Tetraamine-derived bifunctional chelators for technetium-99m labelling: synthesis, bioconjugation and evaluation as targeted SPECT imaging probes for GRP-receptor-positive tumours

Owing to its optimal nuclear properties, ready availability, low cost and favourable dosimetry, (99m)Tc continues to be the ideal radioisotope for medical-imaging applications. Bifunctional chelators based on a tetraamine framework exhibit facile complexation with Tc(V)O(2) to form monocationic species with high in vivo stability and significant hydrophilicity, which leads to favourable pharmacokinetics. The synthesis of a series of 1,4,8,11-tetraazaundecane derivatives (01-06) containing different functional groups at the 6-position for the conjugation of biomolecules and subsequent labelling with (99m)Tc is described herein. The chelator 01 was used as a starting material for the facile synthesis of chelators functionalised with OH (02), N(3) (04) and O-succinyl ester (05) groups. A straightforward and easy synthesis of carboxyl-functionalised tetraamine-based chelator 06 was achieved by using inexpensive and commercially available starting materials. Conjugation of 06 to a potent bombesin-antagonist peptide and subsequent labelling with (99m)Tc afforded the radiotracer (99m)Tc-N4-BB-ANT, with radiolabelling yields of >97% at a specific activity of 37 GBq micromol(-1). An IC(50) value of (3.7+/-1.3) nM was obtained, which confirmed the high affinity of the conjugate to the gastrin-releasing-peptide receptor (GRPr). Immunofluorescence and calcium mobilisation assays confirmed the strong antagonist properties of the conjugate. In vivo pharmacokinetic studies of (99m)Tc-N4-BB-ANT showed high and specific uptake in PC3 xenografts and in other GRPr-positive organs. The tumour uptake was (22.5+/-2.6)% injected activity per gram (% IA g(-1)) at 1 h post injection (p.i.). and increased to (29.9+/-4.0)% IA g(-1) at 4 h p.i. The SPECT/computed tomography (CT) images showed high tumour uptake, clear background and negligible radioactivity in the abdomen. The promising preclinical results of (99m)Tc-N4-BB-ANT warrant its potential candidature for clinical translation.

Quantum modeling of bioconjugated nanomaterials

In recent years, the bio-conjugated nanostructured materials have emerged as a new class of materials for the bio-sensing and medical diagnostics applications. In spite of their multi-directional applications, interfacing nanomaterials with bio-molecules has been a challenge due to somewhat limited knowledge about the underlying physics and chemistry behind these interactions and also for the complexity of biomolecules. The main objective of this dissertation is to provide such a detailed knowledge on bioconjugated nanomaterials toward their applications in designing the next generation of sensing devices. Specifically, we investigate the changes in the electronic properties of a boron nitride nanotube (BNNT) due to the adsorption of different bio-molecules, ranging from neutral (DNA/RNA nucleobases) to polar (amino acid molecules). BNNT is a typical member of III-V compounds semiconductors with morphology similar to that of carbon nanotubes (CNTs) but with its own distinct properties. More specifically, the natural affinity of BNNTs toward living cells with no apparent toxicity instigates the applications of BNNTs in drug delivery and cell therapy. Our results predict that the adsorption of DNA/RNA nucleobases on BNNTs amounts to different degrees of modulation in the band gap of BNNTs, which can be exploited for distinguishing these nucleobases from each other. Interestingly, for the polar amino acid molecules, the nature of interaction appeared to vary ranging from Coulombic, van der Waals and covalent depending on the polarity of the individual molecules, each with a different binding strength and amount of charge transfer involved in the interaction. The strong binding of amino acid molecules on the BNNTs explains the observed protein wrapping onto BNNTs without any linkers, unlike carbon nanotubes (CNTs). Additionally, the widely varying binding energies corresponding to different amino acid molecules toward BNNTs indicate to the suitability of BNNTs for the biosensing applications, as compared to the metallic CNTs. The calculated I-V characteristics in these bioconjugated nanotubes predict notable changes in the conductivity of BNNTs due to the physisorption of DNA/RNA nucleobases. This is not the case with metallic CNTs whose transport properties remained unaltered in their conjugated systems with the nucleobases. Collectively, the bioconjugated BNNTs are found to be an excellent system for the next generation sensing devices.

