Diagnostic Approach for Venous Thromboembolism in Cancer Patients.

Venous thromboembolic disease (VTE) is a common complication in cancer patients. The currently recommended VTE diagnostic approach involves a step-by-step algorithm, which is based on the assessment of clinical probability, D-dimer measurement, and/or diagnostic imaging. While this diagnostic strategy is well validated and efficient in the noncancer population, its use in cancer patients is less satisfactory. Cancer patients often present nonspecific VTE symptoms resulting in less discriminatory power of the proposed clinical prediction rules. Furthermore, D-dimer levels are often increased because of a hypercoagulable state associated with the tumor process. Consequently, the vast majority of patients require imaging tests. In order to improve VTE exclusion in cancer patients, several approaches have been developed. The first approach consists of ordering imaging tests to all patients, despite overexposing a population known to have mostly multiple comorbidities to radiations and contrast products. The second approach consists of new diagnostic algorithms based on clinical probability assessment with different D-dimer thresholds, e.g., the YEARS algorithm, which shows promise in improving the diagnosis of PE in cancer patients. The third approach uses an adjusted D-dimer threshold, to age, pretest probability, clinical criteria, or other criteria. These different diagnostic strategies have not been compared head-to-head. In conclusion, despite having several proposed diagnostic approaches to diagnose VTE in cancer patients, we still lack a dedicated diagnostic algorithm specific for this population.

Granulosa tumor: two spontaneous pregnancies after combined medico-surgical treatment: case report and review of the literature.

BACKGROUND: Granulosa tumor is a rare tumor that arises from the mesenchyme and the sexual cord of the ovary. The prognosis is generally excellent, and treatment is mainly based on surgery, followed by chemotherapy depending on the extension of the disease. However, "the obstetrical prognosis" is compromised. CASE PRESENTATION: We report the case of a 32-year-old Caucasian patient who was diagnosed during a primary infertility assessment with an ultrasound image of a 39 mm organic left ovarian cyst confirmed on pelvic magnetic resonance imaging with infiltration of the uterosacral space. Tumor markers, including cancer antigen 125, alpha fetoprotein, and ß-human chorionic gonadotropin, were normal. Histological study of biopsies of the ovarian lesion taken during exploratory laparoscopy confirmed the diagnosis of adult granulosa tumor. After a normal extension assessment including a thoracoabdominopelvic computed tomography scan and a positron emission tomography scan, the patient underwent complete conservative surgery and the disease was classified as stage Ic. Three cycles of adjuvant chemotherapy according to the "BEP" protocol combining bleomycin, etoposide, and cisplatin were performed after oocyte cryopreservation. After a 5-year follow-up period, the patient had no sign of tumor progression and had two spontaneous pregnancies, the first occurring 3 months after the end of chemotherapy and the second 14 months later. CONCLUSION: Granulosa cell tumor remains a rare tumor whose management considerably compromises fertility and reduces the chances of having a spontaneous pregnancy. The particularity of our observation is that the diagnosis of the granulosa tumor was made following a primary infertility assessment and that the patient had two spontaneous pregnancies 3 months after the end of a medico-surgical treatment known to be very gonadotoxic.

Long-Term Treatment of Cancer-Associated Thrombosis (CAT) Beyond 6 Months in the Medical Practice: USCAT, a 432-Patient Retrospective Non-Interventional Study.

