The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression.

PURPOSE: A significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis. PATIENTS AND METHODS: We studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA. RESULTS: Whole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3+) helper T-cell population, with the proportion of LAG-3+ cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation. CONCLUSION: Numerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient's constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility. TRIAL REGISTRATION: ClinicalTrials.gov NCT01816607; registration date: 22 March 2013.

Security and reliability of CUSTOMBONE cranioplasties: A prospective multicentric study.

BACKGROUND: Repairing bone defects generated by craniectomy is a major therapeutic challenge in terms of bone consolidation as well as functional and cognitive recovery. Furthermore, these surgical procedures are often grafted with complications such as infections, breaches, displacements and rejections leading to failure and thus explantation of the prosthesis. OBJECTIVE: To evaluate cumulative explantation and infection rates following the implantation of a tailored cranioplasty CUSTOMBONE prosthesis made of porous hydroxyapatite. One hundred and ten consecutive patients requiring cranial reconstruction for a bone defect were prospectively included in a multicenter study constituted of 21 centres between December 2012 and July 2014. Follow-up lasted 2 years. RESULTS: Mean age of patients included in the study was 42±15 years old (y.o), composed mainly by men (57.27%). Explantations of the CUSTOMBONE prosthesis were performed in 13/110 (11.8%) patients, significantly due to infections: 9/13 (69.2%) (p<0.0001), with 2 (15.4%) implant fracture, 1 (7.7%) skin defect and 1 (7.7%) following the mobilization of the implant. Cumulative explantation rates were successively 4.6% (SD 2.0), 7.4% (SD 2.5), 9.4% (SD 2.8) and 11.8% (SD 2.9%) at 2, 6, 12 and 24 months. Infections were identified in 16/110 (14.5%): 8/16 (50%) superficial and 8/16 (50%) deep. None of the following elements, whether demographic characteristics, indications, size, location of the implant, redo surgery, co-morbidities or medical history, were statistically identified as risk factors for prosthesis explantation or infection. CONCLUSION: Our study provides relevant clinical evidence on the performance and safety of CUSTOMBONE prosthesis in cranial procedures. Complications that are difficulty incompressible mainly occur during the first 6 months, but can appear at a later stage (>1 year). Thus assiduous, regular and long-term surveillances are necessary.

Tyrosine hydroxylase and ß2-adrenergic receptor expression in leukocytes of spontaneously hypertensive rats: putative peripheral markers of central sympathetic activity

The sympathetic nervous system (SNS) plays a fundamental role in the pathophysiology of cardiovascular diseases, including primary arterial hypertension. In this study, we aimed to investigate whether the expression of the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and the β2-adrenergic receptor (β2-AR) in immune cells from peripheral blood, reflect central SNS activity in spontaneously hypertensive rats (SHR). TH expression in the lower brainstem and adrenal glands and β2-AR expression in the lower brainstem were analyzed by western blot analyses. In the leukocytes, TH and β2-AR expression was evaluated by flow cytometry before and after chronic treatment with the centrally-acting sympathoinhibitory drug clonidine. Western blot analyses showed increased TH and β2-AR expression in the lower brainstem and increased TH in adrenal glands from SHR compared to normotensive Wistar Kyoto rats (WKY). Lower brainstem from SHR treated with clonidine presented reduced TH and β2-AR levels, and adrenal glands had decreased TH expression compared to SHR treated with vehicle. Flow cytometry showed that the percentage of leukocytes that express β2-AR is higher in SHR than in WKY. However, the percentage of leukocytes that expressed TH was higher in WKY than in SHR. Moreover, chronic treatment with clonidine normalized the levels of TH and β2-AR in leukocytes from SHR to similar levels of those of WKY. Our study demonstrated that the percentage of leukocytes expressing TH and β2-AR was altered in arterial hypertension and can be modulated by central sympathetic inhibition with clonidine treatment.

[Using cancer case identification algorithms in medico-administrative databases: Literature review and first results from the REDSIAM Tumors group based on breast, colon, and lung cancer]. / Recherche d'algorithmes d'identification des cancers dans les bases médico-administratives : premiers résultats des travaux du groupe REDSIAM Tumeurs sur les cancers du sein, du côlon-rectum et du poumon.

