EUS-Guided Thrombin Injection and Coil Implantation for Gastric Varices: Feasibility, Safety, and Outcomes.

BACKGROUND AND AIMS: Gastric varices (GV) are reported in up to 20% of patients with portal hypertension, and bleeding is often more severe and challenging than oesophageal variceal bleeding. There is limited data on prophylaxis of GV bleeding or management in the acute setting, and different techniques are utilised. This study aims to evaluate outcomes following endoscopic ultrasound (EUS) guided placement of coils in combination with thrombin to manage GV. METHODS: We retrospectively reviewed all patients treated with combination EUS-guided therapy with coils and thrombin between October 2015 and February 2020. RESULTS: 20 patients underwent 33 procedures for GV therapy; 16/20 (80%) were type 1 Isolated GV (IGV1), and the remainder were type 2 Gastroesophageal Varices (GOV2). Median follow-up was 842 days (Interquartile range (IQR) 483-961). 17/20 (85%) had underlying cirrhosis, the most common aetiologies being alcohol-related liver disease and non-alcoholic steatohepatitis (NASH). The median Child-Pugh (CP) score was 6 (IQR 5-7). In 11/20 (55%) cases, the indication was secondary prophylaxis to prevent rebleeding; in 2/20 (10%), the bleeding was acute. Technical success was achieved in 19/20 (95%) of cases. During follow-up, the obliteration of flow within the varices was achieved in 17/20 (85%) cases. The 6-week survival was 100%, and 2 adverse events were reported: cases of rebleeding at day 5 and day 37; both rebleeds were successfully managed endoscopically. CONCLUSIONS: EUS-guided GV obliteration combining coil placement with thrombin, in our experience, is technically safe with good medium-term efficacy. A multicenter randomised controlled trial comparing different treatment strategies would be desirable to understand options better.

Technical and clinical outcomes following EUS-guided thrombin injection and coil implantation for parastomal varices.

BACKGROUND AND AIMS: Bleeding from parastomal varices causes significant morbidity and mortality. Treatment options are limited, particularly in high-risk patients with significant underlying liver disease and other comorbidities. The use of EUS-guided embolisation coils combined with thrombin injection in gastric varices has been shown to be safe and effective. Our institution has applied the same technique to the treatment of parastomal varices. METHODS: A retrospective review was performed of 37 procedures on 24 patients to assess efficacy and safety of EUS-guided injection of thrombin, with or without embolisation coils for treatment of bleeding parastomal varices. All patients had been discussed in a multidisciplinary team meeting, and correction of portal hypertension was deemed to be contraindicated. Rebleeding was defined as stomal bleeding that required hospital admission or transfusion. RESULTS: All patients had significant parastomal bleeding at the time of referral. 100% technical success rate was achieved. 70.8% of patients had no further significant bleeding in the follow-up period (median 26.2 months) following one procedure. 1-year rebleed-free survival was 80.8% following first procedure. 7 patients (29.1%) had repeat procedures. There was no significant difference in rebleed-free survival following repeat procedures. Higher age was associated with higher risk of rebleeding. No major procedure-related complications were identified. CONCLUSIONS: EUS-guided thrombin injection, with or without embolisation coils, is a safe and effective technique for the treatment of bleeding parastomal varices, particularly for patients for whom correction of portal venous hypertension is contraindicated.

Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma has a poor clinical outcome and responses to immunotherapy are suboptimal. Stromal fibroblasts are a dominant but heterogenous population within the tumor microenvironment and therapeutic targeting of stromal subsets may have therapeutic utility. Here, we combine spatial transcriptomics and scRNA-Seq datasets to define the transcriptome of tumor-proximal and tumor-distal cancer-associated fibroblasts (CAFs) and link this to clinical outcome. Tumor-proximal fibroblasts comprise large populations of myofibroblasts, strongly expressed podoplanin, and were enriched for Wnt ligand signaling. In contrast, inflammatory CAFs were dominant within tumor-distal subsets and expressed complement components and the Wnt-inhibitor SFRP2. Poor clinical outcome was correlated with elevated HIF-1α and podoplanin expression whilst expression of inflammatory and complement genes was predictive of extended survival. These findings demonstrate the extreme transcriptional heterogeneity of CAFs and its determination by apposition to tumor. Selective targeting of tumor-proximal subsets, potentially combined with HIF-1α inhibition and immune stimulation, may offer a multi-modal therapeutic approach for this disease.

