Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications.

Macrophage activation is increased in diabetes and correlated with the onset and progression of vascular complications. To identify drugs that could inhibit macrophage activation, we developed a cell-based assay and screened a 1,040 compound library for anti-inflammatory effects. Beta2-adrenergic receptor (ß2AR) agonists were identified as the most potent inhibitors of phorbol myristate acetate-induced tumor necrosis factor-α production in rat bone marrow macrophages. In peripheral blood mononuclear cells isolated from streptozotocin-induced diabetic rats, ß2AR agonists inhibited diabetes-induced tumor necrosis factor-α production, which was prevented by co-treatment with a selective ß2AR blocker. To clarify the underlying mechanisms, THP-1 cells and bone marrow macrophages were exposed to high glucose. High glucose reduced ß-arrestin2, a negative regulator of NF-κB activation, and its interaction with IκBα. This subsequently enhanced phosphorylation of IκBα and activation of NF-κB. The ß2AR agonists enhanced ß-arrestin2 and its interaction with IκBα, leading to downregulation of NF-κB. A siRNA specific for ß-arrestin2 reversed ß2AR agonist-mediated inhibition of NF-κB activation and inflammatory cytokine production. Treatment of Zucker diabetic fatty rats with a ß2AR agonist for 12 weeks attenuated monocyte activation as well as pro-inflammatory and pro-fibrotic responses in the kidneys and heart. Thus, ß2AR agonists might have protective effects against diabetic renal and cardiovascular complications.

Uremic toxin p-cresol induces Akt-pathway-selective insulin resistance in bone marrow-derived mesenchymal stem cells.

We reported a functional incompetence in mesenchymal stem cells (MSCs) under uremia, but the mechanisms have not been explored. To study the mechanisms of dysfunctional MSCs induced by uremia, we characterized insulin signaling in MSCs and investigated the effect of uremic toxin, p-cresol, on the proangiogenic actions of insulin. In MSCs, insulin induced hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor, and stromal cell-derived factor 1α expressions via PI3K/Akt-dependent pathway. MSCs treated with p-cresol exhibited altered insulin signaling in a selective manner for insulin receptor substrate-1/PI3K/Akt pathway, whereas ERK pathway remained active. The insulin-induced increase of HIF-1α was blunted by p-cresol treatment. This Akt-selective insulin resistance was also observed in MSCs isolated from chronic kidney disease (CKD) mice. In mice model of hindlimb ischemia, blood flow recovery, capillary density, and local production of angiogenic factors in the ischemic limb treated with CKD MSCs were significantly inferior to those promoted by control MSCs. However, modifying CKD MSCs by overexpression of HIF-1α restored all of these changes. Taken together, these data suggest that p-cresol contributes to insulin resistance in a selective manner for Akt pathway. This might be a biological explanation for the functional incompetence of MSCs under uremia through defects in the insulin-induced elevation of HIF-1α protein expression.

MicroRNA-5010-5p ameliorates high-glucose induced inflammation in renal tubular epithelial cells by modulating the expression of PPP2R2D.

INTRODUCTION: We previously reported the significant upregulation of eight circulating exosomal microRNAs (miRNAs) in patients with diabetic kidney disease (DKD). However, their specific roles and molecular mechanisms in the kidney remain unknown. Among the eight miRNAs, we evaluated the effects of miR-5010-5p on renal tubular epithelial cells under diabetic conditions in this study. RESEARCH DESIGN AND METHODS: We transfected the renal tubular epithelial cell line, HK-2, with an miR-5010-5p mimic using recombinant plasmids. The target gene of hsa-miR-5010-5p was identified using a dual-luciferase assay. Cell viability was assessed via the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Moreover, mRNA and protein expression levels were determined via real-time PCR and western blotting, respectively. RESULTS: High glucose levels did not significantly affect the intracellular expression of miR-5010-5p in HK-2 cells. Transfection of the miR-5010-5p mimic caused no change in cell viability. However, miR-5010-5p-transfected HK-2 cells exhibited significantly decreased expression levels of inflammatory cytokines, such as the monocyte chemoattractant protein-1, interleukin-1ß, and tumor necrosis factor-ɑ, under high-glucose conditions. These changes were accompanied by the restored expression of phosphorylated AMP-activated protein kinase (AMPK) and decreased phosphorylation of nuclear factor-kappa B. Dual-luciferase assay revealed that miR-5010-5p targeted the gene, protein phosphatase 2 regulatory subunit B delta (PPP2R2D), a subunit of protein phosphatase 2A, which modulates AMPK phosphorylation. CONCLUSIONS: Our findings suggest that increased miR-5010-5p expression reduces high glucose-induced inflammatory responses in renal tubular epithelial cells via the regulation of the target gene, PPP2R2D, which modulates AMPK phosphorylation. Therefore, miR-5010-5p may be a promising therapeutic target for DKD.