BACKGROUND: The development and use of healthcare databases accentuates the need for dedicated tools, including validated selection algorithms of cancer diseased patients. As part of the development of the French National Health Insurance System data network REDSIAM, the tumor taskforce established an inventory of national and internal published algorithms in the field of cancer. This work aims to facilitate the choice of a best-suited algorithm. METHOD: A non-systematic literature search was conducted for various cancers. Results are presented for lung, breast, colon, and rectum. Medline, Scopus, the French Database in Public Health, Google Scholar, and the summaries of the main French journals in oncology and public health were searched for publications until August 2016. An extraction grid adapted to oncology was constructed and used for the extraction process. RESULTS: A total of 18 publications were selected for lung cancer, 18 for breast cancer, and 12 for colorectal cancer. Validation studies of algorithms are scarce. When information is available, the performance and choice of an algorithm are dependent on the context, purpose, and location of the planned study. Accounting for cancer disease specificity, the proposed extraction chart is more detailed than the generic chart developed for other REDSIAM taskforces, but remains easily usable in practice. CONCLUSIONS: This study illustrates the complexity of cancer detection through sole reliance on healthcare databases and the lack of validated algorithms specifically designed for this purpose. Studies that standardize and facilitate validation of these algorithms should be developed and promoted.

Respiratory hypersensitivity reactions to NSAIDs in Europe: the global allergy and asthma network (GA2 LEN) survey.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prevalent drugs inducing hypersensitivity reactions. The aim of this analysis was to estimate the prevalence of NSAID-induced respiratory symptoms in population across Europe and to assess its association with upper and lower respiratory tract disorders. METHODS: The GA2 LEN survey was conducted in 22 centers in 15 European countries. Each of 19 centers selected random samples of 5000 adults aged 15-74 from their general population, and in three centers (Athens, Munich, Oslo), a younger population was sampled. Questionnaires including questions about age, gender, presence of symptoms of asthma, allergic rhinitis, chronic rhinosinusitis, smoking status, and history of NSAID-induced hypersensitivity reactions were sent to participants by mail. Totally, 62 737 participants completed the questionnaires. RESULTS: The mean prevalence of NSAID-induced dyspnea was 1.9% and was highest in the three Polish centers [Katowice (4.9%), Krakow (4.8%), and Lodz (4.4%)] and lowest in Skopje, (0.9%), Amsterdam (1.1%), and Umea (1.2%). In multivariate analysis, the prevalence of respiratory reactions to NSAIDs was higher in participants with chronic rhinosinusitis symptoms (Odds Ratio 2.12; 95%CI 1.78-2.74), asthma symptoms in last 12 months (2.7; 2.18-3.35), hospitalization due to asthma (1.53; 1.22-1.99), and adults vs children (1.53; 1.24-1.89), but was not associated with allergic rhinitis. CONCLUSION: Our study documented significant variation between European countries in the prevalence of NSAID-induced respiratory hypersensitivity reactions, and association with chronic airway diseases, but also with environmental factors.

Integrated care pathways for airway diseases (AIRWAYS-ICPs).

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

Stroke volume optimization after anaesthetic induction: An open randomized controlled trial comparing 0.9% NaCl versus 6% hydroxyethyl starch 130/0.4.

