Preoperative Rectal Cancer Management: Wide International Practice Makes Outcome Comparison Challenging: Reply

In a letter to the editor Dr. Hottenrott provides valuable comments on our survey describing international preoperative rectal cancer management. In our opinion, three key messages are derived from our survey: First, most surgeons agree to neoadjuvant treatment when there is an increased risk of finding histologically positive circumferential margins. In addition, we found more than 40 other indications for neoadjuvant treatment (see our Table 4). This emphasizes the need for an international agreement, as different indications for neoadjuvant treatment will select noncomparable groups of patients in outcome studies. Second, we have shown (see our Table 6) that multidisciplinary team (MDT) meetings significantly influence several important decisions in preoperative rectal cancer management. Interestingly, centers with regular MDT have a higher rate of using magnetic resonance imaging (MRI) (Odds Ratio [OR] = 3.62) and consider a threatened circumferential resection margin (CRM) as indication for neoadjuvant treatment (OR = 5.67). We believe that MDT improves preoperative management of rectal cancer by increasing adherence to national guidelines. Similar discussions in international rectal cancer societies are needed aiming towards an international consensus statement. Finally, our survey revealed sparse use (35% of all cases) of MRI. The goal for the radiologic examination in rectal cancer is to explore the tumor’s relation to nearby anatomical structures. This evaluation will conclude with TNM staging, important for chemoradiotheraphy, surgical treatment, and prognosis. Magnetic resonance imaging has a central role in this evaluation and should be the first choice radiologic modality. Not only is MRI crucial in detection of TNM stage but also plays a central role in determination of the tumor’s distance to the mesorectal fascia and the CRM. Magnetic resonance imaging has moderate sensitivity on T1 and T2 tumors, and should be supplemented with rectal ultrasound

Controlling the Response: Predictive Modeling of a Highly Central, Pathogen-Targeted Core Response Module in Macrophage Activation

We have investigated macrophage activation using computational analyses of a compendium of transcriptomic data covering responses to agonists of the TLR pathway, Salmonella infection, and manufactured amorphous silica nanoparticle exposure. We inferred regulatory relationship networks using this compendium and discovered that genes with high betweenness centrality, so-called bottlenecks, code for proteins targeted by pathogens. Furthermore, combining a novel set of bioinformatics tools, topological analysis with analysis of differentially expressed genes under the different stimuli, we identified a conserved core response module that is differentially expressed in response to all studied conditions. This module occupies a highly central position in the inferred network and is also enriched in genes preferentially targeted by pathogens. The module includes cytokines, interferon induced genes such as Ifit1 and 2, effectors of inflammation, Cox1 and Oas1 and Oasl2, and transcription factors including AP1, Egr1 and 2 and Mafb. Predictive modeling using a reverse-engineering approach reveals dynamic differences between the responses to each stimulus and predicts the regulatory influences directing this module. We speculate that this module may be an early checkpoint for progression to apoptosis and/or inflammation during macrophage activation

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

The role of contracting strategies in social value implementation

There has been an increasing demand for social value (SV) implementation to assume a cardinal position in the infrastructure delivery efforts of infrastructure client organisations (ICOs). However, whereas successful implementation has been recorded in some projects, monumental failures have also been recorded in others. This variance in implementation performance is a cause for concern. The mode of governance applied in an infrastructure delivery endeavour has been identified as capable of influencing the implementation of SV. This observation makes imperative an investigation into the role of contracting strategies – an integral part of governance modes – adopted by ICOs on SV implementation performance. This is the aim of this study. Using a case study approach, three infrastructure projects which used different contracting strategies were selected from two different countries, the UK and Nigeria. Semistructured interviews were conducted with ICO representatives on these projects and subsequently analysed using qualitative content analysis. Findings confirmed that the kind of contract adopted by ICOs influenced their ability to drive the successful implementation of desirable SV objectives through their supply chain. It is therefore recommended that ICOs ensure that the selected contracting strategies are capable of ensuring successful implementation of the desired objectives

Clonal Evolution through Loss of Chromosomes and Subsequent Polyploidization in Chondrosarcoma

Near-haploid chromosome numbers have been found in less than 1% of cytogenetically reported tumors, but seem to be more common in certain neoplasms including the malignant cartilage-producing tumor chondrosarcoma. By a literature survey of published karyotypes from chondrosarcomas we could confirm that loss of chromosomes resulting in hyperhaploid-hypodiploid cells is common and that these cells may polyploidize. Sixteen chondrosarcomas were investigated by single nucleotide polymorphism (SNP) array and the majority displayed SNP patterns indicative of a hyperhaploid-hypodiploid origin, with or without subsequent polyploidization. Except for chromosomes 5, 7, 19, 20 and 21, autosomal loss of heterozygosity was commonly found, resulting from chromosome loss and subsequent duplication of monosomic chromosomes giving rise to uniparental disomy. Additional gains, losses and rearrangements of genetic material, and even repeated rounds of polyploidization, may affect chondrosarcoma cells resulting in highly complex karyotypes. Loss of chromosomes and subsequent polyploidization was not restricted to a particular chondrosarcoma subtype and, although commonly found in chondrosarcoma, binucleated cells did not seem to be involved in these events

