Evaluation of the Efficacy and Safety of DW1903 in Patients with Gastritis: A Randomized, Double-Blind, Noninferiority, Multicenter, Phase 3 study.

Background/Aims: H2 receptor antagonists (H2RA) have been used to treat gastritis by inhibiting gastric acid. Proton pump inhibitors (PPIs) are more potent acid suppressants than H2RA. However, the efficacy and safety of low-dose PPI for treating gastritis remain unclear. The aim was to investigate the efficacy and safety of low-dose PPI for treating gastritis. Methods: A double-blind, noninferiority, multicenter, phase 3 clinical trial randomly assigned 476 patients with endoscopic erosive gastritis to a group using esomeprazole 10 mg (DW1903) daily and a group using famotidine 20 mg (DW1903R1) daily for 2 weeks. The full-analysis set included 319 patients (DW1903, n=159; DW1903R1, n=160) and the per-protocol set included 298 patients (DW1903, n=147; DW1903R1, n=151). The primary endpoint (erosion improvement rate) and secondary endpoint (erosion and edema cure rates, improvement rates of hemorrhage, erythema, and symptoms) were assessed after the treatment. Adverse events were compared. Results: According to the full-analysis set, the erosion improvement rates in the DW1903 and DW1903R1 groups were 59.8% and 58.8%, respectively. According to the per-protocol analysis, the erosion improvement rates in the DW1903 and DW1903R1 groups were 61.9% and 59.6%, respectively. Secondary endpoints were not significantly different between two groups except that the hemorrhagic improvement rate was higher in DW1903 with statistical tendency. The number of adverse events were not statistically different. Conclusions: DW1903 of a low-dose PPI was not inferior to DW1903R1 of H2RA. Thus, lowdose PPI can be a novel option for treating gastritis (ClinicalTrials.gov Identifier: NCT05163756).

Clinical outcomes of esophageal granular cell tumors with different endoscopic resection methods.

Esophageal granular cell tumors (GCTs), the second most common subepithelial tumors (SETs) of the esophagus, are potentially malignant with no definite management guidelines available. We retrospectively enrolled 35 patients with endoscopically resected esophageal GCTs between December 2008 and October 2021 and evaluated the clinical outcomes from the various methods performed. Several modified endoscopic mucosal resections (EMRs) were performed for treating esophageal GCTs. Clinical and endoscopic outcomes were evaluated. Mean age of patients was 55.8 ± 8.2, with majority being men (57.1%). Mean tumor size was 7.2 ± 2.6 mm, most (80.0%) were asymptomatic and present in the distal third of the esophagus (77.1%). Endoscopic characteristics predominantly included broad-based (85.7%) and whitish-to-yellowish color changes (97.1%). Endoscopic ultrasound (EUS) of 82.9% of the tumors revealed homogeneous hypoechoic SETs originating from the submucosa. The five endoscopic treatment methods used were: ligation-assisted (77.1%), conventional (8.7%), cap-assisted (5.7%), and underwater (5.7%) EMRs and ESD (2.9%). Mean procedure time was 6.6 ± 2.1 min, and no procedure-associated complications were noted. The en-bloc and complete histologic resection rates were 100% and 94.3%, respectively. No recurrences were noted during follow-up, and no significant differences in the clinical outcomes of the different methods of endoscopic resection were found. Based on tumor characteristics and therapeutic outcomes, modified EMR methods can be effective and safe. However, there were no significant differences in the clinical outcomes of the different methods of endoscopic resection.

Clinical and endoscopic characteristics of sessile serrated lesions with dysplasia/carcinoma.

