Publications by authors named "Hui-Young Lee"

105 Publications

Deletion of KLF10 Leads to Stress-Induced Liver Fibrosis upon High Sucrose Feeding.

Int J Mol Sci 2020 Dec 30;22(1). Epub 2020 Dec 30.

Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon 21999, Korea.

Liver fibrosis is a consequence of chronic liver injury associated with chronic viral infection, alcohol abuse, and nonalcoholic fatty liver. The evidence from clinical and animal studies indicates that transforming growth factor-β (TGF-β) signaling is associated with the development of liver fibrosis. Krüppel-like factor 10 (KLF10) is a transcription factor that plays a significant role in TGF-β-mediated cell growth, apoptosis, and differentiation. In recent studies, it has been reported to be associated with glucose homeostasis and insulin resistance. In the present study, we investigated the role of KLF10 in the progression of liver disease upon a high-sucrose diet (HSD) in mice. Wild type (WT) and 10 knockout (KO) mice were fed either a control chow diet or HSD (50% sucrose) for eight weeks. 10 KO mice exhibited significant hepatic steatosis, inflammation, and liver injury upon HSD feeding, whereas the WT mice exhibited mild hepatic steatosis with no apparent liver injury. The livers of HSD-fed 10 KO mice demonstrated significantly increased endoplasmic reticulum stress, oxidative stress, and proinflammatory cytokines. 10 deletion led to the development of sucrose-induced hepatocyte cell death both in vivo and in vitro. Moreover, it significantly increased fibrogenic gene expression and collagen accumulation in the liver. Increased liver fibrosis was accompanied by increased phosphorylation and nuclear localization of Smad3. Here, we demonstrate that HSD-fed mice develop a severe liver injury in the absence of KLF10 due to the hyperactivation of the endoplasmic reticulum stress response and CCAAT/enhance-binding protein homologous protein (CHOP)-mediated apoptosis of hepatocytes. The current study suggests that KLF10 plays a protective role against the progression of hepatic steatosis into liver fibrosis in a lipogenic state.
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http://dx.doi.org/10.3390/ijms22010331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794950PMC
December 2020

Allogeneic transplant can abrogate the risk of relapse in the patients of first remission acute myeloid leukemia with detectable measurable residual disease by next-generation sequencing.

Bone Marrow Transplant 2020 Dec 5. Epub 2020 Dec 5.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada.

In patients with acute myeloid leukemia (AML) consolidation treatment options are between allogeneic hematopoietic stem cell transplantation (HCT) and chemotherapy, based on disease risk at the time of initial presentation and age. Measurable residual disease (MRD) following induction chemotherapy could be incorporated as a useful parameter for treatment decisions. The present study evaluated treatment outcomes according to the next-generation sequencing (NGS)-based MRD status and the type of consolidation therapy in patients with normal karyotype (NK)-AML. By sequencing 278 paired samples collected at diagnosis and first remission (CR1), we identified 361 mutations in 124 patients at diagnosis and tracked these at CR1. After excluding mutations associated with age-related clonal hematopoiesis, 82 mutations in 50 of the 124 patients (40.3%) were detected at CR1. Survival benefit was observed in favor of allogeneic HCT over chemotherapy consolidation in the MRD subgroup with respect to overall survival (HR 0.294, p = 0.003), relapse-free survival (HR 0.376, p = 0.015) and cumulative incidence of relapse (HR 0.279, p = 0.004) in multivariate analysis, but not in the MRD subgroup. In summary, these data support allogeneic HCT in NK-AML patients with detectable MRD by NGS in CR1. Randomized clinical trials will be required to confirm this observation.
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http://dx.doi.org/10.1038/s41409-020-01165-xDOI Listing
December 2020

RNA sequencing as an alternative tool for detecting measurable residual disease in core-binding factor acute myeloid leukemia.

Sci Rep 2020 11 18;10(1):20119. Epub 2020 Nov 18.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.

DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. However, the same methodology cannot be applied to fusion gene-driven subtypes of AML such as core-binding factor AML (CBF-AML). Here in this study, we evaluated the effectiveness of using DNA and RNA sequencing in MRD detection and in tracking clonal dynamics in CBF-AML. Using RNA-seq, we were able to quantify expression levels of RUNX1-RUNX1T1 and CBFB-MYH11 at diagnosis and their levels of reduction during remission (P < 6.3e-05 and P < 2.2e-13). The level of reduction of RUNX1-RUNX1T1 as measured by RNA-seq and qPCR were highly correlated (R = 0.74, P < 5.4e-05). A decision tree analysis, based on 3-log reduction of RUNX1-RUNX1T1 and cKIT-D816 at diagnosis, stratified RUNX1-RUNX1T1 AML patients into three subgroups. These three subgroups had 2-year overall survival rates at 87%, 74%, and 33% (P < 0.08) and 2-year relapse incidence rates at 13%, 42%, and 67% (P < 0.05). On the other hand, although low residual allelic burden was common, it was not associated with long-term outcome, indicating that mutation clearance alone cannot be interpreted as MRD-negative. Overall, our study demonstrates that the clinical utility of RNA sequencing as a potential tool for MRD monitoring in fusion gene-driven AML such as RUNX1-RUNX1T1 AML.
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http://dx.doi.org/10.1038/s41598-020-76933-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674449PMC
November 2020

Revisiting the Bacterial Phylum Composition in Metabolic Diseases Focused on Host Energy Metabolism.

Diabetes Metab J 2020 10 9;44(5):658-667. Epub 2020 Jul 9.

Laboratory of Mitochondrial and Metabolic Diseases, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.

