Endoscopic treatment of an esophageal perforation in eosinophilic esophagitis by insertion of a self-expanding metal stent.

We present the case of a 29-year-old patient with multiple allergies, mild asthma and rhinoconjunctivitis who reported a history of esophageal impactions after ingestion of solid foods. These episodes resolved spontaneously at home and by self-induced vomiting and never required endoscopic removal. The patient presented to the emergency department due to a sensation of food impaction lasting more than 12 hours after eating meat the night before, which did not subside with the intake of liquids or self-induced vomiting. Endoscopic evaluation was requested for foreign body extraction. A meat bolus impacted in the distal esophagus was easily removed using a Roth basket, revealing a severe esophageal stricture that prevented passage of the endoscope into the gastric cavity. Furthermore, in the same area where the foreign body was previously located, a deep esophageal tear was seen. Given the high suspicion of perforation, the patient was examined, and thoracic and cervical crepitation was observed. It was decided to immediately insert, with only endoscopic control, a partially covered Ultraflex® esophageal stent measuring 18 mm in diameter and 15 cm in length. After insertion, clinical improvement and cessation of crepitation were observed.

ERCP for common bile duct stones in the elderly: refining the procedure to improve outcomes.

Removal of common bile duct stones in patients with a previous cholecystectomy was one of the first indications for ERCP with biliary sphincterotomy. Thanks to a minimally invasive procedure, patients were prevented from having a new operation. Subsequently, as the technique proved to be successful, ERCP was extended to all patients with choledocholithiasis, regardless of whether or not they had gallbladder. Also contributing was the fact that, at least in the beginnings, surgical interventions on the bile duct with laparoscopic cholecystectomy were more difficult. Nowadays, many surgeons prefer to perform cholecystectomy with a bile duct clean of stones. In this issue of the Spanish Journal of Gastroenterology, Gardenyes et al. present a study on ERCP for common bile duct stones in elderly patients. The novelty of this study is not only to analyze the ERCP procedure, which we already knew has similar success and complication rates to younger patients, but also to focus on the long-term outcome, considering the frailty that frequently accompanies aging. The study concludes that older patients may benefit from enhanced care protocols to reduce medical adverse events and improve outcomes. For us gastroenterologists and endoscopists, another conclusion that can be drawn from this study is that we should not be satisfied that ERCP in older patients has the same success and complication rates as in younger patients, but rather we should strive to ensure that the results are even better.

Endoscopic drainage of malignant distal biliary obstruction. Will ERCP no longer be necessary?

We read with interest the Editorial by Vila et al. on the paradigm shift for endoscopic biliary drainage of malignant distal biliary obstruction (MDBO) which places Endoscopic Ultrasound (EUS) drainage as the first option instead of traditional ERCP drainage. The modern biliary endoscopist must have the duodenoscope in one hand and the therapeutic echoendoscope in the other. ERCP training alone is no longer appropriate because the goal is to drain the obstruction during a single session. That is why in more and more centers the patient signs a single consent for endoscopic biliary drainage, whether by ERCP, EUS or combined. Should EUS drainage be used first for MDBO without attempting ERCP? A possible protocol for endoscopic drainage of MDBO could be to start with the duodenoscope for ERCP. If the papilla of Vater is accessible, try cannulation considering the ESGE criteria for a difficult cannulation: more than 5 contacts with the papilla; more than 5 minutes spent attempting to cannulate following visualization of the papilla; more than one unintended pancreatic duct cannulation or opacification. If biliary cannulation is not achieved, immediately switch to EUS drainage during the same session. Occasionally, the double guidewire technique or even transpancreatic biliary sphincterotomy could be used, but not needle-knife precut.

Fewer endoscopists should perform more ERCPs.

This year, 2023, marks the fiftieth anniversary of the introduction of therapeutic endoscopic retrograde cholangiopancreatography (ERCP), which completely changed the management of biliary and pancreatic diseases. As in other invasive procedures, two intrinsically related concepts soon appeared: drainage success and complications. It was observed that ERCP is the most dangerous procedure regularly performed by gastrointestinal endoscopists, with a morbidity and mortality of 5-10 % and 0.1-1 %, respectively. ERCP is by far one of the best examples of a complex endoscopic technique.

Use a biodegradable stent in ERCP and it will never be forgotten.

The easiest way to drain the bile duct or the main pancreatic duct by means of ERCP is the insertion of a plastic stent. Once cannulation has been achieved, which is generally the most complex and limiting step in ERCP, stent insertion is straightforward and rewarding. The main problem in benign pancreato-biliary conditions comes in the follow-up. Indications for biliary stent insertion in non-neoplastic diseases are common bile duct (CBD) stones that could not be completely extracted, benign strictures and leaks. In the pancreas stents are frequently inserted to prevent post-ERCP pancreatitis and for benign strictures and other less frequent conditions such as main pancreatic duct disruption. Currently in all centers more and more ERCPs are performed in patients without naive Papilla of Vater, generally for stent extraction or exchange. For example, in the recent study by Barakat and Banerjee, carried out in a tertiary care academic medical center, only 25% were index or initial ERCP, without previous sphincterotomy or stent, and subsequent procedures comprised the remaining 75 %.

