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BACKGROUND: There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. METHODS: Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. RESULTS: Acceptable safety was reported for the first three patients (infliximab 5 mg kg⻹) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg⻹ were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand-foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS6 31%); median PFS and overall survival were 6 and 14 months, respectively. CONCLUSION: Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencenosulfonatos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Piridinas/administración & dosificación , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencenosulfonatos/efectos adversos , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Progresión de la Enfermedad , Femenino , Humanos , Infliximab , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Piridinas/efectos adversos , Sorafenib , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
A general theory of steady-state diffractive vector modes for lasers with polarizing optical elements is reviewed. The problems inherent in including radially birefringent media such as solid-state rods are emphasized. A trade-off between ease of implementation, ease of interpretation, and cost of computation arises from the choices of representations of the field. In the scalar theory for axisymmetric resonators, the polar representation with expansion of the field in azimuthal Fourier series yields separation into an integral equation for each azimuthal index. A theoretical investigation of this approach for the vector case is presented. For a simple resonator composed of two mirrors and a bifocal lens, separation into coupled pairs of integral equations is obtained. Numerical solutions that use fast Hankel transforms from scalar theory are straightforward. Complications arise when other optical elements are introduced into the resonator. Methods for handling the general case are discussed.
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The geometrical optics approximation is used to form a model of axisymmetric unstable resonators having distributed focus, gain, and loss. A tapered reflectivity feedback mirror is included. The rate equations for propagation through the focusing gain medium are derived. A unique grid is found for propagation without interpolation along eigenrays in each direction. Numerical examples show the effects of distributed gain and focus on the axial and transverse intensity distributions.
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Inositol glycans were prepared from reductively radiomethylated human erythrocyte acetylcholinesterase by sequential treatment with Proteinase K, methanolic KOH, and phosphatidylinositol-specific phospholipase C. Four glycans denoted alpha-delta were resolved by anion exchange high performance liquid chromatography (HPLC). Each glycan was subjected to hydrolysis in 4 M trifluoroacetic acid, and their hexose and hexose phosphate compositions were determined by anion exchange HPLC. The predominant glycan alpha showed a relative stoichiometry of 2 mannoses, 1 mannose 6-phosphate, 1 radiomethylated glucosamine, 1 radiomethylated ethanolamine, and 1 inositol. In contrast, the stoichiometry of glycan beta was 1 mannose, 2 mannose 6-phosphates, 1 radiomethylated glucosamine, 2 radiomethylated ethanolamines, and 1 inositol. Glycans alpha and beta were analyzed by electrospray ionization-mass spectrometry, and respective parent ions of m/z 1266 and 1417 were observed. The fragmentation pattern produced by collision-induced dissociation mass spectrometry of these parent ions was consistent with a common linear core glycan sequence prior to radiomethylation of ethanolamine-phosphate-mannose - mannose - mannose - glucosamine - inositol. Glycan alpha contained a single additional radiomethylated phosphoethanolamine branching from the mannose adjacent to glucosamine, whereas glycan beta contained two additional radiomethylated phosphoethanolamines, one branching from each of the mannoses nearest to glucosamine. Trifluoroacetic acid hydrolysis did not cleave within the N,N-dimethylglucosamine-inositol-phosphate moiety in these glycans, and this component was resolved by anion exchange HPLC and structurally confirmed by mass spectrometry. Dephosphorylation of this component by treatment with 50% HF produced N,N-dimethylglucosamine-inositol, and this conjugate was shown to have a characteristic elution time on cation exchange chromatography in an amino acid analyzer. Both of these fragments involving an intact radiomethylated glucosamine-inositol bond are proposed as new diagnostic indicators in the search for minor glycoinositol phospholipids in cells and tissues.
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Acetilcolinesterasa/sangre , Eritrocitos/enzimología , Glucolípidos/química , Fosfatidilinositoles/química , Polisacáridos/química , Ácido Trifluoroacético/química , Secuencia de Carbohidratos , Cromatografía en Gel , Cromatografía por Intercambio Iónico , Glicosilfosfatidilinositoles , Humanos , Espectrometría de Masas , Datos de Secuencia MolecularRESUMEN
An analytic solution for the bare cavity eigenmodes of a nonsymmetric self-filtering unstable resonator is obtained by a modal expansion in prolate functions, which is a complete and orthogonal set of eigenmodes for a symmetric confocal stable resonator. An accurate representation within the aperture is shown to require only three terms. An efficient use of Gaussian quadrature for the various calculations is described.
