The Efficacy of Peroral Endoscopic Myotomy vs Pneumatic Dilation as Treatment for Patients With Achalasia Suffering From Persistent or Recurrent Symptoms After Laparoscopic Heller Myotomy: A Randomized Clinical Trial.

BACKGROUND & AIMS: For patients with achalasia experiencing persistent or recurrent symptoms after laparoscopic Heller myotomy (LHM), pneumatic dilation (PD) is the most frequently used treatment. Per-oral endoscopic myotomy (POEM) is increasingly being investigated as rescue therapy. This study aimed to determine the efficacy of POEM vs PD for patients with persistent or recurrent symptoms after LHM. METHODS: This randomized multicenter controlled trial included patients after LHM with an Eckardt score >3 and substantial stasis (≥2 cm) on timed barium esophagogram and randomized to POEM or PD. The primary outcome was treatment success, defined as an Eckardt score of ≤3 and without unscheduled re-treatment. Secondary outcomes included the presence of reflux esophagitis, high-resolution manometry, and timed barium esophagogram findings. Follow-up duration was 1 year after initial treatment. RESULTS: Ninety patients were included. POEM had a higher success rate (28 of 45 patients [62.2%]) than PD (12 of 45 patients [26.7%]; absolute difference, 35.6%; 95% CI, 16.4%-54.7%; P = .001; odds ratio, 0.22; 95% CI, 0.09-0.54; relative risk for success, 2.33; 95% CI, 1.37-3.99). Reflux esophagitis was not significantly different between POEM (12 of 35 [34.3%]) and PD (6 of 40 [15%]). Basal lower esophageal sphincter pressure and integrated relaxation pressure (IRP-4) were significantly lower in the POEM group (P = .034; P = .002). Barium column height after 2 and 5 minutes was significantly less in patients treated with POEM (P = .005; P = .015). CONCLUSIONS: Among patients with achalasia experiencing persistent or recurrent symptoms after LHM, POEM resulted in a significantly higher success rate than PD, with a numerically higher incidence of grade A-B reflux esophagitis. NETHERLANDS TRIAL REGISTRY: NL4361 (NTR4501), https://trialsearch.who.int/Trial2.aspx?TrialID = NTR4501.

Long versus short peroral endoscopic myotomy for the treatment of achalasia: results of a non-inferiority randomised controlled trial.

OBJECTIVE: Peroral endoscopic myotomy (POEM) has become standard treatment for achalasia with comparable efficacy to surgery. In most of published series, the length of myotomy is 12-13 cm. Shorter cuts could have the advantage of shorter procedure time and possibly reduced gastro-oesophageal reflux disease (GORD) rate. DESIGN: This single-centre, patient-blinded, randomised, non-inferiority clinical trial included 200 patients, who were randomly allocated, to receive either a long-POEM (13 cm; 101 patients) or a short-POEM (8 cm; 99 patients). Primary outcome was defined as an Eckardt symptom score of ≤3 at 24 months after the procedure; a non-inferiority design was chosen with an accepted success range of 6% between the two treatments. Secondary outcomes included operating time, complication rate, postoperative manometry, GORD rate and quality of life. RESULTS: In the intention-to-treat analysis, clinical success rates were 89.1% in the long-POEM and 98.0% in the short-POEM group, resulting in an absolute between-group difference of -8.9% (90% CI -14.5 to -3.3).Procedure time was significantly reduced in the short-POEM as compared with the long-POEM group (40 vs 50 min, p<0.0001). Severe adverse events occurred in one patient in both groups.No differences were observed in postoperative GORD: acid exposure >6% on pH monitoring study at 6 months was seen in 34.3% (long-POEM) vs 31.1% (short-POEM), while endoscopic oesophagitis was diagnosed in 37.6% vs 51.5% at 6 months and in 21% vs 24.5% at 24 months. Regular proton pump inhibitor use was not different either (36.8% vs 37.5%). CONCLUSIONS: Our study demonstrates non-inferiority of a shorter cut length of POEM as compared with the standard treatment, which saved some procedural time. GORD rate was not reduced by reducing cutting length. TRIAL REGISTRATION NUMBER: NCT03450928.

External validation of the Ruptured Arteriovenous Malformation Grading Scale (RAGS) in a multicenter adult cohort.

