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We present an updated account of breast cancer treatment and of progress toward "precision" cancer therapy; we focus on new developments in diagnostic molecular pathology and breast cancer that have emerged during the past 2 years. Increasing awareness of new prognostic and predictive methodologies, and introduction of next generation sequencing has increased understanding of both tumor biology and clinical behavior, which offers the possibility of more appropriate therapeutic choices. It remains unclear which of these testing methodologies provides the most informative and cost-effective actionable results for predictive and prognostic pathology. It is likely, however, that an integrated "step-wise" approach that uses the traditional clinical-pathologic paradigms coordinated with molecular characterization of breast tumor tissue, will offer the most comprehensive and cost-effective options for individualized, "precision" therapy for patients with breast cancer.
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Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Medicina de Precisão , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Genes erbB-2/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica/normas , Imuno-Histoquímica/tendências , Família Multigênica , Receptores de Progesterona/genéticaRESUMO
This corrects the article DOI: 10.1103/PhysRevLett.108.065701.
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A VISAR (Velocity Interferometer System for Any Reflector) is a Doppler velocity interferometer which is an important optical diagnostic in shockwave experiments at the national laboratories, used to measure equation of state (EOS) of materials under extreme conditions. Unwanted reflection of laser light from target windows can produce an additional component to the VISAR fringe record that can distort and obscure the true velocity signal. Accurately removing this so-called ghost artifact component is essential for achieving high accuracy EOS measurements, especially when the true light signal is only weakly reflected from the shock front. Independent of the choice of algorithm for processing the raw data into a complex fringe signal, we have found it beneficial to plot this signal as a Lissajous and seek the proper center of this path, even under time varying intensity which can shift the perceived center. The ghost contribution is then solved by a simple translation in the complex plane that recenters the Lissajous path. For continuous velocity histories, we find that plotting the fringe magnitude vs nonfringing intensity and optimizing linearity is an invaluable tool for determining accurate ghost offsets. For discontinuous velocity histories, we have developed graphically inspired methods which relate the results of two VISARs having different velocity per fringe proportionalities or assumptions of constant fringe magnitude to find the ghost offset. The technique can also remove window reflection artifacts in generic interferometers, such as in the metrology of surfaces.
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Clinical decisions regarding the suitability of adjuvant systemic therapy for individual patients with breast cancer depends on comprehensive assessment of the underlying biology of each patient's tumor. The previous clinical-pathologic paradigm for treatment, which had been used for decades, now has been augmented by significant advances in molecular analysis of breast tumor tissue samples. Molecular testing has the potential to understand better both tumor biology and clinical behavior, which enables more appropriate therapy choices to be made. We review the rapid evolution in profiling breast cancer tissues, and discuss the current evidence for clinical use of this information and how the emerging molecular paradigm can be integrated into the clinical-pathologic context as we progress toward "precision" therapy for patients with breast cancer and other solid tumors.
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Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Imuno-Histoquímica , Animais , Bioensaio/métodos , Neoplasias da Mama/terapia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , PrognósticoRESUMO
Radiation-driven, low-adiabat, cryogenic DT layered plastic capsule implosions were carried out on the National Ignition Facility (NIF) to study the sensitivity of performance to peak power and drive duration. An implosion with extended drive and at reduced peak power of 350 TW achieved the highest compression with fuel areal density of ~1.3±0.1 g/cm2, representing a significant step from previously measured ~1.0 g/cm2 toward a goal of 1.5 g/cm2. Future experiments will focus on understanding and mitigating hydrodynamic instabilities and mix, and improving symmetry required to reach the threshold for thermonuclear ignition on NIF.
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Dynamic compression by multiple shocks is used to compress iron up to 560 GPa (5.6 Mbar), the highest solid-state pressure yet attained for iron in the laboratory. Extended x-ray absorption fine structure (EXAFS) spectroscopy offers simultaneous density, temperature, and local-structure measurements for the compressed iron. The data show that the close-packed structure of iron is stable up to 560 GPa, the temperature at peak compression is significantly higher than expected from pure compressive work, and the dynamic strength of iron is many times greater than the static strength based on lower pressure data. The results provide the first constraint on the melting line of iron above 400 GPa.
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Mixing of plastic ablator material, doped with Cu and Ge dopants, deep into the hot spot of ignition-scale inertial confinement fusion implosions by hydrodynamic instabilities is diagnosed with x-ray spectroscopy on the National Ignition Facility. The amount of hot-spot mix mass is determined from the absolute brightness of the emergent Cu and Ge K-shell emission. The Cu and Ge dopants placed at different radial locations in the plastic ablator show the ablation-front hydrodynamic instability is primarily responsible for hot-spot mix. Low neutron yields and hot-spot mix mass between 34(-13,+50) ng and 4000(-2970,+17 160) ng are observed.