Over a hundred billion bacteria are found in human intestines. This has emerged as an environmental factor in metabolic diseases, such as obesity and related diseases. The majority of these bacteria belong to two dominant phyla, Bacteroidetes and Firmicutes. Since the ratio of Firmicutes to Bacteroidetes increases in people with obesity and in various animal models, it has been assumed that phylum composition causes the increase in occurrence of metabolic diseases over the past decade. However, this assumption has been challenged by recent studies that have found even an opposite association of phylum composition within metabolic diseases. Moreover, the gut microbiota affects host energy metabolism in various ways including production of metabolites and interaction with host intestinal cells to regulate signaling pathways that affect energy metabolism. However, the direct effect of gut bacteria on host energy intake, such as energy consumption by the bacteria itself and its effects on intestinal energy absorption, has been underestimated. This review aims to discuss whether increased ratio of Firmicutes to Bacteroidetes is associated with the development of metabolic diseases, and whether energy competition between the bacteria and host is a missing part of the mechanism linking gut microbiota to metabolic diseases.
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http://dx.doi.org/10.4093/dmj.2019.0220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643595PMC
October 2020

The essential role of fructose-1,6-bisphosphatase 2 enzyme in thermal homeostasis upon cold stress.

Exp Mol Med 2020 03 16;52(3):485-496. Epub 2020 Mar 16.

Department of Medicine, Gachon University College of Medicine, Incheon, 21565, Korea.

Skeletal muscle is a major organ for glucose disposal and thermogenesis. While hepatic fructose-1,6-bisphosphatase is well known as a key enzyme for gluconeogenesis, the role of muscle fructose-1,6-bisphosphatase 2 (Fbp2) in glucose disposal and thermogenesis is unknown. Here, using Fbp2 knockout (KO) mice, we assessed the physiological role of Fbp2 in energy and glucose metabolism and thermogenesis. In vivo assessments of energy metabolism, glucose metabolism, and thermogenesis were performed by indirect calorimetry, hyperinsulinemic-euglycemic clamp, and cold challenge studies, respectively. Under both feeding and fasting conditions, Fbp2 KO mice showed similar phenotypes regarding energy and glucose metabolism compared to wild-type (WT) mice. However, Fbp2 KO mice were severely intolerant to cold challenge under fasting conditions. Mechanistically, the cold-induced intramuscular conversion of lactate to glycogen (glyconeogenesis) is completely abolished in the KO muscle, which leads to a lack of glycogen source for thermogenesis in Fbp2 KO mice. The cold-intolerant phenotype of KO mice disappeared after feeding, and the KO mice were equally as cold tolerant as the WT mice and survived during the cold challenge for three weeks. Taken together, these data demonstrate that Fbp2 is essential for muscle thermogenesis by replenishing the intramuscular glycogen pool through glyconeogenesis when the exogenous glucose source is limited. These data imply the physiological importance of Fbp2 in thermal homeostasis and suggest a potential novel therapy targeted to increase glycogen replenishment upon cold stress.
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http://dx.doi.org/10.1038/s12276-020-0402-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156669PMC
March 2020

A protective mechanism of probiotic Lactobacillus against hepatic steatosis via reducing host intestinal fatty acid absorption.

Exp Mol Med 2019 08 13;51(8):1-14. Epub 2019 Aug 13.

Laboratory of Mitochondrial and Metabolic Diseases, Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Korea.

The gut microbiome has been known to contribute up to ~30% of the energy absorption of the host. Although various beneficial mechanisms of probiotics have been suggested for non-alcoholic fatty liver disease (NAFLD), whether and which probiotics impact the host's intestinal energy absorption have not yet been quantitatively studied. Here, we suggest a novel mechanism of probiotics against NAFLD, in which Lactobacillus rhamnosus GG, the most common probiotic, shares intestinal fatty acids and prevents the development of diet-induced hepatic steatosis. By using quantitative methods (radioactive tracers and LC-MS) under both in vitro and in vivo conditions, we found that bacteria and hosts competed for fatty acid absorption in the intestine, resulting in decreased weight gain, body fat mass, and hepatic lipid accumulation without differences in calorie intake and excretion in mice fed the probiotic bacteria.
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http://dx.doi.org/10.1038/s12276-019-0293-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802638PMC
August 2019

Intrinsic expression of viperin regulates thermogenesis in adipose tissues.

Proc Natl Acad Sci U S A 2019 08 24;116(35):17419-17428. Epub 2019 Jul 24.

Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 03722 Seoul, Republic of Korea;

Viperin is an interferon (IFN)-inducible multifunctional protein. Recent evidence from high-throughput analyses indicates that most IFN-inducible proteins, including viperin, are intrinsically expressed in specific tissues; however, the respective intrinsic functions are unknown. Here we show that the intrinsic expression of viperin regulates adipose tissue thermogenesis, which is known to counter metabolic disease and contribute to the febrile response to pathogen invasion. Viperin knockout mice exhibit increased heat production, resulting in a reduction of fat mass, improvement of high-fat diet (HFD)-induced glucose tolerance, and enhancement of cold tolerance. These thermogenic phenotypes are attributed to an adipocyte-autonomous mechanism that regulates fatty acid β-oxidation. Under an HFD, viperin expression is increased, and its function is enhanced. Our findings reveal the intrinsic function of viperin as a novel mechanism regulating thermogenesis in adipose tissues, suggesting that viperin represents a molecular target for thermoregulation in clinical contexts.
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http://dx.doi.org/10.1073/pnas.1904480116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717265PMC
August 2019

Plasma CRABP2 as a Novel Biomarker in Patients with Non-Small Cell Lung Cancer.

J Korean Med Sci 2018 Jun 16;33(26):e178. Epub 2018 May 16.

Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea.

