D2 dissection improves disease-specific survival in advanced gastric cancer patients: 15-year follow-up results of the Italian Gastric Cancer Study Group D1 versus D2 randomised controlled trial.

BACKGROUND: The extended lymphadenectomy (D2) was recently introduced in several guidelines as the optimal treatment for gastric cancer, based only on the 15-year follow-up results of the Dutch randomised trial, while the British Medical Research Council (MRC) study failed to demonstrate a survival benefit over the more limited D1 dissection. The Italian Gastric Cancer Study Group randomised controlled trial (RCT) was also undertaken to compare D1 versus D2 gastrectomy, and a tendency to improve survival in patients with advanced resectable disease (pT > 1N+) was documented despite negative results in the entire patient population. Now we present the 15-year follow-up results of survival and gastric cancer-related mortality. METHODS: Between June 1998 and December 2006, eligible patients with gastric cancer who signed the informed consent were randomised at 5 centres to either D1 or D2 gastrectomy. Intraoperative randomisation was implemented centrally by phone call. Primary outcome was overall survival (OS); secondary end-points were disease-specific survival, postoperative morbidity and mortality. Analyses were by intention to treat. Strict quality control measures for surgery, lymph node removal, pathology and patient follow-up were implemented and monitored. Registration number: ISRCTN11154654 (http://www.controlled-trials.com). FINDINGS: A total of 267 eligible patients were assigned to either D1 (133 patients) or D2 (134) procedure. Median follow-up time was 16.76 years. Analyses were done both in overall patient population and in pT > 1N+. One hundred patients (38.5) were alive without recurrence. OS and disease-specific survival (DSS) were very high in both arms. In overall population, they were not different between D1 and D2 arm (51.3% vs. 46.8% and 65% vs. 67% respectively, p = 0.31 and p = 0.94). DSS was significantly higher after D2 in pT > 1N+ patients (29.4% vs. 51.4%, p = 0.035). OS and DSS were better after D1 in patients older than 70 years (p = 0.003 and p = 0.006). DSS was higher after D1 also in early stages (p = 0.01). INTERPRETATION: After 15-year follow up, despite no relevant difference in overall population, DSS and gastric cancer-related mortality of patients with advanced disease and lymph node metastases are improved by D2 procedure. Further data available from this trial suggest that D1 procedure should be preferably used in older patients and in early disease. As accurate detection of advanced diseases can be currently provided by adequate preoperative workup in referral centres, D2 procedure should be recommended in these cases. FUNDING: Piedmont Regional fund for Finalized Healthy Research Project, Application 2003 for data collection.

Aesthetic results following breast cancer surgery: A prospective study on 6515 cases from ten Italian Senonetwork breast centers.

Breast cancer treatment has deeply changed in the last decades, since clinical and oncological cure cannot be achieved without patient's satisfaction in term of aesthetic outcomes. Several methods have been proposed to objectively assess these results. However, Italian breast centers have not yet agreed on measurable, reproducible and validated aesthetic outcome indicators to monitor their performance. METHODS: The study was designed and conducted by Senonetwork, a not-for-profit association of Italian breast centers. Ten breast centers were selected based on specific eligibility criteria. This multicentre observational prospective study recruited 6515 patients with diagnosis of in situ or invasive breast cancer who underwent breast surgery in the years 2013-2016. Thirteen indicators of aesthetic results and of related quality of care were analyzed. Data collection and analysis were conducted using a common study database. RESULTS: On average, seven out of ten centers were able to collect data on the proposed indicators with a proportion of missing values < 25%. By expert consensus based on study results, some seven indicators have been defined as "mandatory" while the remaining six have been defined as "recommended" because they require further refinement before they can be proposed for monitoring aesthetic outcomes or because there are doubts on the feasibility of data collection. The minimum standard is reached for 5 of 13 indicators. This finding and the wide range between centers reveal that there is ample room for improvement. CONCLUSIONS: From the present study useful measurable aesthetic parameters have emerged, leading to the definition of target objectives that breast centers can use for benchmarking and improvement of quality of care.

