tbuckley/cabot-search huggingface dataset:
Abstract 2924: Constitutively active androgen receptor splice variants function independently of full-length androgen receptor in a cell-based model of castrate-resistant prostate cancer
Authors: Peter E. Lonergan, Lucas P. Nacusi, Lucy J. Schmidt, Kevin M. Regan, Furkan U. Ertem, Zhifu Sun, Stephen A. Boorjian, Donald J. Tindall
Journal: Cancer Research (2012)

Abstract Recent studies suggest that progression to castrate-resistant prostate cancer (CRPC) is due to generation of androgen receptor (AR) splice variants, lacking the ligand binding domain. These AR variants originally identified in cell-based models of CRPC, have also been detected in benign and malignant human prostate tissue, with the highest levels observed in late state CRPC. The diversity and complexity of AR variants is well appreciated but not fully understood. Using RT-PCR we assessed the expression of a number of AR variants in cell-based models of both castrate-resistant and androgen-dependent prostate cancer. Several AR variants were expressed in both 22Rv1 and VCaP cells, but not in LNCaP cells. Coding sequences for AR variants were cloned into expression vectors and constitutive transcriptional activity was observed using a luciferase reporter assay. Augmented transcriptional activity of AR variants was observed in cells that express full-length AR, when full-length AR was silenced using shRNA targeting exons 7/8. This observation suggests the constitutive activity of AR variants may be independent of full-length AR. We profiled the AR variant transcriptome in 22Rv1 cells, using the Illumina HumanHT12 v4 whole-genome expression array platform. shRNA targeting exon 1 was used to silence all AR isoforms and shRNA targeting exons 7/8 was used to silence full-length AR. 5,256 genes were modulated by knocking down all AR isoforms and 5,086 genes were modulated by knocking down full-length AR. A total of 3,714 genes were common to both groups, leaving 1542 genes modulated by AR variants and 1372 modulated by full-length AR (p&amp;lt;0.05). The represents a subset of genes differentially regulated by AR variants independently of full length AR. Aggregate function of multiple AR variants may confer a CRPC phenotype independent of full-length AR. Pathway analysis of these genes differentially regulated by AR variants may reveal potential targets for therapeutic intervention in patients who progress despite androgen deprivation or anti-androgen therapy. (Supported by NIH grants CA125747, CA091956 and CA121277, T.J. Martell Foundation and the Mayo Clinic Prostate Cancer SPORE). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2924. doi:1538-7445.AM2012-2924
EVOLUCION DE LA CAPSULA ENDOSCOPICA EN NUESTRO MEDIO
Authors: A Castellot Martín, C Sánchez Vilar, M Lorente Arencibia, A Cruz Bonilla, A Monescillo Francia, L Betancor Hernandez, E Jiménez Mutiloa, A González Almeida, JM Marrero Monroy, A Sierra Hernández
Journal: Endoscopy (2013)

Introducción: Las indicaciones de cápsula endoscópica (CE) han ido en aumento en los últimos años. Objetivo: Valorar si existen diferencias entre dos periodos de tiempo en cuanto a las indicaciones y hallazgos de la CE. Material y Método: Análisis retrospectivo de estudios con CE realizados en nuestro centro desde 2006 a 2013. Se administraron dos tipos de cápsula (Pillcam y Mirocam). Se hicieron dos grupos para comparar evolución, uno que abarcaba los primeros 4 años (2006 – 2009) y otro con los siguientes cuatro años (2010 – 2013). La lectura de la cápsula se realizó por una única endoscopista. No se usó cápsula trazadora en ningún caso. Resultados:
EFFICACY OF ANTICOAGULATION IN PREVENTING THROMBOEMBOLISM AFTER BIO PROSTHETIC AORTIC VALVE REPLACEMENT: A META-ANALYSIS
Authors: Abhilash Akinapelli, Muhammad Soubhi Azzouz, Hemantha Koduri, Mohamed Ayan, Venkata Alla, Dennis Esterbrooks
Journal: Journal of the American College of Cardiology (2016)
THU0390 Efficacy of Anakinra in Refractory Adult-Onset Still's Disease: Multicenter Open-Label Study of 34 Patients: Table 1
Authors: F.M. Ortiz Sanjuán, R. Blanco, A. Olivé, A. Riveros, S. Castañeda, M.L. Velloso-Feijoo, F.J. Narváez, I. Jiménez-Moleόn, C. Ordόñez, J.A. Bernal, W.A. Sifuentes-Giraldo, C. Gόmez-Arango, E. Galíndez-Agirregoikoa, V. Ortiz-Santamaria, J. del Blanco-Barnusell, J.R. De Dios, M. Moreno, J. Fiter, J. Loricera, V. Calvo-Río, T. Pina, M.A. González-Gay
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Adult-onset Still9s disease (AOSD) is frequently refractory to standard therapy. Anakinra (ANK) is an interleukin-1 (IL-1) receptor antagonist. The ANK has demonstrated efficacy in single cases or in small series of AOSD. We assessed the efficacy of ANK in a multicenter study. <h3>Objectives</h3> We assessed the efficacy of ANK in a multicenter study. <h3>Methods</h3> Retrospective open-label study of 34 patients with AOSD. ANK was used because of inadequate response to corticosteroids and at least 1 standard synthetic immunosuppressive drug, and in many cases also to biologic agents. <h3>Results</h3> Patients (22 women/12 men) had a mean age of 33.1±13.2 years and a median [interquartile range- IQR] AOSD duration of 1.6 [0.1-24] years before ANK onset. At ANK onset, the most frequent clinical manifestations were: joint manifestations (n=30), fever (n=25) and cutaneous manifestations (n=20). In reference to laboratory parameters, high C reactive protein (CRP) (n=31), high erythrocyte sedimentation rate (ESR) (n=27), leukocytosis (n=22) or anemia (n=18). ANK yielded rapid and maintained clinical and laboratory improvement (Table). After one year of ANK therapy, joint manifestations had decreased from 88.2% to 17.6%, fever from 73.5% to 5.9%, cutaneous manifestations from 58.8 to 2.9%, and lymphadenopathy from 20.6% to 0%. Also, a dramatic reduction of laboratory markers of inflammation including CRP, ESR and ferritin was achieved. The median [IQR] dose of prednisone was also reduced from 20 [0-100] mg/day at ANK onset to 5 [0-40] at 12 months. After a median [IQR] follow-up of 16 [1-206] months, the most important side effects were: cutaneous (n=6), mild leukopenia (n=2), myopathy with elevation of muscle enzymes (n=1), phalanx osteomyelitis (n=1) and urinary tract infection (n=1). <h3>Conclusions</h3> ANK is associated with rapid and maintained clinical and laboratory improvement in refractory AOSD. However, joint manifestations seem to be more refractory than systemic manifestations. <h3>Acknowledgements</h3> This study was supported by a grant from "Fondo de Investigaciones Sanitarias" PI12/00193 (Spain). This work was also partially supported by RETICS Programs, RD08/0075 (RIER) and RD12/0009/0013 from "Instituto de Salud Carlos III" (ISCIII) (Spain). <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5607
OP0094 Cost-Effectiveness of Biologic Versus Conventional Combination Treatment in Early Rheumatoid Arthritis: 2-Year Results of the Randomised Controlled Swefot Trial
Authors: J. Eriksson, J. A. Karlsson, J. Bratt, I. F. Petersson, R. F. van Vollenhoven, S. Ernestam, P. Geborek, M. Neovius