PURPOSE: While Ruptured Arteriovenous Malformation Grading Scale (RAGS) has recently been validated in children, the literature lacks validation on adults exclusively. Therefore, we aimed to determine the validity of RAGS on the external multicenter adult cohort and compare its accuracy with other scales. METHODS: A retrospective analysis was performed in five neurosurgical departments to extract patients who presented with the first episode of acute brain arteriovenous malformation (bAVM) rupture between 2012 and 2019. Standard logistic regression and area under the receiver operating curve (AUROC) calculations were performed to determine the value of the following scales: intracerebral hemorrhage (ICH), AVM-associated ICH (AVICH), Spetzler-Martin (SM), Supplemented SM (Supp-SM), Hunt and Hess (HH), Glasgow Coma Scale (GCS), World Federation of Neurological Surgeons (WFNS), and RAGS to predict change in categorical and dichotomized modified Rankin Scale (mRS) across three follow-up periods: within the 6 months, 6 months to 1 year, and above 1 year. RESULTS: Sixty-one individuals with a mean age of 43.6 years were included. The RAGS outperformed other grading scales during all follow-up time frames. It showed AUROC of 0.78, 0.74, and 0.71 at the first 6 months, between 6 and 12 months, and after 12 months of follow-up, respectively, when categorized mRS was applied, while corresponding values were 0.79, 0.76, and 0.73 for dichotomized mRS, respectively. CONCLUSION: The RAGS constitutes a reliable scale predicting clinical outcomes following bAVM rupture among adults. Furthermore, the RAGS proved its generalizability across medical centers with varying treatment preferences.

Management of patients after failed peroral endoscopic myotomy: a multicenter study.

BACKGROUND: Although peroral endoscopic myotomy (POEM) is highly effective for the management of achalasia, clinical failures may occur. The optimal management of patients who fail POEM is not well known. This study aimed to compare the outcomes of different management strategies in patients who had failed POEM. METHODS: This was an international multicenter retrospective study at 16 tertiary centers between January 2012 and November 2019. All patients who underwent POEM and experienced persistent or recurrent symptoms (Eckardt score > 3) were included. The primary outcome was to compare the rates of clinical success (Eckardt score ≤ 3) between different management strategies. RESULTS : 99 patients (50 men [50.5 %]; mean age 51.4 [standard deviation (SD) 16.2]) experienced clinical failure during the study period, with a mean (SD) Eckardt score of 5.4 (0.3). A total of 29 patients (32.2 %) were managed conservatively and 70 (71 %) underwent retreatment (repeat POEM 33 [33 %], pneumatic dilation 30 [30 %], and laparoscopic Heller myotomy (LHM) 7 [7.1 %]). During a median follow-up of 10 (interquartile range 3 - 20) months, clinical success was highest in patients who underwent repeat POEM (25 /33 [76 %]; mean [SD] Eckardt score 2.1 [2.1]), followed by pneumatic dilation (18/30 [60 %]; Eckardt score 2.8 [2.3]), and LHM (2/7 [29 %]; Eckardt score 4 [1.8]; P = 0.12). A total of 11 patients in the conservative group (37.9 %; mean Eckardt score 4 [1.8]) achieved clinical success. CONCLUSION : This study comprehensively assessed an international cohort of patients who underwent management of failed POEM. Repeat POEM and pneumatic dilation achieved acceptable clinical success, with excellent safety profiles.

Outcomes of single-endoscopist-performed needle-knife fistulotomy for selective biliary access in 842 consecutive patients: learning curve and changes over a 14-year period in a retrospective study.

BACKGROUND AND AIMS: Needle-knife fistulotomy (NKF) has emerged as the preferred precut technique. From a late strategy, NKF has shifted to an early rescue technique and has been used recently as a primary method for biliary access. It is unknown how these changes have affected NKF outcomes. We analyzed the outcomes of NKF over time in a large cohort of patients. METHODS: Multicenter retrospective cohort study of 842 patients who underwent NKF for biliary access between 2006 and 2019. Patients were divided into four study periods according to a late or early cannulation strategy and to the use of post-ERCP pancreatitis prophylaxis (Period 1-Period 4). We assessed outcomes of NKF, learning curves and shifts over time. RESULTS: Bile duct access was obtained in 88.0% of the patients. The initial cannulation rate increased significantly from 77.5% in P1 to 92.0% in P4 (p < .001). An endoscopist can obtain 80% success rate after performing 100 NKF procedures (95% CI: 0.79-0.86) and a 95% success rate after 830 procedures (95% CI: 0.92-0.98). Adverse events and pancreatitis were observed in 6.5% and 4.9% of patients respectively. The rate of pancreatitis was not significantly different during the 4 periods (p = .190). A decline in the pancreatitis rate was observed from 2006 until 2016 (no trainees) and then an increase until 2019 (trainees involved). The presence of trainees increased the rate of pancreatitis in the last period by 9.9%. CONCLUSIONS: The success of NKF has increased significantly over the years, initially in a rapid manner and then more slowly. It is associated with a low rate of complications, which tend to decrease with experience. The involvement of trainees is associated with an increased rate of pancreatitis.

