Biogenesis, functions, and clinical implications of circular RNAs in non-small cell lung cancer

Lung cancer (LC) is the leading cause of cancer-related deaths worldwide, with high morbidity and mortality. Non-small cell lung cancer (NSCLC) is a major pathological type of LC and accounts for more than 80% of all cases. Circular RNAs (circRNAs) are a large class of non-coding RNAs (ncRNAs) with covalently closed-loop structures, a high abundance, and tissue-specific expression patterns. They participate in various pathophysiological processes by regulating complex gene networks involved in proliferation, apoptosis, migration, and epithelial-to-mesenchymal transition (EMT), as well as metastasis. A growing number of studies have revealed that the dysregulation of circRNAs contributes to many aspects of cancer progression, such as its occurrence, metastasis, and recurrence, suggesting their great potential as efficient and specific biomarkers in the diagnosis, prognosis, and therapeutic targeting of NSCLC. In this review, we systematically elucidate the characteristics, biogenesis, and functions of circRNAs and focus on their molecular mechanisms in NSCLC progression. Moreover, we highlight their clinical implications in NSCLC treatment. READ ARTICLE

Molecular Therapy - Nucleic Acids DOI:10.1016/j.omtn.2021.11.013

Authors: Ying Liu, Xiang Ao, Wanpeng Yu, Yuan Zhang, Jianxun Wang

ALK Inhibitors or Chemotherapy for Third Line in ALK-positive NSCLC? Real-world Data

We conducted a real-world multi-institutional analysis, aiming to compare the efficacy of third-line ALKi versus chemotherapy in these patients. Consecutive ALK-positive metastatic NSCLC patients treated with at least one ALKi were identified in the working databases of 7 Israeli oncology centers (the full cohort). Demographic and clinical data were collected. Patients receiving any systemic treatment beyond 2 ALKi comprised the third-line cohort, whether a third ALKi (group A) or chemotherapy (group B). Groups A and B were compared in terms of overall survival (OS) and time-to-next-treatment line (TNT). At a median follow-up of 41 months (95% confidence interval [CI]: 32-55), 80 (47.1%) have died. Median OS (mOS) in the full cohort (n = 170) was 52 months (95% CI: 32-65). Number of ALKi (hazard ratio [HR] 0.765; 95% CI: 0.61-0.95; P = .024) and age (HR 1.02, 95% CI: 1.01-1.04, P = .009) significantly associated with OS in the full cohort. The third-line cohort included 40 patients, of..... READ ARTICLE

The Oncologist DOI:10.1093/oncolo/oyab005

Authors: Moskovitz, Mor, Dudnik, Elizabeth, Shamai, Sivan, Rotenberg, Yakir, Popovich-Hadari, Noa, Wollner, Mira, Zer, Alona, Gottfried, Maya, Mishaeli, Moshe, Rosenberg, Shoshana Keren, Onn, Amir, Merimsky, Ofer, Urban, Damien, Peled, Nir, Maimon, Natalie, Bar, Jair

Patient Selection for Local Aggressive Treatment in Oligometastatic Non-Small Cell Lung Cancer.

One-fourth of all patients with metastatic non-small cell lung cancer presents with a limited number of metastases and relatively low systemic tumor burden. This oligometastatic state with limited systemic tumor burden may be associated with remarkably improved overall and progression-free survival if both primary tumor and metastases are treated radically combined with systemic therapy. This local aggressive therapy (LAT) requires a multidisciplinary approach including medical oncologists, radiation therapists, and thoracic surgeons. A surgical resection of the often advanced primary tumor should be part of the radical treatment whenever feasible. However, patient selection, timing, and a correct treatment allocation for LAT appear to be essential. In this review, we aimed to summarize and discuss the current evidence on patient selection criteria such as characteristics of the primary tumor and metastases, response to neoadjuvant or first-line treatment, molecular characteristics, mediastinal lymph node involvement, and other factors for LAT in oligometastatic NSCLC. READ ARTICLE

Cancers DOI:10.3390/cancers13246374

Authors: Werner, R.S. and Opitz, I.

