European e-Delphi process to define expert consensus on electrochemotherapy treatment indications, procedural aspects, and quality indicators in melanoma.

BACKGROUND: Skin metastases are an important co-morbidity in melanoma. Despite broad adoption, electrochemotherapy implementation is hindered by a lack of treatment indications, uncertainty regarding procedural aspects, and the absence of quality indicators. An expert consensus may harmonize the approach among centres and facilitate comparison with other therapies. METHODS: An interdisciplinary panel was recruited for a three-round e-Delphi survey. A literature-based 113-item questionnaire was proposed to 160 professionals from 53 European centres. Participants rated each item for relevance and degree of agreement on a five-point Likert scale, and received anonymous controlled feedback to allow revision. The items that reached concordant agreement in two successive iterations were included in the final consensus list. In the third round, quality indicator benchmarks were defined using a real-time Delphi method. RESULTS: The initial working group included 122 respondents, of whom 100 (82 per cent) completed the first round, thus qualifying for inclusion in the expert panel (49 surgeons, 29 dermatologists, 15 medical oncologists, three radiotherapists, two nurse specialists, two clinician scientists). The completion rate was 97 per cent (97 of 100) and 93 per cent (90 of 97) in the second and third rounds respectively. The final consensus list included 54 statements with benchmarks (treatment indications, (37); procedural aspects, (1); quality indicators, (16)). CONCLUSION: An expert panel achieved consensus on the use of electrochemotherapy in melanoma, with a core set of statements providing general direction to electrochemotherapy users to refine indications, align clinical practices, and promote quality assurance programmes and local audits. The residual controversial topics set future research priorities to improve patient care.

Electrochemotherapy is an effective locoregional therapy for skin metastases from melanoma, a problem faced by almost half of patients with metastatic disease. The lack of comparative studies and the heterogeneity of its clinical application among centres make it challenging to support consistent, evidence-based recommendations. To address this unmet need, a three-round online survey was conducted to establish a consensus on treatment indications, standard operating procedures, and quality indicators. In the survey, a panel of 100 European melanoma experts agreed on 56 statements that can be used to improve patient selection, homogenize treatment application, and monitor outcomes.

Polypropylene meshes coated with a polysaccharide based bioadhesive for intra-abdominal mesh fixation in a rabbit model.

BACKGROUND: In this study, we evaluate a new bioadhesive for intra-abdominal onlay mesh fixation of a polypropylene-polyvinylchloride graft. METHODS: Three pieces of a commercially available polypropylene/polyvinylfluoride mesh, each 3 × 3 cm in size, and three pieces of the same mesh coated with a polysaccharide bioadhesive were fixated to the surface of the anterior abdominal wall of 30 New Zealand white rabbits. The fixation was performed either by using four transabdominal Prolene(®) 4/0 sutures, four spiral tacks (Protack 5 mm Tyco), or cyanoacrylate glue (Glubran(®) GEM, Viareggio, Italy). Each mesh position and the according kind of fixation were randomized before implantation. The animals were sacrificed 12 weeks postoperatively. After determining the extent of intra-abdominal adhesions, the meshes were excised en bloc with the anterior abdominal wall for tensile strength measurements and histological analysis. RESULTS: All meshes coated with the bioadhesive adhered to the intact peritoneum without extra fixation. Irrespective of the fixation technique coated meshes led to more and stronger adhesions. Mesh shrinkage by scarring was increased in coated meshes fixed with glue and low in uncoated meshes fixed with tacks. Testing the tensile strength, coated meshes fixed with transfascial sutures achieved the best results (16.14 ± 6.1 N), whereas coated meshes fixed with glue showed the lowest strength (10.39 ± 4.81 N). The foreign body reaction was considerably more distinctive using coated mesh. The mesh ingrowth was not influenced by this reaction. CONCLUSIONS: All meshes coated with the new bioadhesive were self-adhesive in that way; they stayed in position when attached to the peritoneum. Although this may facilitate intra-operative mesh fixation, the bioadhesive displayed several disadvantages, such as stronger adhesions and an increased shrinkage of the implant. The tensile strength was not influenced by the use of the bioadhesive. At present, we see no major advantage for polysaccharide bioadhesive applied in this study.

Activation of peroxisome proliferator-activated receptor-gamma by glitazones reduces the expression and release of monocyte chemoattractant protein-1 in human mesothelial cells.

