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Background & Aims: Colorectal lesions measuring greater than 20 mm are unsuitable for en bloc endoscopic mucosal resection (EMR): piecemeal EMR (PM-EMR) and endoscopic submucosal dissection (ESD) are needed. The European Society of Gastrointestinal Endoscopy (ESGE) recommends ESD only for microinfiltrative lesions, although Japanese teams perform en bloc ESD for all lesions. We report the outcomes obtained in our endoscopy unit for these lesions and assess the hybrid "knife-assisted piecemeal EMR" (KAPM-EMR) technique. The main aim was to assess the short-term outcomes (C1). The secondary objectives were to evaluate the long-term results (C2), adverse event rate and management of recurrence. Methods: We retrospectively analyzed data from patients treated by PM-EMR, KAPM-EMR and ESD for a colorectal lesion measuring greater than 20 millimeters using prospective inclusion over four years. Results: Data from 167 patients (median age: 70) with a median follow-up of 15.1 months were analyzed after excluding 95 patients. A total of 131 lesions were removed by PM-EMR, 24 by KAPM-EMR and 12 by ESD; 146/167 (87.4%) patients were considered in remission at C1. Recurrence was treated by endoscopy in 20/21 patients (95%); 86/89 (96.6%) were in remission at C2. A total of 16/167 patients developed adverse events, all of whom except one were endoscopically managed. KAPM-EMR was associated with a higher perforation risk (p=0.037). No differences in postoperative bleeding were found among the three groups (p=0.576). Conclusions: Piecemeal resection remains an effective and safe technique for large colorectal adenomas. KAPM-EMR may be useful but should be applied with caution due to the risk of perforation. [ABSTRACT FROM AUTHOR]

Résumé: En 2022, la ponction sous écho-endoscopie à l'aide d'un écho-endoscope linéaire est une des indications principales de l'écho-endoscopie diagnostique. Elle est la pierre angulaire de la prise en charge des masses pancréatiques solides, mais également d'autres lésions péri-digestives (lésions kystiques, GIST, etc.). Les aiguilles cytologiques, sûres et efficaces avec une sensibilité supérieure à 85 % et une spécificité supérieure à 95 %, sont supplantées par le développement des aiguilles histologiques « nouvelle génération » permettant d'obtenir un matériel histologique de meilleure qualité sans majorer la morbidité. Ces évolutions adaptées à la médecine de plus en plus personnalisée et guidée par les marqueurs théranostiques ont progressivement changé la technique, en particulier la gestion de l'anatomo-pathologie. In 2022, EUS-guided sampling with linear EUS scope is one of the main diagnosis EUS indication. EUS-guided sampling is the building block concerning management of pancreatic solid mass but also other peridigestive lesions (cystic lesion, GIST, etc.). EUS fine needle aspiration (EUS-FNA), safe and efficient with sensibility over 85% and specificity over 95%, is gradually supplanted by EUS fine needle biopsy (EUS-FNB) which allows better histological materiel acquisition without increasing morbidity. These evolutions, perfectly adapted to modern medicine (personalized with theranostic markers) changed the EUS usage in particular cytopathology management. [ABSTRACT FROM AUTHOR]

Background The long-term outcomes and safety of endoscopic mucosal resection (EMR) of sporadic duodenal adenoma (SDA), and the management of adverse events need to be confirmed. Methods A bicentric retrospective study was performed including all patients who underwent EMR for SDAs from 2003-2016. The primary aim was to evaluate the efficiency of EMR for SDA. The secondary objectives were to assess safety, recurrence management, predictive factors for treatment success, and adverse events. Results One hundred thirty patients (134 procedures) were included (median age 65 years, 49.3% male). The mean SDA size was 20.7 (range 5-50) mm. Of the SDAs, 58.2% were category 3 of the Vienna classification, 35.8% were category 4, and 5.9% were category 5. The median follow up was 25.0 (range 2-120) months. Complete mucosal resection was achieved for 129/134 lesions (96.2%), with en bloc resection in 59/134 (44%). Recurrence occurred in 28.6% of cases (30/105 procedures). Recurrence was successfully treated by new endoscopic procedures in 72.2% (13/18) and by surgery in 27.8% (5/18). Delayed bleeding occurred in 13.4% of cases (18/134) and was successfully managed endoscopically. The perforation rate was 3.7% (5/134); perforations were managed without surgery in 60% (3/5 patients) of cases. Conclusions Endoscopic treatment of SDA appears to be effective and relatively safe in tertiary centers. All bleeding complications were endoscopically controlled, and perforation was rare. Recurrence was frequent but could be managed endoscopically. EMR is confirmed as a first-line treatment in cases of SDA, and surgery is useful only if repeated EMRs fail. [ABSTRACT FROM AUTHOR]

