CASE OF HEMORRHAGE FROM A DUODENAL DIVERTICULUM TREATED SUCCESSFULLY BY ENDOSCOPIC INJECTIONS OF EPINEPHRINE

Although duodenal diverticula are found relatively frequently in adult gastrointestinal tracts, the majority are asymptomatic. We report a case of duodenal diverticulum complicated with hemorrhage. A 74‐year‐old woman developed hematemesis and tarry stools. An emergent upper gastrointestinal endoscopy revealed a diverticulum, about 3 cm in diameter, in the posteromedial aspect of the second duodenal segment, right oral to the papilla. The diverticulum was filled with blood clots. After removing them by gentle suction, a linear ulcer became visible and an actively oozing site was seen at one edge of the ulcer. Three injections of epinephrine in a 2.5% sodium chloride solution (epinephrine concentration 0.05 mg/mL), each 1.0 mL for a total volume of 3.0 mL, were made at the oozing site. The exuding ceased immediately after the third injection and bleeding did not reappear. In our patient, successful and complete hemostasis was obtained by this endoscopic injection of epinephrine, although most cases of duodenal diverticulum complicated with hemorrhage had been treated surgically. We think that endoscopic, instead of surgical treatment is considerably becoming another choice for treating patients with a bleeding duodenal diverticulum.     

MANAGEMENT OF ENDOSCOPIC SPHINCTEROTOMY‐INDUCED BLEEDING

Bleeding is one of the most common and potentially serious complications of endoscopic sphincterotomy (ES) and the overall frequency ranges from 2% to 5%. Patients with coagulopathy and anticoagulant therapy should be excluded from ES. ES using microprocessor‐controlled electrosurgical generator setting for Endocut mode, and a step‐wise manner of controlled incision may reduce the frequency of bleeding. Once ES‐induced bleeding occurs, diluted epinephrine irrigation, coagulation using papillotome, and balloon tamponade may be effective. If the bleeding continues, vessel ligation with a hemoclip should be performed to achieve a permanent hemostasis. Diluted epinephrine injection is an alternative technique when the point of bleeding is not identified. All endoscopists who perform ES should have suitable knowledge of management of bleeding and be experts in hemostasis.     

ENDOSCOPIC BAND LIGATION WITH A WATER‐JET SCOPE FOR THE TREATMENT OF COLONIC DIVERTICULAR HEMORRHAGE

Although lower gastrointestinal bleeding generally has a less severe course and stops spontaneously in most cases without therapeutic intervention, some patients require endoscopic, surgical, or angiographic treatment depending on the nature of the bleeding. We applied endoscopic band ligation (EBL) with a water‐jet scope to bleeding colonic diverticula and evaluated the efficacy and safety of EBL retrospectively. Five consecutive patients were diagnosed as having colonic diverticular hemorrhage, and were treated with EBL at St Luke's International Hospital in Tokyo from June 2009 to August 2009. Comorbid diseases, usage of anti‐platelet agents, hemoglobin level on admission, procedural time, complications such as perforation and abscess formation, and rebleeding after EBL were retrospectively evaluated. In all cases, EBL achieved successful immediate hemostasis without any procedural complications. In four of five cases, bleeding colonic diverticula were everted after EBL. The mean length of hospital stay after EBL was 5 days (range 4–8 days). No patient exhibited clinical evidence of further bleeding during the mean follow‐up period of 3 months (range 2–4 months), and no further intervention was needed after EBL. EBL with a water‐jet scope is considered to be a safe and effective endoscopic treatment for colonic diverticular hemorrhage.     

ENDOSCOPIC SUBMUCOSAL DISSECTION OF COLORECTAL LESION

Endoscopic submucosal dissection (ESD) has been developed for en‐bloc resection of mucosal lesions of the gastrointestinal tract. It enables us to resect almost all mucosal and slightly submucosal invasive tumors, regardless of size and shape, even in the colon. Therefore, preoperative diagnosis, especially for the depth of invasion, is very important to determine the treatment strategy. The shape of the lesion, its pit pattern and also EUS findings are very useful in estimating the depth of invasion. We use an EndoEcho system with ultrasonic probe, which gives us both radial and linear image of the lesions. Remodeled three‐dimensional (3D) images are also very useful in evaluating the size and the expansion of the lesion when it is located on a fold. Although the large intestine involves structural and technical difficulties, we conduct en‐bloc resection by ESD while exercising various ingeunities in preparation, endoscopes, use of instruments and local injections. ESD is the reliable technique, which allows en‐bloc resection of gastrointestinal mucosal lesions, and has a excellent chance of success in the treatment of early stage colorectal cancer.     