Human peritoneal mesothelial cells (MC) play an important role in inflammatory processes of the peritoneal cavity by producing various cytokines and chemokines, such as monocyte chemoattractant protein-1 (MCP-1). The present study was designed to assess the effect of the peroxisome proliferator-activated receptor-gamma- (PPARγ-) activator rosiglitazone on the mesothelial MCP-1 expression and release. Primary cultures of MC were obtained from omental tissue. MCP-1 antigen concentrations were measured in the cell supernatant by ELISA and MCP-1 mRNA levels by real-time polymerase chain reaction. The presence of PPARγ on MC was assayed in a Western Blot analysis. MC constitutively express PPARγ. Activation of this receptor via rosiglitazone (0,1-10 µmol/L) resulted in significantly reduced amounts of mesothelial MCP-1 release as well as MCP-1 mRNA. The use of the PPARγ inhibitor GW-9662 could completely prevent the rosiglitazone effects. Rosiglitazone was also effective in reducing TNFα-induced enhanced secretion of MCP-1. Our findings indicate that glitazones are effective in reducing constitutive and TNFα-stimulated mesothelial MCP-1 mRNA expression and release.

Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study.

BACKGROUND AND AIMS: Dendritic cell (DC)-based vaccination can induce antitumor T cell responses in vivo. This clinical pilot study examined feasibility and outcome of DC-based tumor vaccination for patients with advanced pancreatic adenocarcinoma. METHODS: Tumor lysate of patients with pancreatic carcinoma was generated by repeated freeze-thaw cycles of surgically obtained tissue specimens. Patients were eligible for DC vaccination after recurrence of pancreatic carcinoma or in a primarily palliative situation. DC were generated from peripheral blood mononuclear cells (PBMC), loaded with autologous tumor lysate, stimulated with TNF-α and PGE(2) and injected intradermally. All patients received concomitant chemotherapy with gemcitabine. Disease response was the primary endpoint. Individual immunological responses to DC vaccination were analyzed by T cell-based immunoassays using pre- and post-vaccination samples of non-adherent PBMC. RESULTS: Twelve patients received DC vaccination and concomitant chemotherapy. One patient developed a partial remission, and two patients remained in stable disease. Median survival was 10.5 months. No severe side effects were observed. Tumor-reactive T cells could be detected prior to vaccination. DC vaccination increased the frequency of tumor-reactive cells in all patients tested; however, the degree of this increase varied. To quantify the presence of tumor-reactive T cells, stimulatory indices (SI) were calculated as the ratio of proliferation-inducing capacity of lysate-loaded versus -unloaded DC. The patient with longest overall survival of 56 months had a high SI of 6.49, indicating that the presence of a pre-vaccination antitumor T cell response might be associated with prolonged survival. Five patients survived 1 year or more. CONCLUSION: DC-based vaccination can stimulate an antitumoral T cell response in patients with advanced or recurrent pancreatic carcinoma receiving concomitant gemcitabine treatment.

Cyanoacrylate glue for intra-abdominal mesh fixation of polypropylene-polyvinylidene fluoride meshes in a rabbit model.

BACKGROUND: Cyanoacrylate glues are tissue adhesive with high adherent and hemostatic properties. The aim of this study was to evaluate the efficacy of cyanoacrylates glue for polypropylene-polyvinylidene fluoride (PP-PVDF) intraperitoneal onlay mesh (IPOM) fixation in a rabbit model. MATERIALS AND METHODS: In 40 New Zealand white rabbits, three pieces (3×3cm) of a PP-PVDF mesh (n=120) were fixed in IPOM technique on both sides of a midline laparotomy. For mesh fixation we used spiral tacks, nonabsorbable sutures, or cyanoacrylate glue in a randomized manner. All animals were killed after 12 wk. The prosthetic materials were excised en bloc with the anterior abdominal wall for evaluation of the tensile strength and histologic analysis. Results are presented as mean and standard deviation. RESULTS: Meshes fixed with glue showed a significantly higher tenacity of adhesions (2.75±0.97) compared with those with tacks (2.44±0.97 sutures versus 1.91±0.92 tacks). The percentage of adhesions in the glue group was comparable to the suture group (36.50% ± 27.60% glue, 37.62% ± 27.36% suture). The tensile strength of stapled and sutured meshes was significantly higher than the tensile strength glued mesh (14.15±0.97N suture versus 14.84±0.74 stapler versus 9.64±0.78N glue). Mesh shrinkage was irrespective of the fixation technique. The inflammation reaction was more pronounced in the glue group. CONCLUSIONS: Although cyanoacrylate glue showed a considerable cellular ingrowth in this rabbit model, sutures and tacks proved to be superior for IPOM fixation of PP-PVDF meshes in terms of tensile strength.

