Insulin-like growth factor-1 receptor inhibitor, AMG-479, in cetuximab-refractory head and neck squamous cell carcinoma

Background Recurrent head and neck squamous cell carcinoma (HNSCC) remains a difficult cancer to treat. Here, we describe a patient with HNSCC who had complete response to methotrexate (MTX) after progressing on multiple cytotoxic agents, cetuximab, and AMG-479 (monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]). Methods The clinical information was collected by a retrospective medical record review under an Institutional Review Board-approved protocol. From 4 tumors and 2 normal mucosal epithelia, global gene expression, and IGF-1R and dihydrofolate reductase (DHFR) protein levels were determined. Results Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho-IGF-1R after treatment with AMG-479. Decreased level of DHFR and conversion of a gene expression profile associated with cetuximab-resistance to cetuximab-sensitivity were also observed. Conclusion This suggests that the combination of AMG-479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC

Fluorine-19 MRI at 21.1 T: enhanced spin-lattice relaxation of perfluoro-15-crown-5-ether and sensitivity as demonstrated in ex vivo murine neuroinflammation

OBJECTIVE: Fluorine MR would benefit greatly from enhancements in signal-to-noise ratio (SNR). This study examines the sensitivity gain of (19)F MR that can be practically achieved when moving from 9.4 to 21.1 T. MATERIALS AND METHODS: We studied perfluoro-15-crown-5-ether (PFCE) at both field strengths (B(0)), as a pure compound, in the form of nanoparticles (NP) as employed to study inflammation in vivo, as well as in inflamed tissue. Brains, lymph nodes (LNs) and spleens were obtained from mice with experimental autoimmune encephalomyelitis (EAE) that had been administered PFCE NPs. All samples were measured at both B(0) with 2D-RARE and 2D-FLASH using (19)F volume radiofrequency resonators together. T(1) and T(2) of PFCE were measured at both B(0) strengths. RESULTS: Compared to 9.4 T, an SNR gain of > 3 was observed for pure PFCE and > 2 for PFCE NPs at 21.1 T using 2D-FLASH. A dependency of (19)F T(1) and T(2) relaxation on B(0) was demonstrated. High spatially resolved (19)F MRI of EAE brains and LNs at 21.1 T revealed signals not seen at 9.4 T. DISCUSSION: Enhanced SNR and T(1) shortening indicate the potential benefit of in vivo (19)F MR at higher B(0) to study inflammatory processes with greater detail

Fluorine ((19)F) MRI for assessing inflammatory cells in the kidney: experimental protocol

Inflammation is one underlying contributing factor in the pathology of acute and chronic kidney disorders. Phagocytes such as monocytes, neutrophils and dendritic cells are considered to play a deleterious role in the progression of kidney disease but may also contribute to organ homeostasis. The kidney is a target of life-threatening autoimmune disorders such as the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Neutrophils and monocytes express ANCA antigens and play an important role in the pathogenesis of AAV. Noninvasive in vivo methods that can quantify the distribution of inflammatory cells in the kidney as well as other organs in vivo would be vital to identify the causality and significance of inflammation during disease progression. Here we describe an noninvasive technique to study renal inflammation in rodents in vivo using fluorine ((19)F) MRI. In this protocol we chose a murine ANCA-AAV model of renal inflammation and made use of nanoparticles prepared from perfluoro-5-crown-15-ether (PFCE) for renal (19)F MRI.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This experimental protocol chapter is complemented by two separate chapters describing the basic concept and data analysis

Enhanced fluorine-19 MRI sensitivity using a cryogenic radiofrequency probe: technical developments and ex vivo demonstration in a mouse model of neuroinflammation

Neuroinflammation can be monitored using fluorine-19 ((19)F)-containing nanoparticles and (19)F MRI. Previously we studied neuroinflammation in experimental autoimmune encephalomyelitis (EAE) using room temperature (RT) (19)F radiofrequency (RF) coils and low spatial resolution (19)F MRI to overcome constraints in signal-to-noise ratio (SNR). This yielded an approximate localization of inflammatory lesions. Here we used a new (19)F transceive cryogenic quadrature RF probe ((19) F-CRP) that provides the SNR necessary to acquire superior spatially-resolved (19)F MRI. First we characterized the signal-transmission profile of the (19) F-CRP. The (19) F-CRP was then benchmarked against a RT (19)F/(1)H RF coil. For SNR comparison we used reference compounds including (19)F-nanoparticles and ex vivo brains from EAE mice administered with (19)F-nanoparticles. The transmit/receive profile of the (19) F-CRP diminished with increasing distance from the surface. This was counterbalanced by a substantial SNR gain compared to the RT coil. Intraparenchymal inflammation in the ex vivo EAE brains was more sharply defined when using 150 μm isotropic resolution with the (19) F-CRP, and reflected the known distribution of EAE histopathology. At this spatial resolution, most (19)F signals were undetectable using the RT coil. The (19) F-CRP is a valuable tool that will allow us to study neuroinflammation with greater detail in future in vivo studies

B(1) inhomogeneity correction of RARE MRI at low SNR: quantitative in vivo (19)F MRI of mouse neuroinflammation with a cryogenically-cooled transceive surface radiofrequency probe