How to take advantage of a failed precut to achieve biliary cannulation in ERCP.

After nearly 50 years of therapeutic endoscopic retrograde cholangio-pancreatography (ERCP), deep cannulation of the desired duct, whether biliary or pancreatic, remains primarily an art. Most ERCP procedures are performed for biliary drainage.

Safety in digestive endoscopy during the ongoing COVID-19 pandemic.

We read with interest the study by Hernández-Camba et al. about the low value of antibody testing for COVID-19 before endoscopic procedures and we would like to make some comments. Nine months after the first state of alarm was declared in Spain due to the SARS-CoV-2 pandemic, we knew that infections in endoscopy staff were scarce if adequate protection was worn and non-urgent procedures were postponed in patients with an active infection. Therefore, the conclusions of the study currently appear to be self-evident. However, things were different at the time it was performed.

Straight plastic stents in tumors at the hepatic hilum and related duodenal perforations.

We read with interest the paper on the endoscopic treatment of a duodenal perforation related to a plastic biliary stent that was reported by Roa et al. We would like to add some comments about biliary stents inserted during endoscopic retrograde cholangiopancreatography (ERCP) to palliate malignant jaundice in hilar strictures. It is our belief that the most convenient strategy in non-operable patients should be the insertion of at least one uncovered self-expanding metal stent.

The best plastic pancreatic stent to prevent post-ERCP pancreatitis.

We consider very interesting the comments made by Serrano Díaz et al. on pancreatic stents inserted as prophylaxis for acute post-ERCP pancreatitis. As we recently stated in an editorial related to the prevention of this frequent complication, the aggressive way in which the pancreatic gland may respond to contact with the devices that are used for common bile duct cannulation via the papilla of Vater is almost philosophically surprising. It is our opinion that, usually, a pancreatic stent should only be inserted if the guidewire has spontaneously entered the main pancreatic duct (MPD). In ERCPs aiming at bile duct drainage, even when bile duct cannulation has been troublesome with extensive papillary manipulation, attempting cannulation of the MPD with the sole purpose of stent insertion can be more harmful than beneficial.

Should we administer rectal anti-inflammatory drugs in all ERCPs in order to prevent pancreatitis? At least, it does not harm!

Acute pancreatitis is the most common complication of endoscopic retrograde cholangio-pancreatography (ERCP). The sensitivity of the pancreas, which may respond with such violence to the slightest pressure exerted at the entrance to its main duct in the papilla of Vater, is even philosophically surprising. In fact, each touch on the papilla increases the potential for pancreatitis development. The initial stimulus resulting in obstruction of pancreatic secretion may be the edema caused by the catheter's physical contact, the thermal effect of sphincterotomy, or the overdistension induced by the injected contrast. The triggering fact is followed by a release of inflammatory cytokines, which induce changes in pancreatic microcirculation.

Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2.

The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.

HERCing: Structural and Functional Relevance of the Large HERC Ubiquitin Ligases.

Homologous to the E6AP carboxyl terminus (HECT) and regulator of chromosome condensation 1 (RCC1)-like domain-containing proteins (HERCs) belong to the superfamily of ubiquitin ligases. HERC proteins are divided into two subfamilies, Large and Small HERCs. Despite their similarities in terms of both structure and domains, these subfamilies are evolutionarily very distant and result from a convergence phenomenon rather than from a common origin. Large HERC genes, HERC1 and HERC2, are present in most metazoan taxa. They encode very large proteins (approximately 5,000 amino acid residues in a single polypeptide chain) that contain more than one RCC1-like domain as a structural characteristic. Accumulating evidences show that these unusually large proteins play key roles in a wide range of cellular functions which include neurodevelopment, DNA damage repair, and cell proliferation. To better understand the origin, evolution, and function of the Large HERC family, this minireview provides with an integrated overview of their structure and function and details their physiological implications. This study also highlights and discusses how dysregulation of these proteins is associated with severe human diseases such as neurological disorders and cancer.

The best approach to treat concomitant gallstones and common bile duct stones. Is ERCP still needed?

The authors analyze what should be the best approach to treat patients who had concomitant gallstones and common bile duct stones (CBDS). Laparoscopic common bile duct exploration (LCBDE) appears to be an atractive way to cure all kind of biliary stones in a single procedure. However, when scientific literature is reviewed most patients continue to need from ERCP for CBDS removal. ERCP can be performed before, after or during the same LC procedure. Patients with LCBDE had less pancreatitis rate because the Papilla of Vater is not manipulated but more bile leaks. Large CBDS continue to need, in general, from ERCP techniques.

Endoscopic biliary stenting: indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline - Updated October 2017.