Hydroxyl radicals and oxidative stress: the dark side of Fe corrosion.

Fe-based materials are considered for the manufacture of temporary implants that degrade through the corrosion of Fe by oxygen. Here we document the generation of hydroxyl radicals (HO) during this corrosion process, and their deleterious impacts on human endothelial (ECs) and smooth muscle cells (SMCs) in vitro. The generation of HO was documented by two independent acellular assays, terephtalic acid hydroxylation (fluorescence) and spin trapping technique coupled with electron paramagnetic resonance spectroscopy. All Fe-based materials tested exhibited a strong potential to generate HO. The addition of catalase prevented the formation of HO. Cellular responses were assessed in two ECs and SMCs lines using different cytotoxicity assays (WST-1 and CellTiter-Glo). Cells were exposed directly to Fe powder in the presence/absence of catalase, or to extracts obtained from the corrosion of Fe. Cell viability was dose-dependently affected by the direct contact with Fe materials, but not in the presence of catalase or after indirect exposure to cell extracts. The deleterious effect of HO on ECs and SMCs was confirmed by the dose-dependent increase of the transcripts of the oxidative stress gene heme oxygenase-1 4 h or 6 h after direct exposure to the particles, but not in presence of catalase or after indirect exposure. The demonstration of HO production during corrosion and consequent oxidative stress on human ECs and SMCs newly reveals a deleterious consequence of Fe-corrosion that should be integrated in the assessment of the biocompatibility of Fe-based alloys.

Time trends (2006-2015) of quality indicators in EUSOMA-certified breast centres.

AIM OF THE STUDY: The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast centres to establish minimum standards and ensure specialist multidisciplinary care. Prospectively collected anonymous information on primary breast cancer cases diagnosed and treated in the units is transferred annually to a central EUSOMA data warehouse for continuous monitoring of quality indicators (QIs) to improve quality of care. Units have to comply with the EUSOMA Breast Centre guidelines and are audited by peers. The database was started in 2006 and includes over 110,000 cancers from breast centres located in Germany, Switzerland, Belgium, Austria, The Netherlands, Spain, Portugal and Italy. The aim of the present study is assessing time trends of QIs in EUSOMA-certified breast centres over the decade 2006-2015. MATERIALS AND METHODS: Previously defined QIs were calculated for 22 EUSOMA-certified breast centres (46122 patients) during 2006-2015. RESULTS: On the average of all units, the minimum standard of care was achieved in 8 of 13 main EUSOMA QIs in 2006 and in all in 2015. All QIs, except removal of at least 10 lymph nodes at axillary clearance and oestrogen receptor-negative tumours (T > 1 cm or N+) receiving adjuvant chemotherapy, improved significantly in this period. The desirable target was reached for two QIs in 2006 and for 7 of 13 QIs in 2015. CONCLUSION: The EUSOMA model of audit and monitoring QIs functions well in different European health systems and results in better performance of QIs over the last decade. QIs should be evaluated and adapted on a regular basis, as guidelines change over time.

The effect of EUSOMA certification on quality of breast cancer care.

AIM OF THE STUDY: The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast units to establish minimum standards and ensure specialist multidisciplinary care. In the present study we assess the impact of EUSOMA certification for all breast units for which sufficient information was available before and after certification. MATERIALS AND METHODS: For 22 EUSOMA certified breast units data of 30,444 patients could be extracted from the EUSOMA database on the evolution of QI's before and after certification. RESULTS: On the average of all units, the minimum standard of care was achieved for 12/13 QI's before and after EUSOMA certification (not met for DCIS receiving just one operation). There was a significant improvement of 5 QI's after certification. The proportion of patients with invasive cancer undergoing an axillary clearance containing >9 lymph nodes (91.5% vs 89.4%, p 0.003) and patients with invasive cancer having just 1 operation (83.1% vs 80.4%, p < 0.001) dropped, but remained above the minimum standard. The targeted standard of breast care was reached for the same 4/13 QI's before and after EUSOMA certification. CONCLUSION: Although the absolute effect of EUSOMA certification was modest it further increases standards of care and should be regarded as part of a process aiming for excellence. Dedicated units already provide a high level of care before certification, but continuous monitoring and audit remains of paramount importance as complete adherence to guidelines is difficult to achieve.

