Direct endoscopic necrosectomy at the time of transmural stent placement results in earlier resolution of complex walled-off pancreatic necrosis: Results from a large multicenter United States trial.

BACKGROUND AND OBJECTIVES: EUS-guided drainage, and direct endoscopic necrosectomy (DEN) of walled-off necrosis (WON) using a lumen-apposing metal stent (LAMS) is safe and effective. Early debridement of WON may improve overall clinical outcomes. The aim of this study is to perform a multicenter retrospective study to compare the clinical outcomes and predictors of success for endoscopic drainage of WON with LAMS followed by immediate or delayed DEN performed at standard intervals. METHODS: Patients with WON managed by EUS-guided drainage with LAMS were divided into 2 groups: (1) those that underwent immediate DEN at the time of stent placement and (2) those that underwent delayed DEN 1 week after stent placement. DEN was subsequently performed every 1-2 week (s). Technical success (successful placement of LAMS), adverse events (AEs), and clinical success (complete resolution of the WON) were evaluated. RESULTS: Totally, 271 patients underwent WON drainage with LAMS: 69 who underwent immediate DEN and 202 who underwent delayed DEN. The technical success for LAMS placement was 100% in both groups. There was no significant difference in the overall procedural AEs between the immediate and delayed DEN groups (P = 7.2% vs. 9.4%; P = 0.81). Stent dislodgement during index endoscopy occurred in three patients in the immediate DEN group compared to zero in the delayed DEN group (P = 0.016); all three dislodgements occurred during necrosectomy. Clinical success for WON resolution in the immediate DEN group was 91.3% compared to 86.1% in the delayed DEN group (P = 0.3). The mean number of necrosectomy sessions for WON resolution was significantly lower in the immediate DEN group compared to the delayed DEN group (3.1 vs. 3.9, P < 0.001). Performing DEN at the time of stent placement was an independent predictor for resolution of WON with lesser number of DEN sessions (odds ratio 2.3; P = 0.004). CONCLUSIONS: DEN at the time of initial stent placement reduces the number of necrosectomy sessions required for successful clinical resolution of WON.

Long-term outcomes of palliative colonic stenting versus emergency surgery for acute proximal malignant colonic obstruction: a multicenter trial.

Background and study aims Long-term data are limited regarding clinical outcomes of self-expanding metal stents as an alternative for surgery in the treatment of acute proximal MBO. The aim of this study was to compare the long-term outcomes of stenting to surgery for palliation in patients with incurable obstructive CRC for lesions proximal to the splenic flexure. Patients and methods Retrospective multicenter cohort study of obstructing proximal CRC patients with who underwent insertion of a SEMS (n = 69) or surgery (n = 36) from 1999 to 2014. The primary endpoint was relief of obstruction. Secondary endpoints included technical success, duration of hospital stay, early and late adverse events (AEs) and survival. Results Technical success was achieved in 62/69 (89.8 %) patients in the SEMS group and in 36 /36 (100 %) patients who underwent surgery (P = 0.09). In the SEMS group, 10 patients underwent stenting as a bridge to surgery and 59 underwent stent placement for palliation. Clinical relief was achieved in 78 % of patients with stenting and in 100 % of patients who underwent surgery (P < 0.001). Patients with SEMS had significantly less acute AEs compared to the surgery group (7.2 % vs. 30.5 %, P = 0.003). Hospital mortality for the SEMS group was 0 % compared to 5.6 % in the surgery group (P = 0.11). Patients in the SEMS group had a significantly shorter median hospital stay (4 days) as compared to the surgery group (8 days) (P < 0.01). Maintenance of decompression without the recurrence of bowel obstruction until death or last follow-up was lower in the SEMS group (73.9 %) than the surgery group (97.3 %; P = 0.003). SEMS placement was associated with higher long-term complication rates compared to surgery (21 % and 11 % P = 0.27). Late SEMS AEs included occlusion (10 %), migration (5 %), and colonic ulcer (6 %). At 120 weeks, survival in the SEMS group was 5.6 % vs. 0 % in the surgery group (P = 0.8). Conclusions Technical and clinical success associated with proximal colonic obstruction are higher with surgery when compared to SEMS, but surgery is associated with longer hospital stays and more early AEs. SEMS should be considered the initial mode of therapy in patients with acute proximal MBO and surgery should be reserved for SEMS failure, as surgery involves a high morbidity and mortality.

