Prognostic Factors for Severe-to-Fatal Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: A Multicenter Prospective Cohort Study.

The prognostic factors associated with severe-to-fatal post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remain unclear despite the extensive number of studies on PEP. In total, 3739 ERCP patients with biliary disease with an intact papilla and indicated for ERCP were prospectively enrolled at 36 centers from April 2017 to March 2018. Those with acute pancreatitis diagnosed before ERCP, altered gastrointestinal anatomy, and an American Society of Anesthesiologists (ASA) physical status > 4 were excluded. Univariate and multivariate logistic regression analyses were performed on patient-related factors, operator-related factors, procedure-related factors, and preventive measures to identify potential prognostic factors for severe-to-fatal PEP. Multivariate analyses revealed pancreatic guidewire-assisted biliary cannulation (OR 13.59, 95% CI 4.21-43.83, p < 0.001), post-ERCP non-steroidal anti-inflammatory drug (NSAID) administration (OR 11.54, 95% CI 3.83-34.81, p < 0.001), and previous pancreatitis (OR 6.94, 95% CI 1.45-33.33, p = 0.015) as significant risk factors for severe-to-fatal PEP. Preventive measures included endoscopic biliary sphincterotomy (EST; OR 0.29, 95% CI, 0.11-0.79, p = 0.015) and prophylactic pancreatic stents (PPSs; OR 0.11, 95% CI, 0.01-0.87, p = 0.036). In biliary ERCP, pancreatic guidewire-assisted biliary cannulation, NSAID administration after ERCP, and previous pancreatitis were risk factors for severe-to-fatal PEP, whereas EST and PPS were significant preventive measures for severe-to-fatal PEP.

Adverse events of self-expandable metal stent placement for malignant distal biliary obstruction: a large multicenter study.

BACKGROUND AND AIMS: Endoscopic placement of self-expandable metal stents (SEMSs) for malignant distal biliary obstruction (MDBO) may be accompanied by several types of adverse events. The present study analyzed the adverse events occurring after SEMS placement for MDBO. METHODS: The present study retrospectively investigated the incidence and types of adverse events in patients who underwent SEMS placement for MDBO between April 2018 and March 2021 at 26 hospitals. Risk factors for acute pancreatitis, cholecystitis, and recurrent biliary obstruction (RBO) were evaluated by univariate and multivariate analyses. RESULTS: Of the 1425 patients implanted with SEMSs for MDBO, 228 (16.0%) and 393 (27.6%) experienced early adverse events and RBO, respectively. Pancreatic duct without tumor involvement (P = .023), intact papilla (P = .025), and SEMS placement across the papilla (P = .037) were independent risk factors for acute pancreatitis. Tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis (P < .001). Use of fully and partially covered SEMSs was an independent risk factor for food impaction and/or sludge. Use of fully covered SEMSs was an independent risk factor for stent migration. Use of uncovered SEMSs and laser-cut SEMSs was an independent risk factor for tumor ingrowth. CONCLUSIONS: Pancreatic duct without tumor involvement, intact papilla, and SEMS placement across the papilla were independent risk factors for acute pancreatitis, and tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis. The risk factors for food impaction and/or sludge, stent migration, and tumor ingrowth differed among types of SEMSs.

Low-dose gemcitabine plus nab-paclitaxel versus standard-dose gemcitabine plus nab-paclitaxel in elderly patients with metastatic pancreatic cancer: A randomized Phase II trial.

Background and Aim: A multicenter, open-label randomized Phase II trial was conducted to determine whether low-dose gemcitabine plus nab-paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard-dose GnP for elderly patients with metastatic pancreatic cancer. Methods: Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low- or standard-dose groups with a 1:1 ratio. Patients in the low-dose GnP group received gemcitabine at a dose of 250 mg/m2 and nab-paclitaxel at 125 mg/m2. Results: Low-dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression-free survival (7.3 vs 8 months) were comparable between the low- and standard-dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non-hematologic treatment-related adverse events was comparable between the two groups. Conclusion: Low-dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events.

Dexmedetomidine is safe and effective for reducing intraprocedural pain in colorectal endoscopic submucosal dissection.

