The solid predominant subtype as an independent risk factor for recurrence in patients with pathologic stage I lung adenocarcinoma / 고신대학교의과대학학술지

Background@#Increasingly many patients have been diagnosed with stage I adenocarcinoma due to the use of low-dose chest computed tomography for lung cancer screening. Therefore, this study aimed to analyze tumor recurrence based on the predominant subtype in patients with stage I lung adenocarcinoma who underwent lobectomy. @*Methods@#We retrospectively analyzed 114 patients who underwent lobectomy for pathologic stage I lung adenocarcinoma from June 2001 to July 2019. @*Results@#In univariate analyses, significant factors were current smoking at the time of surgery (p=0.029), pathologic tumor size (p=0.006), central tumor location (p=0.003), maximum standardized uptake value on positron emission tomography-computed tomography (p=0.001), and the solid predominant subtype (p=0.012). In the multivariate analysis, only the solid predominant subtype (hazard ratio, 9.702; 95% confidence interval, 1.179–79.874; p=0.035) was an independent risk factor. @*Conclusions@#If the solid subtype is predominant in pathologic findings, adjuvant chemotherapy after standard surgical resection may be considered to help reduce the risk of tumor recurrence and increase survival.

Incidence of arterial steno-occlusive disease and related factors in patients undergoing coronary artery bypass graft surgery / 고신대학교의과대학학술지

Background@#Patients who undergo coronary artery bypass graft (CABG) surgery receive regular physical examinations and medications on an outpatient basis. However, these patients are at risk of developing other vascular diseases, such as postoperative arterial steno-occlusive disease (SOD). This study investigated the incidence of SOD and related factors. @*Methods@#In total, 246 patients who underwent CABG surgery from January 1, 2017 to December 31, 2021 were investigated. The incidence and risk factors of vascular disease were analyzed by dividing the included patients into SOD and non-SOD groups. Laboratory tests, medical history, surgical information, and family history were investigated through an electronic chart review. @*Results@#Data from 193 patients who met the criteria were analyzed. SOD occurred in 19.1% of patients, and the cerebral artery (38%) was the most common artery involved, followed by the peripheral artery (32%), the coronary artery (22%), and the retinal artery (8%). Risk factors for the development of SOD included estimated glomerular filtration rate (eGFR; odds ratio [OR]=0.977, p=0.008), cholesterol (OR=1.020, p=0.001), and patients with diabetes complications (OR=5.077, p=0.010). The 3-year cumulative incidence rate was 21.6%, and the risk factors for cumulative occurrence were a low eGFR, elevated cholesterol, and complications of diabetes. @*Conclusions@#Low eGFR, high cholesterol, and the presence of diabetic complications before CABG surgery may be associated with postoperative vascular disease. In these cases, close monitoring, proper drug administration, and patient warnings may be required.

Surgical Outcomes of Type A Aortic Dissection at a Small- Volume Medical Center: Analysis according to the Extent of Surgery

Background@#Despite progress in treatment, Stanford type A aortic dissection is still a life-threatening disease. In this study, we analyzed surgical outcomes in patients with Stanford type A aortic dissection according to the extent of surgery at Daegu Catholic University Medical Center. @*Methods@#We retrospectively analyzed 98 patients with Stanford type A aortic dissection who underwent surgery at our institution between January 2008 and June 2018. Of these patients, 82 underwent limited replacement (hemi-arch or ascending aortic replacement), while 16 patients underwent total arch replacement (TAR). We analyzed in-hospital mortality, postoperative complications, the overall 5-year survival rate, and the 5-year aortic event-free survival rate. @*Results@#The median follow-up time was 48 months (range, 1–128 months), with a completion rate of 85.7% (n=84). The overall in-hospital mortality rate was 8.2%: 6.1% in the limited replacement group and 18.8% in the TAR group (p=0.120). The overall 5-year survival rate was 78.8% in the limited replacement group and 81.3% in the TAR group (p=0.78). The overall 5-year aortic event-free survival rate was 85.3% in the limited replacement group and 88.9% in the TAR group (p=0.46). @*Conclusion@#The extent of surgery was not related to the rates of in-hospital mortality, complications, aortic events, or survival. Although this study was conducted at a small-volume center, the in-hospital mortality and 5-year survival rates were satisfactory.

