Kwok Seng Loh
Email Address
entlks@nus.edu.sg
Organizational Units
YONG LOO LIN SCH OF MEDICINE
faculty
OTOLARYNGOLOGY
dept
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Publication High-risk HPV genotypes and P16INK4a expression in a cohort of head and neck squamous cell carcinoma patients in Singapore(Impact Journals LLC, 2016) Tan, L.S.Y; Fredrik, P; Ker, L; Yu, F.G; Wang, D.Y; Goh, B.C; Loh, K.S; Lim, C.M; PHARMACOLOGY; OTOLARYNGOLOGYHuman papillomavirus (HPV), especially HPV16 genotype, is associated with oropharyngeal squamous cell carcinoma (OPSCC). We aim to determine the prevalence and characterize the high-risk (HR)-HPV genotypes in head and neck SCC (HNSCC) in a South-East Asian multi-ethnic society in Singapore and examine its prognostic significance. 159 HNSCC archival tissue samples were retrieved and tumour DNA was screened for 18 HR-HPV genotypes using a PCR-based assay (Qiagen, digene HPV genotyping RH test). P16 protein overexpression was identified using immunohistochemistry (IHC). Statistical correlation between clinical outcomes were performed between HPV-positive and negative HNSCC patients. Six HR-HPVs (HPV16, 18, 31, 45, 56, 68) were detected in 90.6% of HNSCC; and 79.9% had multiple HPV genotypes detected. HPV31 and HPV45 were the most prevalent (79.2% and 87.4%, respectively); and HPV16 was predominantly found in OPSCC (p < 0.001). HPV-DNA PCR assay yielded a high sensitivity (96%) but low specificity (11%) when compared to p16 immunohistochemistry as the reference standard. P16-positive HNSCC was predominantly observed in OPSCC (73.7%; p = 0.005); and p16-positive OPSCC exhibited improved overall survival compared to p16-negative OPSCC (p = 0.022). Similarly, smoking and alcohol consumption were poor prognostic factors of overall survival (p = 0.007; p = 0.01) in OPSCC patients. HR-HPVs were identified in 90.6% of HNSCC patients using the HPV-DNA PCR assay. This test had a poor specificity when compared to p16 IHC; making it an unreliable detection technique in selecting patients for radiation dose de-escalation treatment protocol. P16-positive tumor was predominantly found in the oropharynx these patients demonstrated better overall survival than those with p16-negative OPSCC.Publication Epstein-Barr virus-induced ectopic CD137 expression helps nasopharyngeal carcinoma to escape immune surveillance and enables targeting by chimeric antigen receptors(SPRINGER, 2022-03-17) Prasad, Mukul; Ponnalagu, Sashigala; Zeng, Qun; Luu, Khang; Lang, Si Min; Wong, Hiu Yi; Cheng, Man Si; Wu, Meihui; Mallilankaraman, Karthik; Sobota, Radoslaw Mikolaj; Lim, Yan Ting; Wang, Loo Chien; Goh, Chuan Keng; Tay, Kai Xun Joshua; Loh, Kwok Seng; Wang, Cheng-; Lee, Wen-Hsien; Goh, Boon Cher; Lim, Chwee Ming; Schwarz, Herbert; Assoc Prof Herbert Schwarz; MEDICINE; PHYSIOLOGY; MICROBIOLOGY AND IMMUNOLOGY; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); OTOLARYNGOLOGY; BIOLOGICAL SCIENCESNon-keratinizing nasopharyngeal carcinoma (NPC) is a malignancy with a poor prognosis for relapsing patients and those with metastatic disease. Here, we identify a novel disease mechanism of NPC which may be its Achilles’ heel that makes it susceptible to immunotherapy. CD137 is a potent costimulatory receptor on activated T cells, and CD137 agonists strongly enhance anti-tumor immune responses. A negative feedback mechanism prevents overstimulation by transferring CD137 from T cells to CD137 ligand (CD137L)-expressing antigen presenting cells (APC) during cognate interaction, upon which the CD137-CD137L complex is internalized and degraded. We found ectopic expression of CD137 on 42 of 122 (34.4%) NPC cases, and that CD137 is induced by the Epstein-Barr virus latent membrane protein (LMP) 1. CD137 expression