Current status of endoscopic submucosal dissection for the management of early gastric cancer:A Korean perspective

The early diagnosis of gastric cancer allows patients and physicians to pursue the option of endoscopic resection,which is significantly less invasive than conventional surgical resection.In Korea,the use of endoscopic submucosal dissection(ESD) has been increasing,and many reports on ESD have been published.In addition,Korean gastroenterologists from several hospitals performing ESD have conducted formal meetings to discuss useful information regarding ESD.Here,we discuss the Korean experience with ESD,including outcomes and prospects of endoscopic treatments.

Clinical effectiveness of diquafosol ophthalmic solution 3%in Korean patients with dry eye disease:a multicenter prospective observational study

AIM:To investigate the effectiveness of diquafosol ophthalmic solution 3%administered in Korean patients with dry eye disease in real-world clinical settings.METHODS:Diquafosol was administered for 8 wk to 3 patient groups who received diquafosol as add-on therapy to existing medication(Add group,n=150);received diquafosol only(Monotherapy group,n=196);or discontinued part of their existing medication in favor of diquafosol(Switch group,n=11).Tear break-up time(TBUT),cornea and conjunctival staining based on National Eye Institute/Industry scoring scheme,subjective symptoms using the Ocular Surface Disease Index(OSDI)questionnaire,and meibum quality and expressibility were evaluated at baseline,week 4,and week 8.RESULTS:The mean TBUT increased(from 3.46,3.92,and 5.84 s,respectively,to 5.15,5.53,and 8.59 s,respectively)and corneal staining score decreased(from 2.23,2.24,and 3.09,respectively,to 0.85,0.97,and 1.64,respectively)in a time-dependent manner from baseline to week 8 in all three groups.Conjunctival staining score,OSDI questionnaire,and meibum quality and expressibility improved over time from baseline to week 8 in the Add and Monotherapy groups,but differences were not statistically significant in the Switch group.CONCLUSION:Diquafosol improves subjective symptoms and objective signs in patients treated with existing medicines combined with diquafosol and treated solely with diquafosol.Diquafosol can be used as an effective therapeutic agent for dry eye disease or additionally applied in patients who have insufficient response to existing medicines.

Efficacy and safety of oral SK3530 for the treatment of erectile dysfunction in Korean men： a multicenter, randomized, doubleblind, placebo-controlled, fixed dose, parallel group clinical trial

Aim： To evaluate the efficacy and safety of SK3530, a newly developed type 5 phosphodiesterase inhibitor （PDE5I）, in Korean men with erectile dysfunction （ED）. Methods： A total of 119 patients were randomized at 10 centers in Korea to receive either SK3530 （50, 100, or 150 mg; n = 89） or placebo （n = 30） taken 1 h before anticipated sexual activity for an 8-week period. The patients were evaluated at baseline and 4 and 8 weeks after beginning therapy. Efficacy was assessed using the International Index of Erectile Function （IIEF）, Sexual Encounter Profile （SEP）, and the Global Assessment Question （GAQ）. Safety was analyzed by adverse events, laboratory values and vital signs. Results： At the end of the study, all the primary and secondary efficacy end-points were statistically significantly improved by SK3530 compared with placebo （P 〈 0.05）. Of the 89 patients in the treatment arm, 36 （42.3 %） achieved normal erectile function after treatment, including six patients with severe ED. Treatment-related adverse events occurred in 32 patients. The most common adverse events were flushing, headache, dizziness and eye redness （10.9%, 7.6%, 2.5% and 2.5%, respectively）, and most were mild. Only two patients discontinued treatment during the study period because of adverse events. Conclusion： The results of our phase Ⅱ study have confirmed the efficacy and safety of SK3530 in a broad population of men with ED of various etiologies and severity. The optimal doses in terms of efficacy and safety were determined to be 50 mg and 100 mg, respectively.

Advances,breakthroughs,and challenges in gastric cancer surgery

Gastric cancer(GC)remains a substantial health burden worldwide,ranking fifth in incidence and third in mortality among all cancer types.Surgeons have persistently attempted to address this growing burden through surgical management of GC encompassing various aspects of surgery,including advances in surgical techniques and tools for minimally invasive surgery,novel technology for real-time image-guided surgery,and function-preserving and oncometabolic surgeries,aimed at improving patients’quality of life.The current perspective discusses the five most critical dimensions of the recent technical improvements and conceptual changes in GC surgery.We recommend further exploration of long-term benefits of these advancements,identification of breakthrough solutions to address current challenges,and delivery of the best quality of care.

