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Dysregulation of epigenetic mechanisms, reflected by loss of expression of 5-hydroxymethylcytosine (5-hmC) is being increasingly recognized as a marker of aggressive behavior in several neoplasms; however, the role of such epigenetic modifiers in pancreatic neuroendocrine tumors (PanNETs) has not been studied. Annotated cohort of 60 PanNETs was evaluated for 5-hmC expression using immunohistochemistry. Univariable and multivariable analyses were performed. To determine intratumor heterogeneity of 5-hmC expression, 26 additional synchronous metastatic deposits of PanNETs from 8 patients were evaluated for 5-hmC expression. 5-hmC level showed significant association with the presence of distant metastases (P=0.02), female sex (P=0.04), and Ki-67 proliferation index (P=0.002). A multivariate model created using the stepwise logistic regression analysis showed the presence of nodal metastases (odds ratio=6.15), lymphovascular invasion (odds ratio=4.07) and lack of 5-hmC expression (odds ratio=5.34) were predictive of the risk of distant metastasis in PanNETs with a c-statistic of 0.845. Epigenetic intratumoral heterogeneity of 5-hmC expression was seen in 37.5% cases (3/8). Our work provides evidence that epigenetic regulators are involved in the pathobiology of PanNETs and immunohistochemical analysis of 5-hmC may be able to refine prognostic evaluation of these tumors.

Pancreatic neuroendocrine tumors (PNETs) are a rare group of neoplasms originating from the endocrine pancreas. PNETs are classified as functional or non-functional tumors. PNETs are more often diagnosed at a higher stage with distant metastases or advanced locoregional disease. The majority of individuals with hepatic metastases will ultimately die of liver failure; therefore, the treatment of liver tumor burden is critical to providing a survival impact. While surgical resection remains the only chance of cure for disease confined to the pancreas or for locoregional disease, the treatment of advanced or metastatic PNETs is more complex and often requires a multimodal approach. This review focuses on treatment options for well and moderately differentiated PNETs with metastatic disease to the liver. These include surgery, liver-directed therapies including ablative and intra-arterial therapies, and systemic therapies such as somatostatin analogues, targeted therapies, chemotherapy, and peptide receptor radionuclide therapy. Developing an individualized treatment strategy requires careful assessment of liver tumor burden and predicted biological behavior. Aggressive surgical resection of hepatic metastases secondary to PNET primary tumors is associated with improved survival in multiple retrospective studies. General goals of treatment for metastatic disease include prolonging overall survival and progression free survival, improving quality of life, and control of symptoms.

This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.

This study aims to determine the efficacy of calcimimetics in improving bone mineral density (BMD) in patients with primary hyperparathyroidism (pHPT) and compare those results to patients undergoing parathyroidectomy.Parathyroidectomy has been shown to improve BMD in pHPT, but calcimimetics have recently been advocated as a medical alternative to parathyroidectomy for pHPT.We identified 17 patients that were treated with calcimimetics for pHPT. Seventeen patients with pHPT who underwent parathyroidectomy served as surgical controls. Serum calcium level, parathyroid hormone (PTH) level, and femur and spine BMD T scores were compared before and 1 year after therapy.Both groups were demographically matched. Calcium levels normalized in 70.6% of medically versus 100% of surgically treated patients (P = 0.026). PTH levels normalized in 35% of patients treated with calcimimetics versus 76% of surgical patients (P = 0.036). Femur BMD improved in 18.8% of medically treated patients versus 58.8% of surgical patients (P = 0.032). Spine BMD improved in 70.6% of medically treated patients versus 82.4% of surgical patients (P = 0.69). Further analysis demonstrated that regardless of treatment, normalization of PTH was associated with significant improvement in femur (P = 0.03) and spine BMD (P0.001). Normalization of calcium without normalization of PTH did not impact BMD.Parathyroidectomy results in greater normalization of serum calcium and PTH levels and significantly improves cortical BMD compared to calcimimetics. Regardless of treatment, normalization of PTH is associated with significant improvement in spine and femur BMD, suggesting that the superior effects of surgery may be mediated by better control of PTH.

As metallic cations are essential to microbial adherence, biofilm formation, and bacterial growth, efforts have been directed toward utilizing metal-binding chelators that have the capability of inhibiting bacterial growth by disrupting surface adherence and preventing biofilm production. This review focuses on recent advances in the role of chelators in biofilm disruption and prevention of catheter-related bloodstream infections.The most important factor in the pathogenesis of catheter-related bloodstream infections is the intraluminal colonization of the central venous catheters through the formation of bacterial biofilm matrix in which microbial organisms embed themselves and eventually become a source of catheter-related bloodstream infections. It has been demonstrated that high-affinity metal-binding chelators including ethylenediamine-tetraacetic acid and citrate have the capacity of inhibiting microbial growth by disrupting surface adherence and preventing biofilm production. Furthermore, ethylenediamine-tetraacetic acid and citrate have been clinically shown to be highly effective and outperform heparin in the prevention and treatment of catheter-related bloodstream infections when used as a component of antimicrobial catheter lock solutions.It is suggested that the addition of chelators such as ethylenediamine-tetraacetic acid and citrate to antimicrobial lock solutions provides an innovative and superior alternative to heparin lock solution in the prevention and treatment of catheter-related bloodstream infections.

