Publications by authors named "Kit Man Wong"

25 Publications

  • Page 1 of 1

Untangling the Multidisciplinary Care Web: Streamlining Care Through an Immune-Related Adverse Events (IRAE) Tumor Board.

Target Oncol 2020 08;15(4):541-548

Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA.

Immune-related adverse events (IRAEs) are becoming increasingly common as the use of immune checkpoint inhibitors expands into more tumor types and treatment settings. Although the majority of IRAEs are mild and can be managed in the outpatient setting by the medical oncologist, severe IRAEs can be life threatening and often require complex care coordination among multiple providers. These providers include a variety of non-oncology specialists who have interest and expertise in managing IRAEs. Multiple systems-based solutions have been proposed in the literature, but these need to be tailored to the needs and resources of each practice setting. In this article, we highlight the challenges of IRAE care by presenting an illustrative case from our institution. We then describe the format and structure of the IRAE Tumor Board established at the University of Washington/Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center. Finally, we discuss how this tumor board attempts to address clinical issues related to complex IRAE presentations and provide IRAE education.
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http://dx.doi.org/10.1007/s11523-020-00739-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489785PMC
August 2020

Investigating the Impact of Geographic Location on Colorectal Cancer Stage at Diagnosis: A National Study of the SEER Cancer Registry.

J Rural Health 2020 06 27;36(3):316-325. Epub 2019 Aug 27.

WWAMI Rural Health Research Center, Department of Family Medicine, University of Washington School of Medicine, Seattle, WA.

Background: Early detection of colorectal cancer (CRC) is associated with decreased mortality and potential avoidance of chemotherapy. CRC screening rates are lower in rural communities and patient outcomes are poorer. This study examines the extent to which United States' rural residents present at a more advanced stage of CRC compared to nonrural residents.

Methods: Using the 2010-2014 Surveillance, Epidemiology and End Results Incidence data, 132,277 patients with CRC were stratified using their county of residence and urban influence codes into 5 categories (metro, adjacent micropolitan, nonadjacent micropolitan, small rural, and remote small rural). Logistic regression was used to investigate the relationship between late stage at diagnosis and county-level characteristics including level of rurality, persistent poverty, low education and low employment, and patient characteristics.

Results: In the adjusted analysis the rate of stage 4 CRC at diagnosis differed across geographic classification, with patients living in remote small rural counties having the highest rate of stage 4 disease (range: 19.2% in nonadjacent micropolitan counties to 22.7% in remote small rural counties). Other factors, such as patient characteristics, insurance status, and regional practice variation were also significantly associated with late-stage CRC diagnosis.

Conclusions: Geographic residence is associated with the rate of stage 4 disease at presentation. Additional patient factors are associated with stage 4 CRC disease at diagnosis. Cancer outcomes are worse for rural patients, and late stage at diagnosis may partially account for this disparity. These differences have persisted over time and suggest areas for further research, patient engagement, and education.
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http://dx.doi.org/10.1111/jrh.12392DOI Listing
June 2020

Biomarker-Driven and Molecular Targeted Therapies for Hepatobiliary Cancers.

Semin Oncol 2018 06 16;45(3):116-123. Epub 2018 Mar 16.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Medical College at Cornell University, New York, NY. Electronic address:

The recent accumulation of molecular profiling data for primary hepatobiliary malignancies, including hepatocellular carcinoma and biliary tract cancers, has led to a proliferation of promising therapeutic investigations in recent years. Treatment with pathway-specific targeted inhibitors and immunotherapeutic agents have demonstrated promising early clinical results. Key molecular alterations in common hepatobiliary cancers and ongoing interventional clinical trials of molecularly targeted systemic agents focusing on hepatocellular carcinoma and biliary tract cancer are reviewed.
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http://dx.doi.org/10.1053/j.seminoncol.2018.03.002DOI Listing
June 2018

Phase I study of the anti-α5β1 monoclonal antibody MINT1526A with or without bevacizumab in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2018 08 15;82(2):339-351. Epub 2018 Jun 15.

California Cancer Associates for Research & Excellence, Encinitas, CA, USA.

