Metal-Ligand Cooperation with Thiols as Transient Cooperative Ligands: Acceleration and Inhibition Effects in (De)Hydrogenation Reactions.

ConspectusOver the past two decades, we have developed a series of pincer-type transition metal complexes capable of activating strong covalent bonds through a mode of reactivity known as metal-ligand cooperation (MLC). In such systems, an incoming substrate molecule simultaneously interacts with both the metal center and ligand backbone, with one part of the molecule reacting at the metal center and another part at the ligand. The majority of these complexes feature pincer ligands with a pyridine core, and undergo MLC through reversible dearomatization/aromatization of this pyridine moiety. This MLC platform has enabled us to perform a variety of catalytic dehydrogenation, hydrogenation, and related reactions, with high efficiency and selectivity under relatively mild conditions.In a typical catalytic complex that operates through MLC, the cooperative ligand remains coordinated to the metal center throughout the entire catalytic process, and this complex is the only catalytic species involved in the reaction. As part of our ongoing efforts to develop new catalytic systems featuring MLC, we have recently introduced the concept of transient cooperative ligand (TCL), i.e., a ligand that is capable of MLC when coordinated to a metal center, but the coordination of which is reversible rather than permanent. We have thus far employed thiol(ate)s as TCLs, in conjunction with an acridanide-based ruthenium(II)-pincer catalyst, and this has resulted in remarkable acceleration and inhibition effects in various hydrogenation and dehydrogenation reactions. A cooperative thiol(ate) ligand can be installed in situ by the simple addition of an appropriate thiol in an amount equivalent to the catalyst, and this has been repeatedly shown to enable efficient bond activation by MLC without the need for other additives, such as base. The use of an ancillary thiol ligand that is not fixed to the pincer backbone allows the catalytic system to benefit from a high degree of tunability, easily implemented by varying the added thiol. Importantly, thiols are coordinatively labile enough under typical catalytic conditions to leave a meaningful portion of the catalyst in its original unsaturated form, thereby allowing it to carry out its own characteristic catalytic activity. This generates two coexisting catalyst populations─one that contains a thiol(ate) ligand and another that does not─and this may lead to different catalytic outcomes, namely, enhancement of the original catalytic activity, inhibition of this activity, or the occurrence of diverging reactivities within the same catalytic reaction mixture. These thiol effects have enabled us to achieve a series of unique transformations, such as thiol-accelerated base-free aqueous methanol reforming, controlled stereodivergent semihydrogenation of alkynes using thiol as a reversible catalyst inhibitor, and hydrogenative perdeuteration of C═C bonds without using D2, enabled by a combination of thiol-induced acceleration and inhibition. We have also successfully realized the unprecedented formation of thioesters through dehydrogenative coupling of alcohols and thiols, as well as the hydrogenation of organosulfur compounds, wherein the cooperative thiol serves as a reactant or product. In this Account, we present an overview of the TCL concept and its various applications using thiols.

Polyoxymethylene Upcycling into Methanol and Methyl Groups Catalyzed by a Manganese Pincer Complex.

Polyoxymethylene (POM) is a commonly used engineering thermoplastic, but its recycling by conventional means, i.e., mechanical recycling, is not practiced to any meaningful extent, due to technical limitations. Instead, waste POM is typically incinerated or disposed in landfills, where it becomes a persistent environmental pollutant. An attractive alternative to mechanical recycling is upcycling, namely, the conversion of waste POM into value-added chemicals, but this has received very little attention. Herein, we report the upcycling of POM into useful chemicals through three different reactions, all of which are efficiently catalyzed by a single pincer complex of earth-abundant manganese. One method involves hydrogenation of POM into methanol using H2 gas as the only reagent, whereas another method converts POM into methanol and CO2 through a one-pot process comprising acidolysis followed by Mn-catalyzed disproportionation. The third method utilizes POM as a reagent for the methylation of ketones and amines.

Thioxobimanes.

Dioxobimanes, colloquially known as bimanes, are a well-established family of N-heterobicyclic compounds that share a characteristic core structure, 1,5-diazabicyclo[3.3.0]octadienedione, bearing two endocyclic carbonyl groups. By sequentially thionating these carbonyls in the syn and anti isomers of the known (Me,Me)dioxobimane, we were able to synthesize a series of thioxobimanes, representing the first heavy-chalcogenide bimane variants. These new compounds were extensively characterized spectroscopically and crystallographically, and their aromaticity was probed computationally. Their potential role as ligands for transition metals was demonstrated by synthesizing a representative gold(I)-thioxobimane complex.

