A concept for trial institutions focussing on randomised controlled trials in surgery

<p>Abstract</p> <p>Background</p> <p>Although considered the reference standard for generating valid scientific evidence of a treatment's benefits and harms, the number of Randomised Controlled Trials (RCT) comparing surgical techniques remains low. Much effort has been made in order to overcome methodological issues and improve quality of RCTs in surgery. To the present there has been, however, only little emphasis on development and maintenance of institutions for implementation of adequately designed and conducted surgical RCTs.</p> <p>Mehods/Design</p> <p>Description of the developments in surgical RCT infrastructure in Germany between 2001 and 2006. Cross sectional evaluation of completed and ongoing surgical RCTs within the German Surgical Society and the Clinical Study Centre, Department of Surgery, University of Heidelberg.</p> <p>Results</p> <p>Foundation of a national Clinical Trial Centre (CTC) for the organisation of multi-centre RCTs in the surgical setting (Study Center of the German Surgical Society, SDGC). Establishment of a network of CTCs with affiliated Clinical Sites (CSs) to enhance patient recruitment and shorten the duration of RCTs. Since its foundation four surgical RCTs with a total sample size of 1650 patients (1006 of these randomised) have been supervised by the SDGC with 35 CSs involved in patient recruitment. Five further CTCs were set up in 2006. Together with their affiliated CSs a network has been organised providing improved conditions for the conduction of surgical RCTs.</p> <p>Conclusion</p> <p>Improvement of infrastructure substantially facilitates integration of RCTs into routine surgical practice. A network of collaborating CTCs and CSs can provide an adequate infrastructure for the conduction of multi-centre RCTs.</p

Expression of CXCL10 is associated with response to radiotherapy and overall survival in squamous cell carcinoma of the tongue

Five-year survival for patients with oral cancer has been disappointingly stable during the last decades, creating a demand for new biomarkers and treatment targets. Lately, much focus has been set on immunomodulation as a possible treatment or an adjuvant increasing sensitivity to conventional treatments. The objective of this study was to evaluate the prognostic importance of response to radiotherapy in tongue carcinoma patients as well as the expression of the CXC-chemokines in correlation to radiation response in the same group of tumours. Thirty-eight patients with tongue carcinoma that had received radiotherapy followed by surgery were included. The prognostic impact of pathological response to radiotherapy, N-status, T-stage, age and gender was evaluated using Cox's regression models, Kaplan-Meier survival curves and chi-square test. The expression of 23 CXC-chemokine ligands and their receptors were evaluated in all patients using microarray and qPCR and correlated with response to treatment using logistic regression. Pathological response to radiotherapy was independently associated to overall survival with a 2-year survival probability of 81 % for patients showing a complete pathological response, while patients with a non-complete response only had a probability of 42 % to survive for 2 years (p = 0.016). The expression of one CXC-chemokine, CXCL10, was significantly associated with response to radiotherapy and the group of patients with the highest CXCL10 expression responded, especially poorly (p = 0.01). CXCL10 is a potential marker for response to radiotherapy and overall survival in patients with squamous cell carcinoma of the tongue

Unraveling the effects of management and climate on carbon fluxes of U.S. croplands using the USDA Long-Term Agroecosystem (LTAR) network

Understanding the carbon fluxes and dynamics from a broad range of agricultural systems has the potential to improve our ability to increase carbon sequestration while maintaining crop yields. Short-term, single-location studies have limited applicability, but long-term data from a network of many locations can provide a broader understanding across gradients of climate and management choices. Here we examine eddy covariance measured carbon dioxide (CO2) fluxes from cropland sites across the United States Department of Agriculture’s Long-Term Agroecosystem Research (LTAR) network. The dataset was collected between 2001 and 2020, spanning 13 sites for a total of 182 site-years. Average seasonal patterns of net ecosystem CO2 exchange (NEE), gross primary productivity (GPP), and ecosystem respiration (Reco) were determined, and subsequent regression analysis on these “flux climatologies” was used to identify relationships to mean annual temperature (MAT), mean annual precipitation (MAP), cropping systems, and management practices. At rainfed sites, carbon fluxes were better correlated with MAP (r2 ≤ 0.5) than MAT (r2 ≤ 0.22). Net carbon balance was different among cropping systems (p \u3c 0.001), with the greatest net carbon uptake occurring in sugarcane (Saccharum spp. hybrids) and the least in soybean (Glycine max) fields. Crop type had a greater effect on carbon balance than irrigation management at a Nebraska site. Across cropping systems, grain crops often had higher GPP and were more likely to have net uptake when compared to legume crops. This multi-site analysis highlights the potential of the LTAR network to further carbon flux research using eddy covariance measurements