Purpose: MINT1526A is a monoclonal antibody that blocks the interaction of integrin alpha 5 beta 1 (α5β1) with its extracellular matrix ligands. This phase I study evaluated the safety and pharmacokinetics of MINT1526A with or without bevacizumab in patients with advanced solid tumors.

Methods: MINT1526A was administered every 3 weeks (Q3W) as monotherapy (arm 1) or in combination with bevacizumab 15 mg/kg, Q3W (arm 2). Each arm included a 3 + 3 dose-escalation stage and a dose-expansion stage.

Results: Twenty-four patients were enrolled in arm 1 (dose range 2-30 mg/kg) and 30 patients were enrolled in arm 2 (dose range 3-15 mg/kg). Monocyte α5β1 receptor occupancy was saturated at a dose of 15 mg/kg. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached in either arm. The most common adverse events, regardless of causality, included abdominal pain (25%), diarrhea (25%), nausea (21%), vomiting (21%), and fatigue (21%) in arm 1 and nausea (40%), fatigue (33%), vomiting (30%), dehydration (30%), headache (30%), and hypertension (30%) in arm 2. No grade ≥ 3 bleeding events were observed in either arm. No confirmed partial responses (PR) were observed in arm 1. In arm 2, one patient with thymic carcinoma experienced a confirmed PR and two patients with hepatocellular carcinoma (HCC) experienced durable minor radiographic responses.

Conclusions: MINT1526A, with or without bevacizumab, was well-tolerated. Preliminary evidence of combination efficacy, including in patients with HCC, was observed, but cannot be distinguished from bevacizumab monotherapy in this phase I study.
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http://dx.doi.org/10.1007/s00280-018-3622-8DOI Listing
August 2018

Targeting the Tumor Stroma: the Biology and Clinical Development of Pegylated Recombinant Human Hyaluronidase (PEGPH20).

Curr Oncol Rep 2017 Jul;19(7):47

Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.

The tumor stroma is increasingly recognized as a key player in tumorigenesis through its effects on cell signaling, immune responses, and access of therapeutic agents. A major component of the extracellular matrix is hyaluronic acid (HA), which raises the interstitial gel fluid pressure within tumors and reduces drug delivery to malignant cells, and has been most extensively studied in pancreatic ductal adenocarcinoma (PDA). Pegylated recombinant human hyaluronidase (PEGPH20) is a novel agent that degrades HA and normalizes IFP to enhance the delivery of cytotoxic agents. It has demonstrated promising preclinical results and early clinical evidence of efficacy in the first-line treatment of metastatic PDA with acceptable tolerability. Moreover, intratumoral HA content appears to be a predictive biomarker of response. Phase 2 and 3 trials of PEGPH20 plus chemotherapy are ongoing in metastatic PDA, and it is also being evaluated in other malignancies and in combination with radiation and immunotherapy.
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http://dx.doi.org/10.1007/s11912-017-0608-3DOI Listing
July 2017

Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924).

Invest New Drugs 2017 02 25;35(1):11-25. Epub 2016 Oct 25.

Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.

Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models. Gene expression microarray and gene set enrichment analyses were performed in cell lines to determine the expression profiles and pathways of sensitivity/resistance. Pharmacodynamic changes in treated-PDTX were also characterized. Results Pevonedistat effectively inhibited cell viability (IC < 0.3 μM) and induced apoptosis in a subset of melanoma cell lines. Sensitive and resistant cell lines exhibited distinct gene expression profiles; sensitive models were enriched for genes involved in DNA repair, replication and cell cycle regulation, while immune response and cell adhesion pathways were upregulated in resistant models. Pevonedistat also reduced tumor growth in melanoma cell line xenografts and PDTX with variable responses. An accumulation of pevonedistat-NEDD8 adduct and CDT1 was observed in sensitive tumors consistent with its mechanism of action. Conclusions This study provided preclinical evidence that NAE inhibition by pevonedistat has anti-tumor activity in melanoma and supports the clinical benefits observed in recent Phase 1 trials of this drug in melanoma patients. Further investigations are warranted to develop rational combinations and determine predictive biomarkers of pevonedistat.
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http://dx.doi.org/10.1007/s10637-016-0398-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296256PMC
February 2017

A Cost-Effectiveness Analysis of Using the JBR.10-Based 15-Gene Expression Signature to Guide Adjuvant Chemotherapy in Early Stage Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2017 01 9;18(1):e41-e47. Epub 2016 Jul 9.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Electronic address:

Background: Adjuvant chemotherapy (ACT) improved survival in the NCIC Clinical Trials Group JBR.10 trial of resected stage IB/II non-small-cell lung cancer. A prognostic 15-gene expression signature was developed, which may also predict for benefit from ACT. An exploratory economic analysis was conducted to assess the potential cost-effectiveness of using the 15-gene signature in guiding ACT decisions.

