International cancer seminars: a focus on esophageal squamous cell carcinoma.

The International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) have initiated a series of cancer-focused seminars [Scelo G, Hofmann JN, Banks RE et al. International cancer seminars: a focus on kidney cancer. Ann Oncol 2016; 27(8): 1382-1385]. In this, the second seminar, IARC and NCI convened a workshop in order to examine the state of the current science on esophageal squamous cell carcinoma etiology, genetics, early detection, treatment, and palliation, was reviewed to identify the most critical open research questions. The results of these discussions were summarized by formulating a series of 'difficult questions', which should inform and prioritize future research efforts.

Sex steroid hormones in relation to Barrett's esophagus: an analysis of the FINBAR Study.

Previously, we observed strong positive associations between circulating concentrations of free testosterone and free dihydrotestosterone (DHT) in relation to Barrett's esophagus in a US male military population. To replicate these findings, we conducted a second study of sex steroid hormones and Barrett's esophagus in the Factors Influencing the Barrett/Adenocarcinoma Relationship (FINBAR) Study based in Northern Ireland and Ireland. We used mass spectrometry to quantitate EDTA plasma concentrations of nine sex steroid hormones and ELISA to quantitate sex hormone-binding globulin in 177 male Barrett's esophagus cases and 185 male general population controls within the FINBAR Study. Free testosterone, free DHT, and free estradiol were estimated using standard formulas. Multivariable logistic regression estimated odds ratios (OR) and 95% confidence intervals (95%CI) of associations between exposures and Barrett's esophagus. While plasma hormone and sex hormone-binding globulin concentrations were not associated with all cases of Barrett's esophagus, we did observe positive associations with estrogens in younger men (e.g. estrone + estradiol ORcontinuous per ½IQR  = 2.92, 95%CI:1.08, 7.89), and free androgens in men with higher waist-to-hip ratios (e.g. free testosterone ORcontinuous per ½IQR  = 2.71, 95%CI:1.06, 6.92). Stratification by body mass index, antireflux medications, and geographic location did not materially affect the results. This study found evidence for associations between circulating sex steroid hormones and Barrett's esophagus in younger men and men with higher waist-to-hip ratios. Further studies are necessary to elucidate whether sex steroid hormones are consistently associated with esophageal adenocarcinogenesis.

Coupling volume-excluding compartment-based models of diffusion at different scales: Voronoi and pseudo-compartment approaches.

Numerous processes across both the physical and biological sciences are driven by diffusion. Partial differential equations are a popular tool for modelling such phenomena deterministically, but it is often necessary to use stochastic models to accurately capture the behaviour of a system, especially when the number of diffusing particles is low. The stochastic models we consider in this paper are 'compartment-based': the domain is discretized into compartments, and particles can jump between these compartments. Volume-excluding effects (crowding) can be incorporated by blocking movement with some probability. Recent work has established the connection between fine- and coarse-grained models incorporating volume exclusion, but only for uniform lattices. In this paper, we consider non-uniform, hybrid lattices that incorporate both fine- and coarse-grained regions, and present two different approaches to describe the interface of the regions. We test both techniques in a range of scenarios to establish their accuracy, benchmarking against fine-grained models, and show that the hybrid models developed in this paper can be significantly faster to simulate than the fine-grained models in certain situations and are at least as fast otherwise.

Thoracic Endovascular Aortic Repair of Aortic Arch Pathologies with the Conformable Thoracic Aortic Graft: Early and 2 year Results from a European Multicentre Registry.