BACKGROUND: extended anticoagulant therapy beyond the initial 6 months is suggested in patients with cancer-associated thrombosis (CAT) and active cancer. Few data are available on patient management and outcomes on the period between 6 and 12 months after the venous thromboembolism (VTE) event. OBJECTIVES: our objective was to document patient management and outcomes beyond 6 months and up to 12 months in CAT patients initially treated for 6 months with tinzaparin. METHODS: adult CAT patients with a cancer still alive at the end of an initial 6-month treatment period were eligible to participate in this retrospective non-interventional French multicenter study. RESULTS: a total of 432 patients aged 66.5 ± 12.7 years were available to participate in this study. Out of the patients included in the study, the anticoagulant treatment was maintained in 348 of 422 documented patients (82.5%) while it was discontinued in 74 (17.5%) patients (before the end or at the end of the initial 6-month treatment period). Between 6 and 12 months, 24 patients (5.7%) experienced VTE recurrence, while 21 (5.1%) patients had clinically relevant bleeding, 11 patients (2.7%) had major bleeding and 96 patients (22.3%) died, mostly from cancer. VTE recurrence was more frequent in patients with lung (14.3%) and colorectal cancer (6.0%) while major bleeding was more frequent in patients with colorectal cancer (6.0%). CONCLUSION: clinical outcomes were consistent with previous observations and variable according to the type of cancer. Further clinical research is required to orient the management of patients with CAT beyond 6 months based on cancer-specific treatment strategies.

Patients experience of living with cancer associated thrombosis in France (Le PELICAN).

INTRODUCTION: Previous research in the United Kingdom and Spain has identified several areas of unmet clinical and support need for cancer patients diagnosed with cancer associated thrombosis (CAT). These included lack of information, which was directly associated with distress. Appropriate information has been shown to improve tolerance and compliance with self-injecting low molecular weight heparin (LMWH). It is not known whether such experiences are restricted to those particular countries healthcare systems and/or cultures. METHODS: Purposive sampling of patients with CAT were recruited from an academic hospital in Colombes, France. Semi structured interviews were audio recorded and transcribed. Transcripts were coded using Invivo software. Analysis was undertaken using framework analysis. RESULTS: Twenty four patients participated. Three major themes with associated subthemes were identified: Patients received minimal information regarding risks of CAT or how to treat it once diagnosed. However, this was not associated with distress. Patients adopted a passive role whereby the doctor was always right. They were intolerant injections and found it inconvenient to await community nurses. CONCLUSION: The doctor patient relationship in France differs from other countries, with patients adopting a passive role with respect to information requirements. This dynamic appears to be a "two edged sword" whereby distress around CAT was minimal yet a lack of knowledge impacted on acceptability of LMWH. This has implications for the choice of anticoagulant particularly now that the DOACS have been evaluated for this indication.

[Cancer and venous thromboembolism recurrence: The keys for an optimal management]. / Cancer et récidive thromboembolique veineuse : les clés d'une prise en charge optimale.

Low-molecular-weight heparins (LMWH) are to date the standard for 3-to-6-month treatment of cancer-associated thrombosis (CAT) as they are consistently recommended by international clinical practice guidelines. Despite the high risk of VTE recurrence and death in patients with cancer and the favorable benefit-risk profile of LMWH demonstrated in randomized-control studies, the implementation of treatment guidelines remains insufficient in the clinical practice. A systematic review of observational studies, registries and surveys reveals that approximately only 50% of patients with CAT are treated according to practice guidelines while both physicians and patients may be accountable for this situation. Based on the few available published data, we have observed differences between guidelines and clinical practice and we have identified factors influencing patient's management with the perspective to improve adherence to clinical practice guidelines in patients with CAT. Improving the implementation of clinical practice guidelines requires a better knowledge of physician and patient-related factors that influence therapeutic decisions. A global approach of patients with CAT is warranted to optimize the therapeutic management of cancer-associated VTE.

The Clinical Course of Venous Thromboembolism May Differ According to Cancer Site.