enables NPC to hijack the inbuilt negative feedback mechanism to downregulate the costimulatory CD137L on APC, facilitating its escape from immune surveillance. Further, the ectopically expressed CD137 signals into NPC cells via the p38-MAPK pathway, and induces the expression of IL-6, IL-8 and Laminin γ2. As much as ectopic CD137 expression may support the growth and spread of NPC, it may be a target for its immunotherapeutic elimination. Natural killer cells that express a CD137-specific chimeric antigen receptor induce death in CD137+ NPC cells, in vitro, and in vivo in a murine xenograft model. These data identify a novel immune escape mechanism of NPC, and lay the foundation for an urgently needed immunotherapeutic approach for NPC.Publication Tailoring distant metastatic imaging for patients with clinically localized undifferentiated nasopharyngeal carcinoma(2004) Kumar, M.B.; Lu, J.J.; Shakespeare, T.P.; Loh, K.S.; Tan, K.S.L.; Chong, L.M.J.; Soo, R.; Goh, B.C.; PHARMACOLOGY; OTOLARYNGOLOGYPurpose: The 2000 practice guidelines of the National Comprehensive Cancer Network recommend World Health Organization Type 2-3 nasopharyngeal carcinoma (NPC) be staged for distant disease using chest X-ray and bone scan. Our aim was to evaluate these modalities plus liver ultrasonography for American Joint Committee on Cancer/International Union Against Cancer 1997 clinical Stage I-IVB NPC. Methods and Materials: Between February 1999 and May 2002, all patients with clinical (examination plus CT/MRI of head and neck) Stage I-IVB undifferentiated NPC were prospectively evaluated for distant disease with chest X-ray, liver ultrasonography, and bone scan. Suspicious lesions underwent confirmatory investigation, and patients were reevaluated at 4 months. Results: In the 139 patients evaluated, the positive yield was 3.6% and prevalence was 5.8% (0.7% lung, 2.2% skeletal, and 2.9% liver metastases). The prevalence increased by N stage (p = 0.004) and overall stage (p = 0.05). Compared with N3 disease (odds ratio 1.0), the odds of metastases for N0, N1, and N2 disease was 0, 0.12, and 0.33, respectively. The positive yield was 0%, 1.8%, 4.8%, and 14.3% for N0, N1, N2, and N3 disease, respectively. Conclusion: This is the first study to evaluate the use of distant staging investigations for American Joint Committee on Cancer/International Union Against Cancer 1997 staged NPC. We recommend alterations to the 2000 National Comprehensive Cancer Network guidelines as follows: high-risk (N3) disease should be fully staged with chest X-ray, bone scan, and liver ultrasonography; intermediate risk (N1 and N2) disease may be staged using all three modalities on an institutional basis. No evidence supports distant imaging for low-risk (N0 or Stage I) disease. © 2004 Elsevier Inc.Publication Prospective phase II trial of concomitant boost radiotherapy for stage II nasopharyngeal carcinoma(2008) Lu, J.J.; Shakespeare, T.P.; Zhang, Q.; Lee, K.M.; Kong, L.; Loh, K.S.; Luke, Tan K.S.; OTOLARYNGOLOGYStage II nasopharyngeal carcinoma (NPC) treated with conventionally fractionated radiotherapy results in suboptimal outcome. This report aims to document the outcome of Stage II NPC patients treated with external beam radiotherapy delivered using an accelerated concomitant boost (C-Boost) schedule. Forty-seven 1997 AJCC Stage II NPC patients were enrolled and analyzed in this prospective phase II clinical trial. The primary tumor and clinically involved nodes received a total dose of 72 Gy in 42 fractions. C-Boost for gross disease consisted of 18 Gy in 12 fractions commencing on day 19, and delivered at least 6 h after the first dose. Patients were assessed for response, survival and toxicity. With a median follow-up of 30 months, 4 patients