Prognostic relevance of regional lymph-node distribution in patients with N1-positive non-small cell lung cancer: A retrospective single-center analysis.

OBJECTIVE: Lymph node (LN) metastases predict survival in patients with non-small cell lung cancer (NSCLC) treated with curative surgery. Nevertheless, prognostic differences within the same nodal (N) status have been reported. Consequently, the International Association for the Study of Lung Cancer (IASLC) proposed to stratify patients with limited nodal disease (pN1) from low (pN1a) to high (pN1b) nodal tumor burden. This study aimed to validate the IASLC proposal in a large single-center surgical cohort of patients with pN1 NSCLC. MATERIAL AND METHODS: Data from 317 patients with pN1 NSCLC treated between January 2012 and December 2016, were retrospectively analyzed. Associations between distribution of LN metastases and survival were analyzed for different classification models-toward nodal extension (pN1a: one station involved; pN1b: multiple stations involved) and toward location (pN1 in the hilar [LN#10/11] or peripheral zone [LN#12-14]). RESULTS: Tumor-specific survival (TSS) in the entire pN1 cohort was 67.1% at five years. Five-year TSS rates for pN1a and pN1b patients were comparable (67.6% vs. 66.5%, p = 0.623). Significant survival differences from pN1a to pN1b were observed only in patients with adenocarcinoma histology and completed adjuvant chemotherapy (5-year TSS: pN1a, 80.4% vs. pN1b, 49.6%; p = 0.005). TSS for LN metastases in the hilar zone/peripheral zone or in both zones was 68.2% and 59.9%, respectively (p = 0.068). In multivariate analysis, adjuvant chemotherapy, squamous cell histology, and nodal disease limited to one zone nodal disease were identified as independent beneficial prognostic factors (p < 0.05). CONCLUSION: pN1 in only one region (hilar or lobar) was associated with better outcome than metastatic affection of both regions after surgery and adjuvant therapy. A stratification towards single (pN1a) and multiple (pN1b) N1-metastases was found of prognostic relevance only in adenocarcinoma. Prospective multicenter analysis of prognostic subgroups in N1 NSCLC is required to evaluate its clinical impact for consideration in future TNM classification.

PD-L1 expression in large cell neuroendocrine carcinoma of the lung.

OBJECTIVES: Large cell neuroendocrine carcinoma of the lung (LCNEC) is associated with an unfavorable prognosis and only few patients are eligible for surgery. In most patients, chemotherapy is recommended alone or in addition to resection. Novel immunotherapies blocking the PD-L1 pathway have been introduced into therapeutic regimens for NSCLC with great success. In order to evaluate a possible efficacy of an anti-PD-L1 therapy, we analyzed the frequency of PD-L1 expression in LCNEC. MATERIAL AND METHODS: We retrospectively reviewed data from 76 patients with LCNEC treated in our institution between 1998 and 2010. The expression of PD-L1 was examined on the tumor cells and the tumor surrounding tissue by immunohistochemistry. An expression of >1% was considered as positive. Statistical analysis was performed to determine significant predictors for survival. RESULTS: 56 of 76 patients with LCNEC were treated with a potentially therapeutic surgical approach. Tumor-specific survival (TSS) of the entire cohort was 29% at five years. 17 patients (22.3%) had PD-L1 positive tumors and 12 of these had no additional PD-L1 expression in the adjacent immune cell infiltrate. Tumor-flanking immune cells were found PD-L1 positive 28 patients; 16 of these had no additional expression on the tumor cells. The most considerable difference in survival was found when comparing patients with isolated PD-L1 expression on tumor cells and PD-L1 negative immune cell infiltrate to their counterpart (positive immune-cell infiltrate and PD-L1 negative tumor cell surface; 5-year TSS: 0% vs. 60%; p < 0.017). CONCLUSION: PD-L1 expression in LCNEC was associated with poorer survival whereas PD-L1 expression in the tumor microenvironment seemed to have a beneficial effect. Therapeutic approaches have to be evaluated in future.

[Pulmonary Echinococcosis: Surgical Aspects]. / Pulmonale Echinokokkose: chirurgische Aspekte.

Pulmonary cystic echinococcosis is a very rare disease in Germany. It is caused by the larvae of the dog tapeworm (echinococcus granulosus). The liver is the most affected organ, followed by the lungs. Surgery remains the main therapeutic approach for pulmonary CE. Whenever possible, parenchyma-preserving lung surgery should be preferred over anatomic lung resections. To ensure best therapeutic results, surgery needs to be performed under precise consideration of important infectiological aspects and patients should be treated in specialised centres based on interdisciplinary consensus. In addition to surgical aspects, this review summarises special infectiological features of this disease, which are crucial to the surgical approach.