Randomized clinical trial comparing survival after D1 or D2 gastrectomy for gastric cancer.

BACKGROUND: It is still unclear whether D2 lymphadenectomy improves the survival of patients with gastric cancer and should therefore be performed routinely or selectively. The aim of this multicentre randomized trial was to compare D2 and D1 lymphadenectomy in the treatment of gastric cancer. METHODS: Between June 1998 and December 2006, patients with gastric adenocarcinoma were assigned randomly to either D1 or D2 gastrectomy. Intraoperative randomization was implemented centrally by telephone. Primary outcome was overall survival; secondary endpoints were disease-specific survival, morbidity and postoperative mortality. RESULTS: A total of 267 eligible patients were allocated to either D1 (133 patients) or D2 (134) resection. Morbidity (12.0 versus 17.9 per cent respectively; P = 0.183) and operative mortality (3.0 versus 2.2 per cent; P = 0.725) rates did not differ significantly between the groups. Median follow-up was 8.8 (range 4.5-13.1) years for surviving patients and 2.4 (0.2-11.9) years for those who died, and was not different in the two treatment arms. There was no difference in the overall 5-year survival rate (66.5 versus 64.2 per cent for D1 and D2 lymphadenectomy respectively; P = 0.695). Subgroup analyses showed a 5-year disease-specific survival benefit for patients with pathological tumour (pT) 1 disease in the D1 group (98 per cent versus 83 per cent for the D2 group; P = 0.015), and for patients with pT2-4 status and positive lymph nodes in the D2 group (59 per cent versus 38 per cent for the D1 group; P = 0.055). CONCLUSION: No difference was found in overall 5-year survival between D1 and D2 resection. Subgroup analyses suggest that D2 lymphadenectomy may be a better choice in patients with advanced disease and lymph node metastases. REGISTRATION NUMBER: ISRCTN11154654 (http://www.controlled-trials.com).

Physicochemical and toxicological profiling of ash from the 2010 and 2011 eruptions of Eyjafjallajökull and Grímsvötn volcanoes, Iceland using a rapid respiratory hazard assessment protocol.

The six week eruption of Eyjafjallajökull volcano in 2010 produced heavy ash fall in a sparsely populated area of southern and south eastern Iceland and disrupted European commercial flights for at least 6 days. We adopted a protocol for the rapid analysis of volcanic ash particles, for the purpose of informing respiratory health risk assessments. Ash collected from deposits underwent a multi-laboratory physicochemical and toxicological investigation of their mineralogical parameters associated with bio-reactivity, and selected in vitro toxicology assays related to pulmonary inflammatory responses. Ash from the eruption of Grímsvötn, Iceland, in 2011 was also studied. The results were benchmarked against ash from Soufrière Hills volcano, Montserrat, which has been extensively studied since the onset of eruptive activity in 1995. For Eyjafjallajökull, the grain size distributions were variable: 2-13 vol% of the bulk samples were <4 µm, with the most explosive phases of the eruption generating abundant respirable particulate matter. In contrast, the Grímsvötn ash was almost uniformly coarse (<3.5 vol%<4 µm material). Surface area ranged from 0.3 to 7.7 m2 g(-1) for Eyjafjallajökull but was very low for Grímsvötn (<0.6 m2 g(-1)). There were few fibre-like particles (which were unrelated to asbestos) and the crystalline silica content was negligible in both eruptions, whereas Soufrière Hills ash was cristobalite-rich with a known potential to cause silicosis. All samples displayed a low ability to deplete lung antioxidant defences, showed little haemolysis and low acute cytotoxicity in human alveolar type-1 like epithelial cells (TT1). However, cell-free tests showed substantial hydroxyl radical generation in the presence of hydrogen peroxide for Grímsvötn samples, as expected for basaltic, Fe-rich ash. Cellular mediators MCP-1, IL-6, and IL-8 showed chronic pro-inflammatory responses in Eyjafjallajökull, Grímsvötn and Soufrière Hills samples, despite substantial differences in the sample mineralogy and eruptive styles. The value of the pro-inflammatory profiles in differentiating the potential respiratory health hazard of volcanic ashes remains uncertain in a protocol designed to inform public health risk assessment, and further research on their role in volcanic crises is warranted.

