Endoscopic features of synchronous multiple early gastric cancers: Findings from a nationwide cohort.

INTRODUCTION: We investigated the factors associated with synchronous multiple early gastric cancers and determined their localization. METHODS: We analyzed 8191 patients who underwent endoscopic submucosal dissection for early gastric cancers at 33 hospitals in Japan from November 2013 to October 2016. Background factors were compared between single-lesion (n=7221) and synchronous multi-lesion cases (n=970) using univariate and multivariate analyses. We extracted cases with two synchronous lesions (n=832) and evaluated their localization. RESULTS: Significant independent risk factors for synchronous multiple early gastric cancer were older age (≥75 years old) (OR=1.257), male sex (OR=1.385), severe mucosal atrophy (OR=1.400), tumor localization in the middle (OR=1.362) or lower region (OR=1.404), and submucosal invasion (OR=1.528 (SM1), 1.488 (SM2)). Depressed macroscopic type (OR=0.679) and pure undifferentiated histology OR=0.334) were more common in single early gastric cancers. When one lesion was in the upper region, the other was more frequently located in the lesser curvature of the middle region. When one lesion was in the middle region, the other was more frequently located in the middle region or the lesser curvature of the lower region. When one lesion was in the lower region, the other was more frequently located in the lesser curvature of the middle region or the lower region. CONCLUSION: Factors associated with synchronous multiple early gastric cancer included older age, male sex, severe mucosal atrophy, tumor localization in the middle or lower region, and tumor submucosal invasion. Our findings provide useful information regarding specific areas that should be examined carefully when one lesion is detected.

Clinical Utility of Helicobacter pylori Stool Antigen Testing with a Bioluminescent Enzyme Immunoassay Using a Fecal Occult Blood Test Container.

Background A dedicated stool container is required for Helicobacter pylori stool antigen testing. If H. pylori fecal antigen can be measured from a fecal occult blood test container (S fecal collection container or S container), which is widely used for colorectal cancer screening, screening of the upper and lower gastrointestinal tract can be performed with a single stool sample. We investigated the clinical usefulness of an H. pylori stool antigen assay using an S container. Patients and Materials A total of 347 patients who underwent esophagogastroduodenoscopy (EGD) were included. After the procedure, H. pylori stool antigen was measured using the S container and collection container recommended for H. pylori stool antigen (BL-stool collection container or BL container), and the qualitative outcomes of each were compared. A bioluminescent enzyme immunoassay (BLEIA) was used to measure H. pylori stool antigen. Results The overall agreement between S containers and BL containers was 100% (347/347), indicating that the qualitative outcomes were equivalent. As a secondary analysis, the results of the S container samples were evaluated according to the diagnosis made by physicians, and the overall agreement rate was 99.7% (345/346), indicating a high correlation. Conclusion The detection of H. pylori stool antigen using the S container is clinically useful because the results are equivalent to those obtained by the usual method. Screening of the upper and lower gastrointestinal tract is expected to be possible with a single stool sample in the future.

Characteristic endoscopic findings in early-stage autoimmune gastritis.

Background and study aims Until recently, autoimmune gastritis (AIG) was usually diagnosed at late stages based on typical endoscopic findings, including corpus-dominant advanced atrophy. Early-stage AIG prior to complete gastric atrophy had rarely been diagnosed due to a lack of knowledge about its endoscopic characteristics. The present study sought to identify the endoscopic characteristics of early-stage AIG, enabling its early diagnosis. Patients and methods The clinical and endoscopic findings of 12 patients diagnosed with early-stage AIG between 2016 and 2021 were retrospectively evaluated. Patients were included if they were: (1) positive for serum anti-parietal cell antibody; (2) diagnosed with histological early-stage AIG; and (3) endoscopically positive for folds on the greater curvature of the gastric corpus. Results Two characteristic endoscopic findings of early-stage AIG were identified: longitudinal alignment of pseudopolyps (i.e., a bamboo joint-like appearance) and swelling of gastric areas with erythema (i.e., a salmon roe-like appearance). Conclusions Endoscopic findings characteristic of early-stage AIG include a bamboo joint-like appearance and a salmon roe-like appearance. Studies in large numbers of patients with long-term follow-up are needed to confirm these findings.