OBJECTIVE: To assess safety, effectiveness and clinical outcome of the conformable thoracic aortic endograft (CTAG) in the treatment of aortic arch pathologies. METHODS: Between October 2009 and December 2010, 100 consecutive patients (65 men; mean age 65 years) with aortic arch pathologies were treated with the CTAG device in five European centres. Indications were thoracic aortic aneurysm (n = 57), Type B dissection (n = 24), intramural haematoma (n = 4), penetrating aortic ulcer (n = 9), and traumatic transection (n = 6). Emergency procedures were performed in 33%. The proximal landing zone (LZ) was LZ 0 in 7%, LZ 1 in14%, LZ 2 in 43%, and LZ 3 in 36%. Data were collected prospectively and analysed for technical and clinical success. Conformability and deployment accuracy were analysed on intra-operative angiography and post-operative computed tomography. Mean follow up was 24 ± 19 months (range, 0.3-36 months). RESULTS: The 30 day, 1 and 2 year survival rates were 90%, 81%, and 74% respectively. The 2 year survival was 80% in the elective and 62% in the emergency groups (p = .20). The major 30 day complication rate was 34%: primary Type Ia endoleak affected 1%, retrograde dissection in 1%, and the paraplegia and stroke rates at 30 days were 4% and 11%. Age > 70 years was an independent predictor for mortality and complications. The primary technical success rate was 92%; device deployment was successful in 100% and accurate in 99%. Conformability to the aortic arch was achieved in 95%. CONCLUSION: The CTAG stent graft shows high deployment accuracy, good conformability, and clinical effectiveness in the treatment of aortic arch pathologies. However, thoracic endovascular aortic repair in the arch is associated with a relatively high stroke rate. Further studies with more patients and longer follow up are needed to evaluate the long-term results.

The effect of moderate alcohol consumption on biomarkers of inflammation and hemostatic factors in postmenopausal women.

BACKGROUND/OBJECTIVES: Inflammation and hemostasis contribute to the etiology of cardiovascular disease. We previously demonstrated that moderate alcohol consumption (1-2 drinks/day) may decrease risk for cardiovascular disease because of an improved lipid profile. In addition to these beneficial changes, the alcohol-mediated reduction in risk may be through its effect on inflammation and hemostasis. The objective of the study was to evaluate the effect of moderate alcohol consumption on biomarkers of inflammation and hemostasis in postmenopausal women. SUBJECTS/METHODS: As part of a controlled diet study, 53 postmenopausal women each consumed a weight-maintaining diet plus 0, 15 and 30 g/day of alcohol for 8 weeks, in a randomized crossover design. The controlled diet contained 15%, 53% and 32% of energy from protein, carbohydrate and fat, respectively. RESULTS: Soluble intercellular adhesion molecule-1 decreased by 5% (P<0.05) with consumption of both 15 and 30 g of alcohol. Fibrinogen concentrations decreased by 4% and 6% (P<0.05) after consumption of 15 and 30 g alcohol, respectively. Fibrin D-dimer decreased by 24% (P<0.05) after consumption of 30 g of alcohol. Plasminogen activator inhibitor-1 (PAI-1) concentrations were increased 27 and 54% (P<0.05) after consumption of 15 and 30 g of alcohol. Plasma high-sensitivity C-reactive protein, interleukin-6 and factor VII coagulant activity did not change with alcohol consumption. CONCLUSIONS: These data suggest that moderate alcohol consumption may have beneficial effects on inflammation and hemostasis in postmenopausal women, and this may be somewhat mitigated by an increase in PAI-1.

Reconciling transport models across scales: The role of volume exclusion.

Diffusive transport is a universal phenomenon, throughout both biological and physical sciences, and models of diffusion are routinely used to interrogate diffusion-driven processes. However, most models neglect to take into account the role of volume exclusion, which can significantly alter diffusive transport, particularly within biological systems where the diffusing particles might occupy a significant fraction of the available space. In this work we use a random walk approach to provide a means to reconcile models that incorporate crowding effects on different spatial scales. Our work demonstrates that coarse-grained models incorporating simplified descriptions of excluded volume can be used in many circumstances, but that care must be taken in pushing the coarse-graining process too far.

Deriving appropriate boundary conditions, and accelerating position-jump simulations, of diffusion using non-local jumping.

