Efficiency of recombinant human TNF in human cancer therapy.

Recombinant human tumour necrosis factor (TNF) has a selective effect on angiogenic vessels in tumours. Given that it induces vasoplegia, its clinical use has been limited to administration through isolated limb perfusion (ILP) for regionally advanced melanomas and soft tissue sarcomas of the limbs. When combined with the alkylating agent melphalan, a single ILP produces a very high objective response rate. In melanoma, the complete response (CR) rate is around 80% and the overall objective response rate greater than 90%. In soft tissue sarcomas that are inextirpable, ILP is a neoadjuvant treatment resulting in limb salvage in 80% of the cases. The CR rate averages 20% and the objective response rate is around 80%. The mode of action of TNF-based ILP involves two distinct and successive effects on the tumour-associated vasculature: first, an increase in endothelium permeability leading to improved chemotherapy penetration within the tumour tissue, and second, a selective killing of angiogenic endothelial cells resulting in tumour vessel destruction. The mechanism whereby these events occur involves rapid (of the order of minutes) perturbation of cell-cell adhesive junctions and inhibition of alphavbeta3 integrin signalling in tumour-associated vessels, followed by massive death of endothelial cells and tumour vascular collapse 24 hours later. New, promising approaches for the systemic use of TNF in cancer therapy include TNF targeting by means of single chain antibodies or endothelial cell ligands, or combined administration with drugs perturbing integrin-dependent signalling and sensitizing angiogenic endothelial cells to TNF-induced death.

Clinical studies with a vascular vasopressin antagonist.

The effect of circulating arginine vasopressin (AVP) on blood pressure, heart rate, and skin blood flow was assessed in normotensive subjects, mild hypertensive patients, and patients with congestive heart failure, utilizing the specific antagonist of AVP at the vascular receptor level, d(CH2)5Tyr(Me)AVP (5 micrograms/kg i.v.). The renin system of the normal volunteers treated with the AVP antagonist was either intact or acutely blocked with the angiotensin converting-enzyme inhibitor captopril (25 mg p.o.). In some volunteers, the cardiovascular effect of AVP released by Finnish sauna or cigarette smoking was studied. In patients with congestive heart failure, hemodynamic measurements (pressures and cardiac output) were obtained invasively. Acute blockade of AVP vascular receptors produced no cardiovascular effect unless plasma AVP levels were markedly elevated. In our experience, abnormally high circulating AVP appears to be responsible for the decrease in skin blood flow induced by cigarette smoking and to some extent for the maintenance of vascular tone in the rare patients with particularly severe congestive heart failure.

Les cures hybrides des lésions anévrismales [Hybrid treatment of aortic aneurysms]

The hybrid treatment of aortic aneurysms is indicated in patients having the ostia of supra aortic or visceral branches taken in to the aneurysm. Indeed, these lesions are not eligible for classic endovascular treatment because the existing endoprostheses cannot provide perfusion of the side branches without inducing major endoleaks. The surgical technique consists of 2 steps: firstly, a by-pass between normal aorta and the major aortic branches involved in the aneurysm is performed to guarantee the perfusion of the organs such as brain, bowel, and after endoprosthesis deployment. Secondly, the endoprosthesis is deployed using the classical technique to isolate the aneurysm. The hybrid approach provides safe and reliable treatment of complex aortic aneurysms with mortality and morbidity rate far below the classical open surgery.

Analgesic efficacy of intravenous perfusion of lidocaine, ketamine or a combination after laparotomy in a placebo-controlled, randomized, double-blind prospective study

