The risk of metastatic recurrence after non-curative endoscopic resection with negative deep margins for early colorectal cancer: Two-center retrospective cohort study.

INTRODUCTION: Non-curative endoscopic resection of T1 colorectal cancers (CRC) carries a substantial risk of recurrence. However, previous studies have reported a significant proportion of cases in which the deep margin of endoscopic resection was positive for cancer due to the technical difficulties of colorectal endoscopic submucosal dissection (ESD). With the advancement of endoscopic technology and techniques resulting in the reduction of positive resection margins, it is important to reassess the long-term prognosis and major risk factors for recurrence in cases of negative deep margins. METHODS: We conducted a retrospective cohort study of consecutive patients with T1 CRC who underwent endoscopic resection between January 2006 and December 2021 with negative deep margins. Histological findings of the resected specimens were analyzed to determine the risk factors associated with the primary outcomes of this study, including recurrence and cancer-related deaths. RESULTS: The median age of the 190 patients was 70 years, of which 63% were male, and endoscopic treatment was performed in 64% by endoscopic mucosal resection and 36% by ESD. Eighty two patients were in the curative resection (CR) group and 108 were in the non-curative resection (NCR) group, wherein the latter comprised 79 patients who underwent additional surgery (AS) and 29 patients who did not receive AS. Five-year recurrence-free survival rates were 98.4% (95% CI 89.3-99.8) for CR, 98.3% (95% CI 88.8-99.8) for NCR with AS, and 73.7% (95% CI 46.5-88.5) for NCR without AS. Lymphatic invasion and budding grade 2/3 were the major risk factors for recurrence, with hazard ratios of 40.7 (p<0.001) and 23.1 (p=0.007), respectively. Of the patients in the NCR group without AS, the five-year recurrence-free rate was 85.6% (95% CI 52.5-96.3) if there were no major risk factors (i.e. no lymphatic invasion or budding grade 2/3) (n=21), whereas the prognosis was poor in the presence of one or more of the major risk factors, with a median recurrence-free survival and disease-specific survival of 2.5 and 3.1 years, respectively (n=8). DISCUSSION/CONCLUSION: In endoscopically resected T1 CRC with negative deep margins, lymphatic invasion or budding grade 2/3 may indicate a higher risk of recurrence when followed up without additional surgery.

Risk factors for postgastric endoscopic submucosal dissection bleeding in direct oral anticoagulant users.

OBJECTIVES: Bleeding after endoscopic submucosal dissection (ESD) for gastric tumors in patients taking antithrombotic drugs, in particular direct oral anticoagulants (DOACs), remains unresolved; therefore, we evaluated the risk factors for post-ESD bleeding and drug differences in patients taking DOACs. METHODS: We included 278 patients taking antithrombotic drugs who underwent gastric ESD between January 2017 and March 2022. Antithrombotic drugs were withdrawn following the 2017 guidelines (Appendix on anticoagulants including DOACs). To further clarify differences in antithrombotic agents' effects, the peri-cancerous mucosa in the resected specimen was pathologically evaluated according to the Updated Sydney System. Multivariate analysis was performed to assess the risk of post-ESD bleeding. RESULTS: The incidence of post-ESD bleeding in patients taking DOACs was 19.6% (10/51). Among patients taking antithrombotic drugs, DOACs were identified as a possible factor involved in post-ESD bleeding (odds ratio [OR] 4.92). Among patients taking DOACs, possible factors included resection length diameter ≥30 mm (OR 3.72), presence of neutrophil infiltration (OR 2.71), lesions occurring in the lower third of stomach (OR 2.34), and preoperative antiplatelet use (OR 2.22). Post-ESD bleeding by DOAC type was 25.0% of patients (4/16) receiving apixaban, in 20.0% (3/15) receiving edoxaban, in 21.4% (3/14) receiving rivaroxaban, and in none of those receiving dabigatran. CONCLUSIONS: The administration of DOACs was shown to be a possible factor involved in post-ESD bleeding, and risk factors for patients taking DOACs included neutrophil infiltration. The pharmacological differences in the effects of DOACs contributing to bleeding in gastric ulcers suggest comparatively less bleeding with dabigatran after ESD.

PMEL p.Leu18del dilutes coat color of Kumamoto sub-breed of Japanese Brown cattle.

