Dosimetric performance of the Elekta Unity MR-linac system: 2D and 3D dosimetry in anthropomorphic inhomogeneous geometry.

Following the clinical introduction of the Elekta Unity MR-linac, there is an urgent need for development of dosimetry protocols and tools, not affected by the presence of a magnetic field. This work presents a benchmarking methodology comprising 2D/3D passive dosimetry and involving on-couch adaptive treatment planning, a unique step in MR-linac workflows. Two identical commercially available 3D-printed head phantoms (featuring realistic bone anatomy and MR/CT contrast) were employed. One phantom incorporated a film dosimetry insert, while the second was filled with polymer gel. Gel dose-response characteristics were evaluated under the Unity irradiation and read-out conditions, using vials and a cubic container filled with gel from the same batch. Treatment plan for the head phantoms involved a hypothetical large C-shape brain lesion, partly surrounding the brainstem. An IMRT step-and-shoot 7-beam plan was employed. Pre-treatment on-couch MR-images were acquired in order for the treatment planning system to calculate the virtual couch shifts and perform adaptive planning. Absolute 2D and relative 3D measurements were compared against calculations related to both adapted and original plans. Real-time dose accumulation monitoring in the gel-filled phantom was also performed. Results from the vials and cubic container suggest that gel dose-response is linear in the dose range investigated and signal integrity is mature at the read-out timings considered. Head phantom 2D and 3D measurements agreed well with calculations with 3D gamma index passing rates above 90% in all cases, even with the most stringent criteria used (2 mm/2%). By exploiting the 3D information provided by the gel, comparison also involved DVHs, dose-volume and plan quality metrics, which also reflected the agreement between adapted and delivered plans within ±4%. No considerable discrepancies were detected between adapted and original plans. A novel methodology was developed and implemented, suitable for QA procedures in Unity. TPS calculations were validated within the experimental uncertainties involved.

Characterization of a novel 3D printed patient specific phantom for quality assurance in cranial stereotactic radiosurgery applications.

In single-isocenter stereotactic radiosurgery/radiotherapy (SRS/SRT) intracranial applications, multiple targets are being treated concurrently, often involving non-coplanar arcs, small photon beams and steep dose gradients. In search for more rigorous quality assurance protocols, this work presents and evaluates a novel methodology for patient-specific pre-treatment plan verification, utilizing 3D printing technology. In a patient's planning CT scan, the external contour and bone structures were segmented and 3D-printed using high-density bone-mimicking material. The resulting head phantom was filled with water while a film dosimetry insert was incorporated. Patient and phantom CT image series were fused and inspected for anatomical coherence. HUs and corresponding densities were compared in several anatomical regions within the head. Furthermore, the level of patient-to-phantom dosimetric equivalence was evaluated both computationally and experimentally. A single-isocenter multi-focal SRS treatment plan was prepared, while dose distributions were calculated on both CT image series, using identical calculation parameters. Phantom- and patient-derived dose distributions were compared in terms of isolines, DVHs, dose-volume metrics and 3D gamma index (GI) analysis. The phantom was treated as if the real patient and film measurements were compared against the patient-derived calculated dose distribution. Visual inspection of the fused CT images suggests excellent geometric similarity between phantom and patient, also confirmed using similarity indices. HUs and densities agreed within one standard deviation except for the skin (modeled as 'bone') and sinuses (water-filled). GI comparison between the calculated distributions resulted in passing rates better than 97% (1%/1 mm). DVHs and dose-volume metrics were also in satisfying agreement. In addition to serving as a feasibility proof-of-concept, experimental absolute film dosimetry verified the computational study results. GI passing rates were above 90%. Results of this work suggest that employing the presented methodology, patient-equivalent phantoms (except for the skin and sinuses areas) can be produced, enabling literally patient-specific pre-treatment plan verification in intracranial applications.

Accuracy of leptin serum level in diagnosing ventilator-associated pneumonia: a case-control study.