Background & Aims: The use of endoscopic treatment for early colorectal cancer (ECC) is increasing. The European guidelines suggest performing piecemeal endoscopic resection (pmR) for benign lesions and en bloc resection for ECC, especially for patients with favorable lymph node involvement risk evaluations. However, en bloc resections for lesions larger than two centimeters require invasive endoscopic techniques. Our retrospective single-center study aimed to determine the clinical impact of performing pmR for ECC rather than traditional en bloc resection. Methods: A single-center study was performed between January 2012 and September 2017. All ECC patients were included. The main objective was to evaluate the number of patients who potentially underwent unnecessary surgery due to piecemeal resection. The secondary endpoints were as follows: disease-free survival (DFS), defined as the time from pmR to endoscopic failure (local recurrence not treatable by endoscopy), complication rate, number of patients who did not undergo surgery by default, and factors predictive of outcomes and complications. Results: One hundred and forty-six ECC endoscopically treated patients were included. In total, 85 patients were excluded (71 who underwent en bloc resection, 14 with pending follow-up). Data from 61 patients (33 women and 28 men) were analyzed. Two patients underwent potentially unnecessary surgery [3.28% (0.9%- 11.2%)]. The DFS rate was 87% (75%-93%) at 6 months and 85% [72%-92%] at 12 months. The median followup time was 16.5 months (12.4-20.9). Three patients (4.9%) had complications. One patient did not undergo surgery by default. A Paris classification of 0-2c (HR=9.3 (2.4-35.9), p<0.001) and Vienna classification of 5 [HR=16.3 (3.3-80.4), p<0.001] were factors associated with poor DFS. Conclusion: Performing pmR in place of en bloc resection for ECC had a limited impact on patients. If the pathology (especially deep margins) is analyzable, careful monitoring could be acceptable in ECC patients who undergo pmR. [ABSTRACT FROM AUTHOR]

B Video 1 b After several failed rendezvous procedures, a novel rendezvous technique is performed using cholangioscopy for the endoscopic retrograde cholangiopancreatography to visualize the stricture, along with percutaneous cholangioscopy using a bronchoscope. A second attempt using simultaneous percutaneous cholangioscopy and ERCP was scheduled for a few days later (Video 1), but this repeat classical rendezvous technique was a failure too. [Extracted from the article]

Background Currently, colonoscopy and polypectomy are the gold standard methods for the prevention of incident cases of colorectal cancer. The use of a new colonoscope (Fuse©, EndoChoice®) with a larger view of up to 330° appears to improve the adenoma detection rate (ADR). We performed a prospective observational study concerning this scope. The primary endpoint was potentially omitted adenomas (POA), i.e. adenomas seen on the side screens that will not appear on the central display during colonoscopy withdrawal without oriented movements. Secondary endpoints included our ADR, Fuse® impact on ADR, time to cecal intubation and withdrawal time. Methods We performed a single-center prospective study in one French center. We enrolled patients over 18 years of age between January 2015 and March 2016. Results We included 141 patients; 3 were excluded because their colonoscopies were incomplete. Our study included 78 men and 60 women (sex ratio 1.3). The mean age was 60.4 years. A total of 130 polyps were resected. In all, 88/130 were adenomas (68%) and 34/88 adenomas (39%) were POA. The mean time to cecum was 10 min and the mean withdrawal time was 12 min. ADR was 35% for men and 31% for women. The estimated ADR without POA was 29% for men and 19% for women. Conclusions The Fuse® system appears to be safe and efficient. POA represented 39% of all adenomas. The impact of the panoramic view on the ADR was considered substantial. The main limitations are the lack of randomization and the absence of a control group. [ABSTRACT FROM AUTHOR]

