted. Because of a frame-shift in exon 6, the transmembrane and cytoplasmic domains are replaced with a unique COOH-terminal domain, making asTF soluble. Both alternatively spliced human tissue factor (asHTF) and full-length tissue factor (flTF) are expressed in human pancreatic cancer lines and in pancreatic cancer specimens. We studied the role of asHTF and flTF in a mouse model of pancreatic cancer. Although lacking procoagulant activity, asTF promotes primary growth of human pancreatic cancer cells in mice and augments tumor-associated angiogenesis. This body of work suggests a new paradigm for the role of TF in pancreatic cancer: that asHTF contributes to cancer growth, independent of procoagulant activity.

Introduction: Cancer patients can develop hypercoagulability, leading to stroke. The pathophysiology of cancer-mediated hypercoagulability, however, is poorly understood and biomarkers associated with stroke in cancer patients are uncertain. Methods: We performed a pilot cross-sectional study at a tertiary-care cancer center to evaluate potential hematological biomarkers of stroke in cancer patients. From October 2013 through May 2014, we prospectively identified 15 inpatients with active systemic cancer and acute ischemic stroke and 15 inpatients with active systemic cancer and no stroke. Using collected plasma, we compared six potential biomarkers of stroke, selected in advance based on expert opinion and prior data, which included markers of coagulation (thrombin-antithrombin complex and D-dimer), platelet function (P-selectin), and endothelial activation state (sICAM-1, vICAM-1, and thrombomodulin). We used the Wilcoxon rank-sum test to compare biomarker levels between groups. Results: Each group comprised 14 patients with solid cancer and one patient with hematological cancer. All patients in the cancer and stroke group had stage 4 disease, while only 60% of the cancer and no stroke group had stage 4 disease. Age and demographics were similar between groups. Median levels of thrombin-antithrombin complex, D-dimer, P-selectin, sICAM-1, and vICAM-1 were significantly increased in cancer patients with stroke, but thrombomodulin was not (Table). Our results were substantially unchanged in a sensitivity analysis limited to patients with only stage 4 cancer. Conclusion: These preliminary data suggest that thrombin-antithrombin complex, D-dimer, P-selectin, sICAM-1, and vICAM-1 could serve as the focus of future prospective studies to elucidate the potential predictive, diagnostic, or etiologic role of hematological biomarkers for stroke in the cancer population.

Angiostatin4.5 (AS4.5) is the product of plasmin autoproteolysis and consists of kringles 1 to 4 and ∼85% of kringle 5. In culture, cancer cell surface globular β-actin mediates plasmin autoproteolysis to AS4.5. We now show that plasminogen binds to prostate cancer cells and that the binding colocalizes with surface β-actin, but AS4.5 does not bind to the cell surface. Plasminogen and plasmin bind to immobilized β-actin similarly, with a Kd of ∼140 nmol/L. The binding is inhibited by ε-aminocaproic acid (εACA), indicating the requirement for a lysine-kringle domain interaction. Using a series of peptides derived from β-actin in competitive binding studies, we show that the domain necessary for plasminogen binding is within amino acids 55 to 69 (GDEAQSKRGILTLKY). Substitution of Lys61 or Lys68 with arginine results in the loss of the ability of the peptide to block plasminogen binding, indicating that Lys61 and Lys68 are essential for plasminogen binding. Other actin peptides, including peptides with lysine, did not inhibit the plasminogen-actin interaction. AS4.5 did not bind actin at concentrations up to 40 μmol/L. Plasminogen, plasmin, and AS4.5 all contain kringles 1 to 4; however, kringle 5 is truncated in AS4.5. Isolated kringle 5 binds to actin, suggesting intact kringle 5 is necessary for plasminogen and plasmin to bind to cell surface β-actin, and the truncated kringle 5 in AS4.5 results in its release from β-actin. These data may explain the mechanism by which AS4.5 is formed locally on cancer cell surfaces and yet acts on distant sites. (Cancer Res 2006; 66(14): 7211-5)

Purpose: Angiostatin4.5 (AS4.5), the endogenous human angiostatin, is derived from plasminogen in a two-step process. A plasminogen activator converts plasminogen to plasmin, then plasmin undergoes autoproteolysis to AS4.5. A free sulfhydryl donor can mediate plasmin autoproteolysis. To translate this process to human cancer therapy, we conducted a phase I trial of administration of a tissue plasminogen activator (tPA) with a free sulfhydryl donor (mesna). Patients and Methods: Fifteen patients with advanced solid tumors were treated. The dose of tPA was escalated (cohorts; 1, 2, 3, 5, and 7.5 mg/h for 6 hours). Mesna was administered as a 240 mg/m2 bolus followed by an infusion of 50 mg/h, concurrent with tPA. Both tPA and mesna were administered 3 consecutive days every 14 days. Results: No dose-limiting toxicity was observed. Two AS4.5 isoforms were generated, Lys-AS4.5 and Glu-AS4.5. Mean baseline Lys-AS4.5 level was 20.4 nmol/L (SE, 2.9). In the 5 mg/h tPA cohort, Lys-AS4.5 levels increased by an average of 143% or 24 nmol/L (SE, 4.9) above baseline. Glu-AS4.5 (Mr ∼ 62,000) was also generated (additional 77 amino acids at amino terminus compared with Lys-AS4.5). Glu-AS4.5 level at baseline was undetectable in four of five patients in the 5 mg/h tPA cohort, but at end of infusion, was ∼67 nmol/L (SE, 20). Two patients in the 5 mg/h tPA cohort experienced decreases in tumor markers with treatment, although no clinical objective responses were observed. Conclusion: This study shows that in vivo generation of AS4.5 is safe in humans and may provide a practical approach to achieve antiangiogenic therapy.