Methods: A decision analytic model was populated by study patients with quantitative reverse transcription polymerase chain reaction tumor profiling, current costs, and quality-adjusted survival. Analysis was performed over the 6-year follow-up from the perspective of the Canadian public health care system in 2015 Canadian dollars (discounted 5%/year). Incremental cost-effectiveness and cost-utility ratios were determined for ACT versus observation using clinical stage, gene signature, or a combined approach to select treatment.

Results: The mean survival gain of ACT versus observation was higher using the gene signature (1.86 years) compared with clinical stage (1.28 years). Although more costly, ACT guided by the gene signature remained cost-effective at $10,421/life-year gained (95% confidence interval [CI], $466-$19,568 Canadian), comparable to stage-directed selection ($7081/life-year gained; 95% CI, -$2370 to $14,721; P = .52). Incremental cost-utility ratios were $13,452/quality-adjusted life-year (95% CI, $373-$31,949) and $9194/quality-adjusted life-year (95% CI, -$4104 to $23,952), respectively (P = .53). Comparing the standard and test-and-treat approaches, use of the gene signature did not significantly alter survival compared with the standard strategy, but it reduced the ACT rate by 25%.

Conclusion: If validated, the use of the 15-gene expression signature to select patients for ACT may increase the survival gain of treatment in patients with high-risk stage IB/II non-small-cell lung cancer, while avoiding toxicities in low-risk patients.
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http://dx.doi.org/10.1016/j.cllc.2016.06.009DOI Listing
January 2017

Validation of a robust PCR-based assay for quantifying fragile X CGG repeats.

Clin Chim Acta 2016 May 3;456:137-143. Epub 2016 Mar 3.

Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, Hong Kong Special Administrative Region; CUHK-Utrecht University Joint Center of Language, Mind and Brain Genetics Core, Hong Kong Special Administrative Region; Angsana Molecular & Diagnostics Laboratory (HK) Ltd., Hong Kong Special Administrative Region. Electronic address:

Background: Sizing of FMR1 trinucleotide repeats in the clinical laboratory requires the use of capillary sequencer by PCR, or by a labor intensive measurement using Southern blot method. Our aim was to validate an accurate and robust PCR assay for quantification of CGG repeats.

Methods: We performed an analytical and clinical validation of a new PCR-based method that utilizes a low-cost capillary electrophoresis instrument and the FragilEase™ reagent kit. First, analytical performance was demonstrated on 12 Coriell reference samples comprising normal through full mutations. Subsequently, a cohort of 112 archived clinical DNA samples, enriched for premutation and full mutations, was analyzed.

Results: All samples were amplified successfully. Quantification of repeat numbers was interpreted by the use of standards with known repeats. Twenty-five full-mutation samples were successfully amplified with the largest allele size measured at 1380 repeats. The repeat numbers from the new assay were concordant with those obtained with the reference method. The intra-assay (CV<2.5%) and inter-assay imprecision was within 1 CGG repeat.

Conclusion: This new PCR-based method is reproducible and capable of identifying all Fragile X alleles. It is an accurate and robust method that facilitates Fragile X testing in a broader spectrum of clinical laboratories.
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http://dx.doi.org/10.1016/j.cca.2016.02.027DOI Listing
May 2016

The changing landscape of phase I trials in oncology.

Nat Rev Clin Oncol 2016 Feb 10;13(2):106-17. Epub 2015 Nov 10.

Developmental Therapeutics Program, University of Colorado Cancer Center, Division of Medical Oncology/Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.