In this paper we explore lattice-based position-jump models of diffusion, and the implications of introducing non-local jumping; particles can jump to a range of nearby boxes rather than only to their nearest neighbours. We begin by deriving conditions for equivalence with traditional local jumping models in the continuum limit. We then generalize a previously postulated implementation of the Robin boundary condition for a non-local process of arbitrary maximum jump length, and present a novel implementation of flux boundary conditions, again generalized for a non-local process of arbitrary maximum jump length. In both these cases we validate our results using stochastic simulation. We then proceed to consider two variations on the basic diffusion model: a hybrid local/non-local scheme suitable for models involving sharp concentration gradients, and the implementation of biased jumping. In all cases we show that non-local jumping can deliver substantial time savings for stochastic simulations.

Association of serum α-tocopherol, ß-carotene, and retinol with liver cancer incidence and chronic liver disease mortality.

BACKGROUND: Micronutrients may influence the development or progression of liver cancer and liver disease. We evaluated the association of serum α-tocopherol, ß-carotene, and retinol with incident liver cancer and chronic liver disease (CLD) mortality in a prospective cohort of middle-aged Finnish male smokers. METHODS: Baseline and 3-year follow-up serum were available from 29,046 and 22,805 men, respectively. After 24 years of follow-up, 208 men were diagnosed with liver cancer and 237 died from CLD. Hazards ratios and 95% confidence intervals were calculated for highest vs lowest quartiles from multivariate proportional hazards models. RESULTS: Higher ß-carotene and retinol levels were associated with less liver cancer (ß-carotene: 0.35, 0.22-0.55, P-trend <0.0001; retinol: 0.58, 0.39-0.85, P-trend=0.0009) and CLD mortality (ß-carotene: 0.47, 0.30-0.75, P-trend=0.001; retinol: 0.55, 0.38-0.78, P-trend=0.0007). α-Tocopherol was associated with CLD mortality (0.63, 0.40-0.99, P-trend=0.06), but not with liver cancer (1.06, 0.64-1.74, P-trend=0.77). Participants with higher levels of ß-carotene and retinol, but not α-tocopherol, at both baseline and year 3 had lower risk of each outcome than those with lower levels. CONCLUSIONS: Our findings suggest that higher concentrations of ß-carotene and retinol are associated with incident liver cancer and CLD. However, such data do not indicate that supplementation should be considered for these diseases.

Effects of α-tocopherol and ß-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the ATBC study.

BACKGROUND: Recent data suggest the possible benefits of α-tocopherol and ß-carotene supplementation on liver cancer and chronic liver disease (CLD), but the long-term trial data are limited. METHODS: We evaluated the efficacy of supplemental 50 mg day(-1) α-tocopherol and 20 mg day(-1) ß-carotene on incident liver cancer and CLD mortality in a randomised trial of 29,105 Finnish male smokers, who received supplementation for 5-8 years and were followed for 16 additional years for outcomes. RESULTS: Supplemental α-tocopherol, ß-carotene, or both, relative to placebo, did not reduce the risk of liver cancer or CLD, either overall, during the intervention or during the post-intervention period. CONCLUSIONS: Long-term supplemental α-tocopherol or ß-carotene had no effect on liver cancer or CLD mortality over 24 years of follow-up.

Low to moderate alcohol consumption on serum vitamin D and other indicators of bone health in postmenopausal women in a controlled feeding study.

The objective of this study was to evaluate the effect of 8 weeks of no alcohol, low (1 drink or 15 g/day) and moderate (2 drinks or 30 g/day) alcohol consumption on markers of bone health: fasting serum 25-hydroxy vitamin D (25(OH)D), osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), urine deoxypyridinoline (DPD) and helical peptide (HP) in postmenopausal women (n=51). Compared with no alcohol, 1 or 2 drinks/day for 8 weeks had no significant impact on any of the bone markers. Within each alcohol group, obese women had significantly lower serum 25(OH)D and higher DPD concentrations than normal weight women. Season significantly affected the concentrations of serum 25(OH)D, but there was no significant interaction between alcohol and season on serum 25(OH)D concentrations. Low or moderate alcohol consumption for 8 weeks had no significant impact on markers of bone health in postmenopausal women.