OBJECTIVE: Postinduction hypotension during general anaesthesia could be corrected by a rapid cardiac preload optimization by fluid infusion. The type of fluid to be used in this context remains debated. The aim of our study was to compare the amount of fluid challenges required to optimize stroke volume after induction of anaesthesia with colloid (HES) or crystalloid (0.9% NaCl). DESIGN: Open randomized prospective parallel-group study. PATIENTS AND METHODS: Fifty-six adult patients scheduled to undergo orthopaedic surgery under general anaesthesia were randomly assigned to receive, either 0.9% NaCl (n=28), or HES (n=28). Cardiac preload optimization directed by oesophageal Doppler was performed after induction with fluid challenges of 250ml of solution until stroke volume (SV) no longer increased by 10%. Primary endpoint was: number of fluid challenges required to achieve SV optimization. Secondary endpoints were: number of patients responding to the first fluid challenge, proportion of patients requiring ephedrine and the ephedrine dose required to restore arterial pressure. RESULTS: Percentages of responders were 61% and 63% in the 0.9% NaCl and HES groups, respectively. Number of fluid challenges necessary for SV optimization was not significantly different between 0.9% NaCl group and HES group (2 [1-2] versus 2 [1-2], P=0.33). Number of patients needing ephedrine, and well as the associated ephedrine dose, did not differ significantly. CONCLUSIONS: Our study suggests that after induction, crystalloid and colloid expand the intravascular volume with equivalent efficacy immediately after administration and correct in a similar way the postinduction hypotension.

Asthma in adults and its association with chronic rhinosinusitis: the GA2LEN survey in Europe.

BACKGROUND: The prevalence of asthma and its association with chronic rhinosinusitis (CRS) have not been widely studied in population-based epidemiological surveys. METHODS: The Global Allergy and Asthma Network of Excellence (GA(2) LEN) conducted a postal questionnaire in representative samples of adults living in Europe to assess the presence of asthma and CRS defined by the European Position Paper on Rhinosinusitis and Nasal Polyps. The prevalence of self-reported current asthma by age group was determined. The association of asthma with CRS in each participating centre was assessed using logistic regression analyses, controlling for age, sex and smoking, and the effect estimates were combined using standard methods of meta-analysis. RESULTS: Over 52,000 adults aged 18-75 years and living in 19 centres in 12 countries took part. In most centres, and overall, the reported prevalence of asthma was lower in older adults (adjusted OR for 65-74 years compared with 15-24 years: 0.72; 95% CI: 0.63-0.81). In all centres, there was a strong association of asthma with CRS (adjusted OR: 3.47; 95% CI: 3.20-3.76) at all ages. The association with asthma was stronger in those reporting both CRS and allergic rhinitis (adjusted OR: 11.85; 95% CI: 10.57-13.17). CRS in the absence of nasal allergies was positively associated with late-onset asthma. CONCLUSION: Geographical variation in the prevalence of self-reported asthma was observed across Europe, but overall, self-reported asthma was more common in young adults, women and smokers. In all age groups, men and women, and irrespective of smoking behaviour, asthma was also associated with CRS.

Chronic rhinosinusitis in Europe--an underestimated disease. A GA²LEN study.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common health problem, with significant medical costs and impact on general health. Even so, prevalence figures for Europe are unavailable. In this study, conducted by the GA²LEN network of excellence, the European Position Paper on Rhinosinusitis and nasal Polyps (EP³OS) diagnostic criteria are applied to estimate variation in the prevalence of Chronic rhinosinusitis (CRS) for Europe. METHOD: A postal questionnaire was sent to a random sample of adults aged 15-75 years in 19 centres in Europe. Participants reported symptoms of CRS, and doctor diagnosed CRS, allergic rhinitis, age, gender and smoking history. Definition of CRS was based on the EP³OS diagnostic criteria: the presence of more than two of the symptoms: (i) nasal blockage, (ii) nasal discharge, (iii) facial pain/pressure or (iv) reduction in sense of smell, for >12 weeks in the past year--with at least one symptom being nasal blockage or discharge. RESULTS: Information was obtained from 57,128 responders living in 19 centres in 12 countries. The overall prevalence of CRS by EP³OS criteria was 10.9% (range 6.9-27.1). CRS was more common in smokers than in nonsmokers (OR 1.7: 95% CI 1.6-1.9). The prevalence of self-reported physician-diagnosed CRS within centres was highly correlated with the prevalence of EP³OS-diagnosed CRS. CONCLUSION: This is the first European international multicentre prevalence study of CRS. In this multicentre survey of adults in Europe, about one in ten participants had CRS with marked geographical variation. Smoking was associated with having CRS in all parts of Europe.

The 2009-2010 H1N1 vaccination campaign for patients with egg allergy in a region of France.

