Extra-abdominal desmoid tumor: A case report

Desmoid tumor represents a rare monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Although histologically benign, desmoids are locally invasive and associated with a high local recurrence rate, but lack of metastatic potential. Many issues regarding the optimal treatment of patients with desmoids remain controversial. Surgical resection and radiotherapy are standard treatment options for these patients. Due to heterogeneity of the biological behavior of desmoids, including long periods of stable disease or even spontaneous regression, treatment needs to be individualized to optimize local tumor control and preserve patient's quality of life. Therapeutic approaches to the treatment of recurrent or unresectable desmoid tumors comprise anti-hormonal therapy, non-steroidal anti-inflammatory drugs, classic chemotherapy regimens and tyrosine kinase inhibitor, with highly variable results. It has not yet been possible to establish an optimal therapy protocol for this disease. In this case report we present our experience with the treatment of recurrent extra-abdominal desmoid tumor.

The effect of anti-vascular endothelial growth factor therapy on circulating VEGF levels in colorectal cancer: Blockade of host-derived VEGF clearance

Einleitung: Der vaskuläre endotheliale Wachstumsfaktor (VEGF), ein wichtiger Regulator der Tumorangiogenese, ist in den letzten Jahrzehnten zu einem wichtigen Ziele bei der Behandlung maligner Erkrankungen geworden. Die Anti-VEGF-Behandlung basiert häufig auf Bevacizumab, einem monoklonalen Antikörper, der alle VEGF-A Isoformen inaktiviert, um die Tumorangiogenese zu hemmen. Es wurde wiederholt berichtet, dass Bevacizumab hohe Spiegel von zirkulierendem VEGF in Patienten induziert. Obwohl VEGF größtenteils antikörpergebunden und inaktiv ist, scheint diese "Rückkopplungs- induktion" von Interesse zu sein und könnte zu einem Resistenzmechanismus beitragen. Bisher wurde die Quelle und Regulation der VEGF-Induktion durch Bevacizumab nicht eindeutig aufgeklärt, weshalb dies Ziel der vorliegenden Doktoratsarbeit war. Methoden: In einer klinischen Studie wurden 60 Patienten mit metastasiertem Kolorektalkarzinom untersucht, die eine Chemotherapie mit oder ohne Bevacizumab erhielten. Veränderungen in den VEGF-Plasmaspiegeln wurden gemessen und die Wirkung von neoadjuvanter versus adjuvanter Behandlung wurde verglichen. Die VEGF- Expression wurde in Gewebeschnitten der resezierten Lebermetastasen evaluiert. Die zelluläre VEGF-Expression als Reaktion auf Bevacizumab wurde mittels in vitro Kulturen von Tumor-, Endothelzellen, Fibroblasten und Plättchen untersucht. Schließlich wurde eine potentielle Proteinstabilisierung, verursacht durch Anti-VEGF-Therapie, analysiert. Ergebnisse: Klinische Daten zeigten einen vergleichbaren Anstieg von zirkulierendem VEGF sowohl in Gegenwart (unter neoadjuvanter Therapie) als auch in Abwesenheit des Tumors (bei adjuvanter Behandlung), was darauf hinweist, dass die VEGF- Rückkopplungsproduktion unter Bevacizumab-Therapie vornehmlich vom Wirtsorganismus stammt. In Übereinstimmung mit diesen Daten war die VEGF Expression in Tumorgewebeschnitten nicht durch Bevacizumab-Behandlung beeinflusst. Die in vitro-Analyse der VEGF-Expression in verschiedenen Zellkulturen ließ keinen Anstieg des zellulären VEGF-Gehalts als Reaktion auf die Bevacizumab-Behandlung erkennen. Die Zugabe von Bevacizumab zu Endothelzellkulturen zeigte