BACKGROUND: Undernutrition causes a reduction of body-fat mass and a decrease in the circulating concentration of leptin which impairs the production of proinflammatory cytokines and increases the incidence of infectious diseases. The main objective of this study was to determine whether leptin deficiency is a risk factor for ventilator-associated pneumonia (VAP). METHODS: This prospective observational case-control study was conducted in a university ICU during a 2-year period. Patients with VAP (cases) were matched (1:1) to patients without VAP (controls) according to all the following criteria: age, gender, SAPS II, and duration of ICU stay before VAP occurrence. In all patients leptin, C-reactive protein (CRP) and procalcitonin (PCT) were measured at ICU admission, and twice a week. In addition, in cases, leptin, CRP and PCT were also measured on the day of VAP diagnosis. RESULTS: Eighty-six cases were matched with 86 controls. No significant difference was found in leptin and PCT levels between cases and controls. CRP level was significantly higher on the day of VAP in cases compared with controls (99 vs. 48 mg/L, P=0.001). Combination of CRP-leptin (CRP ≥78 mg/L and leptin ≥6.2 ng/mL on the day of VAP) was significantly (P=0.009) associated with VAP in univariate analysis. Multivariate analysis identified the combination of CRP-leptin (OR [95% CI] 3.08 [1.18-8.04], P=0.003), LOD score (1.27 [1.08-1.48], P=0.003), neuromuscular-blockers use (6.6 [2.03-21.7], P=0.002), and reintubation (3.3 [1.14-9.6], P=0.027) as independent risk factors for VAP. CONCLUSION: In our study, leptin level was not associated with VAP occurrence. Further studies are needed to confirm our results, and to define the exact inflammatory role of leptin, and its interest as a biomarker in ICU patients.

Intermittent recruitment with high-frequency oscillation/tracheal gas insufflation in acute respiratory distress syndrome.

In acute respiratory distress syndrome (ARDS), recruitment sessions of high-frequency oscillation (HFO) and tracheal gas insufflation (TGI) with short-lasting recruitment manoeuvres (RMs) may improve oxygenation and enable reduction of subsequent conventional mechanical ventilation (CMV) pressures. We determined the effect of adding HFO-TGI sessions to lung-protective CMV on early/severe ARDS outcome. We conducted a prospective clinical trial, subdivided into a first single-centre period and a second two-centre period. We enrolled 125 (first period, n = 54) patients with arterial oxygen tension (P(a,O(2)))/inspiratory oxygen fraction (F(I,O(2))) of <150 mmHg for >12 consecutive hours at an end-expiratory pressure of ≥ 8 cmH(2)O. Patients were randomly assigned to an HFO-TGI group (receiving HFO-TGI sessions with RMs, interspersed with lung-protective CMV; n = 61) or CMV group (receiving lung-protective CMV and RMs; n = 64). The primary outcome was survival to hospital discharge. Pre-enrolment ventilation duration was variable. During days 1-10 post-randomisation, P(a,O(2))/F(I,O(2))), oxygenation index, plateau pressure and respiratory compliance were improved in the HFO-TGI group versus the CMV group (p < 0.001 for group × time). Within days 1-60, the HFO-TGI group had more ventilator-free days versus the CMV group (median (interquartile range) 31.0 (0.0-42.0) versus 0.0 (0.0-23.0) days; p < 0.001), and more days without respiratory, circulatory, renal, coagulation and liver failure (p ≤ 0.003). Survival to hospital discharge was higher in the HFO-TGI group versus the CMV group (38 (62.3%) out of 61 versus 23 (35.9%) out of 64 subjects; p = 0.004). Intermittent recruitment with HFO-TGI and RMs may improve survival in early/severe ARDS.

Nosocomial MRSA pneumonia: data from recent clinical trials.

MRSA infections, especially pneumonia have been associated with considerable morbidity and mortality and the management of MRSA infections is considered as an issue of high priority for scientific societies. Many studies which have been published during the last 10 years have provided evidence for MRSA pneumonia epidemiology, diagnosis and treatment. The main regime of antibiotic treatment recommended for MRSA pneumonia is either vancomycin or linezolid. Despite its pK/pD superiority over vancomycin, linezolid has to date failed to show clear advantage over vancomycin in recent clinical trials.

Adjunctive therapies in severe pneumonia in critical care patients.