BACKGROUND: We hypothesized that the clinical course of venous thromboembolism in patients with active cancer may differ according to the specificities of primary tumor site. AIM AND METHODS: We used data from RIETE (international registry of patients with venous thromboembolism) to compare the clinical venous thromboembolism-related outcomes during the course of anticoagulation in patients with one of the 4 more frequent cancers (breast, prostate, colorectal, or lung cancer). RESULTS: As of September 2014, 3947 cancer patients were recruited, of whom 938 had breast, 629 prostate, 1189 colorectal, and 1191 lung cancer. Overall, 55% had metastatic disease (42%, 36%, 53%, and 72%, respectively). During the course of anticoagulant therapy (mean duration, 139 days), the rate of thromboembolic recurrences was similar to the rate of major bleeding in patients with breast (5.6 [95% confidence interval (CI), 3.8-8.1] vs 4.1 [95% CI, 2.7-5.9] events per 100 patient-years) or colorectal cancer (10 [95% CI, 7.6-13] vs 12 [95% CI, 9.4-15] per 100 patient-years). In contrast, in patients with prostate cancer, the rate of venous thromboembolic recurrences was half the rate of major bleeding (6.9 [95% CI, 4.4-10] vs 13 [95% CI, 9.2-17] events per 100 patient-years), whereas in those with lung cancer, the rate of thromboembolic recurrences was twofold higher than the rate of major bleeding (27 [95% CI, 22-23] vs 11 [95% CI, 8.6-15] per 100 patient-years). CONCLUSIONS: Significant differences in the clinical profile of venous thromboembolic-related outcomes were observed according to the site of cancer. These findings suggest the development of cancer-specific anticoagulant strategies as an area for further research.

[Cancer-associated venous thromboembolic recurrence: disregard of treatment recommendations]. / Cancer et récidive thromboembolique veineuse: non-respect des recommandations de traitement.

Low-molecular-weight heparins (LMWH) are the reference curative treatment of venous thromboembolism (VTE) in patients with cancer. All international guidelines recommend the long-term use of LMWH given their demonstrated superiority compared to vitamin-K antagonists (VKA) in reducing VTE recurrence in this patient population without increased risk of bleeding. However, several studies consistently show a lack of adherence to treatment recommendations, which are applied at the very best in 50% of cases. This results in a loss of chance for patients with fragile prognosis and in whom VTE represents the second cause of death. Given the expected benefit and the increased VTE prevalence in patients with cancer, full awareness is necessary to implement programs aiming at improving the therapeutic management of cancer-associated VTE. This requires multidisciplinary consideration by qualified physicians involved in the management of patients with cancer-associated VTE such as oncologists, internists and those specialized in vascular disease and hemostasis.

New combinational assay using soluble fibrin and d-dimer determinations: a promising strategy for identifying patients with suspected venous thromboembolism.

AIM: To establish a new and reliable assay for quantification of the soluble fibrin (SF) in combination with that of D-dimer for early diagnosis of venous thromboembolism. METHODS AND SAMPLES: The SF assay is based on D-dimer generated after incubation of plasma with tissue-type plasminogen activator (t-PA). SF and standard D-dimer assays, run in blind, were used to test 119 untreated outpatients with clinically suspected deep-vein thrombosis (DVT, 49 patients) or pulmonary embolism (PE, 70 patients) consulting at the emergency unit of the hospital. Thromboses were confirmed by current imaging methods such as ultrasonography, scintigraphy, computed tomographic pulmonary angiography (CTPA) and ventilation/perfusion scan. RESULTS: SF assay was validated in 270 healthy volunteers [51.8% males; mean age years ± SD: 41±13; age range 19 to 65]. Among these normal plasmas, SF levels were ≤200 ng/mL in 97.8% of them, and 200-250 ng/mL in the remainder [26-46 years old; 50% males]. ROC curves were used to determine the SF cut-off value for plasma SF positivity, which was found to be 300 ng/mL. In patients with suspected venous thromboembolism, SF sensitivities for DVT and PE (92% and 94%, respectively) were comparable to those of D-dimer (96% and 94%), whereas SF specificities (86% and 95%) were higher than those of D-dimer (50% and 54%). Positive-predictive values for SF (89% and 94%) were again higher than those of D-dimer (70% and 65%) in DVT and PE. The amount of circulating SF normalized rapidly after anticoagulant therapy. CONCLUSION: Results from this small group of patients suggest that the evaluation of plasma SF, in combination with that of D-dimer, represents a potentially useful tool for the early diagnosis of venous thromboembolism, provided that the patients have not been treated previously by anticoagulants.

