Molecular Profiling for Supernatants and Matched Cell Pellets of Pleural Effusions in Non–Small-Cell Lung Cancer

... Herein, we included 47 advanced non–small-cell lung cancer patients with PE, who had lung cancer driver mutations tested on tumor tissue specimens either at diagnosis or during disease progression. The supernatant and cell pellet of each PE were evaluated for molecular profiles in parallel on an Ion Torrent next-generation sequencing platform... In conclusion, our study indicates that supernatant cfTNA isolated from pleural fluids can be effectively used in clinical practice for molecular analysis by NGS. The Oncomine Lung cfTNA assay allows for detecting extremely low-abundance genomic aberrations in supernatants of pleural effusions, even in cases where corresponding cell pellets or biopsy tissues have failed for the detection. Cell-free supernatants and cell pellets could potentially complement each other and improve the detection rate of somatic genetic variants in pleural effusions. READ ARTICLE

The Journal of Molecular Diagnostics DOI:10.1016/j.jmoldx.2020.01.011

Authors: Chan Xiang, Mingfei Huo, Shengji Ma, Lianying Guo, Ruiying Zhao, Haohua Teng, Jie Zhang, Yuchen Han

Monomerization of ALK Fusion Proteins as a Therapeutic Strategy in ALK-Rearranged Non-small Cell Lung Cancers

Objective: Oncogenic echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) (EML4-ALK) fusion proteins found in non-small cell lung cancers (NSCLC) are constitutively phosphorylated and activated by dimerization via the coiled-coil domain (cc) within EML4. Here, we investigated whether disruption of ALK fusion protein oligomerization via competitive cc mimetic compounds could be a therapeutic strategy for EML4-ALK NSCLC.Methods: A Ba/F3 cell model was created that expressed an ALK intracellular domain in which the dimer/monomer state is ligand-regulated. This novel cell model was used to investigate the effect of disrupting ALK fusion protein oligomerization on tumor cell growth in vitro and in vivo using nude mice. Subsequently, the antiproliferative effects of endogenous cc domain co-expression and mimetic cc peptides were assayed in EML4-ALK cancer cell lines.Results: Cells induced to express monomeric ALK in vitro did not survive. When transplanted..... READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2020.00419

Authors: Hirai Noriko, Sasaki Takaaki, Okumura Shunsuke, Minami Yoshinori, Chiba Shinichi, Ohsaki Yoshinobu

Clinical characteristics and risk factors of drug-induced lung injury by ALK tyrosine kinase inhibitors: A single center retrospective analysis

A total of seven cases were diagnosed with drug induced lung injury (DILI) due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute. Extra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13416

Authors: Ken Koshikawa, Jiro Terada, Mitsuhiro Abe, Shunichiro Iwasawa, Masashi Sakayori, Keiichiro Yoshioka, Yasutaka Hirasawa, Hajime Kasai, Yohei Kawasaki, Kenji Tsushima, Koichiro Tatsumi

Next-generation sequencing to dynamically detect mechanisms of resistance to ALK inhibitors in ALK-positive NSCLC patients: a case report

Tyrosine kinase inhibitors (TKIs) of the anaplastic lymphoma kinase gene (ALK) have significantly improved the quality of life and survival of non-small cell lung cancer (NSCLC) patients whose tumors harbor an ALK translocation. However, most of these patients relapse within 2 to 3 years as the tumor acquires resistance mutations. Unlike beaming and digital PCR (dPCR), which only allow a few mutations to be analyzed, next-generation sequencing (NGS) approaches enable the simultaneous screening of multiple genetic alterations even when the frequencies of the variants are very low. We present the case of a 52-year-old man who was diagnosed with an ALK-positive NSCLC and was treated with crizotinib and, subsequently, ceritinib. The analysis of serial liquid biopsies by NGS detected two asynchronous mutations arising in the ALK locus during disease progression, namely p.Gly1269Ala (c.3806G>C) and p.Gly1202Arg (c.3604G>A), that conferred resistance to crizotinib and ceritinib, respectively...... READ ARTICLE

Translational Lung Cancer Research DOI:10.21037/tlcr.2020.02.07

Authors: Sánchez-Herrero E, Blanco Clemente M, Calvo V, Provencio M, Romero A.