In acute postoperative pain management intravenous lidocaine and/or ketamine have been advocated because of their morphine-sparing effect. The goal of this prospective, randomised, double-blind study was to assess morphine consumption with different regimens of intravenous infusion of lidocaine, ketamine or both during 48 hours following laparotomy. Patients were randomised into four groups. Group L, K, and KL received intravenous lidocaine, ketamine or a combination, respectively, before incision and during 48 hours postoperatively. The control group (C) received a similar volume of saline bolus and infusion. Postoperative analgesia included morphine delivered by a patient-controlled analgesia device. Primary outcome was the cumulative morphine consumption and pain, sedation scores, pressure algometry and side effects were our secondary outcomes. Cognition and psychomotor performance were also tested. Out of 57 eligible patients, 44 completed the study. Lidocaine reduced the cumulative morphine consumption compared with the control group (mean 0.456 mg.kg-1 +/- 0.244 (SD) versus 0.705 +/- 0.442, respectively, Ρ < 0.001). Pain scores during movement were statistically lower in all three treatment groups. Psychometric tests showed that the lidocaine group expressed more depressed feelings and sadness compared to the control group. Lidocaine administration had a morphine-sparing effect with a 36% reduction of morphine consumption while ketamine alone or combined with lidocaine did not. As a whole, our results suggest that intravenous lidocaine may offer advantages for postoperative analgesia. We propose lidocaine as a new alternative for pain control that needs to be studied further in future multicentric studies.

The Acute STroke Registry and Analysis of Lausanne (ASTRAL): design and baseline analysis of an ischemic stroke registry including acute multimodal imaging.

BACKGROUND AND PURPOSE: Stroke registries are valuable tools for obtaining information about stroke epidemiology and management. The Acute STroke Registry and Analysis of Lausanne (ASTRAL) prospectively collects epidemiological, clinical, laboratory and multimodal brain imaging data of acute ischemic stroke patients in the Centre Hospitalier Universitaire Vaudois (CHUV). Here, we provide design and methods used to create ASTRAL and present baseline data of our patients (2003 to 2008). METHODS: All consecutive patients admitted to CHUV between January 1, 2003 and December 31, 2008 with acute ischemic stroke within 24 hours of symptom onset were included in ASTRAL. Patients arriving beyond 24 hours, with transient ischemic attack, intracerebral hemorrhage, subarachnoidal hemorrhage, or cerebral sinus venous thrombosis, were excluded. Recurrent ischemic strokes were registered as new events. RESULTS: Between 2003 and 2008, 1633 patients and 1742 events were registered in ASTRAL. There was a preponderance of males, even in the elderly. Cardioembolic stroke was the most frequent type of stroke. Most strokes were of minor severity (National Institute of Health Stroke Scale [NIHSS] score ≤ 4 in 40.8% of patients). Cardioembolic stroke and dissections presented with the most severe clinical picture. There was a significant number of patients with unknown onset stroke, including wake-up stroke (n=568, 33.1%). Median time from last-well time to hospital arrival was 142 minutes for known onset and 759 minutes for unknown-onset stroke. The rate of intravenous or intraarterial thrombolysis between 2003 and 2008 increased from 10.8% to 20.8% in patients admitted within 24 hours of last-well time. Acute brain imaging was performed in 1695 patients (97.3%) within 24 hours. In 1358 patients (78%) who underwent acute computed tomography angiography, 717 patients (52.8%) had significant abnormalities. Of the 1068 supratentorial stroke patients who underwent acute perfusion computed tomography (61.3%), focal hypoperfusion was demonstrated in 786 patients (73.6%). CONCLUSIONS: This hospital-based prospective registry of consecutive acute ischemic strokes incorporates demographic, clinical, metabolic, acute perfusion, and arterial imaging. It is characterized by a high proportion of minor and unknown-onset strokes, short onset-to-admission time for known-onset patients, rapidly increasing thrombolysis rates, and significant vascular and perfusion imaging abnormalities in the majority of patients.

Perfusion and diffusion MRI of glioblastoma progression in a four-year prospective temozolomide clinical trial.