Acceptability, Safety, and Feasibility of Transnasal and Peroral Ultrathin Endoscopy Using GAGLESS Mouthpieces: A Prospective Randomized Trial.

BACKGROUND/AIM: Esophagogastroduodenoscopy (EGD) is an effective screening method for early detection of gastric cancer. The GAGLESS mouthpiece has a structure that widens the pharyngeal cavity and suppresses the pharyngeal reflex. This study aimed to investigate the acceptability, safety, and feasibility of transnasal and peroral ultrathin endoscopy using GAGLESS mouthpieces (Clinical Trial Number: UMIN000036922). PATIENTS AND METHODS: This study was a multicenter, prospective, randomized, open-label trial performed using a questionnaire. The study included 101 consecutive patients who visited the participating medical institutions between June 2019 and March 2022 (median age=47 years, range=24-87 years; all male). Patients aged ≥20 years at the time of consent acquisition who were the first to undergo EGD were included in the study. The primary endpoint was the degree of distress during EGD, as determined using a visual analog scale (VAS). RESULTS: The VAS score during endoscopic passage through the pharynx was significantly better in the transnasal endoscopy group than in the oral endoscopy group (2.420 vs. 4.092, p=0.001). There was no significant difference in the VAS scores between the two groups during anesthesia or throughout the examination. Compared with nasal endoscopy, oral endoscopy with a GAGLESS mouthpiece did not reduce the VAS score but did significantly improve gastric visibility. CONCLUSION: For patients in whom there was difficulty in inserting a nasal endoscope, using a GAGLESS mouthpiece rather than a conventional mouthpiece may be more useful in reducing pain.

A case of nodular gastritis progression to autoimmune gastritis after 10 years of Helicobacter pylori eradication.

A 61-year-old female patient underwent upper gastrointestinal endoscopy, which confirmed the presence of Helicobacter pylori (H. pylori)-positive nodular gastritis (NG). Routine upper gastrointestinal endoscopy after H. pylori eradication revealed atrophic changes of the corpus, having gradually progressed over the 10 years after successful eradication. Serological and biopsy specimen examination showed hypergastrinemia (1200 pg/mL), positive anti-parietal cell antibody (with a titer of more 160), and endocrine cell micronests after 11 years of H. pylori eradication. The patient was diagnosed with autoimmune gastritis (AIG) based on endoscopic, serological, and histological findings. This is the first report of AIG diagnosed in a patient with NG over a long period of time after H. pylori eradication.

Diagnostic Accuracy of a Novel Stool Antigen Test for Helicobacter pylori Infection in a Medical Checkup Setting: A Prospective Cohort Study.

Objective Of the highly accurate tests for current Helicobacter pylori infection, the urea breath test (UBT) and stool antigen test (SAT) are noninvasive and do not require endoscopy. We conducted a prospective study to evaluate the accuracy of the newly developed SAT in a medical checkup setting. Methods The accuracy of the proposed SAT was examined by determining H. pylori infection status based on a history of eradication therapy, endoscopic H. pylori infection diagnosis, and blood tests (serum H. pylori antibody, serum PG II) in individuals undergoing esophagogastroduodenoscopy (EGD) during a health checkup. Results The new SAT showed 97.3% (108/111) sensitivity for those "currently infected," as well as 99.3% (530/534), 98.0% (402/410), and 98.7% (932/944) specificity for those "never infected," those "previously infected," and those "never/previously infected", respectively. Conclusion The newly developed H. pylori SAT may be useful for diagnosing H. pylori infection. Patients should be suspected of being infected even after H. pylori eradication if they have a high cutoff index in this test.

A Case of Early Barrett's Adenocarcinoma With Eosinophilic Esophagitis.

A 61-year-old man presented with epigastric pain and underwent upper gastrointestinal endoscopy. A strongly erythematous area was found in the short segment of the Barrett's esophagus, and a biopsy revealed well-differentiated adenocarcinoma. Linear furrows were observed in the lower esophagus, and a biopsy of the lesion revealed eosinophil infiltration of 30 eosinophils per high-power field. Therefore, a diagnosis of Barrett's adenocarcinoma with eosinophilic esophagitis was made. Although rare, the incidence of Barrett's adenocarcinoma and eosinophilic esophagitis has been increasing in Japan in recent years, and the number of cases may increase in the future.