Association between oral leukoplakia and upper gastrointestinal cancers: a 28-year follow-up study in the Linxian General Population Trial.

BACKGROUND: Oral leukoplakia is a precancerous disorder that is common among residents in Linxian. However, the associations between oral leukoplakia and upper gastrointestinal cancers have not been reported. We investigated the relationships between oral leukoplakia and upper gastrointestinal cancers in the Linxian General Population Trial cohort. METHODS: The Linxian General Population Trial cohort, with 29,584 healthy adults enrolled in 1985 and followed through the end of 2012. With collected baseline data, hazard ratios (HR) and 95% confidence intervals (95% CI) for developing upper gastrointestinal cancers were estimated using Cox proportional hazard models. RESULTS: During 28 years of follow-up, we confirmed a total of 2924 incident esophageal squamous cell carcinoma (ESCC) cases, 1644 gastric cardia cancers and 590 gastric non-cardia cancers. Overall, participants with oral leukoplakia had significantly higher risk of developing ESCC (HR=1.18, 95% CI: 1.08, 1.29). Among individuals ⩽52 years old at baseline, oral leukoplakia was associated with elevated risk of ESCC (HR=1.31, 95%CI: 1.15, 1.49). No significant associations were observed for gastric cardia or non-cardia cancers in either all subjects or subgroups. CONCLUSIONS: Oral leukoplakia was associated with increased risk of ESCC, particularly in younger population. Future studies are needed to confirm these findings.

Pathology specific early outcome after thoracic endovascular aortic repair.

OBJECTIVES: Endovascular intervention is established for treatment of thoracic aortic dissection and aneurysm. The aim of this study was to compare the incidence of all-cause and aortic-related in-hospital mortality, stroke, spinal cord ischaemia, and major adverse event rate for patients undergoing thoracic aortic endovascular intervention to see if there is a pathology-specific effect. METHODS: Data were collected prospectively and analysed retrospectively for a cohort of 309 consecutive patients with either thoracic aortic dissection or aneurysm over a 14-year period. RESULTS: There were 209 men and 100 women with a median age of 72 years (interquartile range [IQR] 63-78 years). Aneurysm affected 62% (193/309) of patients and 37% (116/309) had complicated type B aortic dissection, of whom 43% (50/116) had acute and 57% (66/116) chronic presentations. In patients with aortic dissection compared to aneurysm, there was no significant difference in all-cause in-hospital mortality (6.9% vs. 8.3% respectively, p = 0.827, relative risk [RR] 0.83, 95% confidence interval [CI] 0.37-1.88), stroke (6.0% vs 6.2%, p = 1.00, RR 0.971, CI 0.39-2.39), spinal cord ischaemia (6.0% vs 6.2%, p = 1.00, RR 1.030, CI 0.42-2.54), or major adverse event rate (16.4% vs. 16.6%, p = 1.00, RR 0.988, CI 0.59-1.66). The rate of aortic related death was four times greater in the dissection than in the aneurysm group (4/8 = 50% vs 2/16 = 12.5%, p = 0.06, RR 6.99, CI 0.92-52.5) although this did not reach statistical significance. CONCLUSIONS: There was no difference in the incidence of in-hospital mortality, stroke, and spinal cord ischaemia between aneurysm and dissection. The higher rate of aortic related death in the dissection group may indicate the need to refine the clinical management of these patients, including procedural planning, endograft design, and operative technique.

Uncomplicated type B dissections: which patients should be treated? Lessons learned from the recent literature.

