Publications by authors named "Victor Lee"

251 Publications

Hematopoietic Wnts Modulate Endochondral Ossification During Fracture Healing.

Front Endocrinol (Lausanne) 2021 24;12:667480. Epub 2021 May 24.

Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.

Wnt signaling plays a critical role in bone formation, homeostasis, and injury repair. Multiple cell types in bone have been proposed to produce the Wnts required for these processes. The specific role of Wnts produced from cells of hematopoietic origin has not been previously characterized. Here, we examined if hematopoietic Wnts play a role in physiological musculoskeletal development and in fracture healing. Wnt secretion from hematopoietic cells was blocked by genetic knockout of the essential Wnt modifying enzyme PORCN, achieved by crossing transgenic mice with mice. Knockout mice were compared with their wild-type littermates for musculoskeletal development including bone quantity and quality at maturation. Fracture healing including callus quality and quantity was assessed in a diaphyseal fracture model using quantitative micro computer-assisted tomographic scans, histological analysis, as well as biomechanical torsional and 4-point bending stress tests. The hematopoietic knockout mice had normal musculoskeletal development, with normal bone quantity and quality on micro-CT scans of the vertebrae. They also had normal gross skeletal dimensions and normal bone strength. Hematopoietic Wnt depletion in the healing fracture resulted in fewer osteoclasts in the fracture callus, with a resultant delay in callus remodeling. All calluses eventually progressed to full maturation. Hematopoietic Wnts, while not essential, modulate osteoclast numbers during fracture healing. These osteoclasts participate in callus maturation and remodeling. This demonstrates the importance of diverse Wnt sources in bone repair.
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http://dx.doi.org/10.3389/fendo.2021.667480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181731PMC
May 2021

Machine learning and orthodontics, current trends and the future opportunities: A scoping review.

Am J Orthod Dentofacial Orthop 2021 Jun 5. Epub 2021 Jun 5.

Department of Orthodontics, School of Dentistry, & Dentofacial Deformities Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Introduction: In recent years, artificial intelligence (AI) has been applied in various ways in medicine and dentistry. Advancements in AI technology show promising results in the practice of orthodontics. This scoping review aimed to investigate the effectiveness of AI-based models employed in orthodontic landmark detection, diagnosis, and treatment planning.

Methods: A precise search of electronic databases was conducted, including PubMed, Google Scholar, Scopus, and Embase (English publications from January 2010 to July 2020). Quality Assessment and Diagnostic Accuracy Tool 2 (QUADAS-2) was used to assess the quality of the articles included in this review.

Results: After applying inclusion and exclusion criteria, 49 articles were included in the final review. AI technology has achieved state-of-the-art results in various orthodontic applications, including automated landmark detection on lateral cephalograms and photography images, cervical vertebra maturation degree determination, skeletal classification, orthodontic tooth extraction decisions, predicting the need for orthodontic treatment or orthognathic surgery, and facial attractiveness. Most of the AI models used in these applications are based on artificial neural networks.

Conclusions: AI can help orthodontists save time and provide accuracy comparable to the trained dentists in diagnostic assessments and prognostic predictions. These systems aim to boost performance and enhance the quality of care in orthodontics. However, based on current studies, the most promising application was cephalometry landmark detection, skeletal classification, and decision making on tooth extractions.
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http://dx.doi.org/10.1016/j.ajodo.2021.02.013DOI Listing
June 2021

Prospective study of stereotactic body radiation therapy for hepatocellular carcinoma on waitlist for liver transplant.

Hepatology 2021 Jun 6. Epub 2021 Jun 6.

Department of Surgery, The University of Hong Kong.

Background & Aims: There is no prospective data on stereotactic body radiation therapy (SBRT) as a bridge to liver transplantation for hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy and safety of SBRT as bridging therapy, with comparison to transarterial chemoembolization (TACE) and high intensity focused ultrasound (HIFU).

Approach And Results: Patients were prospectively enrolled for SBRT under a standardized protocol from July 2015, and compared to a retrospective cohort of patients who underwent TACE or HIFU from 2010. The primary endpoint was tumor control rate at 1-year after bridging therapy. Secondary endpoints included cumulative incidence of dropout, toxicity and post-transplant survival. During the study period, 150 patients were evaluated (SBRT n=40, TACE n=59, HIFU n=51). The tumor control rate at 1-year was significantly higher after SBRT compared to TACE and HIFU(92.3%, 43.5%, and 33.3% respectively, P=0.02). With competing risk analysis, the cumulative incidence of dropout at 1- and 3-year after listing was lower after SBRT(15.1% and 23.3%) compared with TACE(28.9% and 45.8%,P=0.034) and HIFU(33.3% and 45.1%, P=0.032). Time-to-progression at 1- and 3-year was also superior after SBRT(10.8%, 18.5% in SBRT, 45%, 54.9% in TACE and 47.6%, 62.8% in HIFU, P<0.001). The peri-procedural toxicity was similar, without any difference in perioperative complications, and patient and recurrence-free survival rates after transplant. Pathological complete response was more frequent after SBRT compared to TACE and HIFU(48.1% vs. 25% vs. 17.9% respectively, P=0.037). In multivariable analysis, tumor size <3cm, listing AFP <200ng/ml, Child's A and SBRT significantly reduced the risk of dropout.

Conclusions: SBRT was safe, with significantly higher tumor control rate and reduced the risk of waitlist dropout, and should be utilized as an alternative to conventional bridging therapies.
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http://dx.doi.org/10.1002/hep.31992DOI Listing
June 2021

Cost-Effectiveness of Anti-Epidermal Growth Factor Receptor Therapy Bevacizumab in KRAS Wild-Type (WT), Pan-RAS WT, and Pan-RAS WT Left-Sided Metastatic Colorectal Cancer.

Front Oncol 2021 3;11:651299. Epub 2021 May 3.

Department of Clinical Oncology, Tuen Mun Hospital, New Territories West Cluster, Hong Kong, Hong Kong.

Objectives: We aimed to compare the economic value of chemotherapy plus anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) against chemotherapy with bevacizumab (Bev, an anti-vascular endothelial growth factor mAb) as first-line treatment in KRAS wild-type (WT), pan-RAS WT and pan-RAS WT left-sided metastatic colorectal cancer (mCRC) patients from the Hong Kong societal perspective.

Materials And Methods: We developed Markov models and 10-year horizon to estimate costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) of chemotherapy plus anti-EGFR therapy against chemotherapy plus Bev in KRAS WT, pan-RAS WT, and pan-RAS WT left-sided mCRC. We considered two times of the local gross domestic product per capita (GDPpc) as the willingness-to-pay (WTP) threshold (2× GDPpc; US$97,832).

