4042 Background: OSI-7904L is a liposomal TS inhibitor with increased plasma residence and superior preclinical antitumor activity compared to parent drug or 5-FU. Methods: A 2-stage Simon design was used to evaluate the activity of OSI-7904L in G/GEJC, administered at 12 mg/m2 over 30 min every 21 days. Eligibility criteria included pathologically confirmed G/GEJC, ECOG PS 0–2, no prior chemo for advanced disease and ≥1 measurable lesion per RECIST. Secondary endpoints were safety, time to progression (TTP), survival and PK/ PD endpoints (TS genotype, 2’-dU and homocysteine). Results: Fifty of 53 enrolled pts were treated. Median age was 64 years (range 35–82), 62% were male and 90% had ECOG PS 0/1. Primary site was gastric in 80% of pts and GEJ in 20%. Two-thirds of pts had recurrent or metastatic disease; main sites of metastases were liver and lymph node. To date, 215 cycles have been given, median of 4/pt (range 1–12+). Eleven pts required dose reductions, mainly for skin toxicity (8 pts). Reductions and/or prophylaxis with dexamethasone ameliorated symptoms, permitting further treatment. Seven pts had cycle delays. The ORR was 15% (95% CI 6.2 - 28.3) with 7 PRs in 47 evaluable pts. Twenty-three pts (49%) had SD including several minor responses. Median TTP was 17 weeks. G3/4 neutropenia (14%) and thrombocytopenia (4%) were uncommon. The main G3/4 nonhematological toxicities were skin-related 20%, fatigue 19%, mucositis/stomatitis 16% and diarrhea 9%. PK data showed high interpatient variability and significantly higher AUC in pts with G3/4 toxicity and/or dose reductions. Response did not correlate with AUC. Baseline homocysteine did not influence cycle 1 toxicity. TS genotype and 2’-dU elevations as well as tumor biopsies from a subset of pts are being analyzed. Conclusions: OSI-7904L is active in advanced G/GEJC with ORR and TTP comparable with other single agents. Safety profile was favorable and dexamethasone premedication increased tolerability. Study was funded by OSI Pharmaceuticals. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI OSI OSI OSI OSI

Tumor-associated macrophages (TAMs) promote key processes in tumor progression, like angiogenesis, immunosuppression, invasion, and metastasis. Increasing studies have also shown that TAMs can either enhance or antagonize the antitumor efficacy of cytotoxic chemotherapy, cancer-cell targeting antibodies, and immunotherapeutic agents—depending on the type of treatment and tumor model. TAMs also drive reparative mechanisms in tumors after radiotherapy or treatment with vascular-targeting agents. Here, we discuss the biological significance and clinical implications of these findings, with an emphasis on novel approaches that effectively target TAMs to increase the efficacy of such therapies.

Background Recent studies have suggested that vascular endothelial growth factor (VEGF) is an important stimulus for the growth of new blood vessels in the eye. Anti-VEGF therapy is thus a potential treatment for exudative macular degeneration and diabetic retinopathy. Methods Previously described animal models of vascular leakage and ocular neovascularization, including the Miles assay, the rat corneal angiogenesis model, and the mouse retinopathy of prematurity (ROP) model, were used to study this drug. After these studies, a phase IA single ascending dose study of intravitreal injections of the drug was performed in 15 patients with subfoveal choroidal neovascularization secondary to exudative age-related macular degeneration (AMD). Results The Miles assay model showed almost complete attenuation of VEGF-mediated vascular leakage following addition of EYE001, and the corneal angiogenesis model also showed a significant reduction in neovascularization with EYE001. The ROP model showed inhibition of 80% of the retinal neovascularization compared with controls (P = 0.0001). The phase IA safety study of patients with exudative AMD showed no significant safety issues related to the drug. Ophthalmic evaluation revealed that 80% of patients showed stable or improved vision 3 months after treatment and that 27% of eyes demonstrated a three-line or greater improvement in vision on the Early Treatment for Diabetic Retinopathy Study chart at this time. Conclusion Anti-VEGF therapy is a promising new avenue for the treatment of neovascular diseases of the eye, including exudative macular degeneration and diabetic retinopathy. Preclinical data from studies with EYE001 support clinical evaluation of its efficacy in such diseases. This report is the first to describe administration of anti-VEGF therapy in humans for exudative macular degeneration and shows the safety of such therapy for single injections. Further clinical studies are necessary to determine the safety of multiple intravitreal injections of EYE001 and larger studies are needed to prove the efficacy of this novel, potentially therapeutic agent for neovascular AMD.