[Consensus recommendations on regional interdisciplinary standardization of MRI diagnostics for multiple sclerosis in the metropolitan area of Essen]. / Konsensusempfehlungen zur regionalen fächerübergreifenden Standardisierung der MRT-Diagnostik bei Multipler Sklerose im Großraum Essen.

Magnetic resonance imaging (MRI) is of exceptional importance in the diagnostics and monitoring of multiple sclerosis (MS); however, a close interdisciplinary cooperation between neurologists in private practice, (neuro)radiological practices, hospitals or specialized MS centers is only rarely established. In particular, there is a lack of standardized MRI protocols for image acquisition as well as established quality parameters, which guarantee the comparability of MRI records; however, this is a fundamental prerequisite for an effective application of MRI in the treatment of MS patients, e.g., for making the diagnosis or treatment monitoring. To address these challenges a group of neurologists and (neuro)radiologists developed a consensus proposal for standardization of image acquisition, interpretation and transmission of results and for improvement in interdisciplinary cooperation. This pilot project in the metropolitan area of Essen used a modified Delphi process and was based on the most up to date scientific knowledge. The recommendation takes the medical, economic, temporal and practical aspects of MRI in MS into consideration. The model of interdisciplinary cooperation between radiologists and neurologists with the aim of a regional standardization of MRI could serve as an example for other regions of Germany in order to optimize MRI for MS.

Controlled Selectivity through Reversible Inhibition of the Catalyst: Stereodivergent Semihydrogenation of Alkynes.

Catalytic semihydrogenation of internal alkynes using H2 is an attractive atom-economical route to various alkenes, and its stereocontrol has received widespread attention, both in homogeneous and heterogeneous catalyses. Herein, a novel strategy is introduced, whereby a poisoning catalytic thiol is employed as a reversible inhibitor of a ruthenium catalyst, resulting in a controllable H2-based semihydrogenation of internal alkynes. Both (E)- and (Z)-alkenes were obtained efficiently and highly selectively, under very mild conditions, using a single homogeneous acridine-based ruthenium pincer catalyst. Mechanistic studies indicate that the (Z)-alkene is the reaction intermediate leading to the (E)-alkene and that the addition of a catalytic amount of bidentate thiol impedes the Z/E isomerization step by forming stable ruthenium thiol(ate) complexes, while still allowing the main hydrogenation reaction to proceed. Thus, the absence or presence of catalytic thiol controls the stereoselectivity of this alkyne semihydrogenation, affording either the (E)-isomer as the final product or halting the reaction at the (Z)-intermediate. The developed system, which is also applied to the controllable isomerization of a terminal alkene, demonstrates how metal catalysis with switchable selectivity can be achieved by reversible inhibition of the catalyst with a simple auxiliary additive.

Bronchial artery diameter in massive hemoptysis in cystic fibrosis.

BACKGROUND: Massive hemoptysis is a rare but potentially life-threatening condition of patients with cystic fibrosis (CF) and advanced pulmonary disease. Hypertrophied bronchial arteries are understood to cause massive hemoptysis when rupturing. Risk factors to predict massive hemoptysis are scarce and bronchial artery diameters are not part of any scoring system in follow-up of patients with CF. Aim of this study was to correlate bronchial artery diameter with massive hemoptysis in CF. METHODS: Bronchial artery and non-bronchial systemic artery diameters were measured in contrast enhanced computed tomography (CT) scans in patients with massive hemoptysis and compared to patients with end-stage CF and no history of hemoptysis. Demographic and clinical data and side of bronchial artery/non-bronchial systemic artery hypertrophy and coil embolization were documented. RESULTS: In this retrospective multicenter study 33 patients with massive hemoptysis were included for bronchial artery/non-bronchial systemic artery diameter measurements, (13 female, 20 male, median age 30 years (18-55)). Bronchial artery diameters were significantly larger in the case group than in the control group with median 4 mm (2.2-8.2 mm), and median 3 mm (1-7 mm), respectively (p = 0.002). Sensitivity of bronchial arteries ≥ 3.5 mm to be associated with hemoptysis was 0.76 and specificity 0.71 with ROC creating an area under the curve of 0.719. If non-bronchial systemic arteries were present, they were considered culprit and embolized in 92% of cases. CONCLUSION: Bronchial arteries ≥ 3.5 mm and presence of hypertrophied non-bronchial systemic arteries correlate with massive hemoptysis in patients with CF and might serve as risk predictor for massive hemoptysis. Therefore, in patients with advanced CF we propose CT scans to be carried out as CT angiography to search for bronchial arteries ≥ 3.5 mm and for hypertrophied non-bronchial systemic arteries as possible risk factors for massive hemoptysis.