BACKGROUND/AIMS: Some sessile serrated lesions (SSLs) progress into dysplasia and colorectal cancer, however, the clinical and endoscopic characteristics of SSLs with dysplasia remain to be determined. In this study, we elucidated these characteristics in SSLs with dysplasia/carcinoma, compared with those of SSLs without dysplasia. METHODS: We retrospectively collected the clinical, endoscopic, and pathological data of 254 SSLs from 216 patients endoscopically resected between January 2009 and December 2020. RESULTS: All SSLs included 179 without dysplasia and 75 with dysplasia/carcinoma, including 55 with low-grade dysplasia, 10 with high-grade dysplasia, and 10 with submucosal cancer. In clinical characteristics, SSLs with dysplasia/carcinoma were significantly associated with advanced age, metabolic diseases, and high-risk adenomas. In endoscopic characteristics, SSLs with dysplasia/carcinoma were significantly associated with the distal colon, large size, polypoid morphology, surface-changes, no mucus cap, and narrow-band imaging international colorectal endoscopic classification (NICE) type 2/3. In the multivariate analysis, high-risk adenomas (odds ratio [OR], 2.98; p = 0.01), large size (OR, 1.18; p < 0.01), depression (OR, 11.74; p = 0.03), and NICE type 2/3 (OR, 14.97; p < 0.01) were significantly associated with SSLs with dysplasia/carcinoma. CONCLUSION: SSLs had a higher risk of dysplasia in the distal colon than in the proximal colon. SSLs with large size, depression, and adenomatous surface-patterns, as well as those in patients with high-risk adenomas, increased the risk of dysplasia/ carcinoma. This suggests that the clinical and endoscopic characteristics can aid in the diagnosis and management of SSLs with dysplasia/carcinoma.

Efficacy and safety of one-step knife compared to conventional insulated-tip knife for endoscopic submucosal dissection: a preliminary study with prospective data collection and retrospective review.

BACKGROUND: Endoscopic submucosal dissection (ESD) is not as tiresome as gastrectomy, but it is a time-consuming procedure. One-step knife (OSK) is a novel knife that combines a knife for ESD and an injection needle into one sheath. In this study, we aimed to compare the insulated tip type of OSK and conventional knife (CK) in terms of procedure time and complication rate. METHODS: Medical records of patients with ESD using CK between February and September 2020 were retrospectively reviewed. Subsequently, data from patients who underwent ESD using OSK by September 2021 were prospectively collected. Total procedure time, procedure time by location and complication rate in the OSK and CK group were compared. RESULTS: In the study period, a total of 203 patients (OSK, 102 patients; CK, 101 patients) were analyzed. On multivariate analysis, using CK, body location, resection size ≥ 40 mm, and submucosal fibrosis were associated with longer procedure time. The total procedure time was statistically significantly reduced in the OSK group (median 11 vs. 17 min, p < 0.01). The procedure time for each location was more reduced in the body (median 14 vs. 19 min p < 0.01) than the antrum (median 10 vs. 14 min, p = 0.01) in the OSK group. There was no significant difference in post-ESD bleeding and perforation in the two groups (3.9 vs. 3.9%, p = 0.99 and 1.0 vs. 2.0%, p = 0.56). CONCLUSIONS: OSK significantly reduced the total procedure time of ESD. OSK could be an effective and safe knife for gastric ESD, especially for body lesions.

A large and pedunculated inflammatory pseudotumor with pseudosarcomatous change of the cecum mimicking a malignant polyp: a case report and literature review.

Inflammatory pseudotumor (IPT) is a rare benign tumor of unknown etiology that can occur in almost any organ system. It has neoplastic features such as local recurrence, invasive growth, and vascular invasion, leading to the possibility of malignant sarcomatous changes. The clinical presentations of colonic IPT may include abdominal pain, anemia, a palpable mass, and intestinal obstruction. A few cases of colonic IPT have been reported, but colonic IPT with pedunculated morphology is very rare. Furthermore, since it can mimic malignant polyps, understanding the endoscopic findings of colonic IPT is important for proper treatment. Herein, we present a case of colonic IPT with pseudosarcomatous changes, presenting as a large polyp, mimicking a malignant polyp in the cecum, along with a literature review.

Efficacy of combination colonoscopy using modified cap-assisted and water-exchange colonoscopy with prone position for detection of colorectal adenomas.