The SAKK cancer-specific geriatric assessment (C-SGA): a pilot study of a brief tool for clinical decision-making in older cancer patients

BACKGROUND Recommendations from international task forces on geriatric assessment emphasize the need for research including validation of cancer-specific geriatric assessment (C-SGA) tools in oncological settings. The objective of this study was to evaluate the feasibility of the SAKK Cancer-Specific Geriatric Assessment (C-SGA) in clinical practice. METHODS A cross sectional study of cancer patients >=65 years old (N = 51) with pathologically confirmed cancer presenting for initiation of chemotherapy treatment (07/01/2009-03/31/2011) at two oncology departments in Swiss canton hospitals: Kantonsspital Graubunden (KSGR N = 25), Kantonsspital St. Gallen (KSSG N = 26). Data was collected using three instruments, the SAKK C-SGA plus physician and patient evaluation forms. The SAKK C-SGA includes six measures covering five geriatric assessment domains (comorbidity, function, psychosocial, nutrition, cognition) using a mix of medical record abstraction (MRA) and patient interview. Five individual domains and one overall SAKK C-SGA score were calculated and dichotomized as below/above literature-based cut-offs. The SAKK C-SGA was evaluated by: patient and physician estimated time to complete, ease of completing, and difficult or unanswered questions. RESULTS Time to complete the patient questionnaire was considered acceptable by almost all (>=96%) patients and physicians. Patients reported slightly shorter times to complete the questionnaire than physicians (17.33 +/- 7.34 vs. 20.59 +/- 6.53 minutes, p = 0.02). Both groups rated the patient questionnaire as easy/fairly easy to complete (91% vs. 84% respectively, p = 0.14) with few difficult or unanswered questions. The MRA took on average 8.32 +/- 4.72 minutes to complete. Physicians (100%) considered time to complete MRA acceptable, 96% rated it as easy/fairly easy to complete. Individual study site populations differed on health-related characteristics (excellent/good physician-rated general health KSGR 71% vs. KSSG 32%, p = 0.007). The overall mean C-SGA score was 2.4 +/- 1.12. Patients at KSGR had lower C-SGA scores (2.00 +/- 1.19 vs. 2.81 +/- 0.90, p = 0.009) and a smaller proportion (28% vs.65%, p = 0.008) was above the C-SGA cut-off score compared to KSSG. CONCLUSIONS These results suggest the SAKK C-SGA is a feasible practical tool for use in clinical practice. It demonstrated discriminative ability based on objective geriatric assessment measures, but additional investigations on use for clinical decision-making are warranted. The SAKK C-SGA also provides important usable domain information for intervention to optimize outcomes in older cancer patients.

Impact of unlinked deaths and coding changes on mortality trends in the Swiss National Cohort

BACKGROUND Results of epidemiological studies linking census with mortality records may be affected by unlinked deaths and changes in cause of death classification. We examined these issues in the Swiss National Cohort (SNC). METHODS The SNC is a longitudinal study of the entire Swiss population, based on the 1990 (6.8 million persons) and 2000 (7.3 million persons) censuses. Among 1,053,393 deaths recorded 1991-2007 5.4% could not be linked using stringent probabilistic linkage. We included the unlinked deaths using pragmatic linkages and compared mortality rates for selected causes with official mortality rates. We also examined the impact of the 1995 change in cause of death coding from version 8 (with some additional rules) to version 10 of the International Classification of Diseases (ICD), using Poisson regression models with restricted cubic splines. Finally, we compared results from Cox models including and excluding unlinked deaths of the association of education, marital status, and nationality with selected causes of death. RESULTS SNC mortality rates underestimated all cause mortality by 9.6% (range 2.4%-17.9%) in the 85+ population. Underestimation was less pronounced in years nearer the censuses and in the 75-84 age group. After including 99.7% of unlinked deaths, annual all cause SNC mortality rates were reflecting official rates (relative difference between -1.4% and +1.8%). In the 85+ population the rates for prostate and breast cancer dropped, by 16% and 21% respectively, between 1994 and 1995 coincident with the change in cause of death coding policy. For suicide in males almost no change was observed. Hazard ratios were only negligibly affected by including the unlinked deaths. A sudden decrease in breast (21% less, 95% confidence interval: 12%-28%) and prostate (16% less, 95% confidence interval: 7%-23%) cancer mortality rates in the 85+ population coincided with the 1995 change in cause of death coding policy. CONCLUSIONS Unlinked deaths bias analyses of absolute mortality rates downwards but have little effect on relative mortality. To describe time trends of cause-specific mortality in the SNC, accounting for the unlinked deaths and for the possible effect of change in death certificate coding was necessary.