PURPOSE: Low SNR in fluorine-19 (19F) MRI benefits from cryogenically-cooled transceive surface RF probes (CRPs), but strong B(1) inhomogeneities hinder quantification. Rapid acquisition with refocused echoes (RARE) is an SNR-efficient method for MRI of neuroinflammation with perfluorinated compounds but lacks an analytical signal intensity equation to retrospectively correct B(1) inhomogeneity. Here, a workflow was proposed and validated to correct and quantify (19)F-MR signals from the inflamed mouse brain using a (19)F-CRP. METHODS: In vivo (19)F-MR images were acquired in a neuroinflammation mouse model with a quadrature (19)F-CRP using an imaging setup including 3D-printed components to acquire co-localized anatomical and (19)F images. Model-based corrections were validated on a uniform (19)F phantom and in the neuroinflammatory model. Corrected (19)F-MR images were benchmarked against reference images and overlaid on in vivo (1)H-MR images. Computed concentration uncertainty maps using Monte Carlo simulations served as a measure of performance of the B(1) corrections. RESULTS: Our study reports on the first quantitative in vivo (19)F-MR images of an inflamed mouse brain using a (19)F-CRP, including in vivo T(1) calculations for (19)F-nanoparticles during pathology and B(1) corrections for (19)F-signal quantification. Model-based corrections markedly improved (19)F-signal quantification from errors > 50% to < 10% in a uniform phantom (p < 0.001). Concentration uncertainty maps ex vivo and in vivo yielded uncertainties that were generally < 25%. Monte Carlo simulations prescribed SNR ≥ 10.1 to reduce uncertainties < 10%, and SNR ≥ 4.25 to achieve uncertainties < 25%. CONCLUSION: Our model-based correction method facilitated (19)F signal quantification in the inflamed mouse brain when using the SNR-boosting (19)F-CRP technology, paving the way for future low-SNR (19)F-MRI applications in vivo

In vivo detection of teriflunomide-derived fluorine signal during neuroinflammation using fluorine MR spectroscopy

BACKGROUND: Magnetic resonance imaging (MRI) is indispensable for diagnosing neurological conditions such as multiple sclerosis (MS). MRI also supports decisions regarding the choice of disease-modifying drugs (DMDs). Determining in vivo tissue concentrations of DMDs has the potential to become an essential clinical tool for therapeutic drug monitoring (TDM). The aim here was to examine the feasibility of fluorine-19 ((19)F) MR methods to detect the fluorinated DMD teriflunomide (TF) during normal and pathological conditions. METHODS: We used (19)F MR spectroscopy to detect TF in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS) in vivo. Prior to the in vivo investigations we characterized the MR properties of TF in vitro. We studied the impact of pH and protein binding as well as MR contrast agents. RESULTS: We could detect TF in vivo and could follow the (19)F MR signal over different time points of disease. We quantified TF concentrations in different tissues using HPLC/MS and showed a significant correlation between ex vivo TF levels in serum and the ex vivo (19)F MR signal. CONCLUSION: This study demonstrates the feasibility of (19)F MR methods to detect TF during neuroinflammation in vivo. It also highlights the need for further technological developments in this field. The ultimate goal is to add (19)F MR protocols to conventional (1)H MRI protocols in clinical practice to guide therapy decisions

Continuous diffusion spectrum computation for diffusion-weighted magnetic resonance imaging of the kidney tubule system

BACKGROUND: The use of rigid multi-exponential models (with a priori predefined numbers of components) is common practice for diffusion-weighted MRI (DWI) analysis of the kidney. This approach may not accurately reflect renal microstructure, as the data are forced to conform to the a priori assumptions of simplified models. This work examines the feasibility of less constrained, data-driven non-negative least squares (NNLS) continuum modelling for DWI of the kidney tubule system in simulations that include emulations of pathophysiological conditions. METHODS: Non-linear least squares (LS) fitting was used as reference for the simulations. For performance assessment, a threshold of 5% or 10% for the mean absolute percentage error (MAPE) of NNLS and LS results was used. As ground truth, a tri-exponential model using defined volume fractions and diffusion coefficients for each renal compartment (tubule system: D(tubules), f(tubules); renal tissue: D(tissue), f(tissue); renal blood: D(blood), f(blood);) was applied. The impact of: (I) signal-to-noise ratio (SNR) =40–1,000, (II) number of b-values (n=10–50), (III) diffusion weighting (b-range(small)=0-800 up to b-range(large)=0-2,180 s/mm(2)), and (IV) fixation of the diffusion coefficients D(tissue) and D(blood) was examined. NNLS was evaluated for baseline and pathophysiological conditions, namely increased tubular volume fraction (ITV) and renal fibrosis (10%: grade I, mild) and 30% (grade II, moderate). RESULTS: NNLS showed the same high degree of reliability as the non-linear LS. MAPE of the tubular volume fraction (f(tubules)) decreased with increasing SNR. Increasing the number of b-values was beneficial for f(tubules) precision. Using the b-range(large) led to a decrease in MAPE(ftubules) compared to b-range(small). The use of a medium b-value range of b=0-1,380 s/mm(2) improved f(tubules) precision, and further bmax increases beyond this range yielded diminishing improvements. Fixing D(blood) and D(tissue) significantly reduced MAPE(ftubules) and provided near perfect distinction between baseline and ITV conditions. Without constraining the number of renal compartments in advance, NNLS was able to detect the (fourth) fibrotic compartment, to differentiate it from the other three diffusion components, and to distinguish between 10% vs. 30% fibrosis. CONCLUSIONS: This work demonstrates the feasibility of NNLS modelling for DWI of the kidney tubule system and shows its potential for examining diffusion compartments associated with renal pathophysiology including ITV fraction and different degrees of fibrosis

