Pulmonary Metastasectomy in Colorectal Cancer: updated analysis of 93 randomized patients - control survival is much better than previously assumed.

AIM: Lung metastases from colorectal cancer are resected in selected patients in the belief that this confers a significant survival advantage. It is generally assumed that the 5-year survival of these patients would be near zero without metastasectomy. We tested the clinical effectiveness of this practice in Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC), a randomized, controlled noninferiority trial. METHOD: Multidisciplinary teams in 14 hospitals recruited patients with resectable lung metastases into a two-arm trial. Randomization was remote and stratified according to site, with minimization for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, number of metastases and carcinoembryonic antigen level. The trial management group was blind to patient allocation until after intention-to-treat analysis. RESULTS: From 2010 to 2016, 93 participants were randomized. These patients were 35-86 years of age and had between one and six lung metastases at a median of 2.7 years after colorectal cancer resection; 29% had prior liver metastasectomy. The patient groups were well matched and the characteristics of these groups were similar to those of observational studies. The median survival after metastasectomy was 3.5 (95% CI: 3.1-6.6) years compared with 3.8 (95% CI: 3.1-4.6) years for controls. The estimated unadjusted hazard ratio for death within 5 years, comparing the metastasectomy group with the control group, was 0.93 (95% CI: 0.56-1.56). Use of chemotherapy or local ablation was infrequent and similar in each group. CONCLUSION: Patients in the control group (who did not undergo lung metastasectomy) have better survival than is assumed. Survival in the metastasectomy group is comparable with the many single-arm follow-up studies. The groups were well matched with features similar to those reported in case series.

Defect segregation facilitates oxygen transport at fluorite UO2 grain boundaries.

An important challenge for modelling transport in materials for energy applications is that in most applications they are polycrystalline, and hence it is critical to understand the properties in the presence of grain boundaries. Moreover, most grain boundaries are not pristine stoichiometric interfaces and hence dopants are likely to play a significant role. In this paper, we describe our recent work on using atomistic molecular dynamics simulations to model the effect of doped grain boundaries on oxygen transport of fluorite structured UO2. UO2, much like other fluorite grain boundaries, are found to be sinks for oxygen vacancy segregation relative to the grain interior, thus facilitating oxygen transport. Fission products further enhance diffusivity via strong interactions between the impurities and oxygen defects. Doping produces a striking structural alteration in the Σ5 class of grain boundaries that enhances oxygen diffusivity even further. This article is part of a discussion meeting issue 'Energy materials for a low carbon future'.

Unilateral ultra-brief pulse electroconvulsive therapy for depression in Parkinson's disease.

OBJECTIVES: Electroconvulsive therapy (ECT) has demonstrated efficacy in treating core symptoms of Parkinson's disease (PD); however, widespread use of ECT in PD has been limited due to concern over cognitive burden. We investigated the use of a newer ECT technology known to have fewer cognitive side effects (right unilateral [RUL] ultra-brief pulse [UBP]) for the treatment of medically refractory psychiatric dysfunction in PD. MATERIALS AND METHODS: This open-label pilot study included 6 patients who were assessed in the motoric, cognitive, and neuropsychiatric domains prior to and after RUL UBP ECT. Primary endpoints were changes in total score on the HAM-D-17 and GDS-30 rating scales. RESULTS: Patients were found to improve in motoric and psychiatric domains following RUL UBP ECT without cognitive side effects, both immediately following ECT and at 1-month follow-up. CONCLUSIONS: This study demonstrates that RUL UBP ECT is safe, feasible, and potentially efficacious in treating multiple domains of PD, including motor and mood, without clear cognitive side effects.

Meta-analysis of colorectal cancer follow-up after potentially curative resection.

BACKGROUND: After potentially curative resection of primary colorectal cancer, patients may be monitored by measurement of carcinoembryonic antigen and/or CT to detect asymptomatic metastatic disease earlier. METHODS: A systematic review and meta-analysis was conducted to find evidence for the clinical effectiveness of monitoring in advancing the diagnosis of recurrence and its effect on survival. MEDLINE (Ovid), Embase, the Cochrane Library, Web of Science and other databases were searched for randomized comparisons of increased intensity monitoring compared with a contemporary standard policy after resection of primary colorectal cancer. RESULTS: There were 16 randomized comparisons, 11 with published survival data. More intensive monitoring advanced the diagnosis of recurrence by a median of 10 (i.q.r. 5-24) months. In ten of 11 studies the authors reported no demonstrable difference in overall survival. Seven RCTs, published from 1995 to 2016, randomly assigned 3325 patients to a monitoring protocol made more intensive by introducing new methods or increasing the frequency of existing follow-up protocols versus less invasive monitoring. No detectable difference in overall survival was associated with more intensive monitoring protocols (hazard ratio 0·98, 95 per cent c.i. 0·87 to 1·11). CONCLUSION: Based on pooled data from randomized trials published from 1995 to 2016, the anticipated survival benefit from surgical treatment resulting from earlier detection of metastases has not been achieved.