developed local recurrence only, 2 had persistent neck nodal disease or recurrence, and 1 with both locoregional recurrences. Distant metastases were seen in 5 patients, with or without locoregional recurrence. A total of 5 patients succumbed from nasopharyngeal cancer: four from effects of distant metastases and 1 from progressive local disease. The 3-year local, regional, and overall survival rates were 87.1%, 92%, and 85.9%, respectively. All patients experienced some degree of acute and/or late toxicity. Moderate to severe late toxicities (grade 3 and 4) were observed in 17% of cases. This C-Boost radiotherapy regimen administers a higher biologically effective dose compared with conventional radiation schedules. The local control after C-Boost radiation seems high for patients with stage II nasopharyngeal carcinoma, thus justifies further investigation to confirm its efficacy. © 2007 Elsevier Ltd. All rights reserved.Publication Sequential external beam radiotherapy and high-dose-rate intracavitary brachytherapy in T1 and T2 nasopharyngeal carcinoma: An evaluation of long-term outcome(2006) Thiagarajan, A.; Lin, K.; Lu, J.J.; Tan, L.K.S.; Loh, T.K.S.; Goh, B.C.; Lin, K.; Tiong, C.E.; PHARMACOLOGYPublication Epstein–barr virus infection of pseudostratified nasopharyngeal epithelium disrupts epithelial integrity(MDPI AG, 2020) Yu, F.; Lu, Y.; Li, Y.; Uchio, Y.; Pangnguriseng, U.A.; Kartika, A.V.; Iizasa, H.; Yoshiyama, H.; Loh, K.S.; BIOMEDICAL ENGINEERING; OTOLARYNGOLOGYEpstein–Barr virus (EBV) is a human oncogenic virus that causes several types of tumor, such as Burkitt’s lymphoma and nasopharyngeal carcinoma (NPC). NPC tumor cells are clonal expansions of latently EBV-infected epithelial cells. However, the mechanisms by which EBV transforms the nasopharyngeal epithelium is hampered, because of the lack of good in vitro model to pursue oncogenic process. Our primary nasopharyngeal epithelial cell cultures developed pseudostratified epithelium at the air-liquid interface, which was susceptible to EBV infection. Using the highly sensitive RNA in situ hybridization technique, we detected viral infection in diverse cell types, including ciliated cells, goblet cells, and basal cells. EBV-encoded small RNA-positive cells were more frequently detected in the suprabasal layer than in the basal layer. We established the most physiologically relevant EBV infection model of nasopharyngeal epithelial cells. This model will advance our understanding of EBV pathogenesis in the development of NPC. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.Publication A rational approach to pulmonary screening in newly diagnosed head and neck cancer(2005) Loh, K.S.; Brown, D.H.; Baker, J.T.; Gilbert, R.W.; Gullane, P.J.; Irish, J.C.; OTOLARYNGOLOGYPublication Clinical Diagnostic Study of a Novel Injection Molded Swab for SARS-Cov-2 Testing(SPRINGER LONDON LTD, 2021-01-11) Tay, Joshua K; Cross, Gail B; Sun, Louisa; Chia, Alfred; Chee, Jeremy; Loh, Jerold; Lim, Zhenyu; Ngiam, Nicholas; Khang, WenPang; Yeap, Stephanie; Goh, Han Lee; Siow, Chor Hiang; Loh, WoeiShyang; Loh, KwokSeng; Lee, ChunKiat; Yan, Benedict; Chow, Vincent TK; Wang, De Yun; Boey, Freddy; Wong, John EL; Allen, David M; Assoc Prof David Michael Allen; BIOMEDICAL ENGINEERING; MEDICINE; MICROBIOLOGY AND IMMUNOLOGY; OTOLARYNGOLOGYIntroduction: The gold standard for COVID-19 diagnosis is currently a real-time reverse transcriptase polymerase chain reaction (RT-PCR) to detect SARS-CoV-2. This is most commonly performed on respiratory secretions obtained via a nasopharyngeal swab. Due to supply chain limitations and high demand worldwide because of the COVID-19 pandemic, access to commercial nasopharyngeal swabs has not been assured. 