Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy.

BACKGROUND: Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer. We report results of the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer. METHODS: Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3-T4) or hypopharynx (T2-T4), with regional lymph nodes in the neck staged as N0-N2 and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arm. In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles (60 Gy total). All nonresponders underwent salvage surgery and postoperative radiotherapy. The Kaplan-Meier method was used to obtain time-to-event data. RESULTS: The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68 to 1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm. CONCLUSIONS: Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.

BACKGROUND: Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. METHODS: The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. FINDINGS: The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006). Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). INTERPRETATION: Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery. FUNDING: Medical Research Council, the Stroke Association, Sanofi-Synthélabo, European Union.

La prothèse de St Jude medical chez les patients âges de plus de 65 ans [St Jude's Medical prosthesis in patients over 65].

Between September 1979 and December 1982, 56 St Jude Medical valvular prostheses were implanted in 54 patients over 65 years of age. Surgery consisted in simple aortic valve replacement (35 cases), simple mitral valve replacement (12 cases), double aortic and mitral valve replacement (2 cases), valve replacement and coronary artery bypass surgery (3 cases), aortic valve replacement and replacement of the ascending aorta (1 case) and mitral valve replacement and tricuspid annuloplasty (1 case). The operative mortality (within 30 days of surgery) was 3.5% (2 cases). Patients were assessed by clinical examination, ECG, chest X-ray, echocardiogram and laboratory investigations on average 19 months after surgery. There were 3 late deaths (1 endocarditis, 1 cardiac failure and 1 subdural haematoma). No cases of significant haemolysis were observed. There were no cases of thrombosis of the valve or any deaths directly related to the valve. Four patients had cerebral embolism (4.9% per patient/year). None were fatal and only 1 patient had sequellae. Clinical improvement was very significant; 96% of the patients are now in the NYHA Classes I and II whilst 80% were in Class III or IV before surgery. The cardiothoracic ratio decreased significantly from 0.56 to 0.51 (p less than 0.01). The authors conclude that elderly patients may derive great benefits from valvular cardiac surgery and that age in itself is not a contraindication to this type of surgery. The St Jude Medical prosthesis is an excellent prosthesis but thromboembolism remains a major problem as with other mechanical prostheses. Anticoagulation for life is essential.

Interactions between respiration and systemic hemodynamics. Part II: practical implications in critical care.

In Part I of this review, we have covered basic concepts regarding cardiorespiratory interactions. Here, we put this theoretical framework to practical use. We describe mechanisms underlying Kussmaul's sign and pulsus paradoxus. We review the literature on the use of respiratory variations of blood pressure to evaluate volume status. We show the possibilities of attaining the latter aim by investigating with ultrasonography how the geometry of great veins fluctuates with respiration. We provide a Guytonian analysis of the effects of PEEP on cardiac output. We terminate with some remarks on the potential of positive pressure breathing to induce acute cor pulmonale, and on the cardiovascular mechanisms that at times may underly the failure to wean a patient from the ventilator.

Are adolescents with chronic conditions particularly at risk for bullying?

OBJECTIVE: To compare the prevalence and intensity of victimization from bullying, and the characteristics of the victims of bullying, comparing adolescents with and without chronic conditions. DESIGN: School survey. SETTING: Post-mandatory schools. PARTICIPANTS: A total of 7005 students (48% females) aged 16-20 years, distributed into adolescents with chronic conditions (728, 50% females) and controls (6277, 48% females). Chronic condition was defined as having a chronic disease and/or a physical disability.OUTCOME MEASURES: Prevalence of bullying; intensity of bullying; and socio-demographic, bio-psychosocial, familial, school, and violence context characteristics of the victims of bullying. RESULTS: The prevalence of bullying in our sample was 13.85%. Adolescents with chronic conditions were more likely to be victims of bullying (Adjusted Odds Ratio [AOR] 1.53), and to be victims of two or three forms of bullying (AOR 1.92). Victims of bullying with chronic conditions were more likely than non-victims to be depressed (Relative Risk Ratio [RRR] 1.57), to have more physical symptoms (RRR 1.61), to have a poorer relationship with their parents (RRR 1.33), to have a poorer school climate (RRR 1.60), and to have been victims of sexual abuse (RRR 1.79) or other forms of violence (RRR 1.80). Although these characteristics apply to victims in general, in most cases they are less pronounced among victims without chronic conditions. CONCLUSIONS: Chronic conditions seem to be a risk factor for victimization from bullying. Therefore, as adolescents with chronic conditions are increasingly mainstreamed, schools should be encouraged to undertake preventive measures to avoid victimization of such adolescents.

Roles of PPARs in health and disease.

