Comparison of Venae Sectio vs. modified Seldinger Technique for Totally Implantable Access Ports; Portas-trial [ISRCTN:52368201]

BACKGROUND: The insertion of a Totally Implantable Access Port (TIAP) is a routinely employed technique in patients who need a safe and permanent venous access. The number of TIAP implantations is increasing constantly mainly due to advanced treatment options for malignant diseases. Therefore it is important to identify the implantation technique which has the optimal benefit/risk ratio for the patient. STUDY DESIGN: A single-centre, randomized, controlled superiority trial to compare two different TIAP implantation techniques. Sample size: 160 patients will be included and randomized intra-operatively. Eligibility criteria: Age equal or older than 18 years, patients scheduled for primary elective implantation of a TIAP in local anaesthesia and a signed informed consent. Primary endpoint: Primary success rate of the randomized technique. Intervention: Venae Sectio in combination with the Seldinger Technique (guide wire and a peel away sheath) will be used to place a TIAP. Reference treatment: Conventional Venae Sectio will be used with a direct insertion of the TIAP without guide wire or peel away sheath. Duration of study: Approximately 20 months. ORGANISATION/RESPONSIBILITY: The trial will be conducted in compliance with the protocol and in accordance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The trial will also be carried out in keeping with local and regulatory requirements. The Klinisches Studienzentrum Chirurgie (KSC) – Centre of Clinical Trials in Surgery at the Department of Surgery, University Hospital Heidelberg is responsible for planning and conduction of the trial. Documentation of patient's data will be accomplished via electronical Case Report Files (eCRF) with MACRO(®)-Software by the KSC. Randomization, data management, monitoring and biometry are provided by the independent Koordinierungszentrum für Klinische Studien (KKS) – Coordination Centre for Clinical Trails at the University of Heidelberg

Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial–mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149–59. ©2016 AACR

Type Ia Supernova Explosion Models

Because calibrated light curves of Type Ia supernovae have become a major tool to determine the local expansion rate of the Universe and also its geometrical structure, considerable attention has been given to models of these events over the past couple of years. There are good reasons to believe that perhaps most Type Ia supernovae are the explosions of white dwarfs that have approached the Chandrasekhar mass, M_ch ~ 1.39 M_sun, and are disrupted by thermonuclear fusion of carbon and oxygen. However, the mechanism whereby such accreting carbon-oxygen white dwarfs explode continues to be uncertain. Recent progress in modeling Type Ia supernovae as well as several of the still open questions are addressed in this review. Although the main emphasis will be on studies of the explosion mechanism itself and on the related physical processes, including the physics of turbulent nuclear combustion in degenerate stars, we also discuss observational constraints.Comment: 38 pages, 4 figures, Annual Review of Astronomy and Astrophysics, in pres

Pancreatic cancerrelated cachexia: influence on metabolism and correlation to weight loss and pulmonary function

<p>Abstract</p> <p>Background</p> <p>Dramatic weight loss is an often underestimated symptom in pancreatic cancer patients. Cachexia- defined as an unintended loss of stable weight exceeding 10% – is present in up to 80% of patients with cancer of the upper gastrointestinal tract, and has a significant influence on survival. The aim of the study was to show the multiple systemic effects of cachexia in pancreatic cancer patients, in terms of resection rate, effects on pulmonary function, amount of fat and muscle tissue, as well as changes in laboratory parameters.</p> <p>Methods</p> <p>In patients with pancreatic cancer, clinical appearance was documented, including the amount of weight loss. Laboratory parameters and lung-function tests were evaluated, and the thickness of muscle and fat tissue was measured with computed tomography scans. Statistical analysis, including multivariate analysis, was performed using SPSS software. Survival curves were calculated using Kaplan-Meier analysis and the log-rank test. To test for significant differences between the examined groups we used Student's t-test and the Mann-Whitney U test. Significance was defined as p < 0.05.</p> <p>Results</p> <p>Of 198 patients with a ductal adenocarcinoma of the pancreas, 70% were suffering from weight loss when they presented for operation, and in 40% weight loss exceeded 10% of the stable weight. In patients with cachexia, metastases were diagnosed significantly more often (47% vs. 24%, P < 0.001), leading to a significantly reduced resection rate in these patients. Patients with cachexia had significantly reduced fat tissue amounts. Hence, dramatic weight loss in a patient with pancreatic cancer may be a hint of a more progressed or more aggressive tumour.</p> <p>Conclusion</p> <p>Pancreatic cancer patients with cachexia had a higher rate of more progressed tumour stages and a worse nutritional status. Furthermore, patients with cachexia had an impaired lung function and a reduction in fat tissue. Patients with pancreatic cancer and cachexia had significantly reduced survival. If weight loss exceeded 5% there was a significantly reduced resection rate to detect, but the changes were significantly more substantial if weight loss was 10% or more. We propose that a weight loss of 10% be defined as significant in pancreatic cancer.</p