Influence of a novel classification of the papilla of Vater on the outcome of needle-knife fistulotomy for biliary cannulation.

BACKGROUND: Existing proposed classification systems for the Papilla of Vater (PV) suboptimally account for all relevant, encountered PV appearances, are too complex or have not been assessed for intra- or interobserver variability. We proposed a novel endoscopic classification system for PV, determined its inter- and intraobserver rates and used the classification system to assess whether the success and complications of needle-knife fistulotomy (NKF) are influenced by the morphology of the PV. METHODS: The classification system was developed by expert endoscopists. To evaluate the inter- and intraobserver agreement, an online questionnaire was sent to 20 endoscopists from several countries (10 experts and 10 nonexperts) that included 50 images of papillae of Vater divided among various categories. Four weeks later, a second survey, with the images from the first questionnaire randomly reordered, was sent to the same endoscopists. The inter- and intraobserver agreements among the experts and nonexperts was calculated. Using the proposed classification system, all 361 consecutive patients who underwent NKF for biliary access to a naïve papilla were prospectively enrolled in the study. RESULTS: The novel classification system comprises 7 categories: type I, flat type, lacking an oral protrusion; type IIA, prominent tubular nonpleated type, with an oral protrusion and < 1 transverse fold over the oral protrusion; type IIB, prominent tubular pleated type, with an oral protrusion and > 2 transverse folds over the oral protrusion; type IIC: prominent bulging type, with an enlarged and bulging oral protrusion; type IIIA, diverticular-intradiverticular type, with a papillary orifice inside the diverticulum; type IIIB: diverticular-diverticular border type, with a papillary orifice less than 2 cm from the diverticular border; type IV: unclassified papilla, with no morphology classified in the other categories. The interobserver agreement between experts was substantial (K = 0.611, 95% CI 0.498-0.709) and was higher than that between nonexperts (K = 0.516; 95% CI 0.410-0.636). The intraobserver agreement was substantial among both experts (K = 0,651; 95% CI 0.586-0.715) and nonexperts (K = 0.646, 95% CI 0.615-0.677). In a multivariate model, type IIIA and IIIB were the only independent risk factors for difficult rescue NKF biliary cannulation (P = 0.003 and P = 0.019, respectively), and type I and type IIB were the only independent risk factors for a prolonged cannulation time using NKF (P < 0.001 and P = 0.005, respectively). CONCLUSIONS: The novel endoscopic classification system for PV is highly reproducible among experienced ERCPists according to the substantial level of agreement between experts. However, nonexperts require further training in its use. Using the novel classification system, we identified different types of papillae significantly associated with a lower efficacy of NKF and a prolonged time to obtain successful biliary cannulation using NKF.

Fibrin glue injection: Rescue treatment for refractory post-sphincterotomy and post-papillectomy bleedings.

OBJECTIVES: Endoscopic sphincterotomy (ES) and papillectomy (EP) are associated with a non-negligible risk of post-procedural bleeding. Despite first-line endoscopic hemostasis being achieved by several methods, patients may experience bleeding persistence or recurrence. In such cases, fibrin glue (FG) injection may be used as a rescue therapy before more invasive approaches. The aim of this study was to evaluate the efficacy and safety of endoscopic FG injection to treat refractory post-ES and post-EP bleeding. METHODS: Data were collected retrospectively from patients with refractory immediate or delayed bleeding following ES or EP, between October 2007 and November 2019, at a single institution. Clinical success was defined as bleeding control after FG injection. RESULTS: Overall, 70 patients were included. Clinical success was reached in 64 (91.4%) patients after one session of FG injection. Of six (8.6%) patients in whom the treatment failed, one required subsequent insertion of a fully covered self-expanding metal stent (FC-SEMS) due to immediate massive bleeding, while five experienced bleeding recurrence. Such events were managed with an additional session of FG injection that failed in two cases. Therefore, one patient underwent FC-SEMS plus selective embolization, whereas the other underwent diagnostic arteriography. No severe periprocedural complications occurred. Two cases of intrabiliary glue migration were treated by endoscopic removal with a retrieval basket. CONCLUSIONS: Rescue therapy with endoscopic FG injection appears to be effective and safe to treat refractory post-ES and post-EP bleeding. Further studies are required to confirm these preliminary data.

