Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen.

Background: Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+ BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings.Results: We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95% CI: 1.29-3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response.Conclusion: We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.

The potential of metastatic lymph nodes to predict positive resection margins in patients with resectable pancreatic cancer

Objective: Despite progress during recent decades, long-term outcome¦of patients with pancreatic cancer remains dismal. Since positive resection¦margins and metastatic lymph nodes are known risk factors for early tumor¦recurrence, patients at risk should be identified and could potentially benefit¦from preoperative radio-chemotherapy. This study aimed to assess whether the¦presence of lymph node metastasis could be used to predict positive resection¦margins in patients with pancreatic cancer.¦Methods: A series of 146 patients (82 male, 64 female, median age 68 years)¦underwent pancreatic head resection for various malignant diseases (pancreatic¦ductal adenocarcinoma, biliary cancer, periampullary cancer) at our institution¦from 2000 to 2011. Patients were identified from our prospective database¦that collects more than 60 single items of all patients undergoing pancreatic¦resection. Lymph node metastasis and positive resection margins were all¦confirmed by histological evaluation. Positive predictive value (PPV), negative¦predictive value (NPV), sensitivity and specificity were calculated to assess¦the predictive value of metastatic lymph nodes regarding tumor-free (R0) and¦tumor-involved (R1) resection margins.¦Results: There were 110 specimens (76%) with tumor-positive lymph nodes¦and 36 specimens with tumor-negative lymph nodes. Resection margins were¦positive in 47 specimens (32%) and negative in 99 specimens. Sensitivity of¦tumor-positive lymph nodes to detect positive resection margins was 96%, and¦the NPV was 94%. In contrast, specificity was 34% and the PPV was 41%.¦Conclusion: Patients with resectable pancreatic cancer, who have no lymph¦node metastasis, are at very low risk to have positive resection margins (2 of¦36 patients, NPV 94%). In contrast, more than one third of patients with¦metastatic lymph nodes are at increased risk for an incomplete tumor resection¦(sensitivity 96%). If lymph nodesmetastases are highly suspected at preoperative¦staging, a neoadjuvant treatment strategy should be considered to increase the¦R0 resection rate.

Coping with an HIV infection. A multicenter qualitative survey on HIV positive adolescents' perceptions of their disease, therapeutic adherence and treatment.

HIV-positive adolescents face a number of challenges in dealing with their disease and its treatment. In this qualitative study, twenty-nine HIV-positive adolescents aged 13 to 20 years (22 girls), who live in Switzerland, were asked, in a semi-structured interview (duration of 40-110 minutes), to describe their perceptions and experiences with the disease itself and with therapeutic adherence. While younger adolescents most often thought of their disease as fate, older adolescents usually knew that they had received it through vertical transmission, although the topic appeared to be particularly difficult to discuss for those living with their HIV-positive mothers. Based on their attending physician's assessment, 18 subjects were judged highly adherent, 4 fairly and 7 poorly adherent. High adherence appeared linked with adequate psychological adjustment and effective coping mechanisms, as well as with the discussion and adoption of explicit medication-taking strategies. The setting and organisation of health care teams should allow for ongoing discussions with HIV-positive adolescents that focus on their perceptions of their disease, how they cope with it and with the treatment, and how they could improve their adherence.

Continuous positive airway pressure causes lung injury in a model of sepsis.

Continuous positive airway pressure, aimed at preventing pulmonary atelectasis, has been used for decades to reduce lung injury in critically ill patients. In neonatal practice, it is increasingly used worldwide as a primary form of respiratory support due to its low cost and because it reduces the need for endotracheal intubation and conventional mechanical ventilation. We studied the anesthetized in vivo rat and determined the optimal circuit design for delivery of continuous positive airway pressure. We investigated the effects of continuous positive airway pressure following lipopolysaccharide administration in the anesthetized rat. Whereas neither continuous positive airway pressure nor lipopolysaccharide alone caused lung injury, continuous positive airway pressure applied following intravenous lipopolysaccharide resulted in increased microvascular permeability, elevated cytokine protein and mRNA production, and impaired static compliance. A dose-response relationship was demonstrated whereby higher levels of continuous positive airway pressure (up to 6 cmH(2)O) caused greater lung injury. Lung injury was attenuated by pretreatment with dexamethasone. These data demonstrate that despite optimal circuit design, continuous positive airway pressure causes significant lung injury (proportional to the airway pressure) in the setting of circulating lipopolysaccharide. Although we would currently avoid direct extrapolation of these findings to clinical practice, we believe that in the context of increasing clinical use, these data are grounds for concern and warrant further investigation.