Lifting and Transport of Martian Dust by the Ingenuity Helicopter Rotor Downwash as Observed by High-Speed Imaging From the Perseverance Rover.

Martian atmospheric dust is a major driver of weather, with feedback between atmospheric dust distribution, circulation changes from radiative heating and cooling driven by this dust, and winds that mobilize surface dust and distribute it in the atmosphere. Wind-driven mobilization of surface dust is a poorly understood process due to significant uncertainty about minimum wind stress and whether the saltation of sand particles is required. This study utilizes video of six Ingenuity helicopter flights to measure dust lifting during helicopter ascents, traverses, and descents. Dust mobilization persisted on takeoff until the helicopter exceeded 3 m altitude, with dust advecting at 4-6 m/s. During landing, dust mobilization initiated at 2.3-3.6 m altitude. Extensive dust mobilization occurred during traverses at 5.1-5.7 m altitude. Dust mobilization threshold friction velocity of rotor-induced winds during landing is modeled at 0.4-0.6 m/s (factor of two uncertainty in this estimate), with higher winds required when the helicopter was over undisturbed terrain. Modeling dust mobilization from >5 m cruising altitude indicates mobilization by 0.3 m/s winds, suggesting nonsaltation mechanisms such as mobilization and destruction of dust aggregates. No dependence on background winds was seen for the initiation of dust lifting but one case of takeoff in 7 m/s winds created a track of darkened terrain downwind of the helicopter, which may have been a saltation cluster. When the helicopter was cruising at 5-6 m altitude, recirculation was seen in the dust clouds.

The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis.

Recent evidence has led us to propose that transforming growth factor-beta (TGF-beta) is a key inhibitor of atherosclerosis. We show here that a population of patients with advanced atherosclerosis all have less active TGF-beta in their sera than patients with normal coronary arteries, with a fivefold difference in average concentration between the two groups. This correlation with atherosclerosis is much stronger than for other known major risk factors and it may therefore have important diagnostic and prognostic significance. Aspirin medication correlates with an increase in active TGF-beta concentration, indicating that therapeutic interventions for TGF-beta are possible.

Perseverance rover reveals an ancient delta-lake system and flood deposits at Jezero crater, Mars.

Observations from orbital spacecraft have shown that Jezero crater on Mars contains a prominent fan-shaped body of sedimentary rock deposited at its western margin. The Perseverance rover landed in Jezero crater in February 2021. We analyze images taken by the rover in the 3 months after landing. The fan has outcrop faces, which were invisible from orbit, that record the hydrological evolution of Jezero crater. We interpret the presence of inclined strata in these outcrops as evidence of deltas that advanced into a lake. In contrast, the uppermost fan strata are composed of boulder conglomerates, which imply deposition by episodic high-energy floods. This sedimentary succession indicates a transition from sustained hydrologic activity in a persistent lake environment to highly energetic short-duration fluvial flows.

Comparison of three mathematical models for predicting the risk of additional axillary nodal metastases after positive sentinel lymph node biopsy in early breast cancer.

BACKGROUND: Women with breast cancer and a positive axillary sentinel lymph node (SLN) are recommended to undergo complete axillary lymph node dissection; however, further nodal disease is not always present. Mathematical models have been constructed to determine the risk of metastatic disease; three of these were evaluated independently. METHODS: Data from 108 women with breast cancer who had a positive SLN biopsy and completion axillary lymph node dissection were used. Measurements of additional parameters over those usually determined (such as size of SLN metastasis) were assessed under the supervision of two pathologists. These data were used to determine the predicted risk of non-SLN metastases using three mathematical models (from Memorial Sloan-Kettering Cancer Center (MSKCC), Cambridge University and Stanford University) and a comparison made with the observed findings. Analyses were made using the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: Some 53 (49.1 per cent) of 108 patients had a positive non-sentinel axillary lymph node metastasis. The AUC values were 0.63, 0.72 and 0.67 for the MSKCC, Cambridge and Stanford nomograms respectively. CONCLUSION: This independent comparison found no significant difference between the models, although the Cambridge model had the advantage of requiring fewer measurements with a more accurate predictive performance.

Inappropriate use and interpretation of D-dimer testing in the emergency department: an unexpected adverse effect of meeting the "4-h target".