Endoscopic management of non-anastomotic biliary strictures following liver transplantation: Long-term results from a single-center experience.

OBJECTIVES: Studies on endoscopic treatment of non-anastomotic biliary strictures (NABS) following orthotopic liver transplantation (OLT) are scanty and with a short follow-up. The long-term results of endoscopic treatment with plastic stents of NABS following OLT were analyzed. METHODS: Retrospective analysis of consecutive enrolled patients who underwent endoscopic treatment for NABS after OLT between 1997 and 2015. Endoscopic treatment success was defined as stricture resolution, without recurrence. RESULTS: During the study period, 33 patients with NABS underwent endoscopic retrograde cholangiopancreatography (ERCP) in our center. A total of 68 ERCP were performed with a 4.4% of procedure-related adverse events. Mortality related to cholangitis secondary to endoscopic procedures was 12%. After median follow-up of 70.3 months from stents removal, NABS resolution was obtained in 12 out of 24 (50%) patients. Only one case of late NABS recurrence was observed which was successfully retreated endoscopically. According to our data analysis NABS occurring <12 months from OLT showed a worse prognosis (P < 0.04). CONCLUSIONS: The follow-up of this study confirms that endoscopic treatment of NABS is unsatisfactory. However, patients who respond to endoscopic treatment maintain the response over time. Prompt treatment of acute cholangitis due to stents occlusion is advised in these patients to avoid high mortality rates.

Endotherapy of postcholecystectomy biliary strictures with multiple plastic stents: long-term results in a large cohort of patients.

BACKGROUND AND AIMS: Endoscopic therapy of benign biliary strictures with multiple plastic stent (MPS) placement has shown satisfactory results. However, the literature describes various benign biliary stricture etiologies. The aim of this study was to evaluate long-term MPS results in patients with postcholecystectomy biliary strictures (PCBSs). METHODS: PCBS patients without complete bile duct transection were included. ERCP consisted of placing an increasing plastic stent number over time, exchanged at regular intervals (3-4 months), until complete morphologic stricture disappearance. After stent removal, patient follow-up comprised liver function tests and clinical assessment. RESULTS: One hundred fifty-four patients (43.5% men; mean age, 53 years) were enrolled; in 43% of the cases, PCBSs were involved or were close to the main hepatic confluence. PCBS resolution rate was 96.7% (n = 149). A mean maximum number of 4.3 ± 1.6 stents were placed side-by-side; a mean of 4.2 ± 1.5 ERCPs per patient was needed to obtain PCBS resolution during a mean treatment period of 11.8 ± 6.4 months. Unscheduled stent exchange because of cholangitis, jaundice, or pain occurred in 7.4% of cases. Procedure-related mortality was absent. Follow-up data were available in 85.2% of cases. After a mean follow-up of 11.1 ± 4.9 years, stricture recurrence rate was 9.4% (n = 12). Subsequent to retreatment, 83.3% of patients (n = 10) were asymptomatic after a mean time of 9 years, whereas 2 patients underwent hepaticojejunostomy because of failed retreatment. Statistical analysis revealed no risk factors for PCBS recurrence after MPS. CONCLUSIONS: Endoscopic therapy of PCBSs with MPSs is safe and effective at long-term follow-up. PCBSs involving or close to the main hepatic confluence were successfully treated with MPSs. PCBS recurrence rate is low and can be successful endoscopically retreated without precluding possible surgical treatment.