Differentiation of blue ballpoint pen inks by positive and negative mode LDI-MS

Usually, the differentiation of inks on questioned documents is carried out by optical methods and thin layer chromatography (TLC). Therefore, spectrometric methods were also proposed in forensic literature for the analysis of dyes. Between these techniques, laser desorption/ionization mass spectrometry (LDI-MS) has demonstrated a great versatility thanks to its sensitivity to blue ballpoint ink dyes and minimal sample destruction. Previous researches concentrated mostly on the LDI-MS positive mode and have shown that this analytical tool offers higher discrimination power than high performance TLC (HPTLC) for the differentiation of blue ballpoint inks. Although LDI-MS negative mode has already been applied in numerous forensic domains like the studies of works of art, automotive paints or rollerball pens, its potential for the discrimination of ballpoint pens was never studied before. The aim of the present paper is therefore to evaluate its potential for the discrimination of blue ballpoint inks. After optimization of the method, ink entries from 33 blue ballpoint pens were analyzed directly on paper in both positive and negative modes by LDI-MS. Several cationic and anionic ink components were identified in inks; therefore, pens were classified and compared according to their formulations. Results show that additional information provided by anionic dyes and pigments significantly increases the discrimination power of positive mode. In fact, it was demonstrated that classifications obtained by the two modes were, to some extent, complementary (i.e., inks with specific cationic dyes not necessarily contained the same anionic components).

Interobserver agreement and validity of bedside 'positive signs' for functional weakness, sensory and gait disorders in conversion disorder: a pilot study.

BACKGROUND: Conversion disorder (CD) is no longer a diagnosis of exclusion. The new DSM-V criteria highlight the importance of 'positive signs' on neurological examination. Only few signs have been validated, and little is known about their reliability. OBJECTIVE: The aim was to examine the clinical value of bedside positive signs in the diagnosis of CD presenting with weakness, gait or sensory symptoms by assessing their specificity, sensitivity and their inter-rater reliability. PATIENTS AND METHODS: Standardised video recorded neurological examinations were performed in 20 consecutive patients with CD and 20 'organic' controls. Ten previously validated sensory and motor signs were grouped in a scale. Thirteen additional motor/sensory 'positive signs', 14 gait patterns and 1 general sign were assessed in a pilot validation study. In addition, two blinded independent neurologists rated the video recordings to assess the inter-rater reliability (Cohen's κ) of each sign. RESULTS: A score of ≥4/14 on the sensory motor scale showed a 100% specificity (CI 85 to 100) and a 95% sensitivity (CI 85 to 100). Among the additional tested signs, 10 were significantly more frequent in CD than controls. The interobserver agreement was acceptable for 23/38 signs (2 excellent, 10 good, 11 moderate). CONCLUSIONS: Our study confirms that six bedside 'positive signs' are highly specific for CD with good-excellent inter-rater reliability; we propose to consider them as 'highly reliable signs'. In addition 13 signs could be considered as 'reliable signs' and six further signs as 'suggestive signs' while all others should be used with caution until further validation is available.

Adjuvant cisplatin-based combined chemotherapy for lymph node (LN)-positive urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC): a retrospective international study of >1500 patients.