Free radical generation in the toxicity of inhaled mineral particles: the role of iron speciation at the surface of asbestos and silica.

Free radical generation at the particle/biological fluid interface is one of the chemical processes that contributes to pathogenicity. In order to investigate the role played by iron, fibres of crocidolite asbestos have been modified by thermal treatments to alter their surface iron content. Two radical mechanisms, HO* from H2O2 and cleavage of a C-H bond, which are both active on the original fibres, have been tested on the modified fibres. C-H cleavage is dependent on Fe(II) abundance and location and is suppressed by surface oxidation while HO* release appears independent of the oxidation state of iron. Quartz specimens with different levels of iron impurities have been tested in a similar manner. A commercially available quartz (Min-U-Sil 5) containing trace levels of iron is also active in both tests, but reactivity is not fully suppressed by treatment with desferrioxamine, which should remove/inactivate iron. The radical yield attained is close to the level produced by a pure quartz dust, suggesting the presence of active sites other than iron. Ascorbic acid reacts with both crocidolite and quartz, with subsequent depletion of the level of antioxidant defences when particle deposition occurs in the lung lining layer. Following treatment with ascorbic acid the radical yield increases with quartz, but decreases with asbestos. Selective removal of iron and silicon from the surface may account for the differences in behaviour of the two particulates.

Iron inhibits the nitric oxide synthesis elicited by asbestos in murine macrophages.

Crocidolite fibers stimulated nitric oxide synthase (NOS) activity and expression in glial and alveolar murine macrophages: this effect was inhibited by iron supplementation and enhanced by iron chelation. We suggest that in these cells crocidolite stimulates NOS expression by decreasing the iron bioavailability and activating an iron-sensitive transcription factor.

Free radical activity of natural and heat treated amphibole asbestos.

The amphibole minerals amosite and crocidolite were subjected to calcination and to hydrothermal treatment in order to study the effect of these heat treatments on the ability of the minerals to trigger formation of free radicals, which is known to be a main factor causing asbestosis and other asbestos-induced diseases. Free radical activity of the natural and heat treated minerals was studied by using supercoiled DNA (pUC18 plasmid) as a target molecule, and also by means of EPR spectroscopy. It was shown that after calcination of the natural minerals at 1073 K their free radical activity was strongly decreased These results, which may have relevant consequences for asbestos technology, were correlated with concomitant alteration of the structure and surface chemistry of the minerals during calcination.

Spontaneous polymerisation on amphibole asbestos: relevance to asbestos removal.

Taking advantage of the spontaneous polymerisation of eugenol to lignin-like species catalysed by the surface of crocidolite fibres, a procedure is proposed, possibly useful in asbestos removal and disposal, where the polymer avoids the release of airborne fibres and also scavenges ROS (reactive oxygen species).

Surface Properties of Vitreous Fibers.