Protocol for detecting Helicobacter suis infection in gastric biopsies and serum by PCR and ELISA.

Infection with Helicobacter suis, which causes many cases of gastric disease, is not reliably diagnosed. Here, we present a protocol for detecting H. suis infection. We describe steps for collecting gastric biopsies and sera from patients, preparing DNA for PCR, and targeting the H. suis-specific gene. We then define procedures for inoculating biopsies onto primary agar plates and transferring colonies to secondary agar plates. Finally, we detail whole-genome sequencing of bacteria and assess H. suis infection in sera with ELISA. For complete details on the use and execution of these protocols, please refer to Matsui et al.1.

Development of serological assays to identify Helicobacter suis and H. pylori infections.

Helicobacter suis, hosted by hogs, is the most prevalent gastric non-Helicobacter pylori Helicobacter species found in humans. Recent studies have suggested that H. suis infection has caused many cases of gastric disease, but the transmission route from hogs remains unclear. Diagnostic methods based on H. suis urease activity often yield negative results, and there is no reliable method for diagnosing H. suis infection in clinical practice without gastric biopsy specimens. This study presents the world's first use of whole-bacterial cell ELISA to simultaneously assess H. suis and H. pylori infections. The ELISAs showed high accuracy, with an area under the ROC curve of 0.96, 100% sensitivity, 92.6% specificity, 76.9% positive predictive value, and 100% negative predictive value for the H. suis test, and an area under the ROC curve of 0.92, 88.2% sensitivity, 87.5% specificity, 65.2% positive predictive value, and 96.6% negative predictive value for the H. pylori test.

Clinical characteristics and long-term prognosis of type 1 gastric neuroendocrine tumors in a large Japanese national cohort.

OBJECTIVES: Optimal management of type 1 gastric neuroendocrine tumors (T1-GNETs) remains unknown, with few reports on their long-term prognosis. This study investigated the clinical characteristics and long-term prognosis of T1-GNETs. METHODS: We reviewed the medical records of patients diagnosed with T1-GNET during 1991-2019 at 40 institutions in Japan. RESULTS: Among 172 patients, endoscopic resection (ER), endoscopic surveillance, and surgery were performed in 84, 61, and 27, respectively, including 27, 77, and 2 patients with pT1a-M, pT1b-SM, and pT2 tumors, respectively. The median tumor diameter was 5 (range 0.8-55) mm. Four (2.9%) patients had lymph node metastasis (LNM); none had liver metastasis. LNM rates were significantly higher in tumors with lymphovascular invasion (LVI) (15.8%; 3/19) than in those without (1.1%; 1/92) (P = 0.016). For tumors <10 mm, LVI and LNM rates were 18.4% (14/76) and 2.2% (2/90), respectively, which were not significantly different from those of tumors 10-20 mm (LVI 13.3%; 2/15, P = 0.211; and LNM 0%; 0/17, P = 1.0). However, these rates were significantly lower than those of tumors >20 mm (LVI 60%; 3/5, P = 0.021; and LNM 40%; 2/5, P = 0.039). No tumor recurrence or cause-specific death occurred during the median follow-up of 10.1 (1-25) years. The 10-year overall survival rate was 97%. CONCLUSIONS: Type 1 gastric neuroendocrine tumors showed indolent nature and favorable long-term prognoses. LVI could be useful in indicating the need for additional treatments. ER for risk prediction of LNM should be considered for tumors <10 mm and may be feasible for tumors 10-20 mm. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Information Network (UMIN) under the identifier UMIN000029927.

Association between perioperative management of antiplatelet agents and risk of post-endoscopic submucosal dissection bleeding in early gastric cancer: analysis of a nationwide multicenter study.