To assess the relationship between venous thromboembolic disease (VTE) and use of low-estrogen dose (50 microg) combined estrogen-progestin oral contraceptives (OC) and three thrombosis-related gene mutations in a United States population.This case-control study was conducted in 1998-2000 among women ages 15-44 years who were members of the Kaiser Permanente Medical Care Program [KPMCP] (Northern and Southern California). Cases were women with incident VTE; about three times as many women frequency matched for age were randomly selected as controls from the KPMCP membership in the same years. Data were collected in a 1 h face-to-face interview; blood was drawn to extract DNA to test for gene polymorphisms. The analysis data set comprised 196 cases (mean age 35.3 years) and 746 controls (mean age 36.2 years).The adjusted odds ratio (OR) for VTE associated with current OC use was 4.07 (95% confidence interval [CI]: 2.77-6.00). The OR associated with OC use was higher for women who were obese than in the nonobese (p = 0.01 for likelihood test for interaction) and in women without predisposing medical conditions (p = 0.02 for interaction). The adjusted OR for VTE was 7.10 (95% CI: 2.33-21.61) in women with factor V Leiden (G1691A) mutation, 2.83 (95% CI: 0.70-11.63) in women with prothrombin G20210A mutation and 0.26 (95% CI: 0.10-0.65) in women with the MTHFR C677T mutation. The OR for VTE in OC users with factor V Leiden mutation (11.32) was elevated more than in OC users without the mutation (3.20) and women with the mutation who were non-OC users (8.42), but confidence intervals overlapped.The risk of VTE is increased in users of low-estrogen OC formulations. Obese women appear to be at greater risk of VTE when using OCs.

Angiostatin4.5 (AS4.5) is a naturally occurring human angiostatin isoform, consisting of plasminogen kringles 1–4 plus 85% of kringle 5 (amino acids Lys78 to Arg529). Prior studies indicate that plasminogen is converted to AS4.5 in a two-step reaction. First, plasminogen is activated to plasmin. Then plasmin undergoes autoproteolysis within the inner loop of kringle 5, which can be induced by a free sulfhydryl donor or an alkaline pH. We now demonstrate that plasminogen can be converted to AS4.5 in a cell membrane-dependent reaction. Actin was shown previously to be a surface receptor for plasmin(ogen). We now show that β-actin is present on the extracellular membranes of cancer cells (PC-3, HT1080, and MDA-MB231), and β-actin can mediate plasmin binding to the cell surface and autoproteolysis to AS4.5. In the presence of β-actin, no small molecule-free sulfhydryl donor is needed for generation of AS4.5. Antibodies to actin reduced membrane-dependent generation of AS4.5 by 70%. In a cell-free system, addition of actin to in vitro-generated plasmin resulted in stoichiometric conversion to AS4.5. Annexin II and α-enolase have been reported to be plasminogen receptors, but we did not demonstrate a role for these proteins in conversion of plasminogen to AS4.5. Our data indicate that membrane-associated β-actin, documented previously as a plasminogen receptor, is a key cell membrane receptor capable of mediating conversion of plasmin to AS4.5. This conversion may serve an important role in regulating tumor angiogenesis, invasion, and metastasis, and surface β-actin may also serve as a prognostic marker to predict tumor behavior.

Natural products comprise a major source of small molecular weight angiogenesis inhibitors. We have used the transformed endothelial cell line SVR as an effective screen of natural product extracts to isolate anti-angiogenesis and anti-tumor compounds. Aqueous extracts of Magnolia grandiflora exhibit potent activity in our SVR proliferation assays. We found that the small molecular weight compound honokiol is the active principle of magnolia extract. Honokiol exhibited potent anti-proliferative activity against SVR cells in vitro. In addition, honokiol demonstrated preferential inhibition of primary human endothelial cells compared with fibroblasts and this inhibition was antagonized by antibodies against TNF alpha-related apoptosis-inducing ligand. In vivo, honokiol was highly effective against angiosarcoma in nude mice. Our preclinical data suggests that honokiol is a systemically available and non-toxic inhibitor of angiogenesis and should be further evaluated as a potential chemotherapeutic agent.

cGMP-dependent protein kinase (PKG) expression is highly variable and decreases in cultured vascular smooth muscle cells (VSMCs), exposure of cells to nitric oxide (NO), or in response to balloon catheter injury in vivo. In this study, the mechanisms of human type I PKG-alpha (PKG-Ialpha) gene expression were examined. Three structurally unrelated NO donors decreased PKG-Ialpha promoter activity after transfection of a promoter/luciferase construct in VSMCs. Promoter deletion analysis demonstrated that (1) a 120-bp promoter containing tandem Sp1 sites was sufficient to drive basal PKG-Ialpha promoter activity, and (2) NO was inhibitory at this site. Cyclic nucleotide analogues also suppressed PKG-Ialpha promoter activity with cAMP being more potent than cGMP. The effects of cyclic nucleotides to suppress PKG-Ialpha promoter activity were attenuated by a specific cAMP-dependent protein kinase (PKA) inhibitor. Single or double mutation of Sp1 binding sites abolished PKG-Ialpha expression. Moreover, Sp1 binding activity on the PKG-Ialpha promoter was detected in A7r5 cells, and this binding was inhibited by NO and cyclic nucleotides. These results indicate that PKG-Ialpha gene expression is driven by an Sp1 transcription mechanism, and that NO and cAMP inhibit Sp1-mediated PKG-Ialpha gene expression through separate mechanisms.