Lung cancer in never smokers: The role of different risk factors other than tobacco smoking

Lung cancer (LC), the leading cause of cancer-related deaths worldwide, is a complex and highly heterogeneous disease. Additional to its biological complexity, LC patients are often confronted with a high degree of stigma, mostly from the association of the disease with tobacco. Nonetheless, a proportion of LC patients are never-smokers, a population which we are beginning to comprehensively explore. Several risk factors have been linked to LC in never-smokers. Studies have consistently shown that radon exposure and domestic fuel smoke increase LC risk. Additionally, infections such as Mycobacterium tuberculosis, and Human Papilloma Virus are also risk factors. Other less conclusive associations include inflammatory diseases such as asthma and sarcoidosis. Moreover, we are now aware that molecular characteristics of LC vary widely according to smoking history, with important therapeutic implications. This review comprehensively assesses the current knowledge in terms of risk factors an..... READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2020.102895

Authors: Luis Corrales, Rafael Rosell, Andrés F. Cardona, Claudio Martín, Zyanya Lucia Zatarain-Barrón, Oscar Arrieta

EditorialKirk SmithApril 1, 2020Never-smoker, Tobacco, Wood-smoke, RadonTuberculosis, HPV

Clinical characteristics and risk factors of drug-induced lunginjury by ALK tyrosine kinase inhibitors: A single centerretrospective analysis

If anaplastic lymphoma kinase (ALK) gene rearrangement in lungcancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effec-tive treatment. However, the details of drug-induced lung injury (DILI) causedby ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear.This study aimed to investigate the clinical features and the onset risk factors ofDILI by ALK-TKIs in clinical practice.Methods:The clinical features of 56 consecutive patients who receivedcrizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were ret-rospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinicalparameter before the administration of ALK-TKIs was compared between theDILI onset group and the non-onset group.Results:A total of seven cases were diagnosed with DILI due to ALK-TKIs; noDILI-related deaths were observed. Chest computed tomography (CT) scanfind-ings identified six patients with the organizing pneumonia (OP) pat..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13416

Authors: Ken Koshikawa, Jiro Terada, Mitsuhiro Abe, Shunichiro Iwasawa, Masashi Sakayori, Keiichiro Yoshioka, Yasutaka Hirasawa, Hajime Kasai, Yohei Kawasaki, Kenji Tsushima, Koichiro Tatsumi

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

Infant high-grade gliomas appear clinically distinct from their counterparts in older
children, indicating that histopathologic grading may not accurately refl ect the
biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic
review, methylation profi ling, and custom panel, genome, or exome sequencing. After excluding tumors
representing other established entities or subgroups, we identifi ed 130 cases to be part of an “intrinsic” spectrum of disease specifi c to the infant population. These included those with targetable MAPK
alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK ( n = 31),
NTRK1/2/3 ( n = 21), ROS1 ( n = 9), and MET ( n = 4) as their driving alterations, with evidence of effi cacy
of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a
change in diagnostic practice and management. Infant high-grade gliomas in the cerebral hemispheres com..... READ ARTICLE

Cancer Discovery DOI:10.1158/2159-8290

Authors: Matthew Clarke, Alan Mackay, Britta Ismer, Jessica C. Pickles, Ruth G. Tatevossian, Scott Newman, Tejus A. Bale, Iris Stoler, Elisa Izquierdo, Sara Temelso, Diana M. Carvalho, Valeria Molinari, Anna Burford, Louise Howell, Alex Virasami, Amy R. Fairchild, Aimee Avery, Jane Chalker, Mark Kristiansen, Kelly Haupfear, James D. Dalton, Wilda Orisme, Ji Wen, Michael Hubank, Kathreena M. Kurian, Catherine Rowe, Mellissa Maybury, Stephen Crosier, Jeffrey Knipstein, Ulrich Schüller, Uwe Kordes, David E. Kram, Matija Snuderl, Leslie Bridges, Andrew J. Martin, Lawrence J. Doey, Safa Al-Sarraj, Christopher Chandler, Bassel Zebian, Claire Cairns, Rachael Natrajan, Jessica K.R. Boult, Simon P. Robinson, Martin Sill, Ira J. Dunkel, Stephen W. Gilheeney, Marc K. Rosenblum, Debbie Hughes, Paula Z. Proszek, Tobey J. Macdonald, Matthias Preusser, Christine Haberler, Irene Slavc, Roger Packer, Ho-Keung Ng, Shani Caspi, Mara Popović, Barbara Faganel Kotnik, Matthew D. Wood, Lissa Baird, Monika Ashok Davare, David A. Solomon, Thale Kristin Olsen, Petter Brandal, Michael Farrell, Jane B. Cryan, Michael Capra, Michael Karremann, Jens Schittenhelm, Martin U. Schuhmann, Martin Ebinger, Winand N.M. Dinjens, Kornelius Kerl, Simone Hettmer, Torsten Pietsch, Felipe Andreiuolo, Pablo Hernáiz Driever, Andrey Korshunov, Lotte Hiddingh, Barbara C. Worst, Dominik Sturm, Marc Zuckermann, Olaf Witt, Tabitha Bloom, Clare Mitchell, Evelina Miele, Giovanna Stefania Colafati, Francesca Diomedi-Camassei, Simon Bailey, Andrew S. Moore, Timothy E.G. Hassall, Stephen P. Lowis, Maria Tsoli, Mark J. Cowley, David S. Ziegler, Matthias A. Karajannis, Kristian Aquilina, Darren R. Hargrave, Fernando Carceller, Lynley V. Marshall, Andreas von Deimling, Christof M. Kramm, Stefan M. Pfister, Felix Sahm, Suzanne J. Baker, Angela Mastronuzzi, Andrea Carai, Maria Vinci, David Capper, Sergey Popov, David W. Ellison, Thomas S. Jacques, David T.W. Jones and Chris Jones

