157 results on '"Gilberto K.K. Leung"'
Search Results
2. Clinical significance of CRNDE transcript variants in glioblastoma multiforme
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Karrie M.Y. Kiang and Gilberto K.K. Leung
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Genetics ,QH426-470 - Abstract
The long non-coding RNA CRNDE is an oncogene that promotes tumor growth in glioblastoma multiforme (GBM). At least five CRNDE transcript variants with possibly different functional roles have been described in recent studies. Here, we report our preliminary findings on the differential expressions of CRNDE transcript variants in GBM, and their prognostic significance. Our preliminary data suggest that different transcript variants of CRNDE might have different functions in GBM and should be further studied as potential biomarkers for clinical prognostication. Keywords: Long non-coding RNA, CRNDE, Transcript variant, Glioblastoma
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- 2017
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3. Functional survival after acute care for severe head injury at a designated trauma center in Hong Kong
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Benedict B.T. Taw, Alan C.S. Lam, Faith L.Y. Ho, K.N. Hung, W.M. Lui, and Gilberto K.K. Leung
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Functional survival ,severe head injury ,neurorehabilitation ,trauma ,Surgery ,RD1-811 - Abstract
Background: Severe head injury is known to be a major cause of early mortalities and morbidities. Patients' long-term outcome after acute care, however, has not been widely studied. We aim to review the outcome of severely head-injured patients after discharge from acute care at a designated trauma center in Hong Kong. Materials and methods: This is a retrospective study of prospectively collected data of patients admitted with severe head injuries between 2004 and 2008. Patients' functional status post-discharge was assessed using the Extended Glasgow Outcome Score (GOSE). Results: Of a total of 1565 trauma patients, 116 had severe head injuries and 41 of them survived acute hospital care. Upon the last follow-up, 23 (56.1%) of the acute-care survivors had improvements in their GOSE, six (11.8%) experienced deteriorations, and 12 (23.5%) did not exhibit any change. The greatest improvement was observed in patients with GOSE of 5 and 6 upon discharge, but two of the 16 patients with GOSE 2 or 3 also had a good recovery. On logistic regression analysis, old age and prolonged acute hospital stay were found to be independent predictors of poor functional outcome after a mean follow-up duration of 42 months. Conclusion: Multidisciplinary neurorehabilitation service is an important component of comprehensive trauma care. Despite significant early mortalities, a proportion of severely head-injured patients who survive acute care may achieve good long-term functional recovery.
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- 2012
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4. Location-Specific Hematoma Volume Cutoff and Clinical Outcomes in Intracerebral Hemorrhage
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Kay-Cheong Teo, Sze-Man Fong, William C.Y. Leung, Ian Y.H. Leung, Yuen-Kwun Wong, Olivia M.Y. Choi, Ka-Keung Yam, Rachel C.N. Lo, Raymond T.F. Cheung, Shu-Leong Ho, Anderson C.O. Tsang, Gilberto K.K. Leung, Koon-Ho Chan, and Kui-Kai Lau
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Advanced and Specialized Nursing ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine - Abstract
Background: Major intracerebral hemorrhage (ICH) trials have largely been unable to demonstrate therapeutic benefit in improving functional outcomes. This may be partly due to the heterogeneity of ICH outcomes based on their location, where a small strategic ICH could be debilitating, thus confounding therapeutic effects. We aimed to determine the ideal hematoma volume cutoff for different ICH locations in predicting ICH outcomes. Methods: We retrospectively analyzed consecutive ICH patients enrolled in the University of Hong Kong prospective stroke registry from January 2011 to December 2018. Patients with premorbid modified Rankin Scale score >2 or who underwent neurosurgical intervention were excluded. ICH volume cutoff, sensitivity, and specificity in predicting respective 6-month neurological outcomes (good [modified Rankin Scale score 0–2], poor [modified Rankin Scale score 4–6], and mortality) for specific ICH locations were determined using receiver operating characteristic curves. Separate multivariate logistic regression models were also conducted for each location-specific volume cutoff to determine whether these cutoffs were independently associated with respective outcomes. Results: Among 533 ICHs, the volume cutoff for good outcome according to ICH location was 40.5 mL for lobar, 32.5 mL for putamen/external capsule, 5.5 mL for internal capsule/globus pallidus, 6.5 mL for thalamus, 17 mL for cerebellum, and 3 mL for brainstem. ICH smaller than the cutoff for all supratentorial sites had higher odds of good outcomes (all P P P 0.8), except in predicting good outcome for cerebellum. Conclusions: ICH outcomes differed with location-specific hematoma size. Location-specific volume cutoff should be considered in patient selection for ICH trials.
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- 2023
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5. Anti-tumor effects of vitamin D in glioblastoma: mechanism and therapeutic implications
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Gilberto K.K. Leung, Karrie M.Y. Kiang, and Carmen Sze-Ching Lo
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Cell cycle checkpoint ,Apoptosis ,Pathology and Forensic Medicine ,Calcitriol ,Downregulation and upregulation ,Cell Movement ,In vivo ,Cell Line, Tumor ,Glioma ,Vitamin D and neurology ,Animals ,Humans ,Medicine ,Vitamin D ,Molecular Biology ,Cell Proliferation ,Cholecalciferol ,Cancer prevention ,Brain Neoplasms ,business.industry ,Mechanism (biology) ,Cell Cycle Checkpoints ,Vitamins ,Cell Biology ,medicine.disease ,Mechanism of action ,Cancer research ,Receptors, Calcitriol ,medicine.symptom ,Glioblastoma ,business - Abstract
Glioma is the most prevalent primary brain tumor in adults among which glioblastoma is the most malignant and lethal subtype. Its common resistance to conventional chemotherapeutics calls for the development of alternative or concomitant treatment. Taking advantage of its endocrine function as a neurosteroid, vitamin D has become a target of interest to be used in conjunction with different chemotherapies. In this article, we review the mechanisms through which vitamin D and its analogs induce anti-tumor activity in glioblastoma, and the practical issues relevant to their potential application based on in vitro and in vivo studies. Vitamin D has largely been reported to promote cell cycle arrest and induce cell death to suppress tumor growth in glioblastoma. Glioblastoma cells treated with vitamin D have also shown reduced migratory and invasive phenotypes, and reduced stemness. It is worth noting that vitamin D analogs are able to produce similar inhibitory actions without causing adverse effects such as hypercalcemia in vivo. Upregulation of vitamin D receptors by vitamin D and its analogs may also play a role in enhancing its anti-tumor activity. Based on current findings and taking into consideration its potential cancer-protective effects, the clinical application of vitamin D in glioblastoma treatment and prevention will be discussed. With some study findings subject to controversy, further investigation is warranted to elucidate the mechanism of action of vitamin D and to evaluate relevant issues regarding its treatment efficacy and potential clinical application. Vitamin D has recently emerged as a neurosteroid and a regulator of various physiological functions. It has been widely reported to promote tumor-suppressive effects, however this proposal remains controversial. This article reviews the anti-tumoral mechanisms of vitamin D in glioblastoma, current evidence of its therapeutic application as a supplement to standard chemotherapy, and its potential applications for cancer prevention; it endeavors to offer insight into new means of overcoming chemoresistance and improving glioma patient survival.
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- 2022
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6. Pharmacological inhibition of serine synthesis enhances temozolomide efficacy by decreasing O6-methylguanine DNA methyltransferase (MGMT) expression and reactive oxygen species (ROS)-mediated DNA damage in glioblastoma
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Stephen Yin Cheng, Gilberto K.K. Leung, Lei Jin, and Karrie M.Y. Kiang
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chemistry.chemical_classification ,Reactive oxygen species ,Temozolomide ,Chemistry ,Cell growth ,DNA damage ,Wnt signaling pathway ,Cancer ,Cell Biology ,medicine.disease ,Pathology and Forensic Medicine ,Apoptosis ,Cancer cell ,Cancer research ,medicine ,Molecular Biology ,medicine.drug - Abstract
Glioblastoma (GBM) is the most malignant primary tumor in the central nervous system of adults. Temozolomide (TMZ), an alkylating agent, is the first-line chemotherapeutic agent for GBM patients. However, its efficacy is often limited by innate or acquired chemoresistance. Cancer cells can rewire their metabolic programming to support rapid growth and sustain cell survival against chemotherapies. An example is the de novo serine synthesis pathway (SSP), one of the main branches from glycolysis that is highly activated in multiple cancers in promoting cancer progression and inducing chemotherapy resistance. However, the roles of SSP in TMZ therapy for GBM patients remain unexplored. In this study, we employed NCT503, a highly selective inhibitor of phosphoglycerate dehydrogenase (PHGDH, the first rate-limiting enzyme of SSP), to study whether inhibition of SSP may enhance TMZ efficacy in MGMT-positive GBMs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flowcytometry and colony formation assays demonstrated that NCT503 worked synergistically with TMZ in suppressing GBM cell growth and inducing apoptosis in T98G and U118 cells in vitro. U118 and patient-derived GBM subcutaneous xenograft models showed that combined NCT503 and TMZ treatment inhibited GBM growth and promoted apoptosis more significantly than would each treatment alone in vivo. Mechanistically, we found that NCT503 treatment decreased MGMT expression possibly by modulating the Wnt/β-catenin pathway. Moreover, intracellular levels of reactive oxygen species were elevated especially when NCT503 and TMZ treatments were combined, and the synergistic effects could be partially negated by NAC, a classic scavenger of reactive oxygen species. Taken together, these results suggest that NCT503 may be a promising agent for augmenting TMZ efficacy in the treatment of GBM, especially in TMZ-resistant GBMs with high expression of MGMT.
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- 2022
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7. Chemical Exchange Saturation Transfer Magnetic Resonance Imaging for Longitudinal Assessment of Intracerebral Hemorrhage and Deferoxamine Treatment at 3T in a Mouse Model
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Joseph H.C. Lai, Jiaxin Liu, Tian Yang, Jianpan Huang, Yang Liu, Zilin Chen, Youngjin Lee, Gilberto K.K. Leung, and Kannie W.Y. Chan
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Advanced and Specialized Nursing ,Mice ,Animals ,Brain ,Neurology (clinical) ,Deferoxamine ,Protons ,Cardiology and Cardiovascular Medicine ,Magnetic Resonance Imaging ,Amides ,Lipids ,Cerebral Hemorrhage - Abstract
Background: Noninvasive imaging of molecular alterations after intracerebral hemorrhage (ICH) could provide valuable information to guide and monitor treatments. Chemical exchange saturation transfer (CEST) magnetic resonance imaging has demonstrated promises in identifying proliferation, necrosis, and changes in cellularity in brain tumors. Here, we applied CEST magnetic resonance imaging to monitor molecular changes in hematoma without and with treatment noninvasively over 2 weeks at 3T using endogenous contrast. Methods: CEST contrast related to proteins at 3.5 ppm (amide proton transfer) and proteins/lipids at −3.5 ppm (relayed nuclear overhauser effect [rNOE]) were examined over 14 days in a collagenase-induced ICH mouse model. Imaging findings were validated with immunohistochemistry based on the ICH neuropathology. We also examined iron-containing phantoms that mimicked iron concentrations in hematoma to ensure the iron will not attenuate the CEST contrast during disease progression. Based on the validity of the CEST contrast of hematoma, we further examined related molecular alterations under iron-chelation treatment with deferoxamine. Results: We observed the temporal and spatial differences of CEST contrasts between rNOE at −3.5 ppm and amide proton transfer at 3.5 ppm, in which the core and perihematoma could be identified by rNOE on day 3 and day 14, and amide proton transfer on day 1, day 7, and day 14. Moreover, we observed a 25.7% significant reduction ( P Conclusions: Significant rNOE changes correlated well with histologic findings, especially myelin lipids, and regional characteristics in hematoma indicate the uniqueness of CEST magnetic resonance imaging in monitoring molecular changes during ICH and treatment.
