"Innocent as a LAMS": Does Spontaneous Fistula Closure (Secondary Intention), After EUS-Directed Transgastric ERCP (EDGE) via 20-mm Lumen-Apposing Metal Stent, Confer an Increased Risk of Persistent Fistula and Unintentional Weight Gain?

BACKGROUND AND AIMS: Persistent gastrogastric or jejunogastric fistula is theoretically a concerning sequela of EUS-directed transgastric ERCP/EUS (EDGE), as it may functionally reverse the malabsorptive mechanism of Roux-en-Y gastric bypass (RYGB). Prior EDGE studies, using predominantly 15-mm (diameter) lumen-apposing metal stents (LAMS) and fistula closure by primary intent, collectively report 9% persistent fistula rate, without a clear weight gain association. Our study determines the incidence of persistent fistula, and its association with unintentional weight gain, among recipients of EDGE via 20-mm LAMS followed by spontaneous fistula closure (secondary intent). METHODS: We conducted a dual-center prospective cohort study of 22 RYGB patients who underwent EDGE using 20-mm between 3/2018 and 10/2019. After LAMS extraction, all GGFs/JGFs were allowed to heal spontaneously. Objective testing for persistent fistula and total body weight (TBW) occurred a minimum of 8 weeks after LAMS extraction. RESULTS: Persistent fistula was identified in 9 patients (41%). Longer LAMS dwell time (median 77-days) was observed in the persistent fistula group, compared to those with durable spontaneous fistula closure (median 35-days) (p = 0.03). Weight gain of ≥ 5% TBW occurred in 56% (n = 5) of patients with persistent fistula, compared to 15% (n = 2) of patients with spontaneous fistula closure (p = 0.128). Four patients with symptomatic persistent fistulas underwent attempted endoscopic fistula closure a median 7.5 months after LAMS extraction. Durable fistula closure occurred in the single patient who received argon plasma coagulation plus endoscopic suturing, whereas fistula dehiscence occurred in 3/3 (100%) patients with endoscopic suturing monotherapy. CONCLUSIONS: Larger LAMS diameter (20-mm), longer LAMS dwell time, and spontaneous fistula closure may be technical factors that increase the likelihood of post-EDGE persistent fistula. Post-EDGE persistent fistula has not been shown by ours or other studies to be significantly associated with unintentional weight gain; however, this may be due to small sample size. We question the utility of routine fistula closure by primary intent and suggest a personalized approach to post-EDGE fistula management.

Luminal-apposing stents for benign intraluminal strictures: a large United States multicenter study of clinical outcomes.

BACKGROUND: The use of fully covered lumen-apposing metal stents (LAMS) for benign short gastrointestinal (GI) strictures has been reported. This study aimed to evaluate the safety and efficacy of LAMS for refractory GI strictures. METHODS: A retrospective analysis was performed of patients who underwent LAMS placement for benign GI strictures in 8 United States centers. The primary outcomes were technical success and initial clinical response. Secondary outcomes were reintervention rate and adverse events. RESULTS: A total of 51 patients underwent 61 LAMS placement procedures; 33 (64.7%) had failed previous treatments. The most common stricture location was the pylorus (n=17 patients). Various sizes of stents were used, with 15-mm LAMS placed in 45 procedures, 20-mm LAMS in 14 procedures, and 10-mm LAMS in 2 procedures. The overall technical success, short-term clinical response and reintervention rate after stent removal were 100%, 91.8% and 31.1%, respectively. Adverse events were reported in 17 (27.9%) procedures, with stent migration being the most common (13.1%). In subgroup analysis, both 15 mm and 20 mm stents had comparable short-term clinical response and adverse event rates. However, stent migration (15.6%) was the most common adverse event with 15-mm LAMS while pain (14.3%) was the most common with 20-mm LAMS. The reintervention rate was 80% at 200-day follow up after stent removal. CONCLUSIONS: Using LAMS for treatment of short benign GI strictures is safe and effective. Larger LAMS, such as the new 20 mm in diameter, may have a lower stent migration rate compared to smaller diameter LAMS.

Endoscopic endgame for obstructive pancreatopathy: outcomes of anterograde EUS-guided pancreatic duct drainage. A dual-center study.