Efficacy of quality criteria to identify potentially harmful information: a cross-sectional survey of complementary and alternative medicine web sites.

BACKGROUND: Many users search the Internet for answers to health questions. Complementary and alternative medicine (CAM) is a particularly common search topic. Because many CAM therapies do not require a clinician's prescription, false or misleading CAM information may be more dangerous than information about traditional therapies. Many quality criteria have been suggested to filter out potentially harmful online health information. However, assessing the accuracy of CAM information is uniquely challenging since CAM is generally not supported by conventional literature. OBJECTIVE: The purpose of this study is to determine whether domain-independent technical quality criteria can identify potentially harmful online CAM content. METHODS: We analyzed 150 Web sites retrieved from a search for the three most popular herbs: ginseng, ginkgo and St. John's wort and their purported uses on the ten most commonly used search engines. The presence of technical quality criteria as well as potentially harmful statements (commissions) and vital information that should have been mentioned (omissions) was recorded. RESULTS: Thirty-eight sites (25%) contained statements that could lead to direct physical harm if acted upon. One hundred forty five sites (97%) had omitted information. We found no relationship between technical quality criteria and potentially harmful information. CONCLUSIONS: Current technical quality criteria do not identify potentially harmful CAM information online. Consumers should be warned to use other means of validation or to trust only known sites. Quality criteria that consider the uniqueness of CAM must be developed and validated.

Strategies to improve healthcare websites.

Healthcare websites that are influential in healthcare decision-making must be evaluated for accuracy, readability and understandability by the average population. Most existing frameworks for designing and evaluating interactive websites focus on the utility and usability of the site. Although these are significant to the design of the basic site, they are not sufficient. We have developed an iterative framework that considers additional attributes.

Asynchronous ECG time sampling: Saving bits with Golomb-Rice encoding

We present a technique for online compression of ECG signals using the Golomb-Rice encoding algorithm. This is facilitated by a novel time encoding asynchronous analog-to-digital converter targeted for low-power, implantable, long-term bio-medical sensing applications. In contrast to capturing the actual signal (voltage) values the asynchronous time encoder captures and encodes the time information at which predefined changes occur in the signal thereby minimizing the sensor's energy use and the number of bits we store to represent the information by not capturing unnecessary samples. The time encoder transforms the ECG signal data to pure time information that has a geometric distribution such that the Golomb-Rice encoding algorithm can be used to further compress the data. An overall online compression rate of about 6 times is achievable without the usual computations associated with most compression methods.

Automatic multi-resolution shape modeling of multi-organ structures.

Point Distribution Models (PDM) are among the most popular shape description techniques and their usefulness has been demonstrated in a wide variety of medical imaging applications. However, to adequately characterize the underlying modeled population it is essential to have a representative number of training samples, which is not always possible. This problem is especially relevant as the complexity of the modeled structure increases, being the modeling of ensembles of multiple 3D organs one of the most challenging cases. In this paper, we introduce a new GEneralized Multi-resolution PDM (GEM-PDM) in the context of multi-organ analysis able to efficiently characterize the different inter-object relations, as well as the particular locality of each object separately. Importantly, unlike previous approaches, the configuration of the algorithm is automated thanks to a new agglomerative landmark clustering method proposed here, which equally allows us to identify smaller anatomically significant regions within organs. The significant advantage of the GEM-PDM method over two previous approaches (PDM and hierarchical PDM) in terms of shape modeling accuracy and robustness to noise, has been successfully verified for two different databases of sets of multiple organs: six subcortical brain structures, and seven abdominal organs. Finally, we propose the integration of the new shape modeling framework into an active shape-model-based segmentation algorithm. The resulting algorithm, named GEMA, provides a better overall performance than the two classical approaches tested, ASM, and hierarchical ASM, when applied to the segmentation of 3D brain MRI.

ACGT: advancing clinico-genomic trials on cancer - four years of experience.