Long term outcome and quality of life after open incisional hernia repair--light versus heavy weight meshes.

BACKGROUND: Mesh repair of incisional hernia is superior to the conventional technique. From all available materials for open surgery polypropylene (PP) is the most widely used. Development resulted in meshes with larger pore size, decreased mesh surface and lower weight. The aim of this retrospective non randomized study was to compare the quality of life in the long term follow up (> 72 month) after incisional hernia repair with "light weight"(LW) and "heavy weight"(HW) PP meshes. METHODS: 12 patients who underwent midline open incisional hernia repair with a HW-PP mesh (Prolene® 109 g/m2 pore size 1.6 mm) between January 1996 and December 1997 were compared with 12 consecutive patients who underwent the same procedure with a LW-PP mesh (Vypro® 54 g/m2, pore size 4-5 mm) from January 1998. The standard technique was the sublay mesh-plasty with the retromuscular positioning of the mesh. The two groups were equal in BMI, age, gender and hernia size. Patients were routinely seen back in the clinic. RESULTS: In the long term run (mean follow up 112 ± 22 months) patients of the HW mesh group revealed no significant difference in the SF-36 Health Survey domains compared to the LW group (mean follow up 75 ± 16 months). CONCLUSIONS: In this study the health related quality of life based on the SF 36 survey after open incisional hernia repair with light or heavy weight meshes is not related to the mesh type in the long term follow up.

rs224136 on chromosome 10q21.1 and variants in PHOX2B, NCF4, and FAM92B are not major genetic risk factors for susceptibility to Crohn's disease in the German population.

OBJECTIVES: Recently, a North American genome-wide association study identified three novel gene variants in PHOX2B, NCF4, and FAM92B as well as one single nucleotide polymorphisms (SNP; rs224136) in the intergenic region on chromosome 10q21.1 as being associated with Crohn's disease (CD). However, their influence on European CD patients as well as ulcerative colitis (UC) is unknown. Therefore we aimed to replicate these novel CD susceptibility variants in a large European cohort with inflammatory bowel disease and analyzed potential gene-gene interactions with variants in the NOD2/CARD15, IL23R, and ATG16L1 genes. METHODS: Genomic DNA from 2,833 Caucasian individuals including 854 patients with CD, 476 patients with UC, and 1,503 healthy unrelated controls was analyzed for SNPs in PHOX2B (rs16853571), NCF4 (rs4821544), and FAM92B (rs8050910), including rs224136 on chromosome 10q21.1. RESULTS: In our study population, no association of PHOX2B (P=0.563), NCF4 (P=0.506), FAM92B (P=0.401), and rs224136 (P=0.363) with CD was found. Similarly, none of these SNPs was associated with UC. In contrast, all analyzed SNPs in NOD2/CARD15, IL23R, and ATG16L1 were strongly associated with CD with P values ranging from 5.0x10(-3) to 1.6x10(-22), but there was no epistasis with polymorphisms in PHOX2B, NCF4, FAM92B, and rs224136. CONCLUSIONS: In contrast to the North American population, PHOX2B, NCF4, FAM92B, and rs224136 are not associated with CD in the European population, whereas NOD2/CARD15, IL23R, and ATG16L1 are strongly associated with CD in both the North American and European populations, confirming these three genes as major CD susceptibility genes in Caucasian populations.

Role of viral receptors TLR3, RIG-I and MDA5 in mesothelial tissue-type plasminogen activator and plasminogen activator inhibitor-1 synthesis.