Targeting the vasculature of visceral tumors: novel insights and treatment perspectives.

BACKGROUND: Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, describes a crucial process in tumor growth, disease progression, and metastasis. Therefore, the upcoming strategy of inhibiting tumor angiogenesis has generated different treatment modalities, which have been transferred into clinical practice in recent years. Currently, this concept is applied to target the vasculature of different visceral tumors and intensive clinical research has just started. MATERIALS AND METHODS: This review summarizes the modifications of systemic treatment of visceral tumors by targeting the vasculature in the past years. Moreover, novel targets and treatment strategies will be discussed to evaluate future directions. RESULTS: Leading antiangiogenic drugs combined with systemic chemotherapy have been applied with increasing success during the last years. Therefore, the concept of combining vascular targeting agents with established chemotherapeutic regimens has been increasingly adopted into the therapies of different visceral tumors. CONCLUSION: Targeting the vasculature of visceral tumors in combination with established standard tumor therapies includes major clinical potential for future therapy concepts.

[Modern tailored therapy for pleural empyema]. / Stadienadaptierte moderne Therapie des Pleuraempyems.

In spite of the development and widespread avail-ability of modern antibiotics, pleural empyema still represents a serious intrathoracic disease -associated with significant morbidity and mortality. Patients with complicated parapneumonic effusions and empyema have an increased morbidity and mortality due at least in part to inappropriate and delayed management of pleural space infections. Timely diagnosis of pleural empyema and rapid initiation of the appropriate surgical treatment modality represent keystone principles for efficient treatment of thoracic -empyema. Simple drainage, minimally invasive surgical treatment modalities (VATS) and image-guided small-bore catheters in combination with adjunctive fibrinolytic drugs have extended the potential therapeutic arsenal. Individual case management with a flexible selection of the most appropriate treatment modality by experienced thoracic surgeons may lead to improved outcomes. In this context a summary of the most recent opinions and results in thoracic empyema management is outlined in the present review.

Islets of Langerhans are protected from inflammatory cell recruitment during reperfusion of rat pancreas grafts.

BACKGROUND: Ischemia/reperfusion (I/R) injury plays a pivotal role in the development of graft pancreatitis, with ischemia time representing one of its crucial factors. However, it is unclear, whether exocrine and endocrine tissue experience similar inflammatory responses during pancreas transplantation (PTx). This study evaluated inflammatory susceptibilities of islets of Langerhans (ILH) and exocrine tissue after different preservation periods during early reperfusion. METHODS: PTx was performed in rats following 2 h (2h-I) or 18 h (18h-I) preservation. Leukocyte-endothelial cell interactions (LEI) were analyzed in venules of acinar tissue and ILH in vivo over 2 h reperfusion. Nontransplanted animals served as controls. Tissue samples were analyzed by histomorphometry. RESULTS: In exocrine venules leukocyte rolling predominated in the 2h-I group. In the 18h-I group, additionally, high numbers of adherent leukocytes were found. Histology revealed significant edema formation and leukocyte extravasation in the 18h-I group. Notably, LEI in postcapillary venules of ILH were significantly lower. Leukocyte rolling was only moderately enhanced and few leukocytes were found adherent. Histology revealed minor leukocyte extravasation. CONCLUSION: Ischemia time contributes decisively to the extent of the I/R-injury in PTx. However, ILH have a significantly lower susceptibility towards I/R, even when inflammatory reactions in adjacent exocrine tissue are evident.

Src tyrosine kinase inhibition suppresses lymphangiogenesis in vitro and in vivo.