AIM: To review available evidence for the role of adjunctive therapies in severe pneumonia. METHODS: We focused on therapies that have attracted recently interest such as glucocorticosteroids (GCs), statins and recombinant activated protein-C. RESULTS: Experimental animal and human studies showed that GCs are able to modulate the inflammatory response and may offer a benefit in patients with severe sepsis. Randomized trials in pneumonia are few, mostly limited in septic shock and ARDS patients. Recombinant activated protein C is a potent anticoagulant and profibrinolytic enzyme which can inhibit the systemic inflammatory response. Available data, although limited, showed that activated protein C can reduce mortality in severe sepsis, especially in severe pneumonia due to S. Pneumoniae. Statins have pleiotropic properties which can affect the inflammatory cascade. The use of statins has been found to be associated with decreased mortality in some studies with pneumina whereas the use of statins was associated with increased risk of death in others. However, data come from observational or retrospective studies. CONCLUSION: Treatment with GCs may modulate the inflammatory response in critically ill patients with pneumonia but a clear effect of steroids on survival is debatable. The administration of GCs should be considered in patients with severe pneumonia when vasopressor dependent septic shock. Activated protein-C may be considered in patients with severe CAP or HAP and sepsis or organ failure. The role of statins in the management of severe pneumonia remains controversial until data from clinical trails will be available.

Pulmonary hypertension in COPD: pathophysiology and therapeutic targets.

The incidence of mild to moderate pulmonary hypertension (PH) is highly prevalent, reaching to 50% in advanced chronic obstructive pulmonary disease (COPD). However, a subpopulation (1-4% in most studies) with grim prognosis despite moderate airflow limitation, present with "out-of-proportion" severe PH, is arbitrarily defined by a mean PH ≥ 40 mmHg, at rest. The sequence of changes that lead to PH in COPD begins at early disease stages by the impairment of endothelial function, which is associated with impaired release of endothelium-derived vasodilating (nitric oxide, prostacyclin) and vasoconstrictive agents (endothelin-1) and imbalance among them. PH in COPD is caused by vasoconstriction and remodelling of pulmonary arteries, which is characterized by the intimal proliferation of poorly differentiated smooth muscle cells and the deposition of elastic and collagen fibres. Hypoxia, inflammation and toxic effects of cigarette smoke, independently or additively interacting, are confirmed factors leading to PH. To date, long-term supplemental oxygen remains the primary treatment in COPD patients with PH. The administration of new vasodilators (prostanoids, endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors) dedicated to idiopathic pulmonary arterial hypertension in the disproportionate subgroup of patients with "out-of-proportion" PH may be considered in the setting of clinical trials. The use of these drugs in COPD patients with PH < 40 mmHg may worsen gas exchange, and to date, has no proven benefit. Future treatments must target more directly pathogenetic mechanisms. Therefore, novel agents have been proposed and are under active investigation, including 5-HT receptor antagonists, Rho-kinase inhibitors, statins and stem cell therapy.

Hyaluronic acid levels are increased in complicated parapneumonic pleural effusions.

BACKGROUND AND AIM: Hyaluronic acid (HA) is a component of extracellular matrix and may play a role in the pleural inflammation which is implicated in parapneumonic effusions.The aim of the current study was to investigate HA levels in serum and pleura in patients with parapneumonic effusions. METHODS: We prospectively studied pleural and serum levels of HA in 58 patients with pleural effusions due to infection (complicated and uncomplicated parapneumonic effusions), malignant effusions and transudative effusions due to congestive heart failure. In addition to HA, TNF-alpha and IL-beta levels were determined in pleural fluid and serum by ELISA. RESULTS: The median +/- SD HA levels (pg/ml) in pleural fluid of patients with complicated effusions (39.058 +/- 11.208) were significantly increased (p < 0.005), compared to those with uncomplicated parapneumonic effusions (11.230 +/- 1.969), malignant effusions (10.837 +/- 4.803) or congestive heart failure (5.392 +/- 3.133). There was no correlation between pleural fluid and serum HA values. Pleural fluid TNF-alpha levels (146 +/- 127 pg/mL) and IL-1beta levels (133.4 +/- 156 pg/mL) were significantly higher in patients with complicated parapneumonic effusions compared to patients with other types of effusion (p < 0.05). No significant association between HA and TNF-alpha or IL-1beta was found. CONCLUSIONS. HA may play a significant role in the inflammatory process which characterises exudative infectious pleuritis. Further investigation might reveal whether HA is a useful marker in the management of parapneumonic effusions.