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- 2022
8. Micro‐electrodes for in situ temperature and bio‐impedance measurement
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Tengfei Zhang, Gary Kwok Ki Chik, Ge Fang, Paddy K. L. Chan, Boyu Peng, Gilberto K.K. Leung, Derek Shui Hong Siddhartha Dai, Xing Cheng, Ka Wai Kwok, Xudong Ji, Timothy Ka Wai Leung, and Anderson Chun On Tsang
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In situ ,Materials science ,business.industry ,Bio impedance ,in situ ,thermal ablations ,Electrode ,impedance ,TA401-492 ,Optoelectronics ,business ,probes ,Electrical impedance ,Materials of engineering and construction. Mechanics of materials - Abstract
With fast recovery time and effective in situ tumor tissue killing ability, thermal ablation has become a popular treatment for tumors compared with chemotherapy and radiation. The thermal dose measurement of current technology is usually accompanied by monitoring a large area impedance across two ablation catheters and the localized impedance measurement is difficult to achieve. In this work, thermal‐resistive sensor and impedance sensor are fabricated on the curved surface of a capillary tube with 1 mm outer diameter. The device is applied for real‐time in situ tissue impedance monitoring during thermal ablation. The calibrated thermal‐resistive sensors have an average temperature coefficient of resistance (TCR) of 0.00161 ± 5.9% °C‐1 with an accuracy of ±0.7 °C. By adding electro‐polymerized PEDOT:PSS (poly(3,4‐ethylenedioxythiophene)‐poly(styrenesulfonate)) on the 300 µm diameter gold electrodes, the interface impedance reduces two orders from 408 to 3.7 kΩ at 100 Hz. The Randles equivalent circuit model fittings show a two‐order improvement in the electrode capacitance from 7.29 to 753 nF. In the ex vivo porcine liver laser ablation test, the temperature of the porcine liver tissue can reach 70°C and the impedance would drop by 50% in less than 5 minutes. The integration of laser ablation fiber with the impedance and temperature sensors can further expand the laser ablation technique to smaller scale and for precise therapeutics.
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- 2021
9. Fibrinolytic-Facilitated Chronic Subdural Hematoma Drainage—A Systematic Review
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Gilberto K.K. Leung, Yip Mang O, and Shek Long Tsang
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medicine.medical_specialty ,medicine.medical_treatment ,Cochrane Library ,03 medical and health sciences ,0302 clinical medicine ,Hematoma ,Fibrinolytic Agents ,medicine ,Humans ,Injections, Spinal ,Craniotomy ,Urokinase ,business.industry ,Incidence (epidemiology) ,medicine.disease ,Urokinase-Type Plasminogen Activator ,Surgery ,Systematic review ,Chemotherapy, Adjuvant ,Hematoma, Subdural, Chronic ,Tissue Plasminogen Activator ,030220 oncology & carcinogenesis ,Observational study ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Fibrinolytic agent ,medicine.drug - Abstract
Background The current treatment options for chronic subdural hematoma (CSDH) include burr hole drainage, twist drill drainage, and craniotomy with or without postoperative catheter drainage. Although generally effective, these treatments have continued to be complicated by recurrence, especially in partially hemolyzed or septated hematomas. Recently, interest in the use of fibrinolytic agents as an adjunct to surgical treatment to address this limitation has been increasing. We conducted a systematic review, focusing on the efficacy and safety profile of fibrinolytic agents and compared the different fibrinolytic agents. Methods The PubMed, EMBASE, CINAHL Plus, and Cochrane Library databases were searched for trials relevant to fibrinolytic administration in the treatment of CSDH. The findings are reported in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The data from 1702 subjects from 6 retrospective observational studies were qualitatively analyzed. In addition, we included 11 case series and reports for discussion. Results For 1449 patients, the use of urokinase or tissue plasminogen activator improved hematoma drainage and shortened the hospital stay (7.04 days), with an overall hematoma recurrence rate of 1.59%. The incidence of infection, seizure, and intracranial bleeding was 3.18%, 0.80%, and 0.41%, respectively, which compared favorably with previously reported findings for surgical drainage without the use of fibrinolytic agents. Conclusions The routine use of intrathecal urokinase and tissue plasminogen activator could be a new direction in the management of CSDH. Conclusive clinical evidence is lacking, however, and further prospective controlled studies are warranted to confirm the benefit and safety of this treatment strategy and to identify the optimal agent and dosing regimen.
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- 2021
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10. Secondary gliosarcoma: the clinicopathological features and the development of a patient-derived xenograft model of gliosarcoma
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Gilberto K.K. Leung, Karrie Mei-Yee Kiang, and Andrian A Chan
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0301 basic medicine ,Cancer Research ,Pathology ,Cell Cycle Proteins ,Mice ,0302 clinical medicine ,Surgical oncology ,Tumor Cells, Cultured ,Secondary gliosarcoma ,Tumor xenograft ,Brain Neoplasms ,Brain ,Neoplasms, Second Primary ,Chemoradiotherapy ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Magnetic Resonance Imaging ,Oncology ,030220 oncology & carcinogenesis ,Clinicopathological features ,Female ,Craniotomy ,medicine.drug ,Research Article ,medicine.medical_specialty ,Gliosarcoma ,Primary Cell Culture ,Glioblastoma multiforme ,lcsh:RC254-282 ,03 medical and health sciences ,In vivo ,Patient-derived xenograft ,Genetics ,medicine ,Biomarkers, Tumor ,Temozolomide ,Animals ,Humans ,Primary culture ,business.industry ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Tumor progression ,Mutation ,business ,Glioblastoma ,Ex vivo - Abstract
Background Gliosarcoma (GSM) is a distinct and aggressive variant of glioblastoma multiforme (GBM) with worse prognosis and few treatment options. It is often managed with the same treatment modalities with temozolomide (TMZ) as in GBM. However, the therapeutic benefits on GSM from such treatment regimen is largely unknown. Patient-derived xenograft (PDX) models have been used widely to model tumor progression, and subsequently to validate biomarkers and inform potential therapeutic regimens. Here, we report for the first time the successful development of a PDX model of secondary GSM. Methods Tissue obtained from a tumor resection revealed a secondary GSM arising from GBM. The clinical, radiological, and histopathological records of the patient were retrospectively reviewed. Samples obtained from surgery were cultured ex vivo and/or implanted subcutaneously in immunocompromised mice. Histopathological features between the primary GBM, secondary GSM, and GSM PDX are compared. Results In explant culture, the cells displayed a spindle-shaped morphology under phase contrast microscopy, consistent with the sarcomatous component. GSM samples were subcutaneously engrafted into immunocompromised mice after single-cell suspension. Xenografts of serial passages showed enhanced growth rate with increased in vivo passage. We did not observe any histopathological differences between the secondary GSM and its serial in vivo passages of PDX tumors. Conclusions Our PDX model for GSM retained the histopathological characteristics of the engrafted tumor from the patient. It may provide valuable information to facilitate molecular and histopathological modelling of GSM and be of significant implication in future research to establish precise cancer medicine for this highly malignant tumor.
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- 2021
11. The Surgical Strategies and Techniques of Transorbital Nonmissile Brain Injury
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Liang Li, Weiming Liu, Baiyun Liu, Long Xu, Gilberto K.K. Leung, and Feifan Xu
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Adult ,Male ,medicine.medical_specialty ,business.operation ,Traumatic brain injury ,medicine.medical_treatment ,Clinical Decision-Making ,Physical examination ,Neurosurgical Procedures ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Medical imaging ,Head Injuries, Penetrating ,Humans ,Trauma team ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,General surgery ,Middle Aged ,Foreign Bodies ,medicine.disease ,Eye Injuries, Penetrating ,Treatment Outcome ,medicine.anatomical_structure ,Superior orbital fissure ,Brain Injuries ,030220 oncology & carcinogenesis ,Surgery ,Decompressive craniectomy ,Neurology (clinical) ,Foreign body ,business ,Orbit ,Transorbital ,030217 neurology & neurosurgery - Abstract
Objective This study aimed to summarize the experience with the management of transorbital brain injury (TOBI) at our institution that may help inform surgical decision-making. Methods Four adults with TOBIs were admitted to our hospital and received surgical treatment. The patients’ clinical manifestations, physical findings, imaging data, surgical treatment, and postoperative outcome were prospectively collected and subject to retrospective analysis. Results All patients were male. In 2 patients, the entry point of the cranium was the superior orbital fissure, whereas in the other 2, the entry point was the orbital roof. Thorough physical examination and comprehensive diagnostic imaging were performed preoperatively in all patients for careful assessment of the foreign body and its surrounding important structures. In collaboration with our multidisciplinary trauma team, individualized surgeries were successfully designed and performed in the 4 patients to remove the foreign bodies along the path of their trajectories. Three patients had uneventful postoperative courses, whereas 1 patient died because of severe cerebral ischemia and refractory brain swelling after decompressive craniectomy. Conclusions A comprehensive understanding of the regional anatomy of the trajectory is the cornerstone for surgical management of TOBIs. Adequate preoperative imaging examinations are essential for the evaluation of surgical risks and for making a tailored management strategy. Early surgical exploration through multidisciplinary collaboration is highly recommended for achieving a favorable outcome.
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- 2020
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12. Genetic Variants of Targetable Cancer-related Genes in Vestibular Schwannomas
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Gilberto K.K. Leung, Alvin Ho Kwan Cheung, Cesar Wong, William C. Cho, Hin-Fung Andy Tsang, Nancy B.Y. Tsui, Xiao Meng Pei, and Yin Kwan Evelyn Wong
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Sanger sequencing ,Neuroblastoma RAS viral oncogene homolog ,business.industry ,medicine.medical_treatment ,PDGFRA ,Schwannoma ,medicine.disease ,Targeted therapy ,symbols.namesake ,otorhinolaryngologic diseases ,symbols ,Adjuvant therapy ,Cancer research ,Medicine ,Neurofibromatosis type 2 ,business ,Gene - Abstract
Background: Vestibular schwannoma is an intracranial tumor which can lead to devastating neurological deficit and is prone to recurrence after surgery. Patients with inherited neurofibromatosis type 2 (NF2) syndrome are particularly susceptible to bilateral and aggressive schwannomas. However, the genome of vestibular schwannomas is not well known. There is an imminent need of developing effective chemotherapeutic agents either as a primary treatment modality or as adjuvant therapy for these patients. Methods: Here, we subjected both sporadic and NF2-related schwannomas to high-throughput DNA sequencing using a panel of therapeutically important cancer-related genes, in order to determine if targetable genetic changes are present in schwannomas. Results: A number of variants were detected in the genes NRAS, PDGFRA, KIT, and EGFR, in both sporadic and NF2-related cases. The results were confirmed by Sanger sequencing. Conclusion: Our study successfully detected some genetic variants in important cancer-related genes in schwannomas, and further elucidation of their relationship to drug-response will be pursued.
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- 2020
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13. Loss of cytoskeleton protein ADD3 promotes tumor growth and angiogenesis in glioblastoma multiforme
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Gilberto K.K. Leung, Zhiyuan Zhu, Lei Jin, Karrie Mei-Yee Kiang, Ning Li, and Pingde Zhang
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Male ,0301 basic medicine ,Cancer Research ,Microarray ,Angiogenesis ,Mice, Nude ,Apoptosis ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,In vivo ,Glioma ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Cell Proliferation ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,biology ,Brain Neoplasms ,Middle Aged ,Prognosis ,Actin cytoskeleton ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Xenograft Model Antitumor Assays ,nervous system diseases ,Proliferating cell nuclear antigen ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Vascular endothelial growth factor ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Calmodulin-Binding Proteins ,Female ,Glioblastoma - Abstract
Adducin 3 (ADD3) is a crucial assembly factor in the actin cytoskeleton and has been found to be aberrantly expressed in various cancers, including glioblastoma multiforme (GBM). It has previously been studied in array-based studies with controversial findings as to its functional role in glioma. In microarray analyses of 452 glioma specimens, we found significant downregulation of ADD3 in GBM, but not in less malignant gliomas, compared to normal brain tissue, which suggests that its downregulation might underlie critical events during malignant progression. We also found that ADD3 was functionally dependent on cell-matrix interaction. In our in vivo study, the proliferative and angiogenic capacity of ADD3-depleted GBM cells was promoted, possibly through PCNA, while p53 and p21 expression was suppressed, and pro-angiogenic signals were induced through VEGF-VEGFR-2-mediated activation in endothelial cells. With correlative in vitro, in vivo, and clinical data, we provide compelling evidence on the putative tumor-suppressive role of ADD3 in modulating GBM growth and angiogenesis. As a preclinical study, our research offers a better understanding of the pathogenesis of glioma malignant progression for the benefit of future investigations.