The efficacy of cap-assisted and water-exchange colonoscopy, individually or in combination for adenoma detection is well documented. Moreover, prone positioning colonoscopy may also improve adenoma detection by decreasing loop formation. However, the efficacy of triple-combination colonoscopy using the above methods for adenoma detection is unclear. This study aimed to compare the effectiveness of combining modified cap-assisted and water-exchange colonoscopy with prone position (CWP) and conventional colonoscopy (CC) for adenoma detection. A total of 746 patients who underwent either CWP or CC, performed by 2 board-certified gastroenterologists between December 2019 and March 2020, were investigated retrospectively. Cap-assisted colonoscopy was modified using hooking and dragging maneuver. We evaluated the polyp detection rate (PDR), adenoma detection rate (ADR), and the mean number of adenomas detected per procedure (MAP). There was no significant difference in sex, age, the indication of colonoscopy and quality of bowel preparation between the 2 groups. PDR, ADR, and proximal colon MAP were significantly higher in the CWP group than in the CC group (PDR: 84.9% vs 59.8%, P < .01; ADR: 70.1%, vs 49.2%, P < .01; proximal colon MAP: 1.24 vs 0.55, P < .01). CWP is more effective than CC for PDR, ADR, and proximal colon MAP. Although it may facilitate adenoma detection, further studies assessing the synergistic or complementary effects of combining these methods are needed.

Clinical outcomes of gastroduodenal neuroendocrine tumors according to their WHO grade: A single-institutional retrospective analysis.

The management of gastroduodenal neuroendocrine tumor (NET) has been controversial between radical surgical resection and local excision including endoscopic resection. A gastroduodenal NET grade (G), measured by their mitotic rate and Ki67 proliferation index, is important to predict prognosis. In this study, we aimed to compare the clinical outcomes of gastroduodenal NET according to grades in order to identify poor prognostic factors of gastroduodenal NETs. Fifty-four gastroduodenal NETs diagnosed between December 2008 and December 2020 in a tertiary referral hospital were retrospectively reviewed. The clinical outcomes of gastroduodenal NETs, according to tumor grades and factors associated with NET G2-3, were analyzed. A total of 52 gastroduodenal NET patients was enrolled. The mean follow-up period was 56.2 ± 40.1 months. The mean size of gastric and duodenal NET was 7.9 ± 11.0 mm and 9.8 ± 7.6 mm, respectively. During the study period, 72.7% (16/22) of gastric NETs and 83.3% (25/30) of duodenal NETS were G1. All G1 gastroduodenal NETs showed no lymph node or distant metastasis during the study periods. All G3 gastroduodenal NETs showed metastasis (one lymph node metastasis and 3 hepatic metastases). Among metastatic NETs, the smallest tumor size was a 13 mm gastric G3 NET. Factors associated with G2-3 NETs were larger tumor size, mucosal ulceration, proper muscle or deeper invasion, and lymphovascular invasion. A small-sized gastroduodenal NET confined to submucosa without surface ulceration may be suitable for endoscopic resection. After local resection of a gastroduodenal NET (G1) without lymphovascular and muscle proper invasion, follow-up examination without radical surgical resection can be recommended. G3 NETs may be treated by radical surgical resection, regardless of tumor size.

pH and Redox-Dual Sensitive Chitosan Nanoparticles Having Methyl Ester and Disulfide Linkages for Drug Targeting against Cholangiocarcinoma Cells.

The aim of this study is to prepare pH- and redox-sensitive nanoparticles for doxorubicin (DOX) delivery against DOX-resistant HuCC-T1 human cholangiocarcinoma (CCA) cells. For this purpose, L-histidine methyl ester (HIS) was attached to chitosan oligosaccharide (COS) via dithiodipropionic acid (abbreviated as ChitoHISss). DOX-incorporated nanoparticles of ChitoHISss conjugates were fabricated by a dialysis procedure. DOX-resistant HuCC-T1 cells were prepared by repetitive exposure of HuCC-T1 cells to DOX. ChitoHISss nanoparticles showed spherical morphology with a small diameter of less than 200 nm. The acid pH and glutathione (GSH) addition induced changes in the size distribution pattern of ChitoHISss nanoparticles from a narrow/monomodal distribution pattern to a wide/multimodal pattern and increased the fluorescence intensity of the nanoparticle solution. These results indicate that a physicochemical transition of nanoparticles can occur in an acidic pH or redox state. The more acidic the pH or the higher the GSH concentration the higher the drug release rate was, indicating that an acidic environment or higher redox states accelerated drug release from ChitoHISss nanoparticles. Whereas free DOX showed decreased anticancer activity at DOX-resistant HuCC-T1 cells, DOX-incorporated ChitoHISss nanoparticles showed dose-dependent anticancer activity. Intracellular delivery of DOX-incorporated ChitoHISss nanoparticles was relatively increased at an acidic pH and in the presence of GSH, indicating that DOX-incorporated ChitoHISss nanoparticles have superior acidic pH- and redox-sensitive behavior. In an in vivo tumor xenograft model, DOX-incorporated ChitoHISss nanoparticles were specifically delivered to tumor tissues and then efficiently inhibited tumor growth. We suggest that ChitoHISss nanoparticles are a promising candidate for treatment of CCA.