Advances in our knowledge of the molecular pathogenesis of cancer have led to increased interest in molecularly targeted agents (MTAs), which target specific oncogenic drivers and are now a major focus of cancer drug development. MTAs differ from traditional cytotoxic agents in various aspects, including their toxicity profiles and the potential availability of predictive biomarkers of response. The landscape of phase I oncology trials is evolving to adapt to these novel therapies and to improve the efficiency of drug development. In this Review, we discuss new strategies used in phase I trial design, such as novel dose-escalation schemes to circumvent limitations of the classic 3 + 3 design and enable faster dose escalation and/or more-precise dose determinations using statistical modelling; improved selection of patients based on genetic or molecular biomarkers; pharmacokinetic and pharmacodynamic analyses; and the early evaluation of efficacy - in addition to safety. Indeed, new expedited approval pathways that can accelerate drug development require demonstration of efficacy in early phase trials. The application of molecular tumour profiling for matched therapy and the testing of drug combinations based on a strong biological rationale are also increasingly seen in phase I studies. Finally, the shift towards multi-institutional trials and centralized study management results in consequent implications for institutions and investigators. These issues are also highlighted herein.
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http://dx.doi.org/10.1038/nrclinonc.2015.194DOI Listing
February 2016

A comparison of parecoxib and thoracic epidural analgesia for postoperative analgesia following Nuss procedure.

J Pediatr Surg 2015 Dec 28;50(12):2032-4. Epub 2015 Aug 28.

Department of Pediatric Surgery, Chang Gung Children's Hospital, Chang Gung University College of Medicine, Linkou, Taiwan. Electronic address:

Background: The purpose of this study was to compare the results of thoracic epidural analgesia (TEA) and parecoxib in controlling postoperative pain after the Nuss procedure.

Methods: Between August 2005 and July 2014, 120 adolescents and adults underwent Nuss procedures and received either TEA or parecoxib for postoperative pain control. Demographic data, preoperative preparation times, visual analog scale (VAS) pain scores from postoperative day 1 to day 5, medical costs of pain control, days to Foley catheter removal, days to being able to sit up, days to being able to walk, days of hospital stay, nausea/vomiting scores, and complications related to pain control were compared.

Results: A total of 106 patients received TEA, and 14 received parecoxib. No between-group differences in demographics were observed. Patients in the parecoxib group had shorter preparation times (p<0.001), lower VAS pain scores from postoperative day 2 to day 5 (day 2, p=0.006; day 3, p=0.006; day 4, p<0.001; day 5, p<0.001), shorter hospital stays (p<0.001), lower pain control costs (p<0.001), and lower nausea/vomiting scores (p=0.046).

Conclusions: For adolescents and adults undergoing the Nuss procedure, parecoxib affords better pain control efficacy, a shorter hospital stay, lower medical pain control costs, and fewer side effects compared with TEA.
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http://dx.doi.org/10.1016/j.jpedsurg.2015.08.020DOI Listing
December 2015

The changing landscape of phase I trials in oncology.

Am Soc Clin Oncol Educ Book 2015 :3-8

From the Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.

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http://dx.doi.org/10.14694/EdBook_AM.2015.35.3DOI Listing
February 2016

Two BRM promoter insertion polymorphisms increase the risk of early-stage upper aerodigestive tract cancers.

Cancer Med 2014 Apr 12;3(2):426-33. Epub 2014 Feb 12.

Department of Medical Oncology, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada.

Brahma (BRM) has a key function in chromatin remodeling. Two germline BRM promoter insertion-deletion polymorphisms, BRM-741 and BRM-1321, have been previously associated with an increased risk of lung cancer in smokers and head and neck cancer. To further evaluate their role in cancer susceptibility particularly in early disease, we conducted a preplanned case-control study to investigate the association between the BRM promoter variants and stage I/II upper aerodigestive tract (UADT) cancers (i.e., lung, esophageal, head and neck), a group of early-stage malignancies in which molecular and genetic etiologic factors are poorly understood. The effects of various clinical factors on this association were also studied. We analyzed 562 cases of early-stage UADT cancers and 993 matched healthy controls. The double homozygous BRM promoter variants were associated with a significantly increased risk of early stage UADT cancers (adjusted odds ratio [aOR], 2.46; 95% confidence interval [CI], 1.7-3.8). This association was observed in lung (aOR, 2.61; 95% CI, 1.5-4.9) and head and neck (aOR, 2.75; 95% CI, 1.4-5.6) cancers, but not significantly in esophageal cancer (aOR, 1.66; 95% CI, 0.7-5.8). There was a nonsignificant trend for increased risk in the heterozygotes or single homozygotes. The relationship between the BRM polymorphisms and early-stage UADT cancers was independent of age, sex, smoking status, histology, and clinical stage. These findings suggest that the BRM promoter double insertion homozygotes may be associated with an increased risk of early-stage UADT cancers independent of smoking status and histology, which must be further validated in other populations.
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http://dx.doi.org/10.1002/cam4.201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987092PMC
April 2014

Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response.