Efficient Base-Free Aqueous Reforming of Methanol Homogeneously Catalyzed by Ruthenium Exhibiting a Remarkable Acceleration by Added Catalytic Thiol.

Production of H2 by methanol reforming is of particular interest due the low cost, ready availability, and high hydrogen content of methanol. However, most current methods either require very high temperatures and pressures or strongly rely on the utilization of large amounts of base. Here we report an efficient, base-free aqueous-phase reforming of methanol homogeneously catalyzed by an acridine-based ruthenium pincer complex, the activity of which was unexpectedly improved by a catalytic amount of a thiol additive. The reactivity of this system is enhanced by nearly 2 orders of magnitude upon addition of the thiol, and it can maintain activity for over 3 weeks, achieving a total H2 turnover number of over 130 000. On the basis of both experimental and computational studies, a mechanism is proposed which involves outer-sphere dehydrogenations promoted by a unique ruthenium complex with thiolate as an assisting ligand. The current system overcomes the need for added base in homogeneous methanol reforming and also highlights the unprecedented acceleration of catalytic activity of metal complexes achieved by the addition of a catalytic amount of thiol.

Catalytic Oxidative Deamination by Water with H2 Liberation.

Selective oxidative deamination has long been considered to be an important but challenging transformation, although it is a common critical process in the metabolism of bioactive amino compounds. Most of the synthetic methods developed so far rely on the use of stoichiometric amounts of strong and toxic oxidants. Here we present a green and efficient method for oxidative deamination, using water as the oxidant, catalyzed by a ruthenium pincer complex. This unprecedented reaction protocol liberates hydrogen gas and avoids the use of sacrificial oxidants. A wide variety of primary amines are selectively transformed to carboxylates or ketones in good to high yields. It is noteworthy that mechanistic experiments and DFT calculations indicate that in addition to serving as the oxidant, water also plays an important role in assisting the hydrogen liberation steps involved in amine dehydrogenation.

Progression of coronary artery calcification seems to be inevitable, but predictable - results of the Heinz Nixdorf Recall (HNR) study.

AIM: Coronary artery calcification (CAC), as a sign of atherosclerosis, can be detected and progression quantified using computed tomography (CT). We develop a tool for predicting CAC progression. METHODS AND RESULTS: In 3481 participants (45-74 years, 53.1% women) CAC percentiles at baseline (CACb) and after five years (CAC5y) were evaluated, demonstrating progression along gender-specific percentiles, which showed exponentially shaped age-dependence. Using quantile regression on the log-scale (log(CACb+1)) we developed a tool to individually predict CAC5y, and compared to observed CAC5y. The difference between observed and predicted CAC5y (log-scale, mean±SD) was 0.08±1.11 and 0.06±1.29 in men and women. Agreement reached a kappa-value of 0.746 (95% confidence interval: 0.732-0.760) and concordance correlation (log-scale) of 0.886 (0.879-0.893). Explained variance of observed by predicted log(CAC5y+1) was 80.1% and 72.0% in men and women, and 81.0 and 73.6% including baseline risk factors. Evaluating the tool in 1940 individuals with CACb>0 and CACb<400 at baseline, of whom 242 (12.5%) developed CAC5y>400, yielded a sensitivity of 59.5%, specificity 96.1%, (+) and (-) predictive values of 68.3% and 94.3%. A pre-defined acceptance range around predicted CAC5y contained 68.1% of observed CAC5y; only 20% were expected by chance. Age, blood pressure, lipid-lowering medication, diabetes, and smoking contributed to progression above the acceptance range in men and, excepting age, in women. CONCLUSION: CAC nearly inevitably progresses with limited influence of cardiovascular risk factors. This allowed the development of a mathematical tool for prediction of individual CAC progression, enabling anticipation of the age when CAC thresholds of high risk are reached.