First Report of Circulating MicroRNAs in Tumour Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder characterized by recurrent episodes of long-lasting fever and inflammation in different regions of the body, such as the musculo-skeletal system, skin, gastrointestinal tract, serosal membranes and eye. Our aims were to evaluate circulating microRNAs (miRNAs) levels in patients with TRAPS, in comparison to controls without inflammatory diseases, and to correlate their levels with parameters of disease activity and/or disease severity. Expression levels of circulating miRNAs were measured by Agilent microarrays in 29 serum samples from 15 TRAPS patients carrying mutations known to be associated with high disease penetrance and from 8 controls without inflammatory diseases. Differentially expressed and clinically relevant miRNAs were detected using GeneSpring GX software. We identified a 6 miRNAs signature able to discriminate TRAPS from controls. Moreover, 4 miRNAs were differentially expressed between patients treated with the interleukin (IL)-1 receptor antagonist, anakinra, and untreated patients. Of these, miR-92a-3p and miR-150-3p expression was found to be significantly reduced in untreated patients, while their expression levels were similar to controls in samples obtained during anakinra treatment. MiR-92b levels were inversely correlated with the number of fever attacks/year during the 1st year from the index attack of TRAPS, while miR-377-5p levels were positively correlated with serum amyloid A (SAA) circulating levels. Our data suggest that serum miRNA levels show a baseline pattern in TRAPS, and may serve as potential markers of response to therapeutic intervention

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

FACT-MNG: tumor site specific web-based outcome instrument for meningioma patients

To formulate Functional Assessment of Cancer Therapy-Meningioma (FACT-MNG), a web-based tumor site-specific outcome instrument for assessing intracranial meningioma patients following surgical resection or stereotactic radiosurgery. We surveyed the relevant literature available on intracranial meningioma surgery and subsequent outcomes (38 papers), making note of which, if any, QOL/outcome instruments were utilized. None of the surgveyed papers included QOL assessment specific to tumor site. We subsequently developed questions that were relevant to the signs and symptoms that characterize each of 11 intracranial meningioma sites, and incorporated them into a modified combination of the Functional Assessment of Cancer Therapy-Brain (FACT-BR) and SF36 outcome instruments, thereby creating a new tumor site-specific outcome instrument, FACT-MNG. With outcomes analysis of surgical and radiosurgical treatments becoming more important, measures of the adequacy and success of treatment are needed. FACT-MNG represents a first effort to formalize such an instrument for meningioma patients. Questions specific to tumor site will allow surgeons to better assess specific quality of life issues not addressed in the past by more general questionnaires

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Utility of electronic patient records in primary care for stroke secondary prevention trials

BACKGROUND: This study aimed to inform the design of a pragmatic trial of stroke prevention in primary care by evaluating data recorded in electronic patient records (EPRs) as potential outcome measures. The study also evaluated achievement of recommended standards of care; variation between family practices; and changes in risk factor values from before to after stroke.METHODS: Data from the UK General Practice Research Database (GPRD) were analysed for 22,730 participants with an index first stroke between 2003 and 2006 from 414 family practices. For each subject, the EPR was evaluated for the 12 months before and after stroke. Measures relevant to stroke secondary prevention were analysed including blood pressure (BP), cholesterol, smoking, alcohol use, body mass index (BMI), atrial fibrillation, utilisation of antihypertensive, antiplatelet and cholesterol lowering drugs. Intraclass correlation coefficients (ICC) were estimated by family practice. Random effects models were fitted to evaluate changes in risk factor values over time.RESULTS: In the 12 months following stroke, BP was recorded for 90%, cholesterol for 70% and body mass index (BMI) for 47%. ICCs by family practice ranged from 0.02 for BP and BMI to 0.05 for LDL and HDL cholesterol. For subjects with records available both before and after stroke, the mean reductions from before to after stroke were: mean systolic BP, 6.02 mm Hg; diastolic BP, 2.78 mm Hg; total cholesterol, 0.60 mmol/l; BMI, 0.34 Kg/m2. There was an absolute reduction in smokers of 5% and heavy drinkers of 4%. The proportion of stroke patients within the recommended guidelines varied from less than a third (29%) for systolic BP, just over half for BMI (54%), and over 90% (92%) on alcohol consumption.CONCLUSIONS: Electronic patient records have potential for evaluation of outcomes in pragmatic trials of stroke secondary prevention. Stroke prevention interventions in primary care remain suboptimal but important reductions in vascular risk factor values were observed following stroke. Better recording of lifestyle factors in the GPRD has the potential to expand the scope of the GPRD for health care research and practice