Review PaperKirk SmithApril 1, 2020infant high grade glioma, diagnostic practices

Imaging Features and Metastatic Patterns of Advanced ALK-Rearranged Non–Small Cell Lung Cancer

"ALK rearrangements are an established targetable oncogenic driver in non–small cell lung cancer (NSCLC). The goal of this study was to determine the imaging features of the primary tumor and metastatic patterns in advanced ALK-rearranged (ALK+) NSCLC that may be different from those in EGFR-mutant (EGFR+) or EGFR/ALK wild-type (EGFR−/ALK−) NSCLC. CONCLUSION. Advanced ALK+ NSCLC has primary tumor imaging features and patterns of metastasis that are different from those of EGFR+ or EGFR−/ALK− wild type NSCLC at the time of initial presentation. READ ARTICLE

American Journal of Roentgenology DOI:10.2214/AJR.19.21982

Authors: Dexter P. Mendoza, Jessica J. Lin, Marguerite M. Rooney, Tianqi Chen, Lecia V. Sequist, Alice T. Shaw, Subba R. Digumarthy"

Real-World OutcomesKirk SmithApril 1, 2020ALK, anaplastic lymphoma kinase, lung cancer, metastasis

HSR20-084: Real-World Adherence and Persistence of ALK Inhibitors in Non-Small Cell Lung Cancer (NSCLC)

Background: About 5% of NSCLC cases present with anaplastic lymphoma kinase (ALK) fusions and are candidates for an ALK tyrosine kinase inhibitor (ALKi). Evidence on real-world adherence and persistence of ALKi is limited. Objectives: Estimate adherence and persistence of in NSCLC. Results: This study analyzed 1482 patients whose first ALKi was alectinib or crizotinib (n=445 and 1037, respectively) and 880 patients with subsequent ALKis (604 alectinib, 142 brigatinib, 134 ceritinib). Adherence during treatment period (95-97%) and proportions of MPR ³0.8 (92-95%) were similar across all ALKis. Real-world median time to discontinuation was 27.4 vs 8.9 months for alectinib vs crizotinib in the first ALKi cohort. Patients using alectinib as first ALKi were 46% less likely to discontinue ALKi than crizotinib patients (adjusted hazard ratio (aHR) [95% CI]: 0.54 [0.44-0.65]). For subsequent ALKi use, the risk of discontinuation for alectinib was 64% lower vs ceritinib (aHR [95% CI]: 0.36 [0.2..... READ ARTICLE

Journal of the National Comprehensive Cancer Network DOI:10.6004/jnccn.2019.7501

Authors: Ganti, A. K., Ogale, S., Yang, E., & Wong, W.