We describe our experience of the influenza H1N1 vaccination in patients with egg allergy. All patients tolerated the vaccination in a simple or double dose protocol without any significant allergic reaction in this series.

Acute grade III and IV acromioclavicular dislocations: outcomes and pitfalls of reconstruction procedures using a synthetic ligament.

INTRODUCTION: Acromioclavicular dislocation (ACD) is frequent, at 8% of all shoulder traumas. Management in grade III lesions remains controversial. The present study assessed objective and subjective results at medium-term follow-up (mean, 60 months; range, 12-120 mo) in 27 patients managed by Ligastic(®) ligament reconstruction for acute dislocation. PATIENTS AND METHODS: This is a multicenter, multi-surgeon retrospective study. Between 1998 and 2006, 59 patients were operated on for grade III or IV ACD, in one teaching hospital (Lille, France) and one general hospital (Tourcoing, France). Follow-up was performed by an independent (non-operator) observer. The 27 acute cases followed up underwent comparative bilateral radioclinical shoulder examination. Initial X-ray assessment found 14 grade-III (52%) and 13 grade-IV (48%) dislocations using Patte's classification. RESULTS: Mean Constant score was significantly lower on the operated side (82.44 vs 90.04; p<0.05). Specific strength analysis, on the other hand, showed no significant difference with the contralateral shoulder. Coracoclavicular distance was significantly greater on the operated side (p<0.05), with and without traction. Periprosthetic osteolysis was found in 24% of cases, and seemed to worsen over follow-up. There were no cases of fracture on osteolysis. There were no cases of sepsis or of implant intolerance. Four patients, however, required surgical revision. CONCLUSION: In light of literature findings and our own experience, surgery is not to be recommended in grade-III ACD, and the authors have given up use of this device in this group due to the rate of associated osteolysis. LEVEL OF EVIDENCE: Level IV.

[Dosimetric stereotactic radiosurgical accident: Study of 33 patients treated for brain metastases]. / Traitement des métastases cérébrales par radiochirurgie stéréotaxique : étude de 33 cas liés à un accident de "surexposition".

The consequences of a dosimetric radiosurgery accident are not the same as a conventional radiotherapy accident. The objective of this study was to estimate the clinical and radiological outcome of patients treated by radiosurgery for metastasis during the period of the overexposure accident that occurred in the Toulouse Radiosurgery Unit. Between April 2006 and March 2007, 33 patients with 57 metastases were treated in the Toulouse Radiosurgery Unit (Novalis(®), BrainLab). An initial error in the estimation of the scatter factors led to an overexposure to radiation. The median age was 55 years [range, 35-85]. Twenty-one patients (64%) harbored a single metastasis. The primary tumor location was lung (16 cases), kidney (nine cases), breast (four cases), and others (four cases). The mean tumoral volume was 3.2cm(3) [0.04-14.07]. The mean prescribed dose at the isocenter was 20 Gy [range, 10-23], the mean delivered dose was 31.5 Gy [range, 13-52], and the mean overdose was 61.2% [range, 5.6-226.8]. In order to evaluate the consequences of the overdose, three parameters were analyzed: a risk index using dose and volume, the volume of parenchyma that received more than 12 Gy, and the mean dose in a sphere of 20cm(3) surrounding the target volume. Median actuarial survival was 14.1 months, the survival rate was 79.4 % at six months, 59.1% at 12 months, and 27.2% at 24 months. The rate of tumor control was 80.7%. No morbidity was observed. There was no correlation between death and the parameters studied. The survival rates and times observed in our study of the patients treated for brain metastases by radiosurgery and overexposed were among the good results of the international literature. Deaths were not related to the overdose and no side effect was noted. This dosimetric accident has not had worse consequences in this population.

Swanson-type silastic arthroplasties of the PIP joint for rheumatoid arthritis. Results of 19 implants at 5.3 years of follow-up.