Mol Biol Cell 2012 Jun 25;23(12):2240-52. Epub 2012 Apr 25.

Center for Cell Dynamics, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Apoptosis serves as a protective mechanism by eliminating damaged cells through programmed cell death. After apoptotic cells pass critical checkpoints, including mitochondrial fragmentation, executioner caspase activation, and DNA damage, it is assumed that cell death inevitably follows. However, this assumption has not been tested directly. Here we report an unexpected reversal of late-stage apoptosis in primary liver and heart cells, macrophages, NIH 3T3 fibroblasts, cervical cancer HeLa cells, and brain cells. After exposure to an inducer of apoptosis, cells exhibited multiple morphological and biochemical hallmarks of late-stage apoptosis, including mitochondrial fragmentation, caspase-3 activation, and DNA damage. Surprisingly, the vast majority of dying cells arrested the apoptotic process and recovered when the inducer was washed away. Of importance, some cells acquired permanent genetic changes and underwent oncogenic transformation at a higher frequency than controls. Global gene expression analysis identified a molecular signature of the reversal process. We propose that reversal of apoptosis is an unanticipated mechanism to rescue cells from crisis and propose to name this mechanism "anastasis" (Greek for "rising to life"). Whereas carcinogenesis represents a harmful side effect, potential benefits of anastasis could include preservation of cells that are difficult to replace and stress-induced genetic diversity.
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http://dx.doi.org/10.1091/mbc.E11-11-0926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374744PMC
June 2012

Incidence and risk factors for early hepatotoxicity and its impact on survival in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation.

Biol Blood Marrow Transplant 2012 Oct 21;18(10):1589-99. Epub 2012 Apr 21.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Allogeneic hematopoietic cell transplantation (HCT) is commonly associated with hepatic complications. Patients with myelofibrosis (MF) often develop liver dysfunction in the early posttransplantation period; however, this has not yet been studied in a systematic fashion. We retrospectively evaluated 53 patients with MF who underwent HCT to assess the prevalence of acute liver toxicity and risk factors and the impact on survival. We compared the prevalence of acute hepatic complications in that group and a matched control group of 53 patients with myelodysplastic syndrome (MDS). In the MF group, during the first 6 weeks after HCT, the incidence of mild (34.2-102.6 μM), moderate (102.6-342 μM), and severe (>342 μM) hyperbilirubinemia was 34%, 40%, and 4%, respectively (normal, <22 μM). The incidence of mild/moderate transaminitis (2-10 times the upper limit of normal) was 23%, and that of severe transaminitis (>10 times the upper limit of normal) was 6%. Veno-occlusive disease as defined by the Baltimore criteria was observed in 19 patients (36%) in the MF group. Compared with MDS, MF was associated with a significantly higher incidence of moderate/severe hyperbilirubinemia (44% versus 21%; P = .02) and veno-occlusive disease (36% versus 19%; P = .05). A history of portal hypertension, biopsy-proven hepatic iron overload, or splanchnic vein thrombosis was a strong predictor of moderate/severe hyperbilirubinemia (P = .02). Acute hepatocellular injury with moderate/severe hyperbilirubinemia or transaminitis was associated with inferior survival at 12 months (P = .02) in the MF group. We conclude that patients with MF are at significant risk of early hepatotoxicity after HCT, which is associated with an adverse impact on survival.
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http://dx.doi.org/10.1016/j.bbmt.2012.04.011DOI Listing
October 2012

Fever and multiorgan infarcts in a 35-year-old man.

CMAJ 2012 Apr 2;184(7):783-8. Epub 2012 Apr 2.

Department of Medicine, University of Toronto, Toronto, Ont.