Real-World OutcomesKirk SmithMarch 20, 2020Persistence, Inhibitors, Alectinib

Single-center study to determine the safety and efficacy of CT-707 in Chinese patients with advanced anaplastic lymphoma kinase-rearranged non-small-cell lung cancer

Introduction It has been proven that ALK-rearranged non-small cell lung cancer (NSCLC) is sensitive to ALK inhibitors while the chemotherapy resistance is unavoidable. In this study, safety and antitumor activity of the novel ALK inhibitor (ALKi) CT-707 were evaluated in Chinese patients with advanced ALK-rearranged NSCLC. Results A total of 13 patients who were treated with CT-707 from 450 to 600 mg (in the dose increasing phase) were enrolled in this trial (two patients were previously treated with crizotinib). There were 12 patients diagnosed with lung adenocarcinoma and one patient with malignant pleural mesothelioma. After treatment, grade 3 diarrhea (600 mg once a day) was found as dose-limiting toxicity (DLT).The most common adverse events included diarrhea (92%), elevated aspartate aminotransferase (61%), elevated alanine aminotransferase (54%), hair loss (38%), and vomiting (31%). The overall response rate was 77% (10/13). Among all patients, four of the five patients who did..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13376

Authors: Song, P., Zhang, X., Yang, D., Wang, H., Si, X. and Zhang, L

Clinical TrialsKirk SmithMarch 17, 2020ALK, CT-707, NSCLC

Pediatric low-grade glioma in the era of molecular diagnostics

Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior – in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS–mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrell..... READ ARTICLE

Acta Neuropathologica Communications DOI:10.1186/s40478-020-00902-z

Authors: Scott Ryall, Uri Tabori & Cynthia Hawkins

Tree-in-bud Pattern in ALK-positive Lung Adenocarcinoma

A 62-year-old woman presented with a 3-month history of cough and hemoptysis. CT revealed nodular shadows with centrilobular distribution in the left lung. Three sputum smears for acid-fast bacillus were negative. Based on the results of a transbronchial biopsy, she was diagnosed with stage IVA lung lepidic adenocarcinoma harboring ALK translocation. At this point, CT showed progressive shadows, and alectinib was immediately initiated. Acid-fast bacillus culture of bronchoscopic biopsy tissue was negative. One month later, marked remission was observed, providing definitive evidence to exclude mycobacterial infection. The tree-in-bud pattern occurs commonly in patients with mycobacterial infection. Central lung cancer is reportedly another common cause of the treein-bud pattern. Nevertheless, when encountering a treein-bud pattern, physicians tend to be anxious about the possibility of tuberculosis; even when mycobacterial tests are negative, the absence of evidence is not evidence of ..... READ ARTICLE

Internal Medicine (The Japanese Society of Internal Medicine) DOI:10.2169/internalmedicine.4076-19

Authors: Takayuki Shiroyama, Shingo Nasu, Ayako Tanaka and Tomonori Hirashima

Case StudyKirk SmithMarch 12, 2020tree-in-bud, lung adenocarcinoma, ALK, alectinib

Alteration in the sensitivity to crizotinib by Na+/H+ exchanger regulatory factor 1 is dependent to its subcellular localization in ALK-positive lung cancers

Background Na+/H+ exchanger regulatory factor 1 (NHERF1) is an important scaffold protein participates in the modulation of a variety of intracellular signal pathways. NHERF1 was able to enhance the effects of chemo-drugs in breast and cervical cancer cells. Anaplastic lymphoma kinase (ALK) fusion mutations are validated molecules targeted therapy in lung cancers, where crizotinib can be used as the specific inhibitor to suppress tumor progression. However, due to the less frequent occurrence of ALK mutations and the complexity for factors to determine drug responses, the genes that could alter crizotinib sensitivity are unclear. Results The expression level of NHERF1 in ALK-translocated NSCLC was significantly higher than that in other lung cancer tissues. NHERF1 expression in ALK positive lung cancer cells was regulated by ALK activities, and was in return able to alter the sensitivity to crizotinib. The function of NHERF1 to influence crizotinib sensitivity was depending on its subc..... READ ARTICLE

BMC Cancer DOI:10.1186/s12885-020-6687-9

Authors: Yang, F., Hu, M., Chang, S. et al.