Objectives: Endoscopic submucosal dissection (ESD) is effective for the resection of colorectal intramucosal lesions. This study was performed to examine the safety and effectiveness of using dexmedetomidine (DEX) in the anesthesia regimen of patients with colorectal lesions undergoing ESD. Methods: We retrospectively examined 287 consecutive patients who underwent ESD for colorectal lesions in our institution from January 2015 to December 2021. Outcomes including the frequency of intraprocedural pain and adverse events were compared between the DEX and no DEX groups. Moreover, univariate and multivariate analyses were conducted for each clinical factor of intraprocedural pain. Intraprocedural pain was defined as patient-reported abdominal pain or body movement during the procedure. Results: The incidence of intraprocedural pain was significantly lower in the DEX than in the no DEX group (7% vs. 17%, p = 0.02). The incidence of hypotension was also significantly higher in the DEX group (7% vs. 0%, p = 0.01), but no cerebrovascular or cardiac ischemic events occurred. In the univariate analyses, the diameter of the resected specimen, procedure time, no use of DEX, and total midazolam dose was associated with intraprocedural pain. The midazolam dose and DEX administration were significantly negatively correlated and the diameter of resected specimen and procedure time were significantly positively correlated. Multivariate logistic regression showed that no use of DEX was independently associated with intraprocedural pain (p = 0.02). Conclusions: Adding DEX to the anesthesia regimen in patients undergoing colorectal ESD appears to be safe and effective for reducing intraprocedural pain.

Does endoscopic sphincterotomy contribute to the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis after endoscopic biliary stenting for malignant biliary obstruction? A multicenter prospective cohort study.

BACKGROUND: There is no consensus on the necessity of endoscopic sphincterotomy (ES) to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) after endoscopic stenting in patients with malignant biliary obstruction. We investigated the incidence of PEP after endoscopic biliary stenting for malignant biliary obstruction with or without ES in a multicenter prospective cohort study. METHODS: We enrolled 807 patients who underwent endoscopic biliary stenting for malignant biliary obstruction with a native papilla at 36 hospitals between April 2017 and March 2018. The incidence of PEP in patients with or without ES was compared for subgroups based on stent type, placement method, and patient background. Univariate and multivariate analysis was performed to investigate the incidence of PEP in all stenting patients. RESULTS: Plastic and metal stents (MS) were inserted in 598 and 209 patients, respectively. The incidence of PEP in patients with or without ES was 7.9% and 7.4%, respectively among all stenting patients. The incidences of PEP with or without ES in plastic stent insertion patients, patients with MS insertion, stent insertions across the papilla, stent insertions across the papilla in patients without main pancreatic duct obstruction, and fully covered MS insertions across the papilla were compared. There was no overall significant difference in the incidence of PEP between those with or without ES. Multivariate logistic regression analysis for the incidence of PEP in all stenting patients revealed obstruction of the main pancreatic duct at the pancreatic head and epinephrine spraying on the papilla were significant factors; there was no significant difference in the incidence of PEP between patients with or without ES. CONCLUSION: Endoscopic sphincterotomy may not contribute to the prevention of PEP after endoscopic biliary stenting for malignant biliary obstruction, even in cases of insertion with a fully covered MS across the papilla.

Feasibility and efficacy of endoscopic reintervention after covered metal stent placement for EUS-guided hepaticogastrostomy: A multicenter experience.