Mid-Term Results of Using the Seal Thoracic Stent Graft in Cases of Aortopathy: A Single-Institution Experience

BACKGROUND@#The endovascular approach to aortic disease treatment has been increasingly utilized in the past 2 decades. This study aimed to determine the long-term results of using the Seal thoracic stent graft.@*METHODS@#We retrospectively reviewed the outcomes of patients who underwent thoracic endovascular aortic repair or a hybrid procedure using the Seal thoracic stent graft (S&G Biotech, Seongnam, Korea) from January 2008 to July 2018 at a single institution. We investigated in-hospital mortality and the incidence of postoperative complications. We also investigated the mid-term survival rate and incidence of aorta-related complications.@*RESULTS@#Among 72 patients with stent grafts, 15 patients underwent the hybrid procedure and 21 underwent emergency surgery. The mean follow-up period was 37.86±30.73 months (range, 0–124 months). Five patients (6.9%) died within 30 days. Two patients developed cerebrovascular accidents. Spinal cord injury occurred in 2 patients. Postoperative renal failure, postoperative extracorporeal membrane oxygenation support, and pneumonia were reported in 3, 1, and 6 patients, respectively. Stent-related aortic complications were observed in 5 patients (6.8%). The 1- and 5-year survival and freedom from stent-induced aortic event rates were 81.5% and 58.7%, and 97.0% and 89.1%, respectively.@*CONCLUSION@#The use of the Seal thoracic stent graft yielded good mid-term results. Further studies are needed to examine the long-term outcomes of this device.

Preoperative Risk Factors for Pathologic N2 Metastasis in Positron Emission Tomography-Computed Tomography–Diagnosed N0–1 Non-Small Cell Lung Cancer

BACKGROUND@#Accurate mediastinal lymph node staging is vital for the optimal therapy and prognostication of patients with lung cancer. This study aimed to determine the preoperative risk factors for pN2 disease, as well as its incidence and long-term outcomes, in patients with clinical N0–1 non-small cell lung cancer.@*METHODS@#We retrospectively analyzed patients who were treated surgically for primary non-small cell lung cancer from November 2005 to December 2014. Patients staged as clinical N0–1 via chest computed tomography (CT) and positron emission tomography (PET)-CT were divided into two groups (pN0–1 and pN2) and compared.@*RESULTS@#In a univariate analysis, the significant preoperative risk factors for pN2 included a large tumor size (p=0.083), high maximum standard uptake value on PET (p<0.001), and central location of the tumor (p<0.001). In a multivariate analysis, central location of the tumor (p<0.001) remained a significant preoperative risk factor for pN2 status. The 5-year overall survival rates were 75% and 22.9% in the pN0–1 and pN2 groups, respectively, and 50% and 78.2% in the patients with centrally located and peripherally located tumors, respectively. In a Cox proportional hazard model, central location of the tumor increased the risk of death by 3.4-fold (p<0.001).@*CONCLUSION@#More invasive procedures should be considered when pre-operative risk factors are identified in order to improve the efficacy of diagnostic and therapeutic plans and, consequently, the patient’s prognosis.

Erratum: Staged Surgical Treatment of Primary Aortoesophageal Fistula

One author was missed.

