Manual Lung Cancer: State of the Art

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Additionally, serum miR and miRb have been considered as potential markers for lung carcinogenesis [ 51 ]. High hsa-mir and low hsa-let-7a-2 can detect lung cancer correctly [ 54 ]. Fluorescence, interferometric, surface plasmon resonance biosensors SPR , optrode-based fiber, evanescent wave fiber, and resonant mirror biosensors are the main types of optical biosensors. SPR-based sensors are more attractive for lung cancer markers detection, which can be classified as label-free and real-time affinity reaction detection systems.


A high-precision optical system was developed to detect CYFRA based on magnetic enzyme-linked immunoassay [ 73 ]. Experimental results demonstrated that the proposed optical system has potential to become a powerful tool for rapid diagnostic of lung cancer marker with several advantages such as compactness, sensitive, and fast. A plasmonic optical fiber immunosensor was also developed by Ribaut et al.

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Their research findings offered an important milestone towards the clinical detection of biomarkers in tissues. Quartz is a popular crystal to develop analytic devices such as quartz crystal microbalance QCM sensor.

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QCM-based sensors can detect point mutation in lung cancer patients [ 75 ], which measure frequency changes in quartz crystal resonators based on adsorbate recognition, and the mass changes caused by selective binding can be detected by the corresponding changes in crystals. The advantages of piezoelectric sensors include easy-to-use, cost-effective, and sensitive.

Electrochemical biosensors measure the changes of dielectric properties, dimension, shape and charge distribution while antibody—antigen complex occurred on the electrode surface [ 76 ]. Electrochemical biosensors offer high sensitivity and specificity for lung tumor markers detection.

Electrochemical-based transducers generally consists of semiconductors and screen-printed electrodes for constructing the biosensors, which able to detect molecules such as proteins, antibody, DNA, antigen and heavy metal ions. The recent advances in electrochemical nano-biosensors offer promising for diagnosis of molecules with significant benefits in inexpensive, simplicity, reliability and fast-response, high sensitivity and specificity.

Electromagnetic tomography EMT has attracted many attentions worldwide since it offers a promising alternative to existing medical imaging methods, such as CT or MRI. The approach uses non-ionizing radiation in the low GHz region of the EM spectrum. EMT approach is a safe and cost-effective diagnostic tool and provides structural and functional imaging in one device.

Various EMT approaches have been applied for biomedical imaging with particular focus on imaging lung, brain, heart, liver tissue and biological tissues [ 77 — 90 ]. Watson et al. The phase-stable amplifiers and the gradiometers configurations need not be mutually exclusive, and it was reported that the highest measurement precision could be achieved by utilizing both approaches. The EMT image quality would be improved by increasing the number of transmitters and receivers, however, such method also increases the cost, complexity and operation time of the EMT system.

Compared to the conventional systems, the proposed rotational system offered a better field penetration depth towards the center of image.

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  7. Semenov et al. The FDTD method was applied to solve the 3D electromagnetic problem, and the gradient-based approach was used to solve the inverse problem. Their research findings demonstrated that EMT approach has the potential to become a useful tool for brain stroke detection in the future. More recently, Wang et al. The thorax model was located in the middle of the tank and was energized with a magnetic field generated by coils located outside of the tank wall.

    During data collection, the transmitting coils transmitted EM signals into the thorax, and the receiving coils measured the scattered magnetic fields from the thorax. A reconstructed image of the thorax model was obtained using the measured data. To study the feasibility of EMT for lung tumor detection, Wang et al. The system made of 16 circular coils. The finite element approach was applied to compute the voltage and the measured region was divided into triangular meshes. The scattered field measured by any receiver can be modeled as [ 95 ]:. Born Approximation was applied to solve the forward problem, thus Eq.

    The proposed EMT approach offered crucial priority information that can be exploited to improve the capabilities of diagnostics methods. The advantages of the proposed method include simplified imaging processing due to the image quantity is proportional to the dielectric properties contrast. The current available lung screening approaches are effective but have some limitations as detailed above.