Mobilization of monocytic myeloid-derived suppressor cells is regulated by PTH1R activation in bone marrow stromal cells

Myeloid-derived suppressor cells(MDSCs)are bone marrow(BM)-derived immunosuppressive cells in the tumor microenvironment,but the mechanism of MDSC mobilization from the BM remains unclear.We investigated how BM stromal cell activation by PTH1R contributes to MDSC mobilization.PTH1R activation by parathyroid hormone(PTH)or PTH-related peptide(PTHrP),a tumor-derived counterpart,mobilized monocytic(M-)MDSCs from murine BM without increasing immunosuppressive activity.In vitro cell-binding assays demonstrated thatα4β1 integrin and vascular cell adhesion molecule(VCAM)-1,expressed on M-MDSCs and osteoblasts,respectively,are key to M-MDSC binding to osteoblasts.Upon PTH1R activation,osteoblasts express VEGF-A and IL6,leading to Src family kinase phosphorylation in M-MDSCs.Src inhibitors suppressed PTHrP-induced MDSC mobilization,and Src activation in M-MDSCs upregulated two proteases,ADAM-17 and MMP7,leading to VCAM1 shedding and subsequent disruption of M-MDSC tethering to osteoblasts.Collectively,our data provide the molecular mechanism of M-MDSC mobilization in the bones of tumor hosts.

Exploring ideal operative time for best outcomes in gastric cancer surgery:A multi-institutional study based on KLASS-07 database

Objective:While a rushed operation can omit essential procedures,prolonged operative time results in higher morbidity.Nevertheless,the optimal operative time range remains uncertain.This study aimed to estimate the ideal operative time range and evaluate its applicability in laparoscopic cancer surgery.Methods:A prospectively collected multicenter database of 397 patients who underwent laparoscopic distal gastrectomy were retrospectively reviewed.The ideal operative time range was statistically calculated by separately analyzing the operative time of uneventful surgeries.Finally,intraoperative and postoperative outcomes were compared among the shorter,ideal,and longer operative time groups.Results:The statistically calculated ideal operative time was 135.4-165.4 min.The longer operative time(LOT)group had a lower rate of uneventful,perfect surgery than the ideal or shorter operative time(IOT/SOT)group(2.8%vs.8.8%and 2.2%vs.13.4%,all P<0.05).Longer operative time increased bleeding,postoperative morbidities,and delayed diet and discharge(all P<0.05).Particularly,an uneventful,perfect surgery could not be achieved when the operative time exceeded 240 min.Regardless of ideal time range,SOT group achieved the highest percentage of uneventful surgery(13.4%),which was possible by surgeon's ability to retrieve a higher number of lymph nodes and perform≥150 gastrectomies annually.Conclusions:Operative time longer than the ideal time range(especially≥240 min)should be avoided.If the essential operative procedure were faithfully conducted without compromising oncological safety,an operative time shorter than the ideal range leaded to a better prognosis.Efforts to minimize operative time should be attempted with sufficient surgical experience.

