Enhancing stent length and stability with a novel through-the-scope suturing platform: a case series.

Background and Aims: Fully covered self-expandable metal stents are commonly used for managing GI adverse events like perforations, leaks, fistulas, and strictures. Although effective, stent length and migration can be a limitation when dealing with larger defects. Over-the-scope clips and over-the-scope suturing can be used to mitigate migration risk; however, their role is limited for stent-to-stent suturing to create longer stents. We present a novel application of through-the-scope suturing (TTSS) system for creating longer stents to manage larger GI defects. Methods: We demonstrate using a video case series the applicability of TTSS for fixing multiple coaxially placed stents to create a longer stent and simultaneously anchor them to underlying GI wall to mitigate stent migration. Results: We illustrate our success in managing 3 cases of large esophageal and/or gastric pathologies (stenosis and leak) using the TTSS system to create longer stents through stent-in-stent fixation. Conclusions: TTSS is a novel endoscopic suturing platform that is compatible with most endoscopes and can be navigated to challenging narrow and angulated location, giving it an advantage over over-the-scope suturing/over-the-scope clips. Our case series demonstrates that stent-in-stent fixation of multiple fully covered self-expandable metal stents to create longer stents using the TTSS system is an effective technique when managing larger GI defects.

Endoscopic closure of a recto-pelvic fistula with a cardiac septal occluder device.

Video 1Endoscopic closure of a recto-pelvic fistula with a cardiac septal occluder device in a patient for whom other surgical and endoscopic interventions had failed.

Hypereosinophilia as a presenting sign of advanced pancreatic adenocarcinoma: a rare, severe presentation.

Pancreatic adenocarcinoma (PA) is the third most lethal malignancy worldwide with only a 7.7% 5-year survival rate. Prognosis is poor with more than 50% of patients presenting with stage IV disease. Despite focused attention on early detection and treatment, pathogenesis and early symptomatology are not well described. In addition to prodromal symptoms, hypereosinophilia has been identified as a marker of malignancy in both PA and other solid tumour and haematological malignancies. Peripheral hypereosinophilia (PH) secondary to solid organ tumours, however, is rare, with only four cases of PA reported to date. We present a case of advanced PA with associated severe PH in a man in his early 50s. Time from diagnosis to death in this patient was only 6 weeks, emphasising the need to consider malignancy in the differential diagnosis for a patient that presents with a severe PH of unknown origin.

ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors.

The extracellular aggregation of destabilized transthyretin (TTR) variants is implicated in the onset and pathogenesis of familial TTR-related amyloid diseases. One strategy to reduce the toxic, extracellular aggregation of TTR is to decrease the population of aggregation-prone proteins secreted from mammalian cells. The stress-independent activation of the unfolded protein response (UPR)-associated transcription factor ATF6 preferentially decreases the secretion and subsequent aggregation of destabilized, aggregation-prone TTR variants. However, the mechanism of this reduced secretion was previously undefined. Here, we implement a mass-spectrometry-based interactomics approach to identify endoplasmic reticulum (ER) proteostasis factors involved in ATF6-dependent reductions in destabilized TTR secretion. We show that ATF6 activation reduces amyloidogenic TTR secretion and subsequent aggregation through a mechanism involving ER retention that is mediated by increased interactions with ATF6-regulated ER proteostasis factors including BiP and PDIA4. Intriguingly, the PDIA4-dependent retention of TTR is independent of both the single TTR cysteine residue and the redox activity of PDIA4, indicating that PDIA4 retains destabilized TTR in the ER through a redox-independent mechanism. Our results define a mechanistic basis to explain the ATF6 activation-dependent reduction in destabilized, amyloidogenic TTR secretion that could be therapeutically accessed to improve treatments of TTR-related amyloid diseases.

The PathLink Acquired Gestational Tissue Bank: Feasibility of Project PLACENTA.

BACKGROUND: The Vanderbilt Institute for Clinical and Translational Research piloted the development of Project PLACENTA (PathLink Acquired gEstatioNal Tissue bAnk). This project investigated the feasibility of a fresh gestational tissue biobank, which provides tissue linked to electronic medical records for investigators interested in maternal-fetal health. METHODS: We developed a pipeline for collection of placental tissue from Labor and Delivery within approximately 30 minutes of delivery. An email alert was developed, to signal delivery, with the ability to specifically flag patients with certain phenotypic traits. Once collected, 4 to 8 mm punch biopsy cores were snap frozen and subsequently used for DNA, RNA and protein extraction. Tissue was also collected for Formalin Fixed Paraffin Embedded (FFPE) histology, flow cytometry, and quality control measures. RESULTS: Of 60 deliveries using the email notification system, 25 (42%) were sent to Pathology or assigned to other research protocols and were not available for collection, 10 (16%) were discarded prior to arrival at Labor and Delivery, and 25 (42%) were available for collection. Twenty placentas were collected and averaged 38 minutes per collection. DNA extraction yielded an average of 53 µg/µl per sample and RNA extraction yielded 679 ng/µl on average per sample. Proteomic studies showed no degradation of protein, abundant and similar quantities of protein across samples and differentiation between the amnion, decidua, and villi. Histological studies showed good quality for interpretation and occasional pathology including multifocal chronic villitis, meconium laden macrophages, and Stage 2 acute chorioamnionitis. Flow cytometry demonstrated good cell viability after isolation.