Manganese-catalyzed base-free addition of saturated nitriles to unsaturated nitriles by template catalysis.

The coupling of mononitriles into dinitriles is a desirable strategy, given the prevalence of nitrile compounds and the synthetic and industrial utility of dinitriles. Herein, we present an atom-economical approach for the heteroaddition of saturated nitriles to α,ß- and ß,γ-unsaturated mononitriles to generate glutaronitrile derivatives using a catalyst based on earth-abundant manganese. A broad range of such saturated and unsaturated nitriles were found to undergo facile heteroaddition with excellent functional group tolerance, in a reaction that proceeds under mild and base-free conditions using low catalyst loading. Mechanistic studies showed that this unique transformation takes place through a template-type pathway involving an enamido complex intermediate, which is generated by addition of a saturated nitrile to the catalyst, and acts as a nucleophile for Michael addition to unsaturated nitriles. This work represents a new application of template catalysis for C-C bond formation.

Morphological chest CT changes in cystic fibrosis and massive hemoptysis.

BACKGROUND: Massive hemoptysis (MH) is a rare but potentially life-threatening condition of patients with mainly advanced cystic fibrosis (CF). Morphological lung changes are aggravated with disease progression. The aim of this study was to determine whether morphological lung changes differ between patients with CF (pwCF) who have MH and pwCF without MH. METHODS: Chest computed tomography (CT) scans of pwCF and MH acquired at a maximum of 4 months prior to MH (1/2008 to 2/2015) were evaluated for morphological changes and bronchial artery (BA) diameters. Lung lobes with MH were compared with lobes without MH and with matched control patients with end-stage CF and no hemoptysis using the Helbich scoring system. RESULTS: The study included 26 patients with MH (PMH; 15 female, median age 29 years, interquartile range [IQR]: 25-33.75) and 17 matched control patients (11 male, median age 24 years, IQR: 19.5-30). No difference in Helbich score was detected between lobes with MH and matched control patients (p = 0.051). Higher scores were detected in lobes with MH compared to lobes without MH in PMH (p = 0.021), but no difference was detected in the subscores. The BA diameters were larger in PMH (p = 0.02); 85% of PMH had unilateral MH, with 65% of MH involving only one or two lobes. CONCLUSION: Morphological changes are more severe in lobes with MH in the same patient, but there is no difference when compared with matched control patients. Besides abscess/sacculation, no specific changes for MH were identified. Other factors such as BA hypertrophy might play a pivotal role in the pathogenesis of MH in pwCF. Commonly used scores to evaluate chest CT in pwCF cannot be used to assess MH, and other factors, e.g., hypertrophied BA, not represented and not measured in these scores, might be more suitable for assessing the risk for MH.

Hydrogenative alkene perdeuteration aided by a transient cooperative ligand.

Deuterogenation of unsaturated organic compounds is an attractive route for installing C(sp3)-D bonds, but the existing methods typically use expensive D2 and introduce only two deuterium atoms per unsaturation. Herein we report the hydrogenative perdeuteration of alkenes using readily available H2 and D2O instead of D2, catalysed by an acridanide-based ruthenium pincer complex and resulting in the incorporation of up to 4.9 D atoms per C=C double bond in a single synthetic step. Importantly, adding a catalytic amount of thiol, which serves as a transient cooperative ligand, ensures the incorporation of deuterium rather than protium by balancing the rates of two sequential deuteration processes. The current method opens an avenue for installing perdeuteroalkyl groups at specific sites from widely available alkenes under mild conditions.

Fornix damage limits verbal memory functional compensation in multiple sclerosis.