Objective Ovarian vein thrombosis is associated with pregnancy and pelvic surgery. Postpartum ovarian vein thrombosis is associated with infection and a high morbidity rate and is treated with anticoagulant and intravenous antibiotic therapy. The natural history of such thrombotic events after debulking surgery for ovarian cancer has not been well described. Our objective was to characterize the presentation and outcomes for patients with this condition at our institution. Study Design We conducted a retrospective study of patients who underwent surgical debulking for ovarian cancer at Memorial Sloan Kettering Cancer Center between the years 2001 and 2010. Patients were included if contrast computed tomography scans of both the abdomen and pelvis were performed within 12 weeks before and 12 weeks after the surgery. The images were reviewed to assess for the presence and extent of a new postoperative ovarian vein thrombosis. When available, subsequent studies were assessed for thrombus progression. Medical records were reviewed to determine whether anticoagulation was used for treatment of the thrombotic episode and to record the occurrence of any new significant venous thromboembolic event in the next year. Results One hundred fifty-nine patients had satisfactory imaging. New ovarian vein thrombosis was a common complication of debulking surgery, as found in 41 of patients (25.8%). Only 5 women with ovarian vein thrombosis were started on anticoagulation, of which 2 individuals had an independent venous thromboembolic event as indication for treatment. Only 2 of the ovarian vein thromboses (4.9%) progressed to the inferior vena cava or left renal vein on subsequent scan. The estimated cumulative incidence of venous thromboembolism 1 year after the first postoperative scan was 17.1% for patients in the new ovarian vein thrombosis group vs 15.3% of individuals for the group without a postoperative ovarian vein thrombosis ( P = .78). Conclusion Ovarian vein thrombosis is commonly encountered after debulking surgery for ovarian cancer. Anticoagulation is usually not indicated, and clinically meaningful thrombus progression rarely occurs.

Venous thromboembolism (VTE) is a leading cause of mortality and morbidity in cancer patients, and management represents a major cost to the healthcare system. We have previously presented in a cohort of 200 patients with cancer-associated thrombosis, rivaroxaban provides an alternative to low molecular weight heparin (LMWH), with 4.4% recurrent VTE and 2.2% major bleeding at 6 months (Mantha et al, ASH Abstract, 2015). Other recent publications have provided similar support for use of rivaroxaban in treatment of cancer-associated thrombosis (Bott-Kitslaar et al, Am J Med. 2016, Prins et al, Lancet Haem, 2014). In our early experience with rivaroxaban, fewer patients were sent to the Emergency Room (ER) for initiation of rivaroxaban than LMWH. We now characterize the site and cost of initiation of anticoagulation for the full 200 rivaroxaban patient cohort and a similar cohort of patients treated with LMWH demonstrating significant changes in practice and cost savings. In an IRB approved initiative we track all patients with cancer-associated thrombosis at MSKCC. We characterized the site of initiation of anticoagulation of the first 200 cancer patients with a pulmonary embolism (PE) or lower extremity deep vein thrombosis DVT since January 2014, treated with rivaroxaban. A similar cohort from June through December 2013 was treated with enoxaparin. We excluded patients whose VTE developed as an inpatient. Anticoagulation starts were classified as an emergency room (ER) visit or a second return outpatient visit on the same day for patient education and insurance authorization, a single outpatient visit, or telephone communication. Respective billing codes were then used as part of an economic evaluation to estimate the cost of the additional healthcare resources utilized, and therefore the costs saved by reduction in ER visits or second medical office visits. In the first 6 months of rivaroxaban availability, there was no decrease in ER utilization, compared with LMWH use. After 6 months of rivaroxaban availability, there was a significant decrease in ER visits for VTE management (p=0.008), which resulted in a decrease from baseline of 71% to 34% after one year (p=0.0001). Also of note, after one year of rivaroxaban availability, 18% of newly diagnosed VTE were managed by a simple telephone call to the patient or family member, typically after a recent outpatient visit. Only 2 patients who were started on rivaroxaban had required an additional outpatient visit to our Hematology clinic for evaluation. Based on 2016 Medicare billing codes, we calculated the cost for the additional resources utilized, beyond a single outpatient visit. During the first 6 months of rivaroxaban use, the cost of additional resources per 100 outpatient VTE patients ($47,067) was not significantly different than during the LMWH era ($43,144). However, as practice patterns evolved, ER utilization declined and more patients were managed without additional healthcare resources, resulting in an approximately 50% reduction in costs, for a savings of approximately $20,000 per 100 anticoagulation initiations. Management of cancer-associated thrombosis with LMWH is painful to the patient and expensive to the healthcare system. Patient quality of life is improved by treatment with rivaroxaban versus LMWH, with no evidence of loss of safety or efficacy. In this analysis, we expand on our prior observation that demonstrated a marked reduction in ER visits or hematology consults for the purpose of anticoagulation initiation and also show a substantial cost savings, of approximately $20,000 per 100 VTE patients. These changes in practice developed over an 18-month period, presumably reflecting a learning curve as healthcare providers became more familiar and comfortable with rivaroxaban. Of course, some patients with a new cancer-associated thrombosis should be sent to an ER for evaluation, based on their hemodynamic state or co-morbidities. However, our findings suggest that a majority of patients with cancer-associated thrombosis do not require ER visits, improving patient quality of life and sparing healthcare resources. Disclosures Soff: Janssen Pharmaceuticals: Other: Summer Student Internship. Mantha:Janssen Scientific Affairs, LLC: Research Funding. Soff:Janssen Scientific Affairs, LLC: Consultancy, Research Funding.