OBJECTIVE: To compare outcomes of patients with lymph node (LN)-positive urothelial carcinoma of the bladder (UCB) treated with or without cisplatin-based combined adjuvant chemotherapy (AC) after radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively analysed 1523 patients with LN-positive UCB, who underwent RC with bilateral pelvic LN dissection. All patients had no evidence of disease after RC. AC was administered within 3 months. Competing-risks models were applied to compare UCB-related mortality. RESULTS: Of the 1523 patients, 874 (57.4%) received AC. The cumulative 1-, 2- and 5-year UCB-related mortality rates for all patients were 16%, 36% and 56%, respectively. Administration of AC was associated with an 18% relative reduction in the risk of UCB-related death (subhazard ratio 0.82, P = 0.005). The absolute reduction in mortality was 3.5% at 5 years. The positive effect of AC was detectable in patients aged ≤70 years, in women, in pT3-4 disease, and in those with a higher LN density and lymphovascular invasion. This study is limited by its retrospective and non-randomised design, selection bias, the absence of central pathological review and lack in standardisation of LN dissection and cisplatin-based protocols. CONCLUSION: AC seems to reduce UCB-related mortality in patients with LN-positive UCB after RC. Younger patients, women and those with high-risk features such as pT3-4 disease, a higher LN density and lymphovascular invasion appear to benefit most. Appropriately powered prospective randomised trials are necessary to confirm these findings.

Innovative implementation by non-state actors in environment-related areas : towards a positive implementation gap ?

This contribution (presented in the first International Conference on Public Policy (ICPP) in Grenoble in June 2013) explores the phenomena of innovation in action ("innovative implementation"). To do so, we operationalize "innovative implementation" as a strategy by which (coalitions of) non-state actors seek to develop ad hoc solutions to address a given environmental issue, going beyond what is provided for in formal policy designs. Following an inductive research strategy, we elaborate a conceptual framework whose main advantage is to bring the actors and their coalition (in all their diversity) back in the analysis. More concretely, we state that perceiving implementation as broader 'social interaction processes' (De Boer & Bressers 2011) within which actors play strategic 'games' (Bardach 1977, Scharpf 1997) opens interesting lines of research to better account for their innovative and strategic behaviours. In a second step, we apply this framework to three strategies of innovative implementation in different contexts, and identify on this basis empirical regularities in the individual pathways related to the emergence and success (or failure) of these strategies.

Antibiotic susceptibility and molecular epidemiology of Panton-Valentine leukocidin-positive meticillin-resistant Staphylococcus aureus: An international survey

The antibiotic susceptibility and molecular epidemiology of Panton-Valentine leukocidin (PVL)-positive meticillin-resistant Staphylococcus aureus (MRSA) isolates reported from 17 countries in the Americas, Europe and, Australia-Asia were analysed. Among a total of 3236 non-duplicate isolates, the lowest susceptibility was observed to erythromycin in all regions. Susceptibility to ciprofloxacin showed large variation (25%, 75% and 84% in the Americas, Europe and Australia-Asia, respectively). Two vancomycin-intermediate PVL-positive MRSA isolates were reported, one from Hong Kong and the other from The Netherlands. Resistance to trimethoprim/sulfamethoxazole and linezolid was <1%. Among 1798 MRSA isolates from 13 countries that were tested for the requested 10 non-β-lactam antibiotics, 49.4% were multisusceptible. However, multiresistant isolates (resistant to at least three classes of non-β-lactam antibiotics) were reported from all regions. Sequence type 30 (ST30) was reported worldwide, whereas ST80 and ST93 were exclusive to Europe and Australia, respectively. USA300 and related clones (ST8) are progressively replacing the ST80 clone in several European countries. Eight major clusters were discriminated by multilocus variable-number tandem repeat assay (MLVA), showing a certain geographic specificity. PVL-positive MRSA isolates frequently remain multisusceptible to non-β-lactam agents, but multiresistance is already prevalent in all regions. Surveillance of MRSA susceptibility patterns should be monitored to provide clinicians with the most current information regarding changes in resistance patterns.

In vivo effect of flucloxacillin in experimental endocarditis caused by mecC-positive staphylococcus aureus showing temperature-dependent susceptibility in vitro.

Methicillin-resistant Staphylococcus aureus (MRSA) carrying the mecC gene (mecC-MRSA) exhibited at 37°C MICs of oxacillin close to those of methicillin-susceptible S. aureus (MSSA). We investigated whether at this temperature, mecC-MRSA strains respond to flucloxacillin treatment like MSSA strains, using a rat model of endocarditis. Flucloxacillin (human-like kinetics of 2 g intravenously every 6 h) cured 80 to 100% of aortic vegetations infected with five different mecC-MRSA strains. These results suggest that mecC-MRSA infections may successfully respond to treatment with β-lactams.