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http://dx.doi.org/10.1503/cmaj.111709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328522PMC
April 2012

Unraveling the genetics of cancer: genome sequencing and beyond.

Annu Rev Genomics Hum Genet 2011 ;12:407-30

Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 2C4, Canada.

Advances in next-generation sequencing technology are enabling the systematic analyses of whole cancer genomes, providing insights into the landscape of somatic mutations and the great genetic heterogeneity that defines the unique signature of an individual tumor. Moreover, integrated studies of the genome, epigenome, and transcriptome reveal mechanisms of tumorigenesis at multiple levels. Progress in sequencing technologies and bioinformatics will improve the costs, sensitivity, and accuracy of detecting somatic mutations, while large-scale projects are underway to coordinate cancer genome sequencing at the global level to facilitate the generation and dissemination of high-quality uniform genetic data. These developments will create opportunities for deeper studies of cancer genetics and the clinical application of genome sequencing, and will motivate further research in cancer pathogenesis.
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http://dx.doi.org/10.1146/annurev-genom-082509-141532DOI Listing
October 2011

The novel immunoregulatory molecule FGL2: a potential biomarker for severity of chronic hepatitis C virus infection.

J Hepatol 2010 Oct 17;53(4):608-15. Epub 2010 Jun 17.

Multi Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada.

Background & Aims: This report describes the use of a novel sensitive and specific ELISA for the measurement of human fibrinogen-like protein 2 (FGL2/fibroleukin), a novel effector of natural regulatory T (Treg) cells, to predict the course of chronic hepatitis C viral infection (HCV).

Methods: Plasma levels of FGL2 were measured in HCV patients and compared to healthy controls and to patients with alcoholic liver disease.

Results: FGL2 levels were significantly higher in HCV patients (84.3+/-89.1 ng/ml, n=80) compared to healthy controls (36.4+/-21.9 ng/ml, n=30, p<0.001), to a subset of patients who cleared HCV following anti-viral treatment (16.6+/-19.7 ng/ml, n=32, p<0.001), and to patients with inactive alcoholic liver disease (18.8+/-17.4 ng/ml, n=24, p<0.001). Among HCV patients, plasma levels of FGL2 correlated significantly with the stage of fibrosis (p=0.001) and were significantly higher in patients with cirrhosis (164.1+121.8 ng/ml, n=60) compared to non-cirrhotics (57.7+/-52.8 ng/ml, n=20, p=0.001). Genotype 1 patients had significantly higher levels of FGL2 (98.1+/-100.3 ng/ml, n=60) compared to patients with genotype 2/3 (41.5+/-38.6 ng/ml, n=20, p=0.0008). Patients with genotype 2/3 had FGL2 levels similar to healthy controls (41.5+/-38.6 vs. 36.41+/-21.9 ng/ml, p=ns). Infiltrating lymphocytes in liver biopsies of HCV patients were positive for either FGL2 or FoxP3 (a marker of Treg cells) or expressed both markers.

Conclusions: This report documents the development of a sensitive ELISA for measurement of plasma levels of FGL2 an effector Treg cells, which correlates with the severity of HCV infection.
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http://dx.doi.org/10.1016/j.jhep.2010.04.020DOI Listing
October 2010

The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis.

Hepatology 2009 Feb;49(2):387-97

Multi Organ Transplant Program, University of Toronto, Toronto, Ontario, Canada.

Unlabelled: Fulminant viral hepatitis (FH) remains an important clinical problem in which the underlying pathogenesis is not well understood. Here, we present insight into the immunological mechanisms involved in FH caused by murine hepatitis virus strain 3 (MHV-3), indicating a critical role for CD4(+)CD25(+) regulatory T cells (Tregs) and production of the novel Treg effector molecule FGL2. Before infection with MHV-3, susceptible BALB/cJ mice had increased numbers of Tregs and expression of fgl2 messenger RNA (mRNA) and FGL2 protein compared with resistant A/J mice. After MHV-3 infection, plasma levels of FGL2 in BALB/cJ mice were significantly increased, correlating with increased percentage of Tregs. Treatment with anti-FGL2 antibody completely inhibited Treg activity and protected susceptible BALB/cJ mice against MHV-3-liver injury and mortality. Adoptive transfer of wild-type Tregs into resistant fgl2(-/-) mice increased their mortality caused by MHV-3 infection, whereas transfer of peritoneal exudate macrophages had no adverse effect.