Tissue-type plasminogen activator (t-PA) and its specific inhibitor plasminogen activator inhibitor-1 (PAI-1) are key mediators in the regulation of fibrin generation and fibrinolysis. Mesothelial cells (MC) line the inner surface of serosal cavities and are a source of procoagulant and fibrinolytic system components. Viral inflammation and infection of MC are a major problem in several organ systems including pleura, pericardium and peritoneum. MC express the viral receptors Toll-like receptor 3 (TLR3), RIG-I and MDA5. TLRs recognise molecular patterns associated with microbial pathogens and induce an immune response. TLR3 recognises dsRNA of viral origin as exemplified by poly (I:C) RNA, a synthetic analogue of viral dsRNA. The helicases RIG-I and MDA5 may also act as sensors of viral infections. Activation of these receptors by poly (I:C) RNA leads to an time- and dose-dependent increase of mesothelial PAI-1 synthesis and a decrease of t-PA expression. To show the specific effect of viral receptors knockdown experiments with siRNA specific for TLR3, RIG-I and MDA5 were performed. This finding of viral induced changes of t-PA and PAI-1 synthesis may indicate a novel link between viral infections and formation of mesothelial fibrin deposits and progression of viral associated disease of the pleura, peritoneum and pericardium.

Novel role of toll-like receptor 3, RIG-I and MDA5 in poly (I:C) RNA-induced mesothelial inflammation.

Viral inflammation and infection of mesothelial cells (MC) are a major problem in several organ systems including pleura, pericardium and peritoneum. Toll-like receptors (TLRs) are an essential part of the innate immune system for early recognition of pathogen-associated molecular patterns. TLRs recognise molecular patterns associated with microbial pathogens and induce an immune response. TLR3 recognises dsRNA of viral origin as exemplified by poly (I:C) RNA, a synthetic analogue of viral dsRNA. The helicases RIG-I and MDA5 may also act as sensors of viral infections. MC exhibit an expression of TLR3, RIG-I and MDA5. Poly (I:C) RNA stimulation resulted in an up-regulation of proinflammatory cytokines and chemokines as well as type I interferons. This novel finding of functional expression of viral sensors on human MC may indicate a novel link between viral infections and mesothelial inflammation and indicates a pathophysiologic role of viral receptors in these processes.

Role of viral induced vascular endothelial growth factor (VEGF) production in pleural effusion and malignant mesothelioma.

Vascular endothelial growth factor (VEGF) plays a key role in formation of pleural effusions and in tumorigenesis and progression of malignant mesothelioma. Mesothelial cells (MC) express the viral receptors Toll-like receptor 3 (TLR3), RIG-I and MDA5. Activation of these receptors by viral RNA exemplified by poly(I:C) RNA leads to a time- and dose-dependent increase of mesothelial VEGF synthesis. To show the specific effect of viral receptors knockdown experiments with siRNA for TLR3, RIG-I and MDA5 were performed. This finding of viral induced mesothelial VEGF synthesis may indicate a novel link between viral infections and formation of pleural effusions and progression of malignant mesothelioma.

Intraoperative laparoscope augmentation for port placement and resection planning in minimally invasive liver resection.

In recent years, an increasing number of liver tumor indications were treated by minimally invasive laparoscopic resection. Besides the restricted view, two major intraoperative issues in laparoscopic liver resection are the optimal planning of ports as well as the enhanced visualization of (hidden) vessels, which supply the tumorous liver segment and thus need to be divided (e.g., clipped) prior to the resection. We propose an intuitive and precise method to plan the placement of ports. Preoperatively, self-adhesive fiducials are affixed to the patient's skin and a computed tomography (CT) data set is acquired while contrasting the liver vessels. Immediately prior to the intervention, the laparoscope is moved around these fiducials, which are automatically reconstructed to register the patient to its preoperative imaging data set. This enables the simulation of a camera flight through the patient's interior along the laparoscope's or instruments' axes to easily validate potential ports. Intraoperatively, surgeons need to update their surgical planning based on actual patient data after organ deformations mainly caused by application of carbon dioxide pneumoperitoneum. Therefore, preoperative imaging data can hardly be used. Instead, we propose to use an optically tracked mobile C-arm providing cone-beam CT imaging capability intraoperatively. After patient positioning, port placement, and carbon dioxide insufflation, the liver vessels are contrasted and a 3-D volume is reconstructed during patient exhalation. Without any further need for patient registration, the reconstructed volume can be directly augmented on the live laparoscope video, since prior calibration enables both the volume and the laparoscope to be positioned and oriented in the tracking coordinate frame. The augmentation provides the surgeon with advanced visual aid for the localization of veins, arteries, and bile ducts to be divided or sealed.

Bilateral primary adrenal non-Hodgkin's lymphoma and primary adrenocortical carcinoma--review of the literature preoperative differentiation of adrenal tumors.