Relationship between diversion colitis and quality of life in rectal cancer

AIM:To investigated the incidence of diversion colitis(DC) and impact of DC symptoms on quality of life(QoL) after ileostomy reversal in rectal cancer.METHODS:We performed a prospective study with 30 patients who underwent low anterior resection and the creation of a temporary ileostomy for the rectal cancer between January 2008 and July 2009 at the Department of Surgery,Korea University Anam Hospital.The participants totally underwent two rounds of the examinations.At first examination,endoscopies,tissue biopsies,and questionnaire survey about the symptom were performed 3-4 mo after the ileostomy creations.At second examination,endoscopies,tissue biopsies,and questionnaire survey about the symptom and QoL were performed 5-6 mo after the ileostomy reversals.Clinicopathological data were based on the histopathological reports and clinical records of the patients.RESULTS:At the first examination,all of the patients presented with inflammation,which was mild in 15(50%) patients,moderate in 11(36.7%) and severe in 4(13.3%) by endoscopy and mild in 14(46.7%) and moderate in 16(53.3%) by histology.At the second examination,only 11(36.7%) and 17(56.7%) patients had mild inflammation by endoscopy and histology,respectively.There was no significant difference in DC grade between the endoscopic and the histological findings at first or second examination.The symptoms detected on the first and second questionnaires were mucous discharge in 12(40%) and 5(17%) patients,bloody discharge in 5(17%) and 3(10%) patients,abdominal pain in 4(13%) and 2(7%) patients and tenesmus in 9(30%) and 5(17%) patients,respectively.We found no correlation between the endoscopic or histological findings and the symptoms such as mucous discharge,bleeding,abdominal pain and tenesmus in both time points.Diarrhea was detected in 9 patients at the second examination;this number correlated with the severity of DC(0%,0%,66.7%,33.3% vs 0%,71.4%,23.8%,4.8%,P = 0.001) and the symptom-related QoL(r =-0.791,P < 0.001).CONCLUSION:The severity of DC is related to diarrhea after an ileostomy reversal and may adversely affect QoL.

Anti-integrin therapy for inflammatory bowel disease

In inflammatory bowel disease(IBD), tumor necro-sis factor plays an important role in mediating infla-mmation, but several other pathways are also involved in eliciting an inflammatory response. One such pathway is the invasion of the intestinal mucosa by leukocytes. Leukocytes within the systemic circulation move to sites of inflammation, and blocking this pathway could be an important treatment strategy for IBD. Anti-integrin therapy blocks the action of integrin on the surface of circulating immune cells and endothelial cell adhesion molecules, thereby inhibiting the interactions between leukocytes and intestinal blood vessels. Natalizumab, which acts on α4-integrin, was the first such drug to be approved for Crohn's disease, but its use is limited due to the risk of progressive multifocal leukoencephalopathy. Vedolizumab produces few systemic adverse effects because it acts on gut-trophic α4β7 integrin, and has been approved and is being used to treat IBD. Currently, several anti-integrin drugs, including etrolizumab, which acts on β7-integrin, and PF-00547569, which targets mucosal addressin cell adhesion molecule-1, are undergoing clinical trials and the results are being closely watched.

Prevention and management of non-steroidal anti-inflammatory drugs-induced small intestinal injury

Non-steroidal anti-inflammatory drug Nindu cedsmall bowel injury is a topi that deserves attentionsin e the advent of apsule endos opy and balloon enteros opy. N enteropathy is ommon and is mostly asymptomati . However,massive bleeding,stri ture,or perforation may o ur. The pathogenesis of small intestine injury by N s is omplex and different from that of the upper gastrointestinal tra t. No drughas yet been developed that an ompletely preventor treat N enteropathy. There fore,a long-termr and omized study in hroni N users is needed.

Current management of hepatocellular carcinoma:An Eastern perspective

Hepatocellular carcinoma(HCC) is one of the leading causes of cancer death, especially in Eastern areas. With advancements in diagnosis and treatment modalities for HCC, the survival and prognosis of HCC patients are improving. However, treatment patterns are not uniform between areas despite efforts to promote a common protocol. Although many hepatologists in Asian countries may adopt the principles of the Barcelona Clinic Liver Cancer staging system, they are also independently making an effort to expand the indications of each treatment and to combine therapies for better outcomes. Several expanded criteria for liver transplantation in HCC have been developed in Asian countries. Living donor liver transplantation is much more commonly performed in these countries than deceased donor liver transplantation, and it may be preceded by other treatments such as the down-staging of tumors. Local ablation therapies are often combined with transarterial chemoembolization( TACE) and the outcome is comparable to that of surgical resection. The indications of TACE are expanding, and there are new types of transarterial therapies. Although data on drug-eluting beads, TACE, and radioembolization in Asian countries are still relatively sparse compared with Western countries, these methods are gradually gaining popularity because of better tolerability and the possibility of improved response rates. Hepatic arterial infusion chemotherapy and radiotherapy are not included in Western guidelines, but are currently being used actively in several Asian countries. For more advanced HCCs, appropriate combinations of TACE, radiotherapy, and sorafenib can be considered, and emerging data indicate improved outcomes of combination therapies compared with single therapies. To include these paradigm shifts into newer treatment guidelines, more studies may be needed, but they are certainly in progress.