D3S-001, a KRAS G12C inhibitor with rapid target engagement kinetics, overcomes nucleotide cycling and demonstrates robust preclinical and clinical activities.

First-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic "cycling" of KRAS between its GDP- and GTP-bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report D3S-001, a next generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as EGF and HGF, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S-001 contributed to robust anti-tumor activity preclinically and translated into promising clinical activity in an ongoing phase 1 trial (NCT05410145).

Preclinical Study of a Biparatopic METxMET Antibody-Drug Conjugate, REGN5093-M114, Overcomes MET-driven Acquired Resistance to EGFR TKIs in EGFR-mutant NSCLC.

PURPOSE: MET amplification is a frequent mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC), and combined treatment with EGFR TKIs and MET TKIs has been explored as a strategy to overcome resistance. However, durable response is invariably limited by the emergence of acquired resistance. Here, we investigated the preclinical activity of REGN5093-M114, a novel antibody-drug conjugate targeting MET in MET-driven patient-derived models. EXPERIMENTAL DESIGN: Patient-derived organoids, patient-derived cells, or ATCC cell lines were used to investigate the in vitro/in vivo activity of REGN5093-M114. RESULTS: REGN5093-M114 exhibited significant antitumor efficacy compared with MET TKI or unconjugated METxMET biparatopic antibody (REGN5093). Regardless of MET gene copy number, MET-overexpressed TKI-naïve EGFR-mutant NSCLC cells responded to REGN5093-M114 treatment. Cell surface MET expression had the most predictive power in determining the efficacy of REGN5093-M114. REGN5093-M114 potently reduced tumor growth of EGFR-mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior osimertinib and savolitinib treatment. CONCLUSIONS: Altogether, REGN5093-M114 is a promising candidate to overcome the challenges facing functional MET pathway blockade.

Uremia induces functional incompetence of bone marrow-derived stromal cells.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased risk for cardiovascular diseases (CVD). We hypothesized that inadequate angiogenic response in uremic patients could result from dysfunction of bone marrow-derived stromal cells [mesenchymal stem cells (MSCs)]. METHODS: We investigated whether MSCs are functionally competent in uremia induced by partial kidney ablation in C57Bl/6J mice. RESULTS: Uremic MSCs showed decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1 and stromal cell-derived factor (SDF)-1α, increased cellular senescence, decreased proliferation, defects in migration in response to VEGF and SDF-1α and in vitro tube formation. Interestingly, the expression of fibroblast-specific protein-1 was higher in uremic MSCs. Uremia decreased hypoxia-inducible factor-1α, VEGF and VEGFR1 expression under hypoxia and Akt phosphorylation in both basal and VEGF-stimulated states. A diminished mitogenic effect on endothelial proliferation was observed in conditioned media from uremic MSCs. In addition, intravital microscopic analysis showed decreased angiogenesis in uremic MSCs. CONCLUSION: These results clearly demonstrate the functional incompetence in MSCs under uremic conditions and may significantly contribute to the disproportionately high risk for CVD in patients with CKD.