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Adding infliximab (IFX) or sulfasalazine+hydroxychloroquine (SSZ+HCQ) to methotrexate (MTX) in patients with active, early rheumatoid arthritis (RA), resulted in superior radiographic outcome in the IFX group,[1] while disease-activity, utility and work loss improved in both arms, without detectable between-group differences at 21 months[1-3]. <h3>Objectives</h3> To evaluate the cost-effectiveness of biologic vs. conventional combination treatment in early RA-patients responding insufficiently to MTX. <h3>Methods</h3> This multicenter, randomised, controlled, open-label trial enrolled RA-patients (symptoms&lt;1y) in Sweden between 2002 and 2005. After 3-4 months of MTX monotherapy, patients with a remaining DAS28&gt;3.2 were randomised to addition of IFX or SSZ+HCQ. The incremental cost-effectiveness ratio (ICER=€/quality-adjusted life-year [QALY]) was assessed during 21 months from randomisation. Costs of RA-related medications, non-primary healthcare utilisation and work loss were retrieved from nationwide registers, while EuroQol 5-Dimensions utility was collected quarterly. Undiscounted analyses including all patients were performed from the societal (human capital method) and healthcare perspectives. Confidence intervals were estimated by non-parametric bootstrapping. <h3>Results</h3> Of 487 patients initially enrolled, 128 and 130 were randomised to biologic and conventional treatment, respectively. The biologic group had higher drug and healthcare costs (€27,487 vs. 10,364; adjusted mean difference 16,956 [95%CI 14,647;19,162]), while no difference was seen in productivity losses (€33,804 vs. 29,220; 3,961 [-3,986;11,850]), resulting in higher societal cost, as compared to the conventional treatment arm (€61,291 vs. 39,584; 20,916 [12,800;28,660]). Mean accumulated QALYs were 1.10 in the biologic and 1.12 in the conventional treatment group (adjusted mean difference 0.01 [95%CI -0.07;0.08]). The resulting ICER, comparing the biologic to the conventional treatment option, was €2,404,197/QALY from the societal (<b>Figure</b>), and €1,948,919/QALY from the healthcare perspective. <h3>Image/graph</h3> <h3>Conclusions</h3> In early MTX-refractory RA, the addition of IFX, as compared to addition of SSZ+HCQ, was not cost-effective over 21 months at willingness to pay levels generally considered acceptable. <h3>References</h3> van Vollenhoven RF, et al. <i>Lancet</i> 2012;379:1712-1720. Karlsson JA, et al. <i>Ann Rheum Dis</i> 2012. Nov 29 [Epub ahead of print]. Eriksson JK, et al. ACR 2011; Abstract no: 459. <h3>Disclosure of Interest</h3> None Declared
Late Breaking News NCI 1992 Budget: Conferees Still at Work
Authors: Dorothy A. Tisevich
Journal: JNCI Journal of the National Cancer Institute (1991)

Journal Article Late Breaking News NCI 1992 Budget: Conferees Still at Work Get access Dorothy A. Tisevich Dorothy A. Tisevich Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 83, Issue 21, 6 November 1991, Pages 1537–1538, https://doi.org/10.1093/jnci/83.21.1537 Published: 06 November 1991
Drainage of pancreatic pseudocysts with multiple stents using a double wire technique
Authors: AA Hanrath, JM Jansen, EA Rauws, MJ Bruno, P Fockens
Journal: Endoscopy (2006)

Introduction: One of the problems with the endoscopic treatment of pseudocysts is placement of multiple stents. Re-entry into the pseudocyst after placement of a first stent can be particularly cumbersome.