Most of the adrenal tumors that are incidentally detected are benign adenomas. The incidence of malignant adrenal tumors including adrenocortical carcinoma (ACC) and primary adrenal lymphoma (PAL) is rather low. As many patients with ACC and PAL are diagnosed at an advanced stage of disease, the overall survival time of both entities remains poor. The therapeutic strategies for both entities differ. Thus an early differentiation between ACC and PAL is necessary. Unfortunately hitherto preoperative diagnosis of potentially malignant adrenal masses is still a main problem in the treatment of adrenal tumors. We present the case of a 57-year-old male patient with ACC and the case of an 87-year-old male patient with PAL and provide a systematic comparison of the clinical and pathological features of both entities. In both cases clinical and radiological features resulted in an initially false diagnosis. Primary surgical therapy was performed in both patients. The patient with PAL died five months after initial surgery. The patient with ACC showed tumor progression with local and systemic recurrence despite adjuvant therapy with mitotane and additional surgical therapy. Prognosis of patients with ACC and PAL seems to be dependant on the ability to start accurate treatment without any time delay. We propose some guidelines for diagnosis and surgical management of adrenal tumors.

ACE inhibitor and AT1-receptor blocker attenuate the production of VEGF in mesothelial cells.

OBJECTIVE: Human mesothelial cells (HMC) are a major source of intraperitoneal vascular endothelial growth factor (VEGF) and by that are presumably involved in complications of long-term peritoneal dialysis (PD), such as ultrafiltration failure. This prompted us to look for agents that reduce basic mesothelial VEGF production and abrogate VEGF-overproduction induced by proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1alpha (IL-1alpha). Angiotensin-converting enzyme (ACE) inhibition was found to preserve peritoneal function and ameliorate morphologic changes in a rat PD model. The present in vitro study was designed to investigate the effect of the ACE inhibitors captopril and enalapril, and the angiotensin II type 1-receptor (AT1) antagonist losartan on mesothelial VEGF synthesis. METHODS: HMC were isolated from omental tissue and taken into culture. VEGF antigen concentrations were measured in the cell supernatant by ELISA. VEGF mRNA levels were determined by real-time polymerase chain reaction. RESULTS: Incubation of HMC with captopril (100-1000 micromol/L) resulted in a concentration-dependent attenuation of VEGF synthesis. Incubation with captopril (500-1000 micromol/L), enalapril (100-1000 micromol/L), and losartan (1-100 micromol/L) significantly decreased inflammatory mediator (TNF-alpha, IL-1alpha)-induced mesothelial VEGF overproduction. CONCLUSION: The results indicate that ACE inhibitors and AT1-receptor blockers are capable of effectively attenuating the overproduction of VEGF due to proinflammatory cytokine stimuli. These data suggest that locally produced angiotensin II in the peritoneal cavity may be a potential therapeutic target in ultrafiltration failure during longterm PD.

Role of the NFKB1 -94ins/delATTG promoter polymorphism in IBD and potential interactions with polymorphisms in the CARD15/NOD2, IKBL, and IL-1RN genes.

BACKGROUND: Recently, an association of the NFKB1 polymorphism -94ins/delATTG with ulcerative colitis (UC) has been reported. This 4-bp insertion/deletion polymorphism is localized in the promoter region of the NFKB1 gene and appears to be functionally relevant. The aim of the present study was to confirm the association of the -94ins/delATTG (W/D) NFKB1 promoter polymorphism with UC in a population of German origin and to test for a potential association with Crohn's disease (CD). Furthermore, potential interactions of the -94ins/delATTG polymorphism with the IKBL and the IL-1RN genes should be determined. MATERIALS AND METHODS: The study population comprised 630 patients with CD, 365 patients with UC, and 974 healthy controls. Genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism analysis. For statistical evaluation, the chi-square test and the Fisher exact test were used. RESULTS: No significant association of the W/D NFKB1 polymorphism with CD or UC was detected. In addition, no significant interactions between the -94ins/delATTG NFKB1 polymorphism and polymorphisms within the IKBL and the IL-1RN genes, respectively, were found in CD or UC. Also, no significant interactions of the NFKB1 polymorphism with mutations of the CARD15/NOD2 gene and with clinical phenotypes were detected in CD. Moreover, no associations of the NFKB1 polymorphism were found in UC depending on disease localization. CONCLUSIONS: The present study could not confirm the reported association of the -94ins/delATTG NFKB1 polymorphism with UC and also found no evidence for a role of this polymorphism in CD. The results do not give evidence for a role of this NFKB1 polymorphism in the pathogenesis of UC and CD.