INTRODUCTION: D-dimer tests were inappropriately overused in our emergency department as a result of bloods being taken before clinical assessment to help meet the "4-hour target". We introduced a multifaceted intervention to reduce the number of inappropriate D-dimer tests. The secondary aim was to improve the diagnostic workup of suspected pulmonary embolism (PE). METHOD: Rate of D-dimer test and ventilation/perfusion scan requests were compared before, during and after a staggered intervention at two hospitals in one National Health Service Trust. Audits before and after the intervention were done to determine whether test use was appropriate and whether the diagnostic workup was complete. RESULTS: At hospital 1, D-dimer testing after the intervention was almost halved: ratio 0.59 (95% CI 0.55 to 0.63) (p<0.0001). There was also a small reduction at hospital 2 (control): rate 0.88 (95% CI 0.78 to 0.99) (p = 0.03). After the formal introduction of change at hospital 2, there was a further reduction in tests: ratio 0.67 (95% CI 0.58 to 0.76) (p<0.0001). In hospital 1, pretest probability assessment improved by 42% (p = 0.0004) and D-dimer test use was reduced by 12.5% (p = 0.04) between audits. Improvement in the use of D-dimer test according to the pathway was not significant (32.5%, p = 0.11), and there was no change in the proportion of patients with completion of their diagnostic workup for PE: 47.6% (95% CI 38.3% to 56%) before and 45.6% (95% CI 38.3% to 53.1%) after the intervention. CONCLUSION: Implementation of a multifaceted change program reduced the number of D-dimer test requests in both hospitals and may have improved the diagnostic workup for PE at hospital 1. Processes that speed patient transit through the emergency department may impact negatively on other aspects of patient care. This should be the subject of further studies.

Nonrigid reconstruction of 3D breast surfaces with a low-cost RGBD camera for surgical planning and aesthetic evaluation.

Accounting for 26% of all new cancer cases worldwide, breast cancer remains the most common form of cancer in women. Although early breast cancer has a favourable long-term prognosis, roughly a third of patients suffer from a suboptimal aesthetic outcome despite breast conserving cancer treatment. Clinical-quality 3D modelling of the breast surface therefore assumes an increasingly important role in advancing treatment planning, prediction and evaluation of breast cosmesis. Yet, existing 3D torso scanners are expensive and either infrastructure-heavy or subject to motion artefacts. In this paper we employ a single consumer-grade RGBD camera with an ICP-based registration approach to jointly align all points from a sequence of depth images non-rigidly. Subtle body deformation due to postural sway and respiration is successfully mitigated leading to a higher geometric accuracy through regularised locally affine transformations. We present results from 6 clinical cases where our method compares well with the gold standard and outperforms a previous approach. We show that our method produces better reconstructions qualitatively by visual assessment and quantitatively by consistently obtaining lower landmark error scores and yielding more accurate breast volume estimates.

Systematic review of the impact of breast-conserving surgery on cancer outcomes of multiple ipsilateral breast cancers.

BACKGROUND: The clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast-conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC). METHODS: Comprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle-Ottawa Scale. The characteristics and results of identified studies were summarized. RESULTS: Twenty-four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2-23 per cent after BCS at median follow-up of 59·5 (i.q.r. 56-81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2-40 per cent after BCS at a median follow-up of 64 (i.q.r. 57-73) months. One high-quality study reported 10-year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women. CONCLUSION: The available studies were mainly of moderate quality, historical and underpowered, with limited follow-up and biased case selection favouring BCS rather than mastectomy for low-risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

The use of onestep nucleic acid amplification (OSNA) and tumour related factors in the treatment of axillary breast cancer: A predictive model.

AIMS: We aimed to determine the effectiveness of CK19 mRNA copy number and tumour related factors in predicting non-sentinel axillary nodal involvement, in order to facilitate the formulation of local treatment guidelines for axillary clearance (ANC) following intra-operative analysis of the sentinel node biopsy (SNB) using one-step nucleic acid amplification (OSNA). METHODS: Patients due to have (SNB) at our institution for breast cancer as well as patients with high grade ductal carcinoma in situ with pre-operative negative assessment of the axilla were included. Alternate slices of each node were sent for assessment by either OSNA or histopathology. Immediate ANC was performed if OSNA was positive. The CK19 mRNA nodal copy number, the total tumour load (TTL) measured by summation of mRNA copy numbers of all positive nodes, the nodal status at ANC and tumour characteristics for each patient were recorded. A model of risk probability was constructed using TTL and tumour related factors. RESULTS: 664 nodes were analysed from 425 patients who had SNB performed between 2011 and 2014. ANC was performed on 105 of these patients. The concordance between OSNA and histology was 91.4% and negative predictive value (NPV) was 97%. TTL (p = 0.003) and LVI (p = 0.04) were identified as risk factors for non-sentinel nodal involvement. The risk probability model identified all patients with pN2 disease for ANC. CONCLUSION: In the future a decision to perform ANC will be based on a risk stratification model based on TTL and tumour related factors.

