Heart and Blood Diseases

All Conditions

Symptoms and General Pathology

Nervous System Diseases

Thrombosis

Body Weight

Angina Pectoris

Angina, Unstable

Embolism

Embolism and Thrombosis

Vascular Diseases

Coronary Artery Disease

Myocardial Ischemia

Ischemia

Heart Diseases

Pain

Chest Pain

Neurologic Manifestations

Fibrinolytic Agents

Anticoagulants

All Drugs and Chemicals

Heparin

Calcium heparin

Heparin, Low-Molecular-Weight

Tinzaparin

Dalteparin

A. Patients with pathologically or cytologically confirmed diagnosis of advanced solid malignancy.

B. Venous thromboembolism: Deep vein thrombosis (DVT) confirmed by Doppler ultrasound, or pulmonary embolism confirmed by lung ventilation perfusion scan, or computerized tomography.

C. Treatment with therapeutic dose of low molecular weight heparin. D. No major surgery during the last month before investigation. E. No evidence of major infectious disease. F. Serum creatinine level \< 1.5 mg/dl. G. Informed consent

A. Patients with unstable angina pectoris/ atypical chest pain, with no evidence of acute myocardial infarction.

B. Treatment with therapeutic dose of low molecular weight heparin. C. No evidence of VTE. D. No major surgery during the last month before investigation. E. No evidence of major infectious disease. F. No history of malignancy. G. Serum creatinine level \< 1.5 mg/dl. H. Informed consent

Nicola j nasser, MD, PhD

The purpose of the study is to determine the Pharmacokinetics of Low Molecular Weight Heparin (LMWH) in Cancer patients, and compare it to the Pharmacokinetics of LMWH in Patients without cancer. We also intend to detect any correlation between heparanase blood and urine levels and the Pharmacokinetics of LMWH.

Scientific background. The increased risk for venous thromboembolism (VTE) in cancer has long been recognized (1). Since first described by Trousseau in 1865, many aspects of this complex relationship are still obscure (2). Cancer patients have an increased risk for developing thrombosis. Similarly, patients presenting with idiopathic VTE are considered to have a higher risk of developing cancer (3). Approximately 10% of patients with idiopathic VTE harbor an underlying malignancy that can be detected by an extensive diagnostic work-up (4). Clinical data indicate that cancer alone is associated with a 4.1- fold risk of thrombosis, and chemotherapy increases the risk to 6.1- folds (5). Cancer patients develop postoperative VTE at least 2- folds more than patients without cancer undergoing the same surgical procedure (6). Treatment of VTE involves the administration of heparin, low molecular weight heparin (LMWH) or coumarin derivatives. Beside its anticoagulant effects, LMWH may also have an anti-tumoral effect (7-12). The use of LMWH relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute VTE (9). Moreover, addition of LMWH to chemotherapy increased survival of patients with small cell lung cancer (10).

Heparan sulfate proteoglycans (HSPGs) are ubiquitous macromolecules associated with the cell surface and extracellular matrix (ECM) of a wide range of cells of vertebrate and invertebrate tissues. Heparin is structurally related to heparan sulfate (HS), but has higher N- and O-sulfate contents (13). Mammalian endoglycosidase, capable of partially depolymerizing HS chains and commonly referred to as heparanase, has been identified in a variety of cell types and tissues, primarily cancer cells, activated cells of the immune system, platelets, and placenta (14-17). Heparanase is synthesized as a latent 65 kDa precursor whose activation involves proteolytic cleavage at two potential sites located at the N-terminal region of the molecule (Glu109 -Ser110 and Gln157 -lys158), resulting in the formation of two protein subunits that heterodimerize and form the active heparanase enzyme (18). Expression of heparanase correlates with the metastatic potential of human tumor cells (14-16, 19). Furthermore, elevated levels of heparanase were detected in the urine of some patients with aggressive metastatic disease (20). Heparin, LMWH, non-anticoagulant and chemically modified species of heparin (21, 22), as well as other polysaccharides (23, 24) which inhibit experimental metastasis, also inhibit tumor cell heparanase, while other related compounds had a small or no effect on both parameters (21-24). Recently, we demonstrated that the anticoagulant activities of heparin and LMWH can be neutralized by their pre-incubation with heparanase. Transgenic mice overexpressing heparanase, exhibited a hyper-coagulable phenotype expressed by a markedly shorter base-line APTT compared to control mice (25). These results may suggest that resistance to heparin, described in patients with malignancies (26, 27), could be attributed, in part, to high levels of heparanase often observed in cells (28, 29) and body fluids (20) of patients with an aggressive malignant disease. Degradation of heparin and LMWH by heparanase in vivo may be relevant in situations in which heparanase is over-expressed, and treatment with heparin or LMWH is needed (e.g., deep venous thrombosis in patients with pancreatic carcinoma) (29, 30). The pharmacokinetics of LMWH (i.e. the time course of absorption, distribution, metabolism, and degradation) as reflected by its effects upon factor Xa activity, was elucidated in several subgroups of patients (e.g. patients with renal failure, pregnant women...), but to the best of our knowledge was not addressed in patients with advanced solid tumors.