Background: Lung cancer is the most common cause of cancer-related mortality worldwide. We previously reported the identification of a new genetic marker, cellular retinoic acid binding protein 2 (CRABP2), in lung cancer tissues. The aim of this study was to assess plasma levels of CRABP2 from patients with non-small cell lung cancer (NSCLC).

Methods: Blood samples that were collected from 122 patients with NSCLC between September 2009 and September 2013 were selected for the analysis, along with samples from age- (± 5 years), sex-, and cigarette smoking history (± 10 pack-years [PY])-matched controls from the Korea Biobank Network. The control specimens were from patients who were without malignancies or pulmonary diseases. We measured plasma levels of CRABP2 using commercially available enzyme-linked immunosorbent assay kits.

Results: The mean age of the NSCLC patients was 71.8 ± 8.9 years, and the median cigarette smoking history was 32 PY (range, 0-150 PY). Plasma CRABP2 levels were significantly higher in patients with NSCLC than in the matched controls (37.63 ± 28.71 ng/mL vs. 24.09 ± 21.09 ng/mL, < 0.001). Higher plasma CRABP2 levels were also correlated with lower survival rates in NSCLC patients ( = 0.014).

Conclusion: Plasma CRABP2 levels might be a novel diagnostic and prognostic marker in NSCLC.
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http://dx.doi.org/10.3346/jkms.2018.33.e178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010740PMC
June 2018

Adipocyte-Specific Deficiency of De Novo Sphingolipid Biosynthesis Leads to Lipodystrophy and Insulin Resistance.

Diabetes 2017 10 11;66(10):2596-2609. Epub 2017 Jul 11.

Department of Life Science, Gachon University, Sungnam, Korea

Sphingolipids have been implicated in the etiology of chronic metabolic diseases. Here, we investigated whether sphingolipid biosynthesis is associated with the development of adipose tissues and metabolic diseases. SPTLC2, a subunit of serine palmitoyltransferase, was transcriptionally upregulated in the adipose tissues of obese mice and in differentiating adipocytes. Adipocyte-specific SPTLC2-deficient (aSPTLC2 KO) mice had markedly reduced adipose tissue mass. Fatty acids that were destined for the adipose tissue were instead shunted to liver and caused hepatosteatosis. This impaired fat distribution caused systemic insulin resistance and hyperglycemia, indicating severe lipodystrophy. Mechanistically, sphingosine 1-phosphate (S1P) was reduced in the adipose tissues of aSPTLC2 KO mice, and this inhibited adipocyte proliferation and differentiation via the downregulation of S1P receptor 1 and decreased activity of the peroxisome proliferator-activator receptor γ. In addition, downregulation of SREBP (sterol regulatory element-binding protein)-1c prevented adipogenesis of aSPTLC2 KO adipocytes. Collectively, our observations suggest that the tight regulation of de novo sphingolipid biosynthesis and S1P signaling plays an important role in adipogenesis and hepatosteatosis.
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http://dx.doi.org/10.2337/db16-1232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970771PMC
October 2017

Mitochondrial-Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation.

Diabetes 2017 08 5;66(8):2072-2081. Epub 2017 May 5.

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT

We explored the role of reactive oxygen species (ROS) in the pathogenesis of muscle insulin resistance. We assessed insulin action in vivo with a hyperinsulinemic-euglycemic clamp in mice expressing a mitochondrial-targeted catalase (MCAT) that were fed regular chow (RC) or a high-fat diet (HFD) or underwent an acute infusion of a lipid emulsion. RC-fed MCAT mice were similar to littermate wild-type (WT) mice. However, HFD-fed MCAT mice were protected from diet-induced insulin resistance. In contrast, an acute lipid infusion caused muscle insulin resistance in both MCAT and WT mice. ROS production was decreased in both HFD-fed and lipid-infused MCAT mice and cannot explain the divergent response in insulin action. MCAT mice had subtly increased energy expenditure and muscle fat oxidation with decreased intramuscular diacylglycerol (DAG) accumulation, protein kinase C-θ (PKCθ) activation, and impaired insulin signaling with HFD. In contrast, the insulin resistance with the acute lipid infusion was associated with increased muscle DAG content in both WT and MCAT mice. These studies suggest that altering muscle mitochondrial ROS production does not directly alter the development of lipid-induced insulin resistance. However, the altered energy balance in HFD-fed MCAT mice protected them from DAG accumulation, PKCθ activation, and impaired muscle insulin signaling.
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http://dx.doi.org/10.2337/db16-1334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521865PMC
August 2017

Feasibility of Modified FOLFOX in Elderly Patients Aged ≥80 Years with Metastatic Gastric Cancer or Colorectal Cancer.

Oncology 2017 27;93(2):115-121. Epub 2017 Apr 27.

Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, South Korea.

Objective: The aim of this study was to assess the feasibility of a modified FOLFOX regimen as first-line treatment in elderly patients with metastatic gastric cancer (GC) or colorectal cancer (CRC).

Methods: We included chemotherapy-naïve patients over 80 years old with metastatic GC or CRC in our study. From September 2008 to November 2014, 28 consecutive patients were enrolled and treated with modified FOLFOX.

Results: The study population consisted of an equal number of GC and CRC patients. The median age was 82.2 years in the GC group and 81.1 years in the CRC group. The total number of administered cycles was 89 (with a median of 6 per patient) in the GC group and 112 (with a median of 8 per patient) in the CRC group. Median progression-free survival (PFS) and overall survival (OS) were 5.4 and 6.6 months in the GC group and 7.3 and 8.1 months in the CRC group, respectively. There was no significant difference in PFS (p = 0.941) and OS (p = 0.238) between the GC and the CRC group. The 1-year survival rates were 35.7% with GC and 42.9% with CRC. Common grade 3/4 hematology toxicities were neutropenia (10.7%) and anemia (14.3%). Salvage chemotherapy was administered to 1 patient with GC and 7 patients with CRC.