This retrospective study reports the results from 19 PIP Silastic spacers in 11 female patients suffering from inflammatory diseases at a mean of 2.2 and 5.3 years after surgery. The improvement in range of movement decreased with time, evolving from a gain of 18̊ at 2.2 years to only a 4-gain at subsequent follow-up. The fracture rate was high (30%). Objective analysis by physicians reported poor or mild improvements in 75% of cases. Subjective analysis (assessing aesthetics, function and pain) by patients, showed an average score of 5.6/10. At final follow-up, eight out of nine patients did not regret having had surgery. As patients actually hope for pain relief and improved function and quality of life, rather than anatomical recovery, this explains the high acceptability and interest in this rudimentary surgical procedure.

Transtomography for implant placement guidance in non-invasive surgical procedures.

OBJECTIVES: To illustrate the use of transtomography for the placement of implants using a radiopaque radiographic guide and to evaluate the accuracy of transtomography. METHODS: The study included 11 implants inserted with minimally invasive procedures. Pre-operative, intraoperative and post-operative examinations were performed with a ProMax panoramic unit implemented with transtomographic technique (Planmeca Oy, Helsinki, Finland). At each implant site, cross-sectional and longitudinal intraoperative transtomograms were taken through a radiopaque reference guide to control and adjust the drilling axis. The effective axis on post-operative transtomograms was compared with the planned axis correction estimated on intraoperative images. Radiopaque guides, used as the gold standard, were measured on intraoperative cross-sectional slices to evaluate image distortion. RESULTS: Intraoperative transtomograms, with the reference guide inserted in the bone, gave clear images of the cortical plates and accurate information of drilling length and axis, which allowed the surgeon to adjust pilot drilling axis in 6 sites (54.5%) out of 11 sites, including sites with narrow bone ridges. The implant axis on the post-operative tomogram compared with the planned axis correction showed an angle difference ranging from 0.8 degrees to 3.4 degrees. The image distortion on cross-sectional slices ranged from 0.03 mm to 0.52 mm, resulting in a distortion ratio ranging from 0% to 6% when expressed in percentages. CONCLUSIONS: Transtomographic examination performed with a radiographic reference guide during implant surgery can provide the necessary and accurate information for implant placement. Transtomography distortion appears to be less important than in other conventional tomographic systems and comparable with CT scan distortion.

Effects of centrally acting antihypertensive drugs on the microcirculation of spontaneously hypertensive rats

We investigated the acute effects of centrally acting antihypertensive drugs on the microcirculation of pentobarbital-anesthetized spontaneously hypertensive rats (SHR). The effects of the sympatho-inhibitory agents clonidine and rilmenidine, known to activate both alpha2-adrenoceptors and nonadrenergic I1-imidazoline binding sites (I1BS) in the central nervous system, were compared to those of dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H -pyrrol-2-yl)-amine hydrochloride (LNP 509), which selectively binds to the I1BS. Terminal mesenteric arterioles were observed by intravital microscopy. Activation of the central sympathetic system with L-glutamate (125 µg, ic) induced marked vasoconstriction of the mesenteric microcirculation (27 ± 3 percent; N = 6, P < 0.05). In contrast, the marked hypotensive and bradycardic effects elicited by intracisternal injection of clonidine (1 µg), rilmenidine (7 µg) and LNP 509 (60 µg) were accompanied by significant increases in arteriolar diameter (12 ± 1, 25 ± 10 and 21 ± 4 percent, respectively; N = 6, P < 0.05). The vasodilating effects of rilmenidine and LNP 509 were two-fold higher than those of clonidine, although they induced an identical hypotensive effect. Central sympathetic inhibition elicited by baclofen (1 µg, ic), a GABA B receptor agonist, also resulted in vasodilation of the SHR microvessels. The acute administration of clonidine, rilmenidine and LNP 509 also induced a significant decrease of cardiac output, whereas a decrease in systemic vascular resistance was observed only after rilmenidine and LNP 509. We conclude that the normalization of blood pressure in SHR induced by centrally acting antihypertensive agents is paralleled by important vasodilation of the mesenteric microcirculation. This effect is more pronounced with substances acting preferentially (rilmenidine) or exclusively (LNP 509) upon I1BS than with those presenting important alpha2-adrenergic activity (clonidine).