Conclusion: This study demonstrates that FGL2 is an important effector cytokine of Tregs that contributes to susceptibility to MHV-3-induced FH. The results further suggest that targeting FGL2 may lead to the development of novel treatment approaches for acute viral hepatitis infection.
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http://dx.doi.org/10.1002/hep.22684DOI Listing
February 2009

Targeted deletion of fgl2 leads to impaired regulatory T cell activity and development of autoimmune glomerulonephritis.

J Immunol 2008 Jan;180(1):249-60

Multi Organ Transplant Program, Department of Immunology, University of Toronto, Ontario, Canada.

Mice with targeted deletion of fibrinogen-like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild-type recipients reconstituted with fgl2-/- bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, Th 1 polarization, and increased numbers of Ab-producing B cells following immunization with T-independent Ags. Dendritic cells were more abundant in fgl2-/- mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2-/- mice, but their suppressive activity was significantly impaired. Ab to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited dendritic cell maturation and induced apoptosis of B cells through binding to the low-affinity FcgammaRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease.
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http://dx.doi.org/10.4049/jimmunol.180.1.249DOI Listing
January 2008

Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload.

Circ Res 2007 Aug 2;101(4):e32-42. Epub 2007 Aug 2.

Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria.

Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(+/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.
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http://dx.doi.org/10.1161/CIRCRESAHA.107.158659DOI Listing
August 2007

Intubation conditions with low dose rocuronium under sevoflurane induction for children.

Chang Gung Med J 2005 Mar;28(3):174-9

Department of Anesthesiology, Chang Gung Children's Hospital, Chang Gung Memorial Hospital, Taipei.

Background: During short surgical procedures and when there is a need to avoid the use of anticholinesterase at the end of surgery, the use of a smaller intubation dose of neuromuscular blocking drug is preferred. The aim of this study was to evaluate tracheal intubation conditions using smaller doses of rocuronium for children under sevoflurane induction.

Methods: Eighty American Society of Anesthesiologists classification physical status I or II children were enrolled. After mask induction with sevoflurane with nitrous oxide for 3 minutes, 0.3 mg/kg of rocuronium was given. Intubation was performed 60 or 90 seconds thereafter. Study group A included children aged 1 to 3 years and 90 seconds between rocuronium injection and intubation. Group B included children aged 1 to 3 years who had 60 seconds between rocuronium injection and intubation. Group C included children aged 4 to 6 years who had 90 seconds between rocuronium injection and intubation. Group D included children aged 4 to 6 years who had 60 seconds between rocuronium injection and intubation. Intubation conditions were judged based on the scoring of ease of jaw opening and laryngoscopy, position of the vocal cords, and degree of straining after tracheal intubation.

Results: All 80 children underwent successful tracheal intubation without laryngospasm or any complications. Intubation conditions were judged as optimal in all children in group A, 95% in group B, 80% in group C, and 65% in group D.

Conclusions: A total of 0.3 mg/kg of rocuronium was sufficient for tracheal intubation for children 1 to 6 years old under sevoflurane induction. To guarantee optimal intubation conditions for elder children, allow 90 seconds waiting time after rocuronium administration was recommended.
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March 2005

Caudal epidural block for minor gynecologic procedures in outpatient surgery.

Chang Gung Med J 2004 Feb;27(2):116-21

Department of Anesthesiology, Chang Gung Memorial Hospital, Taipei, Taiwan 333, ROC.

Background: Caudal epidural block (CEB) has become increasingly important for pediatric analgesia in recent years. However, data regarding CEB in adult ambulatory surgery are scarce. The aim of this study was to verify whether CEB could be applied as a simple, safe and economic method of anesthesia for adult patients undergoing minor gynecologic procedures (MGP).

Methods: One hundred and seventy-two female patients were enrolled in this study. Each patient received a 20-mL bolus of 1.5% lidocaine caudal epidural injection. The efficacy of CEB was evaluated. Types and duration of surgery, success rate, sensory level of analgesia, caudal epidural depth, complications and duration in the postanesthesia care unit (PACU) were also under investigation.