Pancreatic cancer is one of the deadliest and most difficult cancers to treat. It responds poorly to immunotherapy for instance, despite this approach often succeeding in enlisting immune cells to fight tumours in other organs. This may be due, in part, to a type of cell called fibroblasts. Not only do these wrap pancreatic tumours in a dense, protective layer, they also foster complex relationships with the cancerous cells: some fibroblasts may fuel tumour growth, while other may help to contain its spread. These different roles may be linked to spatial location, with fibroblasts adopting different profiles depending on their proximity with cancer calls. For example, certain fibroblasts close to the tumour resemble the myofibroblasts present in healing wounds, while those at the periphery show signs of being involved in inflammation. Being able to specifically eliminate pro-cancer fibroblasts requires a better understanding of the factors that shape the role of these cells, and how to identify them. To examine this problem, Croft et al. relied on tumour samples obtained from pancreatic cancer patients. They mapped out the location of individual fibroblasts in the vicinity of the tumour and analysed their gene activity. These experiments helped to reveal the characteristics of different populations of fibroblasts. For example, they showed that the myofibroblast-like cells closest to the tumour exhibited signs of oxygen deprivation; they also produced podoplanin, a protein known to promote cancer progression. In contrast, cells further from the cancer produced more immune-related proteins. Combining these data with information obtained from patients' clinical records, Croft et al. found that samples from individuals with worse survival outcomes often featured higher levels of podoplanin and hypoxia. Inflammatory markers, however, were more likely to be present in individuals with good outcomes. Overall, these findings could help to develop ways to selectively target fibroblasts that support the growth of pancreatic cancer. Weakening these cells could in turn make the tumour accessible to immune cells, and more vulnerable to immunotherapies.

Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade.

Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti-PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy.

NK cells in pancreatic cancer demonstrate impaired cytotoxicity and a regulatory IL-10 phenotype.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common tumor subtypes and remains associated with very poor survival. T cell infiltration into tumor tissue is associated with improved clinical outcome but little is known regarding the potential role of NK cells in disease control. Here we analyze the phenotype and function of NK cells in the blood and tumor tissue from patients with PDAC. Peripheral NK cells are present in normal numbers but display a CD16hiCD57hi phenotype with marked downregulation of NKG2D. Importantly, these cells demonstrate reduced cytotoxic activity and low levels of IFN-γ expression but instead produce high levels of intracellular IL-10, an immunoregulatory cytokine found at increased levels in the blood of PDAC patients. In contrast, NK cells are largely excluded from tumor tissue where they display strong downregulation of both CD16 and CD57, a phenotype that was recapitulated in primary NK cells following co-culture with PDAC organoids. Moreover, expression of activatory proteins, including DNAM-1 and NKP30, was markedly suppressed and the DNAM-1 ligand PVR was strongly expressed on tumor cells. As such, in situ and peripheral NK cells display differential features in patients with PDAC and indicate local and systemic mechanisms by which the tumor can evade immune control. These findings offer a number of potential options for NK-based immunotherapy in the management of patients with PDAC.

Endoscopic ultrasound-guided pancreatic fluid collections' transmural drainage outcomes in 100 consecutive cases of pseudocysts and walled off necrosis: a single-centre experience from the United Kingdom.

