IL-1 Signal Inhibition in Alcohol-Related Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial of Canakinumab.

BACKGROUND AND AIMS: Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1ß has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1ß, in the treatment of patients with AH. METHODS: Participants with biopsy-confirmed AH and discriminant function ≥32 but Model for End-Stage Liver Disease ≤27 were randomly allocated 1:1 to receive either CAN 3 mg/kg or placebo (PBO). Liver biopsies were taken before and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analyzed by the modified intention-to-treat principle. RESULTS: Fifty-seven participants were randomized: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data were evaluable from 48 participants. In CAN-treated participants, 14 (58%) of 24 demonstrated histological improvement compared with 10 (42%) of 24 in the PBO group (P = .25). There was no improvement in prognostic scores of liver function. Four (7%) of the 55 participants died within 90 days, 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (P = .04). CONCLUSIONS: CAN therapy in severe AH participants with Model for End-Stage Liver Disease ≤27 did not alter biochemical or clinical outcomes compared with PBO. Nonsignificant histological improvements did not translate into clinical benefit. EudraCT, Number: 2017-003724-79; ClinicalTrials.gov, Number: NCT03775109.

Prostagram magnetic resonance imaging in a screening population: Prostate Imaging-Reporting and Data System or Likert?

OBJECTIVE: To compare biopsy recommendation rates and accuracy of the Prostate Imaging-Reporting and Data System, version 2 (PI-RADSv2) with the Likert scale for detection of clinically significant and insignificant prostate cancer in men screened within the Imperial Prostate 1 Prostate Cancer Screening Trial Using Imaging (IP1-PROSTAGRAM). PATIENTS AND METHODS: Men aged 50-69 years were screened with Prostagram MRI. Scans were prospectively reported using both PI-RADSv2 (excluding dynamic contrast-enhanced sequence score) and 5-point Likert scores by expert uro-radiologists. Systematic and targeted transperineal biopsy was recommended if the scan was scored ≥ 3, based on either reporting system. The proportion of patients recommended for biopsy and detection rates for Grade Groups (GGs) 1 and ≥ 2 were compared. Receiver operating characteristic (ROC) analysis was performed to compare performance. RESULTS: A total of 406 men underwent Prostagram MRI. The median (interquartile range) age and prostate-specific antigen level were 57 (53-61) years and 0.91 (0.56-1.74) ng/mL, respectively. At MRI score ≥ 3, more patients were recommended for biopsy based on Likert criteria (94/406; 23%, 95% confidence interval [CI] 19.2%-27.6%) compared to PI-RADSv2 (72/406; 18%, 95% CI 14.2%-21.9%; P = 0.03). For MRI scores ≥ 4, PI-RADSv2 and Likert scales led to 43/406 (11%, 95% CI 7.9%-14.1%) and 35/406 (9%, 95% CI 6.2%-11.9%) men recommended for biopsy (P = 0.40). For GG ≥ 2 detection, PIRADSv2 and Likert detected 22% (95% CI 11.4%-30.8%, 14/72) and 16% (95% CI 9.5%-25.3%, 15/94), respectively (P = 0.56). For GG1 cancers detection these were 11% (95% CI 4.3%-19.6%, seven of 72) vs 11% (95% CI 4.7%-17.8%, nine of 94; P = 1.00). The accuracy of PI-RADSv2 and Likert scale was similar (area under the ROC curve 0.64 vs 0.65, P = 0.95). CONCLUSIONS: In reporting non-contrast-enhanced Prostagram MRI in a screening population, the PI-RADSv2 and Likert scoring systems were equally accurate; however, Likert scale use led to more men undergoing biopsy without a subsequent increase in significant cancer detection rates. To improve reporting of Prostagram MRI, either the PI-RADSv2 or a modified Likert scale or a standalone scoring system should be developed.

Neuromuscular Electrical Stimulation for Intermittent Claudication (NESIC): multicentre, randomized controlled trial.