Metformin inhibits chronic kidney disease-induced DNA damage and senescence of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are promising source of cell-based regenerative therapy. In consideration of the risk of allosensitization, autologous MSC-based therapy is preferred over allogenic transplantation in patients with chronic kidney disease (CKD). However, it remains uncertain whether adequate cell functionality is maintained under uremic conditions. As chronic inflammation and oxidative stress in CKD may lead to the accumulation of senescent cells, we investigated cellular senescence of CKD MSCs and determined the effects of metformin on CKD-associated cellular senescence in bone marrow MSCs from sham-operated and subtotal nephrectomized mice and further explored in adipose tissue-derived MSCs from healthy kidney donors and patients with CKD. CKD MSCs showed reduced proliferation, accelerated senescence, and increased DNA damage as compared to control MSCs. These changes were significantly attenuated following metformin treatment. Lipopolysaccharide and transforming growth factor ß1-treated HK2 cells showed lower tubular expression of proinflammatory and fibrogenesis markers upon co-culture with metformin-treated CKD MSCs than with untreated CKD MSCs, suggestive of enhanced paracrine action of CKD MSCs mediated by metformin. In unilateral ureteral obstruction kidneys, metformin-treated CKD MSCs more effectively attenuated inflammation and fibrosis as compared to untreated CKD MSCs. Thus, metformin preconditioning may exhibit a therapeutic benefit by targeting accelerated senescence of CKD MSCs.

Fusobacterium nucleatum Accelerates the Progression of Colitis-Associated Colorectal Cancer by Promoting EMT.

Recently, it has been reported that Fusobacterium nucleatum, a major pathogen involved in chronic periodontitis, may play an important role in colorectal cancer (CRC) progression. In addition, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease represent major predisposing conditions for the development of CRC, and this subtype of cancer is called colitis-associated cancer (CAC). Although the importance of F. nucleatum in CRC has attracted attention, its exact role and related mechanism in CAC progression remain unclear. In this study, we investigated the effects of F. nucleatum in experimental colitis induced with dextran sodium sulfate (DSS), which is a well-known colitis-inducing chemical, on the aggressiveness of CAC and its related mechanism in both in vitro and in vivo models. F. nucleatum synergistically increased the aggressiveness and epithelial-mesenchymal transition (EMT) characteristics of CRC cells that were treated with DSS compared to those in non-treated CRC cells. The role of F. nucleatum in CAC progression was further confirmed in mouse models, as F. nucleatum was found to significantly increase the malignancy of azoxymethane (AOM)/DSS-induced colon cancer. This promoting effect of F. nucleatum was based on activation of the EGFR signaling pathways, including protein kinase B (AKT) and extracellular signal-regulated kinase (ERK), and epidermal growth factor receptor (EGFR) inhibition significantly reduced the F. nucleatum-induced EMT alteration. In conclusion, F. nucleatum accelerates the progression of CAC by promoting EMT through the EGFR signaling pathway.

Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury.

Excessive accumulation of extracellular matrix (ECM) in the kidneys and epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells contributes to the renal fibrosis that is associated with diabetic nephropathy. Histone deacetylase (HDAC) determines the acetylation status of histones and thereby controls the regulation of gene expression. This study examined the effect of HDAC inhibition on renal fibrosis induced by diabetes or transforming growth factor (TGF)-beta1 and determined the role of reactive oxygen species (ROS) as mediators of HDAC activation. In streptozotocin (STZ)-induced diabetic kidneys and TGF-beta1-treated normal rat kidney tubular epithelial cells (NRK52-E), we found that trichostatin A, a nonselective HDAC inhibitor, decreased mRNA and protein expressions of ECM components and prevented EMT. Valproic acid and class I-selective HDAC inhibitor SK-7041 also showed similar effects in NRK52-E cells. Among the six HDACs tested (HDAC-1 through -5 and HDAC-8), HDAC-2 activity significantly increased in the kidneys of STZ-induced diabetic rats and db/db mice and TGF-beta1-treated NRK52-E cells. Levels of mRNA expression of fibronectin and alpha-smooth muscle actin were decreased, whereas E-cadherin mRNA was increased when HDAC-2 was knocked down using RNA interference in NRK52-E cells. Interestingly, hydrogen peroxide increased HDAC-2 activity, and the treatment with an antioxidant, N-acetylcysteine, almost completely reduced TGF-beta1-induced activation of HDAC-2. These findings suggest that HDAC-2 plays an important role in the development of ECM accumulation and EMT in diabetic kidney and that ROS mediate TGF-beta1-induced activation of HDAC-2.

Positive feedback loop between plasminogen activator inhibitor-1 and transforming growth factor-beta1 during renal fibrosis in diabetes.