Comparison of the Malignant Predictors in Intrahepatic and Extrahepatic Intraductal Papillary Neoplasm of the Bile Duct.

Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a precancerous lesion of cholangiocarcinoma, for which surgical resection is the most effective treatment. We evaluated the predictors of malignancy in IPNB according to anatomical location and the prognosis without surgery. Methods: A total of 196 IPNB patients who underwent pathologic confirmation by surgical resection or endoscopic retrograde cholangiography or percutaneous transhepatic cholangioscopic biopsy were included. Clinicopathological findings of IPNB with invasive carcinoma or mucosal dysplasia were analyzed according to anatomical location. Results: Of the 116 patients with intrahepatic IPNB (I-IPNB) and 80 patients with extrahepatic IPNB (E-IPNB), 62 (53.4%) and 61 (76.3%) were diagnosed with invasive carcinoma, respectively. Multivariate analysis revealed that mural nodule > 12 mm (p = 0.043) in I-IPNB and enhancement of mural nodule (p = 0.044) in E-IPNB were predictive factors for malignancy. For pathologic discrepancy before and after surgery, IPNB has a 71.2% sensitivity and 82.3% specificity. In the non-surgical IPNB group, composed of nine I-IPNB and seven E-IPNB patients, 43.7% progressed to IPNB with invasive carcinoma within 876 days. Conclusions: E-IPNB has a higher rate of malignancy than I-IPNB. The predictive factor for malignancy is mural nodule > 12 mm in I-IPNB and mural nodule enhancement in E-IPNB.

Olmesartan-associated Enteropathy with Acute Kidney Injury.

Olmesartan, a recently introduced angiotensin II receptor blocker for hypertension, has been reported to cause drug-induced small bowel enteropathy. The diagnosis of olmesartan-associated enteropathy (OAE) needs clinical suspicion and the exclusion of coeliac disease, as it mimics coeliac sprue. Once diagnosed, it can be completely cured with the discontinuation of olmesartan. However, due to the extremely low incidence of OAE in Korea, clinical suspicion and diagnosis may be a challenge. The authors report the first case of OAE presenting with chronic diarrhea and acute kidney injury in Korea.

Endoscopic visualization of graft status in patients with pancreas transplantation.

BACKGROUND: Enteric drainage into the recipient duodenum in pancreas transplantation (PT) can identify the graft duodenum by endoscopy. This study aimed to identify the characteristic endoscopic findings associated with graft failure or acute rejection in patients with PT. METHODS: We reviewed the medical records of patients who underwent PT with duodenoduodenostomy (DD) between January 2015 and August 2019. During this period, there were 44 PTs with DD in 42 patients; 122 endoscopies were performed and analyzed. RESULTS: Overall, pancreatic graft survival was 82% at a mean follow-up of 27 months (range 6-55 months). There were 8 graft failures and 10 acute rejections. In all 8 graft failures, a deep ulcer covered with fibrinous exudates of the graft duodenum was confirmed on endoscopy. Diffuse erythema inside the graft duodenum was observed in 8 of 10 acute rejections. The factors associated with acute rejection were elevated serum lipase level (OR 8.5, p = 0.02) and diffuse erythema inside the graft duodenum on endoscopy (OR 20.5, p < 0.01) in multivariate analysis. CONCLUSIONS: In PT with DD patients, graft failure can be visualized by endoscopy, and diffuse erythema inside the graft duodenum may be a finding of acute rejection.

Long-term outcomes and surveillance timing of patients with large non-pedunculated colorectal polyps with histologically incomplete resection in endoscopic resection.