METHODS: This was an open, multicentre, randomized controlled trial. Patients with intermittent claudication attending vascular surgery outpatient clinics were randomized (1:1) to receive either neuromuscular electrical stimulation (NMES) or not in addition to local standard care available at study centres (best medical therapy alone or plus supervised exercise therapy (SET)). The objective of this trial was to investigate the clinical efficacy of an NMES device in addition to local standard care in improving walking distances in patients with claudication. The primary outcome was change in absolute walking distance, measured by a standardized treadmill test at 3 months. Secondary outcomes included intermittent claudication (IC) distance, adherence, quality of life, and haemodynamic changes. RESULTS: Of 200 participants randomized, 160 were included in the primary analysis (intention to treat, Tobit regression model). The square root of absolute walking distance was analysed (due to a right-skewed distribution) and, although adjunctive NMES improved it at 3 months, no statistically significant effect was observed. SET as local standard care seemed to improve distance compared to best medical therapy at 3 months (3.29 units; 95 per cent c.i., 1.77 to 4.82; P < 0.001). Adjunctive NMES improved distance in mild claudication (2.88 units; 95 per cent c.i., 0.51 to 5.25; P = 0.02) compared to local standard care at 3 months. No serious adverse events relating to the device were reported. CONCLUSION: Supervised exercise therapy is effective and NMES may provide further benefit in mild IC.This trial was supported by a grant from the Efficacy and Mechanism Evaluation Program, a Medical Research Council and National Institute for Health and Care Research partnership. Trial registration: ISRCTN18242823.

Patients with intermittent claudication experience pain in their legs during walking or exercise which ends with rest. This severely impairs physical activity and quality of life. Treatment for such patients typically involves best medical therapy, which includes exercise advice. This study aimed to determine whether a neuromuscular electrical stimulation device improved the walking distance of patients with intermittent claudication compared to local standard care available (which may include supervised exercise therapy) in a trial. Supervised exercise improved walking distances but there was no difference in those that received a device in this patient group.

Adjusting for verification bias in diagnostic accuracy measures when comparing multiple screening tests - an application to the IP1-PROSTAGRAM study.

INTRODUCTION: Novel screening tests used to detect a target condition are compared against either a reference standard or other existing screening methods. However, as it is not always possible to apply the reference standard on the whole population under study, verification bias is introduced. Statistical methods exist to adjust estimates to account for this bias. We extend common methods to adjust for verification bias when multiple tests are compared to a reference standard using data from a prospective double blind screening study for prostate cancer. METHODS: Begg and Greenes method and multiple imputation are extended to include the results of multiple screening tests which determine condition verification status. These two methods are compared to the complete case analysis using the IP1-PROSTAGRAM study data. IP1-PROSTAGRAM used a paired-cohort double-blind design to evaluate the use of imaging as alternative tests to screen for prostate cancer, compared to a blood test called prostate specific antigen (PSA). Participants with positive imaging (index) and/or PSA (control) underwent a prostate biopsy (reference standard). RESULTS: When comparing complete case results to Begg and Greenes and methods of multiple imputation there is a statistically significant increase in the specificity estimates for all screening tests. Sensitivity estimates remained similar across the methods, with completely overlapping 95% confidence intervals. Negative predictive value (NPV) estimates were higher when adjusting for verification bias, compared to complete case analysis, even though the 95% confidence intervals overlap. Positive predictive value (PPV) estimates were similar across all methods. CONCLUSION: Statistical methods are required to adjust for verification bias in accuracy estimates of screening tests. Expanding Begg and Greenes method to include multiple screening tests can be computationally intensive, hence multiple imputation is recommended, especially as it can be modified for low prevalence of the target condition.

Safety and efficacy of an extended-release peptide YY analogue for obesity: A randomized, placebo-controlled, phase 1 trial.

AIM: To report the results from a Phase 1 trial of an extended-release peptide YY analogue, Y14, developed for the treatment of obesity. METHODS: Y14 was evaluated in overweight/obese volunteers in a Phase 1 randomized placebo-controlled trial, conducted in a clinical trial unit in the United Kingdom. Part A was a blinded single-ascending-dose study evaluating doses up to 36 mg. Part B was double-blinded and tested multiple ascending doses between 9 and 36 mg, given at 7- to 14-day intervals, over the course of 28 days, with up to five doses given per participant. The primary outcome was safety and tolerability; the secondary outcome was assessment of pharmacokinetic (PK) characteristics. Exploratory outcomes included food intake, body weight change and glucose tolerance after multiple doses. RESULTS: Between April 11, 2017 and December 24, 2018, 53 participants were enrolled into Part A and 24 into Part B of the trial. The PK characteristics were compatible with administration every 7 to 14 days. The most common adverse events (AEs) were nausea, vomiting or administration site reactions, which were mild in most cases and settled with time. No serious AE occurred. Participants given multiple doses of Y14 lost between -2.87 and -3.58 kg body weight compared with placebo (P <0.0001) at 31 days from the first dose, with profound reductions in food intake of 38% to 55% (P <0.0001, compared to placebo) and there was no evidence of tachyphylaxis. CONCLUSIONS: Our results support the continued development of Y14 as a novel treatment for obesity.