Background and Objectives: Although the use of a long metal stent is favored for EUS-guided hepaticogastrostomy (EUS-HGS) for the relief of malignant biliary obstruction (MBO), endoscopic reintervention (E-RI) at the time of recurrent biliary obstruction (RBO) is challenging due to a long intragastric portion. This study evaluated the feasibility and safety of E-RI after a long partially covered metal stent (L-PCMS) placement during EUS-HGS. Materials and Methods: We performed a multicenter retrospective study between January 2015 and December 2019 examining patients with MBO who underwent E-RI for RBO through the EUS-HGS route after the L-PCMS placement. Technical and clinical success rates, details of E-RI, adverse events (AEs), stent patency, and survival time were evaluated. Results: Thirty-three patients at eight referral centers in Japan who underwent E-RI through the EUS-HGS route were enrolled. The location of MBO was distal in 54.5%. The median intragastric length of the L-PCMS was 5 cm. As the first E-RI attempt, E-RI via the distal end of the existing L-PCMS was successful in 60.6%. The overall technical and clinical success rates of E-RI were 100% and 81.8%, respectively. Liver abscess was noted in one patient. A proximal biliary stricture was associated with the clinical ineffectiveness of E-RI in multivariable analysis (odds ratio, 12.5, P = 0.04). The median survival and stent patency duration after E-RI were 140 and 394 days, respectively. Conclusions: Our study findings suggest that E-RI for RBO after EUS-HGS with a L-PCMS is technically feasible and clinically effective, without any severe AEs, especially for patients with distal MBO.

Association between antispasmodics and detection of lesions by screening esophagogastroduodenoscopy.

Background and Aim: Whether administration of antispasmodics as a component of premedication contributes to detection of lesions by screening esophagogastroduodenoscopy (EGDS) remains unclear. Our primary aim was to investigate this possibility. Methods: The cohort in this retrospective study comprised consecutive asymptomatic individuals who had undergone screening EGDS as part of a health check-up at the Japanese Red Cross Wakayama Medical Center from October 2015 to September 2020. The investigated lesions comprised esophageal squamous cell carcinoma or adenocarcinoma, gastric adenoma or adenocarcinoma, and duodenal adenoma or adenocarcinoma. Results: Targeted lesions were detected in 72 of 31 484 participants (0.23%), 18 260 and 13 224 of whom had received and not received pre-procedure antispasmodics, respectively. The rates of detection of lesions in these groups were 0.21% (38/18260) and 0.26% (34/13224), respectively (P = 0.40). Multivariate logistic regression analysis showed no association between administration of antispasmodics and rates of detection of targeted lesions [P = 0.24, Odds ratio (95% CI): 1.46 (0.78-2.75)]. Conclusions: Antispasmodics, which were administered to more than half of the study cohort, did not improve the rate of detection of targeted lesions.

Primary Hepatic Neuroendocrine Carcinoma with Thrombocytopenia Due to Diffuse Bone Marrow and Splenic Infiltration: An Autopsy Case.

An 82-year-old man with fever and back pain was referred to our hospital and was thus found to be thrombocytopenic. A bone marrow biopsy revealed the diffuse infiltration of poorly differentiated neuroendocrine carcinoma (NEC). Computed tomography revealed a large hepatic mass. Considering the risk of bleeding due to thrombocytopenia, a needle biopsy was not performed. The patient rapidly deteriorated and died 10 days after presentation. An autopsy confirmed the diagnosis of primary hepatic NEC, with diffuse metastasis to the spleen, bone marrow, and systemic lymph nodes. This is an extremely rare case of NEC presenting with thrombocytopenia due to extensive bone marrow and splenic infiltration.

Efficacy of EUS-guided celiac plexus neurolysis in combination with EUS-guided celiac ganglia neurolysis for pancreatic cancer-associated pain: a multicenter prospective trial.

OBJECTIVES: This study evaluated the efficacy of endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in combination with EUS-guided celiac ganglia neurolysis (EUS-CGN) for pancreatic cancer-associated pain. METHODS: This multicenter prospective trial was registered in the University Hospital Medical Information Network (UMIN000031228). Fifty-one consecutive patients with pancreatic cancer-associated pain who presented at one of five Japanese referral centers between February 2018 and March 2021 were enrolled. EUS-CGN was added in cases of visible celiac ganglia. The primary endpoint was effectiveness, defined as a decrease in the numerical rating scale (NRS) by ≥ 3 points. NRS data were prospectively acquired at 1 week after the procedure to evaluate its effectiveness and the extent of pain relief. RESULTS: The technical success rates of EUS-CPN and EUS-CGN were 100% and 80.4%, respectively. The overall efficacy rate was 82.4% [90% confidence interval (CI) 71.2-90.5, P < 0.0001]. The complete pain relief rate was 27.4%. The adverse events rate was 15.7%. The average pain relief period was 72 days. The efficacy rate was higher in the EUS-CPN plus EUS-CGN group than in the EUS-CPN alone group. EUS-CPN plus EUS-CGN was superior to EUS-CPN alone for achieving complete pain relief (P = 0.045). EUS-CGN did not improve the average length of the pain relief period. CONCLUSIONS: EUS-CPN combined with EUS-CGN is safe, feasible, and effective for pain relief in patients with pancreatic cancer. The patients who received additional EUS-CGN had a better short-term response. CLINICAL TRIAL NUMBER: UMIN000031228.