PURPOSE: This study was performed to determine the impact of perfusion and diffusion magnetic resonance imaging (MRI) sequences on patients during treatment of newly diagnosed glioblastoma. Special emphasis has been given to these imaging technologies as tools to potentially anticipate disease progression, as progression-free survival is frequently used as a surrogate endpoint. METHODS AND MATERIALS: Forty-one patients from a phase II temolozomide clinical trial were included. During follow-up, images were integrated 21 to 28 days after radiochemotherapy and every 2 months thereafter. Assessment of scans included measurement of size of lesion on T1 contrast-enhanced, T2, diffusion, and perfusion images, as well as mass effect. Classical criteria on tumor size variation and clinical parameters were used to set disease progression date. RESULTS: A total of 311 MRI examinations were reviewed. At disease progression (32 patients), a multivariate Cox regression determined 2 significant survival parameters: T1 largest diameter (p < 0.02) and T2 size variation (p < 0.05), whereas perfusion and diffusion were not significant. CONCLUSION: Perfusion and diffusion techniques cannot be used to anticipate tumor progression. Decision making at disease progression is critical, and classical T1 and T2 imaging remain the gold standard. Specifically, a T1 contrast enhancement over 3 cm in largest diameter together with an increased T2 hypersignal is a marker of inferior prognosis.

Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice.

Obesity and insulin resistance represent a problem of utmost clinical significance worldwide. Insulin-resistant states are characterized by the inability of insulin to induce proper signal transduction leading to defective glucose uptake in skeletal muscle tissue and impaired insulin-induced vasodilation. In various pathophysiological models, melatonin interacts with crucial molecules of the insulin signaling pathway, but its effects on glucose homeostasis are not known. In a diet-induced mouse model of insulin resistance and normal chow-fed control mice, we sought to assess the effects of an 8-wk oral treatment with melatonin on insulin and glucose tolerance and to understand underlying mechanisms. In high-fat diet-fed mice, but not in normal chow-fed control mice, melatonin significantly improved insulin sensitivity and glucose tolerance, as evidenced by a higher rate of glucose infusion to maintain euglycemia during hyperinsulinemic clamp studies and an attenuated hyperglycemic response to an ip glucose challenge. Regarding underlying mechanisms, we found that melatonin restored insulin-induced vasodilation to skeletal muscle, a major site of glucose utilization. This was due, at least in part, to the improvement of insulin signal transduction in the vasculature, as evidenced by increased insulin-induced phosphorylation of Akt and endoethelial nitric oxide synthase in aortas harvested from melatonin-treated high-fat diet-fed mice. In contrast, melatonin had no effect on the ability of insulin to promote glucose uptake in skeletal muscle tissue in vitro. These data demonstrate for the first time that in a diet-induced rodent model of insulin resistance, melatonin improves glucose homeostasis by restoring the vascular action of insulin.

Are there vascular density gradients along myocardial laser channels?

BACKGROUND: Clinical studies suggest that transmyocardial laser revascularization may improve regional blood flow of the subendocardial layer. The vascular growth pattern of laser channels was analyzed. METHODS: Twenty pigs were randomized to undergo ligation of left marginal arteries (n = 5), to undergo transmyocardial laser revascularization of the left lateral wall (n = 5), to undergo both procedures (n = 5) or to a control group (n = 5). All the animals were sacrificed after 1 month. Computed morphometric analysis of vascular density of the involved area was expressed as number of vascular structures per square millimeter (+/-1 standard deviation). RESULTS: The vascular density of the scar tissue of the laser channel was significantly increased in comparison with myocardial infarction alone: 49.6+/-12.8/mm2 versus 25.5+/-8.6/mm2 (p < 0.0001). The vascular densities of subendocardial and subepicardial channel areas were similar: 52.9+/-16.8/mm2 versus 46.3+/-13.6/mm2 (p = 0.41). The area immediately adjacent to the channels showed a vascular density similar to that of normal tissue: 6.02+/-1.7/mm2 versus 5.2+/-1.9/mm2 (p = 0.08). In the infarction + transmyocardial laser revascularization group, the channels were indistinguishable from infarction scar. CONCLUSIONS: Scars of transmyocardial laser revascularization channels exhibit an increased vascular density in comparison with scar tissue of myocardial infarction, which does not extend into their immediate vicinity. There was no vascular density gradient along the longitudinal axis of the channels.