PURPOSE: The close association of lymphatic and blood vessels and their coordinated development in vivo suggest that there are parallel mechanisms regulating hemangiogenesis and lymphangiogenesis. Here, we hypothesize that inhibition of the Src tyrosine kinase, apart from anti-hemangiogenic effects, results in a suppression of lymphangiogenesis. EXPERIMENTAL DESIGN: The ability of the Src kinase inhibitor PP2 to block Src in isolated lymphatic endothelial cells (LECs) was analyzed by Western Blot. The effects of PP2 on LEC proliferation, migration, and sprouting were assessed by MTT, Boyden chamber, and spheroid assays, respectively. The level of VEGF-C secreted by L3.6pl pancreatic carcinoma cells was measured by ELISA. For in vivo assessment of lymphangiogenesis, Src kinase inhibitor AZM475271 was used in mouse corneal micropocket and lymphangioma models. RESULTS: VEGF-C stimulation of isolated LECs led to an increased phosphorylation of Src kinase that was abrogated by PP2. Treatment with PP2 inhibited spheroid sprouting of LECs at even lower concentrations than suggested by the proliferation assay. Src inhibition significantly reduced the level of VEGF-C in L3.6pl supernatant. Treatment with PP2 also resulted in a significant reduction in the migratory activity of LECs. In vivo, Src inhibition reduced de novo formation of lymphangiomas and corneal neovascularization. CONCLUSIONS: Inhibition of Src kinase shows strong anti-lymphangiogenic activity in vitro and in vivo. Together with anti-angiogenic effects mediated by Src inhibition, this strategy may be attractive in the treatment of lymphatic and hematogeneous metastasis of cancer.

[Acute pancreatitis: is there a need for surgery?]. / Akute Pankreatitis: Wann ist der Chirurg gefragt?

The treatment of acute pancreatitis is primarily non-surgical. An interdisciplinary approach as well as timely and aggressive intensive care has led to a significant improvement of the prognosis in severe necrotising pancreatitis. Early surgical procedures were associated with high morbidity and mortality and therefore were abandoned and replaced with forceful conservative treatment. However, there are still specific indications for surgery during the course of acute pancreatitis. These include cholecystectomy for biliary pancreatitis, surgical debridement of infected necrosis in septic patients and emergency operations for gastrointestinal perforations or haemorrhage. The following article focuses on surgical indications, optimal timing of surgery and competing surgical and non-surgical concepts like laparoscopic or endoscopic management. All mentioned procedures demand the cooperation of an experienced team of gastroenterologists, surgeons, radiologists and intensive care specialists, who are able to manage the potentially life-threatening complications of this disease. All patients with severe necrotising pancreatitis should be transferred to a specialised centre for interdisciplinary therapy.

Inhibition of Src tyrosine kinase reverts chemoresistance toward 5-fluorouracil in human pancreatic carcinoma cells: an involvement of epidermal growth factor receptor signaling.

Resistance to chemotherapy is believed to be a major cause of treatment failure in pancreatic cancer. Thus, it is necessary to explore alternative therapeutic modalities to overcome drug resistance in pancreatic cancer treatment. We tested the hypothesis that Src tyrosine kinase inhibition could augment the chemosensitivity of 5-fluorouracil (5-FU)-resistant human pancreatic cancer cells to 5-FU. As detected by MTT proliferation assay, propidium iodide and annexin V staining, a combination of 5-FU+Src kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) reflected the chemotherapeutic sensitivity and restored the 5-FU-induced apoptosis in 5-FU-resistant cells. Furthermore, when small-interfering RNA approach to silence Src gene expression was applied, the degree of 5-FU-induced apoptosis was increased in all cell lines independently of the chemoresistance status. Western blotting and RT-PCR analysis revealed that the expression of thymidylate synthase (TS) was higher in 5-FU-resistant cells, however, decreased significantly after pretreatment with PP2. Furthermore, the combination of 5-FU+PP2 decreased the 5-FU-induced activation of epidermal growth factor receptor (EGFR)-AKT pathway. Finally, PP2 in combination with 5-FU substantially decreased the in vivo tumor growth and inhibited distant metastases. Taken together, 5-FU chemoresistance can be reversed through indirect TS regulation by inhibiting Src tyrosine kinase. A potential mechanism of action of Src kinase inhibitors on 5-FU chemosensitivity might be linked to the inhibition of 5-FU-induced EGFR-AKT activation.

Contrast enhanced MRI and intravital fluorescence microscopy indicate improved tumor microcirculation in highly vascularized melanomas upon short-term anti-VEGFR treatment.