BACKGROUND/AIMS: Plasminogen activator inhibitor (PAI)-1 is increasingly recognized as a profibrotic factor but the mechanisms are not entirely clear. The present study examined the profibrotic mechanism of PAI-1 focusing on its effect on transforming growth factor (TGF)-beta1 in experimental diabetes. METHODS: PAI-1 knockout (KO) mesangial cells cultured under high glucose (HG) in addition to streptozotocin-induced diabetic PAI-1 KO mice were used. RESULTS: PAI-1 deficiency did not affect plasma glucose significantly but reduced the fractional mesangial area, fibronectin and collagen I expression in the renal cortex after 20 weeks of diabetes as well as in HG-stimulated mesangial cells along with suppression of TGF-beta1 mRNA expression. PAI-1 deficiency also reduced HG-induced betaig-h3, a TGF-beta1-induced gene product, mRNA expression. All these losses-of-function in PAI-1 KO mesangial cells were effectively gained by recombinant PAI-1. Recombinant PAI-1-induced fibronectin and collagen I expression was abrogated by TGF-beta1 receptor inhibitor or anti-TGF-beta antibody suggesting that the effect of PAI-1 was mediated by TGF-beta1. In a similar context, recombinant PAI-1 stimulated TGF-beta1 promoter activity to the same extent as TGF-beta1 itself. CONCLUSION: Since TGF-beta1 is well known to stimulate the PAI-1 promoter, we suggest that TGF-beta1 and PAI-1 together constitute a positive feedback loop in the development of renal fibrosis in diabetes.

Sirt1-hypoxia-inducible factor-1α interaction is a key mediator of tubulointerstitial damage in the aged kidney.

Although it is known that the expression and activity of sirtuin 1 (Sirt1) decrease in the aged kidney, the role of interaction between Sirt1 and hypoxia-inducible factor (HIF)-1α is largely unknown. In this study, we investigated whether HIF-1α could be a deacetylation target of Sirt1 and the effect of their interaction on age-associated renal injury. Five-week-old (young) and 24-month-old (old) C57Bl/6J mice were assessed for their age-associated changes. Kidneys from aged mice showed increased infiltration of CD68-positive macrophages, higher expression of extracellular matrix (ECM) proteins, and more apoptosis than young controls. They also showed decreased Sirt1 expression along with increased acetylated HIF-1α. The level of Bcl-2/adenovirus E1B-interacting protein 3, carbonic anhydrase 9, Snail, and transforming growth factor-ß1, which are regulated by HIF-1α, was significantly higher in aged mice suggesting that HIF-1α activity was increased. In HK-2 cells, Sirt1 inhibitor sirtinol and siRNA-mediated knockdown of Sirt1 enhanced apoptosis and ECM accumulation. During hypoxia, Sirt1 was down-regulated, which allowed the acetylation and activation of HIF-1α. Resveratrol, a Sirt1 activator, effectively prevented hypoxia-induced production of ECM proteins, mitochondrial damage, reactive oxygen species generation, and apoptosis. The inhibition of HIF-1α activity by Sirt1-induced deacetylation of HIF-1α was confirmed by Sirt1 overexpression under hypoxic conditions and by resveratrol treatment or Sirt1 overexpression in HIF-1α-transfected HK-2 cells. Finally, we confirmed that chronic activation of HIF-1α promoted apoptosis and fibrosis, using tubular cell-specific HIF-1α transgenic mice. Taken together, our data suggest that Sirt1-induced deacetylation of HIF-1α may have protective effects against tubulointerstitial damage in aged kidney.

Angiotensin II mediates high glucose-induced TGF-beta1 and fibronectin upregulation in HPMC through reactive oxygen species.