Objectives \& expected significance. In view of the above described biological significance of the heparanase enzyme, and taking into account our recent in vitro and in vivo results (heparanase capability to cleave heparin and LMWH; and the altered coagulation profile in transgenic mice overexpressing heparanase) (25), we propose to focus on the following specific aims:

I) Measure plasma and urine heparanase levels in patients with advanced cancer suffering from VTE, and compare it to controls without cancer.

II) Elucidate the pharmacokinetics of LMWH in patients with advanced solid tumors (AST) suffering from VTE, and compare it to the pharmacokinetics of LMWH in patients with unstable angina pectoris.

III) Determine the correlation between heparanase blood levels and the pharmacokinetics of LMWH, if any.

References

1. Rickles FR. Mechanisms of cancer-induced thrombosis in cancer. Pathophysiol Haemost Thromb. 2006; 35: 103-110.
2. Trousseau A: Phlegmasia alba dolens, in: Clinique Medicale de l'Hotel Dieu de Paris. Vol 3, ed 2. Balliere, Paris, 1865; pp 654-712.
3. Valente M, Ponte E. Thrombosis and cancer. Minerva Cardioangiol. 2000; 48: 117-127.
4. Prandoni P. Cancer and venous thromboembolism. Clinical implications of strong association. Pathophysiol Haemost Thromb. 2006; 35: 111-115.
5. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000; 160: 809-815.
6. Rickles FR, Levine MN. Epidemiology of thrombosis in cancer. Acta Haematol. 2001; 106: 6-12.
7. von Tempelhoff GF, Harenberg J, Niemann F, Hommel G, Kirkpatrick CJ, Heilmann L. Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: A prospective randomized double-blind trial. Int J Oncol. 2000; 16: 815-824.
8. Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RC. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004; 10: 1944-1948.
9. Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005; 23: 2123-2129.
10. Altinbas M, Coskun HS, Er O, Ozkan M, Eser B, Unal A, Cetin M, Soyuer S. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost. 2004; 2: 1266-1271.
11. Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F, Prandoni P, Bos MM, Richel DJ, van Tienhoven G, Buller HR. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005; 23: 2130-2135.
12. Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002; 162:1729-1735.
13. Casu B, Lindahl U. Structure and biological interactions of heparin and heparan sulfate. Adv Carbohydr Chem Biochem. 2001; 57: 159-206.
14. Parish CR, Freeman C, Hulett MD. Heparanase: a key enzyme involved in cell invasion. Biochim Biophys Acta. 2001; 1471: M99-108.
15. Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J Clin Invest. 2001; 108: 341-347.
16. Nakajima M, Irimura T, Nicolson GL. Heparanases and tumor metastasis. J Cell Biochem. 1988; 36:157-167.
17. Dempsey LA, Brunn GJ, Platt JL. Heparanase, a potential regulator of cell-matrix interactions. Trends Biochem Sci. 2000; 25: 349-351.
18. Levy-Adam F, Miao HQ, Heinrikson RL, Vlodavsky I, Ilan N. Heterodimer formation is essential for heparanase enzymatic activity. Biochem Biophy Res Commun. 2003; 308: 885-891.
19. Vlodavsky I, Friedmann Y, Elkin M, Aingorn H, Atzmon R, Ishai-Michaeli R, Bitan M, Pappo O, Peretz T, Michal I, Spector L, Pecker I. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nat Med. 1999; 5: 793-802.
20. Shafat I, Zchria E, Nisman B, Nadir Y, Nakhoul F, Vlodavsky I, Ilan N. An ELISA method for the detection and quantification of human heparanase. Biochem Biophy Res Commun. 2006; 341: 958-963.
21. Vlodavsky I, Mohsen M, Lider O, Svahn CM, Ekre HP, Vigoda M, Ishai-Michaeli R, Peretz T. Inhibition of tumor metastasis by heparanase inhibiting species of heparin. Invasion Metastasis. 1994; 14: 290-302.
22. Parish CR, Coombe DR, Jakobsen KB, Bennett FA, Underwood PA. Evidence that sulphated polysaccharides inhibit tumour metastasis by blocking tumour-cell-derived heparanases. Int J Cancer. 1987; 40: 511-518.
23. Parish CR, Freeman C, Brown KJ, Francis DJ, Cowden WB. Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res. 1999; 59: 3433-3441.
24. Miao HQ, Elkin M, Aingorn E, Ishai-Michaeli R, Stein CA, Vlodavsky I. Inhibition of heparanase activity and tumor metastasis by laminarin sulfate and synthetic phosphorothioate oligodeoxynucleotides. Int J Cancer. 1999; 83: 424-431.
25. Nasser NJ, Sarig G, Brenner B, Nevo E, Goldshmidt O, Zcharia E, Li JP, Vlodavsky I. Heparanase neutralizes the anticoagulation properties of heparin and low-molecular-weight heparin. J Thromb Haemost. 2006; 4: 560-565.
26. Levy JH. Heparin resistance and antithrombin: should it still be called heparin resistance? Journal of cardiovascular anesthesia. 2004; 18: 129-130.
27. Deitcher SR. Cancer and thrombosis: mechanisms and treatment. J Thromb Thrombolysis. 2003; 16: 21-31.
28. Gohji K, Hirano H, Okamoto M, Kitazawa S, Toyoshima M, Dong J, Katsuoka Y, Nakajima M. Expression of three extracellular matrix degradative enzymes in bladder cancer. Int J Cancer. 2001; 95: 295-301.
29. Koliopanos A, Friess H, Kleeff J, Shi X, Liao Q, Pecker I, Vlodavsky I, Zimmermann A, Buchler MW. Heparanase expression in primary and metastatic pancreatic cancer. Cancer Res. 2001; 61: 4655-59.
30. Kim AW, Xu X, Hollinger EF, Gattuso P, Godellas CV, Prinz RA. Human heparanase-1 gene expression in pancreatic adenocarcinoma. J Gastrointest Surg. 2002; 6: 167-172.