Results: Adding anti-EGFR mAb to chemotherapy provides additional 0.24 (95% confidence interval [CI] 0.19-0.29), 0.32 (95% CI 0.27-0.37), and 0.57 (95% CI 0.49-0.63) QALY compared to adding Bev in KRAS WT, pan-RAS WT, and left-sided pan-RAS WT mCRC populations respectively. The corresponding ICER is US$106,847 (95% CI 87,806-134,523), US$88,565 (95% CI 75,678-105,871), US$76,537 (95% CI 67,794-87,917) per QALY gained, respectively.

Conclusions: Anti-EGFR therapy is more cost-effective than Bev as a first-line targeted therapy in left-sided pan-RAS WT and pan-RAS WT, with ICER
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http://dx.doi.org/10.3389/fonc.2021.651299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127841PMC
May 2021

Different definition of sarcopenia and mortality in cancer: A meta-analysis.

Osteoporos Sarcopenia 2021 Mar 19;7(Suppl 1):S34-S38. Epub 2021 Mar 19.

Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong.

Objectives: Sarcopenia has been an emerging theme in clinical oncology. Various definitions of sarcopenia have been proposed, but their prognostic performance have yet to be evaluated and compared. The aim of this meta-analysis is to comprehensively evaluate the performance of different cutoff definitions of sarcopenia in cancer mortality prognostication.

Methods: This is a meta-analysis. Cohort studies on lean mass and mortality published before December 20, 2017 were obtained by systematic search on PubMed, Cochrane Library, and Embase. Inclusion criteria were cohort studies reporting binary lean mass categorized according to clearly defined cutoffs, and with all-cause mortality as study outcome. Studies were stratified according to the cutoff(s) used in defining low lean mass. The cutoff-specific hazard ratios (HRs) and 95% confidence intervals (CIs) of low lean mass on cancer mortality were pooled with a random-effects model and compared.

Results: Altogether 81 studies that studied binary lean mass were included. The pooled HRs on cancer mortality using the 3 most used definitions were: 1.74 (95% CI, 1.46-2.07) using the definition proposed by International Consensus of Cancer Cachexia, 1.45 (95% CI, 1.21-1.75) using that by Martin, and 1.58 (95% CI, 1.35-1.84) using that by Prado. The associations between sarcopenia and cancer mortality using other definitions were all statistically significant, despite different estimates were observed.

Conclusions: The association of low lean mass with increased mortality was consistent across different definitions; this provides further evidence on the poorer survival in cancer patients with sarcopenia. However, further studies evaluating the performance of each definition are warranted.
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http://dx.doi.org/10.1016/j.afos.2021.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088994PMC
March 2021

Sarcopenia and mortality in cancer: A meta-analysis.

Osteoporos Sarcopenia 2021 Mar 30;7(Suppl 1):S28-S33. Epub 2021 Mar 30.

Department of Pharmacology and Pharmacy, Hong Kong.

Objectives: The aim of this meta-analysis is to comprehensively evaluate the effects of lean mass on all-cause mortality across different cancer types.

Methods: This is a meta-analysis. Cohort studies on lean mass and mortality published before December 20, 2017 were obtained by systematic search on PubMed, Cochrane Library, and Embase. Inclusion criteria were cohort studies reporting lean mass measurements by dual-energy X-ray absorptiometry, bioimpedance analysis or computed tomography, and with all-cause mortality as the study outcome. Exclusion criteria were studies using muscle mass surrogates, anthropometric measurement of muscle, rate of change in muscle mass, and sarcopenia defined by composite criteria. Hazard ratios (HRs) and 95% confidence intervals (CIs) of low/reduced lean mass on cancer mortality were pooled with a random-effects model. Subgroup analysis stratifying studies according to cancer type and measurement index was performed.

Results: Altogether 100 studies evaluated the association between lean mass and cancer mortality. The overall pooled HR on cancer mortality was 1.41 (95% CI, 1.24 to 1.59) for every standard deviation decrease in lean mass and 1.69 (95% CI, 1.56 to 1.83) for patients with sarcopenia (binary cutoffs). Overall mortality was also significantly associated with sarcopenia in across various cancer types, except for hematopoietic, breast, ovarian and endometrial, and prostate cancer.

Conclusions: The robust association of decreased lean mass with increased mortality further justified the importance of developing clinical guidelines for managing sarcopenia in cancer patients. Public health initiatives aiming at promoting awareness of muscle health in susceptible individuals are urgently needed.
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http://dx.doi.org/10.1016/j.afos.2021.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088991PMC
March 2021

The effect of different measurement modalities in the association of lean mass with mortality: A systematic review and meta-analysis.

Osteoporos Sarcopenia 2021 Mar 12;7(Suppl 1):S13-S18. Epub 2021 Mar 12.

Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong.

Objectives: Lean mass is commonly measured by 3 modalities, dual energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computerized tomography (CT). CT is considered the most accurate, while lean mass measured by DXA and BIA often consists of non-muscle compartment, and hence considered less accurate when compared with CT. It remains unclear if the association of lean mass with mortality would differ using different measurement modalities.

Methods: A systematic review and meta-analysis of lean mass and mortality was conducted. The analysis was stratified by different measurement modalities and health conditions. Pooled hazard ratios were estimated using a random effects model.

Results: This meta-analysis included 188 studies with 98 468 participants. Reduced lean mass measured by BIA, DXA, and CT, was associated with increased risk of mortality with a hazard ratio (HR) of 1.35 (95% CI, 1.21-1.49), 1.18 (95% CI, 1.06-1.30), and 1.44 (95% CI, 1.32-1.57), respectively. Similarly, low lean mass defined by BIA-, DXA-, and CT-measurement was associated with increased risk of mortality, with an HR of 1.81 (95% CI, 1.56-2.10), 1.44 (95% CI, 1.29-1.60), and 1.78 (95% CI, 1.64-1.93).

Conclusions: Reduced and low lean mass were robustly associated with increased mortality in studies using different measurement modalities.
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http://dx.doi.org/10.1016/j.afos.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088995PMC
March 2021

Systematic review and meta-analysis of lean mass and mortality: Rationale and study description.

Osteoporos Sarcopenia 2021 Mar 11;7(Suppl 1):S3-S12. Epub 2021 Feb 11.

Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Objectives: Muscle mass is one of the key components in defining sarcopenia and is known to be important for locomotion and body homeostasis. Lean mass is commonly used as a surrogate of muscle mass and has been shown to be associated with increased mortality. However, the relationship of lean mass with mortality may be affected by different clinical conditions, modalities used, cut-off point to define low or normal lean mass, and even types of cancer among cancer patients. Thus, we aim to perform a comprehensive meta-analysis of lean mass with mortality by considering all these factors.

Methods: Systematic search was done in PubMed, Cochrane Library and Embase for articles related to lean mass and mortality. Lean mass measured by dual X-ray absorptiometry, bioelectrical impedance analysis, and computerized tomography were included.