Clinical Impact of Switching to Ceritinib After Severe AEs Related to Crizotinib/Alectinib in a Novel PTH2R-ALK Fusion Lung Adenocarcinoma: A Case Report

Lung cancer is still the leading cause of morbidity and mortality by cancer among men, according to the latest epidemiological data in China. Anaplastic lymphoma kinase (ALK) rearrangements act as key oncogenic drivers of non-small cell lung cancer (NSCLC) and have been identified in 5– 6% of NSCLC. Although ALK inhibitors (ALK-TKIs) were proven to be more effective than chemotherapy in ALK-positive NSCLC patients and the safety profile of these drugs was favorable, novel ALK fusions NSCLC might discontinue or switch treatment because of adverse events (AEs) have rarely previously been reported. Here, we describe a male patient with stage IV lung adenocarcinoma who carried a novel PTH2R-ALK fusion identified by next-generation sequencing (NGS). The patient first took crizotinib but switched to alectinib due to gastrointestinal AEs. Although alectinib remained effective on tumors, ceritinib (450 mg) was replaced after the AEs of hyperbilirubinemia occurred. After reducing the dose to 30..... READ ARTICLE

OncoTargets and Therapies DOI:10.2147/OTT.S340984

Authors: Shen G, Du Y, Shen J, Zhang J, Xia X, Huang M and Shen W.

Case Study, group1Kirk SmithDecember 9, 2021PTH2R-ALK, non-small cell lung cancer, ceritinib, adverse events

Comparative Efficacy of Systemic Agents for Brain Metastases From Non-Small-Cell Lung Cancer With an EGFR Mutation/ALK Rearrangement: A Systematic Review and Network Meta-Analysis

Brain metastases (BM) from non-small-cell lung cancer (NSCLC) are frequent and carry significant morbidity, and current management options include varying local and systemic therapies. Here, we performed a systematic review and network meta-analysis to determine the ideal treatment regimen for NSCLC BMs with targetable EGFR-mutations/ALK-rearrangements.</sec><sec>MethodsWe searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs including ≥10 patients were selected. We used a frequentist random-effects model for network meta-analysis (NMA) and assessed the certainty of evidence using the GRADE approach. Our primary outcome of interest was intracranial progression-free survival (iPFS).</sec><sec>ResultsWe included 24 studies representing 19 trials with 1623 total patients. Targeted tyrosine kinase inhibitors (TKIs) significantly improved iPFS, wit..... READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.739765

Authors: Taslimi Shervin, Brar Karanbir, Ellenbogen Yosef, Deng Jiawen, Hou Winston, Moraes Fabio Y., Glantz Michael, Zacharia Brad E., Tan Aaron, Ahluwalia Manmeet S., Khasraw Mustafa, Zadeh Gelareh, Mansouri Alireza

Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

Background: Targeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance.
Conclusions: Lorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.754768

Authors: Ling Peng, Dafeng Lu2, Yang Xia, Shaodong Hong, Giovanni Selvaggi, Justin Stebbing, Yilan Sun, Fei Liang

High Tumor Mutation Burden and DNA Repair Gene Mutations are Associated with Primary Resistance to Crizotinib in ALK-Rearranged Lung Cancer

About 20% of patients with ALK-rearranged non-small cell lung cancer (NSCLC) develop acquired resistance to tyrosine kinase inhibitor (TKI) during the first 6 months. This study aimed to examine the molecular mechanisms of early TKI resistance and prognosis in ALK-rearranged NSCLC.Ten patients with ALK-rearranged NSCLC were included: five who developed rapid resistance to crizotinib (progression-free survival (PFS) ≤3 months) and five who exhibited a good response to crizotinib (PFS ≥36 months). The study finds a higher mutation burden and mutations in DNA repair gene, including TP53, were potentially associated with primary resistance to crizotinib in ALK-rearranged NSCLC. An immune-checkpoint inhibition strategy could be examined, which might overcome primary resistance to crizotinib in ALK-rearranged NSCLC. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S325443

Authors: Dakai Xiao, Qiuhua Deng, Dongyun He, Ying Huang, Wenchi Liang, Fengnan Wang, Haihong Yang

Case StudyKirk SmithSeptember 15, 2021ALK, non-small cell lung cancer, TKI, resistance, prognosis

Immunotherapy and Vaccination in Surgically Resectable Non-Small Cell Lung Cancer (NSCLC)

Early-stage NSCLC (stages I and II, and some IIIA diseases) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases, with surgery being its main treatment modality. The risk of disease recurrence and cancer-related death, however, remains high among NSCLC patients after complete surgical resection. In previous studies on the long-term follow-up of post-operative NSCLC, the results showed that the five-year survival rate was about 65% for stage IB and about 35% for stage IIIA diseases. Platinum-based chemotherapy with or without radiation therapy has been used as a neoadjuvant therapy or post-operative adjuvant therapy in NSCLC, but the improvement of survival is limited. Immune checkpoint inhibitors (ICIs) have effectively improved the 5-year survival of advanced NSCLC patients. Cancer vaccination has also been explored and used in the prevention of cancer or reducing disease recurrence in resected NSCLC. Here, we review studies that have focused on the use of immunotherapies (i.e., ICIs and vaccination) in surgically resectable NSCLC. We present the results of completed clinical trials that have used ICIs as neoadjuvant therapies in pre-operative NSCLC. Ongoing clinical trials investigating ICIs as neoadjuvant and adjuvant therapies are also summarized. READ ARTICLE

Vaccines DOI: 10.3390/vaccines9070689

Authors: Chiu L.-C., Lin S.-M., Lo Y.-L., Kuo S.C.-H., Yang C.-T. and Hsu P.-C.