ARGON PLASMA COAGULATION FOR THE ENDOSCOPIC TREATMENT OF A NON‐RESECTABLE KLATSKIN TUMOR: IN VITRO AND IN VIVO STUDY

Background : Palliative treatment including stenting is limited in patients with Klatskin tumor. Argon plasma coagulation (APC) is a new local treatment modality for the devitalization and debulking of tumors. Argon plasma coagulation could be a candidate method for relief of biliary strictures in patients with non‐resectable Klatskin tumor in whom biliary stenting has failed. This study provides an evaluation of the technical feasibility, safety, and effect of APC as a palliative strategy in patients with non‐resectable Klatskin tumor. Methods : In vitro studies were performed in order to investigate the dimension of coagulation necrosis in 11 human gallbladders. The currents were applied in normal air conditions and a bowl filled with normal saline in five and six specimens, respectively. Argon plasma coagulation was also performed on three patients with Klatskin tumor who showed no effective drainage via percutaneous transhepatic approach with a cholangioscope. Results : A coagulation current was delivered to the specimen even if in normal saline. The maximum depth and diameter of necrosis was 3 and 6.5 mm under normal air conditions, compared with 2 and 5 mm in water conditions. No perforation of the gallbladder wall occurred in any of the lesions. The dimension of the necrosis increased with increasing impact time and energy settings. Argon plasma coagulation application was possible on tumors of patients without severe complication. Conclusion : Argon plasma coagulation seems to be applicable, effective and relatively safe in palliative treatment for advanced non‐resectable Klatskin tumor via cholangioscopy. Longer follow ups and comparative trials with other treatment modalities are, however, required.     

COMBINED DUODENAL STENT PLACEMENT AND ENDOSCOPIC ULTRASONOGRAPHY‐GUIDED BILIARY DRAINAGE FOR MALIGNANT DUODENAL OBSTRUCTION WITH BILIARY STRICTURE

Patients with malignant pancreatobiliary neoplasm sometimes manifest duodenal obstruction and biliary stricture synchronously or metachronously. In this paper, we reviewed our experience with and technique for combined endoscopic duodenal stent placement and endoscopic ultrasonography (EUS)‐guided biliary drainage. Between May 2007 and September 2009, this combined technique was performed on seven patients with distal biliary strictures and duodenal obstructions. The clinical success rate of the procedure, complications, patency periods of duodenal stents and patency periods of biliary stents were retrospectively evaluated. Clinical success was achieved in all seven cases for both procedures. Complications related to EUS‐biliary drainage, namely localized peritonitis due to bile leakage, occurred in two cases. Both patients recovered without additional interventions. Occlusion of a duodenal stent was observed in one patient, but additional intervention could not be performed due to sepsis. Occlusion of both a duodenal stent and a biliary stent was also observed in one patient, and this was resolved with the insertion of an additional duodenal stent and a biliary stent exchange. In conclusion, combined duodenal stent placement and EUS‐guided biliary drainage is a therapeutic option in case of failed endoscopic retrograde cannulation of malignant strictures with a malignant duodenal obstruction.     

SUCCESSFUL ENDOSCOPIC HEMOSTASIS FOR RUPTURED DUODENAL VARICES AFTER BALLOON‐OCCLUDED RETROGRADE TRANSVENOUS OBLITERATION

A 75‐year‐old man with general malaise and appetite loss was transferred to our hospital for assessment and treatment of liver failure. Laboratory findings on admission showed anemia, and gastroduodenoscopy (GDS) revealed linear esophageal varices and tensive duodenal varices (DV) in the second portion of the duodenum. Systemic examinations did not reveal any significant lesion capable of explaining his anemia, except for DV. Balloon‐occluded retrograde transvenous obliteration was carried out to prevent DV bleeding. Good pooling of sclerosant was observed using two balloon catheters. However, contrast‐enhanced computed tomography after the procedure revealed no thrombosis in DV, and the patient complained of tarry stools before additional therapy. Emergent GDS revealed ruptured DV with fresh blood and erosions on the surface. Emergent endoscopic obliteration using the tissue adhesive N‐butyl‐2‐cyanoacrylate was carried out and complete hemostasis was achieved. Although no rebleeding episodes were observed after emergent obliteration, the patient died of sepsis following spontaneous bacterial peritonitis 53 days after admission. Autopsy revealed that DV dropped out, and the deep vein was replaced by granulation tissue. No signs of thrombi were detected, except varices. This autopsy case revealed the difficulty in DV management.     