The study of angiogenesis, and the promise of angiogenesis inhibition as a means of cancer therapy, has dramatically accelerated in the last several years. The discovery and publication of angiostatin by O'Reilly and colleagues in Judah Folkman's lab in 1994 has greatly contributed to this progress. Angiostatin is a kringle-containing fragment of plasminogen, which is a potent inhibitor of angiogenesis in vivo, and selectively inhibits endothelial cell proliferation and migration in vitro. There have been a number of proposed proteolytic mechanisms by which plasminogen is cleaved to form angiostatin, and the resulting cleavage products contain different NH2 and COOH termini of the angiostatin. Therefore, it is possible that there are more than one angiostatin isoforms (or angiostatin-related proteins) which occur in one or more normal or pathophysiological situations. It is also possible that some of the proteolytic processes which can convert plasminogen to angiostatin-like proteins are simply laboratory artifacts. Angiostatin-related proteins exert potent endothelial cell inhibitory activity, including the induction of apoptosis, and inhibition of migration, and the intact kringle structures are believed to be necessary for the antiangiogenic activity. Efforts are now underway to translate the understanding of the biology of angiostatin to clinical practice, which includes phase 1 clinical trials with recombinant angiostatin K1-3 (kringles 1-3) as well as phase 1 trials of an Angiostatin Cocktail, which induces the direct in vivo conversion of plasminogen to angiostatin 4.5 (kringles 1-4, plus most of kringle 5). The translation of the basic science of angiostatin and angiostatin-related proteins to clinical trial promises to provide an important new tool in the treatment of cancer by inhibition of angiogenesis.

Udgivelsesdato: 1999-May-15 Angiostatin, a kringle-containing fragment of plasminogen, is a potent inhibitor of angiogenesis. The mechanism(s) responsible for the anti-angiogenic properties of angiostatin are unknown. We now report that human angiostatin blocks plasmin(ogen)-enhanced in vitro invasion of tissue plasminogen activator (t-PA)-producing endothelial and melanoma cells. Kinetic analyses demonstrated that angiostatin functions as a non-competitive inhibitor of extracellular-matrix (ECM)-enhanced, t-PA-catalysed plasminogen activation, with a Ki of 0.9+/-0.03 microM. This mechanism suggests that t-PA has a binding site for the inhibitor angiostatin, as well as for its substrate plasminogen that, when occupied, prevents ternary complex formation between t-PA, plasminogen and matrix protein. Direct binding experiments confirmed that angiostatin bound to t-PA with an apparent Kd [Kd(app)] of 6.7+/-0.7 nM, but did not bind with high affinity to ECM proteins. Together, these data suggest that angiostatin in the cellular micro-environment can inhibit matrix-enhanced plasminogen activation, resulting in reduced invasive activity, and suggest a biochemical mechanism whereby angiostatin-mediated regulation of plasmin formation could influence cellular migration and invasion.

Angiogenesis, the formation of new capillaries from pre-existing vessels, is essential for tumour progression1,2,3,4,5. Angiostatin, a proteolytic fragment of plasminogen6 that was first isolated from the serum and urine of tumour-bearing mice7, inhibits angiogenesis and thereby growth of primary8 and metastatic7,9,10 tumours. Radiotherapy is important in the treatment of many human cancers, but is often unsuccessful because of tumour cell radiation resistance11,12. Here we combine radiation with angiostatin to target tumour vasculature that is genetically stable and therefore less likely to develop resistance13,14,15. The results show an antitumour interaction between ionizing radiation and angiostatin for four distinct tumour types, at doses of radiation that are used in radiotherapy. The combination produced no increase in toxicity towards normal tissue. In vitro studies show that radiation and angiostatin have combined cytotoxic effects on endothelial cells, but not tumour cells. In vivo studies show that these agents, in combination, target the tumour vasculature. Our results provide support for combining ionizing radiation with angiostatin to improve tumour eradication without increasing deleterious effects.

A key component of the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in smooth muscle cells (SMC) is the type I GMP-dependent protein kinase (PK-G I). Activation of PK-G I mediates the reduction of cytoplasmic calcium concentrations and vasorelaxation. In this manuscript, we demonstrate that continuous exposure of SMC in culture to the nitrovasodilators S-nitroso-N-acetylpenicillamine (SNAP) or sodium nitroprusside (SNP) results in approximately 75% suppression of PK-G I mRNA by 48 h. PK-G I mRNA and protein were also suppressed by continuous exposure to cGMP analogues 8-bromo- and 8-(4-chlorophenylthio) guanosine-3,5-monophosphate or the cAMP analogue dibutyryl cAMP. These results suggest that activation of one or both of the cyclic nucleotide-dependent protein kinases mediates PK-G I mRNA suppression. Using isoform-specific cDNA probes, only the PK-G I alpha was detected in SMC, either at baseline or after suppression, while PK-G I beta was not detected, indicating that isoform switch was not contributing to the gene regulation. Using the transcription inhibitor actinomycin D, the PK-G I mRNA half-life in bovine SMC was observed to be 5 h. The half-life was not affected by the addition of SNAP to actinomycin D, indicating no effect on PK-G I mRNA stability. Nuclear runoff studies indicated a suppression of PK-G I gene transcription by SNAP. PK-G I suppression was also observed in vivo in rats given isosorbide dinitrate in the drinking water, with a dose-dependent suppression of PK-G I protein in the aorta. PK-G I antigen in whole rat lung extract was also suppressed by administration of isosorbide or theophylline in the drinking water. These data may contribute to our understanding of nitrovasodilator resistance, a phenomenon resulting from continuous exposure to nitroglycerin or other nitrovasodilators.