Cross-wired metal stents for endoscopic bilateral stent-in-stent deployment in malignant hilar biliary obstruction: A multicenter, single-arm, prospective study.

Objectives: The endoscopic bilateral stent-in-stent (SIS) deployment is a challenging procedure. Such difficulty is mainly caused by sticking of the tip of the delivery sheath into the self-expandable metal stents (SEMSs) mesh, requiring an additional dilating procedure. Herein, we assessed the clinical results of using cross-wired metal stent for endoscopic bilateral SIS deployment (BONASTENT M-Hilar) in patients with malignant hilar biliary obstruction (MHBO) in both high-volume and non-high-volume centers. Methods: We prospectively enrolled consecutive patients with MHBO between February 2016 and December 2018 at eight centers. Results: Forty-six patients were enrolled during the study period. The proportions of technical success were 93.5% (43/46) and clinical success (CS) on intention-to-treat and per-protocol analyses were 91.3% (42/46) and 93.0% (40/43), respectively. The proportion of an additional dilating procedure during the primary procedure was 50.0% (23/46). Recurrent biliary obstruction (RBO) on intention-to-treat analysis occurred in 32.6% (15/46) of cases. Almost all of the events were caused by stent ingrowth (14/15). The median survival time and time to RBO were 255 and 349 days, respectively. The probability of stent patency at 3, 6, and 12 months was 86.5%, 63.9%, and 47.6%, respectively. Conclusions: The cross-wired metal stent had excellent technical and CS, although non-high-volume centers were included in this study (UMIN000021441).

Comparison of 22-gauge standard and Franseen needles in EUS-guided tissue acquisition for diagnosing solid pancreatic lesions: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: This large multicenter randomized controlled trial compared the diagnostic yields of 22-gauge standard and 22-gauge Franseen needles for EUS-guided tissue acquisition (EUS-TA) of solid pancreatic lesions. METHODS: Consecutive patients with solid pancreatic lesions were prospectively randomized to EUS-TA using standard or Franseen needles. Samples obtained with the first needle pass and with second and subsequent passes were evaluated separately. The primary endpoint was the rate of accuracy for diagnosis of malignancy. Other endpoints were technical success rate, sample cellularity, adverse events, diagnostic accuracy in patient subgroups, and the diagnostic accuracy and numbers of second and subsequent needle passes. RESULTS: Of 523 patients undergoing EUS-TA, 260 were randomized to using standard 22-gauge needles and 263 to 22-gauge Franseen needles. The technical success rate in each group was 99.6%, with similar adverse event rates in the standard (1.5%) and Franseen (.8%) needle groups. First-pass EUS-TA using the Franseen needle resulted in significantly greater diagnostic accuracy (84.0% vs 71.2%, P < .001) and sensitivity (82.4% vs 66.7%, P < .001) than first-pass EUS-TA using a standard needle and also resulted in superior diagnostic accuracy in patients requiring immunostaining. Second and subsequent EUS-TA using Franseen needles showed significantly greater accuracy (94.7% vs 90.0%, P = .049) and sensitivity (94.0% vs 88.6%, P = .047) and required fewer needle passes (1.81 vs 2.03, P = .008) than using standard needles. CONCLUSIONS: EUS-TA with the Franseen needle is superior to EUS-TA with a standard needle with respect to diagnostic accuracy per pass, particularly in patients who require immunostaining, and number of passes when using macroscopic on-site evaluation. (Clinical trial registration numbers: UMIN000030634 and jRCTs052180062.).