BACKGROUND: Coat color is important for registration and maintenance of livestock. Standard coat color of Kumamoto sub-breed of Japanese Brown cattle is solid brown, but individuals with diluted coat color have been observed recently. In this study, we attempted to identify polymorphism(s) responsible for coat color dilution by whole genome analysis. RESULTS: One of the diluted cattle possessed 7302 exonic polymorphisms which could affect genes' function. Among them, 14 polymorphisms in 10 coat color-related genes were assumed to be specific for the diluted cattle. Subsequent genotyping with three diluted cattle and 74 standard cattle elucidated that PMEL p.Leu18del was the causative polymorphism for coat color dilution in this sub-breed. Individuals with del/del type of this polymorphism showed diluted coat color, but coat color of heterozygotes were intermediate with various dilution rates. CONCLUSIONS: Coat color dilution of Kumamoto sub-breed was caused by PMEL p.Leu18del. The causative del allele has been detected in several genetically distant cattle breeds, suggesting that PMEL p.Leu18del can be used as a DNA marker to control cattle coat color.

Dasatinib-induced colitis: clinical, endoscopic and histological findings.

BACKGROUND: Dasatinib, a second-generation tyrosine kinase inhibitor, is widely used in patients with haematological malignancies. The main side effects of dasatinib are myelosuppression and pleural effusion; however, colitis, such as haemorrhagic colitis and cytomegalovirus (CMV) colitis, have been reported as rare side effects. There are only a few studies conducted on dasatinib-induced colitis. AIMS: This study aimed to clarify the clinical, endoscopic and pathological features of dasatinib-induced colitis. METHODS: This retrospective study included 51 consecutive patients who received dasatinib therapy between June 2009 and July 2020. Dasatinib-induced colitis was defined as the presence of colitis symptoms, exclusion of other diseases that could cause colitis, and improvement in symptoms after dasatinib withdrawal or dose reduction. CMV positivity was determined based on the positive result of CMV immunostaining. RESULTS: Dasatinib-induced colitis was diagnosed in nine of 51 patients (17.6%), and most of the symptoms were mild diarrhoea and bloody stools. The endoscopic findings were characterised by loss of vascular pattern (100%) and multiple small erosions (83.3%) which were mainly found in the transverse and descending colon. In a patient who underwent follow-up colonoscopy once a year while taking dasatinib, endoscopic findings changed from initial erythematous spots to multiple erosions, and finally to multiple small round elevations with erosion on the top that disappeared after discontinuation of dasatinib. Anti-CMV therapy was administered to one patient, but the treatment failed. All patients with dasatinib-induced colitis were cured after the discontinuation of dasatinib. CONCLUSION: Physicians should consider CMV reactivation to manage dasatinib-induced colitis.

Long-term outcomes of endoscopic versus surgical resection for MM-SM1 esophageal squamous cell carcinoma using propensity score analysis.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) confined to the muscularis mucosae (MM) or up to 200 µm of the submucosa (SM1) confers the risk for lymph node metastasis, and is defined as relative indication for endoscopic submucosal dissection (ESD) by the Japan Esophageal Society guidelines. Although additional surgical treatment after ESD is recommended, long-term outcomes of ESD compared with those of surgery have not been clarified. This study aimed to evaluate the long-term outcomes of ESD and surgery for cN0M0 relative indication lesions of ESCC. METHODS: Between 2006 and 2016, patients with relative indication lesions of ESCC who underwent ESD or surgery at nine participating hospitals were examined retrospectively. Using propensity score matching, we evaluated survival curves for and hazard ratios associated with endoscopic submucosal dissection and surgery. RESULTS: In total, 155 lesions in the ESD group and 106 lesions in the surgery group met the pathological criteria of relative indication for endoscopic resection. After matching, 50 matched pairs of patients who underwent ESD or surgery were selected. The 5-year overall survival rates were 84.5% [95% confidence interval (CI) 68-93] in the ESD group and 79% [95% CI 60-90] in the surgery group. The hazard ratio of mortality for ESD compared with that for surgery estimated by Cox regression analysis was 0.79 (95% CI 0.3-2.06, p = 0.63). CONCLUSIONS: Compared with surgery, ESD does not compromise long-term outcomes. ESD alone or ESD with chemotherapy and/or radiotherapy may be an option for the treatment of MM and SM1 ESCC.