Results: No side effects occurred and only few hemodynamic changes were noted in the study. All patients experienced excellent surgical anesthesia except seven patients, who required rescue supplement opioids (4.1% of failure rate). The success rate of CEB was 95.9% (165/172). Duration of anesthesia and surgery were 46.66 +/- 11.76 min and 23.08 +/- 9.54 min, respectively. The highest sensory dermatome level reached below T10. The average epidural depth was 3.06 +/- 0.23 cm. No postoperative anti-emetic was given in the study. Only three patients required postoperative narcotics. Four patients had spontaneous voiding before discharge. The average PACU stay was 74.30 +/- 10.80 min.

Conclusion: Single-dose CEB with 1.5% lidocaine 20-mL was an easy and simple technique. It provided satisfactory anesthesia for MGP and did not prolong patients' discharge time. CEB may be another choice of anesthetic technique in such cases of clinical practice.
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February 2004

Aspiration of a dislodged endotracheal tube: a rare cause of acute total airway obstruction.

Chang Gung Med J 2003 Jul;26(7):515-9

Department of Anesthesiology, Chang Gung Memorial Hospital, Taipei, Taiwan, ROC.

We report an unusual cause of acute total airway obstruction after aspiration of a dislodged tube that was separated from its metallic connector. A 5-year-old boy had an emergence agitation and bucking to the endotracheal tube with a vigorous bite before extubation of the trachea. The whole uncuffed endotracheal tube was aspirated deep into the lower trachea causing laryngotracheal obstruction. The patient showed sudden oxygen desaturation and was then in an immediate life-threatening airway obstruction. We could not rescue oxygenation and were unable to establish a patent airway. Mask ventilation failed to relieve the progressive of hypoxemia. Immediate extraction of the tube using a pair of Magill's forceps before irreversible exacerbation was performed. We discuss our experience and the importance of prompt decision making and management for the extraction of the dislodged tube.
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July 2003

Anesthesia for pediatric patients with Prader-Willi syndrome: report of two cases.

Chang Gung Med J 2003 Jun;26(6):453-7

Department of Anesthesiology, Chang Gung Children's Hospital, Taoyuan, Taiwan, R.O.C.

Prader-Willi syndrome (PWS) is a sporadic disorder of chromosome abnormalities with an estimated prevalence of 1 in 15,000. It mainly affects the central nervous system, and often involves the hypothalamus. Both general and regional anesthesia for these patients is difficult mainly due to morbid obesity. Other common problems include hypotonia, disturbance in thermoregulation, arrhythmia, cor pulmonale, diabetes mellitus, behavior problems, and convulsions. We report on 2 pediatric patients with PWS receiving general anesthesia. The first patient experienced life-threatening episodes of severe hypoxemia in the postanesthesia care unit (PACU) as well as in the pediatric intensive care unit (PICU). Nasal continuous positive airway pressure (CPAP) was suggested by the pediatric pulmonary medicine specialist, and thereafter the patient's condition improved. The clinical course of the second patient was uneventful except for transient intermittent episodes of bronchospasms during emergence. In addition, we discuss differences between these 2 cases and our strategy for the prevention of perioperative complications for PWS patients in the future.
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June 2003

Awake fiberoptic intubation for cesarean section in a parturient with odontoid fracture and atlantoaxial subluxation.

Chang Gung Med J 2003 May;26(5):352-6

Department of Anesthesiology, Chang Gung Memorial Hospital, Taipei.

We report on the anesthetic experience of a 38-week pregnant patient in labor with an upper cervical spinal cord injury after an unusual trauma. She was transferred from a district hospital to our medical center with acute quadriplegia and sensory loss. Plain cervical spine x-ray and computed tomographic scan showed a C2 odontoid (dens of axis) process type II fracture and atlantoaxial (C1-C2) subluxation. Due to having regular uterine contractions and labor pain, she was scheduled for an urgent cesarean section. The instability of her cervical spine precluded the use of regional anesthesia; so awake nasal fiberoptic endotracheal intubation followed by general anesthesia was performed. The anesthetic course was uneventful, and the outcome of the parturient and newborn was good. We discuss our anesthetic considerations, intubation techniques and a review of the literature.
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May 2003