Conclusions: The modified FOLFOX regimen can be cautiously considered as a first-line treatment option in extremely elderly patients with metastatic GC or CRC.
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http://dx.doi.org/10.1159/000471767DOI Listing
October 2017

Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance.

Nat Commun 2017 02 16;8:14477. Epub 2017 Feb 16.

Department of Pathology, University of Florida College of Medicine, Gainesville, Florida 32610, USA.

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder in obese individuals. Adenine nucleotide translocase (ANT) exchanges ADP/ATP through the mitochondrial inner membrane, and Ant2 is the predominant isoform expressed in the liver. Here we demonstrate that targeted disruption of Ant2 in mouse liver enhances uncoupled respiration without damaging mitochondrial integrity and liver functions. Interestingly, liver specific Ant2 knockout mice are leaner and resistant to hepatic steatosis, obesity and insulin resistance under a lipogenic diet. Protection against fatty liver is partially recapitulated by the systemic administration of low-dose carboxyatractyloside, a specific inhibitor of ANT. Targeted manipulation of hepatic mitochondrial metabolism, particularly through inhibition of ANT, may represent an alternative approach in NAFLD and obesity treatment.
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http://dx.doi.org/10.1038/ncomms14477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316896PMC
February 2017

A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer.

J Geriatr Oncol 2017 May 21;8(3):170-175. Epub 2017 Jan 21.

Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Objectives: More than half of cases of gastric cancer (GC) are diagnosed in elderly patients (≥70years). While doublet combination with fluoropyrimidines and platinum is currently considered standard first-line chemotherapy in advanced GC, the main goal of chemotherapy remains palliation.

Materials And Methods: In a multi-center phase III trial, patients with chemotherapy-naïve, metastatic GC, aged 70years or older were randomized 1:1 to receive X monotherapy (capecitabine 1000mg/m bid po on days one to fourteen) or XELOX (X plus oxaliplatin 110mg/m iv on D1). Treatment was repeated every 21days until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint was overall survival (OS).

Results: In total, 50 patients with a median age of 77 (range, 70 to 84) were enrolled (X, n=26; XELOX, n=24). No treatment-related serious adverse events or unexpected toxicities were observed. The most frequently observed toxicities were nausea and hand-foot syndrome, with fatigue and peripheral neuropathy more common in XELOX than in X patients. Median OS was 11.1months for XELOX arm and 6.3months for X arm (HR 0.58, 95% CI 0.30-1.12, P=0.108). Although the difference was not significant, on the basis of evidence of superiority of XELOX seen in the first interim analysis, an independent data monitoring committee recommended early stopping of the trial. PFS was significantly longer (HR 0.32, 95% CI 0.17-0.61, P<0.001) with XELOX (7.1months) than with X (2.6months).

Conclusion: Platinum-based combination chemotherapy was associated with survival benefit, as compared with X monotherapy in elderly patients with GC.
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http://dx.doi.org/10.1016/j.jgo.2017.01.002DOI Listing
May 2017

Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect.

Sci Rep 2016 12 15;6:39170. Epub 2016 Dec 15.

Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides (TG) as lipid droplets in the liver. Although lipid-metabolizing enzymes are considered important in NAFLD, the involvement of phospholipase D1 (PLD1) has not yet been studied. Here, we show that the genetic ablation of PLD1 in mice induces NAFLD due to an autophagy defect. PLD1 expression was decreased in high-fat diet-induced NAFLD. Subsequently, PLD1 deficiency led to an increase in hepatic TGs and liver weight. Autophagic flux was blocked in Pld1 hepatocytes, with decreased β-oxidation rate, reduced oxidation-related gene expression, and swollen mitochondria. The dynamics of autophagy was restored by treatment with the PLD product, phosphatidic acid (PA) or adenoviral PLD1 expression in Pld1 hepatocytes, confirming that lysosomal PA produced by PLD1 regulates autophagy. Notably, PLD1 expression in Pld1 liver significantly reduced hepatic lipid accumulation, compared with Pld1 liver. Thus, PLD1 plays an important role in hepatic steatosis via the regulation of autophagy.
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http://dx.doi.org/10.1038/srep39170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156943PMC
December 2016

What factors determine the need for lumbar puncture in patients with fever and headache?

Singapore Med J 2017 Oct 5;58(10):618-622. Epub 2016 Dec 5.

Department of Emergency Medicine, Kangwon National University Hospital, Kangwon National University, Chuncheon, South Korea.

Introduction: We performed this study to find clinical features and laboratory parameters that could facilitate the process of selecting patients who should receive lumbar punctures from among those who present with headache and fever.

Methods: We selected patients aged ≥ 16 years who presented to and received lumbar puncture in the emergency department of Kangwon National University Hospital, South Korea, between 2011 and 2013. Patients who received lumbar punctures were divided into two groups - those who were diagnosed with viral meningitis and those who were not. We compared the clinical features and laboratory data between the two groups. Key indices were then used to develop a scoring system to diagnose viral meningitis in patients and identify those who should receive lumbar punctures.

Results: Among the patients who were included in the study, 42 had viral meningitis and 96 did not. The variables of C-reactive protein level ≤ 1.291 mg/dL, neck stiffness and vomiting were assigned 3 points, 2 points and 1 point, respectively, in the scoring system. Overall scores ≥ 4 yielded a positive likelihood ratio of 7.79 (sensitivity 0.600, specificity 0.923), while negative likelihood ratio decreased to less than 0.1 (0.072) for overall scores < 3.