Summary from only given. Two-beam adaptive phase demodulators are used for noncontact and non-invasive measurements of the small surface displacements produced by ultrasonic waves propagating in an object. As an example the setup of a two-wave mixing-based photorefractive demodulator is shown.

We describe both theoretically and experimentally a polarization independent interferometric adaptive photodetector based on photorefractive two-wave mixing. The configuration is based on the simultaneous recording of two independent gratings in a single photorefractive crystal. Applied to the detection of ultrasonic signals, this interferometric photodetector operates with depolarized beams issued from multimode fibers and gives a detection limit close to the ultimate.

Laser-ultrasonics is an emerging nondestructive technique using lasers for the generation and detection of ultrasound which presents numerous advantages for industrial inspection. In this paper, the problem of detection by laser-ultrasonics of small defects within a material is addressed. Experimental results obtained with laser-ultrasonics are processed using the Synthetic Aperture Focusing Technique (SAFT), yielding improved flaw detectability and spatial resolution. Experiments have been performed on an aluminum sample with a contoured back surface and two flat-bottom holes. Practical interest of coupling SAFT to laser-ultrasonics is also discussed.

their long excited lifetime, thermalization of the excited states and interactions with the host lattice control the emission characteristics, which include a temperature-dependent decay lifetime and intensity. Thus temperature measurement techniques may include either measurements of the lifetime of a selected line or the intensities of one or two emission lines. For imaging, as in this study, the latter approach is employed. By recording the intensity of a temperature-dependent line and dividing it by one that is temperature independent, normalization for nonuniform illumination and coating is achieved. For example, (La,0,SEut3) was previously used for two-dimensional imaging of fields at low temperatures? The mechanisms that make these compounds temperature sensitive varies. One of the most common thermographic phosphors L~,O,S:EU+~ is described by Fonger and S t r ~ c k . ~ However, the temperature sensitivity of this phosphor declines above 500 K, thereby limiting its use to low and moderate temperatures. Yttrium-aluminum-garnet doped at 3% with trivalent dysprosium, YAG:Dyt3, was suggested by Goss et al.5 for high temperature work. Thus, to extend this technique to higher temperatures, YAG:Dy13, with a temperature range of 300-1800 K, was selected. In this phosphor the two closely spaced energy levels, 4F,/, and 4115/2, in the trivalent dysprosium are used for temperature measurement. These levels, which are separated by 1070 cm-', can be excited from the ground state by radiation of 355 nm by use of the third harmonic of a Nd:YAG laser. Because of their long lifetime and relatively close spacing, the population in these states following excitation is controlled by the Boltzmann distribution. Thus, as temperature increases, the population in the G level (41i5/2) increases as does its emission. By contrast the population in the F level (4F,,2) remains relatively unchanged. Emission from this state is used for normalization. To demonstrate this technique, a threesquare cm nickel coupon was coated with YAG:DY+~ 3%. The powder was bonded to the substrate by braising in a 1100 K atmospheric furnace for 12 hours. For calibration, the coated coupon was placed in a temperaturecontrolled furnace with optical access and was illuminated by a 70 mJ/pulse 355 nm tripled output of a Nd:YAG laser. The dispersion spectrum of the emission at several temperatures is shown in Fig. 1. As expected, the emission at 458 nm from the G level increases with temperature, whereas the emission from the F level, at 497 nm, is nearly constant. The variations of the ratio of the emission intensities of these two lines with temperature, which can serve as a calibration curve, is shown in Fig. 2. Clearly, this ratio exhibits a Boltzmann-like dependence with AE = 965 cm-'. For temperature imaging, digital images of this sample were obtained at various temperatures. Two images were recorded at each temperature: a temperature-sensitive image through a 10-nm bandpass filter at 458 nm and a normalization image through a 10-nm bandpass filter at 500 nm. Following calibration, images of the temperature distributions were obtained from a pixel-by-pixel division of these images. 0.14