ENDOSCOPIC MANAGEMENT OF PANCREATICO‐BILIARY STRICTURES: A MALAYSIAN EXPERIENCE

Three thousand one hundred and thirty‐seven endoscopic retrograde cholangiopancreatography procedures were carried out over a 10‐year period from 1993 to 2003. Two thousand three hundred and seventeen (73.9%) procedures were first attempt procedures, and 516 (22.2%) cases were performed for malignant biliary strictures. The majority of tumors were distally located (43.4%) followed by hilar or subhilar strictures (34.5%). Endoscopic retrograde cholangiopancreatography (ERCP) was performed in 35 patients with non‐malignant biliary strictures: 12 were due to chronic pancreatitis and 13 due to postoperative damage one, tuberculous stricture four were benign strictures with no obvious cause, four cases of primary sclerosing cholangitis, and one case of Caroli's disease. Of 936 patients with biliary stone disease, 63 (6.7%) patients had strictures of varying degree and extent. ERCP was performed in only 12 cases of benign pancreatic strictures. Biliary stricture due to tuberculosis was distinctly uncommon and only one case was reported. Pre‐cutting with needle‐knife was used successfully in 27.0% of first attempts at common bile duct (CBD) cannulation. Overall, the use of needle knife precutting facilitated cannulation of the CBD in 159/435 (36.6%) (first and second attempts combined). The overwhelming majority of stents placed were polyethylene stents. Metallic self‐expandable stents were used only in a limited number of patients. Cytology brushings of biliary strictures were infrequently carried out. Multiple polyethylene stents were placed across benign strictures as a dilatation device for up to 12 months. Our experience with long‐term follow‐up (mean 7.7 years) of nine patients following for postoperative benign strictures has demonstrated excellent results with this management approach.     

ENDOSCOPIC SPHINCTEROTOMY ALONE IN THE MANAGEMENT OF LOW‐GRADE BILIARY LEAKS DUE TO CHOLECYSTECTOMY

Aim: Endoscopic retrograde cholangiopancreatography (ERCP) is important in the diagnosis and management of postoperative bile leaks. Endoscopic sphincterotomy (ES) alone, ES with stent or nasobiliary drain (NBD) placement and stent or NBD without ES are the methods of choice. In the present study, we aimed to show the efficacy of ES alone in the management of low‐grade (LGL) cystic duct stump (CDS) leaks due to cholecystectomy. Methods: Between September 2005 and January 2008, ES was carried out on 31 patients with LGL from the CDS due to cholecystectomy who were referred to the endoscopy unit of Izmir Ataturk Training and Research Hospital. Biliary leakage was detected by biliary discharge from a tube drain inserted during the operation. In cases of retaining common bile duct stones, balloon extraction was carried out. If bile discharge continued, a stent was introduced for cessation of the leak as a second procedure. Results: The success rate of ES alone was 87.1% (27 of 31 patients). In four patients (12.9%), ES alone was inadequate, therefore a stent was placed. The biliary leak ceased gradually and stopped in all patients at a mean of 11 (7–21) days. Balloon extraction of retained stones was carried out in six patients (19.6%). In two (6.5%) patients, mild hemorrhage and in two patients self‐limited pancreatitis was seen (6.5%) as complications. Conclusion: Endoscopic retrograde cholangiopancreatography is essential in the management of postoperative biliary leaks. Endoscopic sphincterotomy alone can be the initial procedure in the treatment of LGL from the CDS due to cholecystectomy.     