Expression of protein S100A4 is a predictor of recurrence in colorectal cancer

AIM: To investigate the prognostic significance of S100A4 expression in colorectal cancer and its correlation with expression of E-cadherin and p53. METHODS: A cohort of archival formalin-fixed paraff inembedded specimens was selected from 127 patients with colorectal cancer who underwent surgical resection between April 2000 and March 2004 at the Department of Surgery, Korea University Guro Hospital. The expression of protein S100A4 was evaluated according to the proportion of positively stained cancer cells. In each case, three core biopsies with a diameter of 2 mm were punched out and positioned in a recipient paraff in array block. Four-μm sections of these tissue array blocks were used for immunohistochemical analysis of protein S100A4, E-cadherin, and p53. Clinicopathological data were based on the original histopathologic reports and clinical records of patients. RESULTS: In normal colorectal mucosa, protein S100A4 immunoreactivity was clearly absent in both cytoplasm and nucleus. However, positive immunoreactivity of protein S100A4 was detected in 45 (35.4%) of the tumor cases. There was no significant association between positive immunoreactivity of protein S100A4 and clinicopathological parameters such as tumor differentiation or TNM stage, and also no correlation between the reactivity and E-cadherin or p53 expression. However, positive immunoreactivity of protein S100A4 was found to be associated with tumor recurrence (P = 0.004), and was also associated with significantly worse overall survival in the Kaplan-Meyer survival analysis (P = 0.044). After adjustment for tumor differentiation, tumor depth and nodal status, however, it failed to achieve statistical significance (P = 0.067). CONCLUSION: The expression of protein S100A4 is associated with tumor recurrence and poor overall survival in patients with colorectal cancer.

Clinical importance and surgical decision-making regarding proximal resection margin for gastric cancer

Because of the intramural spread of gastric cancer,a sufficient length of a resection margin has to be attained to ensure complete excision of the tumor.There has been debate on an adequate length of proximal resection margin(PRM) and its related issues.Thus,the objective of this article is to review several studies on PRM and to summarize the current evidence on the subject.Although there is some discrepancy in the recommended values for PRM between authors,a PRM of more than 2-3 cm for early gastric cancer and 5-6 cm for advanced gastric cancer is thought to be acceptable.Once the margin is confirmed to be clear,however,the length of PRM measured in postoperative pathologic examination does not affect the patient's survival,even when it is shorter than the recommended values.Hence,the recommendations for PRM length should be applied only to intraoperative decision-making to prevent positive margins on the final pathology.Given that a negative resection margin is the ultimate goal of determining an adequate PRM,development and improvement of reliable methods to confirm a negative resection margin intraoperatively would minimize the extent of surgery and offer a better quality of life to more patients.In the same context,special attention has to be paid to patients who have advanced stage or diffuse-type gastric cancer,because they are more likely to have a positive margin.Therefore,a wider excision with intraoperative frozen section(IFS) examination of the resection margin is necessary.Despite all the attempts to avoid positive margins,there is still a certain rate of positive-margin cases.Since the negative impact of a positive margin on prognosis is mostly obvious in low N stage patients,aggressive further management,such as extensive re-operation,is required for these patients.In conclusion,every possible preoperative and intraoperative evaluation should be thoroughly carried out to identify in advance the patients with a high risk of having positive margins;these patients need careful management with a wider excision or an IFS examination to confirm a negative margin during surgery.

Biliary phytobezoar resulting in intestinal obstruction

Phytobezoar is the most common type of bezoar.It is composed of indigestible vegetable matter and is usually found in the stomach.Biliary phytobezoar is extremely rare and difficult to diagnose preoperatively.The pathogenesis is not clear,and there have been only a few reports of biliary bezoars associated with sphincteric impairmentat the ampulla of Vater.Here,we present a report of biliary bezoar that resulted in jejunal obstruction.We were unable to identifythe bezoar in the extrahepatic bile duct until it obstructed the small bowel lumen.To our knowledge,this is the first report of small bowel obstruction resulting frommigration of a biliary bezoar.