410P Frequency and spectrum of primary resistance mechanism in Chinese ALK+ non-small cell lung cancer patients progressing on crizotinib: A multicenter study

Background: Anaplastic lymphoma kinase (ALK) have been recognized as the most important predictor of response to crizotinib. However, 20-30% of patients harboring ALK fusion non-small-cell lung cancer patients show a poor response requiring investigation for underlying mechanisms... Conclusions: BCL2L11 loss, PI3K-AKT-mTOR signaling pathway (PTEN, PIK3CA mutations), SMARCA4 mutations or EML4-ALK fusion (non A20) might contribute to molecular mechanisms of primary resistance to crizotinib in ALK+NSCLC.Further investigations are warranted to overcome these primary resistance. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2020.10.404

Authors: W-X. Wang, C. Xu, Q-X. Zhang, W. Zhuang, Z-B. Song, Y-C. Zhu, G. Chen, M-Y. Fang, T-F. Lv, Y. Song

Abstract 4900: An ALK fusion gene regulates different signaling pathways in mortal versus immortalized normal human cells for cellular senescence and transformation

Accumulating results of clinical trials lead targeted therapies to be the first choice for unresectable or recurrent lung cancer with driver mutations. Echinoderm Microtubule Associated Protein Like 4 (EML4) - Anaplastic lymphoma kinase (ALK) fusion is known as such a driver mutation. It presents in 3-6% of non-small cell lung carcinoma (NSCLC). EML4-ALK fusion protein generate the constitutive ALK kinase activity in NSCLC. The basic understanding of EML4-ALK remains insufficient due to the lack of functional studies using normal human cells. We investigated the role of EML4-ALK in mortal and immortalized normal human cells. The expression of EML4-ALK in normal, mortal human fibroblasts caused accumulated DNA damage, telomere shortening and the early induction of cellular senescence with senescence-associated beta-galactosidase activity and upregulation of p16INK4A and p21WAF1. In contrast, when EML4-ALK was expressed in telomerase reverse transcriptase (hTERT)-immortalized normal huma..... READ ARTICLE

Cancer Research DOI:10.1158/1538-7445.AM2020-4900

Authors: Masaru Matsumoto, Akihiko Miyanaga, Jessica Beck, Izumi Horikawa, Mohammed Khan, Delphine Lissa, Masahiro Seike, Akihiko Gemma, Hiroyuki Mano and Curtis Harris

Conference PaperKirk SmithAugust 1, 2020EML4-ALK, non-small cell lung cancer, NSCLC

Detection of ALK fusion transcripts in plasma of non-small cell lung cancer patients using a novel RT-PCR based assay

Detection of genomic rearrangements like ALK fusions are of great interest in non-small cell lung cancer (NSCLC) as those alterations can be targeted by an increasing number of drugs. To overcome tissue limitations, detection of these alterations from liquid biopsies is an unmet need, despite the development of novel NGS-based tests. To allow the detection of ALK rearrangements from circulating-free RNA (cfRNA) from NSCLC patients, we have evaluated a novel RT-PCR based assay and compared the results to tissue-based testing using immunohistochemistry (IHC) or fluorescence in-situ hybridization (FISH).The prototype cobas ALK/RET/ROS1 Fusion Panel assay was able to detect ALK fusion transcripts in the plasma of NSCLC patients at baseline as well as at disease progression. Limited sensitivity could be explained by biological factors influencing nucleic acid shedding by tumours, as well as the presence of fusions not covered by the assay. However, the assay demonstrated high specificity. T..... READ ARTICLE

Cancer Research DOI:10.1158/1538-7445.AM2020-5299

Authors: Simon Heeke, Marius Ilié, Maryline Allegra, Audrey Vallée, Carole Salacroup, Virginie Tanga, Véronique Hofman, Jaya Rajamani, Michael Lee, Ellen Ordinario, Marc G. Denis and Paul Hofman

Conference PaperKirk SmithAugust 1, 2020ALK, non-small cell lung cancer, NSCLC, cobas, RET, ROS1