OBJECTIVE: To demonstrate the presence of an independent renin-angiotensin system (RAS) in the peritoneum and to determine the role of locally produced angiotensin (Ang) II in high glucose-induced upregulation of transforming growth factor (TGF)-beta1 and fibronectin by human peritoneal mesothelial cells (HPMC). METHODS: In cultured HPMC, the expression of mRNAs for angiotensinogen, angiotensin-converting enzyme (ACE), Ang II type 1 receptor (AT1), and TGF-beta1 was evaluated by real-time polymerase chain reaction; ACE, AT1, and fibronectin proteins by Western blot analysis; and Ang I, Ang II, and TGF-beta1 proteins by ELISA. Dichlorofluorescein (DCF)-sensitive cellular reactive oxygen species (ROS) were measured by fluorometry. RESULTS: HPMC constitutively expressed all the components of RAS, and 50 mmol/L D-glucose (high glucose) significantly increased angiotensinogen, ACE, and AT1 mRNAs and ACE, AT1, and Ang II proteins. Ang II increased TGF-beta1 and fibronectin protein expression and DCF-sensitive cellular ROS. Losartan prevented Ang II-induced increase in cellular ROS. Both losartan and captopril inhibited high glucose-induced upregulation of TGF-beta1 and fibronectin expression in HPMC in a dose-dependent manner. Antioxidant catalase and NADPH oxidase inhibitor diphenyleneiodinium effectively inhibited Ang II-induced TGF-beta1 and fibronectin protein expression. CONCLUSIONS: The present data demonstrate that HPMC constitutively express RAS, that Ang II produced by HPMC mediates high glucose-induced upregulation of TGF-beta1 and fibronectin expression, and that Ang II-induced TGF-beta1 and fibronectin expression in HPMC is mediated by NADPH oxidase-dependent ROS. These data suggest that locally produced Ang II and ROS in the peritoneum may be potential therapeutic targets in peritoneal fibrosis during long-term peritoneal dialysis.

Four-channel single incision laparoscopic cholecystectomy using a snake retractor: comparison between 3- and 4-channel SILC 4-channel single incision cholecystectomy

PURPOSE: Single incision laparoscopic cholecystectomy (SILC) is a widely used method of performing cholecystectomy. A common technique used in SILC is a 3-channel method. However, exposure of Calot's triangle is limited in conventional 3-channel SILC. Therefore, we herein report the adequacy and feasibility of 4-channel SILC using a snake retractor. METHODS: Four hundred and fifteen SILC cases were performed between April 2010 and February 2013. We performed 326 SILC cases between April 2010 and September 2012 using the 3-channel method. We introduced a snake retractor for liver traction in October 2012, and 89 cases of 4-channel SILC using snake retractor have been performed since. RESULTS: Thirty patients (9.2%) in the 3-channel SILC group, and 23 patients (25.8%) in the 4-channel SILC group, were treated with percutaneous transhepatic gallbladder drainage insertion because of acute inflammation of the gallbladder (GB) before operation (P < 0.001). The mean operating time was 53.0 +/- 25.8 minutes in the 3-channel SILC group and 51.9 +/- 18.6 minutes in the 4-channel SILC group (P = 0.709). In the 3-channel SILC group, mean hospital stay was 3.0 +/- 3.3 days whereas it was 2.6 +/- 0.9 days in the 4-channel SILC group (P = 0.043). There were a total 9 cases (2.1%) of additional port usages, 6 cases (1.8%) in the 3-channel SILC group and 3 cases (3.4%) in the 4-channel SILC group (P = 0.411), due to cystic artery bleeding and bile leakage from gallbladder bed, but there were no open conversions. CONCLUSION: Benign diseases of the GB can be operated on using SILC with the 4-channel method using a snake retractor.

Single incision laparoscopic cholecystectomy using Konyang Standard Method

PURPOSE: Single incision laparoscopic cholecystectomy (SILC) is a minimally invasive surgery that is growing rapidly among surgical procedures. However, there is no standard method for SILC. Therefore, we evaluated the adequacy and feasibility of SILC using Konyang Standard Method. METHODS: We retrospectively reviewed our series of 307 SILCs performed between April 2010 and August 2012. Initially we excluded the patients who were more than 70 years old, had cardiologic or pulmonologic problems and complications of acute cholecystitis. After 50 cases, we did not apply the exclusion criteria. We performed SILC by Konyang Standard Method using three-trocar single port (hand-made) and long articulated instruments. RESULTS: Three hundred and seven patients underwent SILC. Male were 131 patients and female were 176 patients. Mean age was 51.6 +/- 13.7 years old and mean body mass index was 24.8 +/- 3.6 kg/m2. Ninety-three patients had histories of previous abdominal operation. Patient's pathologies included: chronic cholecystitis (247 cases), acute cholecystitis (30 cases), gall bladder (GB) polyps (24 cases), and GB empyema (6 cases). Mean operating time was 53.1 +/- 25.4 minutes and mean hospital stay was 2.9 +/- 3.4 days. There were four cases of 3-4 ports conversion due to cystic artery bleeding. Complications occurred in 5 cases including wound infection (2 cases), bile duct injury (1 case), duodenal perforation (1 case), and umbilical hernia (1 case). CONCLUSION: SILC using Konyang Standard Method is safe and feasible. Therefore, our standard procedure can be applied to almost all benign GB disease.

