Quantitative imaging test approval and biomarker qualification: interrelated but distinct activities.

UNLABELLED: Quantitative imaging biomarkers could speed the development of new treatments for unmet medical needs and improve routine clinical care. However, it is not clear how the various regulatory and nonregulatory (eg, reimbursement) processes (often referred to as pathways) relate, nor is it clear which data need to be collected to support these different pathways most efficiently, given the time- and cost-intensive nature of doing so. The purpose of this article is to describe current thinking regarding these pathways emerging from diverse stakeholders interested and active in the definition, validation, and qualification of quantitative imaging biomarkers and to propose processes to facilitate the development and use of quantitative imaging biomarkers. A flexible framework is described that may be adapted for each imaging application, providing mechanisms that can be used to develop, assess, and evaluate relevant biomarkers. From this framework, processes can be mapped that would be applicable to both imaging product development and to quantitative imaging biomarker development aimed at increasing the effectiveness and availability of quantitative imaging. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100800/-/DC1.

Biochemical characterization of amandin, the major storage protein in almond (Prunus dulcis L.).

The almond major storage protein, amandin, was prepared by column chromatography (amandin-1), cryoprecipitation (amandin-2), and isoelectric precipitation (amandin-3) methods. Amandin is a legumin type protein characterized by a sedimentation value of 14S. Amandin is composed of two major types of polypeptides with estimated molecular weights of 42-46 and 20-22 kDa linked via disulfide bonds. Several additional minor polypeptides were also present in amandin. Amandin is a storage protein with an estimated molecular weight of 427,300 +/- 47,600 Da (n = 7) and a Stokes radius of 65.88 +/- 3.21 A (n = 7). Amandin is not a glycoprotein. Amandin-1, amandin-2, and amandin-3 are antigenically related and have similar biochemical properties. Amandin-3 is more negatively charged than either amandin-1 or amandin-2. Methionine is the first essential limiting amino acid in amandin followed by lysine and threonine.

Translating clinical trials into meaningful outcomes.

Efforts to unravel the complex biology that is necessary to develop new therapies best suited for an individual with cancer are at a crossroads with a strained health care system and an insufficient clinical trial apparatus. The resulting failures have been described as the "valley of death." Progress into the future will require new considerations and the engagement of a broad band of stakeholders. To identify novel therapeutics that are likely to succeed in late development and to be meaningful for clinical practice, investigators will need to make a paradigm shift in designing clinical trials and endpoints while adhering to scientific rigor when interpreting results and making informed decisions. Large phase III trials that show a modest incremental benefit will continue to diminish in value for patients, clinicians, payers, and industry. Outcomes that are robust in both magnitude and application to the real world will take on increasing importance. Ensuring active participation by patients, lowering barriers to health care access, and protecting patients through health care reform are requirements for the future success of the cancer clinical research enterprise. The challenge today is to develop new approaches to translate scientific discovery into cost-effective and meaningful improvements in cancer outcomes.

Ab initio calculations for industrial materials engineering: successes and challenges.

Computational materials science based on ab initio calculations has become an important partner to experiment. This is demonstrated here for the effect of impurities and alloying elements on the strength of a Zr twist grain boundary, the dissociative adsorption and diffusion of iodine on a zirconium surface, the diffusion of oxygen atoms in a Ni twist grain boundary and in bulk Ni, and the dependence of the work function of a TiN-HfO(2) junction on the replacement of N by O atoms. In all of these cases, computations provide atomic-scale understanding as well as quantitative materials property data of value to industrial research and development. There are two key challenges in applying ab initio calculations, namely a higher accuracy in the electronic energy and the efficient exploration of large parts of the configurational space. While progress in these areas is fueled by advances in computer hardware, innovative theoretical concepts combined with systematic large-scale computations will be needed to realize the full potential of ab initio calculations for industrial applications.

Enhancing drug development and drug monitoring: academia, industry and government chart common goals.

A workshop was hosted by the Biomedical Imaging Science Initiative of the University of Southern California in January 2007, entitled "Imaging-based Tools: Role in Drug Development and Drug Monitoring". This workshop brought together leaders from the pharmaceutical and the imaging industries, from academia and from government, who worked together to identify technical, educational, financial and procedural roadblocks that have delayed progress in the pharmacokinetic imaging field. The outcome has been a report that identifies future actions, including the formation of a Multidisciplinary Advisory Council on Noninvasive Imaging Studies.

Crystal chemistry and electronic structure of the metallic lithium ion conductor, LiNiN.

The layered ternary nitride LiNiN shows an interesting combination of fast Li+ ion diffusion and metallic behavior, properties which suggest potential applications as an electrode material in lithium ion batteries. A detailed investigation of the structure and properties of LiNiN using powder neutron diffraction, ab initio calculations, SQUID magnetometry, and solid-state NMR is described. Variable-temperature neutron diffraction demonstrates that LiNiN forms a variant of the parent Li3N structure in which Li+ ion vacancies are ordered within the [LiN] planes and with Ni exclusively occupying interlayer positions (at 280 K: hexagonal space group Pm2, a = 3.74304(5) A, c = 3.52542(6) A, Z = 1). Calculations suggest that LiNiN is a one-dimensional metal, as a result of the mixed pi- and sigma-bonding interactions between Ni and N along the c-axis. Solid-state 7Li NMR spectra are consistent with both fast Li+ motion and metallic behavior.

Noninvasive methods to study drug distribution.