A clinical experience of single agent bevacizumab in relapsing ovarian cancer.

OBJECTIVE: The objective of this study is to report the efficacy and tolerance of single agent bevacizumab (BEVA) in relapsing ovarian cancer patients treated in a single institution outside a clinical trial. METHODS: To receive single agent BEVA, patients must have to relapse after at least one previous line of chemotherapy and to not have clinical conditions associated with high risk of gastrointestinal perforation. Dose-intensity of BEVA was 2.5mg/kg/week. RESULTS: 37 previously treated patients (33 with platinum resistant disease) were included in this retrospective analysis. The median number of BEVA infusion by patient was 5 (range: 1-61). The most frequent adverse effect was arterial hypertension, observed in 23 patients (62%), including 11 with G3 (30%) and 1 with G4. No intestinal perforation was reported. Tumor response rate according to CA 125 level (GCIG criteria) was 37% (11 of 30 patients). The median PFS and OS were 4 (range: 1 to +56) and 16 (range: 1 to +65) months (ms), respectively. 12-ms PFS was 25% (95% CI: 11-39%). The PFS tended to be better in patients who experienced grade 3-4 arterial hypertension during the first month of treatment (median: 10ms) compared to patients who did not (median: 3ms) (HR: 0.49 (95% CI: 0.18-1.03), p=0.06 by log rank test). CONCLUSION: Single agent BEVA could be a reasonable option with favorable therapeutic index in pretreated ovarian cancer patients who do not want to suffer the side effects of chemotherapy provided to exclude those with high risk of intestinal perforation and carefully monitor blood pressure.

Whole blood clots are more resistant to lysis than plasma clots--greater efficacy of rivaroxaban.

INTRODUCTION: Defective thrombolysis, a thrombotic risk factor, can be attributed to the formation of a compact clot poorly accessible to fibrinolytic enzymes. Venous thrombi, rich in red blood cells (RBCs), and arterial thrombi containing various amounts of RBCS, plasma and whole blood (WB) clot permeability and degradability were compared. The effect of rivaroxaban, a potent direct factor Xa inhibitor, was also evaluated. MATERIALS AND METHODS: Fibrin permeability was determined by flow measurement through the clot. Clot degradability was evaluated by the amount of D-dimer generated by clot perfusion with plasminogen and tissue plasminogen activator. Fibrin clot structure was assessed by confocal microscopy. RESULTS: WB clot permeability (KS) and degradability were 6.7- and 38-fold lower, respectively, compared with plasma clots. This is attributed to 1) occlusion of fibrin pores by RBCs and 2) a consistent increase in thrombin generation due to platelets and RBCs inducing formation of a tighter clot. Rivaroxaban added to plasma or WB before clotting, in reducing thrombin generation, led to the formation of a looser clot that is more degradable by fibrinolytic enzymes. Permeability and degradability of whole blood clots formed in the presence of rivaroxaban were very similar to those of plasma clots. CONCLUSION: The resistance to fibrinolysis of WB clots was reduced considerably when clots were formed with rivaroxaban. These results may have implications for the development of antithrombotic agents.

Endothelial protein C receptor expressed by ovarian cancer cells as a possible biomarker of cancer onset.

Coagulation disorders often accompany cancer onset and evolution, which, if not properly managed, could have grave consequences. Endothelial protein C is an important regulator of homeostasis and acts through its high affinity binding to its transmembrane receptor (EPCR). Soluble (sEPCR) which results from the proteolytic cleavage of the membrane bound form can trap activated endothelial protein C and deprive it of its anti-coagulant function. In this study, the expression of EPCR and its soluble form (sEPCR) released into plasma as a result of proteolytic cleavage were investigated in ovarian, breast, lung and colorectal cancer biopsies, as well as in ascitic cell clusters and peritoneal fluid from ovarian cancer samples. In parallel, breast, ovarian, lung and colorectal cancer cell lines were investigated for the expression of EPCR. The integrity of the EPCR gene sequence as well gene haplotypes were ascertained in the established cancer cell lines in order to understand their eventual regulatory functions. The results from the present study indicate that in cancer patients, the levels of sEPCR are significantly higher than the normal range compared to healthy volunteers. The increase in the levels of sEPCR parallels the increase in CA125, showing a close correlation. Therefore, the detection of sEPCR in cancer and during the post-treatment period could be taken into account as an additional marker that could re-inforce the one obtained using CA125 alone as a marker of cancer cell mass.