Is Biliary Drainage Really Necessary after Laparoscopic Common Bile Duct Exploration?

PURPOSE: Laparoscopic common bile duct exploration (LCBDE) has been the alternative treatment in patients who have failed endoscopic removal. Until now, biliary drainage has been performed as a customary practice after LCBDE in order to prevent complication or to prevent remnant stones from draining out; however, the drainage was often caused by other complications. For this reason, we have been performing LCBDE with primary closure. The aim of this study was to report on the efficacy and safety of primary closure. METHODS: Of 207 cases of common bile duct stones with performance of LCBDE from March 2001 to January 2013, 199 cases were included. Eight cases were excluded due to the open conversion. The 199 patients were subdivided into the primary closure group (P-group) and the drainage group (D-group). RESULTS: Of 199 patients, there were 36 (18.1%) with primary closure, and 163 (81.9%) with drainage. No significant difference in characteristics was observed between the two groups, except for smaller stones in the P-group (11.4+/-6.0 mm, 16.2+/-8.0 mm, p<0.01). Mean number of postoperative hospital days was significantly shorter in the P-group (6.0+/-3.1 days, 7.6+/-3.8 days, p=0.019). The rate of postoperative complications was higher in the D-group, but showed no statistical significance. There were six cases of bile leakage in the D-group, and two cases in the P-group, but without statistical significance (p=0.638). The recurrence rate was significantly lower in the P-group (5.6%, 22.1%, p=0.02). CONCLUSION: In the P-group, the number of mean postoperative hospital days was lower, and a lower rate of recurrence was observed. Compared with other types of drainage after LCBDE, the primary closure would be a sufficient method. Therefore, it can be regarded as safe enough and feasible.

Comparison of Single Incision and Three Port Laparoscopic Cholecystectomy

PURPOSE: Laparoscopic surgery is a minimally invasive surgery which has been widely used in abdominal surgery, such as appendectomy and cholecystectomy. There were several strong points in single incision laparoscopic cholecystectomy (SILC). However, no definite study comparing SILC with three port laparoscopic cholecystectomy (TPLC) has been reported. Therefore, this study focused on feasibility and safety of SILC in comparison with conventional TPLC. METHODS: This study included 86 cases of SILC and 230 cases of TPLC from April, 2010 to February, 2011. The patients were divided into two groups according to the surgical procedure, group 1 was SILC and group 2 was TPLC. All operations were performed by a single surgeon, and the retrograde approach was the fundamental surgical procedure used in both groups. RESULTS: Eighty five patients in group 1 underwent SILC and 229 patients in group 2 underwent TPLC. In comparison of preoperative data, statistical significance regarding age, gender, and preoperative PTGBD insertion was observed between the two groups. In comparison of intraoperative data, the average operation time and average hospital day did not show any statistical significance. Intraoperative multiple port conversion was performed in group 1 to TPLC due to cystic artery bleeding, and in group 2, TPLC was changed into a four port operation due to the same reason. CONCLUSION: In this study, no significant difference in operation result, time, and acute complication was observed between SILC and conventional TPLC. Besides the cancers, SILC could definitely be applied without exclusion criteria mentioned above if improvement of instruments and accumulation of surgeon's experience were satisfied.