Pharmacokinetics of Low Molecular Weight Heparin in Cancer Patients

Pharmacokinetics of Low Molecular Weight Heparin in Cancer Patients Compared to Patients With Unstable Angina Pectoris; The Possible Role of Heparanase

Shaare Zedek Medical Center

study manager

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Acute Coronary Syndrome

Syndrome

Cardiomyopathies

Dyspnea

Takotsubo Cardiomyopathy

Ventricular Dysfunction, Left

Ventricular Dysfunction

Acute Graft Versus Host Disease

Broken Heart Syndrome

Registry of patients with Tako-Tsubo cardiomyopathy

Christof Burgdorf, Dr.

Prospective, multicenter, observational registry collecting data from subjects with Tako-Tsubo (stress-induced) cardiomyopathy (TTC). Uniform, complete, and accurate data will be collected on the subject's medical history, during index hospitalization for TTC, and during follow-up.

The objectives are to evaluate the prevalence and incidence of cancer in patients with TTC, to document the underlying causes of death during hospital stay and during follow-up, to determine the long-term prognosis, and to identify possible predictors of short and long-term mortality.

The prognosis of patients with TTC is believed to be favorable. This assumption is mainly based on the observations of a rapid recovery of global left ventricular function and low cardiac in-hospital mortality. In fact, the clinical course following TTC events after hospital discharge is largely unknown due to a lack of large prospective long-term follow-up studies and inconsistent and limited findings from available studies to date.

The TTAC registry represents the first attempt to initiate an international registry with special focus on comorbidities, particularly malignancies, in patients with TTC to further elucidate the relationship between these diseases. In addition, the TTAC registry will enable documenting the exact underlying causes of death and long-term prognosis of patients with TTC and to identify possible predictors of short and long-term mortality in these patients.

The first objective of this prospective, multicenter, observational registry is to evaluate the prevalence and incidence of cancer in patients with TTC.

The second objective is to document the underlying causes of death during hospital stay and follow-up and to determine the long-term prognosis of patients with TTC.

The third objective is to identify possible predictors of short and long-term mortality in patients with TTC.

Available information is collected from subjects being treated according to routine clinical practice. In addition, during the index hospitalization, each subject is screened for occult cancer disease. During follow-up, cancer screening will be performed according to appropriate legal preventive examinations.

Subjects will be followed at 6 months and annually after the index event for up to 5 years by phone call, office visit, or by contacts with primary physicians or referring cardiologists, according to each investigator's preference.

As regulated by data protection and privacy laws and in accordance with local ethics committee requirements, subjects will be informed and requested to grant their approval after the index procedure (= cardiac catheterization for suspected acute coronary syndrome) to review their medical records and collect and analyze personal medical information. The confidentiality of the records will be maintained at all times. Subjects will be asked to agree to perform a cancer screening during index hospitalization and will also be asked to agree to be contacted during the 5-year follow-up period.

Patients in whom TTC was diagnosed will be informed and requested to grant their approval to review their medical records, to collect and analyze personal medical information, while maintaining the confidentiality of the records at all times. Subjects will be asked to agree to perform a cancer screening during index hospitalization and will also be asked to agree to be contacted during the 5-year follow-up period. Informed consent will be requested after the index procedure (= cardiac catheterization for suspected acute coronary syndrome proving presence of TTC) and the informed consent form (ICF) has to be signed prior to entering subject's data in the database or prior to any follow-up contact, whichever occurs first.

