p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer.

Expression of both P-glycoprotein (P-gp) and mutant p53 have recently been reported to be associated with poor prognosis of breast cancer. The expression of P-gp is associated in vitro and in vivo with cross-resistance to several anti-cancer drugs. p53 plays a regulatory role in apoptosis, and mutant p53 has been suggested to be involved in drug resistance. Interestingly, in vitro experiments have shown that mutant p53 can activate the promoter of the MDR1 gene, which encodes P-gp. We investigated whether p53 and P-gp are simultaneously expressed in primary breast cancer cells and analysed the impact of the co-expression on patients prognosis. Immunohistochemistry was used to investigate P-gp expression (JSB-1, C219) and nuclear p53 accumulation (DO-7) in 20 operable chemotherapy untreated and 30 locally advanced breast cancers undergoing neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. Double immunostaining showed that P-gp expression and nuclear p53 accumulation often occur concomitantly in the same tumour cells. A correlation between p53 and P-gp expression was found in all 50 breast cancers (P = 0.003; Fisher's exact test). P-gp expression, nuclear p53 accumulation, and co-expression of p53 and P-gp were more frequently observed in locally advanced breast cancers than in operable breast cancers (P = 0.0004, P = 0.048; P = 0.002 respectively. Fisher's exact test). Co-expression of p53 and P-gp was the strongest prognostic factor for shorter survival by multivariate analysis (P = 0.004) in the group of locally advanced breast cancers (univariate analysis: P = 0.0007). Only 3 out of 13 samples sequentially taken before and after chemotherapy displayed a change in P-gp or p53 staining. In conclusion, nuclear p53 accumulation is often associated with P-gp expression in primary breast cancer, and simultaneous expression of p53 and P-gp is associated with shorter survival in locally advanced breast cancer patients. Co-expression of P-gp and mutant p53 belong to a series of molecular events resulting in a more aggressive phenotype, drug resistance and poor prognosis

Femorodistal venous bypass evaluated with intravascular ultrasound

Objective:To evaluate the feasibility of intravascular ultrasound imaging during femorodistal venous bypass procedures to assess qualitative and quantitative parameters of the greater saphenous vein and to detect potential causes for (re)stenosis and/or occlusion.Methods:Intravascular ultrasound data obtained from 15 patients were reviewed and compared with angiographic data.Results:Intravascular ultrasound enabled differentiation between normal and thickened vein wall. Venous side-branches could be located. Intact valves could be differentiated from valves disrupted by valve cutting. Patent anastomoses could be distinguished from anastomoses with some degree of obstruction. Intravascular ultrasound imaging of the inflow and outflow tracts revealed obstructive lesions, not evidenced angiographically. Quantitative analysis revealed that the median normal vein wall thickness (tunica intima and tunica media) was 0.25 mm (range 0.17–0.40 mm). The distinct vein wall thickening encountered in three patients measured 0.82, 0.95 and 1.06 mm, respectively, and was associated with narrowing in two patients. In five of 15 patients intravascular ultrasound findings altered surgical management.Conclusion:Intravascular ultrasound is able to assess qualitative and quantitative parameters of the venous bypass and has the potential to influence surgical management based on morphologic and quantitative data

TGN1412: From Discovery to Disaster

After a drug is confirmed as safe and efficacious in preclinical studies, it is tested in healthy human volunteers for first in man trials. In 2006, a phase I clinical study was conducted for a CD28 superagonist antibody TGN1412 in six human volunteers. After very first infusion of a dose 500 times smaller than that found safe in animal studies, all six human volunteers faced life-threatening conditions involving multiorgan failure for which they were moved to intensive care unit. After this particular incident, a lot was changed over how first in man trials are approved by regulatory authorities and the way clinical trials are conducted. This review primarily deals with preclinical studies conducted by TeGenero, results of which encouraged them to test the antibody on human subjects, reasons why this drug failed in human trial and aftermath of this drug trial. In addition, another drug—Fialuridine which failed in phase 2 clinical trial leading to death of five human subjects is briefly reviewed

Long-term cost-effectiveness of digital inhaler adherence technologies in difficult-to-treat asthma

BACKGROUND: Digital inhalers can monitor inhaler usage, support difficult-to-treat asthma management and inform step-up treatment decisions yet their economic value is unknown, hampering wide-scale implementation.OBJECTIVE: We aimed to assess the long-term cost-effectiveness of digital inhaler-based medication adherence management in difficult-to-treat asthma.METHODS: A model-based cost-utility analysis was performed. The Markov model structure was determined by biological and clinical understanding of asthma and was further informed by guideline-based assessment of model development. Internal and external validation was performed using the AdViSHE tool. The INCA Sun randomized clinical trial data were incorporated into the model to evaluate the cost-effectiveness of digital inhalers. Several long-term clinical case scenarios were assessed (reduced number of exacerbations, increased asthma control, introduction of biosimilars [25% price-cut on biologics]).RESULTS: The long-term modelled cost-effectiveness based on a societal perspective indicated 1-year per-patient costs for digital inhalers and usual care (i.e., regular inhalers) of €7,546 and €10,752, respectively, reflecting cost savings of €3,207 for digital inhalers. Using a 10-year intervention duration and time horizon resulted incost savings of €26,309 for digital inhalers. In the first year, add-on biologic therapies accounted for 69% of the total costs in the usual care group, and for 49% in the digital inhaler group. Scenario analyses indicated consistent cost savings ranging from €2,287 (introduction biosimilars) to €4,581 (increased control, decreased exacerbations).CONCLUSION: In patients with difficult-to-treat asthma, digital inhaler based interventions can be cost-saving on the long-term by optimizing medication adherence and inhaler technique and reducing add-on biologic prescriptions.</p

SERIES:eHealth in primary care. Part 4: Addressing the challenges of implementation

Background The implementation of eHealth applications in primary care remains challenging. Enhancing knowledge and awareness of implementation determinants is critical to build evidence-based implementation strategies and optimise uptake and sustainability. Objectives We consider how evidence-based implementation strategies can be built to support eHealth implementation. Discussion What implementation strategies to consider depends on (potential) barriers and facilitators to eHealth implementation in a given situation. Therefore, we first discuss key barriers and facilitators following the five domains of the Consolidated Framework for Implementation Research (CFIR). Cost is identified as a critical barrier to eHealth implementation. Privacy, security problems, and a lack of recognised standards for eHealth applications also hinder implementation. Engagement of key stakeholders in the implementation process, planning the implementation of the intervention, and the availability of training and support are important facilitators. To support care professionals and researchers, we provide a stepwise approach to develop and apply evidence-based implementation strategies for eHealth in primary care. It includes the following steps: (1) specify the eHealth application, (2) define problem, (3) specify desired implementation behaviour, and (4) choose and (5) evaluate the implementation strategy. To improve the fit of the implementation strategy with the setting, the stepwise approach considers the phase of the implementation process and the specific context. Conclusion Applying an approach, as provided here, may help to improve the implementation of eHealth applications in primary care.Prevention, Population and Disease management (PrePoD)Public Health and primary car