The management of type B aortic dissection is complex and decision-making is often based on physician experience and subjective clinical judgment. Thoracic endovascular aortic repair is considered first-line therapy for complicated type B aortic dissection but whether this should be performed in uncomplicated cases has been a matter of debate. Randomized controlled trials have demonstrated the long-term benefit of endovascular treatment to prevent aortic-related mortality, however pre-emptive surgery may not be the solution for all patients because of the occurrence of adverse events such death, stroke and paraplegia. Morphological and false lumen characteristics including aortic diameter, the position, size and number of entry tears and false lumen thrombus volume have been shown to serve as predictors of outcome and may be used to identify high-risk patients. Functional imaging methods such as magnetic resonance and echocardiography are evolving and may be able to provide the clinically-relevant structural, hemodynamic and biomechanical information that is needed for accurate risk stratification of individual patients. A patient-specific approach designed to intervene only in patients that are at high risk of developing complications should improve the long-term outcome of these patients.

Association between serum 25(OH) vitamin D, incident liver cancer and chronic liver disease mortality in the Linxian Nutrition Intervention Trials: a nested case-control study.

BACKGROUND: Although vitamin D deficiency has been noted in cross-sectional studies of chronic liver disease and laboratory studies suggest possible benefits of vitamin D in preventing liver cancer, little epidemiologic data are available. METHODS: We performed a nested case-control study in the Linxian Nutrition Intervention Trials on participants developing incident liver cancer or dying from chronic liver disease over 22 years of follow-up. Baseline serum 25(OH) vitamin D was measured for 226 incident liver cancer cases, 282 chronic liver disease deaths and 1063 age-, sex- and trial-matched controls. Unconditional logistical regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The median serum vitamin D level in controls was low (20 nmol l(-1)). Compared with the lowest quartile, subjects in the fourth quartile had lower risk of chronic liver disease death (OR=0.34, 95% CI=0.21-0.55). For liver cancer incidence, risk estimates were below one, but were not statistically significant. Associations, however, were significant among participants with higher serum calcium levels (Q4 vs Q1, OR=0.43, 95% CI=0.21-0.89). Results for chronic liver disease did not vary by serum calcium level. CONCLUSION: In a low vitamin D population, higher serum 25(OH) vitamin D concentrations were associated with significantly lower risk of chronic liver disease deaths, and among those with higher serum calcium, incident liver cancer. Our results suggest a possible protective role for vitamin D in these diseases.

The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers.

BACKGROUND: Coffee intake is associated with reduced risk of liver cancer and chronic liver disease as reported in previous studies, including prospective ones conducted in Asian populations where hepatitis B viruses (HBVs) and hepatitis C viruses (HCVs) are the dominant risk factors. Yet, prospective studies in Western populations with lower HBV and HCV prevalence are sparse. Also, although preparation methods affect coffee constituents, it is unknown whether different methods affect disease associations. METHODS: We evaluated the association of coffee intake with incident liver cancer and chronic liver disease mortality in 27,037 Finnish male smokers, aged 50-69, in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who recorded their coffee consumption and were followed up to 24 years for incident liver cancer or chronic liver disease mortality. Multivariate relative risks (RRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models. RESULTS: Coffee intake was inversely associated with incident liver cancer (RR per cup per day=0.82, 95% CI: 0.73-0.93; P-trend across categories=0.0007) and mortality from chronic liver disease (RR=0.55, 95% CI: 0.48-0.63; P-trend<0.0001). Inverse associations persisted in those without diabetes, HBV- and HCV-negative cases, and in analyses stratified by age, body mass index, alcohol and smoking dose. We observed similar associations for those drinking boiled or filtered coffee. CONCLUSION: These findings suggest that drinking coffee may have benefits for the liver, irrespective of whether coffee was boiled or filtered.

A 14-year experience with aortic endograft infection: management and results.