BACKGROUND AND AIMS: Data are lacking regarding post-endoscopic submucosal dissection (ESD) bleeding in patients with early gastric cancer (EGC) who take antiplatelet agents (APAs), particularly in those taking thienopyridine and cilostazol. We aimed to clarify the association between the status of APA medication and post-ESD bleeding risk. METHODS: This study is a secondary analysis using data from a recently conducted nationwide multicenter study in Japan. We retrospectively reviewed patients treated with APAs or on no antithrombotic therapy recruited from 33 institutions who underwent ESD for EGC between November 2013 and October 2016. The primary outcome of this study was the relationship between the rate of post-ESD bleeding and the status of each APA medication. RESULTS: A total of 9736 patients were included in the analysis. Among 665 aspirin users, the continuation group was significantly associated with post-ESD bleeding (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.77-4.37). Among 227 thienopyridine users, the aspirin or cilostazol replacement group was not significantly associated with post-ESD bleeding (OR, 1.85; 95% CI, .72-4.78). Among 158 cilostazol users, there was no significant association with post-ESD bleeding, irrespective of medication status. The rate of post-ESD bleeding was approximately 10% to 20% irrespective of the status of APA administration among dual-antiplatelet therapy users. No patients experienced thromboembolic events in this study. CONCLUSIONS: Replacement of thienopyridine with aspirin or cilostazol may be acceptable for minimizing both the risk of post-ESD bleeding and thromboembolism in patients with EGC. In patients on cilostazol monotherapy undergoing ESD, continuation of therapy may be acceptable.

Efficacy and Safety of a Novel Hemostatic Peptide Solution During Endoscopic Submucosal Dissection: A Multicenter Randomized Controlled Trial.

INTRODUCTION: To compare the effectiveness of the novel hemostatic peptide, TDM-621, with that of conventional hemostatic methods in treating intraoperative blood oozing during endoscopic submucosal dissection (ESD). METHODS: This multicenter, open-label, randomized controlled trial involved 227 patients with gastric and rectal epithelial tumors in whom ESD was indicated. Patients in whom the source of blood oozing was difficult to identify with waterjet washing during the procedure and required hemostasis with hemostatic forceps were randomly assigned to the TDM-621 and control groups. The TDM-621 group (in which hemostasis was achieved with TDM-621, followed by coagulation hemostasis with hemostatic forceps, as needed) was compared with the control group (in which hemostasis was achieved with hemostatic forceps). The primary end point was the mean number of coagulations with hemostatic forceps, determined by a blinded independent review committee. The secondary end points were the rate of achievement of hemostasis with only TDM-621, the dosage of TDM-621, and adverse events in the TDM-621 group. RESULTS: The mean number of coagulations with hemostatic forceps was significantly reduced in the TDM-621 group (1.0 ± 1.4) compared with that in the control group (4.9 ± 5.2) ( P < 0.001). The rate of hemostasis achievement with only TDM-621 was 62.2%; the mean dosage of TDM-621 was 1.75 ± 2.14 mL. The rates of grade ≥3 adverse events were 6.2% and 5.0% in the TDM-621 and control groups, respectively. DISCUSSION: TDM-621 is a useful, easily operable hemostatic peptide for treatment of blood oozing during gastric and rectal ESD, with no serious safety concerns.

Bleeding following Endoscopic Submucosal Dissection for Early Gastric Cancer in Surgically Altered Stomach.

INTRODUCTION: Few studies have focused on bleeding following endoscopic submucosal dissection (ESD) in surgically altered stomach. We aimed to reveal the bleeding risk in surgically altered stomach following ESD for early gastric cancer (EGC). METHODS: We enrolled patients with ESD for EGC at 33 institutions between 2013 and 2016. In study 1, we evaluated bleeding risk following ESD in surgically altered stomach, compared with whole stomach. In study 2, we evaluated factors associated with bleeding following ESD in patients with surgically altered stomach. RESULTS: Of 11,452 patients, 445 patients had surgically altered stomach with the bleeding rate following ESD of 4.9%. In study 1, the bleeding risk in surgically altered stomach was not significant (odds ratio [OR], 1.37; 95% confidence interval [CI], 0.87-2.17) in the multivariate logistic regression analysis. No significant results were obtained when the surgically altered stomach was subdivided into various types. In study 2, the multivariate logistic regression analysis revealed that independent risk factors for bleeding following ESD were ischemic heart disease (OR, 7.52; 95% CI, 2.00-28.25) and P2Y12 receptor antagonist (OR, 4.81; 95% CI, 1.21-19.14). DISCUSSION/CONCLUSION: In this nationwide study, we found that the bleeding risk of surgically altered stomach following ESD for EGC did not significantly differ from that of whole stomach. The risk factors for ESD in patients with surgically altered stomach were ischemic heart disease and P2Y12 receptor antagonist.