The challenges faced in the design, conduct and analysis of surgical randomised controlled trials

Randomised evaluations of surgical interventions are rare; some interventions have been widely adopted without rigorous evaluation. Unlike other medical areas, the randomised controlled trial (RCT) design has not become the default study design for the evaluation of surgical interventions. Surgical trials are difficult to successfully undertake and pose particular practical and methodological challenges. However, RCTs have played a role in the assessment of surgical innovations and there is scope and need for greater use. This article will consider the design, conduct and analysis of an RCT of a surgical intervention. The issues will be reviewed under three headings: the timing of the evaluation, defining the research question and trial design issues. Recommendations on the conduct of future surgical RCTs are made. Collaboration between research and surgical communities is needed to address the distinct issues raised by the assessmentof surgical interventions and enable the conduct of appropriate and well-designed trials.The Health Services Research Unit is funded by the Scottish Government Health DirectoratesPeer reviewedPublisher PD

Tumour M2-PK as a stool marker for colorectal cancer: comparative analysis in a large sample of unselected older adults vs colorectal cancer patients

Stool testing based on tumour-derived markers might offer a promising approach for non-invasive colorectal cancer (CRC) screening. The aim of this study was to estimate the potential of a new test for faecal tumour M2-PK to discriminate patients with CRC from a large sample of unselected older adults. Faecal tumour M2-PK concentrations were determined in 65 CRC patients and in a population-based sample of 917 older adults (median age: 65 and 62 years, respectively). Sensitivity and specificity of the test were calculated at different cutoff values, and receiver-operating characteristic curves (ROC) were constructed to visualise the discriminatory power of the test. The median (interquartile range) faecal tumour M2-PK concentration was 8.6 U ml−1 (2.8–18.0) among CRC patients and <2 U ml−1 (<2–3.2; P<0.0001) in the population sample. At a cutoff value of 4 U ml−1, sensitivity (95% confidence interval) was 85% (65–96%) for colon cancer and 56% (41–74%) for rectum cancer. Specificity (95% confidence interval) was estimated to be 79% (76–81%). Given the comparatively high sensitivity of the tumour M2-PK stool test (especially for colon cancer) and its simple analysis, the potential use of the test for early detection of CRC merits further investigation. Possibilities to enhance specificity of the test should be explored

Cyclin H expression is increased in GIST with very-high risk of malignancy

<p>Abstract</p> <p>Background</p> <p>Risk estimation of gastrointestinal stromal tumours (GIST) is based on tumour size and mitotic rate according to the National Institutes of Health consensus classification. The indication for adjuvant treatment of patients with high risk GIST after R₀resection with small molecule inhibitors is still a controversial issue, since these patients represent a highly heterogeneous population. Therefore, additional prognostic indicators are needed. Here, we evaluated the prognostic value of cyclin H expression in GIST.</p> <p>Methods</p> <p>In order to identify prognostic factors of GIST we evaluated a single centre cohort of ninety-five GIST patients. First, GISTs were classified with regard to tumour size, mitotic rate and localisation according to the NIH consensus and to three additional suggested risk classifications. Second, Cyclin H expression was analysed.</p> <p>Results</p> <p>Of ninety-five patients with GIST (53 female/42 male; median age: 66.78a; range 17-94a) risk classification revealed: 42% high risk, 20% intermediate risk, 23% low risk and 15% very low risk GIST. In patients with high risk GIST, the expression of cyclin H was highly predictive for reduced disease-specific survival (p = 0.038). A combination of cyclin H expression level and high risk classification yielded the strongest prognostic indicator for disease-specific and disease-free survival (p ≤ 0.001). Moreover, in patients with tumour recurrence and/or metastases, cyclin H positivity was significantly associated with reduced disease-specific survival (p = 0.016) regardless of risk-classification.</p> <p>Conclusion</p> <p>Our data suggest that, in addition to high risk classification, cyclin H expression might be an indicator for "very-high risk" GIST.</p