Mid-Term Results of Using the Seal Thoracic Stent Graft in Cases of Aortopathy: A Single-Institution Experience / 대한흉부외과학회지

BACKGROUND: The endovascular approach to aortic disease treatment has been increasingly utilized in the past 2 decades. This study aimed to determine the long-term results of using the Seal thoracic stent graft. METHODS: We retrospectively reviewed the outcomes of patients who underwent thoracic endovascular aortic repair or a hybrid procedure using the Seal thoracic stent graft (S&G Biotech, Seongnam, Korea) from January 2008 to July 2018 at a single institution. We investigated in-hospital mortality and the incidence of postoperative complications. We also investigated the mid-term survival rate and incidence of aorta-related complications. RESULTS: Among 72 patients with stent grafts, 15 patients underwent the hybrid procedure and 21 underwent emergency surgery. The mean follow-up period was 37.86±30.73 months (range, 0–124 months). Five patients (6.9%) died within 30 days. Two patients developed cerebrovascular accidents. Spinal cord injury occurred in 2 patients. Postoperative renal failure, postoperative extracorporeal membrane oxygenation support, and pneumonia were reported in 3, 1, and 6 patients, respectively. Stent-related aortic complications were observed in 5 patients (6.8%). The 1- and 5-year survival and freedom from stent-induced aortic event rates were 81.5% and 58.7%, and 97.0% and 89.1%, respectively. CONCLUSION: The use of the Seal thoracic stent graft yielded good mid-term results. Further studies are needed to examine the long-term outcomes of this device.

Preoperative Risk Factors for Pathologic N2 Metastasis in Positron Emission Tomography-Computed Tomography–Diagnosed N0–1 Non-Small Cell Lung Cancer / 대한흉부외과학회지

BACKGROUND: Accurate mediastinal lymph node staging is vital for the optimal therapy and prognostication of patients with lung cancer. This study aimed to determine the preoperative risk factors for pN2 disease, as well as its incidence and long-term outcomes, in patients with clinical N0–1 non-small cell lung cancer. METHODS: We retrospectively analyzed patients who were treated surgically for primary non-small cell lung cancer from November 2005 to December 2014. Patients staged as clinical N0–1 via chest computed tomography (CT) and positron emission tomography (PET)-CT were divided into two groups (pN0–1 and pN2) and compared. RESULTS: In a univariate analysis, the significant preoperative risk factors for pN2 included a large tumor size (p=0.083), high maximum standard uptake value on PET (p<0.001), and central location of the tumor (p<0.001). In a multivariate analysis, central location of the tumor (p<0.001) remained a significant preoperative risk factor for pN2 status. The 5-year overall survival rates were 75% and 22.9% in the pN0–1 and pN2 groups, respectively, and 50% and 78.2% in the patients with centrally located and peripherally located tumors, respectively. In a Cox proportional hazard model, central location of the tumor increased the risk of death by 3.4-fold (p<0.001). CONCLUSION: More invasive procedures should be considered when pre-operative risk factors are identified in order to improve the efficacy of diagnostic and therapeutic plans and, consequently, the patient’s prognosis.

Erratum: Staged Surgical Treatment of Primary Aortoesophageal Fistula / 대한흉부외과학회지

One author was missed.

Leigh Syndrome: Subgroup Aanalysis according to Mitochondrial DNA Mutation / 대한소아신경학회지

PURPOSE: Leigh syndrome (LS) is a rare, progressive neurodegenerative disorder with characteristic abnormalities in the central nervous system. Such patients present with heterogeneous clinical symptoms and genetic abnormalities; thus, prognosis is difficult to anticipate. The present study investigates whether distinct patient characteristics are associated with mitochondrial DNA (mtDNA) mutation in LS patients. METHODS: We retrospectively analyzed data from patients diagnosed with LS at our hospital who were assessed using genomic sequencing of mtDNA. A subgroup analysis was performed to divide patients according to the mtDNA sequencing results. RESULTS: Among the 85 patients enrolled, 18 had mtDNA mutations. Most patients had lactic acidosis and a lactate/pyruvate ratio above 20, indicating respiratory chain abnormalities. In the subgroup analysis, the mutation group had a significantly higher female-to-male ratio, alanine level, ocular involvement, and midbrain and medulla abnormalities on magnetic resonance imaging (MRI). CONCLUSION: The subgroup analysis indicates that mtDNA sequencing is recommended for female patients, or those who exhibit ocular involvement, high alanine levels, or MRI findings with lesions in the midbrain and medulla.