Proposal of minimum elements for screening and diagnosis of gastric cancer by an international Delphi consensus.

The World Endoscopy Organization Stomach and Duodenal Diseases Committee extracted minimum elements for screening and diagnosis of gastric cancer (GC) in aim to support countries that do not have national guidelines on screening and diagnosis of GC. Current national or international guidelines were collected worldwide and recommendations were classified according to the quality of evidence and were finalized through a modified Delphi method. The minimum elements consist of seven categories: [1] Extraction of high-risk patients of GC before esophagogastroduodenoscopy (EGD), [2] Patients who need surveillance of GC, [3] Method to ensure quality of EGD for detection of GC, [4] Individual GC risk assessment by EGD, [5] Extraction of high-risk patients of GC after EGD [6] Qualitative or differential diagnosis of GC by EGD, and [7] Endoscopic assessment to choose the therapeutic strategy for GC. These minimum elements will be a guide to promote the elimination of GC among countries with a high incidence of GC who lack national guidelines or screening programs.

The degree of mucosal atrophy is associated with post-endoscopic submucosal dissection bleeding in early gastric cancer.

BACKGROUND AND AIM: Despite the widespread use of endoscopic submucosal dissection (ESD) for early gastric cancer, post-ESD bleeding remains a significant problem. Intragastric pH plays an important role in intragastric bleeding. Because gastric acid secretion contributes to intragastric pH, both the presence or absence of Helicobacter pylori infection and the degree of gastric mucosal atrophy may affect bleeding. The present study aimed to clarify the relationship between post-ESD bleeding and the degree of gastric mucosal atrophy based on H. pylori infection status. METHODS: We included 8170 patients who underwent ESD for early gastric cancer at 33 hospitals in Japan from November 2013 to October 2016. We analyzed the risk factors contributing to post-ESD bleeding. RESULTS: There were 3935 H. pylori-positive patients and 4235 H. pylori-negative patients. A nonsevere degree of gastric mucosal atrophy was an independent risk factor for post-ESD bleeding in H. pylori-negative patients (odds ratio: 1.51, P = 0.007), but not in H. pylori-positive patients (odds ratio: 0.91, P = 0.600). Further, in H. pylori-negative, but not H. pylori-positive, patients, the rate of post-ESD bleeding increased in a stepwise manner for patients continuing antithrombotic drug use, patients who withdrew antithrombotic drug use, and antithrombotic drug nonusers. CONCLUSIONS: Nonsevere gastric mucosal atrophy was a risk factor for post-ESD bleeding in early gastric cancer in H. pylori-negative patients but not in H. pylori-positive patients.

A study for every second day administration of vonoprazan for maintenance treatment of erosive GERD (ESD von GERD): a multicenter randomized cross-over study.

BACKGROUND: Vonoprazan is a potassium competitive acid blocker used to treat erosive gastroesophageal reflux disease (GERD) with stronger, more stable acid-suppressing effects than proton pump inhibitors (PPIs). This study clarified the usefulness and superiority of vonoprazan administered every second day over PPIs in the maintenance therapy of erosive GERD. METHODS: This is a prospective, multicenter, open-label, two-period randomized cross-over study. Patients were randomized to either the vonoprazan-lansoprazole (VP-LZ) group, who were given vonoprazan 10 mg for the first 4 weeks and then lansoprazole 15 mg for the next 4 weeks both administered once every second day, or the lansoprazole-vonoprazan (LZ-VP) group, who were treated in reverse. GERD symptoms were compared using symptom diaries, the frequency scale for symptoms of GERD (FSSG), and the gastrointestinal symptom rating scale (GSRS). RESULTS: We enrolled 122 patients between December 2017 and May 2019. Symptoms were well controlled in vonoprazan administration and lansoprazole administration were 93.6% and 82.1%, respectively, with a significant difference on McNemar's test (P = 0.003). During the second 4 weeks, 94.4% and 76.7% of patients in the VP-LZ and LZ-VP groups, respectively, were well controlled following for ≥ 6 consecutive days a week (P = 0.009). During the first 4 weeks, 96.7% and 80.0% of patients were well controlled with < 1 weekly in the VP-LZ and LZ-VP groups, respectively, during the first 4 weeks (P = 0.007). GERD symptoms, assessed via FSSG and GSRS, significantly decreased with vonoprazan administration once every second day. CONCLUSIONS: Vonoprazan administered once every second day could be an effective alternative to PPIs in the maintenance treatment of erosive GERD (UMIN000030393).