O145 THE REGULATORY INTERPLAY BETWEEN JNK1 AND JNK2 IS A SINE QUA NON CONDITION AGAINST DRUG-INDUCED LIVER TOXICITY
Authors: F.J. Cubero, W. Hu, G. Zhao, J. Peng, Y.A. Nevzorova, M. Al Masaoudi, M.V. Boekschoten, M. Muller, N. Gassler, R. Weiskirchen, R.J. Davis, C. Liedtke, C. Trautwein
Journal: Journal of Hepatology (2014)
Abstract 4462: The effects of NT-1044, a novel AMPK activator, on endometrial cancer cell proliferation and apoptosis
Authors: Dario R. Roque, Weiya W. Wysham, Chunxiao Zhou, Ken Batchelor, Wendy R. Brewster, Victoria L. Bae-Jump
Journal: Cancer Research (2015)

Abstract Objectives: Obesity and diabetes are associated with increased risk and worse outcomes in endometrial cancer (EC). Anti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 (NovaTarg Therapeutics) is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and 3. We sought to compare the effects of NT-1044 on cell proliferation and apoptosis in human EC cell lines. Methods: Cell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044. Apoptosis was analyzed by Annexin V-FITC assay. Cell cycle progression was evaluated by flow cytometry. Phosphorylated (phos)-S6, phos-AMPK, Cyclin D-1 and CDK-6 were evaluated by Western immunoblotting. Results: NT-1044 significantly inhibited proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 uM for ECC-1; 87 uM for Ishikawa). Treatment with NT-1044 resulted in G1 cell cycle arrest and apoptosis in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of Cyclin-D1 and CDK-6 also decreased in a dose dependent-fashion in both cell lines. Conclusions: NT-1044 suppressed EC cell growth through G1 cell cycle arrest, inducing apoptosis, and inhibition of the mTOR pathway. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes. Citation Format: Dario R. Roque, Weiya W. Wysham, Chunxiao Zhou, Ken Batchelor, Wendy R. Brewster, Victoria L. Bae-Jump. The effects of NT-1044, a novel AMPK activator, on endometrial cancer cell proliferation and apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4462. doi:10.1158/1538-7445.AM2015-4462
Abstract 2054: The BH3-only protein, Noxa, is upregulated by estrogen and promotes cell cycle progression in estrogen receptor-positive breast cancer cells
Authors: Wendy M. Swetzig, Wensheng Liu, Rajesh Medisetty, Gokul M. Das
Journal: Cancer Research (2012)

Abstract According to the American Cancer Society, breast cancer is the second leading cause of cancer-related deaths in American women, with more than 200,000 new cases diagnosed annually. In addition, the vast majority of breast cancers are initially hormone-dependent and 70% are estrogen receptor (ER)-positive (Colditz, J. Natl. Cancer Inst., 1998; Hankinson et al., Breast Cancer Res., 2004; and Harvey et al., J. Clin. Oncol., 1999), highlighting the importance of estrogen signaling pathways in breast oncogenesis. It has been well-established that estrogen/17β-estradiol/E2 stimulates cell growth and inhibits apoptosis in ER-positive breast cancer cells; however, recent reports have demonstrated that E2 paradoxically induces the expression of Noxa/PMAIP1, a BH3-only pro-apoptotic member of the Bcl-2 family. In the present study, we report on the mechanisms by which E2 upregulates Noxa expression and the associated cellular effects on apoptosis and cell cycle progression in ER-positive MCF7 human breast cancer cells. We demonstrate that c-Myc, ERα, and E2F1 are involved in the transcriptional upregulation of Noxa following E2 treatment. Specific knockdown of c-Myc and ERα protein expression using siRNA technology inhibited E2-mediated induction of Noxa expression. Furthermore, E2 also promoted the recruitment of c-Myc and ERα to the NOXA promoter in chromatin immunoprecipitation (ChIP) assays, suggesting that these two proteins are indeed mediators of Noxa upregulation following E2 treatment. Although p53 is an important regulator of Noxa transcription under conditions of cellular stress, our data demonstrate that E2-mediated upregulation of Noxa is a p53-independent process, as knocking down p53 with specific siRNA did not block E2-mediated induction of Noxa. Consistent with this result, E2 treatment failed to induce the recruitment of p53 to the NOXA promoter in ChIP assays. Interestingly, E2-mediated upregulation of Noxa was associated with cell cycle progression but not with apoptosis under normal, unstressed cellular conditions. Cell cycle analysis by flow cytometry showed that siRNA-mediated knockdown of Noxa caused cell cycle arrest in G0/G1-phase and significantly delayed the G1-to-S-phase transition following E2 treatment. Collectively, these data indicate that Noxa expression is required for cell cycle progression in ER-positive breast cancer cells, suggesting a novel role for the BH3-only protein Noxa, outside of its traditional role as an apoptosis sensitizer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2054. doi:1538-7445.AM2012-2054
Platelet Antibody Tests in the Diagnosis of Purpura
Authors: James L. Tullis
Journal: New England Journal of Medicine (1953)

PURPURA is a heterogeneous group of diseases with a single common denominator of spontaneous extravasation of blood. Classically, the purpuras are divided into two major classes: symptomatic and thrombopenic, depending on the presence or absence of a normal platelet count. The former is generally considered of allergic origin. Madison1 has advanced the concept that allergic factors may account for the vascular permeability that is present in both types of purpura. Yet the clinical manifestations are sharply different, since thrombopenic purpura presents the added problem of platelet deficiency, with its resultant coagulation defect and incomplete clot retraction.The present communication deals . . .