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A one-dimensional model of a laser with homogeneously broadened saturable gain and distributed loss is used to calculate the recirculating power and extraction efficiency for the case in which the mirrors are lossless. Accurate numerical results show that optimized single-ended lasers, equivalent symmetric lasers, and optimized symmetric lasers have the same extraction efficiency when the gain is small, but not when it is large. The peak efficiency of the single-ended laser is known to decrease with increasing length of the gain cell at high gain. The efficiency of the symmetric laser is found to decrease much less, so the output power nearly scales linearly with length over the range investigated. Thus past assumptions about equivalences between lasers must be reexamined. An approximate analytic solution of the laser equation is shown to be useful from threshold to closed cavity over a wide range of values of the small signal gain, the distributed loss coefficient, and the length of the gain cell.
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The eigenequation from the geometric theory of unstable resonators with nonuniform reflectivity outcouplers is solved by a series method. Either the reflectivity profile or the dominant mode can be specified and the other can be obtained. A spatially limited output can also be specified, but the resulting mode and reflectivity profile are not guaranteed to be spatially limited. This problem can be avoided, but a good general method for obtaining all of the desired features has not been found.
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An existing geometrical optics method for calculating the longitudinal and transverse dependence of the mode intensities in unstable resonators with sharp-edged feedbacks mirrors and distributed saturable gain is modified to include the nonuniform reflectivity of the outcoupling feedback mirror. Results show that the mode extends increasingly outward as the gain increases, so the size of a limiting aperture must be chosen with care to prevent unwanted diffraction. An attempt to prescribe an arbitrary spatially limited output function of a loaded cavity and to find the required mode and reflectivity profiles yields spatially unlimited functions.
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A brief qualitative experiment and subsequent theoretical study provide new insight concerning off-axis injection of unstable resonators. Theoretical results for aligned resonators show that the regurgitated beam intensity distribution and direction of travel are sensitive to the size, tilt, and other parameters of the injected beam, to the coherence length and number of longitudinal modes of the injecting laser, to clipping and diffraction from apertures, and to resonator length tuning. It is concluded that visual observations of output asymmetries can be used to align the resonator to some degree, but precise alignment using measurement of output asymmetries by a detector array is questionable.
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A ring laser with a beam splitter, an external reverse wave suppressor mirror, and an internal two-way coupling mirror exhibits both traveling wave and standing wave characteristics. A simple 1-D model of this hybrid laser is used to find the frequencies and losses of the steady state longitudinal modes, which depend on the mirror reflectivities and separations in an intricate manner. Adjustment of the suppressor position on a fine scale yields markedly different results for various coarse positions if the internal mirror provides adequate coupling into the reverse wave.
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An optically injected Fabry- Perot cavity containing uniform saturable gain is analyzed. Familiar cubic curves of laser intensity vs injected intensity are obtained for single-ended lasers. The curves for the intensity returning to the injected end of double- ended lasers can have loops, cusps, and undulations if the mirror reflectivities and small- signal gain are properly chosen. The undulations can also occur in doubleended regenerative amplifiers.
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The theoretical characteristics of a 1-D model of a steady-state laser with uniform saturable gain and distributed losses are calculated by iterative solution, using integration of a series representation of the two-way intensity distribution over the length of the laser. Results for this model and for the model with point losses at the end mirrors show that the output can be the same for both models over a range of the point loss factor. This factor becomes unique if the losses are also set equal, but the internal intensity distributions are similar only when the loss is low.
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The deleterious effects of diffraction by the outcoupling aperture on optical resonator intensity profiles, feedback ratios, alignment sensitivities, and dependence of mode separation on Fresnel numbers can be alleviated by adding a phase step near the edge of the feedback mirror. The required locations and magnitudes of the steps for rectangular apertures are shown to be near the values for circular apertures. Improvements in intensity profiles are shown for both centered and off-centered apertures. Failure of the method when one edge of the aperture approaches the optic axis is analyzed.
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Analysis of a particular interferometer shows that severe polarization effects in interferograms of conical optical elements can be prevented. A simple formula is derived for correcting residual polarization effects due to spatially varying reflection coefficients. The formula can be used for estimating whether a correction is required. Several applications are discussed.