Cotton-derived oxidized cellulose in minimally invasive thoracic surgery: a clinicopathological study.

OBJECTIVE: The aim of this study was to identify resorption, clinical performance, and safety of cotton-derived oxidized cellulose gauze applied as a hemostat in minimally invasive oncologic thoracic surgery. METHODS: This is a pilot prospective noncomparative observational human in vivo study. A piece of cotton-derived oxidized cellulose gauze measuring 5 × 20 cm was inserted into the subcarinal space of patients with potentially resectable lung carcinoma at the time of video-assisted mediastinoscopic lymphadenectomy and reexamined several days later for macroscopic and histologic evaluation at the time of subsequent lung resection. The primary endpoint was the local situation at the implantation site described by cellulose remnants, fluid collections, and adhesions. The secondary endpoint was safety, described by the number of adverse events and surgical reinterventions. RESULTS: Twenty-five consecutive eligible patients with potentially resectable lung carcinoma were included. The desired hemostatic effect was achieved in all cases. No adverse events were observed. At re-exploration 10.5 (5-28) days later, the cellulose gauze was found to lose its solid structure from the fifth day on. Remnants were last detected 14 days after insertion. The implantation site exhibited no inflammatory changes and a remarkable small amount of fluid collections and adhesions. CONCLUSIONS: Mediastinal application of cotton-derived oxidized cellulose is safe and effective. A piece of gauze measuring 5 × 20 cm seems to be absorbed completely within 15 days, thus precluding any interference with oncologic restaging and follow-up. The absence of relevant adhesions facilitates further surgical procedures. Larger comparative confirmatory studies are required. For large-scale resorption studies, our clinical model should be translated into a porcine model.

Enforced expression of protein kinase C in skeletal muscle causes physical inactivity, fatty liver and insulin resistance in the brain.

Among the multitude of dysregulated signalling mechanisms that comprise insulin resistance in divergent organs, the primary events in the development of type 2 diabetes are not well established. As protein kinase C (PKC) activation is consistently present in skeletal muscle of obese and insulin resistant subjects, we generated a transgenic mouse model that overexpresses constitutively active PKC-beta(2) in skeletal muscle to test whether activation of PKC is sufficient to cause an aversive whole-body phenotype. Upon this genetic modification, increased serine phosphorylation in Irs1 was observed and followed by impaired (3)H-deoxy-glucose uptake and muscle glycogen content, and transgenic mice exhibited insulin and glucose intolerance as they age. Muscle histochemistry revealed an increase in lipid deposition (intramyocellular lipids), and transgenic mice displayed impaired expression of transcriptional regulators of genes involved in fatty acid oxidation (peroxisome proliferator-activated receptor-gamma, PGC-1beta, acyl-CoA oxidase) and lipolysis (hormone-sensitive lipase). In this regard, muscle of transgenic mice exhibited a reduced capacity to oxidize palmitate and contained less mitochondria as determined by citrate synthase activity. Moreover, the phenotype included a profound decrease in the daily running distance, intra-abdominal and hepatic fat accumulation and impaired insulin action in the brain. Together, our data suggest that activation of a classical PKC in skeletal muscle as present in the pre-diabetic state is sufficient to cause disturbances in whole-body glucose and lipid metabolism followed by profound alterations in oxidative capacity, ectopic fat deposition and physical activity.

Challenges in the treatment of patients with essential thrombocythemia and acute coronary syndrome.

Essential thrombocythemia (ET) is an acquired clonal hematological stem-cell disorder that is characterized by a persistent increase in platelet count over 600,000/microl and elevated megakaryocyte levels in the bone marrow. Patients with ET are on the one hand at risk of thrombosis and on the other hand of hemorrhagic events especially in patients with very high platelet accounts. We report two illustrative cases with ET and acute coronary syndrome from our recent clinical experience illustrating the challenges in the antithrombotic treatment of these patients.

Large proportion of low frequency microsatellite-instability and loss of heterozygosity in pheochromocytoma and endocrine tumors detected with an extended marker panel.

PURPOSE: Pheochromocytoma (PCC) is a usually benign tumor originated in the majority of patients from the adrenal medulla. Regarding sporadic forms of PCC, mechanisms of pathogenesis are largely unknown. Recently, microsatellite-instability (MSI) was discussed as genetic factor contributing to PCC development. Since microsatellite markers used for MSI detection have only been recommended for colorectal carcinoma (CRC), we established an extended marker set for MSI detection in PCC. METHODS: Twenty-two PCC patients were analyzed applying 11 microsatellite markers. Our marker set comprised the reference panel for CRC and six additional markers, which have already been described to detect MSI in tumors other than CRC. Moreover, 23 endocrine tumors with gastrointestinal origin were examined in order to test the applicability of this marker panel. RESULTS: Microsatellite-instability was detected in 41% of PCCs. Twenty-seven percent showed loss of heterozygosity (LOH) events affecting different chromosomal regions. Among the 23 patients with endocrine tumors, only three (one pancreatic endocrine tumor, one duodenal neuro-endocrine tumor, one hepatic metastasis of a primary tumor with unknown origin) demonstrated MSI. CONCLUSIONS: The extended microsatellite panel is qualified to detect MSI in PCC. Nine percent of MSI-positive cases would have not been noticed by the use of the reference panel alone. PCCs are characterized by low frequency MSI pointing to failures in factors involved in DNA replication.