Angiostatin, a potent naturally occurring inhibitor of angiogenesis and growth of tumor metastases, is generated by cancer-mediated proteolysis of plasminogen. Human prostate carcinoma cells (PC-3) release enzymatic activity that converts plasminogen to angiostatin. We have now identified two components released by PC-3 cells, urokinase (uPA) and free sulfhydryl donors (FSDs), that are sufficient for angiostatin generation. Furthermore, in a defined cell-free system, plasminogen activators [uPA, tissue-type plasminogen activator (tPA), or streptokinase], in combination with one of a series of FSDs ( N -acetyl- l -cysteine, d -penicillamine, captopril, l -cysteine, or reduced glutathione] generate angiostatin from plasminogen. An essential role of plasmin catalytic activity for angiostatin generation was identified by using recombinant mutant plasminogens as substrates. The wild-type recombinant plasminogen was converted to angiostatin in the setting of uPA/FSD; however, a plasminogen activation site mutant and a catalytically inactive mutant failed to generate angiostatin. Cell-free derived angiostatin inhibited angiogenesis in vitro and in vivo and suppressed the growth of Lewis lung carcinoma metastases. These findings define a direct mechanism for cancer-cell-mediated angiostatin generation and permit large-scale production of bioactive angiostatin for investigation and potential therapeutic application.

Background: Resistance to activated protein C (aPC) is usually linked to factor V Leiden, but may occur in other disorders associated with hypercoagulability. In this study, we investigated the frequency of resistance to aPC in patients with advanced cancer and examined the relationship of aPC resistance to other markers of coagulation activation. Methods: Patients (n = 39) had an established diagnosis of advanced cancer; controls (n = 20) were healthy persons. aPC resistance was measured as the ratio of activated partial thromboplastin times with and without aPC (aPC-sensitivity ratio, aPC-SR). The factor V Leiden mutation was detected by a polymerase-chain-reaction based technique. Other assays were performed by standard laboratory methods. Data were analyzed using t tests and the Pearson correlation. Results: aPC-SR was below 2 SD for 5 of the cancer patients (13%), but none of the controls; only 1 of the 5 had the factor V Leiden mutation. aPC-SR was inversely correlated (p < 0.01) with factor VIII and fibrinogen in patients and with prothrombin activation fragment 1.2 (F1.2) in controls. Patient factor VIII, von Willebrand factor, (vWF), fibrinogen, F1.2 and D dimer were all significantly increased (p < 0.01); antithrombin III, protein C and proteins were similar to controls. Factor VIII correlated with vWF (p < 0.001) and F1.2 with d-dimer (p < 0.001). Other associations (p < 0.05) were observed between factor V and protein C, fibrinogen and protein C, factor V and antithrombin III and protein C and antithrombin III. Four cancer patients had a history of thromboembolism; their aPC-SR was similar to that of patients without thrombosis. Of the several coagulation measures examined, only vWF was higher in the patients with thrombosis (p = 0.01). Interpretation: Cancer patients have evidence of intravascular coagulation and increases in procoagulants and may have aPC resistance. The aPC resistance is not due to factor V Leiden, but is rather associated with elevated levels of factor VIII and fibrinogen, and in itself does not predict thrombosis.

He died6 months later of gastric cancer.In the approximately 150 years since Trousseau’sobservation,muchhasbeenlearnedabouttheassociationof cancer, activation of the coagulation system, and clin-icalthrombosis.Yet,manyquestionsremain.Ifprocoagu-lant activity is expressed locally by the cancer cellsthemselves, why do thromboses typically develop atdistantsites?Deepveinthrombosesandresultantpulmo-naryembolismaremuchmorecommonthanlocalthrom-bosis at the cancer site. By what mechanism ormechanismsdocancercellsinduceasystemicprothrom-botic state? The new study by Thaler and colleagues, ontissue factor-bearing microparticles (TF-MP) helps toaddress this question. To understand the contribution ofthe Thaler article, it is helpful to first review the context.In addition to the observation that thrombosis ratesaremorecommonincancerpatients,anotherkeyobser-vation,mademynumerousauthors,isthatpatientswithlocally advanced or metastatic cancer who demonstratea thrombotic tendency exhibit a reduced survivalcompared with similar patients without a thrombotictendency. Sorensen et al

Pharmacologic prophylaxis (PP) is recommended for patients undergoing general surgical procedures with at least moderate risk of venous thromboembolism (VTE). The role of PP in patients undergoing hepatectomy is controversial, however, due to concerns regarding postoperative liver dysfunction and bleeding. We conducted a retrospective analysis of a prospectively maintained institutional database in order to clarify the relationship between PP, postoperative INR, and risk of VTE. Postoperative VTE occurred in 55 of 2,147 patients (2.6 %) and was independently associated with advanced age, higher BMI, longer procedure time, and development of a major complication, as well as higher postoperative INR (≥1.5 versus

The association of thrombosis with cancer has been recognized since the middle of the nineteenth century. It remains a common and serious complication of the cancer itself, as well as chemotherapy. Thrombosis is the second leading cause of death in cancer patients, second only to the cancer itself. For many years the treatment options for managing thrombosis in cancer had been static, but the past decade has seen significant evolution in the management, with the clear superiority of low molecular weight heparin over warfarin for secondary prevention of thrombosis. This article will review the understanding and management of thrombosis in cancer.