Hepatocyte toll-like receptor 4 mediates lipopolysaccharide-induced hepcidin expression

Hepcidin expression is induced by inflammatory molecules such as lipopolysaccharide (LPS) via a macrophage-mediated pathway. Although hepatocytes directly respond to LPS, the molecular mechanism underlying toll-like receptor (TLR)-dependent hepcidin expression by hepatocytes is mostly unknown. Here we show that LPS can directly induce the mRNA expression and secretion of hepcidin by hepatocytes via TLR4 activation. Using hepatocytes deficient in TLR4, myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor inducing interferon-β (TRIF), we demonstrated that LPS-induced hepcidin expression by hepatocytes is regulated by its specific receptor, TLR4, via a MyD88-dependent signaling pathway. Hepcidin promoter activity was significantly increased by MyD88-dependent downstream signaling molecules (interleukin-1 receptor-associated kinase (IRAK) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which activate c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1). We then confirmed that LPS stimulation induced the phosphorylation of JNK and c-Jun, and observed strong occupancy of the hepcidin promoter by c-Jun. Promoter mutation analysis also identified the AP-1-binding site on the hepcidin promoter. Finally, bone marrow transplantation between wild-type and TLR4 knockout mice revealed that hepatic TLR4-dependent hepcidin expression was comparable to macrophage TLR4-dependent hepcidin expression induced by LPS. Taken together, these results suggest that TLR4 expressed by hepatocytes regulates hepcidin expression via the IRAK–TRAF6–JNK–AP-1 axis.

Identification of the Mutations in the Prostaglandin Transporter Gene, SLCO2A1 and Clinical Characterization in Korean Patients with Pachydermoperiostosis

Pachydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy, is a rare genetic disease affecting both skin and bones. Both autosomal dominant with incomplete penetrance and recessive inheritance of PDP have been previously confirmed. Recently, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1) were reported as pathogenic genes responsible for PDP. Both genes are involved in prostaglandin E2 (PGE2) degradation. We aimed to identify responsible genes for PDP and the clinical features in Korean patients with PDP. Six affected individuals and their available healthy family members from three unrelated Korean families with PDP were studied. All of the patients displayed complete phenotypes of PDP with finger clubbing, pachydermia, and periostosis. Mutation analysis revealed a novel heterozygous mutation in the SLCO2A1 gene at nucleotide 302 causing a substitution of the amino acid isoleucine to serine at codon 101 (p.IIe101Ser) in affected individuals. We also identified known SLCO2A1 mutations, one homozygous for c.940+1G>A, and another compound heterozygous for c.940+1G>A and c.1807C>T (p.Arg603*) from two PDP families. Genetic analyses of the PDP patients showed no abnormality in the HPGD gene. Our study further supports the role of mutations in the SLCO2A1 gene in the pathogenesis of PDP and could provide additional clues to the genotype-phenotype relations of PDP.

STEP signaling pathway mediates psychomotor stimulation and morphine withdrawal symptoms, but not for reward, analgesia and tolerance

Striatal-enriched protein tyrosine phosphatase (STEP) is abundantly expressed in the striatum, which strongly expresses dopamine and opioid receptors and mediates the effects of many drugs of abuse. However, little is known about the role of STEP in opioid receptor function. In the present study, we generated STEP-targeted mice carrying a nonsense mutation (C230X) in the kinase interaction domain of STEP by screening the N-ethyl-N-nitrosourea (ENU)-driven mutant mouse genomic DNA library and subsequent in vitro fertilization. It was confirmed that the C230X nonsense mutation completely abolished functional STEP protein expression in the brain. STEP(C230X−/−) mice showed attenuated acute morphine-induced psychomotor activity and withdrawal symptoms, whereas morphine-induced analgesia, tolerance and reward behaviors were unaffected. STEP(C230X−/−) mice displayed reduced hyperlocomotion in response to intrastriatal injection of the μ-opioid receptor agonist DAMGO, but the behavioral responses to δ- and κ-opioid receptor agonists remained intact. These results suggest that STEP has a key role in the regulation of psychomotor action and physical dependency to morphine. These data suggest that STEP inhibition may be a critical target for the treatment of withdrawal symptoms associated with morphine.