Extended neoadjuvant chemotherapy in locally advanced breast cancer combined with GM-CSF: effect on tumour-draining lymph node dendritic cells

The effect of long-term administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) on dendritic cell (DC) activation and survival in patients with locally advanced breast cancer (LABC) was studied. To this end, the number of activated DC (i.e. positive for the marker S100) in tumour-draining lymph nodes (TDLN) was determined and compared between LABC patients receiving neoadjuvant chemotherapy with GM-CSF (n=52) or without GM-CSF (n=11), and a control group of chemonaïve breast cancer patients (n=10). A significantly higher mean percentage of S100+ DC in the TDLN of the GM-CSF-treated patients (9.9%) was found compared with each of the respective control groups (5.3 and 5.1%, P=0.002). Moreover, intrapatient comparison before and after treatment showed that the percentage of S100+ DC significantly increased over the course of the GMCSF treatment (P=0.018). In a univariate survival analysis with a median follow-up of 64 months, relatively high percentages of S100+ DC (≥8%) were associated with a longer disease-free survival (DFS) (P=0.078). In patients with a high tumour load, where immunosuppressed conditions generally prevail, long-term administration of GM-CSF may thus contribute to survival through enhanced DC activation and consequently improved chances of effective antitumour immunity

Prevalência de tabagismo e fatores associados em área metropolitana da região Sul do Brasil Prevalence of smoking and associated factors in a metropolitan area of southern Brazil

Com o objetivo de avaliar a prevalência de tabagismo em Porto Alegre, RS, Brasil, e os fatores associados, executou-se estudo observacional, de delineamento transversal e base populacional. Através de amostragem aleatória proporcional, por estágios múltiplos e conglomerados, selecionaram-se 1.091 indivíduos, a partir de 18 anos, que responderam a um questionário, em entrevista domiciliar. Aferiu-se o hábito de fumar através de perguntas dirigidas ao tipo de fumo, freqüência e tempo de exposição. A prevalência foi de 34,9% (IC 31,9 - 37,8), sendo de 41,5% (IC 38,5 - 44,4) entre os homens e 29,5% (IC 26,8 - 32,2) entre as mulheres. O início foi, em média, aos 16 (&plusmn;5,6) e 17,8 (&plusmn;6,7) anos, com moda de 15 e 14 anos, respectivamente. Os homens fumavam 19,0 &plusmn; 14,0 cigarros por dia e as mulheres 14,5 &plusmn; 10,3. Analisaram-se as associações através de regressão logística, incluindo-se no modelo sexo, idade, educação, renda, qualificação profissional e consumo de álcool. O hábito de fumar foi mais freqüente entre os homens, indivíduos de menor nível socioeconômico, dos 30 aos 39 anos, e entre os usuários de bebidas alcoólicas. Conclui-se que o tabagismo é freqüente em Porto Alegre, constituindo-se problema de saúde pública similar ao referido pela literatura. O consumo de álcool deve estar associado ao fumo por serem ambos comportamentos de risco, com determinantes comuns.<br>A cross-sectional study was carried out for the purpose of evaluating, the prevalence of smoking and the factors associated with it in Porto Alegre, a city in southern Brazilian. Through proportional, multiple stage, random sampling, 1.091 individuals (92% of those eligible) of 18 or more years of age, were interviewed at home. Exposure to smoking was measured by a questionnaire that inquired about the type, quantity and frequency of tobacco use. The prevalence of smoking was 34.9% (Cl 31.9 - 37.8). It was higher -among men - 41.5% (Cl 38.5 - 44.4) then women - 29.5% (Cl 26.8 - 32.2). The former started smoking at mean age of 16 (&plusmn; 5.6), with mode of 15 and smoked an average of 19.0 (&plusmn; 14.0) cigarettes per day. Females started at a mean age of 17.8 (&plusmn; 6.7), with mode of 14 years old and smoked 14.5 (&plusmn; 10.3). The association of the drinking habit and demographic and socioeconomic variables with smoking was evaluated through logistic regression. The variables included in the model were sex, age, education, income, professional qualification and alcohol consumption. The prevalence of smoking was greater for men, individuals of lower sociecinomic level, between 30 and 39 years of age, and among those accustomed to consuming alcoholic beverages. In conclusion, this study demonstrated that smoking is a public health problem in Brazil as in another countries. It is associated with sex, age, education and professional qualification, as has been observed elsewhere. The association of alcohol consumption with smoking may be understood as risk behavior, both having similar determinants