The role of Neurotensin and its receptors in non-gastrointestinal cancers: a review.

BACKGROUND: Neurotensin, originally isolated in 1973 has both endocrine and neuromodulator activity and acts through its three main receptors. Their role in promoting tumour cell proliferation, migration, DNA synthesis has been studied in a wide range of cancers. Expression of Neurotensin and its receptors has also been correlated to prognosis and prediction to treatment. MAIN BODY: The effects of NT are mediated through mitogen-activated protein kinases, epidermal growth factor receptors and phosphatidylinositol-3 kinases amongst others. This review is a comprehensive summary of the molecular pathways by which Neurotensin and its receptors act in cancer cells. CONCLUSION: Identifying the role of Neurotensin in the underlying molecular mechanisms in various cancers can give way to developing new agnostic drugs and personalizing treatment according to the genomic structure of various cancers. Video abstract.

Costs and consequences of the Portuguese needle-exchange program in community pharmacies.

BACKGROUND: Needle-exchange programs (NEPs) reduce infections in people who inject drugs. This study assesses the impact community pharmacies have had in the Needle-Exchange Program in Portugal since 2015. METHODS: Health gains were measured by the number of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections averted, which were estimated, in each scenario, based on a standard model in the literature, calibrated to national data. The costs per infection were taken from national literature; costs of manufacturing, logistics and incineration of injection materials were also considered. The results were presented as net costs (i.e., incremental costs of the program with community pharmacies less the costs of additional infections avoided). RESULTS: Considering a 5-year horizon, the Needle Exchange Program with community pharmacies would account for a 6.8% (n = 25) and a 6.5% reduction (n = 22) of HCV and HIV infections, respectively. The present value of net savings generated by the participation of community pharmacies in the program was estimated at €2,073,347. The average discounted net benefit per syringe exchanged is €3.01, already taking into account a payment to community pharmacies per needle exchanged. INTERPRETATION: We estimate that the participation of community pharmacies in the Needle Exchange Program will lead to a reduction of HIV and HCV infections and will generate over €2 million in savings for the health system. CONCLUSIONS: The intervention is estimated to generate better health outcomes at lower costs, contributing to improving the efficiency of the public health system in Portugal.

A multicenter randomized controlled study to evaluate whether neuromuscular electrical stimulation improves the absolute walking distance in patients with intermittent claudication compared with best available treatment.

OBJECTIVE: To assess the clinical efficacy of a neuromuscular electrical stimulation (NMES) device to improve the absolute walking distance in patients with intermittent claudication as an adjunct to the local standard care available at the study sites compared with local standard care alone. METHODS: This open, multicenter, randomized controlled trial included eight participating centers in England. Sites are equally distributed between those that provide supervised exercise therapy programs and those that do not. Patients with intermittent claudication meeting the eligibility criteria and providing consent will be randomized, depending on the center type, to either NMES and locally available standard care or standard care alone. The primary end point is change in absolute walking distance at 3 months (the end of the intervention period) by treadmill testing. Secondary outcomes include quality of life, compliance with the interventions, economic evaluation of the NMES device, and lower limb hemodynamic measures to further the understanding of underlying mechanisms. Recruitment commenced in March 2018 and will continue for a total of 15 months. The Neuromuscular Electrical Stimulation Improves the Absolute Walking Distance in Patients with Intermittent Claudication trial is funded by the UK Efficacy and Mechanism Evaluation Programme, Medical Research Council, and National Institute for Health Research partnership.

The prognostic and therapeutic role of hormones in colorectal cancer: a review.