BACKGROUND: Histologically incomplete resection of large colorectal polyps is frequently encountered; however, the long-term outcomes or surveillance timing is not well known. We evaluated the incidence rate and time of recurrence of these cases during a long-term follow-up. METHODS: We performed a retrospective analysis of patients who underwent endoscopic resection for large (≥10 mm in size) non-pedunculated colorectal polyps at a tertiary academic hospital. Patients who had positive or indeterminate lateral margin in the histology and underwent completed surveillance colonoscopy first at 3-12 months and finally at ≥2 years after initial resection were included. RESULTS: Of 169 polyps (148 patients), 37 (21.9%) and 132 (78.1%) polyps had positive and indeterminate lateral margins, respectively. The median time intervals of the first and last surveillance from the initial resection were 6 (3-12) and 48 (24-114) months, respectively. The recurrence rate was 9.5% (16/169) during follow-up, and the mean time to recurrence was 31.9 months. Thirteen (81.3%) polyps recurred after ≥12 months. Most (14/16, 87.5%) recurrent polyps were benign, and 2 cases had advanced cancer. The only factor that was significantly associated with recurrence in the univariate and multivariate analyses was ≥3 piecemeal resections (odds ratio in the multivariate analysis, 16.92; 95% CI, 1.19-241.81; p = 0.037). CONCLUSION: During the long-term follow-up, the only factor that was significantly associated with recurrence was ≥3 piecemeal resections, and most recurrences occurred after ≥12 months. Thus, a histologically incomplete resection with ≤2 piecemeal resections and no findings of suspected submucosal cancer may be considered as complete resection, and these patients may undergo first surveillance colonoscopy after 1-2 years.

Comparison of biannual and annual endoscopic gastric cancer surveillance after endoscopic resection.

BACKGROUND: Patients who received endoscopic resection (ER) for early gastric cancer (EGC) or high-grade dysplasia (HGD) are at high risk for the subsequent development of metachronous gastric cancer (MGC). This study aims to compare the detection rate and stage of MGC between biannual and annual endoscopic surveillance after ER of EGC or HGD. METHODS: From September 2009 to August 2019, 859 patients who underwent ER for the treatment of EGC or HGD were analyzed, retrospectively. Patients received endoscopic surveillance twice a year (high-intensity group) or annually (low-intensity group) for 3 years. RESULTS: A total of 521 patients were enrolled in this study (267 patients in the high-intensity group and 254 patients in the low-intensity group). During a mean follow-up of 5.3 ± 1.6 years, MGCs were found in 27 patients (16.9%) in the high-intensity group and 18 patients (7.1%) in the low-intensity group (P = 0.219). In patients with moderate to severe atrophy (Kimura-Takemoto grade C3 ~ O3), detection rates of MGC during 3 years from were 8.4% (16/191) and 2.2% (4/186), respectively (P = 0.007). Forty-four patients who received treatment for MGC, including endoscopic or surgical resection, were stage IA. Only one patient in the low-intensity group was diagnosed as stage IIIA advanced gastric cancer. CONCLUSIONS: There was no significant difference in the detection rate of MGC between biannual and annual endoscopic surveillance after ER of EGC or HGD. However, biannual surveillance showed a higher detection rate during the first 3 years, especially for patients with moderate to severe gastric atrophy.

Seven-day triple therapy is sufficient to eradicate infection caused by Helicobacter pylori without 23S rRNA point mutation.

ABSTRACT: Tailored therapy based on dual priming oligonucleotide-based polymerase chain reaction (DPO-PCR) can be considered an alternative to overcome the low eradication rate in high clarithromycin-resistance areas. The triple therapy (TT) duration of the tailored approach in most studies was 7 days for patients without point mutation. However, recent western guidelines have recommended a treatment duration of 14 days. The aim of this study was to compare the success rate of 7 and 14 days of TT for eradicating Helicobacter pylori without point mutation, as determined by DPO-PCR.Between Feb 2016 and Feb 2019, medical records of patients who underwent DPO-PCR were reviewed. Patients without point mutation as determined by DPO-PCR were enrolled in this study. The eradication success rate and adverse events were evaluated.A total of 366 patients without A2142G and A2143G point mutation were enrolled. The success rates of 7-day and 14-day TT were 88.4% (168/190) and 85.9% (151/176) by intention to treat analysis (P = .453) and 90.8% (168/185) and 90.4% (151/167) by per-protocol analysis (P = .900), respectively. The adverse event rates showed no significant difference between the 2 groups.In patients without point mutation based on DPO-PCR results, 7-day TT is as effective as 14-day TT. Therefore, 7 days may be considered as a cost-effective treatment duration in Korea.