[A case of severe colitis caused by immune checkpoint inhibitor].

A 74-year-old male with lung squamous cell carcinoma who was treated with the anti PD-1 antibody nivolumab developed frequent diarrhea four months after initiating treatment. However, his condition did not improve despite prednisolone at 20mg. Endoscopic examination revealed loss of vascular pattern, erosions, and mucosal friability, resembling ulcerative colitis. Colonoscopy revealed punch-out ulcers in the affected mucosa. Therefore, he was definitively diagnosed with severe colitis caused by immune checkpoint inhibitor treatment and cytomegalovirus colitis. Nivolumab was discontinued, and he was treated with 60mg prednisolone and ganciclovir. Although his colitis improved, he developed pneumonia and died thereafter. This case highlights adverse events that are associated with immune checkpoint inhibitors which should be treated properly.

A Case of Diffuse Esophageal Spasm Treated with Peroral Endoscopic Myotomy.

The indications for peroral endoscopic myotomy (POEM) have been expanded to include diffuse esophageal spasm (DES). A 67-year-old Japanese man presented with a 4-year history of dysphagia. Endoscopy and upper gastrography revealed abnormal peristaltic movements involving interruption of normal peristalsis, and a diverticulum located at the 2 o'clock esophageal position. High-resolution manometry indicated DES. POEM with a long (15 cm) myotomy was performed for the abnormal contractions, which subsequently disappeared along with dysphagia improvement. Our results suggest that esophageal motility disorders accompanying a diverticulum may be eliminated by POEM without treating the diverticulum itself. We speculate that POEM ameliorates esophageal diverticulum by reducing internal esophageal pressure.

Ten Initial Cases of Peroral Endoscopic Myotomy for Treatment of Esophageal Motility Disorders at Okayama University Hospital.

Peroral endoscopic myotomy (POEM) for treatment of esophageal motility disorders has recently been reported to be highly effective and less invasive than other treatment. POEM was recently introduced in Okayama University Hospital under the supervision of a physician from a high-volume center. To verify the safety and efficacy of POEM during its introduction in our institution. We examined 10 cases in whom POEM was performed between January 2016 and April 2017. The patients included 7 men and 3 women, with a median age (range) of 49 years (17-74) and median symptom duration of 6 years (1-21). Seven patients had a straight esophagus, and the remaining 3 had a sigmoid esophagus. According to the Chicago classification, 6 patients were diagnosed with type I achalasia, 2 with type II achalasia, and 2 with distal esophagus spasm. Treatment outcomes and adverse events were evaluated. Treatment success was defined as a > 3 decrease in Eckardt score or a score of <3 at the time of discharge. The treatment success rate was 90%, with the average Eckardt score decreasing significantly, from 4.7 to 0.9 (p<0.05). No mucosal perforation, severe infection, mediastinitis, severe bleeding, or gastroesophageal reflux occurred intraoperatively or postoperatively. POEM was introduced to Okayama University Hospital, and the first 10 cases were accomplished safely and effectively under the supervision of an expert physician from a high-volume center.

Lanthanum Deposition in the Stomach: Usefulness of Scanning Electron Microscopy for Its Detection.

After having been treated with lanthanum carbonate administration for 4 years for hyperphosphatemia, a 75-year-old Japanese woman undergoing hemodialysis was diagnosed with lanthanum phosphate deposition in the stomach. The deposition, seen as white microgranules, was observed using esophagogastroduodenoscopy with magnifying observation. To the best of our knowledge, these are the minutest endoscopy images of lanthanum phosphate deposition in the gastric mucosa. Scanning electron microscopy (SEM) observation enabled easier identification of the deposited material, which was visible as bright areas. The present case suggests the usefulness of SEM observation in the detection of lanthanum phosphate deposition in the gastrointestinal tract.

Endoscopic retrograde cholangiopancreatography using a cap-assisted highly flexible colonoscope in patients with Roux-en-Y anastomosis.