Laparoscopic complete mesocolic excision: West meets East

Complete mesocolic excision is a relatively new concept in western literature. It follows the same concept of total mesorectal excision and units' routinely performing complete mesocolic excisions have good pathological results as well as good improvements in overall survival, disease free survival and local recurrence. And yet unlike total mesorectal excision, uptake in the West has been relatively slow with many units sceptical of the true benefits gained by taking up a more technically challenging and potentially more morbid procedure when there is a paucity of literature to support these claims. This article reviews complete mesocolic excision for colon cancer, attempting to identify the risks and benefits of the technique and particularly looking at the reasons why its uptake has not been universal. It also discusses the similarities of a complete mesocolic excision to a colon resection with a D3 lymphadenectomy as well as the role of a laparoscopic approach to this technique. Considering a D3 lymphadenectomy has been the standard of care for stage Ⅱ and Ⅲ colon cancers in many of our Asian neighbours for over 20 years, combining this data with data on complete mesocolic excision may provide enough evidence to support or refute the need for complete mesocolic excisions. Maybe there might be lessons to be learnt from our colleagues in the east.

Intraductal papillary bile duct adenocarcinoma and gastrointestinal stromal tumor in a case of neurofibromatosis type 1

We report our experience with a synchronous case of gastrointestinal stromal tumor(GIST) and intraductal papillary neoplasm of the bile duct(IPNB) in anelderly woman with neurofibromatosis type 1(NF-1). A 72-year-old woman presented with a 2-mo history of right upper abdominal pain unrelated to diet and indigestion. Fourteen years earlier, she had been diagnosed with NF-1, which manifested as café au lait spots and multiple nodules on the skin. Computed tomography(CT) revealed a multilocular low-density mass with septation, and mural nodules in the right hepatic lobe, as well as a 1.7-cm-sized well-demarcated enhancing mass in the third portion of the duodenum. The patient subsequently underwent right hepatectomy and duodenal wedge resection. We present here the first report of a case involving a synchronous IPNB and GIST in a patient with NF-1. Our findings demonstrate the possibility of various tumors in NF-1 patients and the importance of diagnosis at an early

Nuclear imaging for functional evaluation and theragnosis in liver malignancy and transplantation

Currently,nuclear imaging such as positron emission tomography(PET)and single photon emission computed tomography(SPECT)is increasingly used in the management of liver malignancy.18F-fluorodeoxyglucose(FDG)-PET is the most widely used nuclear imaging in liver malignancy as in other cancers,and has been reported to be effective in diagnosis,response monitoring,recurrence evaluation,and prognosis prediction.Other PET imaging such as 11C-acetate PET is also used complementarily to FDG-PET in diagnosis of liver malignancy.Additionally,image-based evaluation of regional hepatic function can be performed using nuclear imaging.Those imaging modalities are also effective for candidate selection,treatment planning,and perioperative evaluation in liver surgery and transplantation.Recently,nuclear imaging has been actively adopted in the transarterial radioembolization therapy of liver malignancy,according to the concept of theragnosis.With the development of new hybrid imaging technologies such as PET/magnetic resonance imaging and SPECT/CT,nuclear imaging is expected to be more useful in the management of liver malignancy,particularly regarding liver surgery and transplantation.In this review,the efficacy and roles of nuclear imaging methods in diagnosis,transplantation and theragnosis are discussed.

Current status of robot-assisted gastric surgery

In an effort to minimize the limitations of laparoscopy,a robotic surgery system was introduced,but its role for gastric cancer is still unclear.The objective of this article is to assess the current status of robotic surgery for gastric cancer and to predict future prospects.Although the current study was limited by its small number of patients and retrospective nature,robot-assisted gastrectomy with lymphadenectomy for the treatment of gastric cancer is a feasible and safe procedure for experienced laparoscopic surgeons.Most studies have reported satisfactory results for postoperative short-term coutcomes,such as:postoperative oral feeding,gas out,hospital stay and complications,compared with laparoscopic surgery;the difference is a longer operation time.However,robotic surgery showed a shallow learning curve compared with the familarity of conventional open surgery;after the accumulation of several cases,robotic surgery could be expected to result in a similar operation time.Robotic-assisted gastrectomy can expand the indications of minimally invasive surgery to include advanced gastric cancer by improving the ability to perform lymphadenectomy.Moreover," total" robotic gastrectomy can be facilitated using a robotsewing technique and gastric submucosal tumors near the gastroesophageal junction or pylorus can be resected safely by this novel technique.In conclusion,robotassisted gastrectomy may offer a good alternative to conventional open or laparoscopic surgery for gastric cancer,provided that long-term oncologic outcomes can be confirmed.