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- 2020
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14. Regional trauma system development in Shenzhen, China: an 8-year journey
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Chung Mau Lo, Joe K. M. Fan, Gilberto K.K. Leung, Guixi Zhang, John Wong, Ronald V. Maier, Eileen M. Bulger, Richard Lo, and Xiaobing Fu
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China ,System development ,Medicine (General) ,business.industry ,MEDLINE ,General Medicine ,medicine.disease ,R5-920 ,Military Science ,Trauma Centers ,medicine ,Humans ,Medical emergency ,business ,Letter to the Editor - Published
- 2021
15. Postcooling But Not Precooling Benefits Motor Recovery by Suppressing Cell Death After Surgical Spinal Cord Injury in Rats
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Ning Li, Charlene Y.C. Chau, Jiaxin Liu, Min Yao, Karrie M.Y. Kiang, Zhiyuan Zhu, Pingde Zhang, Huilin Cheng, and Gilberto K.K. Leung
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Caspase 1 ,Apoptosis ,Hypothermia ,Recovery of Function ,Rats ,Proto-Oncogene Proteins c-bcl-2 ,Spinal Cord ,NLR Family, Pyrin Domain-Containing 3 Protein ,Animals ,Humans ,Surgery ,Neurology (clinical) ,Spinal Cord Injuries ,bcl-2-Associated X Protein - Abstract
Surgical spinal cord injury (SSCI) is often inevitable in patients with intramedullary lesions. Although regional hypothermia (RH) has been demonstrated neuroprotective, the value of priming RH in SSCI has never been studied. Herein, the authors investigated the impact of pre- and post-RH on neurologic recovery in a clinically relevant model.An SSCI model was established at T10. RH was conducted by focal 4RH perfusion successfully created an intramedullary hypothermia approximately at 24Priming RH before surgical incision could not be supported as it caused excessive cell death. In contrast, instant introduction of RH is beneficial in rescuing neurologic function.
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- 2021
16. The Process of Regional Trauma System Development in Shenzhen, China: An 8-Year Journey
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Richard Lo, Chung Mao Lo, Guixi Zhang, Xiaobing Fu, Ronald V. Maier, John Wong, Eileen M. Bulger, Joe King Man Fan, and Gilberto K.K. Leung
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System development ,Economic growth ,Process (engineering) ,Business ,China - Abstract
Background: International experiences have shown that trauma system development significantly reduces preventable deaths and disabilities. During the 8-year study, the aim was to find solutions for trauma system development in Shenzhen, China, so as to reduce trauma mortality and morbidity. Methods: Introducing the ATLS® program to mainland China was started in 2013. A geospatial analysis of traumatic incidents was conducted in 2014. A regional trauma center was illustrated as an example to be used as a reference. The trauma audit meeting was introduced as an approach to continuous trauma quality improvement. The Shenzhen Trauma Surgery Committee was established to finalize the plan for designation of trauma care hospitals. The American College of Surgeons Trauma System Development Guidelines were translated into Chinese. Results: ATLS® provider course was held in Shenzhen and totally 205 doctors received training. A regional trauma center where adopted ATLS® principles as the standard for trauma resuscitation and early trauma care, with results showing significant improvements in trauma team organization, trauma resuscitation, definitive trauma care and a significant reduction in mortality among major trauma patients. The trauma audit meeting was introduced to 8 hospitals. A new trauma system plan for Shenzhen was set up and a consensus was reached on trauma center designation. The American College of Surgeons' “Resources for Optimal Care of the Injured Patient” was translated into Chinese and published in November 2020. Conclusion: The critical steps in establishing the framework for the Shenzhen trauma system included: geospatial analysis of traumatic incidents, trauma care training for providers, trauma center development, regional trauma center designation and development of trauma quality improvement programs. This practical approach can be replicated in other countries seeking to establish a trauma system. We are now working toward extension of this approach to other regions of mainland China.
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- 2021
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17. Prognostic and Clinical Values of Chaperone Protein P4HB in Malignant Glioma
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Gilberto K.K. Leung, Karrie Mei-Yee Kiang, and Stella Sun
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business.industry ,Glioma ,Cancer research ,Medicine ,P4HB ,business ,medicine.disease - Abstract
Introduction. Prolyl 4-hydroxylase, beta polypeptide (P4HB) has previously been identified by our group to play important roles in association with glioma malignancy and temozolomide (TMZ) resistance through the unfolded protein response (UPR). The present study focused on the prognostic value of P4HB in glioma. Methods. P4HB expression was assessed by immunohistochemical staining and semi-quantified by pathologist visual scoring in 73 WHO grade I-IV gliomas. Results were correlated with clinicopathological data. Results. Our results show that P4HB expression was significantly associated several clinicopathological parameters including age (p=0.035), tumour grade (p=0.002), and the number of TMZ treatment cycles received (p=0.043). Using Kaplan-Meier analysis, P4HB expression was positively correlated with mortality (p=0.014) and disease progression (p=0.026). In patients treated with TMZ, high P4HB expression level was significantly associated with poorer overall survival (OS) (p=0.014) and progression free survival (PFS) (p=0.027). The association between MGMT promoter methylation and P4HB expression was also interrogated. Patients with MGMTMethP4HBLow tumours had the most favourable progression free survival (48 months) than patients with other combination of MGMT methylation status and P4HB expression (log rank p=0.001). Multivariate analysis revealed that P4HB was an independent prognostic indicator for OS (p=0.048). Conclusions. P4HB could constitute an independent prognostic marker, especially for high grade glioma with the potential for informing a nuanced pathological stratification during clinical decision-making with respect to MGMT promoter methylation status and TMZ treatment.
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- 2021
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18. Lovastatin Enhances Cytotoxicity of Temozolomide via Impairing Autophagic Flux in Glioblastoma Cells
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Gilberto K.K. Leung, Vincent Kam Wai Wong, Ning Li, Pingde Zhang, Stephen Yin Cheng, Karrie M.Y. Kiang, and Zhiyuan Zhu
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Article Subject ,Cell Survival ,lcsh:Medicine ,Antineoplastic Agents ,Apoptosis ,General Biochemistry, Genetics and Molecular Biology ,Flow cytometry ,Cell Line, Tumor ,Lysosomal-Associated Membrane Protein 2 ,Antineoplastic Combined Chemotherapy Protocols ,Autophagy ,Temozolomide ,medicine ,Humans ,Lovastatin ,Cytotoxicity ,Protein kinase B ,Tumor Stem Cell Assay ,LAMP2 ,General Immunology and Microbiology ,medicine.diagnostic_test ,Brain Neoplasms ,Chemistry ,TOR Serine-Threonine Kinases ,lcsh:R ,Dyneins ,General Medicine ,Drug Resistance, Neoplasm ,Cancer research ,Glioblastoma ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Research Article ,medicine.drug - Abstract
Drug resistance to temozolomide (TMZ) contributes to the majority of tumor recurrence and treatment failure in patients with glioblastoma multiforme (GBM). Autophagy has been reported to play a role in chemoresistance in various types of cancer, including GBM. The anticancer effect of statins is arousing great research interests and has been demonstrated to modulate autophagic function. In this study, we investigated the combinational effects of lovastatin and TMZ on treating U87 and U251 GBM cell lines. Cytotoxicity was measured by MTT and colony formation assays; apoptosis was measured by flow cytometry; the cellular autophagic function was detected by the EGFP-mRFP-LC3 reporter and western blot assay. The results showed that lovastatin might enhance the cytotoxicity of TMZ, increase the TMZ-induced cellular apoptosis, and impair the autophagic flux in GBM cells. Lovastatin triggered autophagy initiation possibly by inhibiting the Akt/mTOR signaling pathway. Moreover, lovastatin might impair the autophagosome-lysosome fusion machinery by suppressing LAMP2 and dynein. These results suggested that lovastatin could enhance the chemotherapy efficacy of TMZ in treating GBM cells. The mechanism may be associated with impaired autophagic flux and thereby the enhancement of cellular apoptosis. Combining TMZ with lovastatin could be a promising strategy for GBM treatment.
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- 2019
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19. Improving Survival with Tranexamic Acid in Cerebral Contusions or Traumatic Subarachnoid Hemorrhage: Univariate and Multivariate Analysis of Independent Factors Associated with Lower Mortality
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Benedict Beng-teck Taw, Wai-Man Lui, Anderson Chun On Tsang, Kevin King Fai Cheng, Wilson Wai Shing Ho, Gilberto K.K. Leung, Jenny Kan-suen Pu, Lai Fung Li, David Yuen Chung Chan, and Frederick Chun Pong Tsang
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Adult ,Male ,medicine.medical_specialty ,Subarachnoid hemorrhage ,Adolescent ,Traumatic brain injury ,Cerebral contusion ,Young Adult ,03 medical and health sciences ,Subarachnoid Hemorrhage, Traumatic ,0302 clinical medicine ,Internal medicine ,Cerebral Hemorrhage, Traumatic ,Humans ,Medicine ,Aged ,Aged, 80 and over ,Univariate analysis ,business.industry ,Mortality rate ,Head injury ,Glasgow Coma Scale ,Brain Contusion ,Middle Aged ,medicine.disease ,Intracranial Hemorrhage, Traumatic ,Tranexamic Acid ,030220 oncology & carcinogenesis ,Multivariate Analysis ,Female ,Surgery ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Tranexamic acid ,medicine.drug - Abstract
Background Fall with head injury is a pervasive challenge, especially in the aging population. Contributing factors for mortality include the development of cerebral contusions and delayed traumatic intracerebral hematoma. Currently, there is no established specific treatment for these conditions. Object This study aimed to investigate the impact of independent factors on the mortality rate of traumatic brain injury with contusions or traumatic subarachnoid hemorrhage. Methods Data were collected from consecutive patients admitted for cerebral contusions or traumatic subarachnoid hemorrhage at an academic trauma center from 2010 to 2016. The primary outcome was the 30-day mortality rate. Independent factors for analysis included patient factors and treatment modalities. Univariate and multivariate analyses were conducted to identify independent factors related to mortality. Secondary outcomes included thromboembolic complication rates associated with the use of tranexamic acid. Results In total, 651 consecutive patients were identified. For the patient factors, low Glasgow Coma Scale on admission, history of renal impairment, and use of warfarin were identified as independent factors associated with higher mortality from univariate and multivariate analyses. For the treatment modalities, univariate analysis identified tranexamic acid as an independent factor associated with lower mortality (P = 0.021). Thromboembolic events were comparable in patients with or without tranexamic acid. Conclusion Tranexamic acid was identified by univariate analysis as an independent factor associated with lower mortality in cerebral contusions or traumatic subarachnoid hemorrhage. Further prospective studies are needed to validate this finding.
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- 2019
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20. Criminalizing medical research fraud: Towards an appropriate legal framework and policy response
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Gilberto K.K. Leung
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050502 law ,Misconduct ,Criminalization ,Political science ,05 social sciences ,Criminal law ,Societal impact of nanotechnology ,Public policy ,General Medicine ,Criminology ,Medical research ,Law ,0505 law - Abstract
Increasing concerns about the societal impact of medical research fraud have led to calls for its criminalization within the United Kingdom, but there has been little discussion of how the criminal law could be applied in this context. The author proposes a legal framework whereby acts of falsification or fabrication may be prosecuted under a general offence of fraud contained within the Fraud Act 2006 in England and Wales. The threshold for prosecution may be determined by assessing the effect of an act on the reliability and robustness of research findings and using a Two-stage Full Code Test modelled on the Crown Prosecution Service Policy for Prosecutors in Respect of Cases of Encouraging or Assisting Suicide. This provides a pragmatic approach to handling an unyielding problem that affects many sectors of society and necessitates the implementation of an explicit government policy aimed at balancing the protection of public interests against the promotion of medical advancement.