In this retrospective study of 10 patients with Roux-en-Y anastomosis, endoscopic retrograde cholangiopancreatography (ERCP) using a cap-assisted thin highly flexible colonoscope was done for treatment of bile duct stones. In five patients, the papilla of Vater was successfully reached using the colonoscope alone. However, in the other five patients, combination with an overtube was needed to reach the papilla. In all cases, complete removal of bile duct stones was accomplished. Procedure-related adverse events occurred in two cases. In conclusion, use of a cap-assisted thin highly flexible colonoscope for ERCP was successful in patients with a Roux-en-Y anastomosis.

Clinicopathological Characteristics of Superficial Barrett's Adenocarcinoma in a Japanese Population: A Retrospective, Multicenter Study.

Objective Although Barrett's adenocarcinoma (BA) remains a minor disease in Japan, its incidence has been gradually increasing. We analyzed the characteristics of BA in Japanese populations. Methods We retrospectively reviewed medical records and analyzed the clinicopathological differences between short-segment Barrett's esophagus (SSBE) and long-segment Barrett's esophagus (LSBE), as well as metastasis. Local recurrence and metachronous lesions were analyzed only in patients who underwent endoscopic resection (ER). Patients Consecutive patients who had pathological T1 BAs resected by ER or surgery from January 2003 to December 2017. Results A total of 168 patients were analyzed, including 139 with SSBE and 29 with LSBE. In total, 67% of the SSBE lesions and 32% of the LSBE lesions were located between 0 and 3 o'clock (p=0.0014). No patients who achieved pathological margin-free resection (pR0) and 17% of patients who did not achieve pR0 experienced local recurrence (p=0.0131). None of the patients without lymphovascular involvement, a poorly differentiated component, lesion size of >30 mm, and submucosal invasion of >500 µm experienced metastasis. The 5-year cumulative incidence rate of metachronous BA after ER was 0% in patients with SSBE and 40% in patients with LSBE (p=0.0005). Conclusion Superficial BA was likely to be detected at the right anterior wall of SSBE in the Japanese population. The risk for metachronous BA after ER was high in Japanese patients with LSBE, as in Western patients.

Screening for Gaucher Disease Using Dried Blood Spot Tests: A Japanese Multicenter, Cross-sectional Survey.

Objective For patients with Gaucher disease (GD), a rare, inherited lysosomal storage disease, obtaining a definitive diagnosis is currently time-consuming and costly. A simplified screening method to measure the glucocerebrosidase (GBA) activity using dried blood spots (DBS) on filter paper has recently been developed. Using this newly developed screening method, we evaluated real-world GD screening in patients suspected of having GD. Methods This multicenter, cross-sectional, observational study with a diagnostic intervention component evaluated real-world screening in patients suspected of having GD based on their clinical symptoms and a platelet count <120,000/µL. The endpoint was the number of patients with low GBA activity determined using DBS. Results In 994 patients who underwent initial DBS screening, 77 had low GBA activity. The assay was not repeated in 1 patient who was diagnosed as having a high possibility of GD due to clinical symptoms, and a further 21 patients completed the study without undergoing the second assay. Of the remaining 55 patients who had 2 DBS assays performed, 11 had a low GBA activity in both assays. Overall, DBS screening identified 12 (1.2%) patients with a low GBA activity, a proportion consistent with prior screening studies. Conclusion These results suggest that the simplified DBS method was less burdensome to patients, was easily utilized by many physicians, and could be a useful first-tier screening assay for GD prior to initiating burdensome genetic testing.

Exploration of the characteristics of chronotypes in upper gastrointestinal tract diseases: a multicenter study in Japan.

Characteristics of the chronotypes of patients with gastrointestinal disease are unknown. We evaluated chronotypes of patients with upper gastrointestinal diseases with the Munich ChronoType Questionnaire (MCTQ). A total of 2027 subjects from 29 institutions in Japan who had undergone esophagogastroduodenoscopy were asked to answer the MCTQ. The subjects' chronotypes were divided into three groups (early, intermediate, and late chronotype) using the sleep-corrected mid-point of sleep on free days (MSFSC) values. According to their endoscopic diagnosis and abdominal symptoms, the subjects were divided into the reflux esophagitis (RE) group, gastroduodenal ulcer (GDU) group, upper gastrointestinal carcinoma (CA) group, functional dyspepsia (FD) group, non-FD group, and control group. In total, 1128 subjects were eligible for the analysis. The MSFSC (average ± standard deviation, clock hours, h) of each disease group was as follows: control group: 02.51 ± 1.22, non-FD group: 02.69 ± 1.14, FD group: 02.91 ± 1.19, RE group: 02.58 ± 1.05, GDU group: 02.47 ± 1.31, and CA group: 02.11 ± 1.08 h. Compared to the control group, the rate of late chronotype of the FD group significantly increased to 33.3%, whereas that of early chronotype of the CA group significantly increased to 38.3% (P = .0177 and 0.0036, respectively). In both the FD and CA groups, chronotype was the independent factor related to the diseases. The adjusted odds ratio of late chronotype to early chronotype was 3.01 [95% CI, 1.23-7.35] in the FD group and 0.44 [95% CI, 0.23-0.85] in the CA group. In conclusion, late chronotype was common in patients with FD, and early chronotype was common in patients with upper gastrointestinal carcinoma.