Conclusion: Using the proposed scoring system, we were able to determine the likelihood of viral meningitis in patients presenting with fever and headache, and to successfully identify those who should receive lumbar punctures.
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http://dx.doi.org/10.11622/smedj.2016184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651509PMC
October 2017

Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis.

Free Radic Biol Med 2016 10 12;99:520-532. Epub 2016 Sep 12.

Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address:

Oxidative stress is important for the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a chronic disease that ranges from hepatic steatosis to nonalcoholic steatohepatitis (NASH). The nuclear factor erythroid 2-related factor 2-Kelch-like ECH associated protein 1 (Nrf2-Keap1) pathway is essential for cytoprotection against oxidative stress. In this study, we found that oxidative stress or inflammatory biomarkers and TUNEL positive cells were markedly increased in NASH patients compared to normal or simple steatosis. In addition, we identified that the hepatic mRNA levels of Nrf2 target genes such as Nqo-1 and GSTA-1 were significantly increased in NASH patients. Ezetimibe, a drug approved by the Food and Drug Administration for the treatment of hypercholesterolemia, improves NAFLD and alleviates oxidative stress. However, the precise mechanism of its antioxidant function remains largely unknown. We now demonstrate that ezetimibe activates Nrf2-Keap1 pathway which was dependent of autophagy adaptor protein p62, without causing cytotoxicity. Ezetimibe activates AMP-activated protein kinase (AMPK), which in turn phosphorylates p62 (p-S351) via their direct interaction. Correspondingly, Ezetimibe protected liver cells from saturated fatty acid-induced apoptotic cell death through p62-dependent Nrf2 activation. Furthermore, its role as an Nrf2 activator was supported by methione- and choline- deficient (MCD) diet-induced NASH mouse model, showing that ezetimibe decreased the susceptibility of the liver to oxidative injury. These data demonstrate that the molecular mechanisms underlying ezetimibe's antioxidant role in the pathogenesis of NASH.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.09.009DOI Listing
October 2016

Effect of ischemic preconditioning on the expression of c-myb in the CA1 region of the gerbil hippocampus after ischemia/reperfusion injury.

Iran J Basic Med Sci 2016 Jun;19(6):624-31

Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea.

Objectives: In the present study, we investigated the effect of ischemic preconditioning (IPC) on c-myb immunoreactivity as well as neuronal damage/death after a subsequent lethal transient ischemia in gerbils.

Materials And Methods: IPC was subjected to a 2 min sublethal ischemia and a lethal transient ischemia was given 5 min transient ischemia. The animals in all of the groups were given recovery times of 1 day, 2 days and 5 days and we examined change in c-myb immunoreactivity as well as neuronal damage/death in the hippocampus induced by a lethal transient ischemia.

Results: A lethal transient ischemia induced a significant loss of cells in the stratum pyramidale (SP) of the hippocampal CA1 region at 5 days post-ischemia, and this insult showed that c-myb immunoreactivity in cells of the SP of the CA1 region was significantly decreased at 2 days post-ischemia and disappeared at 5 days post-ischemia. However, IPC effectively prevented the neuronal loss in the SP and showed that c-myb immunoreactivity was constitutively maintained in the SP after a lethal transient ischemia.

Conclusion: Our results show that a lethal transient ischemia significantly decreased c-myb immunoreactivity in the SP of the CA1 region and that IPC well preserved c-myb immunoreactivity in the SP of the CA1 region. We suggest that the maintenance of c-myb might be related with IPC-mediated neuroprotection after a lethal ischemic insult.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951601PMC
June 2016

Difference in transient ischemia-induced neuronal damage and glucose transporter-1 immunoreactivity in the hippocampus between adult and young gerbils.

Iran J Basic Med Sci 2016 May;19(5):521-8

Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea.

Objectives: The alteration of glucose transporters is closely related with the pathogenesis of brain edema. We compared neuronal damage/death in the hippocampus between adult and young gerbils following transient cerebral ischemia/reperfusion and changes of glucose transporter-1(GLUT-1)-immunoreactive microvessels in their ischemic hippocampal CA1 region.

Materials And Methods: Transient cerebral ischemia was developed by 5-min occlusion of both common carotid arteries. Neuronal damage was examined by cresyl violet staining, NeuN immunohistochemistry and Fluoro-Jade B histofluorescence staining and changes in GLUT-1 expression was carried out by immunohistochemistry.

Results: About 90% of pyramidal neurons only in the adult CA1 region were damaged after ischemia/reperfusion; in the young, about 53 % of pyramidal neurons were damaged from 7 days after ischemia/reperfusion. The density of GLUT-1-immunoreactive microvessels was significantly higher in the young sham-group than that in the adult sham-group. In the ischemia-operated-groups, the density of GLUT-1-immunoreactive microvessels was significantly decreased in the adult and young at 1 and 4 days post-ischemia, respectively, thereafter, the density of GLUT-1-immunoreactive microvessels was gradually increased in both groups after ischemia/reperfusion.

Conclusion: CA1 pyramidal neurons of the young gerbil were damaged much later than that in the adult and that GLUT-1-immunoreactive microvessels were significantly decreased later in the young. These data indicate that GLUT-1 might differently contribute to neuronal damage according to age after ischemic insults.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923473PMC
May 2016

Occult gastric cancer with distant metastasis proven by random gastric biopsy.

World J Gastroenterol 2016 Apr;22(16):4270-4

Sang Hyuk Lee, Kyu-Hyoung Lim, Seo-Young Song, Hui-Young Lee, Sung Chul Park, Chang Don Kang, Sung Joon Lee, Dong Wook Choi, Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24341, South Korea.