Anti-angiogenic therapy by blocking VEGF signalling combined with standard chemotherapy is a novel strategy for clinical cancer treatment. The mechanisms for enhanced antitumoral effects are still a matter of controversial debate. Tumor vessel "normalization" upon anti-angiogenic therapy leading to improved drug delivery has been proposed as possible mechanism. Therefore, aim of the study was to investigate tumor microvascular function upon anti-VEGFR treatment in highly vascularized melanomas. A detailed intravital-microscopic analysis of tumor microcirculation including the distribution pattern of vessel diameters and blood flow velocities was performed in melanomas grown in dorsal skinfold chambers of hamsters. Animals with highly vascularized established tumors were treated by a VEGFR tyrosin kinase inhibitor (SU5416) on 3 repetitive days. Tumor tissue oxygenation was measured by phosphorescence quenching technique. Overall tumor microcirculation of subcutaneous tumors was investigated by contrast enhanced MRI (CE-MRI). Vessel density was significantly decreased in treated animals. A significant shift in the distribution patterns towards increased vessel diameters and faster red blood cell velocities in remaining tumor vessels was observed upon anti-VEGF treatment, compensating reduced vascular density. Moreover, a trend towards elevated pO(2) levels in treated tumors was observed. Compared to controls, inflow kinetics of tumors quantified by CE-MRI as well as overall uptake of contrast agent in tumor tissue were significantly increased following short-term SU5416 treatment. In conclusion the results confirm temporarily improved tumor microvascular function in highly vascularized melanomas upon short term anti-VEGFR treatment leading to enhanced tumor blood supply and oxygenation potentially improving the efficacy of simultaneous chemo- or radiotherapy.

Cationic lipid complexed camptothecin (EndoTAG-2) improves antitumoral efficacy by tumor vascular targeting.

Neo-vascular targeting by cationic colloidal carriers enables to realize an innovative approach for tumor therapy. EndoTag-2 is a novel vascular targeting agent, comprising the mammalian topoisomerase I inhibitor camptothecin in its carboxylate form complexed to cationic lipid (cationic lipid complexed camptothecin). Here we studied tumor vascular targeting properties, antitumoral effects and mode of action of EndoTag-2. Tumor vascular targeting properties of fluorescently labelled EndoTag-2 were investigated by in vivo microscopy using A-MEL-3 tumors grown in the dorsal skinfold chamber preparation and by fluorescence histology of s.c. LLC-1 carcinomas. Therapeutic effects have been investigated in the s.c. LLC-1 carcinoma model and the L3.6pl human pancreatic cancer model implanted orthotopically in athymic nude mice. Antivascular effects have been studied by histological investigation of tumor microvessel density and non invasive investigation of tumor blood flow by dynamic contrast enhanced MRI imaging (DCE-MRI). EndoTag-2 selectively targeted tumor microvessels as confirmed by quantitative fluorescence microscopy. Compared to controls EndoTag-2 revealed remarkable antitumoral efficiency in s.c. LLC-1 carcinomas implanted in C57/Bl6 mice. Growth and metastasis of orthotopic L3.6pl human pancreatic tumors was significantly inhibited by EndoTag-2 treatment. Quantitative analysis of tumor microvessel density revealed significant reduction of microvessel density in lewis lung carcinomas up to 50%. DCE-MRI confirmed significant reduction of intratumoral vascular volume as well as tumor perfusion upon EndoTag-2 treatment. In conclusion this study shows that cationic lipid complexed camptothecin (EndoTag-2) is a markedly active antitumor agent based on an innovative vascular targeting approach.

Secular trends in severe renal failure associated with the use of new antimicrobial agents in critically ill surgical patients.

Randomized controlled trials conducted since 2000 have shown that new antibacterial and antifungal agents may reduce the frequency of kidney injury in selected groups of critically ill patients, yet it is unclear whether these benefits translate to the clinical setting. The aim of the present study was to evaluate longitudinally the successive routine implementation of new antimicrobial agents (caspofungin, voriconazole, linezolid) after February 2002 and the association of these agents with the frequency of mechanical renal replacement therapy in postsurgical critically ill patients at risk of severe kidney failure. A retrospective, observational cohort study was performed using data collected prospectively from 1 March 1993 through 28 February 2005. A cohort of 2,123 consecutive cases who required intensive care therapy for more than 2 days was analysed. A statistically significant decrease in the frequency of renal replacement therapy was observed in the later years of the study. After adjustment for relevant covariates, treatment with new antimicrobial agents after February 2002 was identified as an independent factor linked with a reduced risk of severe kidney failure (odds ratio 0.244; 95% confidence interval 0.136-0.439). Thus, the implementation of new antimicrobial agents with reduced or no nephrotoxicity into routine care of critically ill surgical patients is associated with a reduced need for renal replacement therapy.

Angiogenesis in cancer: molecular mechanisms, clinical impact.