Multicenter prospective cohort study of adverse events associated with biliary endoscopic retrograde cholangiopancreatography: Incidence of adverse events and preventive measures for post-endoscopic retrograde cholangiopancreatography pancreatitis.

OBJECTIVES: The reported incidence of adverse events (AEs) in endoscopic retrograde cholangiopancreatography (ERCP) varies between 2.5% and 14%. The aim of this study was to evaluate the incidence and severity of AEs in biliary ERCP and to specify the risk factors and preventive measures for post-ERCP pancreatitis (PEP). METHODS: Patients with biliary disease with intact papilla were prospectively enrolled at 36 hospitals between April 2017 and March 2018. The primary outcomes were the incidence and severity of AEs. RESULTS: A total of 16,032 ERCP procedures were performed at the 36 hospitals during the study period and 3739 patients were enrolled. The overall incidence of AEs was 10.1% and ERCP-related mortality was 0.08%. PEP developed in 258 cases (6.9%), bleeding in 33 (0.9%), instrumental AEs in 17 (0.5%), infections in 37 (1.0%), cardiovascular AEs in eight (0.2%), pulmonary AEs in eight (0.2%), drug reaction AE in one (0.03%), pain in 15 (0.4%), and other AEs in 15 (0.4%). Multivariable analysis showed significant risk factors for PEP were: female of younger age, pancreatic guidewire-assisted biliary cannulation, temporary guidewire insertion into the pancreatic duct, total procedure time >60 min, and post-ERCP administration of non-steroidal anti-inflammatory drugs. Effective preventive measures were prophylactic pancreatic stenting (PPS) and epinephrine spraying onto the papilla. CONCLUSIONS: In patients with intact papilla who underwent biliary ERCP, the incidence of AEs was 10.1% and the mortality was 0.08%. PPS and epinephrine spraying may prevent PEP. REGISTRATION: This study was registered in the University Hospital Medical Information Network (UMIN000024820).

Utility and Safety of a Novel Fully Covered Metal Stent in Unresectable Distal Malignant Biliary Obstruction.

BACKGROUND: Self-expandable metal stents (SEMSs) are widely used in patients with distal malignant biliary obstruction. A SEMS that can avoid occlusion as much as possible is desirable. AIMS: The aim of this multicenter single-arm prospective study was to assess the clinical effectiveness and safety of a novel fully covered braided SEMS. METHODS: We enrolled consecutive patients with distal malignant biliary obstruction between February 2016 and November 2017 at ten tertiary-care medical centers. RESULTS: We included 79 patients with a median age of 76 years; 47 (59.5%) patients were men. The technical and clinical success rate was 98.7% and 93.6%, respectively. Recurrent biliary obstruction occurred in 14 patients (17.9%); stent ingrowth, overgrowth, migration, and other occurred in five (6.4%), four (5.1%), four (5.1%), and one (1.3%) patients, respectively. All reinterventions in patients with recurrent biliary obstruction were successful via the transpapillary approach. Adverse events occurred in 15 patients (19.2%); cholangitis, pancreatitis, and others occurred in ten (12.8%), three (3.8%), and two (2.6%) patients, respectively. The stent patency probability at 6 months was 48.5%. Median time to stent patency was 171 days, median time to recurrent biliary obstruction was 536 days, and median survival time was 195 days. CONCLUSIONS: We confirmed the utility and safety of a novel fully covered braided SEMS with low axial force and high radial force in patients with malignance biliary obstruction. This novel SEMS is recommended in patients with distal malignant biliary obstruction.

Comparison of a 22-gauge Franseen-tip needle with a 20-gauge forward-bevel needle for the diagnosis of type 1 autoimmune pancreatitis: a prospective, randomized, controlled, multicenter study (COMPAS study).