BACKGROUND AND AIMS: Anterograde endoscopic ultrasound-guided pancreatic duct drainage (EUS-PDD) refers to transmural drainage of the main pancreatic duct via an endoprosthesis passed anterograde through the gastric (or intestinal) wall. Anterograde EUS-PDD is a rescue procedure for recalcitrant cases of benign obstructive pancreatopathy. METHODS: We conducted a dual-center retrospective chart review of 28 patients (mean age, 59 years; 50% female) who underwent attempted anterograde EUS-PDD between April 2016 and September 2019 for chronic pancreatitis (CP) (93%) or pancreaticojejunostomy stenosis (PJS) after Whipple resection (7%). The study endpoint was achievement of transpapillary/transanastomotic drainage (definitive therapy). RESULTS: Gastropancreaticoenterostomy (ring drainage, definitive therapy) was successfully performed during the index procedure in the 2 patients with PJS (technical success, 100%). Clinical success was 100% in the 2 ring drainage recipients during a mean 18-month follow-up period. The remaining 26 patients with CP underwent attempted pancreaticogastrostomy (PG) with 81% technical success, 75% clinical success, and 15% adverse events (AEs). Repeat endoscopic transmural interventions were performed in the 15 patients with clinical success after PG creation. Definitive therapy transpired in all 15 patients after a median 1 repeat procedure per patient. Clinical success after definitive therapy was maintained in all 15 patients (100%) during a median 4.5-month follow-up. CONCLUSIONS: In agreement with previous studies, our study showed mild to moderately high rates of technical failure (19%), clinical failure (25%), and AEs (15%) during index drainage (PG creation). Among patients with CP with both technical and clinical success after index PG creation (n = 15), 100% definitive therapy was achieved and clinical outcomes were excellent (100% clinical success, 0% AEs).

EUS-guided gallbladder drainage in patients with cirrhosis: results of a multicenter retrospective study.

Background and study aims Cirrhosis has historically been considered a relative, if not absolute, contraindication to cholecystectomy. Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) has been developed for use in non-operative candidates with cholecystitis; however, little data exist for use of the procedure in patients with cirrhosis. Patients and methods This was a retrospective series involving two large tertiary referral centers performing EUS-GBD. Patients with cirrhosis who underwent EUS-GBD for cholecystitis between August 2014 and December 2018 were identified. The primary endpoint was the rate of technical success, defined as EUS-guided placement of a lumen-apposing metal stent (LAMS) from duodenum to gallbladder. Patient demographics, procedural details, adverse events (AEs), post-procedural symptoms, and clinical success were recorded. Results Fifteen patients (9 females, 6 males) with cirrhosis underwent EUS-GBD during the study period. Mean patient age was 61 ±â€Š17.1yrs, mean MELD-Na 15 ±â€Š7. Etiology of cirrhosis was HCV (n = 2), alcohol (n = 4), non-alcoholic fatty liver disease (n = 8), and autoimmune hepatitis (n = 1). The technical success rate was 93.3 % and mean procedure time was 64 ±â€Š59 minutes. Initial puncture site was duodenum (n = 11), stomach (n = 3) and jejunum (n = 1) and portion of gallbladder used for drainage was neck (n = 4) and body (n = 11). Fourteen patients went on to clinical success and two AEs occurred in this cohort. One decompensation event occurred in a patient with Child-Pugh class C disease 3 weeks post-procedure. Mean length of follow-up was 373 ±â€Š367.3 days; one death occurred due to underlying malignancy. Conclusion EUS-GBD is safe and efficacious in managing cholecystitis in patients with Child-Pugh A and B cirrhosis who are non-operative candidates. Further studies are needed to determine optimal patient selection and procedural technique.

Bacteria on Urine Microscopy Is Not Associated with Systemic Infection in Patients with Obstructing Urolithiasis.

