EGFR mutation positive stage IV non small-cell lung cancer: treatment beyond progression

Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer for both men en women. Chemotherapy is the mainstay of treatment in advanced disease, but is only marginally effective. In about 30% of patients with advanced NSCLC in East Asia and in 10-15% in Western countries, EGFR mutations are found. In this population, first-line treatment with the tyrosine kinase inhibitors (TKI) erlotinib, gefitinib or afatinib is recommended. The treatment beyond progression is less well-defined. In this paper we present 3 patients, EGFR mutation positive, with local progression after an initial treatment with TKI. These patients were treated with local radiotherapy. TKI was temporarily stopped and restarted after radiotherapy. We give an overview of the literature and discuss the different treatment options in case of progression after TKI: TKI continuation with or without chemotherapy, TKI continuation with local therapy, alternative dosing or switch to next-generation TKI or combination therapy. There are different options for treatment beyond progression in EGFR mutation positive metastatic NSCLC, but the optimal strategy is still to be defined. Further research on this topic is ongoing

Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor treated CML stem cells

Treatment of chronic myelogenous leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKI) fails to eliminate leukemia stem cells (LSC). Patients remain at risk for relapse, and additional approaches to deplete CML LSC are needed to enhance the possibility of discontinuing TKI treatment. We have previously reported that expression of the pivotal proinflammatory cytokine interleukin-1 (IL-1) is increased in CML bone marrow (BM). We show here that CML LSC demonstrated increased expression of the IL-1 receptors, IL-1RAP and IL- 1R1, and enhanced sensitivity to IL-1-induced NF-KB signaling compared to normal stem cells. Treatment with recombinant IL-1 receptor antagonist (IL-1RA) inhibited IL-1 signaling in CML LSC and inhibited growth of CML LSC. Importantly, the combination of IL-1RA with TKI resulted in significantly greater inhibition of CML LSC compared with TKI alone. Our studies also suggest that IL-1 signaling contributes to overexpression of inflammatory mediators in CML LSC, suggesting that blocking IL-1 signaling could modulate the inflammatory milieu. We conclude that IL-1 signaling contributes to maintenance of CML LSC following TKI treatment, and that IL- 1 blockade with IL-1RA enhances elimination of TKI-treated CML LSC. These results provide a strong rationale for further exploration of anti-IL-1 strategies to enhance LSC elimination in CML

Two distinct topological phases in the mixed valence compound YbB6 and its differences from SmB6

We discuss the evolution of topological states and their orbital textures in the mixed valence compounds SmB6 and YbB6 within the framework of the generalized gradient approximation plus onsite Coulomb interaction (GGA+U) scheme for a wide range of values of U. In SmB6, the topological Kondo insulator (TKI) gap is found to be insensitive to the value of U, but in sharp contrast, Kondo physics in isostructural YbB6 displays a surprising sensitivity to U. In particular, as U is increased in YbB6, the correlated TKI state in the weak-coupling regime transforms into a d-p-type topological insulator phase with a band inversion between Yb-5d and B-2p orbitals in the intermediate coupling range, without closing the insulating energy gap throughout this process. Our theoretical predictions related to the TKI and non-TKI phases in SmB6 and YbB6 are in substantial accord with recent angle-resolved photoemission spectroscopy (ARPES) experiments.Comment: 6 pages, 4 figures URL: http://link.aps.org/doi/10.1103/PhysRevB.91.15515

Direct observation of the spin texture in strongly correlated SmB6 as evidence of the topological Kondo insulator

The concept of a topological Kondo insulator (TKI) has been brought forward as a new class of topological insulators in which non-trivial surface states reside in the bulk Kondo band gap at low temperature due to the strong spin-orbit coupling [1-3]. In contrast to other three-dimensional (3D) topological insulators (e.g. Bi2Se3), a TKI is truly insulating in the bulk [4]. Furthermore, strong electron correlations are present in the system, which may interact with the novel topological phase. Applying spin- and angle-resolved photoemission spectroscopy (SARPES) to the Kondo insulator SmB6, a promising TKI candidate, we reveal that the surface states of SmB6 are spin polarized, and the spin is locked to the crystal momentum. Counter-propagating states (i.e. at k and -k) have opposite spin polarizations protected by time-reversal symmetry. Together with the odd number of Fermi surfaces of surface states between the 4 time-reversal invariant momenta in the surface Brillouin zone [5], these findings prove, for the first time, that SmB6 can host non-trivial topological surface states in a full insulating gap in the bulk stemming from the Kondo effect. Hence our experimental results establish that SmB6 is the first realization of a 3D TKI. It can also serve as an ideal platform for the systematic study of the interplay between novel topological quantum states with emergent effects and competing order induced by strongly correlated electrons.Comment: 4 figure

MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells

Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signaling has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass signaling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30-40% of cases, however, the mechanisms underpinning drug-resistance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI-resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overexpression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI-resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation are not sufficient to predict a positive response of NSCLC cells to a cocktail of MET and EGFR inhibitors and highlights the importance of identifying more reliable biomarkers to predict the efficacy of treatments in NSCLC patients resistant to EGFR TKI

Strategi Penggunaan E-tki sebagai Wahana dalam Mengatasi Kesenjangan Informasi

Informasi yang diterima calon TKI dan TKI masih kurang karena pemerintah yang bertugas dalam pelayanan dan penempatan TKI belum optimal dalam memberikan informasi kepada mereka. Berbagai keluhan yang disebabkan oleh kurangnya akses dan fasilitas pelayanan informasi dapat diminimalisir, apabila pemerintah semakin intensif dalam menyampaikan informasi hingga menjangkau tiap calon TKI dan TKI. Informasi ini berguna untuk memberdayakan TKI sehingga mereka tidak mudah percaya kepada sponsor, calo atau Perusahaan jasa tenaga kerja dan berani menolak tindakan sewenang-wenang majikan yang bertentangan dengan hak dan kewajiban mereka sebagai TKI. Metode dalam penulisan ini adalah studi kepustakaan. Hasil analisis menunjukkan bahwa dalam strategi untuk memenuhi informasi itu, peranan difusi inovasi dan teknologi informasi dan komunikasi dapat dimanfaatkan dalam meningkatkan kinerja pelayanan informasi kepada TKI. Penggunaan sarana teknologi informasi dan komunikasi disadari sebagai suatu keharusan untuk mencapai efisiensi dan efektivitas dari tiap upaya memberikan informasi kepada TKI. Pelayanan informasi dapat diberikan tidak hanya melalui komunikasi tatap muka tetapi juga melalui internet atau informasi online yang didukung oleh e-TKI. Penguatan sistem informasi melalui penerapan tahapan strategi difusi inovasi dan informasi ini adalah untuk memberikan pelayanan terhadap informasi TKI yang cepat, mudah, efektif, efisien dan terintegrasi secara online. Kebijakan pengembangan e–TKI ini merupakan komitmen pemerintah untuk terus menyempurnakan sistem pelayanan informasi TKI kepada masyarakat

ANALISIS POLA KONSUMSI KELUARGA TENAGA KERJA INDONESIA (TKI) Studi Kasus Pada Keluarga Mantan TKI Di Kecamatan Losari – Kabupaten Cirebon

ANALISIS POLA KONSUMSI KELUARGA TENAGA KERJA INDONESIA (TKI) Studi Kasus Pada Keluarga Mantan TKI Di Kecamatan Losari – Kabupaten NURUL QOMARIYAH 124030005 ABSTRAK Penelitian ini bertujuan untuk : (1) Mendeskripsikan kondisi TKI di Kecamatan Losari, (2) Menganalisis pola konsumsi keluarga mantan TKI (konsumsi untuk makan, minum, perlengkapan rumah tangga, pendidikan, kesehatan, pakaian, listrik, gas, BBM dan barang mewah) sebelum dan sesudah salah satu anggota keluarga bekerja sebagai TKI, dan (3) Membandingkan perubahan pola konsumsi dan tingkat tabungan sebelum dan sesudah salah satu anggota keluarga bekerja sebagai TKI. Metode yang digunakan adalah kualitatif. Data dikumpulkan melalui wawancara dan dilakukan validasi menggunakan teknik triangulasi data dan triangulasi sumber. Data yang diperoleh dianalisis secara deskriptif dan uji beda (uji t), uji beda dilakukan menggunakan excel. Uji beda dilakukan untuk mengetahui perubahan pola konsumsi dan tingkat tabungan signifikan atau tidak. Hasil penelitian menunjukkan kondisi TKI di Kecamatan Losari dipengaruhi oleh penawaran gaji tinggi bekerja sebagai TKI, keinginan memiliki rumah, memenuhi kebutuhan keluarga, membayar hutang, membantu ekonomi keluarga, pendidikan terakhir TKI dan peran Pemerintah. Pola konsumsi keluarga mantan TKI sesudah salah satu anggota keluarga tidak bekerja sebagai TKI cenderung mengalami penurunan persentase pada komponen konsumsi makan, minum, perlengkapan rumah tangga, pendidikan, kesehatan, pakaian, listrik, gas, BBM dan terjadi peningkatan persentase untuk konsumsi barang mewah. Kondisi ekonomi keluarga mantan TKI mengalami perubahan secara signifikan untuk pendapatan, makan minum perlengkapan rumah tangga, biaya kesehatan, konsumsi pakaian, konsumsi barang mewah sedangkan biaya pendidikan dan tingkat tabungan perubahannya tidak signifikan. Kata Kunci : Pola Konsumsi, TKI, Kecamatan Losar