BACKGROUND AND AIMS: Histologic diagnosis of autoimmune pancreatitis (AIP) using EUS-guided FNA (EUS-FNA) is difficult. To address this issue, new fine-needle biopsy (FNB) needles were recently developed. Here, we prospectively evaluated 2 newly designed EUS-FNB needles for histologic evaluation in patients with type 1 AIP. METHODS: This was a prospective, randomized, multicenter trial comparing biopsy specimens obtained with a 22-gauge Franseen needle or a 20-gauge forward-bevel needle in patients with suspected type 1 AIP. AIP was diagnosed according to international consensus diagnostic criteria. The primary endpoint was the sensitivity of EUS-FNB needles, and secondary endpoints were the amount of specimen obtained, histology of the pancreas based on evaluation of lymphoplasmacytic sclerosing pancreatitis (LPSP), and contribution of histologic findings to the diagnosis of AIP. RESULTS: One hundred ten patients were randomly assigned to the Franseen group (22-gauge Franseen needle) or the forward-bevel group (20-gauge forward-bevel needle). EUS-FNB sampling was successful in all patients. Nine patients were excluded because of diagnoses other than AIP. Compared with the forward-bevel needle, the Franseen needle obtained a significantly greater number of high-power fields. Of 101 patients, 39 patients (78%) in the Franseen group and 23 patients (45%) in the Forward-bevel group were diagnosed with level 1 or 2 LPSP (P = .001). Thirty-six patients could not be diagnosed with type 1 AIP without EUS-FNB specimen results. CONCLUSIONS: The 22-gauge Franseen needle should be routinely used for histologic diagnosis of type 1 AIP. (Clinical trial registration number: UMIN 000027668.).

Conversion to EUS-guided internal gallbladder drainage from percutaneous cholecystostomy: A successful case using a novel plastic stent.

For acute cholecystitis with high surgical risk, endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) has shown high clinical and technical success rates. Dilation of the punctured fistula is a technically challenging aspect of EUS-GBD. Over-dilation makes stent insertion easier; however, it increases the risk of bile leakage. Currently, the endoscopic devices available for EUS-GBD are limited, which presents device-related shortcomings. When the stent cannot pass through the dilated fistula, the deployment of a conventional double-pigtail plastic stent requires discarding of the stent and re-puncturing of the gallbladder. Recently, a novel integral double-pigtail plastic stent tied with a pusher catheter that allows the stent to be pulled back on insertion failure was developed. Here, we describe a patient in whom EUS-GBD was successfully performed using this novel stent that enables adjustment during dilation, making EUS-GBD safer.

Comparison of the Diagnostic Performance of Newly Designed 21-Gauge and Standard 22-Gauge Aspiration Needles in Patients with Solid Pancreatic Masses.

BACKGROUND: Although endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has been widely used for the diagnosis of pancreatic tumors, the ability to obtain adequate pancreatic tumor tissue needs to be improved. AIMS: This study was performed to compare a newly designed 21-gauge needle (EUS Sonopsy CY; Hakko Medical, Nagano, Japan) and a standard 22-gauge needle for tissue sampling of solid pancreatic masses. METHODS: Consecutive patients with solid pancreatic masses who underwent EUS-FNA with either the EUS Sonopsy CY or the 22-gauge needle from June 2014 to December 2016 were enrolled. The primary outcome was comparison of the diagnostic yield of the FNA samples. The secondary outcomes were comparison of technical success, diagnostic ability for malignancy, and complications. RESULTS: A total of 93 patients (40.9% female; mean age, 70.1 years) underwent EUS-FNA with the EUS Sonopsy CY (n = 47) or the standard 22-gauge needle (n = 46). The technical success rate was 100% in both groups, and the overall diagnostic accuracy for malignancy was similar between the groups (100% in the EUS Sonopsy CY group vs. 95.7% in the 22-gauge needle group, P = 0.242). Nevertheless, the EUS Sonopsy CY resulted in significantly higher scores for cellularity (P = 0.006) and lower scores for blood contamination (P < 0.001). The procedure-related complication rate was comparable between the groups (P = 0.148). CONCLUSIONS: The EUS Sonopsy CY provided higher-quality specimens for histological evaluation in terms of both sample cellularity and blood contamination for the diagnosis of solid pancreatic masses. TRIAL REGISTRATION: The study was registered in a clinical trial registry, No. UMIN000032598.