MC1R c.310G>- and c.871G > A determine the coat color of Kumamoto sub-breed of Japanese Brown cattle.

Coat color is one of the important factors characterizing breeds for domestic animals. Melanocortin 1 receptor (MC1R) is a representative responsible gene for this phenotype. Two single-nucleotide polymorphisms (SNPs) in bovine MC1R gene, c.296T > C and c.310G>-, have been well characterized, but these SNPs are not enough to explain cattle coat color. As far as we know, MC1R genotypes of Kumamoto sub-breed of Japanese Brown cattle have not been analyzed. In the current study, genotyping for c.296T > C and c.310G>- was performed to elucidate the role of MC1R in determining the coat color of this sub-breed. As a result, most animals were e/e genotype, suggesting the coat color of this sub-breed is derived from the e allele of MC1R gene. However, we found six animals with E/e genotype, which coat color would be black theoretically. Subsequently, sequence comparison was performed with these animals to identify other polymorphisms affecting coat color, elucidating that these animals possessed the A allele of c.871G > A commonly. c.871G > A was a non-synonymous mutation in the seventh transmembrane domain, suggesting alteration of the function and/or the structure of MC1R protein. Our data indicated that the A allele of c.871G > A might be a loss-of-function mutation.

Diagnostic Role of 18F-Fluorodeoxyglucose Positron Emission Tomography in Gastric Mesenchymal Tumors.

There have been no comparative studies investigating the results of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) in patients with gastric mesenchymal tumors, including leiomyomas, leiomyosarcomas, schwannomas, and gastrointestinal stromal tumors (GISTs). We retrospectively reviewed the data of 142 patients with pathologically diagnosed gastric mesenchymal tumors treated at 11 institutions. We analyzed the correlation between the maximum standardized uptake value (SUVmax) evaluated using fluorodeoxyglucose-positron emission tomography (FDG-PET) and the tumor size. The correlation between the SUVmax and mitotic index was also investigated in GISTs. The SUVmax (mean ± standard deviation) was 0.5 ± 0.6 in very low-risk GISTs (n = 42), 2.1 ± 0.7 in low-risk GISTs (n = 26), 4.9 ± 0.8 in intermediate-risk GISTs (n = 22), 12.3 ± 0.8 in high-risk GISTs (n = 20), 1.0 ± 1.0 in leiomyomas (n = 15), 6.9 ± 1.2 in schwannomas (n = 10), and 3.5 in a leiomyosarcoma (n = 1). The SUVmax of GISTs with an undetermined risk classification was 4.2 ± 1.3 (n = 8). Linear associations were observed between the SUVmax and tumor size in GISTs, leiomyomas, and schwannomas. The SUVmax of GISTs with a high mitotic index was significantly higher than that of GISTs with a low mitotic index (9.6 ± 7.6 vs. 2.4 ± 4.2). In conclusion, we observed positive correlations between the SUVmax and tumor size in GISTs, leiomyomas, and schwannomas. The SUVmax also positively correlated with the mitotic index and risk grade in GISTs. Schwannomas showed a higher FDG uptake than GISTs and leiomyomas.

Continued Aspirin Treatment May Be a Risk Factor of Delayed Bleeding after Gastric Endoscopic Submucosal Dissection under Heparin Replacement: A Retrospective Multicenter Study.