The investigator and/or designee must clearly document the process of obtaining informed consent in the subject's source documents. The voluntary process of obtaining informed consent confirms the subject's willingness to participate in the registry. It is the investigator's responsibility to ensure that the informed consent process is performed in accordance with Good Epidemiological Practice (GEP) - IEA Guidelines for proper conduct of epidemiological research and where applicable country regulations.

Subjects will be followed at 6 months and annually after the index event for up to 5 years by phone calls, office visits, or by contacts with general practitioners or referring cardiologists, according to each investigator's preference.

Laboratory parameters and biomarkers:

* Faecal occult blood test
* Complete blood count including erythrocyte sedimentation rate
* Serum protein electrophoresis
* Prostate-specific antigen (PSA) testing in men

The TAKO-TSUBO And Cancer Registry

A Prospective, Multicenter, Observational Registry to Evaluate the Prevalence and Incidence of Cancer and Long-term Prognosis in Patients With Tako-Tsubo (Stress-induced) Cardiomyopathy.

Deutsches Herzzentrum Muenchen

Neoplasms

Skin and Connective Tissue Diseases

Ganglion Cysts

Coronary Disease

Synovial Cyst

Cysts

Arteriosclerosis

Arterial Occlusive Diseases

Mucinoses

Connective Tissue Diseases

Patients will undergo radiosurgery of the ganglion stellatum (left one or both)

Patients will undergo radiosurgery of ganglion stellatum (left one or both)

Radiosurgery of ganglion stellatum

Jiří Hynčica

Jakub Cvek, Assoc.Prof.,MD,Ing.,PhD

Lukáš Knybel, Ing.,PhD

Miroslav Hudec, MD

Otakar Jiravský, MD

The core hypothesis to be tested is that the radiosurgery of stellate ganglion (left one or both if left-sided without full relief of symptoms) is an effective therapy of refractory angina pectoris in patients with no other therapeutic options - proof of concept study.

Design: prospective, interventional trial (University Hospital Ostrava, Cardiocentre AGEL Podlesi Hospital Trinec)

* radiosurgery of left GS after confirmation of responding to anesthetic blockade
* in case of remaining AP after three months, radiosurgery of right GS in case of response confirmation to anesthetic blockade (patients must be responders of anesthetic blockade of left stellate ganglion)
* Seattle Angina Questionary (SAQ) and amount of nitrate usage for responding confirmation
* Radiotherapy 40 Gy
* 2-year follow-up
* Scheduled follow-up visits: 1, 3, 6, 12, and 24 months (24)

Preliminary examination: selective coronary angiography, transthoracic echocardiography, stress test, 6 min walk test, SAQ (19-item)

Endopoints:

Primary Endpoints: SAQ, safety of the radiosurgery of GS Secondary Endpoints:usage decrease of angina relief drugs, 6 min walk test improvement

Follow-up visits examination, Restage: 6 min walk test, SAQ, amount of nitrate usage, ECG, blood tests incl. NT-proBNP, NSE

Radiosurgery of Ganglion StELlatum In Patients With REFractory Angina Pectoris

Individual participant data may be made available upon request.

The Seattle Angina Questionnaire is a cardiac disease-related quality-of-life measure with 19 items. A lower score corresponds to a lower level of functioning. The scores are classified as "minimal (scores 75-100), mild (50-74), moderate (25-49), and severe (0-24).

Safety of radiosurgery of ganglion stellatum will be observed and assessed according to the occurrence of adverse events

The change of angina pectoris relief drugs will be evaluated

Change in the six-minute walk test will be evaluated before and after the procedure

Nemocnice AGEL Trinec-Podlesi a.s.

University Hospital Ostrava

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pharmacokinetics of Low Molecular Weight Heparin in Cancer Patients	NCT00716898	Cancer Thrombosis Angina Pectoris		18 Years -	Shaare Zedek Medical Center
The TAKO-TSUBO And Cancer Registry	NCT01944826	Tako-Tsubo Card... Stress-induced ... Acute Coronary ...	Registry of pat...	18 Years -	Deutsches Herzzentrum Muenchen
Radiosurgery of Ganglion StELlatum In Patients With REFractory Angina Pectoris	NCT05600751	Coronary Artery... Angina Pectoris Myocardial Isch...	Radiosurgery of...	18 Years -	University Hospital Ostrava
Pharmacokinetics of Low Molecular Weight Heparin in Cancer Patients	NCT00716898	Cancer Thrombosis Angina Pectoris		18 Years -	Shaare Zedek Medical Center

Spots Global Cancer Trial Database for angina pectoris