Reactive Oxygen Species-Sensitive Nanophotosensitizers of Methoxy Poly(ethylene glycol)-Chlorin e6/Phenyl Boronic Acid Pinacol Ester Conjugates Having Diselenide Linkages for Photodynamic Therapy of Cervical Cancer Cells.

The aim of this study is to fabricate nanophotosensitizers composed of methoxy poly(ethylene glycol) (mPEG), chlorin e6 (Ce6), and phenylboronic acid pinacol ester (PBAP) with diselenide linkages for reactive oxygen species (ROS)-sensitive photodynamic therapy (PDT) of cervical cancer cells. To fabricate nanophotosensitizers, Ce6 was conjugated with mPEG via selenocystamine linkage and then remaining carboxylic acid groups of Ce6 was attached to PBAP (mPEGseseCe6PBAP conjugates). Nanophotosensitizers of mPEGseseCe6PBAP conjugates were prepared by dialysis method. In transmission electron microscope (TEM) observation, nanophotosensitizers of mPEGseseCe6PBAP conjugates have spherical shapes and their diameters were less than 150 nm. The average diameter of mPEGseseCe6PBAP nanophotosensitizers was 92.7 ± 9.6 nm in particle size analysis. When H2O2 was added to the nanophotosensitizer solution, nanophotosensitizers were sensitively disintegrated according to the H2O2 concentration and then changed from monomodal distribution to multimodal distribution in particle size distribution. Furthermore, Ce6 release from nanophotosensitizers also increased according to the H2O2 concentration. When H2O2 was added to cell culture of HeLa human cervical cancer cells, intracellular Ce6 uptake of nanophotosensitizers were gradually increased according to the H2O2 concentration, indicating that nanophotosensitizers showed ROS-sensitive delivery of Ce6 against cancer cells.As well as free Ce6, nanophotosensitizers in the absence of light irradiation have low intrinsic cytotoxicity against RAW264.7 cells and HeLa cells. However, nanophotosensitizers induced cell death dose-dependently under light irradiation. Especially, nanophotosensitizers showed significantly higher ROS generation and phototoxicity against HeLa cells in vitro. When nanophotosensitizers were intravenously administered to animal tumor xenograft model of HeLa cells, tumor tissues revealed stronger fluorescence intensity than other tissues by light irradiation while absence of light irradiation induced relatively lower fluorescence intensity in tumor tissues, indicating that nanophotosensitizers have sensitivity against oxidative stress in tumor tissues. We suggest that nanophotosensitizers of mPEGseseCe6PBAP conjugates are promising vehicle for PDT of cervical cancer cells.

Usefulness of intraductal RFA in patients with malignant biliary obstruction.

BACKGROUND/AIMS: Intraductal radiofrequency ablation (ID-RFA) is a novel therapy for unresectable malignant biliary obstructions. ID-RFA for perihilar lesions is associated with a high risk of adverse events. We aimed to evaluate the feasibility and efficacy of temperature-controlled ID-RFA for perihilar malignant biliary obstruction. METHODS: Sixteen patients with pathologically proven perihilar cholangiocarcinoma were prospectively enrolled to evaluate the feasibility of hilar ID-RFA. Clinical efficacy and outcomes were subsequently evaluated in a multicenter retrospective cohort. RESULTS: Nine of the 16 patients in the prospective cohort had Bismuth type IV and 7 had type IIIA perihilar cholangiocarcinoma. The median length of stricture was 34.5 mm. The median number of ID-RFA sessions was three, and all sessions were technically and functionally successful without severe adverse events. Clinical outcomes were assessed using a multicenter hilar ID-RFA cohort of 21 patients; the median stent patency and overall survival were 90 days (range: 35-483 days) and 147 days (range: 92-487 days), respectively. An approximate 16-month patency of the bile duct was maintained in one patient who had an intraductal growth pattern. In a comparison of the self-expandable metallic stent (SEMS) and plastic stent (PS) after hilar ID-RFA, no differences in stent patency (89 vs 90.5 days, respectively; P = .912) and adverse events (20.0% vs 10%, respectively; P = .739) were observed. CONCLUSIONS: ID-RFA at 7 W for 120 seconds is safe and feasible in patients with advanced perihilar cholangiocarcinoma. After ID-RFA, SEMS and PS placement showed comparable patency and survival rates. TRIAL REGISTRATION NUMBER: KCT0003223.