Increased fibrosis and interstitial fluid pressure in two different types of syngeneic murine carcinoma grown in integrin ß3-subunit deficient mice.

Stroma properties affect carcinoma physiology and direct malignant cell development. Here we present data showing that α(V)ß(3) expressed by stromal cells is involved in the control of interstitial fluid pressure (IFP), extracellular volume (ECV) and collagen scaffold architecture in experimental murine carcinoma. IFP was elevated and ECV lowered in syngeneic CT26 colon and LM3 mammary carcinomas grown in integrin ß(3)-deficient compared to wild-type BALB/c mice. Integrin ß(3)-deficiency had no effect on carcinoma growth rate or on vascular morphology and function. Analyses by electron microscopy of carcinomas from integrin ß(3)-deficient mice revealed a coarser and denser collagen network compared to carcinomas in wild-type littermates. Collagen fibers were built from heterogeneous and thicker collagen fibrils in carcinomas from integrin ß(3)-deficient mice. The fibrotic extracellular matrix (ECM) did not correlate with increased macrophage infiltration in integrin ß(3)-deficient mice bearing CT26 tumors, indicating that the fibrotic phenotype was not mediated by increased inflammation. In conclusion, we report that integrin ß(3)-deficiency in tumor stroma led to an elevated IFP and lowered ECV that correlated with a more fibrotic ECM, underlining the role of the collagen network for carcinoma physiology.

Ovarian cancer: Stat3, RhoA and IGF-IR as therapeutic targets.

Seeking to improve ovarian cancer therapy, we compared biological characteristics of the moderately-aggressive OVCAR-3 cell line with two highly aggressive ovarian cancer cell populations: the SK-OV-3 cell line, and HASCJ primary cells isolated from the ascitic fluid of a patient with FIGO stage IV ovarian cancer. Secretion of angiogenic factors was not discriminative, whereas cell invasion through Matrigel and vasculogenic mimicry were much greater in the more aggressive cells. Among 10 agents tested for their ability to decrease cancer cell aggressivity using these two models, inhibitors of Stat3, IGF-IR and Rho GTPase were found to be the most promising.

A randomized, double-blind trial assessing the efficacy and safety of sublingual metopimazine and ondansetron in the prophylaxis of chemotherapy-induced delayed emesis.

The prevention of delayed emesis following chemotherapy remains an important challenge. This randomized, double-blind, double-dummy, multicenter study was designed to compare the efficacy and tolerance of metopimazine and ondansetron at preventing nausea and emesis in patients receiving chemotherapy. Two hundred patients were evaluated for efficacy: 103 patients received metopimazine (7.5 mg x 2 t.i.d.) and 97 received ondansetron (8 mg b.i.d.) for 5 days. Patients were asked to report episodes of nausea and emesis in a diary, and quality of life (QoL) was evaluated using the Functional Living Index--Emesis questionnaire. The incidence of complete response (defined as no nausea and emesis for 5 days) did not differ between the two treatment arms (53.4% for metopimazine versus 49.5% for ondansetron; P=0.58). No significant difference was found for the incidence of emesis (23.3% for metopimazine versus 30.9% for ondansetron) or QoL. Tolerance was as expected for both drugs and comparable, except for the incidence of gastrointestinal disorders, which was significantly lower in the metopimazine group (19.4 versus 32.7%; P=0.03). We conclude that metopimazine is an alternative to ondansetron that is better tolerated for the prevention of delayed emesis in patients receiving chemotherapy.