A novel cleansing score system for capsule endoscopy

AIM:To suggest a new cleansing score system for small bowel preparation and to evaluate its clinical efficacy.METHODS:Twenty capsule endoscopy cases were reviewed and small bowel preparation was assessed with the new scoring system.For the assessment,two visual parameters were used:proportion of visualized mucosa and degree of obscuration.Representative frames from small bowel images were serially selected and scored at 5-min intervals.Intraclass correlation coefficient(ICC)was obtained to assess the reliability of the new scoring system.For efficacy evaluation and validation,scores of our new scoring system were compared with another previously reported cleansing grading system.RESULTS:Concordance with the previous system,inter-observer agreement,and intra-patient agreement were excellent with ICC values of 0.82,0.80,and 0.76,respectively.The intra-observer agreements at four-week intervals were also excellent.The cutoff value of adequate image quality was found to be 2.25.CONCLUSION:Our new scoring system is simple,efficient,and can be considered to be applicable in clinical practice and research.

Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein improves diagnostic accuracy for hepatocellular carcinoma

BACKGROUND Diagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma(HCC)was not fully investigated.AIM To evaluate the diagnostic accuracy of alpha-fetoprotein(AFP),the Lens culinaris agglutinin-reactive fraction of AFP(AFP-L3),and protein induced by vitamin K absence or antagonist-II(PIVKA-II)and their combination for HCC diagnosis.METHODS Patients with newly detected liver mass or elevated serum AFP levels were considered eligible.Serum AFP level,AFP-L3 fraction,and PIVKA-II level were measured at the first visit.RESULTS In total,622 patients were included;355 patients(57.1%)had chronic liver disease,and 208(33.4%)had liver cirrhosis.HCC was diagnosed in 160 patients(25.7%).The area under the receiver operating characteristics curves(AUROCs)of the serum AFP,AFP-L3 fraction,AFP-L3,and PIVKA-II levels for the diagnosis of HCC were 0.775,0.792,0.814,and 0.834,respectively.A novel diagnostic model was developed by classifying patients in a 1:1 ratio into training and validation sets.Using the binary regression analysis of the training cohort,the AFP,AFP-L3 fraction,and PIVKA-II(ALPs)score was calculated as follows:ALPs score=3.8×[serum AFP level(ng/mL)×AFP-L3 fraction(%)×0.01]+0.2×PIVKA-II level(mAU/mL).The AUROC of the ALPs score for diagnosis of HCC was 0.878,significantly higher than that of serum AFP level(P<0.001),AFP-L3 fraction(P<0.001),PIVKA-II level(P=0.036),and AFP-L3 level(P=0.006).The optimal ALPs score cut-off was 5.3(sensitivity,85.0%,specificity 80.1%).The validation cohort showed similar results.CONCLUSION The ALPs score calculated using serum AFP level,AFP-L3 fraction,and PIVKA-II level showed improved accuracy in HCC diagnosis.

Hepatothorax due to a right diaphragmatic rupture related to duodenal ulcer perforation

Here, we present the case of a 53-year-old man with a hepatothorax due to a right diaphragmatic rupture related to duodenal ulcer perforation. On admission, the patient complained of severe acute abdominal pain, with physical examination findings suspicious for a perforated peptic ulcer. Of note, the patient had no history of other medical conditions or recent trauma, and the initial chest radiography and laboratory findings were not specific. A subsequent abdominal computed tomography revealed intrathoracic displacement of the liver, gallbladder, transverse colon and omentum through a right diaphragmatic defect. The patient then underwent an explorative laparotomy that confirmed duodenal ulcer perforation. A primary repair of the duodenal perforation was performed, and the diaphrag-matic defect was repaired using a polytetrafluoroeth-ylene patch after the organs were reduced and the cavity irrigated. This particular case proves interesting as right-sided spontaneous diaphragmatic ruptures are very rare and difficult to diagnose. Additionally, the best treatment for such large diaphragmatic defects is still controversial, especially in cases of intrathoracic or intra-abdominal contamination.