Retrospective Observational Study of ALK-Inhibitor Therapy Sequencing and Outcomes in Patients with ALK-Positive Non-small Cell Lung Cancer

Data are sparse concerning the sequential use of multiple anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC).This study investigated sequencing and outcomes among patients receiving multiple ALK inhibitors.This study provides initial information on real-world treatment patterns following the introduction of new ALK inhibitors, and supports the use of sequential ALK therapies. READ ARTICLE

Drugs - Real World Outcomes DOI:10.1007/s40801-020-00207-6

Authors: David M. Waterhouse, Janet L. Espirito, Marc D. Chioda, Bismark Baidoo, Jack Mardekian, Nicholas J. Robert, Elizabeth T. Masters

Trends in ALK inhibitors for non-small cell lung cancer

Background: Rearrangements in the gene encoding anaplastic lymphocyte kinase (ALK) are found in 3%–5% of patients. Treatment options have significantly expanded with ALK inhibitor drug approvals including crizotinib in 2011, ceritinib in 2014, alectinib in 2015, brigatinib in 2017 and lorlatinib in 2018. We sought to better understand the real-world treatment utilization and cost of ALK inhibitors in lung cancer (LCA) over the most recent period for which adjudicated claims are available, October 2017-September 2018... Conclusions: Our analyses demonstrate alectinib is the preferred first-line ALK inhibitor in the last twelve months of available data. Furthermore, the increased ER and in-patient costs may substantiate the findings of the ALEX trial, notably higher liver toxicity and more nausea, vomiting, and diarrhea for crizotinib. There is not yet sufficient data on the newer ALK inhibitors, brigatinib and lorlatinib in the real-world. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e14046

Authors: Denise Meade, Marie Ng, S Alford

Real-World OutcomesKirk SmithMay 25, 2020ALK, inhibitor, non-small cell lung cancer

Clinical impact of targetable gene alterations on therapeutic outcomes in stage II/III locally advanced non-small cell lung cancer patients

Background: The clinical significance of genetic alterations in stage II/III non-small cell lung cancer (NSCLC) patients has not yet been clarified. We have prospectively analyzed NSCLC patients for cancer-related gene alterations and have followed up clinical course of the patients, establishing a large-scale clinico-genomic database in our nationwide genome screening project (LC-SCRUM-Japan)... Conclusions: In stage II/III NSCLC, the total frequency of targetable gene alterations was similar to that previously evaluated in our stage IV cohort (45%), and the current standard therapies showed early progression in the targetable gene-altered patients. A novel effective multimodality treatment in combination with targeted therapies is needed for this population. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9038

Authors: Yoshitaka Zenke, Shingo Matsumoto, Terufumi Kato, Shingo Miyamoto, Takuma Imakita, Tetsuya Mitsudomi, Hiromi Aono, Ryota Ushio, Naoki Furuya, Kazumi Nishino, Saori Takata, Mika Nakao, Satoshi Hara, Motoko Tachihara, Akimasa Sekine, Jun Sakakibara-Konishi, Ryo Toyozawa, Kiyotaka Yoh, Koichi Goto

Review PaperKirk SmithMay 25, 2020Gene alterations, non-small cell lung cancer

Responses to ALK Inhibitor Treatments in a Patient with Non-Small Cell Lung Cancer Harboring a Novel HPCAL1-ALK Fusion Variant: A Case Report

Anaplastic lymphoma kinase (ALK) fusion is present in approximately 2–7% of patients with lung adenocarcinoma. ALK fusion-positive patients can benefit from targeted therapy. We herein report a 53-year-old Chinese male patient diagnosed as lung adenocarcinoma with a smoking history. Next-generation sequencing was performed to detect somatic mutations of oncogenic drivers and tumor suppressor genes in plasma-derived circulating tumor DNA using an ultra-deep 160-gene panel. A novel HPCAL1-ALK fusion variant was identified in the patient responding to ALK inhibitor treatments, and the fusion variant was also confirmed by fluorescence in situ hybridization and immunohistochemical. Our study expands the mutational spectrum of ALK fusion variants and provides options for the precise treatment of such patients. READ ARTICLE

OncoTargets and therapy DOI:10.2147/OTT.S252210

Authors: Wang R, Qin J, Fan Y, Li Z, Chen C, Su W.