Results: The number of relevant studies has increased continuously since 2002. A total of 188 studies with 98 468 people were included in the meta-analysis. The association of lean mass with mortality was most studied in cancer patients, followed by people with renal diseases, liver diseases, elderly, people with cardiovascular disease, lung diseases, and other diseases. The meta-analysis can be further conducted in subgroups based on measurement modalities, site of measurements, definition of low lean mass adopted, and types of cancer for studies conducted in cancer patients.

Conclusions: This series of meta-analysis provided insight and evidence on the relationship between lean mass and mortality in all directions, which may be useful for further study and guideline development.
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http://dx.doi.org/10.1016/j.afos.2021.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088993PMC
March 2021

The Relationships Between Radiation Dosage and Long-term Swallowing Kinematics and Timing in Nasopharyngeal Carcinoma Survivors.

Dysphagia 2021 Apr 28. Epub 2021 Apr 28.

Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

This study aimed to investigate the relationship between intensity-modulated radiation therapy (IMRT) dosimetry and swallowing kinematic and timing measures. Thirteen kinematic and timing measures of swallowing from videofluoroscopic analysis were used as outcome measures to reflect swallowing function. IMRT dosimetry was accessed for thirteen swallowing-related structures. A cohort of 44 nasopharyngeal carcinoma (NPC) survivors at least 3 years post-IMRT were recruited. The cohort had a mean age of 53.2 ± 11.9 years, 77.3% of whom were male. There was an average of 68.24 ± 14.15 months since end of IMRT; 41 (93.2%) had undergone concurrent chemotherapy. For displacement measures, female sex and higher doses to the cricopharyngeus, glottic larynx, and base of tongue were associated with reduced hyolaryngeal excursion and pharyngeal constriction, and more residue. For timing measures, higher dose to the genioglossus was associated with reduced processing time at all stages of the swallow. The inferior pharyngeal constrictor emerged with a distinctly different pattern of association with mean radiation dosage compared to other structures. Greater changes to swallowing kinematics and timing were observed for pudding thick consistency than thin liquid. Increasing radiation dosage to swallowing-related structures is associated with reduced swallowing kinematics. However, not all structures are affected the same way, therefore organ sparing during treatment planning for IMRT needs to consider function rather than focusing on select muscles. Dose-response relationships should be investigated with a comprehensive set of swallowing structures to capture the holistic process of swallowing.
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http://dx.doi.org/10.1007/s00455-021-10311-6DOI Listing
April 2021

Purpose, Pleasure, Pace and Contrasting Perspectives: Teaching and Learning in the Emergency Department.

AEM Educ Train 2021 Apr 31;5(2):e10468. Epub 2020 May 31.

and the Melbourne Medical School University of Melbourne Melbourne Victoria Australia.

Objectives: Teaching and learning in the clinical setting are vital for the training and development of emergency physicians. Increasing service provision and time pressures in the emergency department (ED) have led to junior trainees' perceptions of a lack of teaching and a lack of support during clinical shifts. We sought to explore the perceptions of learners and supervisors in our ED regarding teaching within this diverse and challenging context.

Methods: Nine ED physicians and eight ED trainees were interviewed to explore perceptions of teaching in the ED. Clinical teaching was described as "on-the-floor" teaching during work shifts. We used a validated clinical teaching assessment instrument to help pilot and develop some of our interview questions, and data were analyzed using qualitative thematic analysis.

Results: We identified three major themes in our study: 1) the strong sense of purpose and the pleasure gained through teaching and learning interactions, despite both groups being unsure of each other's engagement and enthusiasm; 2) contrasting perspectives of teaching with registrars holding a traditional knowledge transmission view, yet shared perspectives of teacher as being ED consultants; and 3) the effect of patient acuity and volume, which both facilitated learning until a critical point of busyness beyond which service provision pressures and staffing limitations were perceived to negatively impact learning.

Conclusions: The ED is a complex and fluid working and learning environment. We need to develop a shared understanding of teaching and learning opportunities in the ED, which helps all stakeholders move beyond learning as knowledge acquisition and sees the potential for learning from teachers of a multitude of professional backgrounds.
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http://dx.doi.org/10.1002/aet2.10468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995923PMC
April 2021

Cord Lining Mesenchymal Stem Cells Have a Modest Positive Effect on Angiogenesis in Hindlimb Ischemia.

Front Cell Dev Biol 2020 8;8:596170. Epub 2021 Mar 8.

Novena Vascular and Varicose Vein Centre, Mount Elizabeth Novena Specialist Centre, Singapore, Singapore.

We investigated the use of human Cord Lining Mesenchymal Stem Cells (CL-MSCs) (US Patent number 9,737,568), in a rabbit hindlimb ischemia model, and evaluated their potential in stimulating neovascularization. Allogenic human CL- MSCs could potentially be used to treat patients with lower limb ischemia and non-healing wounds. Twenty rabbits were divided into two separate groups. We created a hindlimb ischemia model surgically. At 21 and 49 days post-operatively, animals in the treatment group were injected with CL-MSCs (500,000 cells per 0.2 ml on each site) at 10 different sites (Quadriceps- 4 sites, Hamstrings- 4 sites and Calf--2 sites) in the hindlimb muscles. The control group received only saline injection to the corresponding sites at the same time point as the treatment group. We then evaluated the effects of treatment on neovascularization by angiography, laser doppler perfusion imaging, as well as by histology. We evaluated the tissue samples for any signs of local immune reaction to the cell implantation. We also observed the rabbit clinically for any adverse effects after treatment. We found a higher number of CD31 positive cells in the treatment group, with a greater number of capillaries found in the treated muscles. The Rectus Femoris demonstrated a median vessel count/muscle fiber of 0.121 for the treatment group, compared to 0.076 in the control group (median difference 0.04; 95% CI 0.001-0.11; = 0.041). The Gastrocnemius demonstrated a median vessel count/muscle fiber of 0.175 for the treatment group, compared to 0.089 in the control group (median difference 0.087; 95% CI -0.006 to 0.234; = 0.07). Blood perfusion quantification through Laser Doppler Perfusion Imaging (LDPI) also demonstrated a non-statistically significant increase in perfusion in favor of the treatment group. CL-MSCs demonstrated no toxicity associated morbidity and minimal local immune reaction to implantation. CL-MSCs have a positive effect on angiogenesis in a rabbit hindlimb ischemia model. This preliminary data is encouraging and paves the way for future large animal studies or for clinical trials.
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http://dx.doi.org/10.3389/fcell.2020.596170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982459PMC
March 2021

Comprehensive single-cell sequencing reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of nasopharyngeal carcinoma.

Nat Commun 2021 03 9;12(1):1540. Epub 2021 Mar 9.

Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.

The tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME.
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http://dx.doi.org/10.1038/s41467-021-21795-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943808PMC
March 2021

The Most Efficacious Induction Chemotherapy Regimen for Locoregionally Advanced Nasopharyngeal Carcinoma: A Network Meta-Analysis.

Front Oncol 2021 25;11:626145. Epub 2021 Feb 25.

Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.

Background: Induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) for non-metastatic locoregionally advanced nasopharyngeal carcinoma (NPC) has gained considerable attention. However, the most efficacious IC regimens remain investigational. We aimed to compare the survival benefits of all available IC regimens followed by CCRT in this network meta-analysis.

Methods: All randomized-controlled trials of CCRT with or without IC in non-metastatic locoregionally advanced NPC were included, with an overall nine trials of 2,705 patients counted in the analysis. CCRT alone was the reference category. Eight IC regimens followed by CCRT were analyzed: docetaxel + cisplatin (DC), gemcitabine + carboplatin + paclitaxel (GCP), gemcitabine + cisplatin (GP), mitomycin + epirubicin + cisplatin + fluorouracil + leucovorin (MEPFL), cisplatin + epirubicin + paclitaxel (PET), cisplatin + fluorouracil (PF), cisplatin + capecitabine (PX) and cisplatin + fluorouracil (PF), cisplatin + capecitabine (PX). Fixed-effects frequentist network meta-analysis models was applied and P-score was used to rank the treatments.

Results: DC, GP, and PX were the top three IC regimens with the highest probability of benefit on overall survival (OS). Their corresponding hazard ratios (HRs) (95% CIs) compared with CCRT alone were of 0.24 (0.08-0.73), 0.43 (0.24-0.77), and 0.54 (0.27-1.09) and the respective P-scores were 94%, 82%, and 68%. The first three IC regimens showing significantly improved progression-free survival (PFS) were PX, followed by GP and DC with respective HRs of 0.46 (0.24-0.88), 0.51 (0.34-0.77), and 0.49 (0.20-1.20), and P-scores of 82%, 78%, and 74%. Among the studies in the intensity-modulated radiation therapy (IMRT) era, GP and PX were the best performed IC regimens, whilst DC performed the best among non-IMRT studies. Doublet and gemcitabine-based IC regimens had better survival benefits compared to triplet and taxane-based IC regimens, respectively.

Conclusions: Given its consistent superiority in both OS and PFS, DC, GP, and PX ranked among the three most efficacious IC regimens in both the overall and subgroup analysis of IMRT or non-IMRT studies. Exploratory analyses suggested that doublet and gemcitabine-based IC regimens showed better survival performance.
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http://dx.doi.org/10.3389/fonc.2021.626145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951057PMC
February 2021

Post-traumatic seizures following pediatric traumatic brain injury.

Clin Neurol Neurosurg 2021 Apr 10;203:106556. Epub 2021 Feb 10.

Department of Neurosurgery, Yale University School of Medicine, New Haven, 06520, CT, United States. Electronic address:

Objectives: The aim of this study was to investigate the national impact of demographic, hospital, and inpatient risk factors on post-traumatic seizure (PTS) development in pediatric patients who presented to the ED following a traumatic brain injury (TBI).

Patients And Methods: The Nationwide Emergency Department Sample database years 2010-2014 was queried. Patients (<21 years old) with a primary diagnosis of TBI and subsequent secondary diagnosis of PTS were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification coding system. We identified demographic variables, hospital characteristics, pre-existing medical comorbidities, etiology of injuries, and type of injury. Univariate and multivariate logistic regression analyses were performed to identify the factors associated with post-traumatic seizures.

Results: We identified 1,244,087 patients who sustained TBI, of which 10,340 (0.83%) developed PTS. Of the patients who had seizures, the youngest cohort aged 0-5 years had the greatest proportion of seizure development (p < 0.001). Compared to those TBI patients with loss of consciousness (LOC), patients encountering no LOC after TBI had the smallest proportion of seizures while Prolonged LOC with baseline return had the greatest proportion. On univariate analysis of the effect of in-hospital complication on rate of seizures, respiratory, renal and urinary, hematoma, septicemia, and other neurological complications were all significantly associated with seizure development. On multivariate regression, age 6-10 years (OR: 0.48, p < 0.001) 11-15 years (OR: 0.41, p < 0.001), and 16-20 years (OR: 0.51, p < 0.001) were independently associated with decreased risk of developing seizures. Extended LOC with baseline return (OR: 6.33, p < 0.001), extended LOC without baseline return (OR: 1.95, p = 0.009), and Other LOC (OR: 3.02, p < 0.001) were independently associated with increased risk of developing seizures. Subarachnoid hemorrhage (OR: 4.14, p < 0.001), subdural hemorrhage [OR: 7.72, p < 0.001), and extradural hemorrhage (OR: 3.13, p < 0.001) were all independently associated with increased risk of developing seizures.

Conclusion: Out study demonstrates that various demographic, hospital, and clinical risk factors are associated with the development of seizures following traumatic brain injury. Enhancing awareness of these drivers may help provide greater awareness of patients likely to develop post-traumatic seizures such that this complication can be decreased in incidence so as to improve quality of care and decrease healthcare costs.
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http://dx.doi.org/10.1016/j.clineuro.2021.106556DOI Listing
April 2021

MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma.

Oncogene 2021 Mar 9;40(10):1851-1867. Epub 2021 Feb 9.

Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Soft tissue sarcoma (STS) is a heterogeneous disease that arises from connective tissues. Clinical outcome of patients with advanced tumors especially de-differentiated liposarcoma and uterine leiomyosarcoma remains unsatisfactory, despite intensive treatment regimens including maximal surgical resection, radiation, and chemotherapy. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) have been shown to contribute to oncogenic translation via phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). However, little is known about the role of MNK1/2 and their downstream targets in STS. In this study, we show that depletion of either MNK1 or MNK2 suppresses cell viability, anchorage-independent growth, and tumorigenicity of STS cells. We also identify a compelling antiproliferative efficacy of a novel, selective MNK inhibitor ETC-168. Cellular responsiveness of STS cells to ETC-168 correlates positively with that of phosphorylated ribosomal protein S6 (RPS6). Mirroring MNK1/2 silencing, ETC-168 treatment strongly blocks eIF4E phosphorylation and represses expression of sarcoma-driving onco-proteins including E2F1, FOXM1, and WEE1. Moreover, combination of ETC-168 and MCL1 inhibitor S63845 exerts a synergistic antiproliferative activity against STS cells. In summary, our study reveals crucial roles of MNK1/2 and their downstream targets in STS tumorigenesis. Our data encourage further clinical translation of MNK inhibitors for STS treatment.
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http://dx.doi.org/10.1038/s41388-021-01661-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946644PMC
March 2021

Effect of a medicinal and edible decoction YH0618 on chemotherapy-induced dermatologic toxicity: a randomized controlled trial.