Feasibility, safety, and outcomes of a single-step endoscopic ultrasonography-guided drainage of pancreatic fluid collections without fluoroscopy using a novel electrocautery-enhanced lumen-apposing, self-expanding metal stent.

BACKGROUND AND OBJECTIVES: There are currently limited data available regarding the safety of endoscopic ultrasound (EUS)-guided drainage of pancreatic fluid collections (PFCs) using the lumen-apposing metal stent without fluoroscopic guidance. This study aims to evaluate clinical outcomes and safety of EUS-guided drainage of PFC using the electrocautery-enhanced lumen-apposing metal stents (EC-LAMSs) without fluoroscopic guidance. METHODS: We conducted a retrospective study on patients with symptomatic PFC who underwent EUS-guided drainage using EC-LAMS without fluoroscopy. All patients were followed clinically until resolution of their PFC. Technical success (successful placement of EC-LAMS), number of patients who achieved complete resolution of PFC without additional intervention and adverse events were noted. RESULTS: We evaluated 25 patients, including three with pancreatic pseudocysts and 22 with walled-off necrosis (WON). The etiology of the patient's pancreatitis was gallstones (42%), alcohol (27%), and other causes (31%). The mean cyst size was 82 mm (range, 60-170 mm). The indications for endoscopic drainage were abdominal pain, infected WON, or gastric outlet obstruction. Technical success with placement of the EC-LAMS was achieved in all 25 patients. There were no procedure-related complications. The mean patient follow-up was 7.8 months. PFCs resolved in 24 (96%) patients; the one failure was in a patient with WON. Stent occlusion was seen in one patient. There was a spontaneous migration of one stent into the enteral lumen after resolution of WONs. The EC-LAMS were successfully removed using a snare in all the remaining patients. The median number of endoscopy sessions to achieve PFCs resolution was 2 (range, 2-6). CONCLUSIONS: Single-step EUS-guided drainage of PFCs without fluoroscopic guidance using the novel EC-LAMS is a safe and effective endoscopic technique for drainage of PFCs with excellent technical and clinical success rates and no complications. Due to its ease of use, EC-LAMS may simplify and streamline EUS-guided management of PFC and help in its widespread adoption as an alternative to surgery.

A large multicenter study of recurrence after surgical resection of branch-duct intraductal papillary mucinous neoplasm of the pancreas.

BACKGROUND: Surgery for pancreatic branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) is indicated for therapy of symptomatic patients and to prevent development of invasive cancer. There is currently no consensus on management of BD-IPMN patients after surgical resection. The aim of this retrospective multicenter study was to determine the recurrence and long-term survival after surgical resection of BD-IPMN and to determine the predictive factors of recurrence. METHODS: All patients who underwent surgery for BD-IPMN from 2005 to 2011 at 2 centers were identified. The diagnosis of BD-IPMN was based upon imaging and endosonographic analysis, and was confirmed by pathological analysis. The lesions were classified into 4 categories according to the WHO classification. Data on cyst characteristics, operative procedure, recurrence, and follow-up were evaluated. Recurrence was defined as the presence of BD-IPMN or mass in the remnant pancreas after surgery as seen on follow-up imaging. Recurrence suspected on imaging was confirmed via histological analysis when possible. RESULTS: A number of 271 patients (67% female; mean age 63.4 yrs) with BD-IPMN underwent surgical resection. The mean size of the cyst was 24.2mm (range, 12-80). There were 34 (12.5%) patients with an associated mass. 82 (30.3%) patients had worrisome features in the cyst on pre-operative EUS, included mural nodules (N.=25), solid component (N.=27), debris (N.=25), and a dilated major pancreatic duct (N.=5). 144(53%) patients had a pancreaticoduodenectomy for head lesions, 125 (46%) had distal pancreatectomy for tail/body lesions, and 1 (1%) underwent a total pancreatectomy. Histology showed 86% with noninvasive IPMN (adenoma 31%, moderate dysplasia 24%, severe dysplasia or carcinoma in situ 31%) and 14% with invasive IPMN. The mean patient follow-up was 28 months (range, 10-180 months). Recurrence in the remnant pancreas occurred in 34 (12.5%) patients. Of the patients with recurrence, 3/34 had invasive carcinoma and 31/34 had noninvasive cystic lesions; all patients with invasive carcinoma recurrence were those with a previous invasive IPMN. On MVA, risk factors for cyst recurrence were severe dysplasia/intraductal carcinoma in situ and invasive IPMN even after adjusting for elevated CEA (>193 ng/mL), type of surgery, and cyst size (OR 2.8, 95% CI=1.1-7.3; P=0.028). 3 patients who had invasive IPMN and 1 who had severe dysplasia patient with recurrence died, all because of recurrent cancer, with the mean time from recurrence to death being 36 months. CONCLUSIONS: The risk of BD-IPMN recurrence after resection depends upon the histological type, with the highest-risk groups being those with severe dysplasia/intraductal carcinoma in situ and invasive IPMN. Even after negative resection margins, the pancreatic remnant still harbors a risk of recurrence which requires long-term surveillance.