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Clinical laboratory testing for human epidermal growth factor receptor-2 (HER2) in patients with newly diagnosed breast and gastric cancer is critically important for therapeutic decisions about adjuvant treatment. The HER2 pathway is a major molecular driver of disease progression in a subset of these solid tumors and the results of HER2 testing determine which patients are likely to respond to an expanding variety of therapies that target this important biologic pathway. Given the significant clinical impact of these test results on patient management and adjuvant treatment decisions, standardization of the assay for HER2 and assured reliability of these results are critical. We review highlights of the clinical rationale that underlies HER2 testing for both breast and gastric carcinomas, and describe some of the challenges associated with ensuring accurate test results.
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Adenocarcinoma/diagnóstico , Neoplasias da Mama/diagnóstico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Aneuploidia , Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Cromossomos Humanos Par 17 , Feminino , Genes erbB-2 , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Terapia de Alvo Molecular , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/terapiaRESUMO
A platform consisting of a multi-shock drive and an implosion backlighter has been developed for x-ray absorption fine structure (XAFS) measurements on materials compressed to multi-Mbar pressures. The experimental setup, target design, and backlighter characteristics are presented. Extended XAFS (EXAFS) measurements for various materials have been demonstrated. A quintuple-crystal design is described to enhance the efficiency of the x-ray spectrometer, enabling observation of very weak EXAFS signals in a single shot.
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A method of obtaining powder diffraction data on dynamically compressed solids has been implemented at the Jupiter and OMEGA laser facilities. Thin powdered samples are sandwiched between diamond plates and ramp compressed in the solid phase using a gradual increase in the drive-laser intensity. The pressure history in the sample is determined by back-propagation of the measured diamond free-surface velocity. A pulse of x rays is produced at the time of peak pressure by laser illumination of a thin Cu or Fe foil and collimated at the sample plane by a pinhole cut in a Ta substrate. The diffracted signal is recorded on x-ray sensitive material, with a typical d-spacing uncertainty of ~0.01 Å. This diagnostic has been used up to 0.9 TPa (9 Mbar) to verify the solidity, measure the density, constrain the crystal structure, and evaluate the strain-induced texturing of a variety of compressed samples spanning atomic numbers from 6 (carbon) to 82 (lead). Further refinement of the technique will soon enable diffraction measurements in solid samples at pressures exceeding 1 TPa.
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A technique for comparing simulation results directly with radiograph data from backlit capsule implosion experiments will be discussed. Forward Abel transforms are applied to the kappa*rho profiles of the simulation. These provide the transmission ratio (optical depth) profiles of the simulation. Gaussian and top hat blurs are applied to the simulated transmission ratio profiles in order to account for the motion blurring and imaging slit resolution of the experimental measurement. Comparisons between the simulated transmission ratios and the radiograph data lineouts are iterated until a reasonable backlighter profile is obtained. This backlighter profile is combined with the blurred, simulated transmission ratios to obtain simulated intensity profiles that can be directly compared with the radiograph data. Examples will be shown from recent convergent ablation (backlit implosion) experiments at the NIF.
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The compact Wedge Range Filter (WRF) proton spectrometer was developed for OMEGA and transferred to the National Ignition Facility (NIF) as a National Ignition Campaign diagnostic. The WRF measures the spectrum of protons from D-(3)He reactions in tuning-campaign implosions containing D and (3)He gas; in this work we report on the first proton spectroscopy measurement on the NIF using WRFs. The energy downshift of the 14.7-MeV proton is directly related to the total ρR through the plasma stopping power. Additionally, the shock proton yield is measured, which is a metric of the final merged shock strength.
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The National Ignition Facility has been used to compress deuterium-tritium to an average areal density of ~1.0±0.1 g cm(-2), which is 67% of the ignition requirement. These conditions were obtained using 192 laser beams with total energy of 1-1.6 MJ and peak power up to 420 TW to create a hohlraum drive with a shaped power profile, peaking at a soft x-ray radiation temperature of 275-300 eV. This pulse delivered a series of shocks that compressed a capsule containing cryogenic deuterium-tritium to a radius of 25-35 µm. Neutron images of the implosion were used to estimate a fuel density of 500-800 g cm(-3).
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Collection of representative samples of debris following inertial confinement fusion implosions in order to diagnose implosion conditions and efficacy is a challenging endeavor because of the unique conditions within the target chamber such as unconverted laser light, intense pulse of x-rays, physical chunks of debris, and other ablative effects. We present collection of gas samples following an implosion for the first time. High collection fractions for noble gases were achieved. We also present collection of solid debris samples on flat plate collectors. Geometrical collection efficiencies for Au hohlraum material were achieved and collection of capsule debris (Be and Cu) was also observed. Asymmetric debris distributions were observed for Au and Be samples. Collection of Be capsule debris was higher for solid collectors viewing the capsule through the laser entrance hole in the hohlraum than for solid collectors viewing the capsule around the waist of the hohlraum. Collection of Au hohlraum material showed the opposite pattern: more Au debris was collected around the waist than through the laser entrance hole. The solid debris collectors were not optimized for minimal Cu backgrounds, which limited the conclusions about the symmetry of the Cu debris. The quality of the data limited conclusions on chemical fractionation effects within the burning, expanding, and then cooling plasma.