Corrigendum: Moderate and Deep Hypothermia Produces Hyporesposiveness to Phenylephrine in Isolated Rat Aorta

There was an error in article.

Pharmacogenomic Assessment of Outcomes of Pemetrexed-Treated Patients with Adenocarcinoma of the Lung

PURPOSE: The main objective of this study was to evaluate the association between polymorphisms of the target genes of pemetrexed and clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with pemetrexed. MATERIALS AND METHODS: We assessed polymorphisms at 8 sites in 4 genes [thymidylate synthase (TS), dihydrofolate reductase (DHFR; 1610, 680, 317, intron 1), methylenetetrahydrofolate reductase (MTHFR; 677, 1298), glycinamide ribonucleotide formyl transferase (GARFT; 2255)] associated with pemetrexed metabolism using polymerase chain reaction, gene scanning, and restriction fragment length polymorphism analysis in 90 patients with adenocarcinoma of the lung. RESULTS: Survival was significantly longer with pemetrexed in patients with TS 3RGCC/3RGCC or 3RGGC/3RGGC compared with the other groups (PFS; 5.2 months vs. 3.7 months, p=0.03: OS; 31.8 months vs. 18.5 months, p=0.001). Patients with DHFR 680CC experienced fatigue more frequently (50% vs. 8.6%, p=0.008). Polymorphisms of MTHFR and GARFT were not significantly associated with clinical outcomes of pemetrexed. CONCLUSION: The TS genotype was associated with survival and one DHFR polymorphism was associated with fatigue in NSCLC patients treated with pemetrexed. Further large prospective studies are required to identify other biomarkers that affect patients being treated with pemetrexed for adenocarcinoma of the lung.

Moderate and Deep Hypothermia Produces Hyporesposiveness to Phenylephrine in Isolated Rat Aorta

BACKGROUND: Moderate and severe hypothermia with cardiopulmonary bypass during aortic surgery can cause some complications such as endothelial cell dysfunction or coagulation disorders. This study found out the difference of vascular reactivity by phenylephrine in moderate and severe hypothermia. METHODS: Preserved aortic endothelium by excised rat thoracic aorta was sectioned, and then down the temperature rapidly to 25degrees C by 15 minutes at 38degrees C and then the vascular tension was measured. The vascular tension was also measured in rewarming at 25degrees C for temperatures up to 38degrees C. To investigate the mechanism of the changes in vascular tension on hypothermia, NG-nitro-L-arginine methyl esther (L-NAME) and indomethacin administered 30 minutes before the phenylephrine administration. And to find out the hypothermic effect can persist after rewarming, endothelium intact vessel and endothelium denuded vessel exposed to hypothermia. The bradykinin dose-response curve was obtained for ascertainment whether endothelium-dependent hyperpolarization factor involves decreasing the phenylnephrine vascular reactivity on hypothermia. RESULTS: Fifteen minutes of the moderate hypothermia blocked the maximum contractile response of phenylephrine about 95%. The vasorelaxation induced by hypothermia was significantly reduced with L-NAME and indomethacin administration together. There was a significant decreasing in phenylephrine susceptibility and maximum contractility after 2 hours rewarming from moderate and severe hypothermia in the endothelium intact vessel compared with contrast group. CONCLUSION: The vasoplegic syndrome after cardiac surgery might be caused by hypothermia when considering the vascular reactivity to phenylephrine was decreased in the endothelium-dependent mechanism.