Selective atrophy of the hippocampus, in particular the left CA1 subregion, is detectable in relapsing-remitting MS (RRMS) and is correlated with verbal memory performance. We used novel high-resolution imaging techniques to assess the role that functional compensation and/or white matter integrity of mesial temporal lobe (MTL) structures may play in mediating verbal memory performance in RRMS. High-resolution cortical unfolding of structural MRI in conjunction with functional magnetic resonance imaging (fMRI) was used to localize MTL activity in 18 early RRMS patients and 16 healthy controls during an unrelated word-pairs memory task. Diffusion tensor imaging (DTI) and Tract-Based Spatial Statistics (TBSS) were used to assess the integrity of the fornix and the parahippocampal white matter (PHWM), the major efferents and afferents of the hippocampus. RRMS patients showed greater activity in hippocampal and extra-hippocampal areas during unrelated word-pair learning and recall. Increased hippocampal activity, particularly in the right anterior hippocampus and left anterior CA1 was associated with higher verbal memory scores. Furthermore, increased fractional anisotropy (FA) in the fornix was correlated with both greater fMRI activity in this region and better memory performance. Altered hippocampal fMRI activity in RRMS patients during verbal learning may result from both structural damage and compensatory mechanisms. Successful functional compensation for hippocampal involvement in RRMS may be limited in part by white matter damage to the fornix, consistent with the critical role of this pathway in the clinical expression of memory impairment in MS.

Aldehyde binding through reversible C-C coupling with the pincer ligand upon alcohol dehydrogenation by a PNP-ruthenium catalyst.

Primary alcohol dehydrogenation by a PNP-Ru(II) catalyst was probed by low-temperature NMR experiments. Facile dehydrogenation occurred at -30 °C, but the resulting aldehydes were not found in solution, as they were trapped by the catalyst through a new mode of metal-ligand cooperation involving Ru-O coordination and an unusual, highly reversible C-C coupling with the PNP pincer ligand.

Acceptorless dehydrogenative synthesis of primary amides from alcohols and ammonia.

The highly desirable synthesis of the widely-used primary amides directly from alcohols and ammonia via acceptorless dehydrogenative coupling represents a clean, atom-economical, sustainable process. Nevertheless, such a reaction has not been previously reported, and the existing catalytic systems instead generate other N-containing products, e.g., amines, imines and nitriles. Herein, we demonstrate an efficient and selective ruthenium-catalyzed synthesis of primary amides from alcohols and ammonia gas, accompanied by H2 liberation. Various aliphatic and aromatic primary amides were synthesized in high yields, with no observable N-containing byproducts. The selectivity of this system toward primary amide formation is rationalized through density functional theory (DFT) calculations, which show that dehydrogenation of the hemiaminal intermediate into primary amide is energetically favored over its dehydration into imine.

Corpus callosal diffusivity predicts motor impairment in relapsing-remitting multiple sclerosis: a TBSS and tractography study.

Motor deficits in relapsing remitting multiple sclerosis (RRMS) patients are monitored using standard measures of disability that assess performance ranging from walking ability to hand function, thus reflecting involvement of a variety of motor pathways. We investigated the relative contributions of diffuse white matter damage and focal lesions using diffusion tensor imaging (DTI), in predicting future worsening of hand function in RRMS. The nine hole peg test (NHPT), a test of fine hand motor control, was used to measure baseline upper limb function in 16 controls and 25 RRMS patients, and then performed at follow-up on 22 of these patients at 6 and 12 months. Tract-based spatial statistics (TBSS) were used across the whole brain as a non-hypothesis driven method for localizing white matter changes associated with motor deficits. Subsequently, we used probabilistic fiber tractography in the corticospinal tracts (CST) and the transcallosal hand motor (TCHM) fibers to assess the predictive power of diffusion metrics and/or functionally relevant visible lesion volumes on the decline of hand motor function over the next 12 months. While fractional anisotropy (FA) and radial diffusivity (RD) of both pathways were strongly associated with NHPT performance at baseline, only RD of the TCHM fibers was predictive of NHPT decline over the next 12 months. Neither total visible lesion load nor pathway specific lesion loads were indicative of NHPT performance or progression. The TCHM fibers may play an important role in modifying the effects of MS pathology on fine motor control, and RD in these fibers may be a sensitive biomarker for future disability.

Coil embolisation for massive haemoptysis in cystic fibrosis.