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- 2019
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21. Repair of Anterior Skull Base Defect by Dual-Layer/Split-Frontal Pericranial Flap
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Wai-Man Lui, Joseph Chun-kit Chung, Lai-Fung Li, Jenny Kan-suen Pu, and Gilberto K.K. Leung
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Adenoma ,Male ,Reoperation ,medicine.medical_specialty ,Leak ,Surgical Flaps ,Cerebral Ventriculitis ,03 medical and health sciences ,Fatal Outcome ,Postoperative Complications ,0302 clinical medicine ,Cerebrospinal fluid ,medicine ,Nasal septum ,Ventriculitis ,Humans ,Pituitary Neoplasms ,Nose ,Aged ,Skull Base ,Cerebrospinal Fluid Leak ,business.industry ,Dual layer ,medicine.disease ,Surgery ,Skull ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Nasion ,Neurology (clinical) ,business ,Craniotomy ,030217 neurology & neurosurgery - Abstract
Introduction Normal skull base structures are destroyed either by the skull base pathology itself or during surgery that results in cerebrospinal fluid (CSF) leak. Skull base repair is usually performed transnasally by using a nasal septal flap. But when NSF is not available and failed repeated transnasal repair, a cranionasal repair with frontal pericranial flap (PF) can be attempted to achieve the highest successful chance. We performed a dual layer/split PF repair of a skull base defect using cranionasal approach and here we describe the technique. Case Description A 74-year-old man suffered from CSF leak and ventriculitis after multiple transnasal surgeries for pituitary macroadenoma despite multiple repairs with intranasal vascularized flaps. We performed repair by cranionasal approach and using frontal PF. The frontal PF was divided into left and right halves. The left half went intradural, through the chiasmatic window to reach the sella and cover the tubercular and sellar defect from above. The right half went through the nasion into the nose to cover the defect from below. So the defect was covered by two vascularized flap from a single frontal PF. The repair was successful with no CSF leak and infection successfully treated by antibiotics. Conclusion We introduced the cranionasal dual layer/split PF technique to repair anterior skull base and successfully stopped the CSF leak in a patient after multiple EEA surgeries. This technique should only be considered in specific difficult situation where usual repair by EEA is impossible.
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- 2019
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22. BIOM-40. TARGETED GENE EXPRESSION PROFILING PREDICTS MENINGIOMA OUTCOMES AND RADIOTHERAPY RESPONSES
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Nancy Ann Oberheim-Bush, Tai-Chung Lam, Penny K. Sneed, C.H. Lucas, Gilberto K.K. Leung, Javier Villanueva-Meyer, David A. Solomon, Jenny Kan-Suen Pu, William S. Chen, Minh P. Nguyen, Abrar Choudhury, Lai-Fung Li, Nicholas Butowski, Jacob S. Young, Jason Chan, Michael McDermott, David R. Raleigh, Mitchel S. Berger, Arie Perry, Theresa Yu, Stephen Magill, Harish N. Vasudevan, Jessica Schulte, and Steve Braunstein
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Postoperative radiotherapy ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,medicine.disease ,Meningioma ,Gene expression profiling ,Radiation therapy ,Internal medicine ,DNA methylation ,Gene expression ,medicine ,Neurology (clinical) ,business ,Gene ,Exome sequencing - Abstract
BACKGROUND Surgery is the mainstay of meningioma treatment, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. DNA methylation profiling, copy number variants (CNVs), exome sequencing, and RNA sequencing have improved understanding of meningioma biology, but have not superseded histologic grading, or revealed biomarkers for radiotherapy responses. To address these unmet needs, we optimized and validated a targeted gene expression biomarker predicting meningioma outcomes and responses to radiotherapy. METHODS Targeted gene expression profiling was performed on a discovery cohort of 173 meningiomas (median follow-up 8.1 years) and a validation cohort of 331 meningiomas (median follow-up 6.1 years) treated with surgery (n=504) and postoperative radiotherapy (n=73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). Optimized targeted gene expression models predicting clinical outcomes (34 genes) or radiotherapy responses (12 genes) were developed from the discovery cohort, and compared to histologic and molecular classification systems by performing DNA methylation profiling, CNV analysis, exome sequencing, and RNA sequencing on the same meningiomas. RESULTS Targeted gene expression profiling achieved a concordance-index of 0.75 ± 0.03 (SEM) for local freedom from recurrence (LFFR) and 0.72 ± 0.03 for overall survival (OS) in the validation cohort, outperforming WHO grade (5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p=0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p=0.01) for LFFR, disease-specific survival, and OS. The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and identified meningiomas benefiting from radiotherapy (interaction p-value=0.0008), suggesting postoperative radiotherapy could be refined in 30.2% of cases. CONCLUSIONS Targeted gene expression profiling of 504 meningiomas improves discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and predicts radiotherapy responses.
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- 2021
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23. A Targeted Gene Expression Risk Score Predicts Meningioma Outcomes and Responses to Radiotherapy
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D.S. Solomon, Michael McDermott, Patricia Sneed, Jenny Kan-Suen Pu, Gilberto K.K. Leung, William C. Chen, Arie Perry, M.S. Berger, Steve Braunstein, Lai-Fung Li, N.A. Oberheim, Minh P. Nguyen, Abrar Choudhury, Tai-Chung Lam, June M. Chan, N. Butowski, Stephen Magill, Jessica Schulte, Harish N. Vasudevan, C.H. Lucas, David R. Raleigh, and Javier Villanueva-Meyer
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Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation ,Framingham Risk Score ,Proportional hazards model ,business.industry ,medicine.medical_treatment ,medicine.disease ,Radiation therapy ,Meningioma ,Gene expression profiling ,Quartile ,Internal medicine ,Cohort ,medicine ,Biomarker (medicine) ,Radiology, Nuclear Medicine and imaging ,business - Abstract
Purpose/Objective(s) Indications for postoperative radiotherapy after meningioma resection are controversial. DNA methylation profiling identifies meningiomas at risk for recurrence, but logistic and technical barriers have encumbered clinical translation of this approach. The aim of this study was to optimize and validate a clinically-tractable targeted gene expression biomarker to predict meningioma outcomes and responses to postoperative radiotherapy. Materials/Methods Targeted gene expression and Illumina 850k DNA methylation profiling were performed on a discovery cohort of 173 meningiomas (median follow-up 7.8 years) and an external validation cohort of 331 meningiomas (median follow-up 5.8 years) from patients treated with surgery (n = 504) and postoperative radiotherapy (n = 73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). RNA sequencing was performed on the discovery cohort, and 125 genes were selected for targeted gene expression profiling based on associations with meningioma recurrence. Regularized Cox regression was used to develop continuous gene expression risk score for local freedom from recurrence (LFFR). The model (34 meningioma genes and 7 housekeeping genes) and risk quartiles (low, low-intermediate, high-intermediate, and high) were locked and validated on the external cohort. Multivariate regressions (MVR) incorporating WHO grade, DNA methylation grouping, extent of resection, primary versus recurrent presentation, and postoperative radiotherapy were used to assess the risk score across clinical contexts. Results The gene expression risk score (concordance-index 0.78 ± 0.03) outperformed DNA methylation grouping (0.71 ± 0.03) and WHO grade (0.65 ± 0.03) in stratifying meningioma LFFR in the validation cohort (n = 331). The risk score classified 43% of WHO grade 1 meningiomas as high-intermediate (n = 82) or high risk (n = 34), with 5-year LFFR and overall survival (OS) of 83% and 89% for high-intermediate risk WHO grade 1 meningiomas, and 41% and 73% for high risk WHO grade 1 meningiomas, respectively. Low risk WHO grade 1 meningiomas (n = 50) had 5-year LFFR and OS of 92% and 88%, respectively. High and high-intermediate risk scores were independently prognostic for LFFR (HR 2.9, 95% CI 1.2-4.4) and OS (HR 2.7, 95% CI 1.3-5.6) on MVR. An interaction term between postoperative radiotherapy and risk score was predictive for LFFR (P = 0.046) and OS (P = 0.001) on MVR in the validation cohort, suggesting meningiomas with higher risk scores derived greater benefit from postoperative radiotherapy. Conclusion Here we use targeted gene expression profiling to develop a risk score predicting meningioma outcomes and responses to postoperative radiotherapy. This cost-effective assay outperforms DNA methylation grouping and WHO grade in discriminating meningioma outcomes, and may be useful for guiding clinical trial design.
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- 2021
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24. Injury Severity Score (ISS) vs. ICD-derived Injury Severity Score (ICISS) in a patient population treated in a designated Hong Kong trauma centre
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Gilberto K.K. Leung and Sydney S.N. Wong
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Pathology ,medicine.medical_specialty ,iss ,Poison control ,lcsh:Medicine ,Logistic regression ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Injury prevention ,medicine ,Trauma centre ,030212 general & internal medicine ,iciss ,Receiver operating characteristic ,business.industry ,triss ,lcsh:R ,030208 emergency & critical care medicine ,Original Articles ,General Medicine ,receiver operator characteristic curve ,srr ,Patient population ,Injury Severity Score ,trauma scoring ,business ,Trauma scoring - Abstract
Trauma and Injury Severity Score (TRISS) has been the benchmark of mortality riskin trauma centers for over 30 years. TRISS utilizes the Injury Severity Score (ISS) as an index ofanatomical injury. This study investigated the efficacy of a new type of index of anatomical injury called the ICD-derived Injury Severity Score (ICISS) compared to the ISS using a logisticregression analysis and a global chi-square test of the areas under the Receiver OperatorCharacteristic (ROC) curves. We found that the empirically derived ICISS performed as well as the consensus derived ISS with no statistical differences between their respective area under the ROC curves.
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- 2020
25. 3D dissimilar-siamese-u-net for hyperdense Middle cerebral artery sign segmentation
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Wing-ho Chong, Carrie Siu Man Lui, Chi-yeung Chu, Pauline P. S. Woo, Jia You, Wai-lun Poon, Neeraj Ramesh Mahboobani, Eva L. H. Tsui, Gilberto K.K. Leung, Anderson Chun On Tsang, and Philip L. H. Yu
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medicine.medical_specialty ,Middle Cerebral Artery ,medicine.medical_treatment ,Health Informatics ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,medicine.artery ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Segmentation ,Thrombus ,Stroke ,Retrospective Studies ,Radiological and Ultrasound Technology ,business.industry ,Thrombolysis ,medicine.disease ,Computer Graphics and Computer-Aided Design ,Triage ,Feature (computer vision) ,Middle cerebral artery ,Computer Vision and Pattern Recognition ,Radiology ,business ,Tomography, X-Ray Computed ,030217 neurology & neurosurgery ,Sign (mathematics) - Abstract
The hyperdense middle cerebral artery sign (HMCAS) representing a thromboembolus has been declared as a vital CT finding for intravascular thrombus in the diagnosis of acute ischemia stroke. Early recognition of HMCAS can assist in patient triage and subsequent thrombolysis or thrombectomy treatment. A total of 624 annotated head non-contrast-enhanced CT (NCCT) image scans were retrospectively collected from multiple public hospitals in Hong Kong. In this study, we present a deep Dissimilar-Siamese-U-Net (DSU-Net) that is able to precisely segment the lesions by integrating Siamese and U-Net architectures. The proposed framework consists of twin sub-networks that allow inputs of left and right hemispheres in head NCCT images separately. The proposed Dissimilar block fully explores the feature representation of the differences between the bilateral hemispheres. Ablation studies were carried out to validate the performance of various components of the proposed DSU-Net. Our findings reveal that the proposed DSU-Net provides a novel approach for HMCAS automatic segmentation and it outperforms the baseline U-Net and many state-of-the-art models for clinical practice.