Ann Transl Med 2021 Jan;9(1)

School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.

Background: Dermatologic toxicities are the common adverse events (AE) with several chemotherapy agents, but they are usually neglected in the research literature and clinical practice, and there are no clinically safe and effective methods to solve the problem. This study was to determine whether a medicinal and edible decoction YH0618 is effective in accelerating reducing chemotherapy-induced dermatologic toxicity in cancer patients who have completed chemotherapy.

Methods: This was a prospective randomized controlled trial conducted between 2015 and 2017. Cancer patients who have completed chemotherapy (received taxanes or anthracyclines or fluoropyrimidine) within two weeks were enrolled and then they were randomly divided into YH0618 decoction group (n=104) and wait-list control (n=110). The primary end points were the incidence of protocol-specified grade ≥2 dermatologic toxicities after 6-week intervention assessed using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Chinese version 4.0, and changes of fingernails color and skin color evaluated by L*a*b after 6 weeks of intervention. Secondary end points included assessment of quality of life (QOL) and fatigue, and some clinical objective indicators associated with myelosuppression, hepatotoxicity and nephrotoxicity.

Results: The study included 214 participants [mean (SD) age, 52.49 (9.08) years in YH0618 group and 50.44 (9.71) years in wait-list group]. At 6-week, YH0618 significantly reduced the incidence of grade ≥2 in nail discoloration [odds ratio (OR), 0.653; 95% CI, 0.5-0.9; P=0.005] and alopecia (OR, 0.776; 95% CI, 0.6-1.0; P=0.048) compared with control group. Besides, YH0618 increased the L* value and reduced the a* and b* values compared with control group, indicating that YH0618 increased the brightness and reduced hyperpigmentation. YH0618 also significantly reduced chemotherapy-induced fatigue (95% CI, 0.2-4.8; P=0.033).

Conclusions: YH0618 may be a safe method in ameliorating chemotherapy-induced dermatologic toxicity especially nail discoloration, alopecia and skin hyperpigmentation, and on improving fatigue.

Trial Registration: The trial was registered in the Chinese Clinical Trials Registry, ChiCTR-IOR-15006486.
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http://dx.doi.org/10.21037/atm-20-5181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859827PMC
January 2021

Comparison of efficacy and safety of three induction chemotherapy regimens with gemcitabine plus cisplatin (GP), cisplatin plus fluorouracil (PF) and cisplatin plus capecitabine (PX) for locoregionally advanced previously untreated nasopharyngeal carcinoma: A pooled analysis of two prospective studies.

Oral Oncol 2021 03 25;114:105158. Epub 2021 Jan 25.

Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. Electronic address:

Purpose: We compared, in this pooled analysis, the differences in efficacy and safety between three induction chemotherapy regimens including gemcitabine plus cisplatin (GP), cisplatin plus fluorouracil (PF) and cisplatin plus capecitabine (PX) in patients recruited into our two prospective studies for previously untreated locoregionally advanced nasopharyngeal carcinoma (NPC).

Methods: GP, PF or PX followed by radical concurrent chemoradiotherapy was given to patients with previously untreated locoregionally advanced (stage III to IVA) NPC prospectively recruited into our two prospective studies. The study endpoints included progression-free survival (PFS) and overall survival (OS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS), and major acute and late treatment-related toxicities (grade ≥ 3).

Results: From 2006 to 2016, 278 patients were enrolled (84, 94 and 100 patients in GP, PF and PX group respectively). After a median follow-up of 80 months, the 3-year PFS, OS, LRFS, DMFS and CSS of the whole population were 78.7%, 88.1%, 84.9%, 80.9% and 89.8%, respectively. There were no significant differences in prespecified survival endpoints among GP, PF and PX in both stage III and stage IVA patients. GP had lower incidences of severe (grade ≥ 3) anemia and diarrhea in stage III patients, as well as severe anemia, dehydration, renal impairment and vomiting in stage IVA patients. The incidences of grade ≥ 3 late toxicities were similar among these 3 induction regimens.

Conclusion: GP had similar efficacy and potentially fewer treatment-related complications compared with PF and PX as induction chemotherapy for previously untreated locoregionally advanced NPC.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105158DOI Listing
March 2021

Emergency Department Visits for Firearm-Related Injuries among Youth in the United States, 2006-2015.

J Law Med Ethics 2020 12;48(4_suppl):67-73

Victor Lee is at the Department of Therapeutic Radiology at Yale School of Medicine in New Haven, CT. Catherine Camp, M.P.H., is at the Yale Law School in New Haven, CT. Vikram Jairam, M.D., is at the Department of Therapeutic Radiology at Yale School of Medicine in New Haven, CT. Henry S. Park, M.D., M.P.H., is at the Department of Therapeutic Radiology and at the Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale School of Medicine in New Haven, CT. James B. Yu, M.D., M.H.S., is at the Department of Therapeutic Radiology and at the Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale School of Medicine in New Haven, CT.

Firearm injuries are a significant public health problem. Prior studies have analyzed firearm death data or adult firearm injury data, but few studies have analyzed firearm injury data specifically among youth. To inform the current debate surrounding gun policy in the United States, this study aims to provide an estimate of the immense burden of youth firearm injury and its associated risk factors. Therefore, we performed a descriptive analysis of the Nationwide Emergency Department Sample (NEDS), the largest all-payer emergency department database in the United States, from January 2006 to September 2015. All patients age < 21 who presented with any diagnosis of firearm-related injuries were included.There were an estimated 198,839 incidents of firearm-related emergency department visits for patients age < 21 from 2006 through 2015. After presenting to the ED, an estimated 11,909 cases resulted in death. The population adjusted rate of firearm-related emergency department visits was highest in the South and Midwest. This study demonstrates the significant burden of firearm injury among youth. Having a reliable estimate of the number of children harmed by firearms each year is a critical tool for policymakers - and may make common-sense gun safety measures more politically possible.
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http://dx.doi.org/10.1177/1073110520979403DOI Listing
December 2020

UK adaptive radiotherapy practices for head and neck cancer patients.

BJR Open 2020 11;2(1):20200051. Epub 2020 Dec 11.

Department of Medical Physics & Biomedical Engineering, University College London, London, UK.

Objective: To provide evidence on the extent and manner in which adaptive practices have been employed in the UK and identify the main barriers for the clinical implementation of adaptive radiotherapy (ART) in head and neck (HN) cancer cases.

Methods: In December 2019, a Supplementary Material 1, of 23 questions, was sent to all UK radiotherapy centres (67). This covered general information to current ART practices and perceived barriers to implementation.