In developed societies, chronic diseases such as diabetes, obesity, atherosclerosis and cancer are responsible for most deaths. These ailments have complex causes involving genetic, environmental and nutritional factors. There is evidence that a group of closely related nuclear receptors, called peroxisome proliferator-activated receptors (PPARs), may be involved in these diseases. This, together with the fact that PPAR activity can be modulated by drugs such as thiazolidinediones and fibrates, has instigated a huge research effort into PPARs. Here we present the latest developments in the PPAR field, with particular emphasis on the physiological function of PPARs during various nutritional states, and the possible role of PPARs in several chronic diseases.

Long-term outcome of primary endoresection of choroidal melanoma.

BACKGROUND: Endoresection of choroidal melanoma may offer the best hope of conserving vision in some patients but is controversial because of concerns regarding iatrogenic tumour dissemination. METHODS: Retrospective, non-randomised study of consecutive patients who underwent endoresection for choroidal melanoma at the Liverpool Ocular Oncology Centre between 1996 and 2010. RESULTS: The study included 71 patients with a mean age of 58.7 years. The tumour extended within 2 disc diameters of the optic disc in 46 (65%) eyes, involving the disc in 24 (34%) eyes. The mean largest basal tumour diameter and tumour thickness were 9.5 mm and 4.4 mm, respectively. The median follow-up was 4.1 years. The visual acuity at the latest follow-up was better than 6/30 in 31% eyes. The main causes of visual loss were foveal excision, rhegmatogenous retinal detachment (RD) and proliferative vitreo-retinopathy (PVR). Local recurrence developed in two patients (3%), who were treated by enucleation and proton beam radiotherapy, respectively. RD occurred in 16 cases (22%). Three (4%) eyes were enucleated, two because of PVR and one because of local tumour recurrence. Five patients died of metastatic disease. CONCLUSIONS: Endoresection achieved high rates of local tumour control. This operation would seem to be a useful alternative to radiotherapy as a means of conserving vision in eyes with juxtapapillary melanoma.

Characterization of cell-to-cell signaling-deficient Pseudomonas aeruginosa strains colonizing intubated patients.

Cell-to-cell signaling involving N-acyl-homoserine lactone compounds termed autoinducers (AIs) is instrumental to virulence factor production and biofilm development by Pseudomonas aeruginosa. In order to determine the importance of cell-to-cell signaling during the colonization of mechanically ventilated patients, we collected 442 P. aeruginosa pulmonary isolates from 13 patients. Phenotypic characterization showed that 81% of these isolates produced the AI-dependent virulence factors elastase, protease, and rhamnolipids. We identified nine genotypically distinct P. aeruginosa strains. Six of these strains produced AIs [N-butanoyl-homoserine lactone or N-(3-oxo-dodecanoyl)-homoserine lactone] and extracellular virulence factors (elastase, total exoprotease, rhamnolipid, hydrogen cyanide, or pyocyanin) in vitro. Three of the nine strains were defective in the production of both AIs and extracellular virulence factors. Two of these strains had mutational defects in both the lasR and rhlR genes, which encode the N-acyl-homoserine lactone-dependent transcriptional regulators LasR and RhlR, respectively. The third of these AI-deficient strains was only mutated in the lasR gene. Our observations suggest that most, but not all, strains colonizing intubated patients are able to produce virulence factors and that mutations affecting the cell-to-cell signaling circuit are preferentially located in the transcriptional regulator genes.

Hallux valgus: résumé pratique [Hallux valgus: practical summary].

Hallux valgus arises from static and dynamic unbalance of the forefoot. Possibilities of conservative treatment are limited. This paper recalls the essentials of physiopathology and exposes briefly to the non-operators the most current amongst 150 operative techniques described. While becoming more complex, the surgery of hallux valgus has proven to gain efficiency. Surgical indication, based on biomechanics, should be very careful, which gives a greater interest to this discipline.

Intravenous thrombolysis in patients with stroke attributable to small artery occlusion.

BACKGROUND: Intravenous thrombolysis (IVT) for stroke seems to be beneficial independent of the underlying etiology. Recent observations raised concern that IVT might cause harm in patients with strokes attributable to small artery occlusion (SAO). OBJECTIVE: The safety of IVT in SAO-patients is addressed in this study. METHODS: We used the Swiss IVT databank to compare outcome and complications of IVT-treated SAO-patients with IVT-treated patients with other etiologies (non-SAO-patients). Main outcome and complication measures were independence (modified Rankin scale <or=2) at 3 months, intracranial hemorrhage (ICH), and recurrent ischaemic stroke. RESULTS: Sixty-five (6.2%) of 1048 IVT-treated patients had SAO. Amongst SAO-patients, 1.5% (1/65) patients died, compared to 11.2% (110/983) in the non-SAO-group (P = 0.014). SAO-patients reached independence more often than non-SAO-patients (75.4% versus 58.9%; OR 2.14 (95% CI 1.20-3.81; P = 0.001). This association became insignificant after adjustment for age, gender, and stroke severity (OR 1.41 95% CI 0.713-2.788; P = 0.32). Glucose level and (to some degree) stroke severity but not age predicted 3-month-independence in IVT-treated SAO-patients. ICHs (all/symptomatic) were similar in SAO- (12.3%/4.6%) and non-SAO-patients (13.4%/5.3%; P > 0.8). Fatal ICH occurred in 3.3% of the non-SAO-patients but none amongst SAO-patients. Ischaemic stroke within 3 months after IVT reoccurred in 1.5% of SAO-patients and in 2.3% of non-SAO-patients (P = 0.68). CONCLUSION: IVT-treated SAO-patients died less often and reached independence more often than IVT-treated non-SAO-patients. However, the variable 'SAO' was a dependent rather than an independent outcome predictor. The absence of an excess in ICH indicates that IVT seems not to be harmful in SAO-patients.