Colorectal cancer (CRC) is one of the commonest cancers in Western society with a poor prognosis in patients with advanced disease. Targeted therapy is of increasing interest and already, targeted hormone treatment for breast and prostate cancer has improved survival. The aim of this literature review is to summarise the role of hormones in CRC prognosis and treatment. A literature review of all human and animal in vivo and in vitro studies in the last 20 years, which assessed the role of hormones in CRC treatment or prognosis, was carried out. The hormones described in this review have been subdivided according to their secretion origin. Most of the studies are based on in vitro or animal models. The main findings point to adipokines, insulin and the insulin growth factor axis as key players in the link between obesity, type 2 diabetes mellitus and a subset of CRC. Gut-derived hormones, especially uroguanylin and guanylin are being increasingly investigated as therapeutic targets, with promising results. Using hormones as prognostic and therapeutic markers in CRC is still in the preliminary stages for only a fraction of the hormones affecting the GIT. In light of the increasing interest in tailoring treatment strategies, hormones are an important area of focus in the future of CRC management.

Low-frequency ventilation during cardiopulmonary bypass for lung protection: A randomized controlled trial.

OBJECTIVE: Pulmonary dysfunction is a common complication in patients undergoing heart surgery. Current clinical practice does not include any specific strategy for lung protection. To compare the anti-inflammatory effects of low-frequency ventilation (LFV), as measured by nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) p65 pathway activation, for the entire cardiopulmonary bypass (CPB) vs both lungs left collapsed in patients undergoing coronary artery bypass grafting (CABG). METHODS: Two groups parallel randomized controlled trial. The primary outcome was inflammation measured by NF-κB p65 activation in pre- and post-CPB lung biopsies. Secondary outcomes were additional inflammatory markers in both biopsy tissue and blood. RESULTS: Thirty-seven patients were randomly allocated to LFV (18) and to both lungs left collapsed (19). The mean concentration of NF-κB p65 in the biopsies before chest closure (adjusted for pre-CPB concentration) was higher in the LFV group compared to both lungs left collapsed group but this was not significant (0.102, 95% confidence interval, -0.022 to 0.226, P = 0.104). There were no significant differences between groups in the other inflammatory markers measured in tissue and blood. CONCLUSIONS: In patients undergoing elective CABG, the use of LFV during CPB when compared to both lungs left collapsed does not seem to reduce inflammation in lung biopsies and blood.

Temporal Stress in the Operating Room: Brain Engagement Promotes "Coping" and Disengagement Prompts "Choking".

OBJECTIVE: To investigate the impact of time pressure (TP) on prefrontal activation and technical performance in surgical residents during a laparoscopic suturing task. BACKGROUND: Neural mechanisms enabling surgeons to maintain performance and cope with operative stressors are unclear. The prefrontal cortex (PFC) is implicated due to its role in attention, concentration, and performance monitoring. METHODS: A total of 33 residents [Postgraduate Year (PGY)1-2 = 15, PGY3-4 = 8, and PGY5 = 10] performed a laparoscopic suturing task under "self-paced" (SP) and "TP" conditions (TP = maximum 2 minutes per knot). Subjective workload was quantified using the Surgical Task Load Index. PFC activation was inferred using optical neuroimaging. Technical skill was assessed using progression scores (au), error scores (mm), leak volumes (mL), and knot tensile strengths (N). RESULTS: TP led to greater perceived workload amongst all residents (mean Surgical Task Load Index score ±â€ŠSD: PGY1-2: SP = 160.3 ±â€Š24.8 vs TP = 202.1 ±â€Š45.4, P < 0.001; PGY3-4: SP = 123.0 ±â€Š52.0 vs TP = 172.5 ±â€Š43.1, P < 0.01; PGY5: SP = 105.8 ±â€Š55.3 vs TP = 159.1 ±â€Š63.1, P < 0.05). Amongst PGY1-2 and PGY3-4, deterioration in task progression, error scores and knot tensile strength (P < 0.05), and diminished PFC activation was observed under TP. In PGY5, TP resulted in inferior task progression and error scores (P < 0.05), but preservation of knot tensile strength. Furthermore, PGY5 exhibited less attenuation of PFC activation under TP, and greater activation than either PGY1-2 or PGY3-4 under both experimental conditions (P < 0.05). CONCLUSIONS: Senior residents cope better with temporal demands and exhibit greater technical performance stability under pressure, possibly due to sustained PFC activation and greater task engagement. Future work should seek to develop training strategies that recruit prefrontal resources, enhance task engagement, and improve performance under pressure.