The surface properties of various vitreous fibers, suspected to be toxic to humans and animals, were investigated by means of paramagnetic labels covalently linked to the surface. Computer-aided analysis of the electron paramagnetic resonance (EPR) spectra provided structural and dynamic information on the label and its environment. Calorimetric measurements provided information on the hydration mechanism. The results were analyzed in terms of (a) different polarity and interaction abilities of surface regions, (b) presence of ions at the surface, (c) silica contents, (d) vicinity of the interacting sites, (e) fiber dimension and morphology of the surfaces, and (f) water hydration. The mobility of the labels decreased due to interaction of the fibers with ions or ionic and polar groups at the surface. Close interacting sites were identified on the basis of spin-spin effects and were distinguished and quantified in strongly and weakly interacting sites. The spin-labeling technique indicated decreased ability of the surface to interact with decreased silicon concentration and in the presence of contaminants at the surface. The interaction with water revealed in all cases a substantial heterogeneity in hydrophilicity of surface sites. The labels were not easily hydrated. Vitreous fibers of various compositions adsorbed much more water than crystalline or amorphous silica; water coordinated to surface cations played a major role in the overall adsorption. The surface reaction mechanisms were the same on fibers of different compositions, but the surface composition affected the extent of adsorption. Glass wool exhibited a much higher adsorption capacity than rock wool under the same experimental conditions. In conclusion, the combination of EPR and calorimetric measurements provided insight into the surface properties of silica-based fibers. Copyright 2000 Academic Press.

In vitro effects of coal fly ashes: hydroxyl radical generation, iron release, and DNA damage and toxicity in rat lung epithelial cells.

Oxygen radical generation due to surface radicals, inflammation, and iron release has been suggested as the mechanism of adverse effects of quartz, such as emphysema, fibrosis, and carcinogenic effects. Therefore, we measured iron release, acellular generation of hydroxyl radicals, and oxidative DNA damage and cytotoxicity in rat lung epithelial (RLE) cells by different coal fly ashes (CFA) that contain both quartz and iron. Seven samples of CFA with different particle size and quartz content (up to 14.1%) were tested along with silica (alpha-quartz), ground coal, and coal mine dust (respirable) as positive control particles, and fine TiO(2) (anatase) as a negative control. Five test samples were pulverized fuel ashes (PFA), two samples were coal gasification (SCG) ashes (quartz content <0.1%), and one sample was a ground coal. No marked differences between SCG and PFA fly ashes were observed, and toxicity did not correlate with physicochemical characteristics or effect parameters. Stable surface radicals were only detected in the reference particles silica and coal mine dust, but not in CFA. On the other hand, hydroxyl radical generation by all fly ashes was observed in the presence of hydrogen peroxide, which was positively correlated with iron mobilization and inhibited by deferoxamine, but not correlated with iron or quartz content. Also a relationship between acellular hydroxyl radical generation and oxidative DNA damage in RLE cells by CFA was observed. Differences in hydroxyl radical generation and oxidative damage by the CFA were not related to iron and quartz content, but the respirable ashes (MAT023, 38, and 41) showed a very extensive level of hydroxyl radical generation in comparison to nonrespirable fly ashes and respirable references. This radical generation was clearly related to the iron mobilization from these particles. In conclusion, the mechanisms by which CFA and the positive references (silica, coal mine dust) affect rat lung epithelial cells seem to be different, and the data suggest that quartz in CFA does not act the same as quartz in silica or coal mine dust. On the other hand, the results indicate an important role for size and iron release in generation and subsequent effects of reactive oxygen species caused by CFA.

[Heart catheterization via the femoral artery with a 4 French and mobilization at 2 hours]. / Cateterismo cardiaco per via arteriosa femorale con 4 French e mobilizzazione a 2 ore.

The use of small catheters for cardiac catheterization, as well as for other diagnostic and interventional procedures, can reduce iatrogenic trauma on cardiac and vascular structures. Early patient mobilization may thus reduce both patient discomfort and the length and cost of stays. The performance of 4 French catheters was evaluated in a pilot cohort of consecutive in patients who underwent coronary arteriography with the use of the femoral Judkins technique and who had no restriction to full ambulation. Patients were helped to resume full ambulation two hours after the procedure, and the femoral access site was inspected 24 hours later upon discharge. Coronary arteriography with 4 French catheters was performed in 45 patients (10 women) aged 62 +/- 10 years. In one patient with anomalous origin of the right coronary artery, selective catheterization of the coronary ostium required a catheter style available only in 5 French. In all cases, selective opacification with 4 French catheters was adequate for diagnosis. Forty-three patients were mobilized 115 +/- 10 minutes after the end of manual compression. Hematoma, bleeding or limb perfusion disturbances were absent in all cases upon inspection 22 +/- 4 hours later. This pilot experience indicates that coronary arteriography with femoral 4 French Judkins catheters is technically feasible and that patient ambulation 2 hours later is safe. This data requires confirmation in a larger patient cohort and can lead to new standards for both patient comfort and the use of hospital resources in coronary arteriography.