UNLABELLED Adaptive support ventilation (ASV) provides an automatic adaptation of the ventilator settings to patient's passive and active respiratory mechanics. In a randomized controlled study, we evaluated automatic respiratory weaning in ASV for early tracheal extubation after cardiac surgery. Eligible patients were assigned to either an ASV protocol or a standard one consisting of synchronized intermittent ventilation followed by pressure support. Eighteen patients completed the ASV protocol, and 16 completed the standard one. There were no differences between groups in perioperative characteristics, lengths of tracheal intubation and intensive care unit stay, and ventilatory variables, except less peak inspiratory pressure during the initial phase in ASV (17.5 +/- 0.8 versus 22.2 +/- 0.8 cm H(2)O; P < 0.01). ASV patients required fewer ventilatory settings manipulations (2.4 +/- 0.7 versus 4.0 +/- 0.8 manipulations per patient; P < 0.05) and endured less high-inspiratory pressure alarms (0.7 +/- 2.4 versus 2.9 +/- 3.0; P < 0.05). These results suggest that in this specific population of patients, automation of postoperative ventilation with ASV resulted in an outcome similar to the control group. The internal logic of the new device resulted in less manipulation of the setting and alarms that could simplify respiratory management. IMPLICATIONS Adaptive support ventilation (ASV), a ventilatory mode providing automatic adjustment of the settings was compared with standard management for rapid tracheal extubation after cardiac surgery. The two approaches were equal in terms of outcome. In ASV, we observed fewer ventilator settings manipulations and a smaller amount of alarms, suggesting that this automatic mode may simplify postoperative respiratory management without delaying extubation.

Background Adaptive support ventilation (ASV) is a microprocessor-controlled mode of mechanical ventilation that maintains a predefined minute ventilation with an optimal breathing pattern (tidal volume and rate) by automatically adapting inspiratory pressure and ventilator rate to changes in the patient's condition. The aim of the current study was to test the hypothesis that a protocol of respiratory weaning based on ASV could reduce the duration of tracheal intubation after uncomplicated cardiac surgery ("fast-track" surgery). Methods A group of patients being given ASV (group ASV) was compared with a control group (group control) in a randomized controlled study. After coronary artery bypass grafting during general anesthesia with midazolam and fentanyl, patients were randomly assigned to group ASV or group control. Both protocols were divided into three predefined phases, and weaning progressed according to arterial blood gas and clinical criteria. In phase 1, ASV mode was set at 100% of the theoretical value of volume/minute in group ASV, and synchronized intermittent mandatory ventilation mode was used in group control. When spontaneous breathing occurred, ASV setting was reduced by 50% of minute ventilation (phase 2) and again by 50% (phase 3), and the trachea was extubated. In group control, the ventilator was switched to 10 cm H2O inspiratory pressure support (phase 2), then to 5 cm H2O (phase 3) until extubation. Results Forty-nine patients were enrolled. Sixteen patients completed the ASV protocol, and 20 the standard protocol; 7 patients were excluded in group ASV and 6 in group control according to explicit, predefined criteria. There were no differences between groups in perioperative characteristics or in the doses of sedation. The primary outcome of the study, that is, the duration of tracheal intubation, was shorter in group ASV than in group control (median [quartiles]: 3.2 [2.5-4.6] vs. 4.1 [3.1-8.6] h; P < 0.02). Fewer arterial blood analyses were performed in group ASV (median number [quartiles]: 3 [3-4] vs. 4 [3-6]), suggesting that fewer changes in the settings of the ventilator were required in this group. Conclusions A respiratory weaning protocol based on ASV is practicable; it may accelerate tracheal extubation and simplify ventilatory management in fast-track patients after cardiac surgery. The evaluation of potential advantages of the use of such technology on patient outcome and resource utilization deserves further studies.