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- 2020
26. From bedside to webside: A neurological clinical teaching experience
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Gilberto K.K. Leung, Julie Y. Chen, Pamela Pui‐wah Lee, and Anderson Chun On Tsang
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medicine.medical_specialty ,020205 medical informatics ,MEDLINE ,02 engineering and technology ,Session (web analytics) ,Education ,03 medical and health sciences ,0302 clinical medicine ,Treatment plan ,Clinical information ,0202 electrical engineering, electronic engineering, information engineering ,Medicine ,Humans ,Medical physics ,030212 general & internal medicine ,Mri brain ,Radiological imaging ,Clinical teaching ,Education, Medical ,business.industry ,Teaching ,Medical Education Adaptations ,General Medicine ,Laboratory results ,business ,Education, Medical, Undergraduate - Abstract
This was followed by an interactive discussion of investigation and management plan. Appropriate radiological imaging such as an MRI brain scan was shown to the group using the “share‐screen” function. Other clinical information such as laboratory results can likewise be displayed. The session was completed after thorough discussion on the appropriate treatment plan with respect to the patient’s scenario.
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- 2020
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27. More Than a Metabolic Enzyme: MTHFD2 as a Novel Target for Anticancer Therapy?
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Zhiyuan Zhu and Gilberto K.K. Leung
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0301 basic medicine ,Cancer Research ,one carbon metabolism ,cancer metabolism ,Review ,Biology ,Malignancy ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,oncogenicity ,epigenetic modification ,medicine ,chemistry.chemical_classification ,Mechanism (biology) ,Cancer ,Embryo ,metabolic enzyme ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Phenotype ,030104 developmental biology ,Enzyme ,chemistry ,Oncology ,030220 oncology & carcinogenesis ,Methylenetetrahydrofolate dehydrogenase ,Cancer cell ,Cancer research - Abstract
The bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a mitochondrial one-carbon folate metabolic enzyme whose role in cancer was not known until recently. MTHFD2 is highly expressed in embryos and a wide range of tumors but has low or absent expression in most adult differentiated tissues. Elevated MTHFD2 expression is associated with poor prognosis in both hematological and solid malignancy. Its depletion leads to suppression of multiple malignant phenotypes including proliferation, invasion, migration, and induction of cancer cell death. The non-metabolic functions of this enzyme, especially in cancers, have thus generated considerable research interests. This review summarizes current knowledge on both the metabolic functions and non-enzymatic roles of MTHFD2. Its expression, potential functions, and regulatory mechanism in cancers are highlighted. The development of MTHFD2 inhibitors and their implications in pre-clinical models are also discussed.
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- 2020
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28. Vertebral-carotid bypass for common carotid artery occlusion
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Anderson Chun On Tsang, Gilberto K.K. Leung, Wai-Man Lui, Frederick Chun Pong Tsang, Lai-Fung Li, and Kevin King Fai Cheng
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Carotid Artery Diseases ,Male ,medicine.medical_specialty ,Carotid Artery, Common ,Vertebral artery ,information science ,Cerebral Revascularization ,Marfan Syndrome ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,medicine.artery ,parasitic diseases ,medicine ,Humans ,cardiovascular diseases ,Occipital artery ,Common carotid artery ,Carotid Artery Thrombosis ,Radial artery ,Internal jugular vein ,Subclavian artery ,Vertebral Artery ,business.industry ,fungi ,Anastomosis, Surgical ,Thrombosis ,General Medicine ,Middle Aged ,Subarachnoid Hemorrhage ,Surgery ,Neurology ,Bypass surgery ,Ischemic Attack, Transient ,030220 oncology & carcinogenesis ,Radial Artery ,cardiovascular system ,Neurology (clinical) ,business ,Vascular Surgical Procedures ,030217 neurology & neurosurgery - Abstract
One of the treatment options for long segment common carotid artery (CCA) occlusion is bypass surgery with different combinations of donors and receipts. Using vertebral artery (VA) as the donor for CCA occlusion was uncommonly reported. The reported cases were using jump graft to connect V3 segment of VA to either CCA or ICA. We describe our patient using V2 segment as the donor for VA-CCA bypass as treatment for CCA occlusion. Our patient was a 51 years old gentleman with Marfan syndrome and had multiple operations that included total arch replacement. He presented with sudden onset of spontaneous right frontal subarachnoid haemorrhage and repeated episodes of TIA with left upper limb numbness. CTA showed occluded right CCA and anastomosis between branches from subclavian artery and occipital artery. CT perfusion showed hypoperfusion of right hemisphere. To avoid damaging the anastomosis at subclavian artery and occipital artery, we decided for V2-RAG (radial artery graft)-CCA bypass. It was done by exposing the V2 segment at C4/5 level, performing end-to-side anastomoses at V2-RAG and RAG-CCA junctions where the RAG was underneath the internal jugular vein. Patient had no new deficits after surgery and no more TIAs. CTA performed one week after surgery showed patent RAG. In conclusion, using V2 for VA-CCA bypass is technically feasible and may have theoretical advantages over using V3. V2-CCA bypass is an option for CCA occlusion in very selected patients.
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- 2020
29. Automated Hierarchy Evaluation System of Large Vessel Occlusion in Acute Ischemia Stroke
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Jia You, Carrie Siu Man Lui, Pauline P. S. Woo, Anderson Chun On Tsang, Gilberto K.K. Leung, Eva L. H. Tsui, and Philip L. H. Yu
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medicine.medical_specialty ,acute ischemic stroke ,Youden's J statistic ,Biomedical Engineering ,Neuroscience (miscellaneous) ,Logistic regression ,050105 experimental psychology ,lcsh:RC321-571 ,03 medical and health sciences ,0302 clinical medicine ,large vessel occlusion ,medicine ,0501 psychology and cognitive sciences ,Stage (cooking) ,Stroke ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Original Research ,business.industry ,Deep learning ,05 social sciences ,deep learning ,medicine.disease ,Computer Science Applications ,Random forest ,Support vector machine ,machine learning ,Radiology ,Artificial intelligence ,prognosis ,F1 score ,business ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Background The detection of large vessel occlusion (LVO) plays a critical role in the diagnosis and treatment of acute ischemic stroke (AIS). Identifying LVO in the pre-hospital setting or early stage of hospitalization would increase the patients' chance of receiving appropriate reperfusion therapy and thereby improve neurological recovery. Methods To enable rapid identification of LVO, we established an automated evaluation system based on all recorded AIS patients in Hong Kong Hospital Authority's hospitals in 2016. The 300 study samples were randomly selected based on a disproportionate sampling plan within the integrated electronic health record system, and then separated into a group of 200 patients for model training, and another group of 100 patients for model performance evaluation. The evaluation system contained three hierarchical models based on patients' demographic data, clinical data and non-contrast CT (NCCT) scans. The first two levels of modeling utilized structured demographic and clinical data, while the third level involved additional NCCT imaging features obtained from deep learning model. All three levels' modeling adopted multiple machine learning techniques, including logistic regression, random forest, support vector machine (SVM), and eXtreme Gradient Boosting (XGboost). The optimal cut-off for the likelihood of LVO was determined by the maximal Youden index based on 10-fold cross-validation. Comparisons of performance on the testing group were made between these techniques. Results Among the 300 patients, there were 160 women and 140 men aged from 27 to 104 years (mean 76.0 with standard deviation 13.4). LVO was present in 130 (43.3%) patients. Together with clinical and imaging features, the XGBoost model at the third level of evaluation achieved the best model performance on testing group. The Youden index, accuracy, sensitivity, specificity, F1 score, and area under the curve (AUC) were 0.638, 0.800, 0.953, 0.684, 0.804, and 0.847, respectively. Conclusion To the best of our knowledge, this is the first study combining both structured clinical data with non-structured NCCT imaging data for the diagnosis of LVO in the acute setting, with superior performance compared to previously reported approaches. Our system is capable of automatically providing preliminary evaluations at different pre-hospital stages for potential AIS patients.
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- 2020
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30. The effect of downstream resistance on flow diverter treatment of a cerebral aneurysm at a bifurcation: A joint computational-experimental study
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Anderson Chun On Tsang, Gilberto K.K. Leung, Alexander K. K. Poon, Abraham Yik-Sau Tang, Billy Y. S. Yiu, Kwok Wing Chow, Simon S. M. Lai, Wai Choi Chung, and Alfred C. H. Yu
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business.industry ,Mechanical Engineering ,Blood flow ,Mechanics ,Vorticity ,Computational fluid dynamics ,Condensed Matter Physics ,medicine.disease ,030218 nuclear medicine & medical imaging ,Volumetric flow rate ,03 medical and health sciences ,0302 clinical medicine ,Aneurysm ,Flow (mathematics) ,Mechanics of Materials ,Modeling and Simulation ,cardiovascular system ,medicine ,cardiovascular diseases ,business ,Stroke ,030217 neurology & neurosurgery ,Bifurcation ,Geology - Abstract
Intracranial aneurysm can lead to hemorrhagic stroke upon rupture. Deployment of flow diverters can restrict the blood flow into aneurysm and mitigate the rupture risk. Computational fluid dynamics (CFD) and ultrasonography with pulse-wave and color Doppler ultrasound measurements were employed jointly to investigate the complex flow pattern in cerebral aneurysms, both before and after the deployment of flow diverters. Patient-specific configurations of both bifurcation and side-wall aneurysms were selected. The effect of downstream flow resistance was investigated by adjusting the volume flow rate and pressure at the outlet vessels computationally and experimentally. Velocity profiles in the aneurysm measured from ultrasonography showed good agreement with those from computer simulations. The discrepancy in velocity between the computational and experimental sets of data is less than 10%. The downstream resistance can alter the volume flux into a bifurcation aneurysm with a flow diverter deployed by 236%, while the corresponding value of a side-wall aneurysm is negligible. The vorticity of the aneurysmal flow was reduced by more than 80% in both cases after stenting. This study demonstrated that careful investigation of downstream flow resistance of a bifurcation aneurysm is essential to provide an accurate assessment of the aneurysmal flow dynamics after flow diverter deployment.
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- 2018
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31. Forward and reverse mutations in stages of cancer development
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Shen-Jia Duan, Hong Xue, Zhenggang Wu, Taobo Hu, Rong Yin, Timothy Y. C. Ho, Jianfeng Yang, Shui Ying Tsang, Xuqing Zhou, Si Chen, Iram shazia, Ava Kwong, Lin Xu, Xiaofan Ding, Yogesh Kumar, Gilberto K.K. Leung, Wai Sang Poon, Dan-Hua Zhang, Yi Li, Wai-Kin Mat, Cheuk Hin Chan, Hongyang Wang, Jin-Fei Chen, Lei Chen, Siu Kin Ng, Xi Long, Peggy Lee, and En-Xiang Zhou
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0301 basic medicine ,Lineage (genetic) ,DNA Copy Number Variations ,lcsh:QH426-470 ,Loss of Heterozygosity ,lcsh:Medicine ,Biology ,Single-nucleotide variation ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Somatic evolution in cancer ,Metastasis ,Loss of heterozygosity ,03 medical and health sciences ,Neoplasms ,Exome Sequencing ,Drug Discovery ,Genetics ,medicine ,Precancer mutations ,Humans ,Copy-number variation ,Molecular Biology ,Mutation ,Clonal evolution ,Genome, Human ,Copy number variation ,lcsh:R ,High-Throughput Nucleotide Sequencing ,Cancer ,Genomics ,Interstitial loss of heterozygosity ,medicine.disease ,lcsh:Genetics ,030104 developmental biology ,Cancer cell ,Molecular Medicine ,Primary Research ,HeLa Cells - Abstract
Background Massive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations. Methods In the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor. Four published “nontumor”-tumor metastasis trios and 246 pan-cancer pairs analyzed by whole-genome sequencing (WGS) and 67 trios by whole-exome sequencing (WES) were also examined. Results Widespread GOHs enriched with CG-to-TG changes and associated with nearby CNVs and LOHs enriched with TG-to-CG changes were observed. Occurrences of GOH were 1.9-fold higher than LOH in “nontumor” tissues more than 2 cm away from the tumors, and a majority of these GOHs and LOHs were reversed in “paratumor” tissues within 2 cm of the tumors, forming forward-reverse mutation cycles where the revertant LOHs displayed strong lineage effects that pointed to a sequential instead of parallel development from “nontumor” to “paratumor” and onto tumor cells, which was also supported by the relative frequencies of 26 distinct classes of CNVs between these three types of cell populations. Conclusions These findings suggest that developing cancer cells undergo sequential changes that enable the “nontumor” cells to acquire a wide range of forward mutations including ones that are essential for oncogenicity, followed by revertant mutations in the “paratumor” cells to avoid growth retardation by excessive mutation load. Such utilization of forward-reverse mutation cycles as an adaptive mechanism was also observed in cultured HeLa cells upon successive replatings. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers. Electronic supplementary material The online version of this article (10.1186/s40246-018-0170-6) contains supplementary material, which is available to authorized users.