The challenges regarding seamless integration of distributed, heterogeneous and multilevel data arising in the context of contemporary, post-genomic clinical trials cannot be effectively addressed with current methodologies. An urgent need exists to access data in a uniform manner, to share information among different clinical and research centers, and to store data in secure repositories assuring the privacy of patients. Advancing Clinico-Genomic Trials (ACGT) was a European Commission funded Integrated Project that aimed at providing tools and methods to enhance the efficiency of clinical trials in the -omics era. The project, now completed after four years of work, involved the development of both a set of methodological approaches as well as tools and services and its testing in the context of real-world clinico-genomic scenarios. This paper describes the main experiences using the ACGT platform and its tools within one such scenario and highlights the very promising results obtained.

Intelligent Therapy Assistant (ITA) for cognitive rehabilitation in patients with Acquired Brain Injury

This paper presents the design, development and first evaluation of an algorithm, named Intelligent Therapy Assistant (ITA), which automatically selects, configures and schedules rehabilitation tasks for patients with cognitive impairments after an episode of Acquired Brain Injury. The ITA is integrated in "Guttmann, Neuro Personal Trainer" (GNPT), a cognitive tele-rehabilitation platform that provides neuropsychological services.

Feasibility assessment of the interactive use of a Monte Carlo algorithm in treatment planning for intraoperative electron radiation therapy

This work analysed the feasibility of using a fast, customized Monte Carlo (MC) method to perform accurate computation of dose distributions during pre- and intraplanning of intraoperative electron radiation therapy (IOERT) procedures. The MC method that was implemented, which has been integrated into a specific innovative simulation and planning tool, is able to simulate the fate of thousands of particles per second, and it was the aim of this work to determine the level of interactivity that could be achieved. The planning workflow enabled calibration of the imaging and treatment equipment, as well as manipulation of the surgical frame and insertion of the protection shields around the organs at risk and other beam modifiers. In this way, the multidisciplinary team involved in IOERT has all the tools necessary to perform complex MC dosage simulations adapted to their equipment in an efficient and transparent way. To assess the accuracy and reliability of this MC technique, dose distributions for a monoenergetic source were compared with those obtained using a general-purpose software package used widely in medical physics applications. Once accuracy of the underlying simulator was confirmed, a clinical accelerator was modelled and experimental measurements in water were conducted. A comparison was made with the output from the simulator to identify the conditions under which accurate dose estimations could be obtained in less than 3 min, which is the threshold imposed to allow for interactive use of the tool in treatment planning. Finally, a clinically relevant scenario, namely early-stage breast cancer treatment, was simulated with pre- and intraoperative volumes to verify that it was feasible to use the MC tool intraoperatively and to adjust dose delivery based on the simulation output, without compromising accuracy. The workflow provided a satisfactory model of the treatment head and the imaging system, enabling proper configuration of the treatment planning system and providing good accuracy in the dosage simulation.

Supporting patient screening to identify suitable clinical trials.

To support the efficient execution of post-genomic multi-centric clinical trials in breast cancer we propose a solution that streamlines the assessment of the eligibility of patients for available trials. The assessment of the eligibility of a patient for a trial requires evaluating whether each eligibility criterion is satisfied and is often a time consuming and manual task. The main focus in the literature has been on proposing different methods for modelling and formalizing the eligibility criteria. However the current adoption of these approaches in clinical care is limited. Less effort has been dedicated to the automatic matching of criteria to the patient data managed in clinical care. We address both aspects and propose a scalable, efficient and pragmatic patient screening solution enabling automatic evaluation of eligibility of patients for a relevant set of trials. This covers the flexible formalization of criteria and of other relevant trial metadata and the efficient management of these representations.

In vivo NMR and MRI using injection delivery of laser-polarized xenon

Because xenon NMR is highly sensitive to the local environment, laser-polarized xenon could be a unique probe of living tissues. Realization of clinical and medical science applications beyond lung airspace imaging requires methods of efficient delivery of laser-polarized xenon to tissues, because of the short spin-lattice relaxation times and relatively low concentrations of xenon attainable in the body. Preliminary results from the application of a polarized xenon injection technique for in vivo 129Xe NMR/MRI are extrapolated along with a simple model of xenon transit to show that the peak local concentration of polarized xenon delivered to tissues by injection may exceed that delivered by respiration by severalfold.