Background: Strictures are frequent complications of large endoscopic mucosal resections (EMR) and endoscopic submucosal dissections of the esophagus. Local or systemic steroid therapy has shown promise in the prevention of secondary stenosis. The aim of this study was to evaluate the safety and efficacy of systemic steroid therapy following endoscopic resection of at least hemicircumferential esophageal mucosa. Methods: This was a single-center retrospective study in a tertiary center. We evaluated patients who were treated with oral steroids between July 2013 and September 2015, after undergoing a large EMR for Barrett's esophagus associated with dysplasia or carcinoma. The steroid protocol used was an initial dose of 30 mg prednisolone, tapered over 8 weeks. Exclusion criteria were a previous attempt at radiofrequency ablation or resection. Results: Thirty-one patients (27 men) were analyzed: 13 with low-grade dysplasia Barrett's esophagus, 16 with in situ adenocarcinoma, 1 with pT1SM1 adenocarcinoma, and 1 with pT1SM2 adenocarcinoma. Twenty-eight resections (28/31) were completed (R0) in 1-3 sessions (median 2), while 3 resections were R1. The median length of Barrett's esophagus was C3M5 (range C0M2-C10M11) according to the Prague classification. The median follow up was 10 months (range 4-17), during which 4 patients (13%) developed a secondary stenosis. All stenoses were successfully treated by endoscopic dilation (range 1-4). No complications related to dilation or to the steroid therapy were observed. Conclusions Our rate of secondary stricture was lower than expected, given the rates of 17-88% in published studies. Systemic oral steroid therapy seems to be effective in reducing potential esophageal stenosis after EMR. Complementary randomized studies are required to confirm whether systemic steroids are an effective primary prophylaxis for esophageal stenosis. [ABSTRACT FROM AUTHOR]

Background: Post-endoscopic duodenal perforation is a severe adverse event with high morbidity and mortality rates. Managing this rare event is challenging owing to limited clear guidelines. This retrospective study aimed to examine the relationship between time-to-treatment and morbidity among patients with post-endoscopic duodenal perforations. Methods: Over 20 years, 78 consecutive patients with post-endoscopic duodenal perforations were analyzed. Among these, most patients underwent endoscopic procedures at the Paoli-Calmettes Institute, whereas some were referred from other centers after a diagnosis of perforation. We described the characteristics of patients who underwent medical treatment alone or interventional procedures. Among patients who underwent interventional management, we compared the outcomes following early or delayed procedures (later than 24 h post-duodenal perforation diagnosis). Results: Overall, 78 patients with post-endoscopic duodenal perforation were identified between September 2003 and September 2022. Of these, 17 (22%) patients underwent non-operative management, and 61 (78%) with peritonitis or adverse clinical features were treated with endoscopic or surgical procedures. Additionally, among these patients, 40 (65%) underwent immediate invasive procedures, surgically (n = 20) or endoscopically (n = 20). Patients with delayed procedures experienced more major Clavien–Dindo ≥ 3 complications and had an increase by 21 of the median comprehensive complication index. Overall, mortality occurred in 7 (8.9%) patients in the entire cohort and in 3 (14.3%) with delayed invasive procedures. Conclusions: Delayed decision-making is a key factor complicating post-endoscopic duodenal perforation. Therefore, invasive procedures should be performed promptly in cases of adverse conditions requiring additional procedures, ideally within the first 24 h of perforation diagnosis. [ABSTRACT FROM AUTHOR]

Background: Current guidelines consider observation a reasonable strategy for G1 or G2 nonfunctional pancreatic neuroendocrine tumors (nf pNETs) =2 cm. We aimed to characterize their natural behavior and confront the data with the outcomes of patients undergoing upfront surgery. Methods: Data from patients with histologically confirmed nf pNETs =2 cm, managed at a single tertiary referral center between 2002 and 2020, were retrospectively reviewed. Results: Thirty-nine patients (mean age 62.1 years, 56% male) with 43 lesions (mean size 12.7±3.9 mm; 32 grade 1 [G1] and 7 grade 2 lesions [G2]) were managed by careful surveillance. Progression was observed in 15 lesions (35%; mean follow up 47 months). Six patients (18%) underwent secondary surgery because of an increase in tumor size or dilation of the main pancreatic duct; 3 of them had lymph node metastasis in the resected specimen. Surgery was followed by pancreatic fistula in 2/6 patients, 1 of whom died. Fourteen patients (mean age 59 years, 64.3% female, mean size of lesions 11.4±3.1 mm) underwent pancreatic surgery immediately after diagnosis. The surgery-associated complication rate was 57.1% (8/14). Of the 14 patients, 13 remained recurrence free (mean follow up 67 months). Recurrent metastatic disease was observed 3 years after pancreaticoduodenectomy (R0, 15 mm G2 lesion, 0 N+/8 N) in 1 patient. Conclusions: The behavior of small nf pNETs is difficult to predict, as there is evidence for malignant behavior in a subgroup of patients, even after surgical treatment. Optimal management remains challenging, as pancreatic surgery is associated with significant morbidity. [ABSTRACT FROM AUTHOR]