Analysis of tidal breathing flow volume loop in dogs with tracheal masses.

OBJECTIVES: To investigate whether there are any changes in the tidal breathing flow volume loop (TBFVL) in calm, non-dyspnoeic dogs with intratracheal masses. METHODS: We compared 4 dogs with intratracheal masses (group 1) with 10 healthy dogs (group 2). Routine clinical and laboratory examinations of the dogs were unremarkable, except for episodic upper respiratory obstructive signs in the dogs in group 1. Lateral radiography of the neck and thorax showed that group 1 dogs had masses that appeared to protrude into the tracheal lumen. Tracheoscopy and surgery or necropsy was performed to confirm the presence of the mass. Arterial blood gas and TBFVL analysis was carried out in all dogs to assess respiratory status. RESULTS: The shape of the TBFVL for dogs in group 1 was narrower and ovoid compared with that for the group 2 dogs. Tidal volume and expiratory and inspiratory times were significantly reduced, whereas the respiratory rate was increased for dogs in group 1 compared with dogs in group 2. Arterial blood gas analysis was unremarkable for all dogs. CONCLUSIONS: TBFVL is a non-invasive technique that is easy to perform and well tolerated by dogs. In the absence of abnormalities detected by routine diagnostic evaluations and arterial blood gas analysis in dogs with intratracheal masses, the TBFVL contributes to the definition of the physiologic status of the airways at the time of testing, and results suggests that these dogs breathe quite normally when they are calm and non-dyspnoeic.

Impact of dietary shift to higher-antioxidant foods in COPD: a randomised trial.

Chronic obstructive pulmonary disease (COPD) is characterised by increased oxidative stress. Dietary factors, such as ample consumption of foods rich in antioxidants, such as fruit and vegetables, might have beneficial effects in COPD patients. The association between dietary shift to foods rich in antioxidants and lung function in COPD was investigated in a 3-yr prospective study. A total of 120 COPD patients were randomised to follow either a diet based on increased consumption of fresh fruit and vegetables (intervention group (IG)) or a free diet (control group (CG)). The mean consumption of foods containing antioxidants was higher in the IG than in the CG throughout the study period (p<0.05). The relationship between consumption of foods rich in antioxidants and percentage predicted forced expiratory volume in 1 s was assessed using a general linear model for repeated measures; the two groups overall were different in time (p = 0.03), with the IG showing a better outcome. In investigating the effect of several confounders (sex, age, smoking status, comorbid conditions and exacerbation) of group response over time, nonsignificant interactions were found between confounders, group and time. These findings suggest that a dietary shift to higher-antioxidant food intake may be associated with improvement in lung function, and, in this respect, dietary interventions might be considered in COPD management.

Microsatellite DNA instability and COPD exacerbations.

Increased frequency of microsatellite DNA instability (MSI) has been detected in the sputum of chronic obstructive pulmonary disease (COPD) patients. The aim of the present study was to investigate the relationship between MSI in sputum cells and exacerbation frequency, which is an important parameter in the clinical course of the disease. Induced sputum samples and peripheral blood obtained from 36 patients with COPD at stable state were analysed. The control group consisted of 30 nonsmoking healthy subjects. DNA was extracted and analysed for MSI using the following microsatellite markers: RH70958, D5S207, D6S2223, D6S344, D6S263, G29802, D13S71, D14S588, D14S292 and D17S250. Following MSI analysis, exacerbations were recorded for 3 yrs in total. No MSI was detected in healthy nonsmokers. A total of 18 (50%) out of 36 patients exhibited MSI in their sputum cells. Patients who exhibited MSI showed significantly increased frequency of exacerbations compared with patients that did not. In addition, a significantly increased frequency of purulent and of severe type exacerbations was found in patients exhibiting MSI. Patients positive for marker G29802, D13S71 or D14S588 presented increased exacerbation frequency. The significant association between microsatellite DNA instability and chronic obstructive pulmonary disease exacerbations indicates that somatic mutations could be involved in the pathogenesis and natural history of the disease.