Cancer immunoediting by GITR (glucocorticoid-induced TNF-related protein) ligand in humans: NK cell/tumor cell interactions.

Glucocorticoid-induced TNF-related protein (GITR) has been shown to stimulate T cell-mediated antitumor immunity in mice. However, the functional relevance of GITR and its ligand (GITRL) for non-T cells has yet to be fully explored. In addition, recent evidence suggests that GITR plays different roles in mice and humans. We studied the role of GITR-GITRL interaction in human tumor immunology and report for the first time that primary gastrointestinal cancers and tumor cell lines of different histological origin express substantial levels of GITRL. Signaling through GITRL down-regulated the expression of the immunostimulatory molecules CD40 and CD54 and the adhesion molecule EpCAM, and induced production of the immunosuppressive cytokine TGF-beta by tumor cells. On NK cells, GITR is constitutively expressed and up-regulated following activation. Blocking GITR-GITRL interaction in cocultures of tumor cells and NK cells substantially increased cytotoxicity and IFN-gamma production of NK cells demonstrating that constitutive expression of GITRL by tumor cells diminishes NK cell antitumor immunity. GITRL-Ig fusion protein or cell surface-expressed GITRL did not induce apoptosis in NK cells, but diminished nuclear localized c-Rel and RelB, indicating that GITR might negatively modulate NK cell NF-kappaB activity. Taken together, our data indicate that tumor-expressed GITRL mediates immunosubversion in humans.

Influence of NaCl concentrations on coagulation, temperature, and electrical conductivity using a perfusion radiofrequency ablation system: an ex vivo experimental study.

PURPOSE: To determine, by means of an ex vivo study, the effect of different NaCl concentrations on the extent of coagulation obtained during radiofrequency (RF) ablation performed using a digitally controlled perfusion device. METHOD: Twenty-eight RF ablations were performed with 40 W for 10 min using continuous NaCl infusion in fresh excised bovine liver. For perfusion, NaCl concentrations ranging from 0 (demineralized water) to 25% were used. Temperature, the amount of energy, and the dimensions of thermal-induced white coagulation were assessed for each ablation. These parameters were compared using the nonparametric Mann-Whitney test. Correlations were calculated according to the Spearman test. RESULTS: RF ablation performed with 0.9% to 25% concentrations of NaCl produced a mean volume of coagulation of 30.7 +/- 3.8 cm(3), with a mean short-axis diameter of 3.6 +/- 0.2 cm. The mean amount of energy was 21,895 +/- 1,674 W and the mean temperature was 85.4 +/- 12.8 degrees C. Volume of coagulation, short-axis diameter, and amount of energy did not differ significantly among NaCl concentrations (p > 0.5). A correlation was found between the NaCl concentration and the short-axis diameter of coagulation (r = 0.64) and between the NaCl concentration and the mean temperature (r = 0.67), but not between the NaCl concentration and volume of coagulation. CONCLUSION: In an ex vivo model, continuous perfusion with high NaCl concentrations does not significantly improve the volume of thermal-induced coagulation. This may be because the use of a low-power generator cannot sufficiently exploit the potential advantage of better tissue conductivity provided by NaCl perfusion.

Fatal immune-mediated pancytopenia and a TRALI-like syndrome associated with high titers of recipient-type antibodies against donor-derived peripheral blood cells after allogeneic bone marrow transplantation following dose reduced conditioning.

Pancytopenia occurring after bone marrow transplantation is a rare complication. A 47 year old patient with progression of multiple myeloma after standard therapy received an allogeneic marrow graft from a matched unrelated donor. The non-myeloablative conditioning regimen consisted of fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin and total body irradiation. GVHD prophylaxis consisted of cyclosporine. Neutrophil engraftment was as expected and the patient was discharged without signs of acute GvHD. On day +34 the patient presented with clinical and laboratory findings consistent with severe pancytopenia. Antibodies against red cells, platelets, lymphocytes and granulocytes were detected in extremely high titers. Immune-mediated pancytopenia was refractory on multiple immunosuppressive treatment strategies. Proliferation of polyclonal plasma cells of recipient-type that was documented postmortem, was most likely responsible for excessive antibody formation.