INTRODUCTION: Determining whether bacterial presence in urine microscopy represents infection is important as ureteral stent placement is indicated in patients with obstructing urolithiasis and infection. We aim to investigate whether the presence of bacteria on urine microscopy is associated with other markers of infection in patients with obstructing urolithiasis presenting to the emergency room. METHODS: We performed a cross-sectional study of 199 patients with obstructing urolithiasis and divided patients into two groups according to the presence of bacteria on urine microscopy. The primary outcome was serum white blood cell count and secondary outcomes were objective fever, subjective fever, tachycardia, pyuria, and final urine culture. Univariate and multivariate analysis were used to assess whether the presence of bacteria on microscopy was associated with other markers of infection. RESULTS: The study included 72 patients in the bacteriuria group and 127 without bacteriuria. On univariate analysis, the presence of bacteria was not associated with leukocytosis, objective fever, or subjective fever, but it was associated with gender (p < 0.001), pyuria (p < 0.001), positive nitrites (p = 0.001), positive leukocyte esterase (p < 0.001), and squamous epithelial cells (p = 0.002). In a multilinear regression model including the presence of squamous cells, age, and sex, the presence of bacteriuria was not related to serum white blood cell count (coefficient -0.47; 95% confidence interval [CI] -1.1, 0.2; p = 0.17), heart rate (coefficient 0.85; 95% CI -2.5, 4.2; p = 0.62), presence of subjective or objective fever (odds ratio [OR] 1.5; 95% CI 0.8, 3.1; p = 0.18), or the presence of squamous epithelial cells (coefficient -4.4; 95% CI -10, 1.2; p = 0.12). However, the presence of bacteriuria was related to only the degree of pyuria (coefficient 16.4; 95% CI 9.6, 23.3; p < 0.001). CONCLUSIONS: Bacteria on urine microscopy is not associated with other markers of systemic infection and may largely represent a contaminant. Renal colic may be a risk factor for providing a contaminated urine specimen.

International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

Analogs of the novel phytohormone, strigolactone, trigger apoptosis and synergize with PARP inhibitors by inducing DNA damage and inhibiting DNA repair.

Strigolactones are a novel class of plant hormones produced in roots that regulate shoot and root development. We previously reported that strigolactone analogs (SLs) induce G2/M cell cycle arrest and apoptosis in a variety of human cancer cells and inhibit tumor growth of human breast cancer xenografts in mice. SLs had no significant influences on non-transformed cells. Here we report for the first time that SLs induce DNA damage in the form of DNA double-strand breaks (DSBs) and activate the DNA damage response signaling by inducing phosphorylation of ATM, ATR and DNA-PKcs and co-localization of the DNA damage signaling protein, 53BP1, with γH2AX nuclear foci. We further report that in addition to DSBs induction, SLs simultaneously impair DSBs repair, mostly homology-directed repair (HDR) and to a lesser extent non-homologous end joining (NHEJ). In response to SLs, RAD51, the homologous DSB repair protein, is ubiquitinated and targeted for proteasomal degradation and it fails to co-localize with γH2AX foci. Interestingly, SLs synergize with DNA damaging agents-based therapeutics. The combination of PARP inhibitors and SLs showed an especially potent synergy, but only in BRCA1-proficient cells. No synergy was observed between SLs and PARP inhibitors in BRCA1-deficient cells, supporting a role for SLs in HDR impairment. Together, our data suggest that SLs increase genome instability and cell death by a unique mechanism of inducing DNA damage and inhibiting DNA repair.

Taking Control of Castleman Disease: Leveraging Precision Medicine Technologies to Accelerate Rare Disease Research.

Castleman disease (CD) is a rare and heterogeneous disorder characterized by lymphadenopathy that may occur in a single lymph node (unicentric) or multiple lymph nodes (multicentric), the latter typically occurring secondary to excessive proinflammatory hypercytokinemia. While a cohort of multicentric Castleman disease (MCD) cases are caused by Human Herpes Virus-8 (HHV-8), the etiology of HHV-8 negative, idiopathic MCD (iMCD), remains unknown. Breakthroughs in "omics" technologies that have facilitated the development of precision medicine hold promise for elucidating disease pathogenesis and identifying novel therapies for iMCD. However, in order to leverage precision medicine approaches in rare diseases like CD, stakeholders need to overcome several challenges. To address these challenges, the Castleman Disease Collaborative Network (CDCN) was founded in 2012. In the past 3 years, the CDCN has worked to transform the understanding of the pathogenesis of CD, funded and initiated genomics and proteomics research, and united international experts in a collaborative effort to accelerate progress for CD patients. The CDCN's collaborative structure leverages the tools of precision medicine and serves as a model for both scientific discovery and advancing patient care.