Ambulation three hours after elective cardiac catheterisation through the femoral artery.

OBJECTIVE: To test whether very early resumption of ambulation after femoral cardiac catheterisation is feasible and safe in patients with stable symptoms. DESIGN: Prospective study in a selected group of men and women undergoing elective cardiac catheterisation, with next day physical inspection. SETTING: Inpatient study. SUBJECTS: Two hundred consecutive ambulant patients submitted to diagnostic cardiac catheterisation through the femoral arterial route using 5F catheters: a femoral right heart study was done at the same time in 40 patients (20%). RESULTS: No patient had major complications during the study. Early ambulation was not allowed in two patients (1%) because of haematoma formation immediately after sheath removal, and in seven (3%) because of poor haemostasis or haematoma on inspection at 3 h. Early ambulation was interrupted in two patients (1%) because of transient arterial hypotension on standing in one, and the patient's preference in the other. Of 189 patients who resumed full ambulation at 3 h, one (0.5%) had a groin haematoma on discharge the next morning. Overall, haematoma 12 h after cardiac catheterisation was present in seven of the 200 patients initially included in the study (3.5%). None of the 191 patients with attempted early mobilisation had signs or symptoms of vascular complications one month or later after discharge. CONCLUSION: Supervised resumption of ambulation 3 h after uncomplicated cardiac studies with 5F femoral arterial catheters is safe and feasible in most ambulant patients undergoing elective cardiac catheterisation.

[Quality assurance and cost control in invasive and interventional cardiology]. / Quality assurance e controllo dei costi in cardiologia invasiva ed interventistica.

We report our experience of Quality Assurance in a Cardiac Catheterization Laboratory of the National Health Service. An attempt was made to apply these criteria to the medical activities as well as to the management and economic aspects of our work. Limits and perspectives of this experience are discussed as a contribution to ongoing debate among cardiologists and public health Authorities.

[Elective coronary angioplasty in total absence of heart surgery]. / Angioplastica coronarica elettiva in totale assenza di cardiochirurgia.

BACKGROUND: One-hundred consecutive procedures of elective coronary angioplasty were attempted in 95 patients, in the absence of any surgical stand-by. All patients had angina and/or signs of inducible ischemia. METHODS: All patients and attending physicians were informed that no surgical coverage was available, and gave their consent. The choice was made on the basis of the estimate, on clinical and angiographic grounds, of the consequences of vessel occlusion, of the possible help offered by percutaneous bail-out techniques, and of the applicability of surgical stand-by. RESULTS: A primary success was achieved in 92 cases: in 5 cases a Palmaz-Schatz stent was implanted. In 6 cases the procedure was unsuccessful, with no complications. Two patients sustained a myocardial infarction without new Q-waves. No patient died, nor underwent cardiac surgery within 1 month of discharge. CONCLUSIONS: Our initial experience suggests that, in the absence of surgical stand-by, elective coronary angioplasty can be performed in selected patients at an acceptable risk.

[Diagnostic hemodynamics in day-hospital care]. / Emodinamica diagnostica in regime di day-hospital.

Our initial experience with 180 consecutive cases of transfemoral cardiac catheterization in ambulatory patients is presented. It accounts for 21% of 864 diagnostic cardiac catheterization procedures in our laboratory in the first 12 months of activity. There were no complications. Patient satisfaction was high, and a substantial reduction of unnecessary overnight admissions in the cardiology ward could be achieved. This confirms the safety and the advantages of this practice. Implications for the organization of the Catheterization Laboratory are also discussed, as well as possible causes for the sofar limited use of ambulatory cardiac catheterization in our country.