Krukenberg tumor, a rare metastatic ovarian tumor arising from gastrointestinal adenocarcinoma mainly, tends to occur in premenopausal females. Finding the origin of a Krukenberg tumor is crucial for determining prognosis. In Eastern countries, the most common origin of Krukenberg tumor is stomach cancer, which is generally diagnosed via endoscopic biopsy to investigate an abnormal mucosal lesion. Here, we describe a case of huge adnexal mass in a 33-year-old woman who presented with abdominal distension. Two independent endoscopic examinations performed by experts in two tertiary university hospitals revealed no abnormal mucosal lesion. The patient was diagnosed with a Krukenberg tumor according to findings from random endoscopic biopsies taken from normal-looking gastric mucosa in our hospital. It is very rare to be diagnosed via a random biopsy in cases where three well-trained endoscopists had not found any mucosal lesion previously. Thus, in this case, random biopsy was helpful in finding the origin of a Krukenberg tumor.
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http://dx.doi.org/10.3748/wjg.v22.i16.4270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837445PMC
April 2016

AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia.

J Mol Cell Cardiol 2016 Feb 30;91:104-13. Epub 2015 Dec 30.

Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Molecular and Cellular Physiology, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

AMP-activated kinase (AMPK) is a stress responsive kinase that regulates cellular metabolism and protects against cardiomyocyte injury during ischemia-reperfusion (IR). Mitochondria play an important role in cell survival, but the specific actions of activated AMPK in maintaining mitochondrial integrity and function during reperfusion are unknown. Thus, we assessed the consequences of AMPK inactivation on heart mitochondrial function during reperfusion. Mouse hearts expressing wild type (WT) or kinase-dead (KD) AMPK were studied. Mitochondria isolated from KD hearts during reperfusion had intact membrane integrity, but demonstrated reduced oxidative capacity, increased hydrogen peroxide production and decreased resistance to mitochondrial permeability transition pore opening compared to WT. KD hearts showed increased activation of the mitogen activated protein kinase kinase 4 (MKK4) and downstream c-Jun terminal kinase (JNK) and greater necrosis during reperfusion after coronary occlusion. Transgenic expression of mitochondrial catalase (MCAT) prevented the excessive cardiac JNK activation and attenuated the increased myocardial necrosis observed during reperfusion in KD mice. Inhibition of JNK increased the resistance of KD hearts to mPTP opening, contractile dysfunction and necrosis during IR. Thus, intrinsic activation of AMPK is critical to prevent excess mitochondrial reactive oxygen production and consequent JNK signaling during reperfusion, thereby protecting against mPTP opening, irreversible mitochondrial damage and myocardial injury.
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http://dx.doi.org/10.1016/j.yjmcc.2015.12.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839186PMC
February 2016

The role of lipids in the pathogenesis and treatment of type 2 diabetes and associated co-morbidities.

BMB Rep 2016 Mar;49(3):139-48

Department of Molecular Medicine and Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, School of Medicine, Gachon University, Incheon 21999, Korea.

In the past decade, the incidence of type 2 diabetes (T2D) has rapidly increased, along with the associated cardiovascular complications. Therefore, understanding the pathophysiology underlying T2D, the associated complications and the impact of therapeutics on the T2D development has critical importance for current and future therapeutics. The prevailing feature of T2D is hyperglycemia due to excessive hepatic glucose production, insulin resistance, and insufficient secretion of insulin by the pancreas. These contribute to increased fatty acid influx into the liver and muscle causing accumulation of lipid metabolites. These lipid metabolites cause dyslipidemia and non-alcoholic fatty liver disease, which ultimately contributes to the increased cardiovascular risk in T2D. Therefore, understanding the mechanisms of hepatic insulin resistance and the specific role of liver lipids is critical in selecting and designing the most effective therapeutics for T2D and the associated co-morbidities, including dyslipidemia and cardiovascular disease. Herein, we review the effects and molecular mechanisms of conventional anti-hyperglycemic and lipid-lowering drugs on glucose and lipid metabolism. [BMB Reports 2016; 49(3): 139-148].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915228PMC
http://dx.doi.org/10.5483/bmbrep.2016.49.3.268DOI Listing
March 2016

Failure in neuroprotection of remote limb ischemic postconditioning in the hippocampus of a gerbil model of transient cerebral ischemia.

J Neurol Sci 2015 Nov 1;358(1-2):377-84. Epub 2015 Oct 1.

Department of Emergency Medicine, School of Medicine, Kangwon National University, Chuncheon 24289, South Korea. Electronic address:

Remote ischemic postconditioning (RIPoC) has been proven to provide potent protection of the heart and brain against ischemia-reperfusion injury. However, despite the evidence of cerebral protection with RIPoC is compelling, RIPoC-mediated neuroprotection against transient cerebral ischemic insult is still mired in controversy. In this study, we examined the effect of RIPoC induced by sublathal transient hind limb ischemia on neuronal death in the hippocampus following 5 min of transient cerebral ischemia in gerbils. Animals were randomly assigned to sham-, ischemia-, sham plus (+) RIPoC- and ischemia+RIPoC-groups. RIPoC was induced by three cycles of 5-min and 10-min occlusion-reperfusion of both femoral arteries at predetermined points in time (0, 1, 3, 6, 12 and 24h after transient cerebral ischemia). CV staining, F-J B histofluorescence staining and NeuN immunohistochemistry were carried out to examine neuroprotection in the RIPoC-mediated hippocampus 5 days after ischemia-reperfusion. In the ischemia-group, we found a significant loss of pyramidal cells in the stratum pyramidale (SP) of the hippocampal CA1 region at 5 days post-ischemia compared with the sham-group. In all of the ischemia+RIPoC-groups, the loss of pyramidal cells in the CA1 region at 5 days post-ischemia was not different from that in the ischemia-group. Our present findings indicate that RIPoC does not prevent hippocampal CA1 pyramidal cells from neuronal death induced by transient cerebral ischemia.
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http://dx.doi.org/10.1016/j.jns.2015.09.371DOI Listing
November 2015

Effects of Renal Replacement Therapy in Patients Receiving Extracorporeal Membrane Oxygenation: A Meta-Analysis.