Influence of hospital volume on bleeding after endoscopic submucosal dissection for early gastric cancer in Japan: a multicenter propensity score-matched analysis.

BACKGROUND: Information on whether there is a relationship between hospital volume and bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is limited. This study aimed to compare the bleeding rates after ESD for EGC according to the hospital volume. METHODS: Patients who underwent ESD for EGC at 33 institutions in Japan between November 2013 and October 2016 were included in this multicenter retrospective study. Hospital volume was categorized into three groups, based on the average annual number of ESD procedures: low- and medium-volume group (LMVG), high-volume group (HVG), and very high-volume group (VHVG). The bleeding rate after ESD for EGC was compared between the three hospital volume groups after propensity score matching. RESULTS: A total of 10,320 patients, including 2797 patients in the LMVG, 4646 patients in the HVG, and 2877 patients in the VHVG, were identified. Propensity score matching yielded 2002 patients in each hospital volume group, with an improved balance of confounding variables between the three groups. The bleeding rates in the LMVG, HVG, and VHVG were 4.3%, 3.7%, and 4.9%, respectively, and no significant difference was noted between the three groups. CONCLUSIONS: The bleeding rate after ESD for EGC did not differ between hospitals in Japan. The finding indicated that ESD for EGC is equally feasible across Japanese hospitals of different volumes regarding bleeding after ESD.

Endoscopic screening for gastric cancer in Japan: Current status and future perspectives.

The revised 2014 Japanese Guidelines for Gastric Cancer Screening approved gastric endoscopy for use in population-based screening. Thus, it is expected that gastric cancer will be detected earlier, and gastric cancer mortality further decreased, with the widespread use of endoscopy and Helicobacter pylori eradication therapy. However, due to an increasingly aging population and relatively low gastric cancer screening rates, gastric cancer remains the leading cause of cancer death in Japan. While the era of endoscopic gastric cancer screening has begun, it does present challenges, such as limited/varying regional availability of endoscopists. This review describes the history of gastric cancer screening in Japan, achievements in endoscopic gastric cancer screening in Japan and Korea, efforts underway to improve screening by stratifying individuals according to gastric cancer risk, and initiatives by the Japan Gastroenterological Endoscopy Society aimed at improving screening, including the implementation of a board certification program for screening endoscopists.

Risk Factors for Bleeding After Endoscopic Submucosal Dissection for Gastric Cancer in Elderly Patients Older Than 80 Years in Japan.

INTRODUCTION: As the aging of people in a society advances, the number of elderly patients older than 80 years in Japan with gastric cancer continues to increase. Although delayed ulcer bleeding is a major adverse event after endoscopic submucosal dissection (ESD), little is known about characteristic risk factors for bleeding in elderly patients undergoing ESD. This study aimed to evaluate risk factors for delayed bleeding after ESD for gastric cancer in elderly patients older than 80 years. METHODS: We retrospectively evaluated the incidence of delayed bleeding after ESD in 10,320 patients with early-stage gastric cancer resected by ESD between November 2013 and January 2016 at 33 Japanese institutions and investigated risk factors for delayed bleeding in elderly patients older than 80 years. RESULTS: The incidence of delayed bleeding in elderly patients older than 80 years was 5.7% (95% confidence interval [CI]: 4.6%-6.9%, 95/1,675), which was significantly higher than that in nonelderly (older than 20 years and younger than 80 years) patients (4.5%, 4.1%-5.0%, 393/8,645). Predictive factors for ESD-associated bleeding differed between nonelderly and elderly patients. On multivariate analysis of predictive factors at the time of treatment, risk factors in elderly patients were hemodialysis (odds ratio: 4.591, 95% CI: 2.056-10.248, P < 0.001) and warfarin use (odds ratio: 4.783, 95% CI: 1.689-13.540, P = 0.003). DISCUSSION: This multicenter study found that the incidence of delayed bleeding after ESD in Japanese patients older than 80 years was high, especially in patients receiving hemodialysis and taking warfarin. Management of ESD to prevent delayed bleeding requires particular care in patients older than 80 years.