BACKGROUND AND AIM: Endoscopic ultrasound-guided drainage is a minimally invasive first-line modality for the drainage of pancreatic fluid collection (PFC) resulting in a shorter hospital stay and less morbidity compared with surgical cystogastrostomy. Our aim is to evaluate potential differences in the outcomes of endoscopic ultrasound (EUS) guided transmural drainage (EUS-TD) drainage of pancreatic pseudocyst (PP) and walled-off necrosis (WON). METHOD: We retrospectively reviewed 100 consecutive EUS-guided drainages of PFC utilising EUS reports; clinical notes and imaging with follow-up (FU) to 12 months. All procedures were undertaken under conscious sedation with EUS guidance alone (without fluoroscopy) and placement of plastic double pigtail stents. RESULTS: In these 100 sequential cases, there were 78 cases of PP and 22 cases of WON. All 22/22(100%) cases of WON had successful EUS-guided stent placement. In 2/22(9%), there was little or no clinical improvement. These two patients required further computed tomography (CT)-guided drainage and one of these patients (1/22) (4.5%) developed recurrence within 12 months FU after removal of stents. In case of PP, overall stent placement was successful in 76/78 (97%) patients, but 6/78(8%) required 2nd EUS procedure after failure to show clinical improvement; 3/78(2.5%) required further CT-guided drainage. The overall complication rate was 9%(9/100) with 4%(4/100) requiring endoscopic or CT-guided intervention with no overall 30-day mortality. CONCLUSION: This is the largest series from a single UK centre demonstrating that EUS-guided cystogastrostomy of PFC drainage using plastic double pigtail stents is sufficient in majority of cases with PFC including that of WON, with or without infection.

Comparing outcome of radiofrequency ablation in Barrett's with high grade dysplasia and intramucosal carcinoma: a prospective multicenter UK registry.

BACKGROUND AND STUDY AIM: Mucosal neoplasia arising in Barrett's esophagus can be successfully treated with endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA). The aim of the study was to compare clinical outcomes of patients with high grade dysplasia (HGD) or intramucosal cancer (IMC) at baseline from the United Kingdom RFA registry. PATIENTS AND METHODS: Prior to RFA, visible lesions and nodularity were removed entirely by EMR. Thereafter, patients underwent RFA every 3 months until all visible Barrett's mucosa was ablated or cancer developed (end points). Biopsies were taken at 12 months or when end points were reached. RESULTS: A total of 515 patients, 384 with HGD and 131 with IMC, completed treatment. Prior to RFA, EMR was performed for visible lesions more frequently in the IMC cohort than in HGD patients (77 % vs. 47 %; P < 0.0001). The 12-month complete response for dysplasia and intestinal metaplasia were almost identical in the two cohorts (HGD 88 % and 76 %, respectively; IMC 87 % and 75 %, respectively; P = 0.7). Progression to invasive cancer was not significantly different at 12 months (HGD 1.8 %, IMC 3.8 %; P = 0.19). A trend towards slightly worse medium-term durability may be emerging in IMC patients (P = 0.08). In IMC, EMR followed by RFA was definitely associated with superior durability compared with RFA alone (P = 0.01). CONCLUSION: The Registry reports on endoscopic therapy for Barrett's neoplasia, representing real-life outcomes. Patients with IMC were more likely to have visible lesions requiring initial EMR than those with HGD, and may carry a higher risk of cancer progression in the medium term. The data consolidate the approach to ensuring that these patients undergo thorough endoscopic work-up, including EMR prior to RFA when necessary.

Radiofrequency ablation and endoscopic mucosal resection for dysplastic barrett's esophagus and early esophageal adenocarcinoma: outcomes of the UK National Halo RFA Registry.