ESGE recommends against routine preoperative biliary drainage in patients with malignant extrahepatic biliary obstruction; preoperative biliary drainage should be reserved for patients with cholangitis, severe symptomatic jaundice (e. g., intense pruritus), or delayed surgery, or for before neoadjuvant chemotherapy in jaundiced patients. Strong recommendation, moderate quality evidence. ESGE recommends the endoscopic placement of a 10-mm diameter self-expandable metal stent (SEMS) for preoperative biliary drainage of malignant extrahepatic biliary obstruction. Strong recommendation, moderate quality evidence.ESGE recommends SEMS insertion for palliative drainage of of extrahepatic malignant biliary obstruction. Strong recommendation, high quality evidence. ESGE recommends against the insertion of uncovered SEMS for the drainage of extrahepatic biliary obstruction of unconfirmed etiology. Strong recommendation, low quality evidence. ESGE suggests against routine preoperative biliary drainage in patients with malignant hilar obstruction. Weak recommendation, low quality evidence.ESGE recommends uncovered SEMSs for palliative drainage of malignant hilar obstruction. Strong recommendation, moderate quality evidence.ESGE recommends temporary insertion of multiple plastic stents or of a fully covered SEMS for treatment of benign biliary strictures. Strong recommendation, moderate quality evidence.ESGE recommends endoscopic placement of plastic stent(s) to treat bile duct leaks that are not due to transection of the common bile duct or common hepatic duct. Strong recommendation, moderate quality evidence.

Autophagic cell death associated to Sorafenib in renal cell carcinoma is mediated through Akt inhibition in an ERK1/2 independent fashion.

OBJECTIVES: To fully clarify the role of Mitogen Activated Protein Kinase in the therapeutic response to Sorafenib in Renal Cell Carcinoma as well as the cell death mechanism associated to this kinase inhibitor, we have evaluated the implication of several Mitogen Activated Protein Kinases in Renal Cell Carcinoma-derived cell lines. MATERIALS AND METHODS: An experimental model of Renal Cell Carcinoma-derived cell lines (ACHN and 786-O cells) was evaluated in terms of viability by MTT assay, induction of apoptosis by caspase 3/7 activity, autophagy induction by LC3 lipidation, and p62 degradation and kinase activity using phospho-targeted antibodies. Knock down of ATG5 and ERK5 was performed using lentiviral vector coding specific shRNA. RESULTS: Our data discard Extracellular Regulated Kinase 1/2 and 5 as well as p38 Mitogen Activated Protein Kinase pathways as mediators of Sorafenib toxic effect but instead indicate that the inhibitory effect is exerted through the PI3K/Akt signalling pathway. Furthermore, we demonstrate that inhibition of Akt mediates cell death associated to Sorafenib without caspase activation, and this is consistent with the induction of autophagy, as indicated by the use of pharmacological and genetic approaches. CONCLUSION: The present report demonstrates that Sorafenib exerts its toxic effect through the induction of autophagy in an Akt-dependent fashion without the implication of Mitogen Activated Protein Kinase. Therefore, our data discard the use of inhibitors of the RAF-MEK-ERK1/2 signalling pathway in RCC and support the use of pro-autophagic compounds, opening new therapeutic opportunities for Renal Cell Carcinoma.

Pancreatic stent insertion after an unintentional guidewire cannulation of the pancreatic duct during ERCP.

INTRODUCTION: the guidewire (GW) may enter the pancreatic duct during common bile duct (CBD) cannulation attempts in endoscopic retrograde cholangiopancreatography (ERCP). After GW passage into the pancreas, the most effective maneuver for CBD cannulation and pancreatitis prevention has not been determined. AIM: to study CBD cannulation and post-ERCP pancreatitis rates when a pancreatic stent is inserted after an unintentional GW cannulation of the pancreatic duct. MATERIAL AND METHODS: a retrospective analysis of patients undergoing ERCP for biliary drainage that were included prospectively into a database. After unintentional GW cannulation of the pancreatic duct, a straight 5-Fr and 4-cm long plastic stent was inserted. The stents had no internal flaps to facilitate expulsion. CBD cannulation attempts were made above the stent. A pancreatic sphincterotomy was performed in patients older than 60 years before stent insertion. RESULTS: a total of 46 pancreatic stents were inserted during 154 ERCP (29.8%) procedures. In the stent group, CBD cannulation was accomplished in 44/46 (95.6%) subjects. A total of 21/46 (45.6%) pancreatic sphincterotomies were performed. Only 1/46 (2.17%) mild pancreatitis cases were observed and most stents were spontaneously expelled. CONCLUSIONS: in this study, the CBD was eventually reached with the insertion of a plastic pancreatic stent after an unintentional GW passage into the pancreatic duct while attempting a CBD cannulation. No adverse events were observed following pancreatic stent insertion.

Enhancing the current evidence on endoscopist-directed propofol-based sedation.

During the last years, there is more and more scientific evidence about the safety and feasibility of non-anesthesiologist administration of propofol (NAAP) in gastrointestinal endoscopy, reducing sedation induction and recovery time as well as increasing patient and endoscopist satisfaction. Furthermore, a similar risk of adverse events compared with traditional agents or anesthesiologist administration of propofol (AAP) has been described. The present special issue of the Spanish Journal of Gastroenterology (Revista Española de Enfermedades Digestivas) focusses on NAAP in different settings, including complex endoscopic procedures.