BACKGROUND: Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, is fundamental in tumor growth, progression, and metastasis. Inhibiting tumor angiogenesis is a promising strategy for treatment of cancer and has been successfully transferred from preclinical to clinical application in recent years. Whereas conventional therapeutic approaches, e.g. chemotherapy and radiation, are focussing on tumor cells, antiangiogenic therapy is directed against the tumor supplying blood vessels. MATERIALS AND METHODS: This review will summarize important molecular mechanisms of tumor angiogenesis and advances in the design of antiangiogenic drugs. Furthermore, clinical implications of antiangiogenic therapy in surgical oncology will be discussed. RESULTS: First antiangiogenic drugs have been approved for treatment of advanced solid tumors in several countries. Leading antiangiogenic drugs are designed to inhibit vascular endothelial growth factor-mediated tumor angiogenesis. Combining antiangiogenic agents with conventional chemotherapy or radiation is currently investigated clinically with great emphasis to realize a multimodal tumor therapy, targeting both the tumor cell and tumor vascular compartment. CONCLUSION: Antiangiogenic tumor therapy represents a promising strategy for treatment of cancer and will most likely exhibit its clinical potential in combination with established standard tumor therapies in the future.

Paclitaxel encapsulated in cationic lipid complexes (MBT-0206) impairs functional tumor vascular properties as detected by dynamic contrast enhanced magnetic resonance imaging.

Cationic lipid complexes have been shown to be bound and internalized selectively by angiogenic tumor endothelial cells after intravenous injection. Based on this phenomenon, the chemotherapeutic agent paclitaxel was encapsulated into these lipid complexes providing a vascular targeting agent (MBT-0206). As noninvasive imaging techniques are of critical importance for optimizing antivascular cancer treatment in the clinic, we have evaluated the antivascular effects of MBT-0206 in the A-MEL-3 solid tumor model using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Twenty-four hours after three intravenous applications of MBT-0206, tumors of treated animals demonstrated a significant decrease of intratumoral blood volume and an increase of vascular permeability in comparison to size-matched control tumors. In contrast, animals treated with conventional paclitaxel given as Taxol at equal drug dose did not show any significant differences in vascular parameters acquired by DCE-MRI in comparison to controls. Immunohistological analysis confirmed a significant reduction of microvessel density in MBT-0206 treated tumors. Moreover, a significant increase of intratumoral microvascular occlusion following MBT-0206 treatment was observed compared to controls and paclitaxel treated animals. In conclusion, antivascular tumor therapy with MBT-0206 significantly impairs functional tumor microcirculation. DCE-MRI is a promising tool to quantify the antivascular effects of MBT-0206 during treatment.

Platelet-endothelial cell interactions in murine antigen-induced arthritis.

OBJECTIVES: Growing evidence supports the substantial pathophysiological impact of platelets on the development of rheumatoid arthritis. At present there are no methods for studying these cellular mechanisms in vivo. The aim of this study was to visualize and investigate platelet-endothelial cell interaction in the knee joint of mice with antigen-induced arthritis (AiA) by means of intravital microscopy. METHODS: In 14 mice (Balbc) intravital microscopic assessment was performed on day 8 after AiA induction in two groups (controls, AiA). The severity of AiA was assessed by measuring knee joint swelling and by histological scoring. Ex vivo fluorescently labelled rolling and adherent platelets and leucocyte-endothelium interactions were investigated by intravital fluorescence microscopy. RESULTS: Swelling of the knee joint as well as histological score was significantly enhanced in arthritic animals compared with controls. In control mice intravital microscopy revealed low baseline rolling and sticking of leucocytes and fluorescently labelled platelets. AiA induced a significant increase in the fraction of rolling leucocytes (3 times) and rolling platelets (6 times) compared to the control group. Furthermore, AiA induction resulted in a significantly enhanced number of adherent leucocytes (3-fold) and adherent platelets (12-fold) in comparison with control animals. CONCLUSIONS: Platelet kinetics were directly analysed using intravital microscopy in the arthritic microcirculation in vivo for the first time. We provide the first evidence that platelets accumulate in arthritic vessels, indicating platelet activation due to AiA. Platelet recruitment and subsequent activation might play an important role in the pathogenesis of rheumatoid arthritis.

Protamine enhances uptake of cationic liposomes in angiogenic microvessels.