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

The Amino-Terminus of Nitric Oxide Sensitive Guanylyl Cyclase α1 Does Not Affect Dimerization but Influences Subcellular Localization

BACKGROUND: Nitric oxide sensitive guanylyl cyclase (NOsGC) is a heterodimeric enzyme formed by an α- and a β₁-subunit. A splice variant (C-α₁) of the α₁-subunit, lacking at least the first 236 amino acids has been described by Sharina et al. 2008 and has been shown to be expressed in differentiating human embryonic cells. Wagner et al. 2005 have shown that the amino acids 61-128 of the α₁-subunit are mandatory for quantitative heterodimerization implying that the C-α₁-splice variant should lose its capacity to dimerize quantitatively. METHODOLOGY/PRINCIPAL FINDINGS: In the current study we demonstrate preserved quantitative dimerization of the C-α₁-splice by co-purification with the β₁-subunit. In addition we used fluorescence resonance energy transfer (FRET) based on fluorescence lifetime imaging (FLIM) using fusion proteins of the β₁-subunit and the α₁-subunit or the C-α₁ variant with ECFP or EYFP. Analysis of the respective combinations in HEK-293 cells showed that the fluorescence lifetime was significantly shorter (≈0.3 ns) for α₁/β₁ and C-α₁/β₁ than the negative control. In addition we show that lack of the amino-terminus in the α₁ splice variant directs it to a more oxidized subcellular compartment. CONCLUSIONS/SIGNIFICANCE: We conclude that the amino-terminus of the α₁-subunit is dispensable for dimerization in-vivo and ex-vivo, but influences the subcellular trafficking

Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease

Fibroblast growth factors (Fgfs) are proteins with diverse functions in development, repair, and metabolism. The human Fgf gene family with 22 members can be classified into three groups, canonical, intracellular, and hormone-like Fgf genes. In contrast to canonical and intracellular Fgfs identified in invertebrates and vertebrates, hormone-like Fgfs, Fgf15/19, Fgf21, and Fgf23, are vertebrate-specific. The ancestral gene of hormone-like Fgfs was generated from the ancestral gene of canonical Fgfs by gene duplication early in vertebrate evolution. Later, Fgf15/19, Fgf21, and Fgf23 were generated from the ancestral gene by genome duplication events. Canonical Fgfs act as autocrine/paracrine factors in an Fgf receptor (Fgfr)-dependent manner. In contrast, hormone-like Fgfs act as endocrine factors in an Fgfr-dependent manner. Canonical Fgfs have a heparin-binding site necessary for the stable binding of Fgfrs and local signaling. In contrast, hormone-like Fgfs acquired endocrine functions by reducing their heparin-binding affinity during their evolution. Fgf15/19 and Fgf23 require βKlotho and αKlotho as cofactors, respectively. However, Fgf21 might physiologically require neither. Hormone-like Fgfs play roles in metabolism at postnatal stages, although they also play roles in development at embryonic stages. Fgf15/19 regulates bile acid metabolism in the liver. Fgf21 regulates lipid metabolism in the white adipose tissue. Fgf23 regulates serum phosphate and active vitamin D levels. Fgf23 signaling disorders caused by hereditary diseases or tumors result in metabolic disorders. In addition, serum Fgf19 or Fgf21 levels are significantly increased by metabolic disorders. Hormone-like Fgfs are newly emerging and quite unique in their evolution and function