AB0764 The 1st interim analysis of a prospective cohort study of ANCA-associated vasculitides in japan, the remIT-JAV study
Authors: M. Yamamura, K.-E. Sada, T. Fujii, M. Harigai, Y. Arimura, H. Makino
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), Churg-Srauss syndrome (CSS) and microscopic polyangiitis (MPA) constitute the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Treatment response and prognosis, as well as disease evolution and organ involvement, may differ substantially between these diseases. In contrast with the predominance of GPA in Western countries, MPA is much more common than GPA in Japan. <h3>Objectives</h3> To investigate the effectiveness and safety of remission induction therapy currently performed for AAV in Japan. <h3>Methods</h3> Patients with newly diagnosed AAV were enrolled in the RemIT-JAV study by members of the MHLW intractable vasculitis research group. Information regarding patients' disease status and initial immunosuppressive therapy was collected, and their responses were analyzed by categorizing into 3 groups with different disease severity according to BSR/BHPR guidelines. <h3>Results</h3> Data from 132 patients, of the 156 patients enrolled in the study (CSS n=17, GPA n=34, MPA n=94, unclassified n=11), became available at the end of March, 2011. All patients received corticosteroids (CS) in the initial treatment for AAV; and yclophosphamide (CY) was added within 2 weeks in 33.3% (11/33) of patients with localized/early systemic disease and in 35.3% (35/99) of those with generalized or severe disease. 90% and 95% of patients with localized/early systemic disease achieved remission within 6 months when treated with or without CY combination, respectively. Similarly, 86% and 91% of patients with generalized or severe disease did so with and without CY combination, respectively. A total of 7 patients with generalized and severe disease died due to disease progression and concomitant infections, in which 5 patients had been treated with CS alone and 2 patients with CS plus CY therapy. <h3>Conclusions</h3> In our study, Japanese AAV patients, irrelevant to disease severity, showed good responses to CS alone therapy in terms of initial remission rates, which was mostly equivalent to the results of CS plus CY therapy. Further analysis is warranted to determine the role of CY combination in long-term outcomes. <h3>Disclosure of Interest</h3> None Declared
Top Cancer-Related News Stories Focuson Fraud, Breast Cancer, And the Hope of Early Detection
Authors: K. Smigel
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article Top Cancer-Related News Stories Focuson Fraud, Breast Cancer, And the Hope of Early Detection Get access Kara Smigel Kara Smigel Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 87, Issue 1, 4 January 1995, Pages 12–14, https://doi.org/10.1093/jnci/87.1.12 Published: 04 January 1995
748 VIROLOGICAL RESPONSE AND TOLERANCE OF TENOFOVIR DF (TDF) IN THE ELDERLY IS SIMILAR TO YOUNGER PATIENTS IN REAL LIFE PRACTICE
Authors: C. Hézode, X. Causse, D. Larrey, D. Ouzan, G.-P. Pageaux, R. Truchi, A. Pauwels, D. Guyader, V. De L'edinghen, F. Zoulim, J.P. Zarski, J.F. Cadranel, V. Tilliet, O. Libert, C. Stern, P. Marcellin