Incidents and complications of totally implanted vascular access devices in children: a prospective study.

BACKGROUND: Totally implanted vascular access devices are frequently used in children for repeated blood samples or intravenous treatments. This prospective study aims at identifying the risk factors associated with infections, obstructions and surgical complications of these devices in pediatric patients. METHODS: From January 2006 to January 2008, all children older than one year of age with a diagnosis of solid or blood cell malignancy were included in the study. Insertion was performed by the surgeon according to a standardized protocol after landmark-guided puncture of the subclavian or internal jugular vein by a senior anesthesiologist. Dressing and post-operative care were standardized. Every manipulation was prospectively recorded by specialized dedicated nurses, and all patients were screened for complications one month post-surgery. RESULTS: 45 consecutive patients 1 to 16 years old were enrolled in the study. Mean age at the time of procedure was 8.5 years (range 1.3-15.6; SD +/- 4.88). There were 12 peroperative adverse events in 45 procedures (27%), detailed as follows: 3 pneumothoraces (7%), 3 hematomas (7%), 6 arterial punctures (13%). Among these events, intervention was necessary for two pneumothorax and one arterial puncture. There was no air embolism. At one month, we recorded 5 post-operative complications (11%): 2 thrombotic obstructions, one unsightly scar, and one scapular pain of unknown etiology. One patient needed repositioning of the catheter. There was no catheter-related infection. CONCLUSION: Prospective recording of TIVA insertion in children reveals a significant number of early incidents and complications, mainly associated with the percutaneous puncture technique. We found no infection in this series. Results of a longer follow-up in the same population are pending.

Neural control of vascular reactions: impact of emotion and attention.

This study investigated the neural regions involved in blood pressure reactions to negative stimuli and their possible modulation by attention. Twenty-four healthy human subjects (11 females; age = 24.75 ± 2.49 years) participated in an affective perceptual load task that manipulated attention to negative/neutral distractor pictures. fMRI data were collected simultaneously with continuous recording of peripheral arterial blood pressure. A parametric modulation analysis examined the impact of attention and emotion on the relation between neural activation and blood pressure reactivity during the task. When attention was available for processing the distractor pictures, negative pictures resulted in behavioral interference, neural activation in brain regions previously related to emotion, a transient decrease of blood pressure, and a positive correlation between blood pressure response and activation in a network including prefrontal and parietal regions, the amygdala, caudate, and mid-brain. These effects were modulated by attention; behavioral and neural responses to highly negative distractor pictures (compared with neutral pictures) were smaller or diminished, as was the negative blood pressure response when the central task involved high perceptual load. Furthermore, comparing high and low load revealed enhanced activation in frontoparietal regions implicated in attention control. Our results fit theories emphasizing the role of attention in the control of behavioral and neural reactions to irrelevant emotional distracting information. Our findings furthermore extend the function of attention to the control of autonomous reactions associated with negative emotions by showing altered blood pressure reactions to emotional stimuli, the latter being of potential clinical relevance.

Calcifications vasculaires et déficit en vitamine K: un facteur de risque modifiable dans l'insuffisance rénale chronique [Vascular calcifications and vitamin K deficiency: a modifiable risk factor in chronic kidney disease].

The mechanisms of vascular calcifications in chronic renal failure are complex. Apart for clotting factors, vitamin K-dependent proteins include matrix Gla protein. Glutamic acid residues in matrix Gla protein are carboxylated by vitamin K-dependent gamma-carboxylase, which enables it to inhibit calcification. The purpose of this review is to discuss available evidence implicating vitamin K as a modifiable risk factor in the pathogenesis of vascular calcification in renal diseases.

Krypton laser photocoagulation induces retinal vascular remodeling rather than choroidal neovascularization.