Ann Thorac Surg 2015 Oct 2;100(4):1485-95. Epub 2015 Sep 2.

Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon-si, Kangwon-do, Republic of Korea; Division of Nephrology, School of Medicine, Kangwon National University, Chuncheon-si, Kangwon-do, Republic of Korea. Electronic address:

The use of renal replacement therapy (RRT) in patients receiving extracorporeal membrane oxygenation (ECMO) is increasing, but the effect of RRT on ECMO is controversial. We performed a meta-analysis to determine whether RRT is related to higher mortality in patients receiving ECMO. We searched MEDLINE, EMBASE, the Cochrane Library, and KoreaMed and found 43 observational studies with 21,624 patients receiving ECMO and then compared inpatient mortality rates of patients receiving ECMO both with and without RRT. The risk ratio (RR) of mortality between patients receiving RRT and those not receiving RRT tended to decrease as the mortality of the group not receiving RRT increased. Among patients with RRT use rates of 30% and higher, the overall mortality rates for all patients receiving ECMO tended to decrease. We found that the increase in the RR for RRT tended to be greater the longer the initiation of RRT was delayed. We suggest that in patients receiving ECMO who have high RRT use rates, RRT may decrease mortality rates.
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http://dx.doi.org/10.1016/j.athoracsur.2015.06.018DOI Listing
October 2015

Single intramuscular injection of diclofenac sodium in febrile pediatric patients.

Indian J Pharmacol 2015 May-Jun;47(3):275-9

Department of Emergency Medicine, Kangwon National University Hospital, College of Medicine, Kangwon National University, Chuncheon-si, Republic of Korea.

Objectives: There are few reports on the effectiveness and safety of intramuscular (IM) antipyretic injections in pediatric patients. This study reports the efficacy and adverse effects of a single IM injection of diclofenac sodium in pediatric patients.

Materials And Methods: This was an observational study in which records of febrile pediatric patients presenting to the emergency department were analyzed. Subjects included pediatric patients presenting to the emergency department with a temperature of 38°C or higher. Infants under 12 months of age were excluded. Patients were excluded if they received antipyretics within 4 h prior to presenting to the emergency department. Body temperature was measured at 30-60 min intervals following diclofenac sodium injections. Fever alleviation was defined as the temperature decline to 1°C below the temperature at presentation. Patients who received diclofenac sodium twice or more on different days were observed for side effects such as allergic reaction. Records from the emergency department and outpatient clinics were analyzed.

Results: The dose of diclofenac sodium injected was approximately 2 mg/kg. The average time elapsed until antipyresis was 69.1 ± 23.8 min. The average temperature reduction after 1 h was 1.1 ± 0.6°C. The average proportion of temperature change after 1 h was 40.6 ± 22.2%. During the period at the emergency department, there were no reported serious side effects.

Conclusions: A single dose of diclofenac sodium provided effective antipyresis in pediatric patients. Serious side effects were not observed.
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http://dx.doi.org/10.4103/0253-7613.157122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450552PMC
May 2016

Short-term food restriction followed by controlled refeeding promotes gorging behavior, enhances fat deposition, and diminishes insulin sensitivity in mice.

J Nutr Biochem 2015 Jul 13;26(7):721-8. Epub 2015 Mar 13.

Department of Human Sciences, College of Education and Human Ecology, The Ohio State University, Columbus, OH 43210, USA. Electronic address:

Rodents are commonly used in food restriction refeeding studies to investigate weight regain. Mice that are rationed food every 24 h may consume all allocated food in a short time (gorge) and therefore undergo a brief well-fed period followed by an extended fasted period until the next day's food allotment. These exaggerated metabolic states are not typical in mice fed ad libitum (nibbling). The aim of the current study was to elucidate the intraday and cumulative metabolic consequences of gorging (induced by food restriction) in mice during controlled refeeding. Accordingly, following a temporary food restriction, mice were fed rations similar to intakes of controls fed ad libitum. Temporary food restriction initiated gorging behavior that persisted during refeeding; consequently, metabolism-related measurements were obtained in the gorging mice during their daily fed and fasted metabolic states. Robust differences in adipose tissue lipogenic and inflammatory gene expression were found in the gorging mice by metabolic state (fed versus fasted). Additionally, despite a reduced cumulative food intake compared to mice fed ad libitum, restriction-induced gorging mice had increased intraabdominal fat accumulation, diminished hepatic and peripheral insulin sensitivity, and a gene expression profile favoring lipid deposition. Our findings highlight the intraday differences in gene expression in gorging mice before and after feeding that confound comparisons with mice fed ad libitum, or nibbling. The present study also provides evidence that weight regain following food restriction is associated with cumulative metabolic and behavioral abnormalities in mice.
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http://dx.doi.org/10.1016/j.jnutbio.2015.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461460PMC
July 2015

Activation of sphingosine kinase 2 by endoplasmic reticulum stress ameliorates hepatic steatosis and insulin resistance in mice.

Hepatology 2015 Jul 22;62(1):135-46. Epub 2015 Apr 22.

Department of Life Science, Gachon University, Sungnam, Korea.