BACKGROUND & AIMS: Patients with Barrett's esophagus (BE) and high-grade dysplasia (HGD) or early neoplasia increasingly receive endoscopic mucosal resection and radiofrequency ablation (RFA) therapy. We analyzed data from a UK registry that follows the outcomes of patients with BE who have undergone RFA for neoplasia. METHODS: We collected data on 335 patients with BE and neoplasia (72% with HGD, 24% with intramucosal cancer, 4% with low-grade dysplasia [mean age, 69 years; 81% male]), treated at 19 centers in the United Kingdom from July 2008 through August 2012. Mean length of BE segments was 5.8 cm (range, 1-20 cm). Patients' nodules were removed by endoscopic mucosal resection, and the patients then underwent RFA every 3 months until all areas of BE were ablated or cancer developed. Biopsies were collected 12 months after the first RFA; clearance of HGD, dysplasia, and BE were assessed. RESULTS: HGD was cleared from 86% of patients, all dysplasia from 81%, and BE from 62% at the 12-month time point, after a mean of 2.5 (range, 2-6) RFA procedures. Complete reversal dysplasia was 15% less likely for every 1-cm increment in BE length (odds ratio = 1.156; SE = 0.048; 95% confidence interval: 1.07-1.26; P < .001). Endoscopic mucosal resection before RFA did not provide any benefit. Invasive cancer developed in 10 patients (3%) by the 12-month time point and disease had progressed in 17 patients (5.1%) after a median follow-up time of 19 months. Symptomatic strictures developed in 9% of patients and were treated by endoscopic dilatation. Nineteen months after therapy began, 94% of patients remained clear of dysplasia. CONCLUSIONS: We analyzed data from a large series of patients in the United Kingdom who underwent RFA for BE-related neoplasia and found that by 12 months after treatment, dysplasia was cleared from 81%. Shorter segments of BE respond better to RFA; http://www.controlled-trials.com, number ISRCTN93069556.

Endoscopic ultrasound assessment of lesions of the ampulla of Vater is of particular value in low-grade dysplasia.

BACKGROUND: The accurate diagnosis of dysplasia or carcinoma within ampullary lesions can be difficult, but, when possible, identifies patients who require endoscopic or surgical resection, respectively. The role of endoscopic ultrasound (EUS) in diagnosing these lesions and the degree of dysplasia is unclear. METHODS: Patients with lesions of the ampulla were identified over 5 years. Patients who did not undergo EUS were compared with those who did. RESULTS: A total of 27 of 58 (47%) patients were investigated with EUS. Pretreatment diagnoses were correct in 93% of the EUS group vs. 78% of the no-EUS group. Rates of diagnostic accuracy in low-grade dysplasia (LGD), high-grade dysplasia (HGD) and adenocarcinoma (ADC) were 72%, 20% and 96%, respectively, in the no-EUS group, and 93%, 50% and 100%, respectively, in the EUS group. Every diagnosis of LGD in the EUS group was correct, whereas these diagnoses accounted for the majority of errors (eight of 13) in the no-EUS group. High-grade dysplasia was frequently misdiagnosed. More patients were treated by endoscopic resection in the EUS group (12 of 27 vs. five of 31; P= 0.025). CONCLUSIONS: Endoscopic ultrasound increases the accuracy of preoperative diagnosis of ampullary lesions and is particularly useful in patients with LGD because it permits safe endoscopic management. Patients with HGD must be reviewed carefully and considered for pancreatoduodenectomy.

Hypopharyngeal perforation during endoscopic ultrasound treated by primary repair.

BACKGROUND: An endoscopic ultrasound scan is a common procedure used to diagnose conditions of the upper gastrointestinal tract. We present a case of hypopharyngeal perforation complicating endoscopic ultrasound scan treated with primary surgical repair. METHODS AND RESULTS: A 62-year-old woman underwent an endoscopic ultrasound scan for investigation of a pancreatic lesion. A high esophageal perforation occurred during the procedure. She underwent emergency repair of this perforation via an external approach. Unfortunately her recovery was complicated by a pleural effusion which required a chest drain. She made a complete recovery, which was confirmed with a barium swallow. DISCUSSION: Upper esophageal perforation is a rare complication of an endoscopic ultrasound scan and, to our knowledge, there have been no reported cases of hypopharyngeal perforation. The risk factors, incidence, and management of perforations are reviewed. Early recognition of hypopharyngeal perforation is important and, in selected cases, immediate repair of the defect can lead to a good result.