Risk factors for smoking among school adolescents in Greece.

OBJECTIVE: We conducted this study among school adolescents to identify factors, which influence schoolchildren to smoke. METHODS: We carried out a cross-sectional study in a sample of 924 students of all classes (ages 12-18 years old) in 15 public high schools in a semi-urban area in Crete, Greece, using a questionnaire. The questionnaire comprised of 46 questions covering children's lifestyle habits regarding daily activities and leisure time, frequency of risk-taking behaviour, knowledge about the hazards and long-term consequences of smoking. RESULTS: 23.9% of participants were experimental smokers and 18.6% were current smokers. 11.4% of the total population was daily smokers. There was a significant increase in the prevalence of experimental and current smokers with school grades, while peaks in last grades were observed. Boys started smoking earlier than girls, mean (standard error) age 13.4 (2.3) years vs. 14.1 (2.3) years, P = 0.01. Stepwise logistic regression analysis showed a positive relationship between current smoking and having brother or sister smoking [odds ratio (95% confidence interval) 2.7 (1.7-4.4) and 1.8 (1.1-3.3) respectively], having more than three friends who were smokers [2.6 (2-3.4)] and last school grade [1.4 (1.2-1.7)]. Students appeared to be informed about long-term smoking hazards and had negative views on children who smoke especially in the lower grades. CONCLUSIONS: Prevention programmes should be imposed early in elementary schools while cessation policies should target at all grades, in particular at critical grades depending on population-specific characteristics.

Electromagnetic navigation diagnostic bronchoscopy for small peripheral lung lesions.

The present study prospectively evaluated the diagnostic yield and safety of electromagnetic navigation-guided bronchoscopy biopsy, for small peripheral lung lesions in patients where standard techniques were nondiagnostic. The study was conducted in a tertiary medical centre on 40 consecutive patients considered unsuitable for straightforward surgery or computed tomography (CT)-guided transthoracic needle aspiration biopsy, due to comorbidities. The lung lesion diameter was mean+/-sem 23.5+/-1.5 mm and the depth from the visceral-costal pleura was 14.9+/-2 mm. Navigation was facilitated by an electromagnetic tracking system which could detect a position sensor incorporated into a flexible catheter advanced through a bronchoscope. Information obtained during bronchoscopy was superimposed on previously acquired CT data. Divergence between CT data and data obtained during bronchoscopy was calculated by the system's software as a measure of navigational accuracy. All but one of the target lesions was reached and the overall diagnostic yield was 62.5% (25-40). Diagnostic yield was significantly affected by CT-to-body divergence; yield was 77.2% when estimated divergence was

Exacerbations and lung function decline in COPD: new insights in current and ex-smokers.

AIM: To investigate whether there is a significant relationship between an increased frequency of exacerbations and the rate of forced expiratory volume in 1s (FEV(1)) decline in COPD patients. METHODS-MEASUREMENTS: About 102 COPD patients (44 smokers, 58 ex-smokers) participated in a 3-year prospective study. Exacerbations were identified as worsening of patient's respiratory symptoms as recorded on diary cards. Spirometry was performed every 6 months. The effect of frequent exacerbations on lung function was investigated using random effects models. RESULTS: The median (mean(95% CI)) annual exacerbation rate was 2.85 (3.1 (2.7-3.6)). Patients with an annual exacerbation rate over the median rate had significantly lower baseline post-bronchodilation FEV(1)(%pred), higher MRC dyspnoea score and chronic cough compared to patients who had an annual exacerbation rate less than the median. The average annual rate of FEV(1)(%pred), adjusted for smoking decline (DeltaFEV(1)), was found significantly increased in frequent compared to infrequent exacerbators (P=0.017). The highest DeltaFEV(1) was observed in smokers frequent exacerbators and a significant interaction between exacerbation frequency and DeltaFEV(1) was also observed in ex-smokers. CONCLUSIONS: Our findings suggest that an increased frequency of exacerbations is significantly associated with FEV(1) decline even in ex-smokers. Thus, smoking and frequent exacerbations may have both negative impact on lung function. Smoking cessation and prevention of exacerbations should be a major target in COPD.