Results: 31 centres responded (46%). 56% responding centres employed ART for between 10 and 20 patients/annum. 96% of respondents were using CBCT either alone or with other modalities for assessing "weight loss" and "shell gap," which were the main reasons for ART. Adaptation usually occurs at week three or four during the radiotherapy treatment. 25 responding centres used an online image-guided radiotherapy (IGRT) approach and 20 used an offline ART approach, either with or without protocol level. Nearly 70% of respondents required 2 to 3 days to create an adaptive plan and 95% used 3-5 mm adaptive planning target volume margins. All centres performed pre-treatment QA. "Limited staff resources" and "lack of clinical relevance" were identified as the two main barriers for ART implementation.

Conclusion: There is no consensus in adaptive practice for HN cancer patients across the UK. For those centres not employing ART, similar clinical implementation barriers were identified.

Advances In Knowledge: An insight into contemporary UK practices of ART for HN cancer patients indicating national guidance for ART implementation for HN cancer patients may be required.
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http://dx.doi.org/10.1259/bjro.20200051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749087PMC
December 2020

Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci.

Commun Biol 2020 12 11;3(1):759. Epub 2020 Dec 11.

Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.

Despite pronounced associations of major histocompatibility complex (MHC) regions with nasopharyngeal carcinoma (NPC), causal variants underlying NPC pathogenesis remain elusive. Our large-scale comprehensive MHC region deep sequencing study of 5689 Hong Kong Chinese identifies eight independent NPC-associated signals and provides mechanistic insight for disrupted transcription factor binding, altering target gene transcription. Two novel protective variants, rs2517664 (T = 4.6%, P = 6.38 × 10) and rs117495548 (G = 3.0%, P = 4.53 × 10), map near TRIM31 and TRIM39/TRIM39-RPP21; multiple independent protective signals map near HLA-B including a previously unreported variant, rs2523589 (P = 1.77 × 10). The rare HLA-B*07:05 allele (OR < 0.015, P = 5.83 × 10) is absent in NPC, but present in controls. The most prevalent haplotype lacks seven independent protective alleles (OR = 1.56) and the one with additional Asian-specific susceptibility rs9391681 allele (OR = 2.66) significantly increased NPC risk. Importantly, this study provides new evidence implicating two non-human leukocyte antigen (HLA) genes, E3 ubiquitin ligases, TRIM31 and TRIM39, impacting innate immune responses, with NPC risk reduction, independent of classical HLA class I/II alleles.
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http://dx.doi.org/10.1038/s42003-020-01487-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733486PMC
December 2020

EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma.

Elife 2020 11 30;9. Epub 2020 Nov 30.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Wnt signaling is downregulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way toward novel therapeutic modalities. We demonstrate that EHMT2 suppresses canonical Wnt signaling by activating expression of the Wnt antagonist . Inhibition of EHMT2 expression or activity in human ERMS cell lines reduced expression and elevated canonical Wnt signaling resulting in myogenic differentiation in vitro and in mouse xenograft models in vivo. Mechanistically, EHMT2 impacted Sp1 and p300 enrichment at the promoter. The reduced tumor growth upon EHMT2 deficiency was reversed by recombinant DKK1 or LGK974, which also inhibits Wnt signaling. Consistently, among 13 drugs targeting chromatin modifiers, EHMT2 inhibitors were highly effective in reducing ERMS cell viability. Our study demonstrates that ERMS cells are vulnerable to EHMT2 inhibitors and suggest that targeting the EHMT2-DKK1-β-catenin node holds promise for differentiation therapy.
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http://dx.doi.org/10.7554/eLife.57683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728445PMC
November 2020

Therapeutic evaluation of palbociclib and its compatibility with other chemotherapies for primary and recurrent nasopharyngeal carcinoma.

J Exp Clin Cancer Res 2020 Nov 26;39(1):262. Epub 2020 Nov 26.

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.

Background: Recent genomic analyses revealed that druggable molecule targets were only detectable in approximately 6% of patients with nasopharyngeal carcinoma (NPC). However, a dependency on dysregulated CDK4/6-cyclinD1 pathway signaling is an essential event in the pathogenesis of NPC. In this study, we aimed to evaluate the therapeutic efficacy of a specific CDK4/6 inhibitor, palbociclib, and its compatibility with other chemotherapeutic drugs for the treatment of NPC by using newly established xenograft models and cell lines derived from primary, recurrent, and metastatic NPC.

Methods: We evaluated the efficacies of palbociclib monotherapy and concurrent treatment with palbociclib and cisplatin or suberanilohydroxamic acid (SAHA) in NPC cell lines and xenograft models. RNA sequencing was then used to profile the drug response-related pathways. Palbociclib-resistant NPC cell lines were established to determine the potential use of cisplatin as a second-line treatment after the development of palbociclib resistance. We further examined the efficacy of palbociclib treatment against cisplatin-resistant NPC cells.

Results: In NPC cells, palbociclib monotherapy was confirmed to induce cell cycle arrest in the G1 phase in vitro. Palbociclib monotherapy also had significant inhibitory effects in all six tested NPC tumor models in vivo, as indicated by substantial reductions in the total tumor volumes and in Ki-67 proliferation marker expression. In NPC cells, concurrent palbociclib treatment mitigated the cytotoxic effect of cisplatin in vitro. Notably, concurrent treatment with palbociclib and SAHA synergistically promoted NPC cell death both in vitro and in vivo. This combination also further inhibited tumor growth by inducing autophagy-associated cell death. NPC cell lines with induced palbociclib or cisplatin resistance remained sensitive to treatment with cisplatin or palbociclib, respectively.

Conclusions: Our study findings provide essential support for the use of palbociclib as an alternative therapy for NPC and increase awareness of the effective timing of palbociclib administration with other chemotherapeutic drugs. Our results provide a foundation for the design of first-in-human clinical trials of palbociclib regimens in patients with NPC.
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http://dx.doi.org/10.1186/s13046-020-01763-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690146PMC
November 2020

Dose-Response Relationship in Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: A Pooled Analysis of an Asian Liver Radiation Therapy Group Study.

Int J Radiat Oncol Biol Phys 2021 Feb 20;109(2):464-473. Epub 2020 Nov 20.

Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Purpose: Despite the worldwide implementation of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC), there is a lack of consensus guideline on prescription dose. Herein, this multinational study aimed to investigate the effects of the prescribed radiation dose on oncologic outcomes of SBRT for HCC.

Methods And Materials: The multi-institutional retrospective cohort included 510 patients treated with SBRT between 2010 and 2016. All relevant clinical factors and factors related to SBRT were analyzed to evaluate freedom from local progression (FFLP) and overall survival (OS). Based on a biologically effective dose (BED) cutoff value of 100 Gy, 198 tumors were selected from each group in propensity score matching (PSM).