Serum S-100B concentration provides additional information fot the indication of computed tomography in patients after minor head injury: a prospective multicenter study.

Ninety percent of patients with minor head injury (MHI) who have cranial computed tomography (CCT) under the present clinical decision rules have normal scans. Serum concentrations of the astroglial protein S-100B were recently found to provide useful information, but these studies were too small to provide a statistically safe basis for changing the present rule. We have investigated whether S-100B concentrations in patients with MHI can provide additional information to improve indication of the need for an initial CCT scan. One thousand three hundred nine patients with MHI were enrolled in this prospective, multicenter study. All had a CCT scan to confirm diagnosis in accordance with the present clinical decision rules. S-100B was measured in serum samples obtained upon admission. Data were analyzed using contingency table and receiver operating characteristic curve and compared with those for healthy donors (n = 540) and with those for patients with moderate to severe head injury (n = 55). Of the 1309 patients studied, 93 exhibited trauma-relevant intracerebral lesions on the CCT scan (CCT+). With a cutoff limit of 0.10-microg/L S-100B (95th percentile of values in healthy volunteers), CCT+ patients were identified with a sensitivity level of 99% (95% confidence interval, 96% - 100%) and a specificity level of 30% (95% confidence interval, 29% - 31%). Adding the measurement of S-100B concentration to the clinical decision rules for a CCT scan in patients with MHI could allow a 30% reduction in scans. A prospective study of the clinical value of S-100B measurement in such patients is now under way.

Intrathecal and systemic concentration of NT-proBNP in patients with severe traumatic brain injury.

Outcome of patients suffering from traumatic brain injury (TBI) depends on the development of secondary brain damage. In this context, recent studies underlined the role of the natriuretic peptides- atrial natriuretic peptide and brain natriuretic peptide (BNP)-in aneurysmatic subarachnoidal hemorrhage (SAH). Especially BNP correlates with intracranial pressure and clinical outcome after SAH. Since its role in TBI remains unclear, the intracranial and systemic concentrations of N-terminal (NT)-proBNP were analyzed in patients suffering from severe TBI. We measured NT-proBNP levels in cerebrospinal fluid (CSF) and serum of 14 patients suffering from severe TBI (GCS15 mm Hg (n=6), the serum (800+/-150 pg/mL) and CSF levels (55+/-9 pg/mL) of NT-proBNP were significantly increased after 24 h, as compared to patients with ICP15 mm Hg. Further studies are currently performed to elucidate the physiologic role of NT-proBNP in TBI.

Rapid measurement of S-100B serum protein levels by Elecsys S100 immunoassay in patients undergoing carotid artery stenting or endarterectomy.

OBJECTIVES: This study was designed to apply the rapid Elecsys S100 immunoassay for real-time measurement of S100 protein serum levels indicating acute brain damage in patients undergoing carotid artery stenting (CAS) or endarterectomy (CEA). DESIGN AND METHODS: Data of 14 CAS patients were compared to those of 43 CEA and 14 control patients undergoing coronary angiography (CA). S100 serum levels were measured by the full-automatic Elecsys S100 immunoassay and compared to those obtained by the well-established LIA-mat S100 system. RESULTS: In contrast to CAS and CA patients, median S100 serum levels of CEA patients significantly increased to 0.24 ng/mL before declamping, but subsequently returned to baseline. Three CEA patients with neurological deficits showed sustained elevated S100 levels 6 h after extubation. Absolute S100 values were not significantly different between the two methods. Bland-Altman plot analyses displayed a good agreement, mostly indicating slightly smaller values applying the Elecsys S100 system. CONCLUSIONS: The Elecsys S100 system appears to be suitable for rapid real-time detection of neurological deficits in patients undergoing CAS and CEA. Persistent elevations of Elecsys S100 levels during CEA were associated with prolonged neurological disorders, whereas transient increases seem to represent impaired blood-brain barrier integrity without neurological deficits.

Comparison of color-Doppler and qualitative and quantitative strain-elastography for differentiation of thyroid nodules in daily practice.