Pre-ClinicalKirk SmithMarch 12, 2020NHERF1, Crizotinib, ALK, Lung cancer, PDZ protein

Structure-based design of 2,4-diaminopyrimidine derivatives bearing a pyrrolyl group as ALK and ROS1 inhibitors

In order to develop potent ALK and ROS1 dual inhibitors, twenty-eight 2,4-diaminopyrimidine derivatives (9a–9n and 10a–10n) bearing a pyrrolyl moiety were designed and synthesized based on the co-crystal structure of ceritinib with ALKwt protein. Most compounds displayed considerable activity against ALK and ROS1 addicted cells; meanwhile, compound 10d showed excellent activity against Karpas299, H2228 and HCC78 with IC50 values of 0.01, 0.08 and 0.042 μM. Subsequently, seven compounds were selected for kinase studies in vitro, resulting in the discovery of 10d with IC50 values of 1.8, 4.3 and 3.6 nM against ALK, ALKL1196M and ROS1, respectively. Furthermore, the biological assays revealed that compound 10d induced cell apoptosis in a dose-dependent manner. Ultimately, molecular docking studies presented reasonable and optimal binding interactions with ALKwt and ROS1. READ ARTICLE

New Journal of Chemistry DOI:10.1039/C9NJ05980F

Authors: Jie Wang, Shangfei Wei, Tong Li, Lingyun Xing, Meng Cao, Nan Jiang, Ming Guo, Daiying Zuo, Xin Zhai

Pre-ClinicalKirk SmithMarch 11, 2020Design, ALK and ROS1 inhibitors

Oncogenic Fusions May Be Frequently Present at Resistance of EGFR Tyrosine Kinase Inhibitors in Patients With NSCLC: A Brief Report

Introduction Despite initial benefit, virtually all patients suffering from EGFR-mutant NSCLC experience acquired resistance to tyrosine kinase inhibitors (TKIs), driven by multiple mechanisms. Recent reports have identified oncogenic kinase fusions as off-target resistance mechanisms; however, these alterations have been rarely investigated at EGFR TKIs progression. Results Six gene fusions were detected in tumor progression biopsies under an EGFR TKI from 62 consecutive patients (9.7%) with EGFR-mutated advanced NSCLC. Among 31 patients progressing to first- or second-generation EGFR TKIs, one (3%) had an Eukaryotic translation initiation factor 4 gamma 2–GRB2 associated binding protein 1 (EIF4G2-GAB1) fusion. Among 31 patients progressing to the third-generation osimertinib, five (16%) presented oncogene fusions of fibroblast growth factor receptor 3–transforming acidic coiled-coil containing protein 3 (FGFR3-TACC3) (n = 2), kinesin family member 5B–Ret proto-oncogene (KIF5B-RET) (n..... READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100023

Authors: Diego Enrico, Ludovic Lacroix, Jeanne Chen, Etienne Rouleau, Jean-Yves Scoazec, Yohann Loriot, Lambros Tselikas, Cécile Jovelet, David Planchard, Anas Gazzah, Laura Mezquita, Maud Ngo-Camus, Stefan Michiels, Christophe Massard, Gonzalo Recondo, Francesco Facchinetti, Jordi Remon, Jean-Charles Soria, Fabrice André, Gilles Vassal, Luc Friboulet, Benjamin Besse

Cost analysis of the management of brain metastases in patients with advanced ALK+ NSCLC: alectinib versus crizotinib

Aim: To estimate management cost of NSCLC ALK+ patients with and without brain metastasis (BM), and to compare annual costs in patients treated with alectinib or crizotinib. Methods: Management cost/year (€ 2018) in patients with and without BM was estimated with disaggregated resource consumption provided by local oncologists, including medical visits, hospitalizations, diagnostic/laboratory tests, imaging techniques and surgical procedures. The comparison of costs/year with alectinib and crizotinib, considered the cumulative 12-month incidence of BM in ALEX trial (9.4 and 41.4%, respectively). Results: Management cost was €6173.42/patient-year without BM and €21,637.50/patient-year with BM. With alectinib, average cost/patient was lower than crizotinib (€4948.51/patient-year) Conclusion: Prevention of BM with alectinib may result in reductions of cost/year in the management of advanced ALK+ NSCLC. READ ARTICLE

LUNG CANCER MANAGEMENT DOI:10.2217/lmt-2019-0011

Authors: Dolores Isla, Bartomeu Massuti, Martín Lázaro, Lucía Ruiz de Alda, Rocio Gordo, Nuria Ortega-Joaquín & Itziar Oyagüez

Is there a place for crizotinib in c-MET alterations? A case of efficacy in ALK positive NSCLC patient with secondary c-MET amplification