A Summation Analysis of Compliance and Complications of Compression Hosiery for Patients with Chronic Venous Disease or Post-thrombotic Syndrome.

OBJECTIVES: Compression stockings are commonly prescribed for patients with a range of venous disorders, but are difficult to don and uncomfortable to wear. This study aimed to investigate compliance and complications of compression stockings in patients with chronic venous disease (CVD) and post-thrombotic syndrome (PTS). METHODS: A literature search of the following databases was carried out: MEDLINE (via PubMed), EMBASE (via OvidSP, 1974 to present), and CINAHL (via EBSCOhost). Studies evaluating the use of compression stockings in patients with CVD (CEAP C2-C5) or for the prevention or treatment of PTS were included. After scrutinising full text articles, compliance with compression and associated complications were assessed. Compliance rates were compared based on study type and degree of compression. Good compliance was defined as patients wearing compression stockings for >50% of the time. RESULTS: From an initial search result of 4303 articles, 58 clinical studies (37 randomised trials and 21 prospective studies) were selected. A total of 10,245 limbs were included, with compression ranging from 15 to 40 mmHg (not stated in 12 studies) and a median follow-up of 12 months (range 1-60 months). In 19 cohorts, compliance was not assessed and in a further nine, compliance was poorly specified. Overall, good compliance with compression was reported for 5371 out of 8104 (66.2%) patients. The mean compliance, weighted by study size, appeared to be greater for compression ≤25 mmHg (77%) versus > 25 mmHg (65%) and greater in the randomised studies (74%) than in prospective observational studies (64%). Complications of stockings were not mentioned in 43 out of 62 cohorts reviewed. Where complications were considered, skin irritation was a common event. CONCLUSIONS: In published trials, good compliance with compression is reported in around two thirds of patients, with inferior compliance in those given higher degrees of compression. Further studies are required to identify predictors of non-compliance, to help inform the clinical management of these patients. Complications of compression are not documented in many studies and should be given more consideration in the future.

Systematic review of blood diagnostic markers in colorectal cancer.

The purpose of this systematic review was to compare the diagnostic ability of blood markers for colorectal cancer (CRC). A systematic review of the literature for diagnostic blood markers for primary human colorectal cancer over the last 5 years was performed. The primary outcome was to assess the diagnostic ability of these markers in diagnosing colorectal cancer. The secondary outcome was to see whether the marker was compared to other markers. The tertiary outcome was to assess diagnostic ability in early versus late CRC, including stage IV disease. We identified 51 studies (29 prospective, 14 retrospective, and 8 meta-analyses). The markers were divided in broadly four groups: nucleic acids (RNA/DNA/messenger RNA/microRNAs), cytokines, antibodies, and proteins. The most promising circulating markers identified among the nucleid acids were NEAT_v2 non-coding RNA, SDC2 methylated DNA, and SEPT9 methylated DNA. The most promising cytokine to detect CRC was interleukin 8, and the most promising circulating proteins were CA11-19 glycoprotein and DC-SIGN/DC-SIGNR. Sensitivities of these markers for detecting primary colorectal carcinoma ranged from 70 to 98% and specificities from 84 to 98.7%. The best studied blood marker was SEPT9 methylated DNA, which showed great variability with sensitivities ranging from 48.2 to 95.6% and specificities from 80 to 98.9%, making its clinical applicability challenging. If combined with fecal immunochemical test (FIT), the sensitivity improved from 78 to 94% in detecting CRC. Methylated SEPT9, methylated SDC2, and -SIGN/DC-SIGNR protein had better sensitivity and specificity than CEA or CA 19-9. With the exception of SEPT9 which is currently being implemented as a screening test for CRC all other markers lacked reproducibility and standardization and were studied in relatively small population samples.

Incidence and prognostic impact of bleeding and transfusion after coronary surgery in low-risk patients.