jedoch eine inhibierende Wirkung auf die Internalisierung und den Abbau von VEGF, was zur Akkumulation von VEGF im Überstand führte. Schlussfolgerung: Der Anstieg des zirkulierenden VEGF als Reaktion auf die Bevacizumab-Therapie ist unabhängig vom Tumor. Die in-vitro Untersuchungen zeigen, dass Bevacizumab an VEGF bindet, wodurch die rezeptorvermittelte Endozytose und der Abbau des Proteins verhindert werden, was den Anstieg des zirkulierenden VEGF in Bevacizumab-behandelten Patienten erklären könnte. Daher ist der Bevacizumab- induzierte VEGF-Anstieg primär vom Wirt abgeleitet und sollte nicht als Tumorresistenzmechanismus betrachtet werden.Introduction: Vascular endothelial growth factor (VEGF), a major mediator of tumor angiogenesis, has become an important target in the treatment of malignant diseases over the past two decades. Anti-VEGF treatment is frequently based on bevacizumab, a monoclonal antibody designed to inactivate all VEGF-A isoforms, to inhibit tumor angiogenesis. It has been repeatedly reported that bevacizumab therapy induces high levels of circulating VEGF. Even though VEGF is mostly antibody-bound and inactive, this “feedback induction” seems of interest and may contribute to a tumor escape or resistance mechanism. Since the mechanism of VEGF induction by bevacizumab had not been decisively revealed, it was the aim of this doctoral thesis to identify its source and mode of regulation. Methods: In a clinical study we evaluated 60 patients with metastasized colorectal cancer who received chemotherapy with or without the addition of bevacizumab. Changes in VEGF plasma levels were determined and the effect of neoadjuvant versus adjuvant treatment was compared. Furthermore, VEGF expression was assessed in tissue sections of the resected liver metastases. The cellular source of VEGF expression in response to bevacizumab was investigated with in vitro cultures of tumor cells, endothelial cells, fibroblasts and platelets. Finally, potential protein stabilization caused by anti-VEGF therapy was analyzed. Results: The clinical data showed a comparable increase of circulating VEGF in both the presence (neoadjuvant setting) and absence of the tumor (adjuvant setting), indicating a predominance of the host response in VEGF feedback production upon bevacizumab therapy. Also, the bevacizumab treatment did not alter the VEGF expression in tumor tissue sections. The in vitro analysis of VEGF expression in different cell cultures did not show an increase in cellular VEGF content or release in response to bevacizumab treatment. However, the addition of bevacizumab to endothelial cell cultures showed an inhibiting effect on endocytotic VEGF internalization and degradation, which led to accumulation of VEGF in the supernatant. Conclusion: The increase of circulating VEGF as a response to bevacizumab therapy is independent of the tumor. The in vitro investigations indicate that bevacizumab binds to VEGF, preventing the receptor-mediated endocytosis and degradation of the protein, which may explain the increase of circulating VEGF in patients treated with bevacizumab. Therefore, the bevacizumab induced VEGF increase is primarily host-derived and should not be considered a tumor resistance mechanism.submitted by Lejla Alidzanovic NurkanovicAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersArbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprüftMedizinische Universität Wien, Diss., 2018(VLID)286442