The purpose of this study is to analyze the retina and choroid response following krypton laser photocoagulation. Ninety-two C57BL6/Sev129 and 32 C57BL/6J, 5-6-week-old mice received one single krypton (630 nm) laser lesion: 50 microm, 0.05 s, 400 mW. On the following day, every day thereafter for 1 week and every 2-3 days for the following 3 weeks, serial sections throughout the lesion were systematically collected and studied. Immunohistology using specific markers or antibodies for glial fibrillary acidic protein (GFAP) (astrocytes, glia and Muller's cells), von Willebrand (vW) (vascular endothelial cells), TUNEL (cells undergoing caspase dependent apoptosis), PCNA (proliferating cell nuclear antigen) p36, CD4 and F4/80 (infiltrating inflammatory and T cells), DAPI (cell nuclei) and routine histology were carried out. Laser confocal microscopy was also performed on flat mounts. Temporal and spatial observations of the created photocoagulation lesions demonstrate that, after a few hours, activated glial cells within the retinal path of the laser beam express GFAP. After 48 h, GFAP-positive staining was also detected within the choroid lesion center. "Movement" of this GFAP-positive expression towards the lasered choroid was preceded by a well-demarcated and localized apoptosis of the retina outer nuclear layer cells within the laser beam path. Later, death of retinal outer nuclear cells and layer thinning at this site was followed by evagination of the inner nuclear retinal layer. Funneling of the entire inner nuclear and the thinned outer nuclear layers into the choroid lesion center was accompanied by "dragging" of the retinal capillaries. Thus, from days 10 to 14 after krypton laser photocoagulation onward, well-formed blood capillaries (of retinal origin) were observed within the lesion. Only a few of the vW-positive capillary endothelial cells stained also for PCNA p36. In the choroid, dilatation of the vascular bed occurred at the vicinity of the photocoagulation site and around it. Confocal microscopy demonstrates that the vessels throughout the path lesion are located within the neuroretina while in the choroid (after separation of the neural retina) only GFAP-positive but no lectin-positive cells can be seen. The involvement of infiltrating inflammatory cells in these remodeling and healing processes remained minimal throughout the study period. During the 4 weeks following krypton laser photocoagulation in the mouse eye, processes of wound healing and remodeling appear to be driven by cells (and vessels) originating from the retina.

Continuous arterial spin labeling of mouse cerebral blood flow using an actively-detuned two-coil system at 9.4T.

Among numerous magnetic resonance imaging (MRI) techniques, perfusion MRI provides insight into the passage of blood through the brain's vascular network non-invasively. Studying disease models and transgenic mice would intrinsically help understanding the underlying brain functions, cerebrovascular disease and brain disorders. This study evaluates the feasibility of performing continuous arterial spin labeling (CASL) on all cranial arteries for mapping murine cerebral blood flow at 9.4 T. We showed that with an active-detuned two-coil system, a labeling efficiency of 0.82 ± 0.03 was achieved with minimal magnetization transfer residuals in brain. The resulting cerebral blood flow of healthy mouse was 99 ± 26 mL/100g/min, in excellent agreement with other techniques. In conclusion, high magnetic fields deliver high sensitivity and allowing not only CASL but also other MR techniques, i.e. (1)H MRS and diffusion MRI etc, in studying murine brains.

Epithelial to mesenchymal transition in the pathogenesis of uterine malignant mixed Müllerian tumours: the role of ubiquitin proteasome system and therapeutic opportunities.

Malignant mixed Müllerian tumours (malignant mixed mesodermal tumours, MMMT) of the uterus are metaplastic carcinomas with a sarcomatous component and thus they are also called carcinosarcomas. It has now been accepted that the sarcomatous component is derived from epithelial elements that have undergone metaplasia. The process that produces this metaplasia is epithelial to mesenchymal transition (EMT), which has recently been described as a neoplasia-associated programme shared with embryonic development and enabling neoplastic cells to move and metastasise. The ubiquitin proteasome system (UPS) regulates the turnover and functions of hundreds of cellular proteins. It plays important roles in EMT by being involved in the regulation of several pathways participating in the execution of this metastasis-associated programme. In this review the specifi c role of UPS in EMT of MMMT is discussed and therapeutic opportunities from UPS manipulations are proposed.