BACKGROUND: Excessive bleeding and blood transfusion are associated with adverse outcome after cardiac surgery, but their mechanistic effects are difficult to disentangle in patients with increased operative risk. This study aimed to evaluate the incidence and prognostic impact of bleeding and transfusion of blood products in low-risk patients undergoing coronary artery bypass grafting (CABG). STUDY DESIGN AND METHODS: Sixteen tertiary European centers of cardiac surgery contributed to the prospective European registry of CABG (E-CABG). The severity of bleeding was defined by the E-CABG bleeding severity classification and universal definition of perioperative bleeding (UDPB) classification. RESULTS: Of 1213 patients with EuroSCORE II of less than 2% (mean, 1.1 ± 0.4%), 18.5% suffered from mild bleeding (E-CABG bleeding Grade 1) and 3.4% experienced severe bleeding (E-CABG bleeding Grade 2-3). Similarly, 19.7% had UDPB Class 2 and 5.9% had UDPB Classes 3 and 4. Mild and severe bleeding defined by the E-CABG and UDPB classifications were associated with an increased risk of several adverse events as adjusted by multiple covariates. The risk of death, stroke, and acute kidney injury was particularly increased in patients with severe bleeding. CONCLUSION: Severe bleeding is rather uncommon in low-risk patients undergoing CABG, but it is associated with an increased risk of major adverse events. Prevention of excessive perioperative bleeding and patient blood management may improve the outcome of cardiac surgery also in low-risk patients.

A Meta-Analysis of the Effects of Abdominoplasty Modifications on the Incidence of Postoperative Seroma.

BACKGROUND: Seroma is the most common complication of abdominoplasty. Certain modifications to abdominoplasty may reduce the risk of seroma. OBJECTIVES: The authors evaluated the incidence of seroma for 3 abdominoplasty techniques: preservation of Scarpa's fascia, placement of progressive tension (or quilting) sutures, and application of fibrin glue. METHODS: In this systematic review and meta-analysis, the Cochrane Library, MEDLINE, Embase, and the International Clinical Trials Registry Platform (World Health Organization) were searched to identify studies of patients who underwent abdominoplasty with seroma as a potential "outcome." RevMan 5.3 was utilized for data management, statistical analyses, and graph preparation. RESULTS: Fifteen studies (1824 total patients) met the criteria for inclusion in this review. The overall risk of bias was high, mainly owing to the nonrandomized nature of most studies. Abdominoplasty with preservation of Scarpa's fascia or placement of progressive tension sutures was associated with a significantly reduced incidence of seroma compared with that of standard abdominoplasty (P < 0.0001 and P < 0.0002, respectively). Abdominoplasty with application of fibrin glue was similar to standard abdominoplasty in terms of seroma development. CONCLUSIONS: Placement of progressive tension sutures or preservation of Scarpa's fascia during abdominoplasty may reduce the likelihood of postoperative seroma. Application of fibrin glue has no impact on seroma formation. LEVEL OF EVIDENCE: 2.

In vitro comparison of contemporary radiographic imaging techniques for the measurement of inter-radicular width.

OBJECTIVE: To assess the reliability of inter-radicular measurements taken using dental pantomograms (DPT), long cone periapical radiographs (LCPA) and cone bean computed tomography (CBCT). MATERIALS/METHODS: A typodont simulating a hypodontia patient undergoing fixed appliance treatment was used. LCPAs, DPT, I-CAT and Accuitomo CBCT images were taken and the distances between the edentulous spans were measured at the midpoint of the roots and the cemento-enamel junctions (CEJ) of adjacent teeth. The results of each modality were compared to each other to the actual inter-radicular space. RESULTS: The DPT overestimated inter-radicular widths by 2 mm or more [mean: 2.48; 95% confidence interval (CI): -1.09 to 6.05 mm]. The LCPA overestimated the inter-radicular widths by 1.5 mm with a 95% CI of -0.095 to 4.03 mm. The mean differences between gold standard (model) and Accuitomo was 0.57 mm (95% CI: -0.37 to 1.51 mm) for the root mean and 0.22 mm (95% CI: -0.52 to 0.96 mm) for the CEJ. This was similar to the differences between the model and I-CAT where the inter-radicular root mean difference was 0.38 mm (95% CI: -0.38 to 1.14 mm) and the CEJ mean difference was 0.21 mm (95% CI: -0.50 to 0.92 mm). CONCLUSION: The CBCT overestimated the root distance by 0.48 mm and the CEJ width by 0.22 mm, which is clinically irrelevant for implant placement. The DPT overestimated inter-radicular width by 2 mm and the LCPA by 1.5 mm and this difference may put roots of adjacent teeth at risk during implant placement.