Mitochondrial dysfunction and activation of iNOS are responsible for the palmitate-induced decrease in adiponectin synthesis in 3T3L1 adipocytes

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are considered the key determinants of insulin resistance. Impaired mitochondrial function in obese animals was shown to induce the ER stress response, resulting in reduced adiponectin synthesis in adipocytes. The expression of inducible nitric oxide synthase (iNOS) is increased in adipose tissues in genetic and dietary models of obesity. In this study, we examined whether activation of iNOS is responsible for palmitate-induced mitochondrial dysfunction, ER stress, and decreased adiponectin synthesis in 3T3L1 adipocytes. As expected, palmitate increased the expression levels of iNOS and ER stress response markers, and decreased mitochondrial contents. Treatment with iNOS inhibitor increased adiponectin synthesis and reversed the palmitate-induced ER stress response. However, the iNOS inhibitor did not affect the palmitate-induced decrease in mitochondrial contents. Chemicals that inhibit mitochondrial function increased iNOS expression and the ER stress response, whereas measures that increase mitochondrial biogenesis (rosiglitazone and adenoviral overexpression of nuclear respiratory factor-1) reversed them. Inhibition of mitochondrial biogenesis prevented the rosiglitazone-induced decrease in iNOS expression and increase in adiponectin synthesis. These results suggest that palmitate-induced mitochondrial dysfunction is the primary event that leads to iNOS induction, ER stress, and decreased adiponectin synthesis in cultured adipocytes.

EGFR Polymorphism as a Predictor of Clinical Outcome in Advanced Lung Cancer Patients Treated with EGFR-TKI

PURPOSE: Mutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of the efficacy of treatment with EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR gene were associated with clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with EGFR-TKI. MATERIALS AND METHODS: A polymorphic dinucleotide repeat in intron 1 [CA simple sequence repeat in intron 1(CA-SSR1)] in intron 1 and single nucleotide polymorphisms (SNP-216) in the promoter region of the EGFR gene were evaluated in 71 NSCLC patients by restriction fragment length polymorphism and DNA sequencing. The relationship between genetic polymorphisms and clinical outcomes of treatment with EGFR-TKIs was evaluated. RESULTS: SNP-216G/T polymorphisms were associated with the efficacy of EGFR-TKI. The response rate for the SNP-216G/T tended to be higher than that for G/G (62.5% vs. 27.4%, p=0.057). The SNP-216G/T genotype was also associated with longer progression-free survival compared with the GG genotype (16.7 months vs. 5.1 months, p=0.005). However, the length of CA-SSR1 was not associated with the efficacy of EGFR-TKI. CONCLUSION: SNP-216G/T polymorphism was a potential predictor of clinical outcomes in NSCLC patients treated with EGFR-TKI.

Severe Mitral Regurgitation due to Traumatic Anterolateral Papillary Muscle Rupture: A Case Report

A 29-year-old man was admitted for abrupt dyspnea and hemoptysis. An echocardiogram revealed severe mitral regurgitation due to papillary muscle rupture for which an emergency mitral valve replacement operation was performed 4 days after admission. Herein, we report our experience with this case along with a review of the literature.

A Korean Patient with Kniest Syndrome associated with Lipomeningomyelocele

Kniest syndrome (OMIM #156550) is a rare autosomal dominant disorder caused by a dysfunction of type II collagen, which is encoded by the COL2A1 gene (OMIM +120140) mapped to chromosome 12q13.11. Type II collagen, a molecule found mostly in the cartilage and vitreous tissues, is essential for the normal development of bones and other connective tissues. Kniest syndrome is a type II collagenopathy that presents as skeletal abnormality associated with disproportionate dwarfism, kyphoscoliosis, enlarged joints, visual loss, hearing loss, and cleft palate. This report describes a Korean patient with Kniest syndrome who was diagnosed with typical clinical features and radiologic findings. The patient presented with disproportionately short stature and kyphoscoliosis from birth. A skeletal survey revealed fused lamina in the thoracic spine, hemivertebrae, flexion deformities in multiple joints, and plagiocephaly.