Expression of urokinase-type plasminogen activator (uPA) by malignant cells correlates with an aggressive phenotype, including increased invasiveness, tumor-associated angiogenesis, and metastases. Plasminogen activator inhibitor type 1 (PAI-1) is undetectable in cells of some aggressive malignancies, but present in the stroma of tumor-associated microvasculature. This analysis of an athymic mouse model of prostate carcinoma further defines the role of the uPA/PAI-1/plasmin system in primary growth and metastasis. A marked increase in PAI-1 expression was induced in clones of the aggressive human prostate carcinoma line, PC-3, by stable transfection. Primary PC-3 tumors, in mice, were significantly smaller when derived from PAI-1 expressing versus control cells. PAI-1 expression reduced the density of tumor-associated microvasculature by 22-38%. Microscopic metastases were quantitated using stable expression of the chromogenic label (beta-galactosidase) in control and PAI-1 expressing cells. PAI-1 expression resulted in a significant inhibition of lung metastases, and liver metastases. Expression of PAI-1 by malignant prostate cells resulted in a less aggressive phenotype, presumably by inhibition of uPA activity, suggesting pharmacologic or molecular inhibition of uPA activity as a potential therapeutic target.

Anemia is prevalent in 30% to 90% of patients with can- cer. Anemia can be corrected through either treating the underlying cause or providing supportive care through transfusion with packed red blood cells or administration of erythropoiesis-stimulating agents (ESAs), with or without iron supplementation. Recent studies showing detrimental health effects of ESAs sparked a series of FDA label revisions and a sea change in the perception of these once com- monly used agents. In light of this, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer- and Chemotherapy-Induced Anemia underwent substantial revisions this year. The purpose of these NCCN Guidelines is twofold: 1) to operationalize the evaluation and treatment of anemia in adult cancer patients, with an emphasis on those who are receiving concomitant chemotherapy, and 2) to en- able patients and clinicians to individualize anemia treatment options based on patient condition. (JNCCN 2012;10:628-653)

Background: Venous thromboembolism (VTE) is a leading cause of mortality and morbidity in cancer patients. The current standard of care is to treat cancer-associated VTE with Low Molecular Weight Heparin (LMWH), which is more effective than vitamin K antagonists, such as warfarin. However, LMWH injections are painful, expensive, and a burden in healthcare resource utilization. Further, many of these patients are referred to an emergency room for education on self-injection techniques, an added health care cost. The Hematology/Anticoagulation Management Service at Memorial Sloan Kettering Cancer Center is developing rivaroxaban as a safe and effective alternative to LMWH for cancer-associated VTE. In this report, we demonstrate a significant reduction in the referral of patients to the MSKCC Urgent Care Center (UCC), our in-house emergency room, to initiate anticoagulation, resulting in a significant reduction in resource utilization. Methods: As a Quality Assessment Initiative, we track all patients with cancer-associated VTE at MSKCC receiving rivaroxaban since January 2014, and have a similar database of cancer-associated VTE from June through December 2013, treated with enoxaparin. For this utilization of resources study we evaluated where anticoagulation was initiated for treatment of a new pulmonary embolism or lower extremity deep vein thrombosis, specifying either a single outpatient visit, two outpatient visits on the same day, a telephone call, or a visit to the UCC. When patients had a second outpatient visit on the same day as diagnosis of the VTE, the second visit was for patient education on injection technique and insurance authorization. The site of anticoagulation initiation was by the judgment and discretion of the physician managing the patient's cancer. Patients who developed a VTE during a hospital stay or were managed at an outside emergency room were not included in this analysis, as our program has no influence in those settings. Statistical analysis was with the Chi-square test. Comparison of safety and efficacy of rivaroxaban and LMWH is the subject of a separate study. Results: As anticipated, changing from a parenteral anticoagulant to rivaroxaban (an oral agent) resulted in significant changes in practice (Table). Significantly fewer rivaroxaban patients required visits to the UCC than with enoxaparin (p=0.009). Fewer patients required a second outpatient, as well. When viewed in the aggregate of UCC or second outpatient visit, 82% of patients treated with enoxaparin required additional medical resources for initiation of anticoagulation, beyond a single outpatient visit, which decreased to 59% with rivaroxaban (p Discussion: In addition to the burden of morbidity and mortality, management of cancer-associated VTE with LMWH is painful to the patient and expensive to the healthcare system. In our QAI we have been developing rivaroxaban as an oral alternative. Safety and efficacy are being analyzed separately. In addition to the markedly lower cost of rivaroxaban compared with enoxaparin, and patient quality of life preference, we also demonstrate a significant reduction in the healthcare resources associated with initiation of anticoagulation. Cancer patients tend to be higher risk and more complex than general medical patients and it remains appropriate for some to be evaluated in an emergency room for diagnosis and management. Despite this, we observed a reduction in emergency room visits for patients in this setting. One limitation to our findings is that our study was within a single institution, with a devoted Hematology/Anticoagulation Management Service. It would be appropriate to perform a similar analysis in other institutions, including non-cancer patients, to confirm these findings. Table 1. Sites of Initiation of Anticoagulation Enoxaparin Rivaroxaban UCC/Emergency Room (p=0.009) 127 (71%) 101 (57%) Two Outpatient Visits On The Same Day 20 (11%) 4 (2%) Outpatient, Single Visit 32 (18%) 53 (30%) Telephone 0 19 (11%) Total 179 177 Disclosures No relevant conflicts of interest to declare.