Consumption of red wine polyphenols reduces the susceptibility of low-density lipoproteins to oxidation in vivo.

Red wine polyphenols (RWPPs) were obtained from red wine by absorption and elution from a resin column. Red wine (375 mL/d), white wine (375 mL/d), RWPPs (1 g/d, equivalent to 375 mL red wine/d) in capsules, RWPPs (1 g/d) dissolved in white wine, or a control alcoholic drink (40 g ethanol/d) was given to groups of 6-9 healthy men for 2 wk. Plasma LDL was separated by ultracentrifugation and desalted by dialyzing against a phosphate buffer without EDTA. In the copper-catalyzed peroxidation of LDL (copper-diene assay), the mean lag time increased by 17.8 min after red wine, 14.2 min after RWPP capsules, and 11.7 min after RWPPs in white wine. These groups also showed decreases in thiobarbituric acid-reactive substances, lipid peroxides, and conjugated dienes and increases in plasma and LDL polyphenols. The only change with white wine was an increase in thiobarbituric acid-reactive substances; there were no changes after the control drink. In a second study, RWPPs (1 and 2 g/d) and vitamin E [1000 IU (671 mg)/d] were given for 2 wk. In the copper-diene assay the addition of 10 micromol EDTA/L abolished the increased lag time of 17.7 min seen with 1 g RWPP/d and changed the increased lag time from 13.2 to 4.5 min seen with 2 g RWPP/d. Vitamin E increased lag time by 67.6 min with dialysis without EDTA and by 50.5 min with EDTA. When the column method was used for desalting LDL, all 3 treatments produced an increase in lag time. The failure of some authors to obtain antioxidant effects with the consumption of red wine may be due to the differing techniques.

Regional pulmonary distribution of krypton-81m gas delivered by different breathing systems.

Regional pulmonary distribution of 81mKr gas delivered by three breathing systems was determined. Data from 18 patients were analyzed. Posterior images were obtained using each breathing system in turn. Distribution of Kr gas was determined in terms of penetration and zonal indices. For penetration indices each lung was divided into a central, intermediate, and peripheral region and these indices, defined as the ratio of counts/cell in the intermediate or the peripheral region over those in the central region, were calculated. For the zonal indices each lung was divided equally into upper and lower zones and the percentage ratio of the counts in each zone to the total counts in both lungs was calculated. For all patients, in addition, the size, height, and width of each lung were determined from computer images. These parameters were compared between the breathing systems using a paired t-test. It was found that there were no statistical differences among the three breathing systems, either in the regional pulmonary distribution of the 81mKr gas or in the overall shapes of the lungs.

Acute ingestion of red wine by men activates platelets but does not influence endothelial markers: no effect of white wine.

Long-term moderate alcohol use is associated with a better cardiovascular risk profile than total abstinence, although the short-term effect of a bolus of alcohol is unclear. The hypothesis tested in this study was that an acute bolus of alcohol would adversely affect the endothelium and platelets. Blood was taken before and 4 h after the ingestion of red or white wine by nine volunteers per group, and by 11 control water-only drinkers at the same time points. Plasma was obtained and markers of platelet activity (beta-thromboglobulin and soluble P selectin) and endothelial cell function (von Willebrand factor and soluble thrombomodulin) measured by enzyme-linked immunosorbent assay. The only marker to change significantly was beta-thromboglobulin, which increased from a median of 10 ng/ml (interquartile range, 8.5-15) before drinking red wine to 16 ng/ml (interquartile range, 14-20) 4 h later (P = 0.0067). We conclude that an acute bolus of red wine, but not white wine, activates platelets but has no substantial effect on the endothelium.

Estimation of ascitic fluid volume using 99Tcm labelled macroaggregated albumin.