Recently, Moro-Sibilot et al.1 presented the results of the AcSé study that evaluated the efficacy of crizotinib in non-small-cell lung cancer (NSCLC) with ROS1 fusions and c-MET mutations or overexpressions. The excellent performance of crizotinib in ROS1 fusions was confirmed. Nevertheless, in the c-MET cohort there was a lack of activity which was not sufficient to justify its use as targeted therapy in this population. Similar results were found in the analogous METROS trial.2
Despite this evidence, we present a case where crizotinib showed clinical activity, even in a life-threatening condition, thanks to double anaplastic lymphoma kinase (ALK) and c-MET inhibition. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2019.11.016

Authors: M.Mazzotta, M.Filetti, A.Rossi, M.Roberto, M.Occhipinti, A.Pernazza, A.Di Napoli, S.Scarpino, A.Vecchione, R.Giusti, P.Marchetti

Junction Location Identifier (JuLI): Accurate Detection of DNA Fusions in Clinical Sequencing for Precision Oncology

Accurate detection of genomic fusions by high-throughput sequencing in clinical samples with inadequate tumor purity and formalin-fixed, paraffin-embedded tissue is an essential task in precise oncology. We developed the fusion detection algorithm Junction Location Identifier (JuLI) for optimization of high-depth clinical sequencing... In clinical setting, although sensitivity is important, maintaining PPV is also essential to reduce the number of false positives. In particular, if the prevalence is relatively low, such as that of the ALK fusion in NSCLC (2% to 7%),29 several wrong decisions can be made when PPV is not guaranteed. Clinical decisions based on false test results are risky and may lead to inappropriate treatment strategies. Therefore, if the PPV cannot provide a sufficiently high confidence level, it will be difficult to use the method for diagnostic purposes. Because JuLI has better PPV relative to the existing algorithms, it is likely to deliver accurate fusion profil..... READ ARTICLE

The Journal of Molecular Diagnostics DOI:10.1016/j.jmoldx.2019.10.015

Authors: Hyun-Tae Shin, Nayoung K. D. Kim, Jae Won Yun, Boram Lee, Sungkyu Kyung, Ki-Wook Lee, Daeun Ryu, Jinho Kim, Joon Seol Bae, Donghyun Park, Yoon-La Choi, Se-Hoon Lee, Myung-Ju Ahn, Keunchil Park, Woong-Yang Park

Melanoregulin-Anaplastic Lymphoma Kinase (ALK), a Novel ALK Rearrangement That Responds to Crizotinib in Lung Adenocarcinoma

Here, we report a novel melanoregulin (MREG)-ALK fusion, which is sensitive to crizotinib, in a patient with lung adenocarcinoma and brain metastasis. A 65-year-old nonsmoking Chinese woman was admitted to the local hospital with cough since 2 months. She had no fever, expectoration, or headache. Computed tomography scans of her chest reported an irregular nodular mass in the left main bronchial wall and the left lingual lobe, with a narrowing of the left lower lobe bronchi, Meanwhile, cranial computed tomography and magnetic resonance imaging revealed a space-occupying lesion in the frontal lobe, accompanied by bone destruction, which was considered a metastatic tumor. A biopsy through fiberoptic bronchoscopy was performed, and pathologic analysis reported a poorly differentiated lung adenocarcinoma with mucin production in cytoplasm. Formalin-fixed, paraffin-embedded specimens from bronchoscopy biopsy were sent for genomic testing by next-generation sequencing. Results revealed that ..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.019

Authors: Leiming Wang, Shuyang Yao, Lianghong Teng, Weiwei Zhang, Li Chen

Case StudyKirk SmithMarch 1, 2020Melanoregulin-ALK, Crizotinib, Lung Adenocarcinoma

Biomarkers in Lung Cancer

Key Points: Biomarkers can be used for risk assessment, detection, diagnosis, and prognosis and to personalize treatment in lung cancer. Clinically useful biomarkers for selection of high-risk patients for lung cancer screening and to differentiate early lung cancer from benign pulmonary nodules are needed. Biomarkers for nodule management and determination of high-risk groups for lung cancer screening are at all phases of development, from discovery to clinical utility studies. Current trends in lung cancer biomarker development include the integration of clinical and radiologic features with molecular biomarkers, the application of artificial intelligence to molecular and imaging biomarker development, the use highly sensitive technologies such as next-generation sequencing for molecular exploration, and a commitment to high-quality clinical validation and utility studies. READ ARTICLE

Clinics in Chest Medicine. DOI: 10.1016/j.ccm.2019.10.004

Authors: Catherine R. Sears, Peter J. Mazzone