Results: Baseline characteristics in the BED <100 Gy group were unfavorable (Child-Pugh class B, 19%; advanced stage, 72%; median tumor size was 4 cm) compared with the BED ≥100 Gy group. With a median follow-up of 22 (interquartile range, 9.8-37.6) months, the 2-year FFLP and OS rates were 77% and 73%, respectively. Patients treated with a BED ≥100 Gy showed better rates of 2-year FFLP and OS than patients treated with a BED <100 Gy (FFLP, 89% vs 69%; OS, 80% vs 67%; P < .001). In the multivariable analysis before and after PSM, BED ≥100 Gy was identified as the main prognostic factor for both FFLP and OS (P < .01). Additionally, a dose-response relationship was observed between FFLP and BED (odds ratio, 0.92 per 5 Gy, P = .048).

Conclusions: A BED ≥100 Gy was significantly associated with outcomes, and a dose-response relationship was observed between local tumor progression and BED. Given that SBRT is being increasingly used in HCC, detailed consensus guidelines regarding SBRT dose prescription should be established.
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http://dx.doi.org/10.1016/j.ijrobp.2020.09.038DOI Listing
February 2021

YJ5 as an immunohistochemical marker of osteogenic lineage.

Pathology 2021 Feb 10;53(2):229-238. Epub 2020 Nov 10.

Department of Pathology, National University Singapore, Singapore. Electronic address:

Overexpression of WLS, an upstream protein in the Wnt pathway, has been implicated in several non-osteogenic tumours. This study represents the first attempt at evaluating WLS expression in various bone and soft tissue tumours using YJ5, a monoclonal antibody specific to WLS, with the aim of elucidating its utility in discerning tumours with aberrant Wnt signalling and as a marker of osteogenic lineage in challenging cases. Tumour tissue sections of 144 bone mass lesions and 63 soft tissue mass lesions were immunostained with the YJ5 antibody following standardised protocols. Subsequent assessment of immunoreactivity segregated cases into one of three groups: absent/weak, moderate, or strong YJ5 immunoreactivity. For the bone tumours, strong YJ5 immunoreactivity was seen in almost all osteosarcomas and chondroblastomas, all osteoblastomas and osteoid osteomas. In contrast, all other cartilaginous tumours, chordomas, aneurysmal bone cysts, chondromyxoid fibromas, most fibrous dysplasias and most giant cell tumours exhibited absent/weak YJ5 immunostaining. For the soft tissue tumours, a more heterogeneous pattern of YJ5 immunoreactivity was observed. Because diffuse and strong YJ5 expression is identified in almost all benign and malignant bone tumours with osteoblastic activity, it can be potentially utilised as an immunohistochemical marker to support osteogenic lineage. If interpreted in the appropriate context, this marker is useful in determining whether a malignant bone tumour is an osteosarcoma, particularly in those subtypes with no or minimal osteoid or unusual morphological features. This marker can also complement SATB2 to denote osteogenic lineage.
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http://dx.doi.org/10.1016/j.pathol.2020.07.017DOI Listing
February 2021

Considerations for Use of Immune Checkpoint Inhibitors in Cancer Therapy for Patients with Co-Existing Thyroid Eye Disease.

Ophthalmol Ther 2021 Mar 4;10(1):5-12. Epub 2020 Nov 4.

Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong.

Immune checkpoint inhibitors (ICIs) have revolutionised the field of oncology. While most ICIs are well-tolerated, severe and fatal immune-related adverse events (irAEs) have been documented, likely related to the strengthened immunity harnessed by ICIs against tumours. Endocrinopathies are some of the most common irAEs, with both hypothyroidism and hyperthyroidism encountered after ICI use. As such, patients with pre-existing autoimmune conditions, such as Graves' disease (GD) with clinically active thyroid eye disease (TED), are excluded from most clinical trials studying ICIs due to concerns of exacerbating pre-existing autoimmune conditions or of increasing the potential for irAE development. The limited information currently available on the safety and efficacy of ICIs in this population poses a clinical challenge for oncologists. The objective of this commentary is to highlight these challenges and provide treatment recommendations pertaining to two specific cohorts of patients with GD, namely GD patients with minimal eye complications and GD patients with previous TED who underwent radiotherapy, surgery or pulse methylprednisolone and whose disease is now quiescent, and to patients with subclinical autoimmune thyroid disease.
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http://dx.doi.org/10.1007/s40123-020-00317-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886920PMC
March 2021

Lymphopenia and Radiation Dose to Circulating Lymphocytes With Neoadjuvant Chemoradiation in Esophageal Squamous Cell Carcinoma.

Adv Radiat Oncol 2020 Sep-Oct;5(5):880-888. Epub 2020 Apr 19.

Department of Clinical Oncology, the University of Hong Kong, Hong Kong.

Purpose: We hypothesized that radiation-induced lymphopenia could be predicted by the effective dose to the circulating immune cells (EDIC) in advanced esophageal squamous cell carcinoma treated with trimodality therapy according to the Dutch ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial regimen. To test this hypothesis, we examined the effect of EDIC on the degree of lymphocyte drop (lymphocyte nadir).

Methods And Materials: Patients with advanced nonmetastatic esophageal squamous cell carcinoma treated in a single tertiary cancer center from 2012 to 2018 were eligible for this study. All patients had to have a radiation therapy plan available for EDIC computation and received neoadjuvant chemoradiation according to the Dutch CROSS trial regimen before radical esophagectomy. The EDIC was calculated as a function of integral doses to the lung, heart, and total body with a verified mathematical model. The association between EDIC and lymphocyte nadir was studied, and the relationships of overall survival (OS) with lymphocyte nadir and EDIC were assessed using multivariable Cox regression model.

Results: This analysis included 92 eligible consecutive patients (77 men and 15 women). The mean EDIC was 2.8 Gy (range, 0.6-4.4). EDIC was significantly correlated with lymphocyte nadir (Spearman coefficient = -0.505; < .01), and lymphocyte nadir was a significant independent factor for shorter OS (hazard ratio = 0.63; < .001). Lymphocyte nadir was also the most significant factor in determining OS among other clinical parameters. Exploratory analysis showed significant OS differences between EDIC groups (<2, 2-4, and >4 Gy). The 2-year OS rates were 66.7%, 42.7%, and 16.7% for EDIC <2, 2 to 4, and >4 Gy, respectively.

Conclusions: There was a significant correlation between radiation dose to circulating immune cells and lymphocyte nadir, which in turn affected OS in patients with advanced nonmetastatic esophageal squamous cell carcinoma treated by trimodality therapy.
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http://dx.doi.org/10.1016/j.adro.2020.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560564PMC
April 2020

Association between early childhood oral health impact scale (ECOHIS) scores and pediatric dental surgery wait times.

BMC Oral Health 2020 10 17;20(1):285. Epub 2020 Oct 17.