Transmyocardial laser revascularization (TMLR) and therapeutic angiogenesis had emerged as potential tools in the treatment of angina refractory to conventional therapies. This combination might potentiate their effects, because angiogenesis is believed to be a basic mechanism in TMLR. The influence of channel connection with endocardial blood flow on angiogenesis is unclear. Twenty-five pigs (mean weight, 72.3 +/- 5 kg) were randomly assigned into five groups. In the transmural laser group, five transmyocardial channels were drilled. In the transmural mixed group, the same protocol was used followed by the injection of 100 microg of bovine bone derived growth factor mixture within each channel. The nontransmural laser group and the nontransmural mixed group underwent the same procedures, respectively, but the laser channels were drilled through the outer two-thirds of the myocardial wall. The control group had sham operations. Animals were allowed to survive for 1 month. Vascular densities were determined by computed morphometric analysis of histologic sections. Vascular counts of areas adjacent to the channels in the non- and transmural laser groups did not differ significantly from control groups (arteriolar counts: 0.27 +/- 0.16 and 0.26 +/- 0.16 vs. 0.29 +/- 0.11/mm2, respectively). When bovine bone protein growth factor mixture is added, neovascularization is increased significantly in non- and transmural mixed groups (1.04 +/- 0.79 and 0.69 +/- 0.37/mm2, respectively, p < 0.001 for both comparisons with corresponding laser groups), and there was no significant difference between mixed groups (p = 0.13). In this porcine model, the combination of TMLR with injection of bone protein growth factor mixture induced angiogenesis around the laser channels. Whether the channels did or did not communicate with the endocardial cavity did not influence the neovascular density.

Background: As heart transplantation has gained wide acceptance, a growing number of recipients are at risk of experiencing extramediastinal surgical problems. Study Design: We retrospectively reviewed our experience in the diagnosis and management of surgical problems occurring in 94 consecutive patients having heart transplantation. During the period of the study, we progressively adopted a policy of low-level immunosuppression, aiming toward monotherapy with cyclosporine. Results: Seventy-four extramediastinal surgical problems developed in 44 of 94 patients (47%). The type of problems were gastrointestinal in 17 of 74 (23%), vascular in 13 of 74 (17.5%), urogenital in 8 of 74 (11%), and neurologic in 4 of 74 (5.5%). There were also 9 of 74 cases of trauma (12%), 9 of 74 skin tumors (12%), and 14 of 74 miscellaneous diseases (19%). Sixty-two surgical diseases occurring in 40 patients required 75 surgical interventions, 11 of them (15%) on an emergency basis. Operations were performed for 12 of 74 neoplasms (16%) and 12 of 74 infectious or potentially infectious diseases (16%). Surgical diseases occurred most commonly within the first 6 months after transplantation (20 of 74; 27%). Complications occurred in 8 of 75 surgical interventions (9%). A high proportion of surgical disease was potentially related to immunosuppressive therapy (37 of 74; 50%) or to transplantation itself (7 of 74; 9%). Conclusions: Extramediastinal diseases after heart transplantation involve most surgical specialties. Most of them are potentially linked with either the immunosuppressive therapy or the transplantation procedure, supporting our low-level immunosuppression policy. Expectant management is not justified in this population, who withstands operations well both early and late after transplantation.

The adverse effects of systemic heparin administration has led to the development of heparin coated devices. Intra-aortic balloons are frequently used in clinical settings in which complications of systemic heparin, especially bleeding, are feared. The current study evaluated the thromboresistance of heparin coated intra-aortic balloons. Six bovine calves were chosen for the experiment. In each animal, three intra-aortic balloons were inserted, and set to the automatic mode: two in the vena cava for 15 min and 45 min, respectively, and one in the aorta for 6 hr. There were nine standard and nine heparin coated intra-aortic balloons. At the end of the procedures, three samples of each intra-aortic balloon were analyzed with scanning electron microscopy for computed analysis of the balloon surface covered with fibrin and cells. The scanning electron microscopy analysis showed no deposit at any time interval on the heparin coated sample surfaces, whereas 3.6% +/- 9.2% (mean +/- SD) of the standard sample surfaces were covered with deposits at 15 min (p = 0.06), 14.8% +/- 24.3% at 45 min (p = 0.01), and 4.4% +/- 12.4% at 6 hr (p = 0.06). Strikingly, none of the 27 heparin coated samples showed any microscopic deposits, whereas 11 of the 27 standard samples did (p < 0.002). Heparin coated intra-aortic balloons appear to be a promising strategy, especially for patients with absolute or relative contraindications to systemic heparinization.

argeting BRAFV600E using nanoliposomal-small nterfering RNA restores the expression of sodium iodide ymporter and increases the uptake of iodide in thyroid ancer cells aniel Buitrago MD, Hasan Aldailami BSC, Alexander Veach BSC, ilippo Filicori MD, Xavier M Keutgen MD, Mike Crowley BSC, oonsoo Jin SCD, Thomas J Fahey III MD, FACS, asa Zarnegar MD, FACS eill Cornell Medical College, New York, NY, Cornell University, thaca, NY and Memorial Sloan Kettering Cancer Center, New ork, NY