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- 2018
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32. A Computational Hemodynamics Analysis on the Correlation Between Energy Loss and Clinical Outcomes for Flow Diverters Treatment of Intracranial Aneurysm
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Anderson Chun On Tsang, Tin Lok Chiu, Kwok Wing Chow, Gilberto K.K. Leung, and Abraham Yik-Sau Tang
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medicine.medical_specialty ,Computer science ,business.industry ,medicine.medical_treatment ,0206 medical engineering ,Biomedical Engineering ,Stent ,02 engineering and technology ,General Medicine ,Computational fluid dynamics ,medicine.disease ,020601 biomedical engineering ,Thrombosis ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Aneurysm ,Flow (mathematics) ,medicine ,Radiology ,Lead (electronics) ,Porous medium ,business ,Flow diverter - Abstract
The rupture of intracranial aneurysms might lead to permanent disability or even death. One possible endovascular treatment is the deployment of flow diverters (FDs), which reduces flow into the sac and promotes thrombosis. Computational fluid dynamics simulations were used to assess the flow patterns and dynamics. The concept of energy loss, as a measure of necessary work done to overcome flow resistance, was utilized to correlate with clinical outcome. If a surgical operation is successful, the flow would be diverted to a shorter path and energy loss should be reduced. Conversely, persistent flow in the sac, associated with treatment failure, would display an increased energy loss as blood is then squeezed through the stent pores. Four illustrative clinical cases, involving both bifurcation and sidewall aneurysms, were selected. To reduce the numerical complexity, earlier works in the literature had used a porous medium approximation for the FDs. Here, the FD was simulated explicitly as a virtual (or computer-generated) stent, which would likely provide a more accurate description. Furthermore, quantitative comparisons between the approaches of virtual stenting and a porous medium with typical parameters were conducted by examining the effective flow influx into the aneurysm.
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- 2018
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33. Quinacrine enhances temozolomide cytotoxicity in temozolomide-sensitive and -resistant glioblastoma cells
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Gloria Wai Man Leung, Gilberto K.K. Leung, Ning Li, Karrie M.Y. Kiang, Zhiyuan Zhu, Pingde Zhang, and Stephen Yin Cheng
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autophagy ,TUNEL assay ,Temozolomide ,Chemistry ,Autophagy ,quinacrine ,Caspase 3 ,Apoptosis ,02 engineering and technology ,temozolomide ,010402 general chemistry ,021001 nanoscience & nanotechnology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,01 natural sciences ,lcsh:RC254-282 ,0104 chemical sciences ,glioblastoma multiforme ,medicine ,Cancer research ,Cytotoxic T cell ,Viability assay ,0210 nano-technology ,Cytotoxicity ,medicine.drug - Abstract
Background: The alkylating agent temozolomide (TMZ) is widely used in glioblastoma multiforme (GBM) therapy. Unfortunately, TMZ-resistance frequently occurs in recurrent GBM and is the major cause of treatment failure. The anti-malarial drug quinacrine (QC) harbors antitumor and chemosensitivity properties, but its interactions with TMZ in GBM remain unclear. This study aimed to investigate whether QC would sensitize TMZ in TMZ-sensitive and TMZ-resistant GBM cells as well as the underlying mechanisms. Materials and Methods: The cytotoxicity of QC and TMZ in TMZ-sensitive and TMZ-resistant GBM cells was evaluated using in vitro cell viability assay and colony formation assay. Cellular apoptosis and protein expression levels were determined using TUNEL assay and immunoblotting, respectively. Results: QC substantially enhanced TMZ cytotoxicity in both TMZ-sensitive and TMZ-resistant cells. Such cytotoxic effect was accompanied by changes in the expression levels of LC3II, p62 and cleaved caspase 3, and increased cellular apoptosis. The results suggested that QC could sensitize GBM cells to TMZ at least partially through apoptosis induction, in which autophagy inhibition might be involved. Conclusion: The antimalarial drug QC may hold promise as a potentiation of TMZ treatment in GBM, especially in cases of TMZ-resistance.
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- 2018
34. An Exploratory Analysis of the Geographical Distribution of Trauma Incidents in Shenzhen, China
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Chung Mao Lo, Gilberto K.K. Leung, Jan O. Jansen, Hong Zhang, Joe K. M. Fan, Susan I. Brundage, Fion S. Chan, Yi Min Yu, and G. X. Zhang
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Adult ,Male ,China ,Emergency Medical Services ,Geographic Mapping ,Poison control ,Hospitals, Community ,Community Health Planning ,Occupational safety and health ,Hospitals, Private ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Trauma Centers ,Injury prevention ,Health care ,medicine ,Emergency medical services ,Cluster Analysis ,Humans ,030212 general & internal medicine ,Hospitals, Teaching ,Retrospective Studies ,business.industry ,Major trauma ,030208 emergency & critical care medicine ,medicine.disease ,Triage ,Community hospital ,Wounds and Injuries ,Female ,Surgery ,Medical emergency ,business - Abstract
The city of Shenzhen, China, is planning to establish a trauma system. At present, there are few data on the geographical distribution of incidents, which is key to deciding on the location of trauma centres. The aim of this study was to perform a geographical analysis in order to inform the development of a trauma system in Shenzhen. Retrospective analysis of trauma incidents attended by Shenzhen Emergency Medical Services (EMS) in 2014. Data were obtained from Shenzhen EMS. Incident distribution was explored using dot and kernel density estimate maps. Clustering was determined using the nearest neighbour index. The type of healthcare facilities which patients were taken to was compared against patients’ needs, as assessed using the Field Triage Decision Scheme. There were 49,082 recorded incidents. A total of 3513 were classed as major trauma. Mapping demonstrates that incidents predominantly occurred in the western part of Shenzhen, with identifiable clusters. Nearest neighbour index was 0.048. Of patients deemed to have suffered major trauma, 8.5% were taken to a teaching hospital, 13.6% to a regional hospital, 42.6% to a community hospital, and 35.3% to a private hospital. The proportions of Step 1 or 2 negative patients were almost identical. The majority of trauma patients, including trauma patients who are at greater likelihood of severe injury, are taken to regional and community hospitals. There are areas with identifiable concentrations of volume, which should be considered for the siting of high-level trauma centres, although further modelling is required to make firm recommendations.
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- 2017
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35. Rutin increases the cytotoxicity of temozolomide in glioblastoma via autophagy inhibition
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Derek Lee, Xiao-Qin Zhang, Stella Sun, Ming Wai Poon, Ning Li, Gilberto K.K. Leung, Pingde Zhang, Amy Suk Wai Ho, Jenny Kan-suen Pu, Yin Stephen Cheng, and Karrie M.Y. Kiang
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0301 basic medicine ,Cancer Research ,Cell Survival ,Rutin ,Mice, Nude ,Apoptosis ,Pharmacology ,Neuroprotection ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Autophagy ,Temozolomide ,medicine ,Animals ,Humans ,Viability assay ,Cytotoxicity ,Brain Neoplasms ,Drug Synergism ,Xenograft Model Antitumor Assays ,Dacarbazine ,030104 developmental biology ,Neurology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Neurology (clinical) ,Glioblastoma ,medicine.drug - Abstract
The chemotherapeutic agent temozolomide (TMZ) is widely used in the treatment of glioblastoma multiforme (GBM). Rutin, a citrus flavonoid ecglycoside found in edible plants, has neuroprotective and anticancer activities. This study aimed to investigate the efficacy and the underlying mechanisms of rutin used in combination with TMZ in GBM. In vitro cell viability assay demonstrated that rutin alone had generally low cytotoxic effect, but it enhanced the efficacy of TMZ in a dose-dependent manner. Subcutaneous and orthotopic xenograft studies also showed that tumor volumes were significantly lower in mice receiving combined TMZ/Rutin treatment as compared to TMZ or rutin alone treatment. Moreover, immunoblotting analysis showed that TMZ activated JNK activity to induce protective response autophagy, which was blocked by rutin, resulting in decreased autophagy and increased apoptosis, suggesting that rutin enhances TMZ efficacy both in vitro and in vivo via inhibiting JNK-mediated autophagy in GBM. The combination rutin with TMZ may be a potentially useful therapeutic approach for GBM patient.
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- 2017
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36. Surgical Outcome for Moyamoya Disease: Clinical and Perfusion Computed Tomography Correlation
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Angus Ka-Cheong Lam, Chun-pong Tsang, Gilberto K.K. Leung, Wai-Shing Wilson Ho, Raymond Lee, Anderson Chun On Tsang, Alvin K.H. Cheung, and Wai-Man Lui
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,Retrospective cohort study ,Superficial temporal artery ,medicine.disease ,030218 nuclear medicine & medical imaging ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,Cerebral blood flow ,Bypass surgery ,medicine.artery ,Middle cerebral artery ,medicine ,Neurology (clinical) ,Moyamoya disease ,business ,Stroke ,030217 neurology & neurosurgery - Abstract
Objectives To compare surgical outcome both radiologically and clinically after interventions for patients with Moyamoya disease. Methods This retrospective observational study included 25 patients who were treated surgically for Moyamoya disease in the past 14 years. Clinical outcomes were analyzed by subgroups stratified by age, disease presentation, and surgical intervention. Serial postoperative brain computed tomography perfusion records were analyzed with respect to the cerebral blood flow and cerebrovascular reserve capacity (CVRC) of the middle cerebral artery territory. Changes in both the intervention ( n = 23) and nonintervtion ( n = 9) cerebral hemispheres were compared. Results All children treated by synangiosis ( n = 9), all adults receiving synangiosis ( n = 5), and 88.9% of adults undergoing bypass ( n = 9) had no neurologic deterioration, with a duration of at least 50.6 months, 85.7 months, and 27.7 months, respectively. Radiologically, CVRC improved more markedly after bypass surgery than synangiosis, particularly 12–24 months postoperatively (51.1% vs. −2.86%). The hemispheres that did not undergo intervention showed similar improvement in cerebral blood flow over time compared with the hemispheres that did undergo intervention, after surgery was performed. Conclusions Bypass surgery improved CVRC greater than synangiosis, which may correlate with decreased future stroke risks. The decision for bypass is to be balanced with a greater risk of postoperative neurologic deterioration in adults after this procedure. The hemisphere that did not undergo intervention also appeared to benefit from surgery performed on the contralateral brain.