SUCCESSFUL MANAGEMENT OF METASTASIS‐INDUCED PANCREATITIS BY ENDOSCOPIC PANCREATIC DUCT STENTING IN A CASE OF LARGE CELL LUNG CANCER

The prognosis for patients with metastasis‐induced acute pancreatitis (MIAP) is extremely poor. Although chemotherapy has been shown to improve overall survival in patients with MIAP, as well as in patients with small cell lung cancer, it is poorly tolerated by patients with severe pancreatitis. Furthermore, patients with a history of chemotherapy often develop multidrug‐resistant tumors. Here we report a first case of MIAP that was successfully managed by endoscopic pancreatic duct stenting. A 54‐year‐old man with pancreatic metastasis from large cell lung cancer developed acute pancreatitis approximately three times per month, despite a continuous conventional therapy for pancreatitis. As his disease was refractory to chemotherapy, he underwent endoscopic pancreatic duct stenting. The procedure was successful in controlling his pancreatitis, and he survived 7 months after the onset of a first acute pancreatitis. Our experience with this case suggests pancreatic duct stenting as one therapeutic method for MIAP.     

SUCCESSFUL ENDOSCOPIC ULTRASOUND‐GUIDED FINE‐NEEDLE ASPIRATION OF THE PELVIC LESION THROUGH THE SIGMOID COLON

Endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) is a useful modality when the target is a lymph node located in the mediastinum, perigastric area or perirectum. Although it is difficult to carry out EUS‐FNA of the colon using an oblique view linear scope, we report two cases of successful EUS‐FNA of the lesions via the proximal sigmoid colon using a recently available new convex type EUS scope. Case 1 was a 77‐year‐old Japanese woman noted to have multiple lymph node swelling in the para‐aortic area and in the pelvis. Case 2 was a 60‐year‐old Japanese woman noted to have a large mass in the left lower abdomen. In case 1, oral EUS showed no lymph node swelling. In both cases, EUS with forward‐viewing radial echoendoscope was carried out via the anus, and multiple lymph‐node swelling or a large mass was observed near the proximal sigmoid colon. In the EUS‐FNA for these cases, we used a new convex‐type EUS scope that has an oblique view, but with a wide‐angled optical device giving a view similar to a forward one. EUS‐FNA was successfully carried out on the lesions. The pathological specimen revealed diffuse large B‐cell lymphoma in case 1 and gastrointestinal stromal tumor (GIST) in case 2.     

ENDOSCOPIC OBSERVATION OF MUCOSAL SPREAD LESION OF CHOLANGIOCARCINOMA USING PERORAL CHOLANGIOSCOPY WITH NARROW BAND IMAGING

A 69‐year‐old man was admitted to Toho University Omori Medical Center complaining of icterus. Abdominal computed tomography, magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography were suspicious of cholangioma of inferior bile duct. Peroral cholangioscopy using narrow band imaging (NBI) was performed and it was possible to diagnose the mucosal spread lesions of cholangioma. Histological findings reflected the endoscopic findings. Mucosal spread lesions of cholangiocarcinoma were successfully diagnosed using the CHF‐B260 for NBI.     

IMPACT OF ENDOSCOPIC TRANSPAPILLARY NASO‐GALLBLADDER DRAINAGE AFTER ENDOSCOPIC SPHINCTEROTOMY IN PATIENTS WITH ACUTE CHOLECYSTITIS AND CHOLEDOCHOLITHIASIS

Aim: To evaluate prospectively the efficacy of endoscopic transpapillary naso‐gallbladder drainage (ETGBD) after endoscopic sphincterotomy (ES) in patients with acute cholecystitis with choledocholithiasis. Patients: Twenty‐six patients with acute cholecystitis and choledocholithiasis, but without pericholecystic liver abscess, were evaluated. After ES and extraction of stones, ETGBD was performed immediately. Results: In 24 of the 26 patients with ES, complete bile duct clearance was achieved. In the other two cases treated with ES, stones could be completely removed in an additional session after ETGBD. ETGBD was successfully performed in 23 patients (88%). In three patients with unsuccessful ETGBD, a percutaneous cholecystostomy (PC) was performed. Of the 23 patients that underwent ETGBD, a positive clinical response at 72 h was seen in 22 (96%) patients. In one patient who did not show a clinical response at 72 h, catheter drainage was continued and a positive clinical response was seen 5 days after the procedure. In three patients treated with PC, a clinical response at 72 h was seen in all cases (100%). No major procedure‐related complications occurred. Conclusions: ETGBD after ES proved useful in the management of acute cholecystitis and choledocholithiasis.     