Background: Recently, there has been growing interest in investigating endoscopic ultrasound‐guided radiofrequency ablation (EUS‐RFA) for the management of small non‐functional pancreatic neuroendocrine tumors (nf pNETs). Patients and Methods: A bicentric retrospective study was performed that included patients with histologically confirmed nf pNETs who were consecutively treated by EUS‐RFA between December 2015 and March 2021 at two tertiary referral centers. Results: In 27 patients (mean age 65.0 years, 52% male), EUS‐RFA was successfully performed. All patients had sporadic G1 lesions (mean size 14.0 ± 4.6 mm, 7% uncinated process, 22% head, 11% body, 19% body/tail junction, and 41% tail). Overall, 9/27 lesions (33%) were cystic. The mean hospital stay was 3.2 days. Complete treatment response was confirmed in 25/27 patients (93%) on cross‐sectional imaging (mean follow‐up 15.7 ± 12.2 months, range 2–41 months). Two patients had two EUS‐RFA sessions until complete necrosis was observed. Periprocedural acute pancreatitis occurred in 4/27 (14.8%), three of them were treated by endoscopic cystogastrostomy (11.1%). One patient underwent secondary surgery. The histopathology of the resected specimen revealed 3 mm of residual tumor tissue. Conclusion: EUS‐RFA seems to be a promising treatment strategy for the management of small nf pNETs with excellent efficacy. Further evidence focusing on long‐term survival, safety profile and recurrence is needed. [ABSTRACT FROM AUTHOR]

Background and purpose: To report the postoperative and oncological outcomes of transhiatal esophagectomy for locally advanced cancer of the gastroesophageal junction. Methods: Medical records of 120 consecutive patients who underwent transhiatal esophagectomy for locally advanced cancer of the gastroesophageal junction with curative intent after neoadjuvant treatment between February 2006 and December 2018 at our center were reviewed. Results: All patients received either chemotherapy (46.7%) or chemoradiation (53.3%). The 90-day mortality and overall morbidity rates were 0.8% and 56.7%, respectively. Respiratory complications were the most common (30.8%). Anastomotic leakage occurred in 19 patients (15.8%), who were treated by local wound care (n = 13) or surgical drainage (n = 6). Recurrent laryngeal nerve injury occurred in 12 patients (9.9%). The median length of hospital stay was 15.5 days. The rate of R0 resection was 95.8%, and the median number of nodes removed was 17.5. Over a median follow-up of 77 months, the rate of recurrence was 40.8%, and the overall survival rates at 1, 3, and 5 years were 91%, 75%, and 65%, respectively. The median survival time was not reached. In multivariate analysis, disease stage was the only independent significant prognostic factor. Conclusions: Transhiatal esophagectomy is a safe and effective procedure with good long-term oncological outcomes for locally advanced tumors after neo-adjuvant treatment. It can be recommended for all patients with cancer of the gastroesophageal junction, regardless of the Siewert classification, tumor stage, and comorbidities. [ABSTRACT FROM AUTHOR]