Differences in microsatellite DNA level between asthma and chronic obstructive pulmonary disease.

Previous studies have shown that microsatellite (MS) DNA instability (MSI) is detectable in sputum cells in chronic obstructive pulmonary disease (COPD) and asthma. The aim of the present study was to investigate whether asthma and COPD could be distinguished at the MS DNA level. DNA was extracted from sputum cells and white blood cells from 63 COPD patients, 60 non-COPD smokers, 36 asthmatics and 30 healthy nonsmokers. Ten MS markers located on chromosomes 2p, 5q, 6p, 10q, 13q, 14q and 17q were analysed. No MSI was detected in non-COPD smokers or healthy nonsmokers. A significantly higher proportion of COPD patients exhibited MSI (49.2%) compared to asthmatics (22.2%). MSI was detected even in the mild stages of COPD (33.3%) and asthma (22.2%). No relationship was found between MSI and COPD severity. The most frequently affected marker was D14S588 (17.5% in COPD and 2.7% in asthma). The markers D6S344, G29802 and D13S71 showed alterations only in COPD, and G29802 was associated with a significantly decreased forced expiratory volume in one second FEV1 (% predicted), whereas MSI in D6S344 was associated with a significantly higher FEV1 (% pred). The frequency of microsatellite instability was higher in chronic obstructive pulmonary disease than in asthma, and microsatellite instability in three workers showed chronic obstructive pulmonary disease specificity. However, further studies are needed to verify the differences between chronic obstructive pulmonary disease and asthma at the microsatellite level.

Posterior fossa subdural hygroma with supratentorial chronic subdural haematoma.

Posterior fossa subdural hygromas are very rare. They tend to occur following direct occipital trauma. We present an unusual case of complex subdural hygroma of the posterior fossa, which was associated with a supratentorial chronic subdural haematoma. This developed after an apparently minor injury to the head. The unusual features of our case are discussed. We also review the literature and discuss the natural history and pathogenesis of subdural hygroma.

Effect of principal polyphenolic components in relation to antioxidant characteristics of aged red wines.

Aged red wines possess significantly different polyphenolic composition compared with young ones, mainly due not only to formation of polymeric compounds but also because of oxidation, hydrolysis, and other transformations that may occur in native grape phenolics during aging. Representative Greek, single-variety, aged red wines were examined for total phenol, total flavanol, and total anthocyanin content using spectrophotometry, and attempts were made to establish correlations with the antiradical, reducing, and hydroxyl free radical scavenging activity. In addition, HPLC analyses were carried out, to ascertain whether individual polyphenols are actually responsible for the antioxidant effects of aged red wines. It was found that total flavanols are the class of polyphenols that account for hydroxyl free radical scavenging efficacy and to a lesser extent for antiradical and reducing ability, whereas there was a less significant link between the antioxidant properties and the total phenolics and only a weak relationship to total anthocyanin content. The correlation of the antioxidant properties with the principal polyphenols showed that individual compounds are weakly associated with all the antioxidant parameters, suggesting that the expression of antioxidant activity in aged red wines is rather a consequence of synergism between various phenolics, and it is not simply attributed to specific constituents.

Domestic processing of onion bulbs (Allium cepa) and asparagus spears (Asparagus officinalis): effect on flavonol content and antioxidant status.

Two commonly consumed plant foods, onion bulbs and asparagus spears, were subjected to typical domestic processing, including chopping, maceration, and boiling. The impact of these processes on flavonol content was assessed. Further, the consequences of these processes on the antioxidant capacity of the tissues were evaluated with the beta-carotene bleaching method. Chopping significantly affected rutin content in asparagus, yielding an 18.5% decrease in 60 min; but in onions, quercetin 3,4'-diglucoside (Q(DG)) and quercetin 4'-glucoside (Q(MG)) were virtually unaffected by chopping. Boiling for 60 min had more severe effects, as it caused overall flavonol losses of 20.6 and 43.9% in onions and asparagus, respectively. Chopping of tissues did not considerably influence the antioxidant capacity, but boiling did provoke notable changes.