We have assessed the usefulness of a radionuclide dilution method for estimation of ascitic fluid volume. 99Tc(m) macroaggregated albumin (10 MBq) was injected into the peritoneal fluid. Multiple samples were taken using a trocath peritoneal dialysis catheter over a 4-h period. Blood samples were taken at the same time and a 4-h urine collection was made during the study. At 4 h a controlled drainage of ascitic fluid, followed by suction drainage, was used and a total drained volume measured. For comparison, peritoneal volumes were measured from the radioactivity of peritoneal fluid activity samples using dilution techniques. The estimated peritoneal fluid volume using the radionuclide method was consistently higher than the drained volume. This was attributed to either a lack of uniform distribution of the activity in the peritoneal cavity by 4 h or early breakdown and absorption of activity from the peritoneal cavity. In two patients it was not possible to measure a volume due to poor distribution of the radionuclide in the peritoneal fluid. We found that in our group of patients the radionuclide dilution is of little value in estimating the peritoneal fluid volume.

A survey of the role of the UK physicist in nuclear medicine: a report of a joint working group of the British Institute of Radiology, British Nuclear Medicine Society, and the Institute of Physics and Engineering in Medicine.

Guidelines for the provision of physics support to nuclear medicine were published in 1999 by a joint working group of the British Institute of Radiology, the British Nuclear Medicine Society, and the Institute of Physics and Engineering in Medicine. Following publication of the guidelines, a survey was conducted by the working group to gather data on the actual level of physicist support in UK hospitals of different types and on the activities undertaken by physicists. The data were collected in the 12 months following the publication of guidelines and cover different hospital models and seven UK regions. The results provide evidence that many of the smaller units - small teaching hospitals and, particularly, small district general hospitals - have insufficient physics support. Although, on average, there is good agreement between the guidelines and the survey data for medium and large district general hospitals, there is wide variation in the level of physics provision between hospitals delivering apparently similar services. This emphasizes the need for national guidelines, against which institutions may be bench-marked and which may be used as a recommendation for the staffing levels necessary to ensure services are delivered safely and standards are not compromised. The complexity and variety of workload is an important factor in determining the level of physics support. As services develop, it is vital that this aspect is recognized to ensure that appropriate resources are available for the required physics input, even if any new service represents only a modest clinical throughput in terms of patient numbers.

Leucocyte copper, a marker of copper body status is low in coronary artery disease.

To elucidate the relationship between leucocyte copper as a reliable, sensitive index of copper body status and extent of atherosclerosis in patients with Coronary Artery Disease (CAD) the present case-control study was carried out. 80 subjects were studied (23 females and 57 males), aged between 30-70, due to have a angiography. Individual angiograms were scored by combining the individual scores in all the major coronary arteries into one score of a scale 1.00 for patency to 0.00 for severe CAD. Serum and leucocyte copper and zinc were determined by GFAAS. No significant difference between patients with advanced CAD and relatively normal arteries were observed in the lipid profile and levels of plasma copper. Leucocyte copper had a significant link with the severity of atherosclerosis which was independent of sex. There was a linear relationship between the degree of decreasing leucocyte copper concentration and angiogram score. These findings give support to the hypothesis that marginal copper status, assessed by decreased leucocyte copper level, is associated with developing CAD.

Vitamin and mineral nutritional status and other biochemical data assessed in groups of men from Crevalcore and Montegiorgio (Italy).

The vitamin and mineral nutritional status of 34 elderly (mean age 77.6 +/- 4.7 years) and 39 younger subjects (mean age 41.7 +/- 7.5 years) from Crevalcore and Montegiorgio (the two rural areas of The Seven Countries Study) was studied. Comparisons have been made between centres, between age groups, and with data obtained from similar surveys performed in 1960 and 1970. Levels of thiamin and riboflavin nutritional status were higher in 1991 than in 1970. Plasma retinol values were above levels of deficiency, but vitamin E and beta-carotene tended to be low. The zinc status of the populations, as assessed by leucocyte zinc concentrations, was generally low. A decline in copper intake during the past ten years may be responsible for the low leucocyte copper concentration which was more apparent in the younger subjects. Serum cholesterol was above, and HDL cholesterol below, the European Atherosclerosis Society recommendations.

Do hydroxy-carotenoids prevent coronary heart disease? A comparison between Belfast and Toulouse.

High intakes of antioxidants in fruit, vegetables and wine are thought to protect against coronary heart disease (CHD). Because people in Toulouse have a much lower incidence of CHD compared with Belfast, the plasma concentrations of antioxidant vitamins and carotenoids in the two populations have been compared. The major difference was in some of the plasma carotenoids. Hydroxy-carotenoids were twice as high in Toulouse in both sexes, notably lutein which occurs principally in dark green vegetables and beta-cryptoxanthin which occurs chiefly in citrus fruits. In addition, alpha-carotene was 50% higher in Toulouse, gamma-tocopherol was 50% higher in Belfast. Other plasma vitamins and carotenoids were not significantly different. If antioxidants play a role in preventing CHD, then the hydroxy-carotenoids are major candidates for further investigation.