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    EMT-based approaches have the potential to become an additional or alternative method to CT for lung disease detection. However, these techniques have some drawbacks, such as heavy computational imaging algorithm, difficult hardware systems for clinical applications, and limited spatial resolution.

    To solve these challenges, many researchers focused on developing a high dynamic hardware implementation system. Additionally, many investigators used more coils to improve the image quality. However, such method increases the mutual coupling signals between coils, which may reduce the detection accuracy. Moreover, the cost and complexities of the hardware implementation system also increased with increasing the number of coils. To solve this problem, a single coil could be applied to replace the multi-coil array. At the present time, molecular predictive factors and gene signatures are investigational.

    Lung Cancer

    Patient selection is of paramount importance. Proper recovery from surgery and the absence of major comorbidities are essential features. Toxicity is significant, but manageable and transient. Neutropenia is the most relevant side effect due to the risk of febrile neutropenia.

    The role of timing of administration, adjuvant radiotherapy RT and of newer drugs under evaluation is also reviewed. Nonetheless, even after an apparently complete resection procedure the risk of recurrence remains substantial. The benefit of adjuvant chemotherapy AC was not demonstrated until one decade ago with the repot of trial exploring the value of active cisplatin combinations along with optimal supportive care measures.

    Synergistic cytotoxicity with chemotherapeutic agents and radiotherapy has been reported and a phase I trial has been concluded Shin et al. Trastuzumab Herceptin is a humanized monoclonal antibody that targets the HER-2 receptor with demonstrated activity in metastatic breast cancer. Strategies targeting angiogenesis can be classified broadly as those targeting the endothelium and those targeting the extracellular matrix. Vascular endothelial growth factor VEGF is the single most commonly upregulated angiogenic factor in both grafted and naturally occurring tumors, thus being a prime target for antivascular therapy Keshet and Ben-Sasson, A phase II randomized trial in advanced NSCLC of bevacizumab combined with carboplatin and paclitaxel has been performed reporting interesting results Johnson et al.

    A randomized phase III study of carboplatin and paclitaxel with or without bevacizumab in stages IIIB and IV NSCLC is ongoing, with the exclusion of the squamous histology because of the high rate of fatal hemoptysis occurring in the phase II study in patients with squamous cell carcinoma.

    In a recent phase II study of SU combined with cisplatin and gemcitabine in advanced cancer patients, an unexpected high rate of thromboembolic events has been reported Kuenen et al. Clinical trials in lung cancer of SU combined with other chemotherapeutic regimens are ongoing. Preclinical studies have shown that ZD inhibits tumor growth both in vitro and in vivo Wedge et al. Phase I study showed minimal-drug-related toxicity Basser et al. Matrix metalloproteinases MMPs are zinc-dependent proteases responsible for degradation of the extracellular matrix promoting angiogenesis and tumor growth.

    Several MMP inhibitors have been developed and tested in clinical trials in different tumor types, including lung cancer. Moreover, prinomastat and other MMPI showed a toxicity profile probably not suitable for chronic administration. However, novel MMPIs with better toxicity profiles are emerging. BMS, combined with carboplatin and paclitaxel Gupta et al. Neovastat, an MMPI extracted from shark cartilage, has shown promising evidence of activity in pretreated lung cancer patients Franqois et al. Pharmacological inhibitors of conventional PKCs block proliferation and promote death of tumor cells and sensitize tumor cells to chemotherapeutic agents Tamaoki and Nakano, Interesting results have been reported in a phase II study of Affinitak plus carboplatin and paclitaxel Yuen et al.

    Swiftly, phase III trials of Affinitak combined with polychemotherapy carboplatin plus paclitaxel or cisplatin plus gemcitabine have started. The first study of carboplatin plus paclitaxel plus or minus Affinitak failed to demonstrate any advantage for patients treated with Affinitak Lynch et al. The second study of cisplatin and gemcitabine plus or minus Affinitak has been interrupted early. Ras is a membrane-bound G protein involved in signal transduction of numerous intracellular pathways leading to cell proliferation, cell differentiation, cell cycle regulation, and angiogenesis.