Endoscopic ultrasound in pancreatic cancer: innovative applications beyond the basics.

Endoscopic ultrasound (EUS) has become a mainstay in assisting in the diagnosis and staging of pancreatic cancer. In addition, EUS provides a modality to treat chronic pain through celiac plexus neurolysis. Currently, there is growing data and utilization of EUS in more diverse and innovative applications aimed at providing more sophisticated diagnostic, prognostic and therapeutic options for patients with pancreatic cancer. EUS delivery of chemotherapy, viral and biological vectors and fiducial markers may eventually revolutionize the way clinicians approach the care of a patient with pancreatic cancer.

EUS-guided drainage of peripancreatic fluid collections and necrosis by using a novel lumen-apposing stent: a large retrospective, multicenter U.S. experience (with videos).

BACKGROUND AND AIMS: EUS-guided drainage of peripancreatic fluid collection (PFC) (pancreatic pseudocyst [PP] or walled-off necrosis [WON]) by using a novel lumen-apposing, fully covered, self-expandable metal stent (LAMS) has been promising, but few of these data are from the United States. The aim of this study was to evaluate clinical outcomes and safety of EUS-guided drainage of pancreatic pseudocysts and WON by using the LAMS. METHODS: We conducted a multicenter, retrospective study on 82 patients with symptomatic PFC who underwent EUS-guided drainage by using the LAMS at 4 U.S. tertiary care centers. Outcomes evaluated included successful placement of the LAMS, the number of patients in whom complete resolution of PPs or WON was achieved, the number of procedures performed per patient to achieve PFC resolution, and adverse events. RESULTS: The mean size of the PFC was 11.8 cm. LAMSs were successfully placed in 80 patients (97.5%). Twelve patients had PP and 68 had WON. The median stent in-dwelling time was 2 months (range 1-3 months). Endoscopic debridement with the LAMS in WON was performed in 54 patients. The patency of the stent was maintained in 98.7% of the patients (77/78). There was spontaneous dislodgment of 2 LAMSs. Successful endoscopic therapy by using the LAMS was successful in 12 of 12 patients (100%) with PP compared with 60 of 68 patients (88.2%) with WON. All stents were endoscopically removed from all patients after peripancreatic fluid collection (PFC) resolution. There was 1 PFC recurrence during the 3-month median follow-up period. Procedure-related adverse events occurred in 8 patients (9.8%), and included stent maldeployment (n = 2), and self-limited bleeding (n = 6). In 1 patient with stent maldeployment gastric perforation developed, and the patient underwent surgical repair. CONCLUSION: EUS-guided drainage of PFCs by using the novel LAMS has high technical and long-term success rates. Due to its ease of use, the LAMSs may simplify and streamline EUS-guided management of PFCs, particularly for the endoscopic debridement of WON, and may help in its widespread adoption as an alternative to surgery.

Akt kinase C-terminal modifications control activation loop dephosphorylation and enhance insulin response.

The Akt protein kinase, also known as protein kinase B, plays key roles in insulin receptor signalling and regulates cell growth, survival and metabolism. Recently, we described a mechanism to enhance Akt phosphorylation that restricts access of cellular phosphatases to the Akt activation loop (Thr(308) in Akt1 or protein kinase B isoform alpha) in an ATP-dependent manner. In the present paper, we describe a distinct mechanism to control Thr(308) dephosphorylation and thus Akt deactivation that depends on intramolecular interactions of Akt C-terminal sequences with its kinase domain. Modifications of amino acids surrounding the Akt1 C-terminal mTORC2 (mammalian target of rapamycin complex 2) phosphorylation site (Ser(473)) increased phosphatase resistance of the phosphorylated activation loop (pThr(308)) and amplified Akt phosphorylation. Furthermore, the phosphatase-resistant Akt was refractory to ceramide-dependent dephosphorylation and amplified insulin-dependent Thr(308) phosphorylation in a regulated fashion. Collectively, these results suggest that the Akt C-terminal hydrophobic groove is a target for the development of agents that enhance Akt phosphorylation by insulin.