n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.

BACKGROUND: The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown. METHODS: In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here. RESULTS: During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups. CONCLUSIONS: Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).

Hypernatrémie: une question d'eau [Hypernatremia: a matter of water]

Hypernatremia is defined as a serum sodium concentration above the upper laboratory reference range, usually > 145 mmol/l. It is a common electrolyte disorder in the very young and the very old patient. Hospitalization itself is a risk factor for developing hypernatremia. Free water deficit is the main cause of this condition. It induces hyperosmolality and an intracellular dehydration. Clinical manifestations are mostly neurological but non-specific. A blood sample analysis is needed to establish the diagnosis. Hypernatremia is associated with a high mortality and morbidity. Treatment consists of correcting the underlying cause and the volume deficit. A brief review of this condition is proposed.

Critical appraisal of single port access cholecystectomy.

BACKGROUND: Single port access (SPA) cholecystectomy is a new concept in laparoscopic surgery. A review of existing results was performed to evaluate critically the current state of SPA with specific reference to feasibility, safety, learning curve, indications and cost-effectiveness. METHODS: All papers identified in MEDLINE until 15 February 2010 and all other relevant papers obtained from cited references were reviewed, without any language restriction. Case reports and series of fewer than three patients were excluded. RESULTS: After selection, 24 studies including 895 patients were analysed. None was randomized. Feasibility seems to be established, with a conversion rate of 2 per cent. SPA was not standardized and there was much technical variation. The learning curve could not be determined. Median follow-up time was 3 (range 0.25-12) months. The overall published complication rate was 5.4 per cent and the biliary complication rate 0.7 per cent. The rate of umbilical complications ranged from 2 to 10 per cent. CONCLUSION: SPA cholecystectomy seems feasible, but standardization, safety and the real benefits for patients need further assessment. Uncontrolled wide adoption of this approach may be responsible for a rise in biliary complications.

Elevated inflammatory markers combined with positive pneumococcal urinary antigen are a good predictor of pneumococcal community-acquired pneumonia in children.

BACKGROUND: Our objective was to evaluate procalcitonin (PCT) and C-reactive protein (CRP) as predictors of a pneumococcal etiology in community-acquired pneumonia (CAP) in hospitalized children. METHODS: Children requiring hospitalization for CAP were prospectively enrolled. The following indices were determined: antibodies against pneumococcal surface proteins (anti-PLY, pneumococcal histidine triad D, pneumococcal histidine triad E, LytB and pneumococcal choline-binding protein A), viral serology, nasopharyngeal cultures and polymerase chain reaction for 13 respiratory viruses, blood pneumococcal polymerase chain reaction, pneumococcal urinary antigen, PCT and CRP. Presumed pneumococcal CAP (P-CAP) was defined as a positive blood culture or polymerase chain reaction for Streptococcus pneumoniae or as a pneumococcal surface protein seroresponse (≥2-fold increase). RESULTS: Seventy-five patients were included from which 37 (49%) met the criteria of P-CAP. Elevated PCT and CRP values were strongly associated with P-CAP with odds ratios of 23 (95% confidence interval: 5-117) for PCT and 19 (95% confidence interval: 5-75) for CRP in multivariate analysis. The sensitivity was 94.4% for PCT (cutoff: 1.5 ng/mL) and 91.9% for CRP (cutoff: 100 mg/L). A value≤0.5 ng/mL of PCT ruled out P-CAP in >90% of cases (negative likelihood ratio: 0.08). Conversely, a PCT value≥1.5 ng/mL associated with a positive pneumococcal urinary antigen had a diagnostic probability for P-CAP of almost 80% (positive likelihood ratio: 4.59). CONCLUSIONS: PCT and CRP are reliable predictors of P-CAP. Low cutoff values of PCT allow identification of children at low risk of P-CAP. The association of elevated PCT or CRP with a positive pneumococcal urinary antigen is a strong predictor of P-CAP.