3D printing methods have been used to meet the shortfall. For longer-term considerations, 3D printing may not compare well with injection molding as a production method due to the challenging scalability and greater production costs of 3D printing. Methods: To secure sufficient nasopharyngeal swab availability for our national healthcare system, we designed a novel injection molded nasopharyngeal swab (the IM2 swab). We performed a clinical diagnostic study comparing the IM2 swab to the Copan FLOQSwab. Forty patients with a known diagnosis of COVID-19 and 10 healthy controls were recruited. Paired nasopharyngeal swabs were obtained from the same nostril of each participant and tested for SARS-CoV-2 by RT-PCR. Results: When compared to the Copan FLOQswab, results from the IM2 swab displayed excellent overall agreement and positive percent agreement of 96.0% and 94.9%, respectively. There was no significant difference in mean RT-PCR cycle threshold values for the ORF1ab (28.05 vs. 28.03, p = 0.97) and E-gene (29.72 vs. 29.37, p = 0.64) targets, respectively. We did not observe any significant adverse events and there was no significant difference in patient-reported pain. Conclusion: In summary, the IM2 nasopharyngeal swab is a clinically safe, highly accurate option to commercial nasopharyngeal swabs.Publication Use of complementary and alternative medicine in head and neck cancer patients(2010) Lim, C.M.; Ng, A.; Loh, K.S.; OTOLARYNGOLOGYPublication SARS-CoV-2 in migrant worker dormitories: Geospatial epidemiology supporting outbreak management(ELSEVIER SCI LTD, 2021-02-01) Gorny, Alexander W; Bagdasarian, Natasha; Koh, Azriel Hong Kiat; Lim, Yong Chin; Ong, Jacqueline Soo May; Ng, Bryan Su Wei; Hooi, Benjamin; Tam, Wai Jia; Kagda, Fareed Husain; Chua, Gerald Seng Wee; Yong, Michael; Teoh, Hock Luen; Cook, Alex Richard; Sethi, S.K.; Young, Dan Yock; Loh, Thomas; Lim, Aymeric Yu Tang; Aw, Andrew Kian-Li; Mak, Kenneth Seck Wai; Fisher, Dale; Prof Yu Tang, Aymeric Lim; MEDICINE; ORTHOPAEDIC SURGERY; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; ANAESTHESIA; PAEDIATRICS; PATHOLOGYBackground: Migrant worker dormitories—residential complexes where 10–24 workers share living spaces—account for the majority of cases of SARS-CoV-2 infection in Singapore. To prevent overspill of transmission to the wider population, starting in early April 2020, residents were confined to their dormitories while measures were put in place to arrest the spread of infection. This descriptive study presents epidemiological data for a population of more than 60 000 migrant workers living in two barracks-style and four apartment-style dormitories located in western Singapore from April 3 to June 10, 2020. Methods: Our report draws from data obtained over the first 50 days of outbreak management in order to describe SARS-CoV-2 transmission in high-density housing environments. Cumulative counts of SARS-CoV-2 cases and numbers of housing units affected were analyzed to report the harmonic means of harmonic means of doubling times and their 95% confidence intervals (CI). Results: Multiple transmission peaks were identified involving at least 5467 cases of SARS-CoV-2 infection across six dormitories. Our geospatial heat maps gave an early indication of outbreak severity in affected buildings. We found that the number of cases of SARS-CoV-2 infection doubled every 1.56 days (95% CI 1.29–1.96) in barracks-style buildings. The corresponding doubling time for apartment-style buildings was 2.65 days (95% CI 2.01–3.87). Conclusions: Geospatial epidemiology was useful in shaping outbreak management strategies in dormitories. Our results indicate that building design plays an integral role in transmission and should be considered in the prevention of future outbreaks.