Background: Venous thromboembolism (VTE) is a common complication in cancer patients. Anticoagulation (AC) remains the standard of care for treatment of cancer-associated VTE, but inferior vena cava filters (IVCF) are often used in place of or in addition to AC for various indications. Data are limited addressing the role for IVCF in cancer patients. We examine the efficacy of IVCF in a large cohort of cancer patients with prior pulmonary embolism (PE), to assess for rates recurrent VTE within 1-yr of initial VTE and overall survival (OS). Methods: This is a retrospective, single institution study. The study population comprised of all patients diagnosed with a PE at Memorial Sloan Kettering Cancer Center (MSKCC) from 2008-2009 (N= 1272). Patients had diverse primary tumors including lung (N= 246), colorectal (N= 139), gynecologic (N= 130), and breast (N= 103). The majority of patients (96%) were placed on therapeutic AC at time of diagnosis of PE (within 7 days of PE diagnosis). Subsequent interruptions in AC could not be captured. The cumulative incidence for recurrent DVT/PE was calculated from date of initial PE diagnosis to date of recurrent DVT/PE, death, or last followup. Deaths without recurrent DVT/PE were considered a competing event. Patients alive without event are censored at 12 months. Gray's k-test and Fine & Gray regression were used in analyzing the relationship between recurrent DVT/PE and IVCF placement. OS was calculated from date of initial PE diagnosis to date of death or last follow up. Log-rank test was used to compare OS by IVCF placement. Results: 25% (N=317) of the 1272 cancer-associated PE cohort had IVCF placed, either within 30 days following the initial PE (N=274), or prior to the initial PE (N=43). These 317 patients are compared to the 955 patients without IVCF. The indications for IVCF placement included AC contraindicated (39%), pre-operative (16%), AC failure (16%), poor cardiopulmonary reserve (6%) or indication unclear (23%). Composite 12-month rate of all recurrent VTE rate was higher with IVCF (14%) than non-IVCF (8%), (p = 0.016). Adjusting for whether patients were placed on AC at time of initial PE, this difference remained statistically significant with p = 0.014. After adjusting for AC, the risk of recurrent PE was similar between the IVCF cohort (5%) and non-IVCF (4%), (p = 0.43), but the risk of DVT was significantly higher in the IVCF group, 9% versus 5% (p = 0.014). Median OS for IVCF patients was 7.4 months, versus 13.5 months in non-IVCF patients, (p = Radiographic evidence IVCF thrombosis was observed in 13% (N= 42). Interestingly, 55% (N=23) of these patients were on AC at time of IVCF thrombosis, suggesting that AC is not fully protective against this complication. Other complications include filter projection to outside IVC walls (N=6), which in 1 case was associated with erosive changes to L3 vertebral body from the IVCF strut, and filter migration to right renal vein (N=1). Conclusions: In this population of cancer patients with newly diagnosed PE, IVCF use was common and was associated with poorer OS, higher rates of recurrent DVT and similar rates of recurrent PE, even when adjusting for AC at initial PE diagnosis. Limitations include the retrospective, non-randomized nature of this study. Further, we were unable to account for AC interruptions following initial PE diagnosis, which likely influenced the recurrent VTE rates. The poorer survival with IVCF may reflect poorer performance status and generally sicker nature associated with patients undergoing IVCF placement. Still, the absence of significant reduction in PE rates with the IVCF is noteworthy. A putative partial protective effect of IVCF on PE rates may have been counterbalanced by a higher VTE risk associated with poorer performance status in those receiving the IVCF. However, this large cohort study should give pause before placement of IVCF in many cancer patients, especially with advanced stage disease. Figure 1. Gray's k-test comparing the incidence curves by filter group is 0.0162. The p-value for filter (adjusting for AC at initial PE) is 0.014. Figure 1. Gray's k-test comparing the incidence curves by filter group is 0.0162. The p-value for filter (adjusting for AC at initial PE) is 0.014. Disclosures No relevant conflicts of interest to declare.