Journal: Journal of Hepatology (2013)
Prospective Validation of Rapid Plasma Genotyping for the Detection of<i>EGFR</i>and<i>KRAS</i>Mutations in Advanced Lung Cancer
Authors: Adrian G. Sacher, Cloud Paweletz, Suzanne E. Dahlberg, Ryan S. Alden, Allison O’Connell, Nora Feeney, Stacy L. Mach, Pasi A. Jänne, Geoffrey R. Oxnard
Journal: JAMA Oncology (2016)

<h3>Importance</h3> Plasma genotyping of cell-free DNA has the potential to allow for rapid noninvasive genotyping while avoiding the inherent shortcomings of tissue genotyping and repeat biopsies. <h3>Objective</h3> To prospectively validate plasma droplet digital PCR (ddPCR) for the rapid detection of common epidermal growth factor receptor (<i>EGFR</i>) and<i>KRAS</i>mutations, as well as the<i>EGFR </i>T790M acquired resistance mutation. <h3>Design, Setting, and Participants</h3> Patients with advanced nonsquamous non–small-cell lung cancer (NSCLC) who either (1) had a new diagnosis and were planned for initial therapy or (2) had developed acquired resistance to an EGFR kinase inhibitor and were planned for rebiopsy underwent initial blood sampling and immediate plasma ddPCR for<i>EGFR</i>exon 19 del, L858R, T790M, and/or<i>KRAS</i>G12X between July 3, 2014, and June 30, 2015, at a National Cancer Institute–designated comprehensive cancer center. All patients underwent biopsy for tissue genotyping, which was used as the reference standard for comparison; rebiopsy was required for patients with acquired resistance to EGFR kinase inhibitors. Test turnaround time (TAT) was measured in business days from blood sampling until test reporting. <h3>Main Outcomes and Measures</h3> Plasma ddPCR assay sensitivity, specificity, and TAT. <h3>Results</h3> Of 180 patients with advanced NSCLC (62% female; median [range] age, 62 [37-93] years), 120 cases were newly diagnosed; 60 had acquired resistance. Tumor genotype included 80<i>EGFR</i>exon 19/L858R mutants, 35<i>EGFR</i>T790M, and 25<i>KRAS</i>G12X mutants. Median (range) TAT for plasma ddPCR was 3 (1-7) days. Tissue genotyping median (range) TAT was 12 (1-54) days for patients with newly diagnosed NSCLC and 27 (1-146) days for patients with acquired resistance. Plasma ddPCR exhibited a positive predictive value of 100% (95% CI, 91%-100%) for<i>EGFR</i>19 del, 100% (95% CI, 85%-100%) for L858R, and 100% (95% CI, 79%-100%) for<i>KRAS</i>, but lower for T790M at 79% (95% CI, 62%-91%). The sensitivity of plasma ddPCR was 82% (95% CI, 69%-91%) for<i>EGFR</i>19 del, 74% (95% CI, 55%-88%) for L858R, and 77% (95% CI, 60%-90%) for T790M, but lower for<i>KRAS </i>at 64% (95% CI, 43%-82%). Sensitivity for<i>EGFR</i>or<i>KRAS</i>was higher in patients with multiple metastatic sites and those with hepatic or bone metastases, specifically. <h3>Conclusions and Relevance</h3> Plasma ddPCR detected<i>EGFR</i>and<i>KRAS</i>mutations rapidly with the high specificity needed to select therapy and avoid repeat biopsies. This assay may also detect<i>EGFR</i>T790M missed by tissue genotyping due to tumor heterogeneity in resistant disease.