SPECC1L-ALK: A novel gene fusion response to ALK inhibitors in non-small cell lung cancer

There was a case report showed that a novel pleckstrin homology and RUN domain containing M2 (PLEKHM2)- anaplastic lymphoma kinase (ALK) gene rearrangement in small cell lung cancer (SCLC) patient had long-term benefit from ALK inhibitors [ [1] ]. Actually, the case report demonstrated that next generation sequence (NGS) maybe a very useful method for detecting a new subtype of ALK fusion and it may provide a better understanding of ALK- tyrosine kinase inhibitors (TKIs) treatment. Here, we identified a novel type of ALK rearrangement responding to ALK inhibitors in non-small cell lung cancer (NSCLC) by NGS. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.03.017

Authors: Li Ma, Quan Zhang, Yujie Dong, Haoyang Li, Jinghui Wang

Case StudyKirk SmithMay 1, 2020SPECC1L-ALK, gene fusion, ALK, inhibitors, non-small cell lung cancer

Efficacy and safety of ceritinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer: A systematic review and meta-analysis

What is known and objective: Ceritinib is a new, oral, potent and selective second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the Food and Drug Administration of the United States in April 2014. It is active in crizotinib-re-sistant patients, especially in patients with non-small cell lung cancer (NSCLC) and brain metastasis. The aim of this study was to analyse the effects and side effects of ceritinib in ALK-rearranged NSCLC.Methods: We searched articles published from January 1980 to March 2019 in PubMed, EMBASE, Cochrane Library and Web of Science. The pooled estimate and 95% CI were calculated with DerSimonian-Laird method and the random effect model.Results and discussion: From 15 articles, 2,598 patients were included in the meta-analysis. Eleven studies reported the ORR, and the DCR was presented in 10 stud-ies. The ORR and DCR of ceritinib were 0.48 (95% CI, 0.39-0.57) and 0.76 (95% CI, 0.69-0.82), respectively. The PFS and OS were presented in nine and ..... READ ARTICLE

Journal of Clinical Pharmacy and Therapeutics DOI:10.1111/jcpt.13157

Authors: Wei Tian, Ping Zhang, Yuan Yuan, Xiao-Hui Deng, Rui Yue, Xiao-Zhu Ge

Clinicopathological and Prognostic Significance of EML4-ALK Rearrangement in Patients with Surgically Resected Lung Adenocarcinoma: A Propensity Score Matching Study

Objective The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene is a key oncogenic driver in non-small cell lung cancer (NSCLC). This study analyzed the clinicopathological characteristics and prognostic significance of EML4-ALK fusion gene in patients with surgically resected adenocarcinoma. Methods The clinicopathological characteristics of 1056 consecutive patients with surgically resected stage I–IIIA adenocarcinoma were collected from February 2014 to October 2014, and EML4-ALK rearrangement was detected using real-time polymerase chain reaction (RT-PCR) technology. To compare the imaging and pathological features, a propensity score matching (PSM) method was performed. The follow-up information was collected to evaluate the long-term outcomes of patients with EML4-ALK rearrangement. Results The prevalence of EML4-ALK rearrangement was 6.6% in 1056 consecutive patients. A total of 70 EML4-ALK-positive and 210 EML4-ALK-negative patie..... READ ARTICLE

Cancer management and research DOI:10.2147/CMAR.S229217

Authors: Shi J, Gu W, Zhao Y, Zhu J, Jiang G, Bao M, Shi J.

Overcoming resistance by ALK compound mutation (I1171S + G1269A) after sequential treatment of multiple ALK inhibitors in non-small cell lung cancer

Background: Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%–5% of non-small cell lung cancers (NSCLCs). ALK inhibitors show a very high response rate to ALK-positive NSCLCs. However, the emergence of acquired resistance is inevitable. In this study, we investigated the drugs for overcoming resistance especially compound mutations after sequential treatment with crizotinib, alectinib, and lorlatinib. Conclusions: With the sequential ALK inhibitors treatment, cancer cells accumulate new mutations in addition to mutations acquired previously. The identified compound mutation (I1171S + G1269A) was found to be sensitive to ceritinib and brigatinib, and indeed the patient's tumor partially responded to ceritinib. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13299

Authors: Ken Takahashi, Yosuke Seto, Koutaroh Okada, Shinya Uematsu, Ken Uchibori, Mika Tsukahara, Tomoko Oh-hara, Naoya Fujita, Noriko Yanagitani, Makoto Nishio, Kenichi Okubo, Ryohei Katayama

Differences Between the East and the West in Managing Advanced-Stage Non-small Cell Lung Cancer

Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highligh..... READ ARTICLE

Clinical Oncology DOI:10.1016/j.clon.2019.07.014

Authors: V. H. F. Lee, T. S. K. Mok, Y. Goto, V. C. C. Hsue, L. Yang, Y. Jiang, D. K. C. Leung, K. S. Lau, P. Y. Tse