Unlabelled: The endoplasmic reticulum (ER) is the principal organelle in the cell for protein folding and trafficking, lipid synthesis, and cellular calcium homeostasis. Perturbation of ER function results in activation of the unfolded protein response (UPR) and is implicated in abnormal lipid biosynthesis and development of insulin resistance. In this study, we investigated whether transcription of sphingosine kinase (Sphk)2 is regulated by ER stress-mediated UPR pathways. Sphk2, a major isotype of sphingosine kinase in the liver, was transcriptionally up-regulated by tunicamycin and lipopolysaccharides. Transcriptional regulation of Sphk2 was mediated by activation of activating transcription factor (ATF)4 as demonstrated by promoter assays, immunoblotting, and small interfering RNA analyses. In primary hepatocytes, adenoviral Sphk2 expression elevated cellular sphingosine 1 phosphate (S1P) and activated protein kinase B phosphorylation, with no alteration of insulin receptor substrate phosphorylation. Hepatic overexpression of Sphk2 in mice fed a high-fat diet (HFD) led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and liver. Hepatic accumulation of lipid droplets by HFD feeding was reduced by Sphk2-mediated up-regulation of fatty acid (FA) oxidizing genes and increased FA oxidation in liver. In addition, glucose intolerance and insulin resistance were ameliorated by improved hepatic insulin signaling through Sphk2 up-regulation.

Conclusion: Sphk2 is transcriptionally up-regulated by acute ER stress through activation of ATF4 and improves perturbed hepatic glucose and FA metabolism.
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http://dx.doi.org/10.1002/hep.27804DOI Listing
July 2015

p63 Expression in the Gerbil Hippocampus Following Transient Ischemia and Effect of Ischemic Preconditioning on p63 Expression in the Ischemic Hippocampus.

Neurochem Res 2015 May 18;40(5):1013-22. Epub 2015 Mar 18.

Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 200-701, South Korea.

p63 is a transcription factor of p53 gene family, which are involved in development, differentiation and cell response to stress; however, its roles in ischemic preconditioning (IPC) in the brain are not clear. In the present study, we investigated the effect of IPC on p63 immunoreactivity caused by 5 min of transient cerebral ischemia in gerbils. IPC was induced by subjecting the gerbils to 2 min of transie ischemia 1 day prior to 5 min of transient ischemia. The animals were randomly assigned to four groups (sham-operated-group, ischemia-operated-group, IPC plus (+)-sham-operated-group and IPC + ischemia-operated-group). The number of viable neurons in the stratum pyramidale of the hippocampal CA1 region (CA1) was significantly increased by IPC + ischemia-operated-group compared with that in the ischemia-operated-group 5 days after ischemic insult. We found that strong p63 immunoreactivity was detected in the CA1 pyramidal neurons in the sham-operated-group, and the immunoreactivity was decreased with time after ischemia-reperfusion. In addition, strong p63 immunoreactivity was newly expressed in microglial cells of the CA1 region from 2 days after ischemia-reperfusion. In all the IPC + sham-operated-groups, p63 immunoreactivity in the CA1 pyramidal neurons was similar to that in the sham-operated-group, and the immunoreactivity was well maintained in the IPC + ischemia-operated-groups after cerebral ischemia. In brief, our present findings show that IPC dramatically protected the reduction of p63 immunoreactivity in the pyramidal neurons of the CA1 region after ischemia-reperfusion, and this result suggests that the expression of p63 may be necessary for neurons to survive after transient cerebral ischemia.
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http://dx.doi.org/10.1007/s11064-015-1556-7DOI Listing
May 2015

A case of primary palmoplantar kaposi sarcoma: an unusual presentation.

Ann Dermatol 2015 Feb 3;27(1):94-6. Epub 2015 Feb 3.

Department of Dermatology, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.5021/ad.2015.27.1.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323613PMC
February 2015

The efficacy of low-dose transdermal fentanyl in opioid-naïve cancer patients with moderate-to-severe pain.

Korean J Intern Med 2015 Jan 30;30(1):88-95. Epub 2014 Dec 30.

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background/aims: Little is known about the efficacy of low-dose transdermal fentanyl (TDF) patches in opioid-naïve patients with moderate-to-severe cancer pain.

Methods: This study had an open-label, prospective design, and was conducted between April 2007 and February 2009 in seven tertiary cancer hospitals; 98 patients were enrolled. TDF was started using a low-dose formulation (12.5 µg/hr), and the dose was adjusted according to the clinical situation of individual patients. Pain intensity, the TDF doses used, and adverse events (AEs) were monitored over 4 weeks. Data were analyzed using the intent-to-treat and per-protocol principles.

Results: Of the 98 patients enrolled, 64 (65%) completed the study. The median pain intensity decreased from 6.0 to 3.0 (p < 0.001) at the follow-up visit. The efficacy of low-dose TDF on pain relief was consistent across groups separated according to gender (p < 0.001), age (p < 0.001), metastasis (p < 0.001), previous treatment (p < 0.001), and baseline pain intensity (p < 0.001). The decrease in pain intensity was significantly greater in the severe group compared with the moderate group (mean ± SD, 5.10 ± 2.48 vs. 2.48 ± 1.56; p < 0.001). TDF dose (27.8 µg/hr vs. 24.8 µg/hr, p = 0.423) and the mean treatment time (7.5 days vs. 7.9 days, p = 0.740) required for pain control were not different between the two pain-intensity groups. Patients had AEs of only mild or moderate intensity; among these, nausea (38%) was the most common, followed by vomiting (22%) and somnolence (22%).

Conclusions: Low-dose TDF was an effective treatment for patients with cancer pain of moderate-to-severe intensity. Further randomized trials assessing the efficacy of TDF for severe pain and/or optimal starting doses are warranted.
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http://dx.doi.org/10.3904/kjim.2015.30.1.88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293569PMC
January 2015