The generation and the detection of ultrasound at distance by lasers present many advantages over conventional piezo electric based methods. In particular, this technique can be used on surfaces of complex geometry and on products at elevated temperature on a production line.1

The optical detection of transient surface motion has many practical applications which include, in particular, the vibration monitoring of engineering structures (aircraft, power plants,...) and the detection of ultrasound produced by piezoelectric transducer or by pulse laser excitation. This last application where ultrasound is generated and detected by lasers, presents many advantages over conventional piezoelectric based methods. First, laser-ultrasonics is a remote sensing technique. Consequently it can be used, for example, for inspecting hot materials and products moving on a production line. Second, surfaces of complex shapes can also very easily be probed. For many applications, these advantages compensate the usually lower sensitivity of the laser-based technique compared to piezoelectric transduction.

The characteristics of an interferometric system based on two-wave mixing at 1.06 mu m in photorefractive InP:Fe under an applied field for the detection of ultrasonic motion of a scattering surface are described. A theoretical analysis of possible configurations for the detection of small phase modulation in the undepleted-pump approximation is presented. Experimental assessment of the device for both cw and pulse regimes is performed: The sensitivity, the etendue, the response time, and the behavior under ambient vibrations or moving inspected samples are provided. This adaptive device many features appropriate for industrial inspection and compares advantageously with the passive confocal Fabry-Perot device that is now widely used. (C) 1997 Optical Society of America.

We present and describe different techniques based on the photorefractive effect that are used for the optical detection of ultrasonic signals. These techniques use the wavefront adaptation properties of the photorefractive effect. They are : the photorefractive beam combiner, the double phase conjugate heterodyne detection and the adaptive photodetector based on non steady state photoelectromotive force. Their respective advantages and drawbacks, will be overviewed. We will insist on the latest development and performances obtained with the photorefractive beam combiner that seems to us the most promising technique for the detection of ultrasonic signals on rough surfaces. We will show that a sensor with near optimum sensitivity can be developed with the same photorefractive crystal at different wavelength in the range of 1 mu m to 1.55 mu m.

Nondestructive methods previously developed for the detection of flaws, such as delaminations, or for the evaluation of the elastic properties of materials, could be judiciously adapted in order to get a better assessment of plasma-sprayed coatings. Laser ultrasonics is a nondestructive evaluation method which relies on both optics and ultrasonics. A short-pulse laser generates an ultrasonic wave into the material to be inspected, and a long-pulse laser, coupled to an interferometer, detects the resulting ultrasonic displacement. Laser ultrasonics is a remote sensing method and therefore could be used for the monitoring of hot plasma-sprayed coatings during the deposition process. In this work, experiments were performed on samples composed of ZrO2 sprayed under different conditions onto thick copper substrates. The samples were first probed by conventional ultrasonic transducers and then by a non contact laser-ultrasonic scanning system. The two series of measurements agreed well. These experiments showed that, after calibration, the coating thickness could be measured during the deposition process, with a relatively good accuracy, by laser ultrasonics. The laser-ultrasonic scanning system also revealed non uniformity of more than 10% in the coating thickness of the tested samples. This thickness variation is possibly caused by a temperature gradient induced in the coatings during spraying.

Optical techniques for ultrasonic measurements present several advantages over conventional piezoelectric methods. First, they are remote sensing techniques and can be, for example, used for the inspection of materials at elevated temperature or products moving on a production line. Secondly, surfaces of complex shape can be easily probed since these techniques work with scattered light. For specific applications, these advantages compensate the usually lower sensitivity of optical techniques.

We present and describe two techniques used for optical detection of ultrasonic signals based on the photorefractive effect. These techniques used the wavefront adaptation properties of the photorefractive effect. In the photorefractive beam combiner, a local oscillator matched to the signal wavefront is created, leading to an homodyne detection system having a large etendue. In the double phase conjugate heterodyne detection system the signal beam wavefront is cleaned by a double phase conjugate mirror and transformed in a plane wave that is sent on a classical heterodyne detection system. Both systems are characterized and used to detect ultrasound.