Endoscopic management of gastrointestinal motility disorders - part 1: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

ESGE recommends the use of a graded pneumatic dilation protocol in achalasia, starting with a 30-mm dilation and followed by a 35-mm dilation at a planned interval of 2 - 4 weeks, with a subsequent 40-mm dilation when there is insufficient relief, over both a single balloon dilation procedure or the use of a larger balloon from the outset.Strong recommendation, high quality of evidence, level of agreement 100 %.ESGE recommends being cautious in treating spastic motility disorders other than achalasia with peroral endoscopic myotomy (POEM).Strong recommendation, very low quality of evidence, level of agreement 87.5 %.ESGE recommends against the routine use of botulinum toxin injections to treat patients with non-achalasia hypercontractile esophageal motility disorders (Jackhammer esophagus, distal esophageal spasm). However, if, in individual patients, endoscopic injection of botulinum toxin is chosen, ESGE recommends performing injections into four quadrants of the lower esophageal sphincter and in the lower third of the esophagus.Strong recommendation, low quality of evidence, level of agreement 78.6 %.ESGE recommends that endoscopic pylorus-directed therapy should be considered only in patients with symptoms suggestive of gastroparesis in combination with objective proof of delayed gastric emptying using a validated test, and only when medical therapy has failed.Strong recommendation, very low quality of evidence, level of agreement 100 %.ESGE recommends against the use of botulinum toxin injection in the treatment of unselected patients with gastroparesis. Strong recommendation, high quality of evidence, level of agreement 92.9 %.ESGE recommends consideration of gastric peroral endoscopic myotomy (G-POEM) in carefully selected patients only, because it is an emerging procedure with limited data on effectiveness, safety, and durability. G-POEM should be performed in expert centers only, preferably in the context of a clinical trial.Strong recommendation, low quality of evidence, level of agreement 100 %.

Endoscopic management of gastrointestinal motility disorders - part 2: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

ESGE suggests flexible endoscopic treatment over open surgical treatment as first-line therapy for patients with a symptomatic Zenker's diverticulum of any size.Weak recommendation, low quality of evidence, level of agreement 100 %.ESGE recommends that emerging treatments for Zenker's diverticulum, such as Zenker's peroral endoscopic myotomy (Z-POEM) and tunneling, be considered as experimental; these treatments should be offered in a research setting only.Strong recommendation, low quality of evidence, level of agreement 100 %.ESGE recommends against the widespread clinical use of transoral incisionless fundoplication (TIF) as an alternative to proton pump inhibitor (PPI) therapy or antireflux surgery in the treatment of gastroesophageal reflux disease (GERD), because of the lack of data on the long-term outcomes, the inferiority of TIF to fundoplication, and its modest efficacy in only highly selected patients. TIF may have a role for patients with mild GERD who are not willing to take PPIs or undergo antireflux surgery.Strong recommendation, moderate quality of evidence, level of agreement 92.8 %.ESGE recommends against the use of the Medigus ultrasonic surgical endostapler (MUSE) in clinical practice because of insufficient data showing its effectiveness and safety in patients with GERD. MUSE should be used in clinical trials only.Strong recommendation, low quality evidence, level of agreement 100 %.ESGE recommends against the use of antireflux mucosectomy (ARMS) in routine clinical practice in the treatment of GERD because of the lack of data and its potential complications.Strong recommendation, low quality evidence, level of agreement 100 %.ESGE recommends endoscopic cecostomy only after conservative management with medical therapies or retrograde lavage has failed.Strong recommendation, low quality evidence, level of agreement 93.3 %.ESGE recommends fixing the cecum to the abdominal wall at three points (using T-anchors, a double-needle suturing device, or laparoscopic fixation) to prevent leaks and infectious adverse events, whatever percutaneous endoscopic cecostomy method is used.Strong recommendation, very low quality evidence, level of agreement 86.7 %.ESGE recommends considering endoscopic decompression of the colon in patients with Ogilvie's syndrome that is not improving with conservative treatment.Strong recommendation, low quality evidence, level of agreement 93.8 %.ESGE recommends prompt endoscopic decompression if the cecal diameter is > 12 cm and if the Ogilvie's syndrome exists for a duration of longer than 4 - 6 days.Strong recommendation, low quality evidence, level of agreement 87.5 %.

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies.

Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aß), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3ß), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies.

Quantitative Ultrastructural Morphometry and Gene Expression of mTOR-Related Mitochondriogenesis within Glioblastoma Cells.