Pulmonary metastasectomy: a call for better data collection, presentation and analysis.

A systematic review of the literature for outcomes in pulmonary metastasectomy has revealed the variability in reporting and the paucity of data that would allow a clear understanding of the effectiveness of this operation. The authors, a surgeon and a mathematician, start from the experience of assessing the evidence on which the practice of pulmonary metastasectomy is based and give some simple examples on a more adequate approach to the collection and analysis of surgical data and the importance of its correct interpretation. Retrospective data analysis is constrained by the availability of data. While this can give insight on certain aspects, it is important to discern what data are necessary to give a complete understanding of the effectiveness of a practice. Typically well designed prospective studies and randomised controlled trials with a pre-specified data collection plan give more complete, consistent and reliable data than follow-up or retrospective studies. Pulmonary metastasectomy lends itself well as an example of practice based on uncertain evidence and biased reporting. All the available published studies are follow-up studies, there is no randomised controlled trial, so no control data to estimate its treatment effect on patient's survival. The pool of colorectal or sarcoma patients from which patients are selected to have a pulmonary metastasectomy is never reported on, thus it is hard to estimate the degree of selection and the influence of the surgeon's decision.

Pulmonary metastasectomy: what is the practice and where is the evidence for effectiveness?

Pulmonary metastasectomy is a commonly performed operation and is tending to increase as part of a concept of personalised treatment for advanced cancer. There have been no randomised trials; belief in effectiveness of metastasectomy is based on registry data and surgical follow-up studies. These retrospective series are comprised predominately of solitary or few metastases with primary resection to metastasectomy intervals longer than 2-3 years. Five-year survival rates of 30-50% are recorded, but as case selection is based on favourable prognostic features, an apparent association between metastasectomy and survival cannot be interpreted as causation. Cancers for which lung metastasectomy is used are considered in four pathological groups. In non-seminomatous germ cell tumour, for which chemotherapy is highly effective, excision of residual pulmonary disease guides future treatment and in particular allows an informed decisions as to further chemotherapy. Sarcoma metastasises predominately to lung and pulmonary metastasectomy for both bone and soft tissues sarcoma is routinely considered as a treatment option but without randomised data. The commonest circumstance for lung and liver metastasectomy is colorectal cancer. Repeated resections and ablations are commonplace but without evidence of effectiveness for either. For melanoma, results are particularly poor, but lung metastases are resected when no other treatment options are available. In this review, the available evidence is considered and the conclusion reached is that in the absence of randomised trials there is uncertainty about effectiveness. A randomised controlled trial, Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC), is in progress and randomised trials in sarcoma seem warranted.

Surgery in the treatment of malignant pleural mesothelioma: recruitment into trials should be the default position.

BACKGROUND: Europe is at the peak of an epidemic of malignant pleural mesothelioma and the burden of disease is likely to continue rising in the large areas of the world where asbestos remains unregulated. Patients with mesothelioma present with thoracic symptoms and radiological changes so respiratory physicians take a leading role in diagnosis and management. Belief that the modest survival times reported after radical surgery, whether alone or as part of multimodal therapy, are longer than they it would have been without surgery relies on data from highly selected, uncontrolled, retrospectively analysed case series. The only randomised study, the Mesothelioma and Radical Surgery (MARS) trial showed no benefit. A simple modelling study of registry patients, described here, shows that an impression of longer survival is eroded when patients who were never candidates for operation on grounds of histology, performance status and age are sequentially excluded from the model. CONCLUSION: Whenever the question arises `Might an operation help me?' there are two responses that can and should be given. The first is that there is doubt about whether there is any survival or symptomatic benefit from surgery but we know that there is harm. The second is that there are on-going studies, including two randomised trials, which patients should be informed about. The authors suggest that the default position for clinicians should be to encourage recruitment into these trials.