Role of endoscopic ultrasound-guided fine-needle aspiration in the diagnosis of solid pancreatic and peripancreatic lesions: is onsite cytopathology necessary?

OBJECTIVES: The reported median diagnostic yield from endoscopic ultrasound (EUS) fine-needle aspiration (FNA) cytology is 78% (range 39-93%). The aim of this study is to describe a single-centre experience in the diagnostic work-up of solid pancreatic and peripancreatic masses without the benefit of an onsite cytopathologist. METHODS: In a consecutive series of 429 EUS examinations performed over a 12-month period by a single operator, 108 were on non-cystic pancreatic or biliary lesions. Data were collected prospectively and the accuracy of FNA was assessed retrospectively using either surgery or repeat imaging as the benchmark in the presence or absence of malignancy. RESULTS: Of the 108 FNAs, 102 (94%) were diagnostic, four were falsely negative (FN) and two were atypical and considered equivocal. There were 78 pancreatic lesions, of which 65 were true positives (TP), 11 true negatives (TN) and two FN, giving an overall accuracy of 97% (76/78). Of nine periampullary lesions, two were TP, six were TN and one was FN, giving an overall accuracy of 89% (8/9). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of EUS-FNA for pancreatic and periampullary lesions combined were 96%, 100%, 100% [95% confidence interval (CI) 95-100%], 85% (95% CI 62-97%) and 97%, respectively. There were 21 bile duct lesions, of which 10 were TP, eight TN, two atypical and one FN, giving an overall accuracy of 86% (18/21). The sensitivity, specificity, PPV, NPV and accuracy of EUS-FNA for biliary lesions were 91%, 100%, 100% (95% CI 69-100%), 91% (95% CI 59-100%) and 95%, respectively. CONCLUSIONS: The diagnostic accuracy of EUS-FNA for pancreatic lesions in our series was 97% and the PPV for the three subgroups of lesion type was 100%; these figures are comparable with the best rates reported in the literature, despite the absence of onsite cytopathology. These rates are potentially a direct result of high-volume practice, dedicated endosonography and cytopathology. These results show that it is possible to achieve high rates of accuracy in places where logistical issues make it impossible to maintain a cytopathologist in the endoscopy suite. In addition, our results contribute to the limited, collective global experience on the effectiveness of EUS-FNA in periampullary and biliary lesions.

Pancreatic insulinoma co-existing with gastric GIST in the absence of neurofibromatosis-1.

BACKGROUND: Gastrointestinal stromal tumours (GIST) frequently occur in patients with neurofibromatosis type 1 (NF-1). It has been reported that GIST may co-exist with pancreatic endocrine tumors but this has only been in association with NF-1. CASE PRESENTATION: A 76 year old woman presented with a 12 month history of hypoglycaemia symptoms. Abdominal CT scan demonstrated a 13 mm insulinoma localized in the tail of her pancreas. She was commenced on diazoxide and later underwent surgery for enucleation of insulinoma when a small (< 1 cm) incidental tumour was discovered on her stomach wall which was identified as GIST. CONCLUSION: This is the first case report of a pancreatic insulinoma co-existing with a GIST in a patient without NF-1. In addition, we make the first report of rapidly growing cystic GIST recurrence following resection of a primary GIST tumour.

Acute spontaneous compartment syndrome in recent onset type 1 diabetes.

Acute spontaneous compartment syndrome is a rare orthopaedic emergency that usually presents to general physicians as an acute medical admission. Most cases reported to date, in patients with diabetes, are in those with long-standing disease or with evidence of diabetic complications. An acute spontaneous compartment syndrome in a girl with recent diagnosis of type 1 diabetes is reported here. Awareness of the condition allows early recognition and diagnosis, thereby preventing more severe muscle necrosis and disability.