Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [18F]fluoromethyl-(1,2-2H4)-choline.

Purpose: The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [18F]fluoromethyl-(1,2-2H4) choline ([18F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). Experimental design: [18F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [18F]fluorodeoxyglucose ([18F]FDG) scans. Results: Oxidation of [18F]D4-FCH to [18F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [18F]D4-FCH-derived uptake (SUV60max) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [18F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [18F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. Conclusions: [18F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.

A classification of information-based environmental regulation: Voluntariness, compliance and beyond.

Alternative approaches to environmental regulation have gained much attention in recent years. Information-based regulation is an increasingly popular type of instrument that refers to the use of ratings, rankings, labels, online inventories and similar public disclosure practices by regulators. Such schemes vary in their design, disclosure formats, mechanisms to influence behaviour and performance. Theoretical and practical questions remain about whether and how regulators can use voluntary and/or beyond compliance disclosures. The article develops a classification of information-based schemes based on whether the scheme is mandatory or voluntary, and whether the disclosures reveal compliance or beyond compliance performance behaviours. The classification is used to show how the different schemes (traditional, assurance, performance and proactive) work in practice with their associated risks, benefits and mechanisms. While regulators are experimenting with this new frontier of regulation, it is not yet clear whether all types of schemes will be sufficiently robust to deliver on the promise they hold for enthusiasts of smart regulation. We conclude with implications and future research questions on the nature of voluntariness and compliance in information-based regulation.

Does manual therapy provide additional benefit to breathing retraining in the management of dysfunctional breathing? A randomised controlled trial.

PURPOSE: Dysfunctional breathing (DB) is associated with an abnormal breathing pattern, unexplained breathlessness and significant patient morbidity. Treatment involves breathing retraining through respiratory physiotherapy. Recently, manual therapy (MT) has also been used, but no evidence exists to validate its use. This study sought to investigate whether MT produces additional benefit when compared with breathing retraining alone in patients with DB. METHODS: Sixty subjects with primary DB were randomised into either breathing retraining (standard treatment; n = 30) or breathing retraining plus MT (intervention; n = 30) group. Both the groups received standardised respiratory physiotherapy, which included: DB education, breathing retraining, home regimen, and audio disc. Intervention group subjects additionally received MT following further assessment. Data from 57 subjects were analysed. RESULTS: At baseline, standard treatment group subjects were statistically younger (41.7 + 13.5 versus 50.8 + 13.0 years; p = 0.001) with higher Nijmegen scores (38.6 + 9.5 versus 31.5 + 6.9; p = 0.001). However, no significant difference was found between the groups for primary outcome Nijmegen score (95% CI (-1.1, 6.6) p = 0.162), or any secondary outcomes (Hospital Anxiety & Depression Score, spirometry or exercise tolerance). CONCLUSION: Breathing retraining is currently the mainstay of treatment for patients with DB. The results of this study suggest MT provides no additional benefit in this patient group. IMPLICATIONS FOR REHABILITATION: Dysfunctional breathing (DB) is associated with significant patient morbidity but often goes unrecognised, leading to prolonged investigation and significant use of health care resources. Breathing retraining remains the primary management of this condition. However, physiotherapists are also using manual therapy (MT) as an adjunctive treatment for patients with DB. However, the results of this study suggest that MT provides no further benefit and cannot be recommended in the clinical management of this condition.

FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2.

Patients with small cell lung cancer (SCLC) die because of chemoresistance. Fibroblast growth factor-2 (FGF-2) increases the expression of antiapoptotic proteins, XIAP and Bcl-X(L), and triggers chemoresistance in SCLC cells. Here we show that these effects are mediated through the formation of a specific multiprotein complex comprising B-Raf, PKCepsilon and S6K2. S6K1, Raf-1 and other PKC isoforms do not form similar complexes. RNAi-mediated downregulation of B-Raf, PKCepsilon or S6K2 abolishes FGF-2-mediated survival. In contrast, overexpression of PKCepsilon increases XIAP and Bcl-X(L) levels and chemoresistance in SCLC cells. In a tetracycline-inducible system, increased S6K2 kinase activity triggers upregulation of XIAP, Bcl-X(L) and prosurvival effects. However, increased S6K1 kinase activity has no such effect. Thus, S6K2 but not S6K1 mediates prosurvival/chemoresistance signalling.

A novel accelerometer tilt switch device for switch actuation in the patient with profound disability.

We describe the design and operation of a new switch that can be operated by patients with severely limited movement. The basis for the switch is an inexpensive single-chip accelerometer device. The switch responds to a relatively rapid rotation of the active components. We have ensured that the sensitivity of the switch device is adjustable over a wide range. The device automatically adjusts for changes in attitude of the device that result from a patient changing posture. We show that the device can operate in a wide range of attitudes. We describe 2 case studies in which the switch was successfully used as a head tilt switch.