Department of Preventive Dental Science, Dr. Gerald Niznick College of Dentistry, Rady Faculty of Health Sciences, University of Manitoba, 507 - 715 McDermot Avenue, Winnipeg, Manitoba, R3E 3P4, Canada.

Background: Severe Early Childhood Caries (S-ECC) is an aggressive form of tooth decay that often requires pediatric dental rehabilitative surgery. The Early Childhood Oral Health Impact Scale (ECOHIS) measures oral health-related quality of life (OHRQL). The purpose of this study was to determine whether there is an association between ECOHIS scores and surgery wait times for children undergoing dental treatment for S-ECC under general anesthesia (GA).

Methods: The hypothesis was that there is no present association between wait times and ECOHIS score. Children under 72 months of age with S-ECC were recruited on the day of their slated dental surgery under GA. Parents/caregivers completed a questionnaire that included the ECOHIS. Data were merged with other ECOHIS scores from a previous study. Wait times were acquired from the Patient Access Registry Tool (PART) database. Data analysis included descriptive statistics and bivariate analyses. A p-value of ≤0.05 was considered statistically significant; 95% confidence intervals (CIs) were reported for each correlation coefficient. This study was approved by the University of Manitoba's Health Research Ethics Board.

Results: Overall, 200 children participated, the majority of whom were Indigenous (63%) and resided in Winnipeg (52.5%). The mean age was 47.6 ± 13.8 months and 50.5% were female. Analyses showed ECOHIS scores were not significantly correlated with children's wait times. Observed correlations between ECOHIS and children's wait times were low and not statistically significant, ranging from ρ = 0.11 for wait times and child impact section (CIS) scores (95% CI: - 0.04, 0.26; p = 0.14), ρ = - 0.08 for family impact section (FIS) scores (95% CI: - 0.23, 0.07; p = 0.28), and ρ = 0.04 for total ECOHIS scores (95% CI: - 0.11, 0.19; p = 0.56).

Conclusion: No significant associations were observed between ECOHIS scores and wait times. In fact, those with worse OHRQL appeared to wait longer for surgery. ECOHIS scores could, however, still be used to help prioritize children for dental surgery to ensure that they receive timely access to dental care under GA. This is essential given the challenges posed by COVID-19 on timely access to surgical care.
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http://dx.doi.org/10.1186/s12903-020-01263-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568462PMC
October 2020

Biomimetic Synthesis Enables the Structure Revision of Littordials E and F and Drychampone B.

Org Lett 2020 10 6;22(20):8161-8166. Epub 2020 Oct 6.

Department of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia.

Structural reassignments for littordial E, littordial F, and drychampone B are proposed on the basis of consideration of their biosynthetic origin. The key step in the proposed biosynthesis of each of these meroterpenoids is an intermolecular hetero-Diels-Alder reaction between an -quinone methide and caryophyllene or humulene. Biomimetic total synthesis of the natural products gave sufficient material to allow their structure revision by NMR studies.
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http://dx.doi.org/10.1021/acs.orglett.0c03156DOI Listing
October 2020

Evaluation of a digital triage platform in Uganda: A quality improvement initiative to reduce the time to antibiotic administration.

PLoS One 2020 2;15(10):e0240092. Epub 2020 Oct 2.

Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Sepsis is the leading cause of death in children under five in low- and middle-income countries. The rapid identification of the sickest children and timely antibiotic administration may improve outcomes. We developed and implemented a digital triage platform to rapidly identify critically ill children to facilitate timely intravenous antibiotic administration.

Objective: This quality improvement initiative sought to reduce the time to antibiotic administration at a dedicated children's hospital outpatient department in Mbarara, Uganda.

Intervention And Study Design: The digital platform consisted of a mobile application that collects clinical signs, symptoms, and vital signs to prioritize children through a combination of emergency triggers and predictive risk algorithms. A computer-based dashboard enabled the prioritization of children by displaying an overview of all children and their triage categories. We evaluated the impact of the digital triage platform over an 11-week pre-implementation phase and an 11-week post-implementation phase. The time from the end of triage to antibiotic administration was compared to evaluate the quality improvement initiative.

Results: There was a difference of -11 minutes (95% CI, -16.0 to -6.0; p < 0.001; Mann-Whitney U test) in time to antibiotics, from 51 minutes (IQR, 27.0-94.0) pre-implementation to 44 minutes (IQR, 19.0-74.0) post-implementation. Children prioritized as emergency received the greatest time benefit (-34 minutes; 95% CI, -9.0 to -58.0; p < 0.001; Mann-Whitney U test). The proportion of children who waited more than an hour until antibiotics decreased by 21.4% (p = 0.007).

Conclusion: A data-driven patient prioritization and continuous feedback for healthcare workers enabled by a digital triage platform led to expedited antibiotic therapy for critically ill children with sepsis. This platform may have a more significant impact in facilities without existing triage processes and prioritization of treatments, as is commonly encountered in low resource settings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240092PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531789PMC
November 2020

Second primary cancer after intensity-modulated radiotherapy for nasopharyngeal carcinoma: A territory-wide study by HKNPCSG.

Oral Oncol 2020 12 24;111:105012. Epub 2020 Sep 24.

Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong.

Objectives: Long-term risk of second primary cancer (SPC) after definitive intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) remains unclear. This study aims to evaluate the risk, predictive factors and survival impact of SPC in a large territory-wide cohort of NPC survivors in an endemic region.

Materials And Methods: In this multicenter study, consecutive NPC patients (n = 3166) who underwent definitive IMRT in all six public oncology centers in Hong Kong between 2001 and 2010 were included. SPC risks were quantified by standardized incidence ratios (SIRs) and absolute excess risks (AERs) estimated from corresponding age-, sex-, and calendar year-specific population cancer incidence data from the Hong Kong Cancer Registry. Predictive factors and SPC-specific mortality were analyzed.

Results: Over a median follow-up period of 10.8 years, 290 cases of SPC were observed with a crude incidence of 9.2%. Cancer risk in NPC survivors was 90% higher than that in general population [SIR, 1.9; 95% confidence interval (CI), 1.7-2.2], with an AER of 52.1 (95% CI, 36.8-67.3) per 10,000 person-years at risk. Significant excess cancer risks were observed for oral cavity, sarcoma, oropharynx, paranasal sinus, salivary gland, thyroid, skin and lung. Advanced age, smoking, hepatitis B status, and re-irradiation were independent predictive factors. SPC accounted for 9.4% of all deaths among NPC survivors during the study period, and 10-year SPC-specific mortality was 3.4%.

Conclusions: Second cancer risk after IMRT was substantial among NPC patients. SPC impairs long-term survival, and close surveillance is warranted as part of survivorship care.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105012DOI Listing
December 2020