Background High-grade dysplasia (HGD) and intramucosal carcinoma (IMC) in Barrett’s esophagus (BE) are now well-established indications for endoscopic resection (ER). Radiofrequency ablation (RFA) can be combined with ER in case of flat or long-segment BE ablation. We report here our experience of complementary RFA after widespread ER of neoplastic BE in daily practice. Method We retrospectively reviewed data of 89 patients, treated between 2006 and 2013 by ER alone (group 1) or by ER combined with RFA (group 2). Results Fifty-five patients in group 1 (7F/48M, mean age 68 years) underwent widespread ER with eradication of residual non-dysplastic BE. Complete eradication of HGD/IMC and intestinal metaplasia (IM) was achieved in 32/32 (100%) and 48/55 (87.3%) patients, respectively. Thirty-four patients in group 2 (3F/31M, mean age 67 years) had a multimodal treatment strategy, with widespread ER followed by RFA. Mean Prague classification of BE in this group was significantly longer (C4.4M6.6 vs. C2.7M4.5, P<0.001). Complete eradication of HGD/IMC and non-dysplastic BE was confirmed in 26/27 (96.3%) and 20/34 (58.8%) patients, respectively. There was no significant difference between groups concerning adverse events (16.4% vs. 23.5%, P=0.58) or recurrence rate of HGD/IMC (9.1% vs. 14.7%, P=0.42). The mismatch rate between preoperative and final histological diagnosis was high in both groups, at 45.5% and 26.5%. Conclusions A combination of ER and RFA can treat significantly longer neoplastic BE than ER alone, with the same efficiency and safety. Widespread ER, in contrast, is the only method of obtaining a reliable histological diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Glandular metastases and more precisely pancreatic metastases (PM) from renal cell carcinoma (mRCC) are associated with a long survival. Focal treatment in order to control oligo-metastatic disease and avoid systemic therapy is a standard in RCC. However, pancreatic radiofrequency ablation remains a marginal and under evaluated technic. Standard treatment remains pancreatectomy with hazardous outcomes. We report here the largest series of endoscopic radiofrequency ablation (EUS-RFA) on PM for patient treated at Institut Paoli-Calmettes for a mRCC. Patients with progressive PM was treated under general anesthesia with an ultrasound guided endoscopic radiofrequency ablation procedure then followed by CT-scan. We prospectively included 12 patients, median age was 70.5 years old and median size and number of PM at inclusion was 17 mm and 1 respectively. All 26 procedures performed went as planned and no immediate complications were experienced. After 27.7 months of follow-up, the 6- and 12-month focal control rates were 84% and 73% respectively. Two severe complications occurred after EUS-RFA but were totally resolved after specific treatment. In total, EUS-RFA is feasible and displayed an excellent focal control and should be integrated in the arsenal to treat PM from mRCC in order to spare systemic therapy and/or pancreatic surgery. Background: Pancreatic metastases (PM) from renal cell carcinoma (RCC) are rare, are associated with favorable outcomes and are usually handled by surgery or VEGFR inhibitors, which both have side effects. Endoscopic Ultrasound (EUS)-guided radiofrequency ablation (RFA) is an innovative approach to treat focally deep metastases and could be a relevant technique to control PM from RCC. Methods: This monocentric, prospective study aimed to evaluate the safety and efficacy of EUS-RFA to treat PM. We included patients with confirmed and progressive PM from RCC. PM was ablated under general anesthesia with a linear EUS scope and a EUS-RFA 19-gauge needle electrode placed into the tumor. Results: Twelve patients from Paoli-Calmettes Institute were recruited between May 2017 and December 2019. Median age was 70.5 years (range 61–75), 50% were female, 100% were ECOG 0–1. At inclusion, mean PM size was 17 mm (range 3–35 mm); and all were progressive before EUS-RFA. Seven patients had EUS-RFA as the only treatment for RCC. We performed 26 EUS-RFA procedures and 21 PM was ablated. Median follow up was 27.7 months (range 6.4–57.1). For evaluable PM, the 6- and 12-month focal control rates were 84% and 73% respectively. One patient treated with TKI developed a paraduodenal abscess 2 months after EUS-RFA and another patient with biliary stent developed hepatic abscesses few days after EUS-RFA. No other severe side effects were experienced. Conclusions: in this series, which is the largest ever reported, we showed that EUS-RFA is feasible and yields an excellent local control rate for PM from mRCC. With manageable complications, it could be a valuable alternative to pancreatic surgery in well-selected patients. [ABSTRACT FROM AUTHOR]