In glioblastoma (GBM) cells, an impairment of mitochondrial activity along with autophagy suppression occurs. Autophagy suppression in GBM promotes stemness, invasion, and poor prognosis. The autophagy deficit seems to be due, at least in part, to an abnormal up-regulation of the mammalian target of rapamycin (mTOR), which may be counteracted by pharmacological mTORC1 inhibition. Since autophagy activation is tightly bound to increased mitochondriogenesis, a defect in the synthesis of novel mitochondria is expected to occur in GBM cells. In an effort to measure a baseline deficit in mitochondria and promote mitochondriogenesis, the present study used two different GBM cell lines, both featuring mTOR hyperactivity. mTORC1 inhibition increases the expression of genes and proteins related to autophagy, mitophagy, and mitochondriogenesis. Autophagy activation was counted by RT-PCR of autophagy genes, LC3- immune-fluorescent puncta and immune-gold, as well as specific mitophagy-dependent BNIP3 stoichiometric increase in situ, within mitochondria. The activation of autophagy-related molecules and organelles after rapamycin exposure occurs concomitantly with progression of autophagosomes towards lysosomes. Remarkably, mitochondrial biogenesis and plasticity (increased mitochondrial number, integrity, and density as well as decreased mitochondrial area) was long- lasting for weeks following rapamycin withdrawal.

Long-term follow-up after multiple plastic stenting for refractory pancreatic duct strictures in chronic pancreatitis.

BACKGROUND: Dominant pancreatic duct strictures in chronic pancreatitis are often managed by endoscopic placement of a single plastic stent. Insertion of multiple plastic stents (MPS) has been proven to be effective in managing refractory strictures, but data are still limited. The aim of this study was to investigate the efficacy and long-term results of MPS to dilate pancreatic duct strictures in chronic pancreatitis. METHODS: 48 patients (34 men; mean age 44 years) with chronic pancreatitis and a single pancreatic stent through a refractory stricture in the pancreatic head underwent the following protocol: 1) removal of the single pancreatic stent; 2) balloon dilation of the stricture; 3) insertion of the maximum number of stents; 4) stent removal after 6 - 12 months. RESULTS: The median number of pancreatic plastic stents placed was 3 (diameter 7 - 11.5 Fr, length 3 - 7 cm). Five patients (10.4 %) had persistent strictures after MPS removal. During a mean follow-up of 9.5 years (0.3 - 15.5 years) after stent removal, 74.4 % (32/43) of the patients were asymptomatic, and 25.6 % (11/43) experienced pancreatitis recurrence or pancreatic type pain after a mean time of 26.4 months (8/43, 18.6 % underwent plug extraction without evidence of stricture recurrence; 3/43, 7.0 % had stricture recurrence). No major complications were recorded. CONCLUSION: Endoscopic multiple plastic stenting of chronic pancreatitis-related pancreatic duct strictures showed satisfactory long-term results, with the option of re-treatment. This procedure can be considered an important therapeutic alternative for painful pancreatic duct strictures located in the head of the pancreas in the setting of chronic pancreatitis.

Multicenter Evaluation of Clinical Efficacy and Safety of Per-oral Endoscopic Myotomy in Children.

OBJECTIVES: Per-oral endoscopic myotomy (POEM) is a recommended treatment modality for achalasia, but there is little published data for its use in children. The objective of the present study was to evaluate whether POEM is clinically effective and safe for children. METHODS: International multicenter retrospective study conducted in 14 tertiary centers that included consecutive children who underwent POEM between January 2012 and August 2018. Outcomes, such as clinical response were assessed whenever available. Adverse events and factors associated with clinical failure were also investigated. RESULTS: A total of 117 patients (mean ±â€ŠSD age: 14.2 ±â€Š3.7 years) underwent POEM for achalasia (type I, n = 36; type II n=66; type III, n=8). Among these, 30 (26%) were pretreated (botulinum injection and/or pneumatic dilatation). Mean ±â€ŠSD baseline Eckardt score was 7.5 ±â€Š2.0. Clinical success was achieved in 90.6% of cases (95%CI [83.8%;95.2%]) in the intention-to-treat analysis. The mean ±â€ŠSD Eckardt score post-POEM was 0.9 ±â€Š1.2 (P < 0.001). The mean duration of follow-up time 545 days (range: 100-1612). A total of 7 adverse events occurred (4 mucosotomies, 2 subcutaneous emphysema, 1 esopleural fistula). Gastroesophageal reflux symptoms were seen in 17 patients (15%); missing data for 10 patients (9%). There was a trend towards more frequent clinical failure in achalasia associated with genetic disorders (40% vs 8%, P = 0.069). CONCLUSIONS: POEM in pediatric patients appears to be effective and safe, although there was a trend towards more frequent clinical failure achalasia associated with genetic disorders. Further studies are needed to assess the long-term outcomes, especially the consequences of GERD.