    Its potential utility in lung cancer is related to the capability of also inhibiting the growth of the K-ras mutant and nonmutant human tumor xenografts. Preliminary results of a phase II study in advanced pretreated NSCLC have been reported with no objective response and some disease stabilizations Dang et al. Ras proteins are normally synthetized as pro-ras proteins, which undergo a number of post-translational modifications, the most important of which is farnesylation that allows anchorage of ras proteins to the inner surface plasma membrane and their consequential functioning.

    Farnesyl transferase is the key enzyme for this post-translational modification. Inhibitors of this enzyme, farnesyl transferase inhibitors FTIs , interfere with this ras modification and disrupt signal transduction. Bcl-2 is a key regulator of the cell death pathway and an antiapoptotic protein Reed et al. Its expression is correlated with poor prognosis of several malignancies Berardo et al. Oblimersen G is an oligonucleotide antisense compound targeting the Bcl-2 mRNA and therefore inducing apoptosis.

    Preclinical studies have shown that Oblimersen can circumvent chemoresistance and increase cytotoxicity when administered concurrently with chemotherapeutic agents Zangemeister-Wittke et al. Arachidonic acid has been suggested to be a potential mitogenic signal, and it is also the precursor for several eicosanoids with potent biological effects, including cellular inflammation and growth.

    Arachidonic acid can be metabolized by three major pathways: the cyclooxygenase COX pathway, which leads to the formation of prostaglandins PGs and thromboxane; the lypoxygenase LOX pathway, which forms hydroxyeicosatetraenoic acids HETEs and leukotrienes; and the cytochrome P monooxygenase pathway, which leads to the formation of epoxides.

    COX and LOX pathways seem to play an important role in tumorigenesis as well as cancer development and metastatic spread. Two isoforms of COX exist. COX-1 is constitutively expressed, while COX-2 is inducible by growth factors, oncogenes, carcinogens, and tumor-promoting phorbol esters. COX-2 is overexpressed in various human malignancies Soslow et al.

    Mechanisms involved in COX-2 participation in tumor growth include xenobiotic metabolism, angiogenesis stimulation, invasiveness, inflammation, inhibition of immune surveillance, and inhibition of apoptosis. The most studied COX-2 inhibitors are celecoxib, rofecoxib, valdecoxib, and etoricoxib. Synergistic cytotoxicity has been observed in NSCLC cell lines with a combination of coxibs and several chemotherapeutic agents or radiation therapy Hida et al.

    To date, few clinical studies on this issue have been reported.

    Another phase II study of celecoxib plus docetaxel as a second-line treatment in NSCLC has shown a similar response rate to that reported for single-agent docetaxel, but an unexpectedly high rate of neutropenic fever Gadgeel et al. Altorki et al. LOXs represent a family of enzymes that carry out the stereo- and regio-specific conversion of 1,4- cis , cis double bonds in unsaturated fatty acids to 1,3 cis , trans hydroperoxides.

    Numerous studies have shown that compounds that inhibit various LOX activities can prevent or reduce malignant disease. LY multiple eicosanoid pathway modulator is a novel oral agent that inhibits 5-LOX synthesis. The improved understanding of the molecular basis of tumorigenesis and cancer diffusion allows several novel targeted agents to be introduced in clinical evaluation.

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    Currently, the minority of these new drugs offer promise of improved outcomes and negative results are more common to be reported than positive ones. Disappointing results should not be considered definitive and important lessons can be learned from this first generation of clinical trials that should be considered as the first step of clinical research in this field. Probably, the optimal methodology for clinical trials and the best way to combine biologic and cytotoxic agents is not well known yet.

    Moreover, there are multilevel stimulation of their targets along several pathways of signal transduction that lead to neoplastic events, and blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Preclinical evidences of synergistic antitumor activity achievable combining targeted agents that block multiple signaling pathways are recently emerging Normanno et al. Another point to be considered when designing future clinical trials is the phenomenon of unrecognized molecular heterogeneity Betensky et al.

    Modern cDNA array and proteomics-based approaches and correlations of their data with clinical response Ramaswamy and Golub, may provide a set of molecular markers predictive of response. Adjei AA. Cancer Inst. Cancer , 82 , — Cancer Res. Ciardiello F and Tortora G.