PRIMARY EXTRA‐AMPULLARY DUODENAL NEUROENDOCRINE CARCINOMA IN AN ADULT MALE

A primary extra‐ampullary duodenal neuroendocrine carcinoma was found in a 40‐year‐old man who presented with upper abdominal pain and weight loss. Duodenoscopy and hypotonic duodenography revealed a protruding fungating mass with luminal occlusion at the third part of the duodenum (D3). Although the metastatic work‐up was normal, the tumor was inoperable intraoperatively, hence a palliative bypass was carried out followed by chemotherapy with 5‐fluorouracil and leucovorin. Examination of the biopsy by immunohistochemistry and ultrastructural study revealed it to be neuroendocrine in nature, expressing synaptophysin, chromogranin and cytokeratin and containing dense core cytoplasmic granules. However, there was no evidence of clinical endocrinopathy. The present case emphasizes the need for better detection, further analysis and evaluation of such rare cases to identify their clinical course and effective treatment modalities.     

CLINICAL EVALUATION OF EMERGENCY ENDOSCOPIC HEMOSTASIS WITH BIPOLAR FORCEPS IN NON‐VARICEAL UPPER GASTROINTESTINAL BLEEDING

The present study was designed to evaluate the usefulness and safety of bipolar hemostatic forceps, known as a less invasive and highly safe means of thermal coagulation used for hemostasis in cases of non‐variceal upper gastrointestinal bleeding. This technique of bipolar forceps is simple, safe and unlikely to induce complications, and is therefore promising as a new technique of endoscopic hemostasis. The study involved 39 cases where hemostasis was attempted with bipolar forceps to deal with non‐variceal upper gastrointestinal bleeding, including 28 cases of gastric ulcer, six cases of duodenal ulcer, three cases of bleeding after endoscopic submucosal dissection (ESD), one case of Mallory‐Weiss syndrome and one case of postoperative bleeding from the anastomosed area. There were 34 males and five females, with a mean age of 63.6 years. Bipolar forceps were the first‐line means of hemostasis in cases of oozing bleeding (venous bleeding), pulsatile or spurting bleeding (arterial bleeding) and exposed vessels without active bleeding. The primary hemostasis success rate was 92.3%, and the re‐bleeding rate was 0%. In cases where the bleeding site was located along the tangential line or in cases where large respiration‐caused motions hampered identification of the bleeding site, hemostasis by means of coagulation was easily effected by application of electricity while the forceps were kept open and compressed the bleeding area. In addition, there were no complications. This technique of bipolar forceps is simple, safe and unlikely to induce complications, and is therefore promising as a new technique of endoscopic hemostasis.     

INTRADUCTAL ULTRASONOGRAPHY OF THE GALLBLADDER IN APPLICATION OF THE ENDOSCOPIC NASO‐GALLBLADDER DRAINAGE

Background: Although endoscopic naso‐gallbladder drainage (ENGBD) for gallbladder disease is useful, the procedure is difficult and investigations involving many cases are lacking. Furthermore, reports on transpapillary intraductal ultrasonography (IDUS) of the gallbladder using a miniature probe are rare. Methods: A total of 150 patients (119 suspected of having gallbladder carcinoma, 24 with acute cholecystitis (AC), and seven with Mirizzi’s syndrome (MS)) were the subject. (i) ENGBD: We attempted to put ENGBD tube into the GB. (ii) IDUS of the gallbladder: Using the previous ENGBD tube, we attempted to insert the miniature probe into the gallbladder and perform transpapillary IDUS of the gallbladder. In five patients, we attempted three‐dimensional intraductal ultrasonography (3D‐IDUS). Results: (i) ENGBD: Overall success rate was 74.7% (112/150); the rate for the patients suspected of having gallbladder carcinoma was 75.6% (90/119), and was 71.0% (22/31) for the AC and MS patients. Inflammation and jaundice improved in 20/22 successful patients with AC and MS. Success rate was higher when cystic duct branching was from the lower and middle parts of the common bile duct than from the upper part, and was higher when branching was upwards than downwards. (ii) IDUS of the gallbladder: Success rate for miniature probe insertion into the gallbladder was 96.4% (54/56). Lesions could be visualized in 50/54 patients (92.6%). Of these, detailed evaluation of the locus could be performed in 41. In five patients attempted 3D‐IDUS, the relationship between the lesion and its location was readily grasped. Conclusion: IDUS of the gallbladder is superior for diagnosing minute images. Improvement on the device will further increase its usefulness.     