Effect of Peroral Endoscopic Myotomy vs Pneumatic Dilation on Symptom Severity and Treatment Outcomes Among Treatment-Naive Patients With Achalasia: A Randomized Clinical Trial.

Importance: Case series suggest favorable results of peroral endoscopic myotomy (POEM) for treatment of patients with achalasia. Data comparing POEM with pneumatic dilation, the standard treatment for patients with achalasia, are lacking. Objective: To compare the effects of POEM vs pneumatic dilation as initial treatment of treatment-naive patients with achalasia. Design, Setting, and Participants: This randomized multicenter clinical trial was conducted at 6 hospitals in the Netherlands, Germany, Italy, Hong Kong, and the United States. Adult patients with newly diagnosed achalasia and an Eckardt score greater than 3 who had not undergone previous treatment were included. The study was conducted between September 2012 and July 2015, the duration of follow-up was 2 years after the initial treatment, and the final date of follow-up was November 22, 2017. Interventions: Randomization to receive POEM (n = 67) or pneumatic dilation with a 30-mm and a 35-mm balloon (n = 66), with stratification according to hospital. Main Outcomes and Measures: The primary outcome was treatment success (defined as an Eckardt score ≤3 and the absence of severe complications or re-treatment) at the 2-year follow-up. A total of 14 secondary end points were examined among patients without treatment failure, including integrated relaxation pressure of the lower esophageal sphincter via high-resolution manometry, barium column height on timed barium esophagogram, and presence of reflux esophagitis. Results: Of the 133 randomized patients, 130 (mean age, 48.6 years; 73 [56%] men) underwent treatment (64 in the POEM group and 66 in the pneumatic dilation group) and 126 (95%) completed the study. The primary outcome of treatment success occurred in 58 of 63 patients (92%) in the POEM group vs 34 of 63 (54%) in the pneumatic dilation group, a difference of 38% ([95% CI, 22%-52%]; P < .001). Of the 14 prespecified secondary end points, no significant difference between groups was demonstrated in 10 end points. There was no significant between-group difference in median integrated relaxation pressure (9.9 mm Hg in the POEM group vs 12.6 mm Hg in the pneumatic dilation group; difference, 2.7 mm Hg [95% CI, -2.1 to 7.5]; P = .07) or median barium column height (2.3 cm in the POEM group vs 0 cm in the pneumatic dilation group; difference, 2.3 cm [95% CI, 1.0-3.6]; P = .05). Reflux esophagitis occurred more often in the POEM group than in the pneumatic dilation group (22 of 54 [41%] vs 2 of 29 [7%]; difference, 34% [95% CI, 12%-49%]; P = .002). Two serious adverse events, including 1 perforation, occurred after pneumatic dilation, while no serious adverse events occurred after POEM. Conclusions and Relevance: Among treatment-naive patients with achalasia, treatment with POEM compared with pneumatic dilation resulted in a significantly higher treatment success rate at 2 years. These findings support consideration of POEM as an initial treatment option for patients with achalasia. Trial Registration: Netherlands Trial Register number: NTR3593.

Prion Protein in Glioblastoma Multiforme.

The cellular prion protein (PrPc) is an evolutionarily conserved cell surface protein encoded by the PRNP gene. PrPc is ubiquitously expressed within nearly all mammalian cells, though most abundantly within the CNS. Besides being implicated in the pathogenesis and transmission of prion diseases, recent studies have demonstrated that PrPc contributes to tumorigenesis by regulating tumor growth, differentiation, and resistance to conventional therapies. In particular, PrPc over-expression has been related to the acquisition of a malignant phenotype of cancer stem cells (CSCs) in a variety of solid tumors, encompassing pancreatic ductal adenocarcinoma (PDAC), osteosarcoma, breast cancer, gastric cancer, and primary brain tumors, mostly glioblastoma multiforme (GBM). Thus, PrPc is emerging as a key in maintaining glioblastoma cancer stem cells' (GSCs) phenotype, thereby strongly affecting GBM infiltration and relapse. In fact, PrPc contributes to GSCs niche's maintenance by modulating GSCs' stem cell-like properties while restraining them from differentiation. This is the first review that discusses the role of PrPc in GBM. The manuscript focuses on how PrPc may act on GSCs to modify their expression and translational profile while making the micro-environment surrounding the GSCs niche more favorable to GBM growth and infiltration.