OBJECTIVES: The management of thoracic and abdominal aortic endograft infection is complex and associated with high mortality. Cases are rare: a recent systematic review identified 117 reported cases; the largest reported series comprises 12 infected endografts. METHODS: We report 22 consecutive patients with infected abdominal or thoracic aortic endovascular devices implanted from 1998 to 2012. Management included extension with new devices, aneurysm sac drainage of pus/irrigation with antibiotics, endograft explantation, and axillo-(bi)femoral reconstruction. RESULTS: Twenty-two patients (16 men) were identified. Median age was 71 years (range, 43-88 years). Index devices were infra-renal endovascular repair (n = 13), and thoracic endovascular repair (n = 9) all for aneurysmal or pseudoaneurysmal disease. Seven (32%) had prior aortic surgery. Follow-up was complete in all cases; in survivors follow-up was a median of 29 (range, 12-45) months. The mortality from explantation of ten infra-renal devices was 1/10 (10%) on-table and a further 2/10 (20%) within 30 days. Device retention led to disease progression and death in all patients with infected endografts. Sac drainage/irrigation provided only temporary control of sepsis. Device extension can treat rupture, but additional devices became infected. CONCLUSION: Abdominal endograft explantation is high risk but may be curative. Appropriate selection of patients for infected endograft explantation remains a major challenge.

Endovascular treatment of isolated iliac artery aneurysms using a custom-made stent graft with proximal barb fixation: early outcome.

Current endovascular treatments for isolated iliac artery aneurysms (IIAAs) include the use of aortoiliac stent grafts with coverage of the distal aorta or stent grafts confined to the iliac artery without active proximal fixation. We report our experience in the use of custom-made Cook Zenith(TM) iliac limb stent grafts with proximal barb fixation. Patients treated from July 2009 to February 2011 were included. All imaging and patient records were assessed for perioperative and early outcomes. Nine IIAAs (seven patients) were treated. The mean patient age was 80 years (range 58-91 years). The mean aneurysm size was 48 mm (35-80 mm), and the mean length of the proximal landing zone (PLZ) was 29 mm (10-50 mm). The distal landing zone was in the external iliac artery after coil embolization of the internal iliac artery. The Mean diameter of the PLZ was 21 mm (20-24 mm). Technical success was achieved in eight cases. Perioperative complications included reoperation in one patient for groin bleeding and ischemia. On follow-up (mean 12 months, range 1-26), all aneurysms were successfully excluded from the circulation and there was no stent graft migration or thrombosis. Use of custom-made stent grafts with proximal barb fixation in treatment of IIAAs is a feasible option which may reduce the risk of migration when compared with stent grafts with lack of proximal fixation.

Carotid endarterectomy in the elderly: risk factors, intraoperative carotid hemodynamics and short-term complications: a UK tertiary center retrospective analysis.

This retrospective analysis aims to demonstrate the safety of carotid endarterectomy (CE) in patients >75 years with particular attention paid to intraoperative hemodynamics. Four hundred and ninety-six consecutive patients with >70% symptomatic and asymptomatic stenosis who underwent CE were prospectively assessed and divided into those <75 years (n = 408; mean 64 years) and those >75 years (n = 88; mean 78 years). Associated risk factors, hemodynamic parameters, surgical techniques and 30-day perioperative complications were compared. Carotid artery stump pressures of <25 mmHg (13 versus 29%) and middle cerebral artery velocities of <20 cm/sec (46 versus 29%) were more common in those >75 years (P = 0.0001 and P <0.005, respectively). However, there was no difference in the frequency of intraluminal shunt (34% in both groups) or synthetic patch usage (primary patching: 12.5%, older group versus 11%, younger group; secondary patching: 34% in both groups), and no difference in the combined 30-day stroke and death rates (3.4%, >75 years versus 1.1%, <75 years; P = 0.425). CE in this cohort of patients >75 years was not associated with increased morbidity or mortality. Altered intraoperative hemodynamics were not associated with increased use of shunting or patching. This analysis supports CE as a safe procedure in the elderly.