NEW METHOD OF STENTING TREATMENT FOR MALIGNANT DUODENAL STENOSIS: USING DOUBLE‐BALLOON ENTEROSCOPY

Recently, a self‐expandable metallic stent has been recognized for treatment of malignant duodenal stenosis. But the complications by stenting are important problems even now. In the present study, we report our new method of duodenal stenting by using of double‐balloon enteroscopy considered safe and effective.     

PANCREATIC PSEUDOCYSTS IN POST‐GASTRECTOMY PATIENTS TREATED VIA THE DUODENAL MINOR PAPILLA WITH AN OBLIQUE‐VIEWING ENDOSCOPE

Endoscopic retrograde cholangiopancreatography (ERCP) in patients after Billroth II or Roux‐en‐Y reconstruction is challenging because of difficulties in insertion of the endoscope into the afferent loop, which is a great distance away from the papilla of Vater, and cannulation into the desired duct from a reverse position. To facilitate ERCP, various endoscopes have been selected according to operator preference. Previously, we reported that an oblique‐viewing endoscope (XK‐200; Olympus, Tokyo, Japan) can contribute to successful performance of ERCP and associated procedures in Billroth II gastrectomy patients. We report here our experience with two post‐gastrectomy patients with chronic pancreatitis who were treated with an oblique‐viewing endoscope from the minor papilla.     

CLINICAL EVALUATION OF THE MULTI‐BENDING SCOPE IN VARIOUS ENDOSCOPIC PROCEDURES OF THE UPPER GI TRACT

The multi‐bending scope is one of the technological innovations that is making possible new techniques in endoscopic diagnosis and treatment. The multi‐bending function makes it easier to approach sites that would be hard to reach with conventional scopes. Not only is this useful for observation and biopsies of difficult‐to‐approach sites, it is also expected to be very useful in various endoscopic treatments such as endoscopic submucosal dissection, endoscopic mucosal resection, and endoscopic hemostasis. Unfortunately, despite these obvious advantages, the incorporation of multifunctionality and high image quality results in a heavier and wider scope with reduced maneuverability. For practical clinical use, a balance between functionality and maneuverability is essential. We believe that making further improvements in this area is crucial to the successful development of this technology.     

Second‐look endoscopy with thermal coagulation or injections for peptic ulcer bleeding: A meta‐analysis

Background and Aims: In the management of peptic ulcer bleeding, the benefits of second‐look endoscopic treatment with thermal coagulation or injections in controlling recurrent bleeding is unsure. This study set out to compare efficacy of routine second‐look endoscopy with treatment using either thermal coagulation or injections versus single endoscopy by pooling data from published work. Methods: Full publications in the English‐language published work as well as abstracts in major international conferences were searched over the past 10 years, and six trials fulfilling the search criteria were found. Outcome measurements included: (i) recurrent bleeding; (ii) requirement of surgical intervention; and (iii) mortality. We examined heterogeneity of trials and pooled the effects by meta‐analysis. The quality of studies was graded according to the prospective randomization, methods of patient allocation, the list of exclusion criteria, outcome definitions and the predefined salvage procedures for uncontrolled bleeding. Results: Among 998 patients recruited in these five randomized trials, 119 received routine second‐look endoscopy with thermal coagulation, and 374 received second‐look with endoscopic injection and 505 had single endoscopic therapy. Less recurrent bleeding was reported after thermal coagulation (4.2%) than single endoscopy (15.7%) (relative risk [RR] = 0.29; 95% confidence interval [CI] = 0.11–0.73), but no reduction was reported for the requirement of surgical intervention and all‐cause mortality. Injection therapy did not reduce re‐bleeding (17.6%) when compared to single endoscopy (20.8%; RR = 0.85; 95% CI = 0.63–1.14), requirement for surgery and mortality. Conclusion: Routine second‐look endoscopy with thermal coagulation, but not injection therapy, reduced recurrent peptic ulcer bleeding. There is no proven benefit in reducing surgical intervention and overall mortality.