The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor featuring rapid cell proliferation, treatment resistance, and tumor relapse. This is largely due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation, and in particular, to a small subset of tumor cells displaying stem cell-like properties. This is the case of glioma stem cells (GSCs), which possess a powerful self-renewal capacity, low differentiation, along with radio- and chemo-resistance. Molecular pathways that contribute to GBM stemness of GSCs include mTOR, Notch, Hedgehog, and Wnt/ß-catenin. Remarkably, among the common biochemical effects that arise from alterations in these pathways, autophagy suppression may be key in promoting GSCs self-renewal, proliferation, and pluripotency maintenance. In fact, besides being a well-known downstream event of mTOR hyper-activation, autophagy downregulation is also bound to the effects of aberrantly activated Notch, Hedgehog, and Wnt/ß-catenin pathways in GBM. As a major orchestrator of protein degradation and turnover, autophagy modulates proliferation and differentiation of normal neuronal stem cells (NSCs) as well as NSCs niche maintenance, while its failure may contribute to GSCs expansion and maintenance. Thus, in the present review we discuss the role of autophagy in GSCs metabolism and phenotype in relationship with dysregulations of a variety of NSCs controlling pathways, which may provide novel insights into GBM neurobiology.

Fully covered self-expandable metal stents to dilate persistent pancreatic strictures in chronic pancreatitis: long-term follow-up from a prospective study.

BACKGROUND AND AIMS: Symptomatic main pancreatic duct (MPD) strictures secondary to chronic pancreatitis (CP) may benefit from endoscopic insertion of single or multiple plastic stents. MPD stricture resolution after single plastic stent removal is uncommon. The use of removable fully covered, self-expandable metal stents (FC-SEMSs) to dilate MPD strictures secondary to CP was evaluated. METHODS: Patients with CP and symptomatic MPD stricture located in the head of the pancreas persisting for 3 months or more after placement of a single plastic stent were enrolled in a prospective single-arm trial. A nitinol FC-SEMS was inserted and removed after 6 months. The FC-SEMS diameter and length were chosen according to the stricture anatomy and MPD diameter above the stricture. Our primary objective was FC-SEMS removability. Secondary outcomes were MPD stricture resolution rate and adverse events. RESULTS: Between December 2012 and October 2014, 15 patients (10 male, mean age 60 years) were enrolled. Pancreatic calcifications were present in 6 (40%) patients. Four patients (27%) had a history of alcohol abuse. In 10 patients, the FC-SEMS was inserted through the major papilla, whereas 5 patients (3 pancreas divisum, 2 dominant dorsal duct) received the stent through the minor papilla. One patient developed cholangitis after 24 hours due to occlusion of the biliary sphincterotomy from the FC-SEMS; cholangitis resolved after insertion of a plastic biliary stent. Complete distal migration of the FC-SEMS was reported in 7 patients (47%) (5 asymptomatic, 2 symptomatic with recurrence of pancreatitis). All migrations occurred with the 3-cm-long FC-SEMS. Four patients (27%) developed de novo stricture induced by the FC-SEMS at the level of the flared end and were excluded from the follow-up; 1 patient with FC-SEMS migration had failed stricture resolution. One patient was lost to follow-up. Finally, 9 patients with MPD stricture resolution had a mean follow-up of 38.9 months (range, 5.3-55.3 months), and 89% were asymptomatic. CONCLUSIONS: FC-SEMS removability from the MPD in CP was feasible in all cases, and 90% of the patients were asymptomatic after 3 years. Migration seems more frequent with the 3-cm-long FC-SEMS. Occurrence of FC-SEMS-induced pancreatic strictures is a major issue and deserves further assessment. According to our experience, pancreatic FC-SEMSs have promising results, but a careful evaluation in the setting of clinical trials is needed.