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- 2017
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37. HGG-27. ANTI-CANCER POTENTIAL OF ARGINASE FOR HIGH-GRADE GLIOMA IN VITRO & IN-VIVO
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Gilberto K.K. Leung, M K L Fung, Gcf Chan, Chan S, P D Zhang, and Stella Sun
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Cancer Research ,Programmed cell death ,Necrosis ,Temozolomide ,business.industry ,Cancer ,medicine.disease ,nervous system diseases ,Arginase ,Oncology ,Cell culture ,Glioma ,medicine ,Cancer research ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Neurology (clinical) ,medicine.symptom ,Cytotoxicity ,business ,High Grade Glioma ,neoplasms ,medicine.drug - Abstract
BACKGROUND High-grade glioma is currently incurable. It was reported that glioma may be auxotrophic to arginine due to the lack of urea cycle genes expressions, suggesting arginase may be a potential agent for high grade glioma. AIM: We investigated the efficacy of pegylated arginase I (pegArg-I) or in combination with other anti-cancer drugs for high-grade glioma in vitro and in vivo. METHODS 4 high-grade glioma cell lines (U87, U373, U138, D54) were treated with pegArg-I in vitro. The molecular mechanism of pegArg-I-induced cytotoxicity was tested in U87. The ultra-morphological changes of pegArg-I-treated U87 was investigated by both scanning and transmission electron microscopy. Orthotopic glioma xenograft model with luciferase-transfected U87 cell line was tested for anti-cancer efficacy of peg-Arg I in vivo. RESULTS We showed that pegArg-I induced significant cell death in all 4 cell lines in vitro. Temozolomide, difluoromethyornithine and chloroquine (CQ) were then tested together with pegArg-I in U87 in vitro. We found that only CQ showed additive effect with pegArg-I against glioma in vitro. Such additive cytotoxic effect may be associated with enhanced autophagy and necrosis as shown in transmission electron microscopy and autophagy markers’ expression by Western blotting. PegArg-I prolonged the survival of glioma mice, suggesting its possible anti-glioma efficacy. However, CQ+pegArg-I didn’t show further significant anti-cancer efficacy in vivo. CONCLUSION PegArg-I may be useful in slowing the progression of glioma, but additional drug candidate which works synergistically with pegArg-I remains to be explored.
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- 2020
38. Safe Conduct of Professional Examinations During the COVID-19 Pandemic in Hong Kong: A Descriptive Study
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Eric Mok, Patrick C. Y. Woo, Jessica Chiu, Janet Yuen Ha Wong, Fiona K. Y. Wong, Horace C.W. Choi, Gabriel M. Leung, Susanna K. P. Lau, Zoe Lai Han Ng, Gilberto K.K. Leung, Iva Hung, Vincent C.C. Cheng, Victor C. S. Lee, Julie Lau, Samson S. Y. Wong, and Kit Yan Tang
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medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,education ,Declaration ,Family medicine ,Pandemic ,medicine ,Basal body temperature ,Infection control ,Descriptive research ,business ,Cohort study ,Accreditation - Abstract
Background: Many medical schools and specialist accreditation bodies worldwide have cancelled or postponed professional examinations due to the COVID-19 pandemic. In Hong Kong, final-year medical students are not required to sit public examinations to qualify; rather rely on internal assessment. We therefore proceeded to administer all scheduled final-year statutory examinations during the months of April and May 2020. Methods: All 206 graduating medical students sat both written and objective structured clinical (OSCE) examinations under conditions of strict infection control, including self-reported health declaration forms (HDF), temperature screening and viral polymerase chain reaction (PCR) testing. Findings: Between 201 and 203 students who submitted a clean HDF were permitted to attend the examination venues. Fifteen (7·3%) students were found to have a tympanic temperature of ≥37·5°C on April 1, 2020, but their posterior oropharyngeal saliva samples taken on the same day were COVID-19 PCR-negative. Another 2 and 1 students were found to have a temperature ≥37·5°C on April 3, 2020 and April 9, 2020 respectively, but who were also tested COVID-19 PCR-negative. The tympanic temperatures of these 18 candidates were significantly higher than the rest throughout all examination days of the written (p≤0·0014) and OSCE (p≤0·039) examinations (except on April 15, 2020), suggestive of a higher basal body temperature. All staff members and participating patients with close contacts with the candidates/staff were free from COVID-19 before and after all examinations, up to 14 days post hoc. Interpretation: Rigorous clinical professional examinations could be safely conducted during the COVID-19 pandemic provided stringent infection control measures were followed. The choice of body temperature cutoff could significantly impact the assessment process for which we propose a number of mitigating measures for future reference. Funding Statement: None Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This cohort study was approved by HKUMed and designed by the investigators.
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- 2020
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39. Prevalence of Burnout in Medical and Surgical Residents: A Meta-Analysis
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Cyrus S.H. Ho, Gilberto K.K. Leung, Long H. Nguyen, Vivek Sharma, Wilson W.S. Tam, Zhi Xuan Low, Brett Y. Lu, Chun Chiang Sin Fai Lam, Roger C.M. Ho, Keith A. Yeo, Roger S. McIntyre, Anthony P. S. Guerrero, and Bach Xuan Tran
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Health, Toxicology and Mutagenesis ,education ,prevalence ,Specialty ,Prevalence ,lcsh:Medicine ,Subgroup analysis ,Review ,Burnout ,Burnout, Psychological ,medical ,03 medical and health sciences ,0302 clinical medicine ,Primary outcome ,surgical ,Depersonalization ,medicine ,Humans ,030212 general & internal medicine ,Emotional exhaustion ,Burnout, Professional ,Occupational Health ,burnout ,junior doctors ,business.industry ,lcsh:R ,Public Health, Environmental and Occupational Health ,Internship and Residency ,meta-analysis ,Meta-analysis ,medicine.symptom ,business ,residency ,030217 neurology & neurosurgery ,Demography - Abstract
The burnout syndrome is characterized by emotional exhaustion, depersonalization, and reduced personal achievement. Uncertainty exists about the prevalence of burnout among medical and surgical residents. Associations between burnout and gender, age, specialty, and geographical location of training are unclear. In this meta-analysis, we aimed to quantitatively summarize the global prevalence rates of burnout among residents, by specialty and its contributing factors. We searched PubMed, PsycINFO, Embase, and Web of Science to identify studies that examined the prevalence of burnout among residents from various specialties and countries. The primary outcome assessed was the aggregate prevalence of burnout among all residents. The random effects model was used to calculate the aggregate prevalence, and heterogeneity was assessed by I2 statistic and Cochran’s Q statistic. We also performed meta-regression and subgroup analysis. The aggregate prevalence of burnout was 51.0% (95% CI: 45.0−57.0%, I2 = 97%) in 22,778 residents. Meta-regression found that the mean age (β = 0.34, 95% CI: 0.28−0.40, p < 0.001) and the proportion of males (β = 0.4, 95% CI = 0.10−0.69, p = 0.009) were significant moderators. Subgroup analysis by specialty showed that radiology (77.16%, 95% CI: 5.99−99.45), neurology (71.93%, 95% CI: 65.78−77.39), and general surgery (58.39%, 95% CI: 45.72−70.04) were the top three specialties with the highest prevalence of burnout. In contrast, psychiatry (42.05%, 95% CI: 33.09−51.58), oncology (38.36%, 95% CI: 32.69−44.37), and family medicine (35.97%, 95% CI: 13.89−66.18) had the lowest prevalence of burnout. Subgroup analysis also found that the prevalence of burnout in several Asian countries was 57.18% (95% CI: 45.8−67.85); in several European countries it was 27.72% (95% CI: 17.4−41.11) and in North America it was 51.64% (46.96−56.28). Our findings suggest a high prevalence of burnout among medical and surgical residents. Older and male residents suffered more than their respective counterparts.
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- 2019
40. Burden of large vessel occlusion stroke and the service gap of thrombectomy: A population-based study using a territory-wide public hospital system registry
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Philip L. H. Yu, Anderson Chun On Tsang, Lai Fung Li, Gilberto K.K. Leung, Jia You, Eva L. H. Tsui, Frederick Chun Pong Tsang, and Pauline P. S. Woo
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Health Services Accessibility ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Sex Factors ,medicine ,Humans ,Registries ,Stroke ,Aged ,Ischemic Stroke ,Thrombectomy ,Service (business) ,Aged, 80 and over ,business.industry ,Incidence (epidemiology) ,Age Factors ,Length of Stay ,Middle Aged ,medicine.disease ,Population based study ,Neurology ,Public hospital ,Emergency medicine ,Ischemic stroke ,Hong Kong ,Female ,business ,030217 neurology & neurosurgery ,Large vessel occlusion - Abstract
Background Ischemic stroke due to large vessel occlusion can be effectively treated with thrombectomy but access to this treatment is limited in many parts of the world. Local incidence of large vessel occlusion is critical in determining the development of thrombectomy service, but reliable data from Asian countries are lacking. Aims We performed a population-based study to estimate the burden of large vessel occlusion and the service gap for thrombectomy in Hong Kong. Methods All acute ischemic stroke patients admitted in 2016 to the public healthcare system, which provided 90% of the emergency healthcare in the city, was identified from the Hong Kong Hospital Authority’s central electronic database. The diagnosis of large vessel occlusion was retrospectively verified by two independent cerebrovascular specialists in a randomly sampled cohort based on clinical and neuroimaging data. The incidence of large vessel occlusion in the population was estimated through weighting the sample results and compared with the thrombectomy data in the same period. Results There were 6859 acute ischemic stroke patients treated in the public health system in 2016. Amongst the 300 patients randomly sampled according to diagnosis coding, 130 suffered from anterior circulation large vessel occlusion. This translated to 918 patients (95% CI 653–1180) and 13.3% of all ischemic stroke patients. The estimated incidence of anterior circulation large vessel occlusion was 12.5 per 100,000 persons per year (95% CI 11.7–13.4). Large vessel occlusion stroke patients were more commonly female than male (67.4% vs. 31.6%, p = 0.003), and were older than non-large vessel occlusion stroke patients (mean of 80.5 years vs. 71.4 years, p = Conclusion The estimated incidence of anterior circulation large vessel occlusion in the Hong Kong Chinese population is lower than that in the West. There is however a substantial service gap for endovascular thrombectomy with less than 10% of large vessel occlusion patients receiving thrombectomy.
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- 2019
41. Abstract 2484: Detection of loss of heterozygosity in GBM revealed the role of a tumor suppressive gene in regulating glioma progression and tumor recurrence
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Gilberto K.K. Leung, Mei-Yee Kiang, and Stella Sun
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Loss of heterozygosity ,Cancer Research ,Oncology ,Glioma ,medicine ,Cancer research ,Biology ,medicine.disease ,Gene ,Tumor recurrence - Abstract
Adducin 3 (ADD3) is a major cytoskeleton protein in glioma cells. Our previous studies demonstrated a significant downregulation of ADD3 in GBM when compared with lower-grade gliomas, and that ADD3 knockdown promoted malignant phenotypes. GBMs are usually characterized by high levels of genomic instability, including frequent loss of heterozygosity (LOH) of chromosome 10q, whilst ADD3 is also located in chromosome 10q25.1-25.2 where it is known to be a tumor-suppressor region. However, it is not known whether ADD3 downregulation in malignant gliomas is associated with allelic loss in 10q. To determine 10q LOH on different polymorphic DNA loci (covering ADD3 locus) on glioma tissues, specimens of Normal, Grade II, Grade III, Grade IV GBM and recurrent GBM tissue were included. DNA fragments were evaluated by using a PCR-based microsatellite capillary electrophoresis and analyzed by a fragment analyzer. LOH status were correlated with patient survival for potential prognostic and diagnostic implications. LOH on ADD3 locus was detected in high grade and recurrent GBMs. It is revealed that downregulation of ADD3 level in GBM is associated with genetic instability of LOH in 10q and associated with recurrence disease. This study would provide significant implications, particularly for understanding pathogenesis of GBM and add valuable credits on the diagnostic as well as prognostic implications. Citation Format: Mei-Yee Kiang, Stella Sun, Gilberto Ka-Kit Leung. Detection of loss of heterozygosity in GBM revealed the role of a tumor suppressive gene in regulating glioma progression and tumor recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2484.
