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      First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study

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          Abstract

          Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction. Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts. Results: MTD was 3 mg/m 2 tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t 1/2(terminal) of 8 to 9 h without accumulation in daily administrations. Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.

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          Most cited references 38

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          Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis.

          Phage that display a surface peptide with the NGR sequence motif home selectively to tumor vasculature in vivo. A drug coupled to an NGR peptide has more potent antitumor effects than the free drug [W. Arap et al., Science (Washington DC), 279: 377-380, 1998]. We show here that the receptor for the NGR peptides in tumor vasculature is aminopeptidase N (APN; also called CD13). NGR phage specifically bound to immunocaptured APN and to cells engineered to express APN on their surface. Antibodies against APN inhibited in vivo tumor homing by the NGR phage. Immunohistochemical staining showed that APN expression is up-regulated in endothelial cells within mouse and human tumors. In another tissue that undergoes angiogenesis, corpus luteum, blood vessels also expressed APN, but APN was not detected in blood vessels of various other normal tissues stained under the same conditions. APN antagonists specifically inhibited angiogenesis in chorioallantoic membranes and in the retina and suppressed tumor growth. Thus, APN is involved in angiogenesis and can serve as a target for delivering drugs into tumors and for inhibiting angiogenesis.
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            Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma.

            Sunitinib and sorafenib are tyrosine kinase inhibitors (TKIs) that have considerable efficacy in metastatic renal cell carcinoma. TKI-associated cardiotoxicity was reported in approximately 10% of the patients. Detailed cardiovascular monitoring during TKI treatment may reveal early signs of myocardial damage. In this observational, single-center study, all patients intended for TKI treatment were analyzed for coronary artery disease (CAD) risk factors, history or evidence of CAD, hypertension, rhythm disturbances, and heart failure. Monitoring included assessment of symptoms, ECGs, and biochemical markers (ie, creatine kinase-MB, troponin T). Echocardiography was performed at baseline in selected patients and in all patients who experienced a cardiac event. A cardiac event was defined as the occurrence of increased enzymes if normal at baseline, symptomatic arrhythmia that required treatment, new left ventricular dysfunction, or acute coronary syndrome. A total of 86 patients were treated with either sunitinib or sorafenib. Among 74 eligible patients, 33.8% experienced a cardiac event, 40.5% had ECG changes, and 18% were symptomatic. Seven patients (9.4%) were seriously compromised and required intermediate care and/or intensive care admission. All patients recovered after cardiovascular management (ie, medication, coronary angiography, pacemaker implantation, heart surgery) and were considered eligible for TKI continuation. Statistically, there was no significant survival difference between patients who experienced a cardiac event and those who did not experience a cardiac event. Our observations indicate that cardiac damage from TKI treatment is a largely underestimated phenomenon but is manageable if patients have careful cardiovascular monitoring and cardiac treatment at the first signs of myocardial damage.
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              Assessing risk of venous thromboembolism in the patient with cancer.

              Patients with cancer are increasingly at risk for venous thromboembolism (VTE). Rates of VTE, however, vary markedly among patients with cancer. This review focuses on recent data derived from population-based, hospital-based, and outpatient cohort studies of patients with cancer that have identified multiple clinical risk factors as well as candidate laboratory biomarkers predictive of VTE. Clinical risk factors for cancer-associated VTE include primary tumor site, stage, initial period after diagnosis, presence and number of comorbidities, and treatment modalities including systemic chemotherapy, antiangiogenic therapy, and hospitalization. Candidate predictive biomarkers include elevated platelet or leukocyte counts, tissue factor, soluble P-selectin, and D-dimer. A recently validated risk model, incorporating some of these factors, can help differentiate patients at high or low risk for developing VTE while receiving chemotherapy. Identifying patients with cancer who are most at risk for VTE is essential to better target thromboprophylaxis, with the eventual goal of reducing the burden as well as the consequences of VTE for patients with cancer.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                07 June 2020
                June 2020
                : 12
                : 6
                Affiliations
                [1 ]Department of Medicine A, Hematology, Oncology, University Hospital Muenster, D-48149 Muenster, Germany; Christoph.Schliemann@ 123456ukmuenster.de (C.S.); s.harrach@ 123456gmx.net (S.H.); christian.schwoeppe@ 123456uni-muenster.de (C.S.); Anna.Hansmeier@ 123456ukmuenster.de (A.A.H.); linus.angenendt@ 123456ukmuenster.de (L.A.); andrew.berdel@ 123456ukmuenster.de (A.F.B.); u.stalmann@ 123456erasmusmc.nl (U.S.); JoernChristian.Albring@ 123456ukmuenster.de (J.A.); georg.lenz@ 123456ukmuenster.de (G.L.); Torsten.Kessler@ 123456ukmuenster.de (T.K.); Rolf.Mesters@ 123456ukmuenster.de (R.M.M.)
                [2 ]Institute for Clinical Radiology, University Hospital Muenster, D-48149 Muenster, Germany; Mirjam.Gerwing@ 123456ukmuenster.de (M.G.); Moritz.wildgruber@ 123456med.uni-muenchen.de (M.W.); tobias.kraehling@ 123456uni-muenster.de (T.K.); heindel@ 123456uni-muenster.de (W.H.)
                [3 ]Department of Medicine B, Gastroenterology, University Hospital Muenster, D-48149 Muenster, Germany; Hauke.Heinzow@ 123456ukmuenster.de (H.H.); Christian.Wilms@ 123456ukmuenster.de (C.W.); hepar@ 123456ukmuenster.de (H.S.)
                [4 ]Oncology Practice, D-48431 Rheine, Germany; bjoerna.berning@ 123456icloud.com
                [5 ]Group Practice Hematology Oncology, D-48149 Muenster, Germany; kratzalbers@ 123456onkologie-muenster.de
                [6 ]Department of Medicine, Marienhospital Osnabrück, D-49074 Osnabrück, Germany; kristina.middelberg-bisping@ 123456mho.de
                [7 ]Department of Hematology Oncology, St. Franziskus Hospital, D-48145 Muenster, Germany; Stefanie.Wiebe@ 123456SFH-MUENSTER.de
                [8 ]Gerhard-Domagk-Institute for Pathology, University of Muenster, D-48149 Muenster, Germany; Wolfgang.Hartmann@ 123456ukmuenster.de (W.H.); Eva.Wardelmann@ 123456ukmuenster.de (E.W.)
                [9 ]Institute of Biostatistics and Clinical Research, University of Muenster, D-48149 Muenster, Germany; Joachim.Gerss@ 123456ukmuenster.de (J.G.); Eike.Bormann@ 123456ukmuenster.de (E.B.)
                Author notes
                [* ]Correspondence: berdel@ 123456uni-muenster.de ; Tel.: +49-2518352672
                [†]

                Current Address for M. Wildgruber: Klinik und Poliklinik für Radiologie, Klinikum der Universität München, D-81377 Munich, Germany.

                Article
                cancers-12-01488
                10.3390/cancers12061488
                7352358
                32517329
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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