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Laser-driven shock compression experiments reveal the presence of a phase transition in MgSiO(3) over the pressure-temperature range 300-400 GPa and 10 000-16 000 K, with a positive Clapeyron slope and a volume change of â¼6.3 (±2.0) percent. The observations are most readily interpreted as an abrupt liquid-liquid transition in a silicate composition representative of terrestrial planetary mantles, implying potentially significant consequences for the thermal-chemical evolution of extrasolar planetary interiors. In addition, the present results extend the Hugoniot equation of state of MgSiO(3) single crystal and glass to 950 GPa.
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An x-ray streak camera platform has been characterized and implemented for use at the National Ignition Facility. The camera has been modified to meet the experiment requirements of the National Ignition Campaign and to perform reliably in conditions that produce high electromagnetic interference. A train of temporal ultra-violet timing markers has been added to the diagnostic in order to calibrate the temporal axis of the instrument and the detector efficiency of the streak camera was improved by using a CsI photocathode. The performance of the streak camera has been characterized and is summarized in this paper. The detector efficiency and cathode measurements are also presented.
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The introduction of targeted cancer therapies into clinical practice, in which patients are selected for novel treatments based on results of companion molecular testing of their tumor specimens, has created significant new challenges for the surgical pathology laboratory. These include standardization of tissue handling and sample preparation with accurate documentation to ensure optimal quality of clinical samples to reduce the risk of errors in molecular biology tests. The assay of tumor tissues for biomarkers that can provide predictive data for prognosis or treatment should enable selection of the most appropriate therapies (Yaziji et al. 2008, Hicks and Kulkarni 2008). Major advances have been made in the ability to profile clinical samples for research at the DNA, RNA and protein levels. To translate this new information into the clinical setting, however, the quality of the starting material, in this case the tumor tissue, determines the accuracy and reliability of companion diagnostic assay results and therefore optimal therapeutic strategies. Inaccurate results owing to compromised tissue quality can lead to false positive or false negative results with therapeutic consequences that can harm patients and affect their eventual outcome.
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Biomarcadores/análise , Isquemia Fria/normas , Patologia Cirúrgica/normas , Pesquisa Translacional Biomédica/normas , Neoplasias da Mama/química , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Isquemia Fria/métodos , Erros de Diagnóstico/prevenção & controle , Feminino , Técnicas de Preparação Histocitológica/métodos , Técnicas de Preparação Histocitológica/normas , Humanos , Patologia Cirúrgica/métodos , Controle de Qualidade , Padrões de Referência , Manejo de Espécimes/métodos , Manejo de Espécimes/normas , Fixação de Tecidos/métodos , Fixação de Tecidos/normasRESUMO
Adenocarcinomas of the esophagus and stomach constitute a substantial number of cancer cases worldwide. Most patients in the United States are diagnosed at an advanced or metastatic stage and, therefore, the prognoses have been poor. New treatments are needed to augment standard surgical and medical management. Recent studies have shown that a subset of esophageal and gastric adenocarcinomas overexpress the HER2 protein, similar to the overexpression seen in breast cancer. Because trastuzumab, a monoclonal antibody to the HER2 receptor, has been used with success in primary and HER2 positive metastatic breast cancers, the phase III ToGA trial was designed to assess the impact of trastuzumab in patients with HER2 positive gastric cancers. They have reported an increase in overall survival time for patients treated with chemotherapy and trastuzumab compared to those treated with chemotherapy alone. They have reported an increase in overall survival time for patients treated with chemotherapy and trastuzumab compared to those treated with chemotherapy alone. This means that accurate HER2 testing in gastric and esophageal carcinomas is necessary. While the breast cancer scoring system can be used to determine HER2 status in most cases, modifications are necessary to accommodate the heterogeneity and incomplete membrane staining that are observed more frequently in gastric cancers. An understanding of the scoring modifications is required for proper stratification of gastric cancer patients for treatment.
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Adenocarcinoma/química , Biomarcadores Tumorais/análise , Neoplasias Esofágicas/química , Receptor ErbB-2/análise , Neoplasias Gástricas/química , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Quimioterapia Combinada , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , TrastuzumabRESUMO
The fuel entropy and required drive energy for an inertial confinement fusion implosion are set by a sequence of shocks that must be precisely timed to achieve ignition. This Letter reports measurements of multiple spherical shock waves in liquid deuterium that facilitate timing inertial confinement fusion shocks to the required precision. These experiments produced the highest shock velocity observed in liquid deuterium (U(s) = 135 km/s at â¼2500 GPa) and also the first observation of convergence effects on the shock velocity. Simulations model the shock-timing results well when a nonlocal transport model is used in the coronal plasma.
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The velocity and remaining ablator mass of an imploding capsule are critical metrics for assessing the progress toward ignition of an inertially confined fusion experiment. These and other ablator rocket parameters have been measured using a single streaked x-ray radiograph. A regularization technique has been used to determine the ablator density profile ρ(r) at each time step; moments of ρ(r) then provide the areal density, average radius, and mass of the unablated, or remaining, ablator material, with the velocity determined from the time derivative of the average radius. The technique has been implemented on experiments at the OMEGA laser facility.