INTRODUCTION: Cationic liposomes have been shown to target angiogenic endothelial cells of solid tumours. Supposing a charge-related mechanism might be responsible for liposome-endothelial interaction, we investigated the effect of intravenous pre-injection of the charged molecules protamine, a polycationic protein, and fucoidan, a polyanionic polysaccharide on the accumulation of cationic liposomes within the blood vessels of a solid tumour. MATERIALS AND METHODS: Experiments were performed using the amelanotic hamster melanoma A-Mel-3 growing in a dorsal skinfold chamber of hamsters. Accumulation of fluorescently-labelled cationic liposomes was quantified by intravital macroscopy and digital image analysis of tumour (t) and surrounding normal host tissue (n) over an observation period of 6 h. All animals received an i.v. injection of cationic liposomes. Animals of the control group were pre-treated with an i.v. injection of 0.9% saline, while animals of group 2 received positively charged protamine and animals of group 3 negatively charged fucoidan prior to liposome injection. RESULTS: In control animals i.v. injection of cationic liposomes revealed a preferential targeting of the tumour vessels, indicated by a maximal t/n ratio of 2.2 +/- 0.24 and a maximal fluorescence intensity (fmax) corresponding to the tumour of 66 +/- 12 [% standard]. While there were no significant differences of liposome accumulation within normal host tissue, accumulation of cationic liposomes within the tumour was significantly enhanced after the pre-administration of protamine (fmax: 117 +/- 12 [% standard]). The t/n ratio was significantly increased in protamine pre-treated animals (5.3 +/- 1.7) in comparison to control and fucoidan treated animals. In contrast, pre-injection of fucoidan resulted in reduced maximal fluorescence intensities in tumour (47 +/- 8 [% standard]) and normal surrounding host tissue. CONCLUSION: Pre-administration of protamine increases the accumulation of cationic liposomes in a solid tumour animal model causing an increased selectivity of cationic liposomes in targeting angiogenic microvessels.

Platelet kinetics in the pulmonary microcirculation in vivo assessed by intravital microscopy.

Growing evidence supports the substantial pathophysiological impact of platelets on the development of acute lung injury. Methods for studying these cellular mechanisms in vivo are not present yet. The aim of this study was to develop a model enabling the quantitative analysis of platelet kinetics and platelet-endothelium interaction within consecutive segments of the pulmonary microcirculation in vivo. New Zealand White rabbits were anesthetized and ventilated. Autologous platelets were separated from blood and labeled ex vivo with rhodamine 6G. After implantation of a thoracic window, microhemodynamics and kinetics of platelets were investigated by intravital microscopy. Velocities of red blood cells (RBCs) and platelets were measured in arterioles, capillaries and venules, and the number of platelets adhering to the microvascular endothelium was counted. Kinetics of unstimulated platelets was compared with kinetics of thrombin-activated platelets. Velocity of unstimulated platelets was comparable to RBC velocity in all vessel segments. Unstimulated platelets passed the pulmonary microcirculation without substantial platelet-endothelial interaction. In contrast, velocity of activated platelets was decreased in all vascular segments indicating platelet margination and temporal platelet-endothelium interaction. Thrombin-activated platelets adhered to arteriolar endothelium; in capillaries and venules adherence of platelets was increased 8-fold and 13-fold, respectively. In conclusion, using intravital microscopy platelet kinetics were directly analyzed in the pulmonary microcirculation in vivo for the first time. In contrast to leukocytes, no substantial platelet-endothelium interaction occurs in the pulmonary microcirculation without any further stimulus. In response to platelet activation, molecular mechanisms enable adhesion of platelets in arterioles and venules as well as retention of platelets within capillaries.

[Antivascular strategies--a new concept for diagnosis and therapy of head and neck cancer. A review]. / Antivaskuläre Strategien--ein neues Konzept zur Diagnose und Therapie von Kopf-Hals-Tumoren--Eine Ubersicht.

BACKGROUND: The development of a blood supply is a crucial step in the progression and metastasis of head and neck cancer. While conventional therapeutic approaches, e. g. chemotherapy and radiation, are focusing on tumor cells, antivascular therapy is directed against the tumor supplying blood vessels. Antivascular treatment can be divided in anti-angiogenesis and vascular targeting. While antiangiogenic therapy prevents neovascularisation by inhibiting new blood vessel growth, the aim of vascular targeting is the destruction of already existing tumor vasculature. METHODS: This review will summarise current pathophysiological mechanisms underlying tumor angiogenesis and the concepts of antivascular therapy with respect to possible applications in head and neck cancer. RESULTS: With experimental antivascular strategies a retardation of tumor growth or tumor remission may be achieved, demonstrating proof of principle. At present, numerous drugs are preclinically and clinically evaluated. CONCLUSIONS: Antivascular strategies are a promising concept for treatment of patients with head and neck carcinomas. They will most likely exhibit their potential in combination with standard tumor therapies in the future.