Background: Gastric hyperplastic polyps (GHPs) have a risk of neoplastic transformation reaching 5 %. Current endoscopic resection techniques appear suboptimal with a high risk of local recurrence. This study assessed the outcomes of endoscopic resection for GHPs and identified risk factors for recurrence and neoplastic transformation.Methods: This retrospective, multicenter, European study included adult patients with at least one GHP ≥ 10 mm who underwent endoscopic resection and at least one follow-up endoscopy. Patients with recurrent GHPs or hereditary gastric polyposis were excluded. All data were retrieved from the endoscopy, pathology, and hospitalization reports.Results: From June 2007 to August 2018, 145 GHPs in 108 patients were included. Recurrence after endoscopic resection was 51.0 % (74 /145) in 55 patients. R0 resection or en bloc resection did not impact the risk of polyp recurrence. In multivariate analysis, cirrhosis was the only risk factor for recurrence (odds ratio [OR] 4.82, 95 % confidence interval [CI] 1.33 - 17.46; P = 0.02). Overall, 15 GHPs (10.4 %) showed neoplastic transformation, with size > 25 mm (OR 10.24, 95 %CI 2.71 - 38.69; P < 0.001) and presence of intestinal metaplasia (OR 5.93, 95 %CI 1.56 - 22.47; P = 0.01) being associated with an increased risk of neoplastic transformation in multivariate analysis.Conclusions: Results confirmed the risk of recurrence and neoplastic transformation of large GHPs. The risk of neoplastic change was significantly increased for lesions > 25 mm, with a risk of high grade dysplasia appearing in polyps ≥ 50 mm. The risk of recurrence was high, particularly in cirrhosis patients, and long-term follow-up is recommended in such patients. [ABSTRACT FROM AUTHOR]

Background: Endotherapy in cases of neoplastic Barrett esophagus (BE) relapse after successful initial endoscopic management is commonly accepted, but few studies analyze this topic and also take into account the metachronous lesions.Aims: To evaluate the efficiency of endotherapy in the case of neoplastic BE relapse after successful complete endoscopic eradication of neoplastic BE and metaplastic BE.Methods: Retrospective review of medical records was collected in a computerized and prospective manner between 2000 and 2015, in a single tertiary care center. Recurrence was defined by histological presence of high-grade dysplasia or superficial adenocarcinoma at least 6 months after the end of successful initial endotherapy.Results: Eighteen patients were assessed (1F/17 M). Delay between initial treatment and relapse was 16.6 months (range 6-33). Endotherapy for relapse obtained a sustained and complete remission for 8/18 (44%) patients, with an average endoscopic follow-up of 28 months. The complication rate of endotherapy was 6%. Surgical management was required in 33% (2 pT2N0M0, 2 pTisN0M0, 1 pTm2N0M0 and 1 pTm3N0M0) and salvage radiochemotherapy in 17% (3/18). One patient treated by 6 sessions of ER was considered as a failure given the multiple sessions of endotherapy. Multivariate analysis showed that length of BE (>5 cm), late stenosis adverse events and the quality of vertical margin during initial ER are predictive factors for disease-free survival (p value < 0.01, Hazard Ratio up to 0.076).Conclusion: Endotherapy could be a treatment for management of neoplastic BE relapse, but should be carefully used, with strict follow-up. [ABSTRACT FROM AUTHOR]

Radiofrequency ablation (RFA) is a curative option for hepatocellular carcinoma (HCC), the most common primary malignancy of the liver. This bicentric retrospective study includes 46 patients admitted for their first percutaneous RFA for HCC. Sixty-three nodules were treated, with an average size of 32.5 mm. Our study confirms the efficiency of this technique for attaining necrosis of HCC nodules, with few complications. Subgroup studies according to RFA mode (mono- or multipolar), etiology of cirrhosis (alcoholic or viral), and HCC size showed better efficiency for multipolar RFA when applied to small tumors and better survival when the cirrhosis was due to viral infection. However, we noted a high rate of local recurrence in our and other recent works compared to previous studies, probably due to improved imaging techniques. The main problem is still de novo intrahepatic recurrence in diseased livers. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

The article describes the case of a 51-year-old woman with a pancreatic pseudocyst. The patient manifested intraperitoneal active bleeding through angioscan after a cystogastrostomy was performed. A splenopancreatectomy was implemented to address the bleeding. Possible adverse reaction for the transmural drainage of a pseudocyst is also presented including bleeding, pneumoperitoneum, and infection.