Positron emission tomography (PET) and nuclear magnetic resonance spectroscopy (MRS) are two techniques that allow the noninvasive monitoring of drug distribution in living systems (humans, animals), and dynamic contrast-enhanced magnetic resonance imaging (dMRI) provides noninvasive physiological information relevant for drug distribution. PET yields series of cross-sectional images that can be used to monitor the absolute radioactivity concentrations in tissues pixel-by-pixel, but does not allow direct identification of each of the products present. MRS produces spectra showing changes in the concentration of both the parent drug and of the metabolites separately for a sensitive volume, but does not provide a simple means for measuring absolute concentrations. dMRI, which measures the changes in the rates of relaxation of water, proportional to the concentrations of the contrast agent (usually Gd-DTPA), readily allows the determination of functional changes in cross-sectional images down to a pixel-by-pixel level. All of these methods are of special interest to evaluate the amounts of drug that can reach the target tissue, penetrate it, remain present at such targets for a sufficient length of time, and how they are metabolized at the target site. Such information may be of particular interest in the study of solid malignant tumors and may become very relevant for determining better treatment strategies. This article presents examples of successful studies of tissue pharmacokinetics with MRS and dMRI. The following article is devoted to PET.

New food technologies and processes and their impact on nutrition.

An evaluation of new technologies already applied or still under investigation has shown that those procedures allow a mild treatment mostly of liquid food materials. If also Osmotic Processing, Ionising Irradiation, Carbon-Dioxide High-Pressure-Gas treatment, Ultra-Sound treatment and Gas-Plasma treatment are considered a large array of new processes is available for processing of food with minimum impact on compounds of nutritional relevance. Those processes must however be operated under very special conditions in order to comply with hygienic standards. Since all this processes require very sophisticated equipment it is too early at the moment to predict which one of the New Technologies will survive the fierce competition with the classic and well established processes and which do not fall under the Novel Food Regulation of the EU. It must be stated however that the pressure which did arise from the New Technologies has initiated many developments in the area of the classical technologies which had at the very end an impact also on the quality of products produced with those procedures.

Does leucovorin alter the intratumoral pharmacokinetics of 5-fluorouracil (5-FU)? A Southwest Oncology Group study.

PURPOSE AND DESIGN: We previously documented that there was an association between the intra-tumoral pharmacokinetics (TPK) of 5-FU and response to therapy with 5-FU and leucovorin (p < .0001). Since we have shown that other modulators of 5-FU, such as methotrexate, interferon and neutrexin alter its TPK, it was of interest to determine if the modulating effect of leucovorin would also alter the tumoral PK of 5-FU. In order to determine the effect of leucovorin on intratumoral 5-FU pharmacokinetics, 23 patients (21 evaluable) underwent 19F magnetic resonance spectroscopy (19F-MRS) twice. The first 19F-MRS was following 5-FU 600 mg/m2 alone, and the second 19F-MRS was following by leucovorin 500 mg/m2 and then 5-FU 600 mg/m2. RESULTS: A comparison of the intratumoral 5-FU pharmacokinetics indicated that there was no general effect of leucovorin on the intratumoral half-life of 5-FU. In only two of these 21 patients was the half-life of 5-FU altered, and in both cases it was decreased by more than 20%. Partial responses to 5-FU plus leucovorin therapy were seen only in patients with a long intratumoral half-life (trapping) of 5-FU (3 PR in 11 patients with T1/2 > or = 20 minutes, compared to 0 PR in 11 patients with T1/2 < 20 minutes). There was a statistically significant correlation between tumor response and the intratumoral T1/2 of 5-FU, consistent with our prior results in a larger number of patients. However, there was no statistically significant correlation of time-to-progression or survival with classification of the patients into trappers or non-trappers, probably due to the small sample size in this current study. CONCLUSION: The data reported here are compatible with the hypothesis that leucovorin enhancement of 5-fluorouracil antitumor responses is not mediated by the levels of 5-FU in tumors, but rather, is due to the modulation by leucovorin of cellular metabolic processes that follow the uptake of free 5-FU into the tumor cell. The MRS technique may be useful in selected instances for elucidating the possible metabolic interactions of drugs in vivo.

Value of intravascular ultrasound for endovascular stent-graft placement in aortic dissection and aneurysm.

BACKGROUND: Endovascular stent-graft placement is a new concept for the treatment of aortic dissection and aneurysm. Intravascular ultrasound (IVUS) with established diagnostic features may be instrumental in guiding endovascular procedures. METHODS: We performed IVUS and digital angiography before, during, and after implantation of 47 stent grafts in 40 patients with Stanford type B dissection (26 patients, 28 stent grafts), thoracic aneurysm (9 patients, 11 stent grafts), and abdominal aneurysm (5 patients, 8 stent grafts). RESULTS: IVUS could clearly identify the aortic anatomy and differentiate between true and false lumen in all cases of dissection. In four patients with type B dissection extending from the thoracic to the abdominal aorta the true lumen was exclusively identified by IVUS, and thus, essential for safe execution of the procedure. In another patient stent-graft placement in the aorta was optimized by covering a second entry detected by IVUS, but undetected by angiography. The site of stent implantation, the true and false lumen, as well as entry and reentry were always identified in both thoracic and abdominal aorta. In comparison with angiography, IVUS information led to additional balloon molding due to incomplete stent apposition in seven cases. CONCLUSIONS: As an adjunctive imaging modality IVUS is likely to improve stent-graft placement in aortic type B dissection, especially in patients with abdominal extension.