Background: Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. LMWH injections are painful and costly. Rivaroxaban, an oral direct factor Xa inhibitor, was FDA approved in 2012 for treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but there has been a knowledge gap for its use in patients with cancer-associated thrombosis (CAT). Under a Quality Assurance Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT, and began to offer rivaroxaban as an alternative to enoxaparin, in January 2014, for patients who met appropriate clinical criteria. We are tracking all cancer patients with PE or symptomatic proximal DVT, whose full course of anticoagulation is with rivaroxaban (allowing up to 3 days of initial parenteral anticoagulation). We now report the characteristics of the first 200 patients, and an outcome analysis of our first 100 patients, who have been treated for at least 6 months or otherwise reached an endpoint. Materials and Methods: The Clinical Pathway guidelines will be available on request, pending publication. Patients were not treated with rivaroxaban if they had active gastrointestinal or genitourinary lesions, or had undergone gastric resection due to anticipated excess bleeding risk or reduced absorption. This excluded under 5% of patients. The Pathway provided dosing guidelines in the setting of thrombocytopenia, advanced age, transient renal, or hepatic dysfunction. Primary endpoints include new or recurrent PE, symptomatic proximal lower extremity DVT, major bleeding (ISTH definition), clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. Considering those outcomes as competing risks, the cumulative incidence of each event type was calculated using R 3.2.0 for Windows and package "Survival". Results: The characteristics of our first 200 patients are in Table 1. 70% of the patients had PE. Of the solid tumor patients, 65.6% had metastatic disease. The first 100 patients have completed at least 6 months of rivaroxaban anticoagulation or otherwise reached a primary endpoint. At 6 months, the cumulative incidence of death was 14.4% (95% CI=6.8-21.4%), new or recurrent VTE was 4.3% (95% CI=0.1-8.4%), major bleeding was 1.1% (95% CI=0-3.1%), and clinically relevant non-major bleeding leading to rivaroxaban discontinuation was 7.9% (95% CI=2.1-13.3%). Conclusions: In the analysis of the first 100 patients entered into our QAI program, the rates of major bleeding, and new or recurrent VTE compare favorably to two published studies of LMWH for treatment of cancer associated thrombosis. In the CLOT study (Lee et al, NEJM, 2003) and the Daltecan study (Francis et al, JTH, 2015), the 6-month rates of new or recurrent VTE were approximately 9%, and the rates of major bleeding were 6% and 9.5% respectively. Our final analysis awaits the completion of 6 months follow-up on 200 patients, to be completed in December 2015. But the rates of major bleeding and recurrent VTE at this point suggest safety and efficacy to be at least non-inferior to LMWH, with the advantage of reduced patient burden, and support the ongoing use of our Clinical Pathway. Our low rate of major bleeding likely is influenced by the exclusion of patients with active GI or GU lesions, who would be expected to have a high bleeding risk with an oral direct anticoagulant. However, we estimate this excluded less than 5% of cancer patients with VTE. Further, we anticipated reduced drug clearance in the elderly, and used a reduced dose for patients greater than 75 years of age. This appeared to be associated with no loss in efficacy, and helped maintain a low rate of major bleeding. A randomized trial is the optimal approach to establish non-inferiority or superiority of rivaroxaban to LMWH for cancer associated thrombosis. However, our QAI Clinical Pathway provides guidance and reassurance for rivaroxaban use until a randomized trial is conducted. Table. Baseline Characteristics of Patients Characteristic Number of Individuals Gender Male 82 Female 118 Event Type PE, with or without DVT 140 Proximal, Symptomatic Lower extremity DVT 60 Cancer Type Solid Tumor 186 Hematologic Malignancy 14 Cancer Stage (Of Solid Tumors) No Evidence of Disease (Post-Cancer Surgery) 11 (5.9%) 1 1 (0.5%) 2 4 (2.2%) 3 16 (8.6%) 4 122 (65.6%) Unknown 32 (17.2%) Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Cyclic GMP-dependent protein kinase (cGMP kinase) is the major receptor protein for cGMP in vascular smooth muscle. Vascular smooth muscle cells (VSMC) isolated from the rat aorta express type I cGMP kinase at high levels, but expression decreases markedly upon passage of the cells. In primary or early passage, the expression of cGMP kinase is lowest when cells are plated at low density as assessed by immunological and Northern analyses. Expression increases at confluence and is maintained in postconfluent cultures. With repeated passaging, however, the levels of cGMP kinase decrease even in confluent and postconfluent cultures so that after several passages enzyme levels are undetectable. The decrease in expression in passaged cells is not due to exposure to serum-derived growth factors, but rather on the repeated exposure of cells to conditions in which cell density is reduced (i.e., subculturing). These results indicate that aortic VSMC grown at low density or those repetitively passaged have reduced expression of cGMP kinase, and thus may not represent appropriate cultures with which to investigate the role of nitric oxide and cGMP in VSMC function.

Objectives: To describe the clinical characteristics, diagnostic features, prognosis, and outcome of patients with prostate cancer and disseminated intravascular coagulation with excessive fibrinolysis (DIC XFL). Methods: We performed a retrospective analysis of prostate cancer patients seen at a single center from March 21, 2000, to July 31, 2006, with a fibrinogen level 9/l, D-dimer >0.5 µg/ml, prothrombin time and activated partial thromboplastin time exceeding normal values, hemorrhage and/or thrombosis. Patients with comorbid conditions that cause coagulopathy were excluded. Results: Forty-two patients met the inclusion criteria. Most patients had high-grade prostate cancer (26% had Gleason 7 and 45% had Gleason 8–10). Three patients developed DIC XFL following surgery and 39 patients in the setting of metastatic disease; 93% were resistant to castration, and 50% had received prior taxanes. No deep-vein thromboses were documented. Management included blood transfusion, heparin, hormones, and chemotherapy. Median survival was 4 weeks. DIC XFL reversal was seen in 20% of metastatic patients, all of whom received new chemotherapy regimens. Median survival in this group was 26 weeks. Conclusions: DIC XFL is a rare complication of prostate cancer. Untreated, the risk of hemorrhage is high and the prognosis poor. Reversal of DIC XFL appears to correlate with response to new anticancer therapy.

Purpose This study was designed to determine the incidence of venous and arterial thromboembolic events (TEEs) in patients treated with cisplatin-based chemotherapy and to analyze the prognostic value of patients' baseline and treatment characteristics in predicting TEE occurrence. Patients and Methods We performed a large retrospective analysis of all patients treated with cisplatin-based chemotherapy for any type of malignancy at Memorial Sloan-Kettering Cancer Center in 2008. A TEE was cisplatin-associated if it occurred between the time of the first dose of cisplatin and 4 weeks after the last dose. Results Among 932 patients, 169 (18.1%) experienced a TEE during treatment or within 4 weeks of the last dose. TEEs included deep vein thrombosis (DVT) alone in 49.7%, pulmonary embolus (PE) alone in 25.4%, DVT plus PE in 13.6%, arterial TEE alone in 8.3%, or DVT plus arterial TEE in 3.0%. TEEs occurred within 100 days of initiation of treatment in 88% of patients. By univariate analysis, sex, age, race, Karnofsky performance status (KPS), exposure to erythropoiesis-stimulating agents, presence of central venous catheter (CVC), site of cancer, stage of cancer, leukocyte and hemoglobin levels, and Khorana score were all identified as risk factors. However, by multivariate analysis, only age, KPS, presence of CVC, and Khorana score retained significance. Conclusion This large retrospective analysis confirms the unacceptable incidence of TEEs in patients receiving cisplatin-based chemotherapy. In view of the controversy associated with prophylactic anticoagulation in patients with cancer treated with chemotherapy, randomized studies are urgently needed in this specific cancer population treated with cisplatin-based regimens.