OBJECTIVE: Strain-elastography provides a new ultrasound-based method that can offer information about the stiffness of thyroid nodules as an indicator of malignancy. The aim of our study was to compare the utility of color-Doppler and strain-elastography in differentiating between benign and malignant nodules. DESIGN AND METHODS: 77 thyroid nodules (70 benign and 7 malignant) from 70 unselected patients (48 female/22 male, mean age 49.7±14.3 years) were evaluated with color-Doppler and elastography based on a five-scale elastogram score for qualitative elastography and strain ratio for quantitative elastography. As reference tissue we chose normal thyroid tissue [strain ratio a (SR a)] and cervical muscles [strain ratio b (SR b)]. The cytological or histological results were used as a reference standard. Diagnostic performances of qualitative and quantitative elastography were compared using ROC curves. RESULTS: Vascularization score 3 or 4 was associated with malignancy (p=0.024) as well as elastogram score 4 or 5 (p=0.070, n.s.s.). SR a was indicatively higher and SR b lower in the group of malignant nodules (p=0.065 and p=0.246, n.s.s.). The best cut-off points predicting malignancy were 3.32 for SR a (66.7% sensitivity, 83.3% specificity) and 0.10 for SR b (71.4% sensitivity, 67.1% specificity). CONCLUSION: In our study, the accuracy of elastography did not surpass other sonographic parameters in differentiating thyroid nodules. The technique can play a role as a supplementary parameter in assessment of malignancy to improve diagnostic efficacy. The best parameter is SR a, but SR b can serve as an alternative if SR a is not assessable.

TNF alpha signaling is associated with therapeutic responsiveness to vascular disrupting agents in endocrine tumors.

ASA404 (Vadimezan) belongs to a class of agents with disrupting properties against tumor vasculature, which is partly mediated by TNFα-signaling. Preclinical and early clinical studies have indicated promising results for ASA404, while extended clinical trials performed poorly. Our aim was to investigate the potential therapeutic applicability of ASA404 against endocrine tumors. Moreover, as the reason for the unpredictable clinical anti-tumor activity of ASA 404 remained uncertain in previous studies, we compared two tumor models of endocrine origin with different responses to ASA404 treatment. Specifically, we determined anti-tumoral effects in preclinical models of neuroendocrine tumors of the gastroenteropancreatic system (BON) and adrenocortical cancer (NCI-H295R) in vitro and in xenograft models in vivo. Upon treatment of tumor bearing mice significant anti-tumoral effects, an increase in TNFα as well as activation of TNFα-specific downstream signaling were evident in the BON tumor model while no comparable effects were detectable for NCI-H295R. We identified TNFAIP3/A20, a key molecule of an inhibitory feedback-loop downstream of TNF-receptor 1, CD40, Toll-like receptors, NOD-like receptors and the interleukin-1 receptor signaling cascades, as overexpressed in the adrenocortical carcinoma tumor model. Subsequent analyses of clinical patient samples confirmed a correlation between tumor TNFAIP3 expression levels and overall survival in patients with ACC. Taken together our findings provide evidence that modulation of TNFα-signaling could be of relevance both for the clinical course of ACC patients and as a marker of treatment response.

Assessment of large bowel motility by cine magnetic resonance imaging using two different prokinetic agents: a feasibility study.

OBJECTIVES: We sought to assess large bowel motility, induced by 2 prokinetic agents, senna tea and erythromycin, using functional cine magnetic resonance imaging (MRI). MATERIALS AND METHODS: Twelve volunteers underwent functional cine MRI before and after the administration of senna tea or erythromycin. The protocol consisted of 2 sets of repeated measurements using coronal T2-weighted HASTE sequences, adjusted to the course of the colon. For the assessment of large bowel motility, the changes of the luminal diameter were measured at 5 defined locations in the ascending, transverse, and descending colon. RESULTS: In all examined volunteers after senna tea, the mean number of significant changes in the ascending colon was 8.6 and after erythromycin, 7.2. In the transverse colon, 9.6 diameters changed significantly for senna tea and 7.2 for erythromycin. In the descending colon, 6.6 diameters changed after senna tea and 7.2 after erythromycin. CONCLUSION: Senna tea and erythromycin proved to induce large bowel motility; senna tea was more effective. Functional cine MRI is a reliable, noninvasive method for the assessment of colonic motility.