INTRODUCTION: Massive haemoptysis is a life-threatening event in advanced cystic fibrosis (CF) lung disease with bronchial artery embolisation (BAE) as standard of care treatment. The aim of our study was to scrutinise short-term and long-term outcomes of patients with CF and haemoptysis after BAE using coils. METHODS: We carried out a retrospective cohort study of 34 adult patients treated for massive haemoptysis with super selective bronchial artery coil embolisation (ssBACE) between January 2008 and February 2015. Embolisation protocol was restricted to the culprit vessel(s) and three lobes maximum. Demographic data, functional end-expiratory volume in 1 s in % predicted (FEV1% pred.) and body mass index before and after ssBACE, sputum colonisation, procedural data, time to transplant and time to death were documented. RESULTS: Patients treated with ssBACE showed significant improvement of FEV1% pred. after embolisation (p=0.004) with 72.8% alive 5 years post-ssBACE. Mean age of the patients was 29.9 years (±7.7). Mean FEV1% pred. was 45.7% (±20.1). Median survival to follow-up was 75 months (0-125). Severe complication rate was 0%, recanalisation rate 8.8% and 5-year-reintervention rate 58.8%. Chronic infection with Pseudomonas aeruginosa was found in 79.4%, Staphylococcus areus in 50% and Aspergillus fumigatus in 47.1%. DISCUSSION: ssBACE is a safe and effective treatment for massive haemoptysis in patients with CF with good results for controlling haemostasis and excellent short-term and long-term survival, especially in severely affected patients with FEV<40% pred. We think the data of our study support the use of coils and a protocol of careful and prudent embolisation.

Effect of CO on the oxidative addition of arene C-H bonds by cationic rhodium complexes.

Sequential addition of CO molecules to cationic aryl-hydrido Rh(III) complexes of phosphine-based (PCP) pincer ligands was found to lead first to C-H reductive elimination and then to C-H oxidative addition, thereby demonstrating a dual role of CO. DFT calculations indicate that the oxidative addition reaction is directly promoted by CO, in contrast to the commonly accepted view that CO hinders such reactions. This intriguing effect was traced to repulsive pi interactions along the aryl-Rh-CO axis, which are augmented by the initially added CO ligand (due to antibonding interactions between occupied Rh d(pi) orbitals and occupied pi orbitals of both CO and the arene moiety), but counteracted by the second CO ligand (due to significant pi back-donation). These repulsive interactions were themselves linked to significant weakening of the pi-acceptor character of CO in the positively charged rhodium complexes, which is concurrent with an enhanced sigma-donating capability. Replacement of the phosphine ligands by an analogous phosphinite-based (POCOP) pincer ligand led to significant changes in reactivity, whereby addition of CO did not result in C-H reductive elimination, but yielded relatively stable mono- and dicarbonyl aryl-hydrido POCOP-Rh(III) complexes. DFT calculations showed that the stability of these complexes arises from the higher electrophilicity of the POCOP ligand, relative to PCP, which leads to partial reduction of the excessive pi-electron density along the aryl-Rh-CO axis. Finally, comparison between the effects of CO and acetonitrile on C-H oxidative addition revealed that they exhibit similar reactivity, despite their markedly different electronic properties. However, DFT calculations indicate that the two ligands operate by different mechanisms.

Angiogenic growth factors in tissue homogenates of HNSCC: expression pattern, prognostic relevance, and interrelationships.

Head and neck squamous cell carcinoma has still a poor prognosis. Since angiogenesis is crucial for tumor growth, a better understanding of the potential clinical relevance as well as the interactions between the numerous proangiogenic growth factors is essential to develop improved therapeutic strategies in these tumors. Expression levels of eight growth factors known to induce angiogenesis (HGF, bFGF, VEGF-A, VEGF-D, PDGF-AB, PDGF-BB, G-CSF, and GM-CSF) were quantitatively measured by ELISA in homogenates of 41 head and neck squamous cell carcinomas. In addition, microvessel density and protein localization of growth factors were assessed by immunohistochemistry. Statistical analysis was performed to assess interrelationships between growth factors analyzed and to correlate protein levels with patient outcome. In 90% of the tissues at least 4/8 growth factors analyzed were detectable. Highest amounts and most frequent expression were found for HGF, bFGF and VEGF-A while PDGF-AB and PDGF-BB were present in two-thirds and G-CSF and GM-CSF in approximately half of the cases. Although there was no significant relation to microvessel density, we identified significant associations for bFGF with HGF and G-CSF as well as of PDGF-AB with those of VEGF-A and PDGF-BB. For the first time we demonstrate that expression levels of HGF as well as that of bFGF and G-CSF in head and neck squamous tumors are negative prognostic factors for patient survival. Our data indicate a network of interrelated and prognostically relevant growth factors in these tumors that have to be taken into consideration when planning an antiangiogenic and antitumor therapy.