Topologically Protected Quantum State Transfer in a Chiral Spin Liquid

Topology plays a central role in ensuring the robustness of a wide variety of physical phenomena. Notable examples range from the robust current carrying edge states associated with the quantum Hall and the quantum spin Hall effects to proposals involving topologically protected quantum memory and quantum logic operations. Here, we propose and analyze a topologically protected channel for the transfer of quantum states between remote quantum nodes. In our approach, state transfer is mediated by the edge mode of a chiral spin liquid. We demonstrate that the proposed method is intrinsically robust to realistic imperfections associated with disorder and decoherence. Possible experimental implementations and applications to the detection and characterization of spin liquid phases are discussed.Comment: 14 pages, 7 figure

Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283]

BACKGROUND: Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. METHODS/DESIGN: The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment. DISCUSSION: The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life

Protocol design and current status of CLIVIT: a randomized controlled multicenter relevance trial comparing clips versus ligatures in thyroid surgery

BACKGROUND: Annually, more than 90000 surgical procedures of the thyroid gland are performed in Germany. Strategies aimed at reducing the duration of the surgical procedure are relevant to patients and the health care system especially in the context of reducing costs. However, new techniques for quick and safe hemostasis have to be tested in clinically relevance randomized controlled trials before a general recommendation can be given. The current standard for occlusion of blood vessels in thyroid surgery is ligatures. Vascular clips may be a safe alternative but have not been investigated in a large RCT. METHODS/DESIGN: CLIVIT (Clips versus Ligatures in Thyroid Surgery) is an investigator initiated, multicenter, patient-blinded, two-group parallel relevance randomized controlled trial designed by the Study Center of the German Surgical Society. Patients scheduled for elective resection of at least two third of the gland for benign thyroid disease are eligible for participation. After surgical exploration patients are randomized intraoperatively into either the conventional ligature group, or into the clip group. The primary objective is to test for a relevant reduction in operating time (at least 15 min) when using the clip technique. Since April 2004, 121 of the totally required 420 patients were randomized in five centers. DISCUSSION: As in all trials the different forms of bias have to be considered, and as in this case, a surgical trial, the role of surgical expertise plays a key role, and will be documented and analyzed separately. This is the first randomized controlled multicenter relevance trial to compare different vessel occlusion techniques in thyroid surgery with adequate power and other detailed information about the design as well as framework. If significant, the results might be generalized and may change the current surgical practice

High-Precision, In Vitro Validation of the Sequestration Mechanism for Generating Ultrasensitive Dose-Response Curves in Regulatory Networks

Our ability to recreate complex biochemical mechanisms in designed, artificial systems provides a stringent test of our understanding of these mechanisms and opens the door to their exploitation in artificial biotechnologies. Motivated by this philosophy, here we have recapitulated in vitro the “target sequestration” mechanism used by nature to improve the sensitivity (the steepness of the input/output curve) of many regulatory cascades. Specifically, we have employed molecular beacons, a commonly employed optical DNA sensor, to recreate the sequestration mechanism and performed an exhaustive, quantitative study of its key determinants (e.g., the relative concentrations and affinities of probe and depletant). We show that, using sequestration, we can narrow the pseudo-linear range of a traditional molecular beacon from 81-fold (i.e., the transition from 10% to 90% target occupancy spans an 81-fold change in target concentration) to just 1.5-fold. This narrowing of the dynamic range improves the sensitivity of molecular beacons to that equivalent of an oligomeric, allosteric receptor with a Hill coefficient greater than 9. Following this we have adapted the sequestration mechanism to steepen the binding-site occupancy curve of a common transcription factor by an order of magnitude over the sensitivity observed in the absence of sequestration. Given the success with which the sequestration mechanism has been employed by nature, we believe that this strategy could dramatically improve the performance of synthetic biological systems and artificial biosensors