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- 2021
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42. In Reply to the Letter to the Editor Regarding 'Repair of Anterior Skull Base Defect by Dual-Layer/Split-Frontal Pericranial Flap'
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Gilberto K.K. Leung and Lai-Fung Li
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Skull Base ,Letter to the editor ,business.industry ,Humans ,Dual layer ,Medicine ,Surgery ,Neurology (clinical) ,Anatomy ,business ,Surgical Flaps ,Anterior skull base - Published
- 2021
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43. Global surgery: A new agenda item for surgical training and professional partnership
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Gilberto K.K. Leung
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03 medical and health sciences ,Medical education ,0302 clinical medicine ,business.industry ,030220 oncology & carcinogenesis ,Medicine ,Surgery ,030212 general & internal medicine ,business ,Surgical training ,Professional partnership - Published
- 2017
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44. A joint computational-experimental study of intracranial aneurysms: Importance of the aspect ratio
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Gilberto K.K. Leung, Alfred C. H. Yu, Abraham Yik-Sau Tang, Kwok Wing Chow, Simon S. M. Lai, and Anderson Chun On Tsang
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Jet (fluid) ,Subarachnoid hemorrhage ,Materials science ,Mechanical Engineering ,0206 medical engineering ,Hemodynamics ,02 engineering and technology ,Blood flow ,Mechanics ,Condensed Matter Physics ,medicine.disease ,020601 biomedical engineering ,01 natural sciences ,Aspect ratio (image) ,010305 fluids & plasmas ,Aneurysm ,Mechanics of Materials ,Modeling and Simulation ,0103 physical sciences ,medicine ,Shear stress ,Joint (geology) - Abstract
Rupture of a cerebral aneurysm (abnormal swelling of blood vessel in the brain) will cause subarachnoid hemorrhage, and will result in an alarming rate of mortality and morbidity. A joint computational-experimental study is conducted to assess the importance of the aspect ratio in the dynamics of blood flow. The aspect ratio is defined here to be the ratio of the height of the aneurysm to the linear dimension of the neck. Idealized models of such aneurysms located near a bifurcation point were investigated. Numerical simulations for hemodynamic properties like shear stress and flow rate were performed. The computational results were verified experimentally with specially fabricated phantoms, blood mimicking fluid and Doppler ultrasound imaging. Excellent agreements were obtained. Two features are highlighted, providing information in the intensely debated link between rupture risk and geometric factors. On increasing the aspect ratios, firstly, a jet impinging on the distal part of the neck can be observed, and secondly, a region of positive shear stress gradient can be found there. Furthermore, computational analyses for four patient-specific models were conducted to correlate with the results of idealized models and to provide further clinical insight.
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- 2016
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45. Sacral Nerve Stimulation for Neurogenic Bladder
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Gilberto K.K. Leung, Lai-Fung Li, and Wai-Man Lui
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Nervous system ,medicine.medical_specialty ,Nerve root ,media_common.quotation_subject ,Urinary Bladder ,030232 urology & nephrology ,Urology ,urologic and male genital diseases ,Urination ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Urinary Bladder, Neurogenic ,Spinal cord injury ,media_common ,Spinal Cord Stimulation ,Evidence-Based Medicine ,Urinary bladder ,business.industry ,Urinary retention ,Multiple sclerosis ,Equipment Design ,medicine.disease ,Treatment Outcome ,medicine.anatomical_structure ,Surgery ,Neurology (clinical) ,medicine.symptom ,Spinal Nerve Roots ,business ,Detrusor sphincter dyssynergia ,030217 neurology & neurosurgery - Abstract
Background Neurogenic bladder refers to dysfunction of the urinary bladder secondary to diseases of the nervous system that result in problems with urine storage, micturition, or both. The most common causes are multiple sclerosis and spinal cord injury. Patients commonly present with recurrent UTIs, obstructive uropathies, and urinary retention. Without proper treatment, neurogenic bladder may result in nephropathy and renal failure, both of which have a significant negative impact on the health and life expectancy of patients. Restoration of lost neural function using artificial stimulators is a feasible therapeutic strategy. This article reviews the pathophysiology of neurogenic bladder and the 2 most commonly employed sacral nerve stimulation methods—the Brindley procedure and sacral neuromodulation.
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- 2016
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46. Botulinum toxin injection and rehabilitation for neurosurgical patients with spasticity
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Benedict Beng-teck Taw, Gilberto K.K. Leung, Michael Ka‐Wing See, Linda Yuk‐Ying Chan, Terrence Wing‐Cheung Kwong, Shuk Man Lo, Wai-Man Lui, and Edward Man‐Tai Chan
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030506 rehabilitation ,medicine.medical_specialty ,Activities of daily living ,Rehabilitation ,business.industry ,medicine.medical_treatment ,Modified Ashworth scale ,Caregiver burden ,Botulinum toxin ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine.anatomical_structure ,medicine ,Physical therapy ,Surgery ,Spasticity ,Neurosurgery ,medicine.symptom ,Ankle ,0305 other medical science ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Aim Spasticity gives rise to impairment in motor functions and activities of daily living. Botulinum toxin (BTX) can be injected to temporarily paralyze the affected muscles, which provides a window of opportunity for rehabilitation. We present our 2.5-year experience with BTX injection and a patient-specific rehabilitation program provided by a multidisciplinary team, which consists of neurosurgeons, nurses, physiotherapists, occupational therapists and prosthetic orthotists. Patients and Methods This is a retrospective study of prospectively collected data in a local hospital including 22 patients suffering from spasticity. Outcome measures include goal attainment, caregiver burden and biomechanical assessment by Modified Ashworth Scale and Modified Tardieu Scale (MTS). Results OnabotulinumtoxinA injection together with rehabilitation facilitates the attainment of patient-centred physical goals in daily activities. It reduces caregiver burden. Spasticity is reduced particularly for finger and wrist flexors as well as hip adductors. Responses of ankle plantarflexors are less satisfactory which may be due to inadequate dosages. Initial improvement in the R2 component of the MTS for ankle plantarflexors and hip adductors may be attributable to the application of ankle–foot orthosis and abduction pillow. Conclusions Multidisciplinary management for spasticity is feasible within our healthcare setting and our promising findings indicate its wider adoption in this locality.
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- 2016
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47. Correlating Hemodynamic Changes and Occlusion Time after Flow Diverter Treatment of Bilateral Large Internal Carotid Artery Aneurysms
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Wai Choi Chung, Anderson Chun On Tsang, Abraham Yik-Sau Tang, Gilberto K.K. Leung, and Kwok Wing Chow
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Adult ,Carotid Artery Diseases ,Male ,medicine.medical_specialty ,Computed Tomography Angiography ,Magnetic resonance angiography ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Aneurysm ,Blood vessel prosthesis ,medicine.artery ,Image Interpretation, Computer-Assisted ,Occlusion ,medicine ,Humans ,Computer Simulation ,Radiology, Nuclear Medicine and imaging ,cardiovascular diseases ,Computed tomography angiography ,Cerebral Revascularization ,medicine.diagnostic_test ,business.industry ,Models, Cardiovascular ,Intracranial Aneurysm ,medicine.disease ,Blood Vessel Prosthesis ,Cerebral Angiography ,Treatment Outcome ,Cavernous sinus ,cardiovascular system ,Neurology (clinical) ,Radiology ,Internal carotid artery ,business ,Magnetic Resonance Angiography ,030217 neurology & neurosurgery ,Cerebral angiography - Abstract
A middle-aged lady in good health presented right abducens nerve palsy. Magnetic resonance imaging (MRI) of the brain showed bilateral cavernous ICA aneurysms. The left aneurysm measured 9 × 7 mm whereas the right aneurysm measured 22 × 15 mm, with mass effect on the cavernous sinus, explaining her symptoms (Fig. 1). Both were wide-neck aneurysms and were treated with PED alone sequentially, 3 months apart. She was loaded with Aspirin 300 mg and Clopidogrel 300 mg before treatment, with Aspirin continuing for 6 months and Clopidogrel for 3 months afterwards. There were no procedural complications. Digital subtraction angiogram at 1 year showed that the left aneurysm was completely occluded, whereas the right aneurysm had partially thrombosed but with a persistent filling. The right aneurysm persisted on CT angiogram at 2 years but with significant shrinkage and finally occluded at a 3-year follow-up (Fig. 2). The patient’s diplopia gradually improved after 3 years.
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- 2016
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48. Clinical significance of CRNDE transcript variants in glioblastoma multiforme
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Gilberto K.K. Leung and Karrie M.Y. Kiang
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0301 basic medicine ,lcsh:QH426-470 ,Biology ,Bioinformatics ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,CRNDE ,Genetics ,medicine ,Tumor growth ,Clinical significance ,Molecular Biology ,Transcript variant ,Oncogene ,Biochemistry (medical) ,RNA ,medicine.disease ,Long non-coding RNA ,nervous system diseases ,lcsh:Genetics ,030104 developmental biology ,030220 oncology & carcinogenesis ,Potential biomarkers ,Cancer research ,Glioblastoma - Abstract
The long non-coding RNA CRNDE is an oncogene that promotes tumor growth in glioblastoma multiforme (GBM). At least five CRNDE transcript variants with possibly different functional roles have been described in recent studies. Here, we report our preliminary findings on the differential expressions of CRNDE transcript variants in GBM, and their prognostic significance. Our preliminary data suggest that different transcript variants of CRNDE might have different functions in GBM and should be further studied as potential biomarkers for clinical prognostication. Keywords: Long non-coding RNA, CRNDE, Transcript variant, Glioblastoma
- Published
- 2017
- Full Text
- View/download PDF
49. Montgomery means business and is doing it here
- Author
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Gilberto K.K. Leung
- Subjects
business.industry ,Medicine ,Surgery ,business ,Management - Published
- 2020
- Full Text
- View/download PDF
50. Successful Emergency Rescue Open Embolectomy for Failed Endovascular Thrombectomy in Acute Ischemic Stroke: 2-Dimensional Operative Video
- Author
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David Yuen Chung Chan, Wai Shing Ho, Frederick Chun Pong Tsang, Wai-Man Lui, Anderson Chun On Tsang, Gilberto K.K. Leung, and Lai Fung Li
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Embolectomy ,Arteriotomy ,Brain Ischemia ,chemistry.chemical_compound ,Occlusion ,medicine ,Humans ,Stroke ,Craniotomy ,Ischemic Stroke ,Thrombectomy ,business.industry ,Standard treatment ,Atrial fibrillation ,Middle Aged ,medicine.disease ,United States ,Surgery ,chemistry ,Female ,Neurology (clinical) ,business ,Indocyanine green - Abstract
This operative video demonstrates an open surgical thrombectomy for a 61-yr-old woman with failed endovascular embolectomy in acute ischemic stroke. Good functional outcome can be achieved when this operation is timely performed within the therapeutic window. This patient has atrial fibrillation. She was admitted for sudden onset of left-sided hemiplegia and aphasia. National Institutes of Health Stroke Scale (NIHSS) was 20/42 before the operation. Computed tomography (CT) cerebral angiogram showed right internal cerebral artery (ICA) occlusion from the cervical portion. Urgent intra-arterial (IA) thrombectomy was started 2 h after symptom onset, but failed despite the use of a stentriver and a large-bore aspiration catheter together. Emergency rescue open thrombectomy was performed with right pterional craniotomy 6 h after symptom onset. Sylvian fissure was dissected to expose the supraclinoid ICA, ICA bifurcation, A1, and M1. A transverse arteriotomy was made at the ICA bifurcation and open surgical thrombectomy was performed. Reperfusion was established in 86 min after skin incision. Intraoperative indocyanine green video-angiography showed patent flow over ICA bifurcation to M1 and A1. She had a good recovery with the return of the left-sided power and was discharged home. At 2-mo postoperative assessment, she was able to walk unaided independently. The modified Barthel Index (BI) was 74/100. Her activity of daily living was independent. We must emphasize IA thrombectomy is the standard treatment, and the role of open surgery remains a potential rescue procedure. Good functional outcome can be achieved when emergency rescue open thrombectomy is performed within the therapeutic window.
- Published
- 2018
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