Objective Gastric endoscopic submucosal dissection (ESD) under heparin replacement (HR) of warfarin reportedly has a high risk of delayed bleeding (24-57%). It is possible that the delayed bleeding risk may have changed over the years. We evaluated the current risk of delayed bleeding after gastric ESD under HR of anticoagulant agents. Methods We retrospectively reviewed the delayed bleeding rate and analyzed the risk factors for delayed bleeding. Patients Consecutive patients who underwent gastric ESD under HR of anticoagulant agents from July 2015 to June 2017. Results A total of 32 patients with a solitary early gastric cancer and taking anticoagulant agents were analyzed, including 24 patients on warfarin (the warfarin group) and 8 patients on direct oral anticoagulants (the DOAC group). Three (9.4%) patients experienced delayed bleeding: three (12.5%) patients in the warfarin group and no patients in the DOAC group. Continued aspirin treatment was identified to be a risk factor of delayed bleeding (p=0.01). Conclusion Careful management may be required for patients undergoing gastric ESD under continued aspirin treatment in addition to HR of anticoagulant agents; although the delayed bleeding risk after gastric ESD under HR of anticoagulant agents might have decreased over the years.

Predictive model of bleeding following endoscopic sphincterotomy for the treatment of choledocholithiasis in hemodialysis patients: A retrospective multicenter study.

BACKGROUND AND AIM: Although hemodialysis (HD) is a strong risk factor for postendoscopic sphincterotomy (ES) bleeding, additional risk factors in HD patients remain unclear. There is no model for predicting post-ES bleeding risk in HD patients. Therefore, we conducted a retrospective multicenter study to reveal these risk factors and develop a predictive model of post-ES bleeding in HD patients. METHODS: We retrospectively reviewed the medical records of HD patients who underwent ES at eight hospitals between January 2006 and December 2016, with post-ES bleeding as the main outcome measure. Univariate analyses were performed to extract possible risk factors for post-ES bleeding. Factors that were clinically important and statistically significant in our univariate analyses were then included in our logistic regression analysis for the development of a multivariate predictive model of post-ES bleeding. This predictive model was visualized using a predictive nomogram. RESULTS: Post-ES bleeding occurred in 20 (16.3%) of 123 HD patients. Based on clinically important factors and the results of our univariate analyses, platelet count, prothrombin time (international normalized ratio), and HD duration were included in our predictive model of post-ES bleeding. Receiver operating characteristic analysis found that this model had an area under the curve of 0.715 (95% confidence interval, 0.609-0.822). We developed a predictive nomogram based on these results. CONCLUSIONS: We demonstrated that post-ES bleeding is more common in HD patients than in the general population and succeeded in constructing a predictive model that can effectively identify HD patients at risk of post-ES bleeding.

A singleton distractor updates the inhibitory template for visual marking.

Visual marking, which is based on the assumption that previewing some distractors increases the efficiency of subsequent visual searches, constitutes one of the most efficient inhibitions on visual searches. The preview search task consists of a display of a subset of distractors followed by an additional display containing the remaining distractors and a target. During the preview period, an inhibitory template is thought to be formed, resulting in the prioritization of the subsequently presented items and the inhibition of the previewed items. Although the previous studies have mainly examined the determinants that impair the inhibitory templates resulting in inefficient visual searches, the present study examined the possibility that the template could be updated to increase search efficiency. To this end, we used a preview search task and manipulated the presence of a singleton distractor in the display of the additional items. We examined whether the singleton increased the efficiency of the search performance by determining if the inhibitory template would be updated such that participants would treat the singleton as if it had been previewed. The results demonstrated that the response times were faster with the singleton included, suggesting that an inhibitory template for visual marking could be updated and lead to improved search performance.

Recurrent Bleeding from a Hepatic Artery Pseudoaneurysm after Biliary Stent Placement.

A 78-year-old woman was admitted with benign biliary stenosis. A plastic stent was placed at the left branch to prevent obstructive cholangitis. Two weeks after the procedure, the patient was readmitted with cholangitis caused by hemobilia. However, computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), peroral cholangioscopy, and abdominal angiography failed to establish the bleeding source. At the seventh bleeding, CT revealed a hepatic artery pseudoaneurysm for which coil embolization was successfully performed. Hemobilia after plastic stent placement is extremely rare. We urge clinicians to consider the possibility of a pseudoaneurysm near the stent when trying to identify the bleeding source.