The learning curve for laparoscopic totally extraperitoneal herniorrhaphy by moving average / 대한외과학회지

PURPOSE: Laparoscopic totally extraperitoneal (TEP) herniorrhaphy has been recognized as a treatment option for inguinal hernia. The objective of this study was to clarify the learning curve for laparoscopic TEP herniorrhaphy using the moving average method. METHODS: A total of 90 patients underwent laparoscopic TEP herniorrhaphy by a single surgeon between March 2009 and March 2011. We analyzed medical records including the demographic data, operating time, hospital stay, and postoperative complications. RESULTS: The mean operating time of the initial 30 cases (learning period group) was 66.3 minutes. After the initial 30 cases were performed, the time decreased to 52.8 minutes in the later 60 cases (experienced period group, P = 0.015). This represents the operating time becoming stabilized and then decreasing as the number of performed cases accumulates. Hospital stay was shorter and frequency of pain control, and complication rate were lower in the experienced period, however, there was no statistical significance. CONCLUSION: We suggest that number of patients needed for the learning curve for laparoscopic TEP herniorrhaphy should be 30 cases. The operating time for laparoscopic TEP herniorrhaphy stabilizes after 40 cases in moving average analysis.

Mesenteric Pseudocyst of the Small Bowel in Gastric Cancer Patient: A Case Report

Mesenteric pseudocyst is rare. This term is used to describe the abdominal cystic mass, without the origin of abdominal organ. We presented a case of mesenteric pseudocyst of the small bowel in a 70-year-old man. Esophago-gastro-duodenoscopy showed a 3.5 cm sized excavated lesion on the posterior wall of angle. Endocopic biopsy confirmed a histologic diagnosis of the poorly differentiated adenocarcinoma, which includes the signet ring cell component. Abdominal computed tomography scan showed a focal mucosal enhancement in the posterior wall of angle of the stomach, a 2.4 cm sized enhancing mass on the distal small bowel loop, without distant metastases or ascites in rectal shelf, and multiple gallbladder stones. The patient underwent subtotal gastrectomy with gastroduodenostomy, segmental resection of the small bowel, and cholecystectomy. The final pathological diagnosis was mesenteric pseudocyst. This is the first case report describing incidentally detected mesenteric pseudocyst of the small bowel in gastric cancer patients.

Extensive Visceral Vein Thrombosis Associated with Deep Vein Thrombosis

Extensive visceral vein thrombosis, including the femoral vein, iliac vein, superior mesenteric vein, splenic vein and portal vein, is an uncommon type of thrombosis that is associated with significant mortality and morbidity. Making an early diagnosis and adequate management are very important. We present here the case of a 39-year-old woman with extensive visceral vein thrombosis and complicated small bowel necrosis and perforation. She had no known prothrombotic conditions, but the laboratory findings showed an elevated level of factor VIII. The patient's condition improved without complication after resection of the infarcted and perforated small bowel along with immediate postoperative anticoagulant therapy. On the follow up, the size of the thrombosis was decreased and there was no complication.

Extension of Nonoperative Management on Spleen Injury with Judicious Selection and Embolization; 10 Years of Experience

PURPOSE: We describe clinical outcomes of NOM on spleen injuries with judicious selection and embolization during the past 10 years. METHODS: From March 2000 to November 2009, 151 patients with splenic injury were included. Eighteen patients were excluded because of incomplete data. Patients' medical records were reviewed to examine admission demographics, laboratory results, radiologic findings as well as transfusion requirement, hospital stay, and ultimate outcomes. RESULTS: Twenty patients were chosen for non-operative management (NOM) after splenic embolization and 1/20 (5%) patient failed. There were 32 patients more than 55 years old (range, 55~87 years). Of these patients, 26 (81%) patients were chosen for NOM and 3 (11.5%) patients failed. According to OIS, 51 patients were grade 3; 26 patients, grade 4; and 6 patients, grade 5. Among grade 3, 49 (96%) were chosen for NOM with or without embolization and 1 (2%) patient failed; grade 4, 19 (73%) with NOM, 2 (7.6%) patients failed. Of all 133 patients with NOM or failed NOM (FNOM), there was 0 mortality in grade 3; 2, in grade 4; 2, in grade 5, excluding other causes of death. The mean ISS was significantly higher in the failed NOM group compared with successful NOM group (P=0.01). The group of failed NOM had a significantly higher mean OIS (P=0.00). CONCLUSION: Aggressive but highly selective NOM on the base of clinicoradiologic parameters with the aid of angioembolization would result in a low failure rate and complication in the management of high grades (grade 3 or 4).