Extra-abdominal desmoid tumor: A case report

Desmoid tumor represents a rare monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Although histologically benign, desmoids are locally invasive and associated with a high local recurrence rate, but lack of metastatic potential. Many issues regarding the optimal treatment of patients with desmoids remain controversial. Surgical resection and radiotherapy are standard treatment options for these patients. Due to heterogeneity of the biological behavior of desmoids, including long periods of stable disease or even spontaneous regression, treatment needs to be individualized to optimize local tumor control and preserve patient's quality of life. Therapeutic approaches to the treatment of recurrent or unresectable desmoid tumors comprise anti-hormonal therapy, non-steroidal anti-inflammatory drugs, classic chemotherapy regimens and tyrosine kinase inhibitor, with highly variable results. It has not yet been possible to establish an optimal therapy protocol for this disease. In this case report we present our experience with the treatment of recurrent extra-abdominal desmoid tumor. </p

Thrombocytes Correlate with Lymphangiogenesis in Human Esophageal Cancer and Mediate Growth of Lymphatic Endothelial Cells In Vitro.

Recent data provide evidence for an important role of thrombocytes in lymphangiogenesis within human malignant disease. The aim of this study was to investigate the role of thrombocytes in lymphangiogenesis in human esophageal cancer. Perioperative peripheral blood platelet counts (PBPC) were evaluated retrospectively in 320 patients with esophageal cancer, comprising 184 adenocarcinomas (AC), and 136 squamous cell carcinomas (SCC). Data on lymphangiogenesis evaluated by anti-podoplanin immunostaining were available from previous studies, platelets within the tumor tissue were assessed by CD61 immunostaining. For in vitro studies, human lymphatic endothelial cells (LECs) were isolated and co-cultured with peripheral blood platelets. Stromal thrombocytic clusters (STC) were evident in 82 samples (25.6%), and vascular thrombocytic clusters (VTC) in 56 (17.5%). STC and VTC were associated with a significantly higher PBPC at investigation of all cases. The presence of STC was associated with higher lymphatic microvessel density (p<0.001), PBPC and STC were associated with lymphovascular invasion of tumor cells in a regression model. The presence of STCs was associated with shorter DFS of all patients (p = 0.036, Breslow test), and VTC with shorter DFS in in SCC (p = 0.025, Breslow test). In cell culture, LEC proliferation was enhanced by co-culture with human platelets in a dose- and time-dependent manner mediated by the release of PDGF-BB and VEGF-C. Platelets play an important role in lymphangiogenesis and lymphovascular invasion in esophageal cancer, influencing prognosis. So the disruption of signaling pathways between platelets, tumor cells and lymphatic endothelium might be of benefit for patients

Platelet-Stored Angiogenesis Factors: Clinical Monitoring Is Prone to Artifacts

Background: The analysis of angiogenesis factors in the blood of tumor patients has given diverse results on their prognostic or predictive value. Since mediators of angiogenesis are stored in platelets, their measurement in plasma is sensitive to inadvertent platelet activation during blood processing

Kaplan Meier curves of disease free (DFS) and overall survival (OS) of esophageal cancer patients.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066941#pone-0066941-g002" target="_blank">Fig.2A:</a> Presence of stromal thrombocytic clusters (STC) was associated with shorter DFS in all cases. At investigation of tumor types separately, STC was associated with shorter DFS in squamous cell cancer (SCC) (Fig. 2B) as well as in adenocarcinoma (AC) (Fig. 2C). Fig. 2D: Presence of vascular thrombocytic clusters (VTC) was associated with shorter DFS in SCC. Fig. 2E: Surprisingly, VTC was associated with significantly longer DFS in AC in multivariate analysis. Nevertheless, note that only relatively few events are seen in the VTC+ curve, and curves are crossing each other over, qualifying this finding. Fig. 2F: VTC was associated with shorter OS in SCC.</p

Clinical data of patients and presence of stromal and vascular thrombocytic clusters.

<p>Clinical data of patients and presence of stromal and vascular thrombocytic clusters.</p

Cell culture experiments.

<p>A: LEC proliferation is enhanced by co-culture with human platelets in a dose-dependent manner. LECs were seeded at 1×10∧5 per 30 mm well. After 24 hours isolated platelets were added at 3×10∧7, 10∧6 or 10∧5 per well and cells were cultured for another 48 h. For quantification of cell proliferation, the LEC count was determined (black bars, right scale) and metabolic activity was measured by tetrazolium reduction assay (white bars, left scale). B–E: Corresponding microscopic images to A: B: Control; C: EC+Px10∧7, D: EC+Px10∧6, E: EC+Px10∧5. F: LEC proliferation is enhanced by co-culture with human platelets in a time-dependent manner. LECs were seeded at 1×10∧5 per 30 mm well. 24 hours thereafter isolated platelets were added at 1×10∧7 per well and cells were cultured for another 24, 48 and 72 hours. Cell counts were determined for LEC-platelet co-cultures (solid line) as compared to LECs without platelet addition (dashed line). G+H: Growth factor release during co-culture of LECs and human platelets. LECs were seeded at 1×10∧5 per 30 mm well. After 24 hours isolated platelets were added at 7×10∧7, 10∧6 or 10∧5 per well and cells were cultured for another 48 h. Culture supernatant was harvested, centrifuged (to remove cellular components) and then assayed for the concentration of PDGF-BB (G) and VEGF-C (H) by enzyme-linked immunosorbent assay. I: Platelet-induced LEC proliferation is mediated by PDGFRβ, VEGFR-2 and -3. LECs were seeded at 1×10∧5 per 30 mm well. After 24 hours isolated platelets were added at 7×10∧7 per well with or without blocking reagents against PDGFRß, VEGFR-2 and/or VEGFR-3. Cells were cultured for another 48 h before determining LEC counts.</p

Survival Analysis.

<p>univariate survival analysis of patients age was performed using univariate Cox regression.</p>*<p>AC was associated with significantly better prognosis in multivariate analysis than SCC.</p