Profiling the genes affected by pathogenic TDP-43 in astrocytes.

Mutation in TAR DNA binding protein 43 (TDP-43) is a causative factor of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neurodegeneration may not require the presence of pathogenic TDP-43 in all types of relevant cells. Rather, expression of pathogenic TDP-43 in neurons or astrocytes alone is sufficient to cause cell-autonomous or non-cell-autonomous neuron death in transgenic rats. How pathogenic TDP-43 in astrocytes causes non-cell-autonomous neuron death, however, is not clear. Here, we examined the effect of pathogenic TDP-43 on gene expression in astrocytes. Microarray assay revealed that pathogenic TDP-43 in astrocytes preferentially altered expression of the genes encoding secretory proteins. Whereas neurotrophic genes were down-regulated, neurotoxic genes were up-regulated. Representative genes Lcn2 and chitinase-3-like protein 1 were markedly up-regulated in astrocytes from primary culture and intact transgenic rats. Furthermore, synthetic chitinase-3-like protein 1 induced neuron death in a dose-dependent manner. Our results suggest that TDP-43 pathogenesis is associated with the simultaneous induction of multiple neurotoxic genes in astrocytes, which may synergistically produce adverse effects on neuronal survival and contribute to non-cell-autonomous neuron death. Restricted expression of pathogenic TDP-43 in astrocytes causes non-cell-autonomous motor neuron death in transgenic rats. As revealed by microarray assay, pathogenic TDP-43 in astrocytes preferentially altered expression of the genes encoding secretory proteins. Whereas neurotrophic genes were down-regulated, neurotoxic genes were up-regulated. Therefore, TDP-43 pathogenesis is associated with simultaneous induction of neurotoxic genes and repression of neurotrophic genes in astrocytes.

Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and disrupts endoplasmic reticulum-associated protein degradation.

Protein aggregation is a common feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. How protein aggregates are formed and contribute to neurodegeneration, however, is not clear. Mutation of Ubiquilin 2 (UBQLN2) has recently been linked to ALS and frontotemporal lobar degeneration. Therefore, we examined the effect of ALS-linked UBQLN2 mutation on endoplasmic reticulum-associated protein degradation (ERAD). Compared to its wild-type counterpart, mutated UBQLN2 caused greater accumulation of the ERAD substrate Hong Kong variant of α-1-antitrypsin, although ERAD was disturbed by both UBQLN2 over-expression and knockdown. Also, UBQLN2 interacted with ubiquitin regulatory X domain-containing protein 8 (UBXD8) in vitro and in vivo, and this interaction was impaired by pathogenic mutation of UBQLN2. As UBXD8 is an endoplasmic membrane protein involved in the translocation of ubiquitinated ERAD substrates, UBQLN2 likely cooperates with UBXD8 to transport defective proteins from the endoplasmic reticulum to the cytosol for degradation, and this cell-protective function is disturbed by pathogenic mutation of UBQLN2.

Identification and characterization of multiple similar ligand-binding repeats in filamin: implication on filamin-mediated receptor clustering and cross-talk.

The actin-binding protein filamin links membrane receptors to the underlying cytoskeleton. The cytoplasmic domains of these membrane receptors have been shown to bind to various filamin immunoglobulin repeats. Notably, among 24 human filamin repeats, repeat 17 was reported to specifically bind to platelet receptor glycoprotein Ibalpha and repeat 21 to integrins. However, a complete sequence alignment of all 24 human filamin repeats reveals that repeats 17 and 21 actually belong to a distinct filamin repeat subgroup (containing repeats 4, 9, 12, 17, 19, 21, and 23) that shares a conserved ligand-binding site. Using isothermal calorimetry and NMR analyses, we show that all repeats in this subgroup can actually bind glycoprotein Ibalpha, integrins, and a cytoskeleton regulator migfilin in similar manners. These data provide a new view on the ligand specificity of the filamin repeats. They also suggest a multiple ligand binding mechanism where similar repeats within a filamin monomer may promote receptor clustering or receptor cross-talking for regulation of the cytoskeleton organization and diverse filamin-mediated cellular activities.