Management of Malignant Gastric Outlet Obstruction: A Comprehensive Review on the Old, the Classic and the Innovative Approaches.

Gastrojejunostomy is the principal method of palliation for unresectable malignant gastric outlet obstructions (GOO). Gastrojejunostomy was traditionally performed as a surgical procedure with an open approach butrecently, notable progress in the development of minimally invasive procedures such as laparoscopic gastrojejunostomies have emerged. Additionally, advancements in endoscopic techniques, including endoscopic stenting (ES) and endoscopic ultrasound-guided gastroenterostomy (EUS-GE), are becoming more prominent. ES involves the placement of self-expandable metal stents (SEMS) to restore luminal patency. ES is commonly the first choice for patients deemed unfit for surgery or at high surgical risk. However, although ES leads to rapid improvement of symptoms, it carries limitations like higher stent dysfunction rates and the need for frequent re-interventions. Recently, EUS-GE has emerged as a potential alternative, combining the minimally invasive nature of the endoscopic approach with the long-lasting effects of a gastrojejunostomy. Having reviewed the advantages and disadvantages of these different techniques, this article aims to provide a comprehensive review regarding the management of unresectable malignant GOO.

Outcomes predictors in endoscopic ultrasound-guided choledochoduodenostomy with lumen-apposing metal stent: Systematic review and meta-analysis.

Background and study aims EUS-guided choledochoduodenostomy (EUS-CDS) is a minimally invasive procedure used to treat malignant biliary obstruction (MBO) by transduodenal placement of a lumen-apposing metal stent (LAMS) into the extrahepatic bile duct. To identify factors that contribute to safe and effective EUS-CDS using LAMS, we performed a systematic review of the literature and meta-analysis. Methods The methodology of our analysis was based on PRISMA recommendations. Electronic databases (Medline, Scopus, EMBASE) were searched up to November 2022. Full articles that included patients with distal malignant biliary obstruction who underwent EUS-CDS using LAMS after failed endoscopic retrograde cholangiopancreatography were eligible. Random-effect meta-analysis was performed reporting pooled rates of technical success, clinical success, and adverse events (AEs) by means of a random model. Multivariate meta-regression and subgroup analysis were performed to assess possible associations between the outcomes and selected variables to assess the correlation between outcomes and different variables. Results were also stratified according to stent size. Results Twelve studies with 845 patients were included in the meta-analysis. Pooled technical and clinical success rates were 96% (95% confidence interval [CI] 94%-98%; I 2 = 52.29%) and 96% (95%CI 95%-98%), respectively, with no significant association with baseline characteristics, such are sex, age, common bile duct diameter, or stent size. The pooled AE rate was 12% (95%CI: 8%-16%; I 2 = 71.62%). The AE rate was significantly lower when using an 8 × 8 mm stent as compared with a 6 × 8 mm LAMS (odds ratio 0.59, 0.35-0.99; P = 0.04), with no evidence of heterogeneity (I 2 = 0%). Conclusions EUS-CDS with LAMS is a safe and effective option for relief of MBO. Selecting an appropriate stent size is crucial for achieving optimal safety outcomes.

From Staining Techniques to Artificial Intelligence: A Review of Colorectal Polyps Characterization.

This review article provides a comprehensive overview of the evolving techniques in image-enhanced endoscopy (IEE) for the characterization of colorectal polyps, and the potential of artificial intelligence (AI) in revolutionizing the diagnostic accuracy of endoscopy. We discuss the historical use of dye-spray and virtual chromoendoscopy for the characterization of colorectal polyps, which are now being replaced with more advanced technologies. Specifically, we focus on the application of AI to create a "virtual biopsy" for the detection and characterization of colorectal polyps, with potential for replacing histopathological diagnosis. The incorporation of AI has the potential to provide an evolutionary learning system that aids in the diagnosis and management of patients with the best possible outcomes. A detailed analysis of the literature supporting AI-assisted diagnostic techniques for the detection and characterization of colorectal polyps, with a particular emphasis on AI's characterization mechanism, is provided. The benefits of AI over traditional IEE techniques, including the reduction in human error in diagnosis, and its potential to provide an accurate diagnosis with similar accuracy to the gold standard are presented. However, the need for large-scale testing of AI in clinical practice and the importance of integrating patient data into the diagnostic process are acknowledged. In conclusion, the constant evolution of IEE technology and the potential for AI to revolutionize the field of endoscopy in the future are presented.

Use of endoscopic ultrasound-guided gallbladder drainage as a rescue approach in cases of unsuccessful biliary drainage.

This narrative review provides an overview of the utilization of endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) as a salvage approach in cases of unsuccessful conventional management. EUS-GBD is a minimally invasive and effective technique for drainage in patients with acute cholecystitis with high risk of surgery. The procedure has demonstrated impressive technical and clinical success rates with low rates of adverse events, making it a safe and effective option for appropriate candidates. Furthermore, EUS-GBD can also serve as a rescue option for patients who have failed endoscopic retrograde cholangiopancreatography or EUS biliary drainage for relief of jaundice in malignant biliary stricture. However, patient selection is critical for the success of EUS-GBD, and proper patient selection and risk assessment are important to ensure the safety and efficacy of the procedure. As the field continues to evolve and mature, ongoing research will further refine our understanding of the benefits and limitations of EUS-GBD, ultimately leading to improved outcomes for patients.

The outcomes and safety of patients undergoing endoscopic retrograde cholangiopancreatography combining a single-use cholangioscope and a single-use duodenoscope: A multicenter retrospective international study.

BACKGROUND: Duodenoscope-related multidrug-resistant organism (MDRO) infections raise concerns. Disposable duodenoscopes have been recently introduced in the market and approved by regulatory agencies with the aim to reduce the risk of endoscopic retrograde cholangiopancreatography (ERCP) associated infections. The aim of this study was to evaluate the outcome of procedures performed with single-use duodenoscopes in patients with clinical indications to single-operator cholangiopancreatoscopy. METHODS: This is a multicenter international, retrospective study combining all patients who underwent complex biliopancreatic interventions using the combination of a single-use duodenoscope and a single-use cholangioscope. The primary outcome was technical success defined as ERCP completion for the intended clinical indication. Secondary outcomes were procedural duration, rate of cross-over to reusable duodenoscope, operator-reported satisfaction score (1 to 10) on performance rating of the single-use duodenoscope, and adverse event (AE) rate. RESULTS: A total of 66 patients (26, 39.4% female) were included in the study. ERCP was categorized according to ASGE ERCP grading system as 47 (71.2%) grade 3 and 19 (28.8%) grade 4. The technical success rate was 98.5% (65/66). Procedural duration was 64 (interquartile range 15-189) min, cross-over rate to reusable duodenoscope was 1/66 (1.5%). The satisfaction score of the single-use duodenoscope classified by the operators was 8.6 ± 1.3 points. Four patients (6.1%) experienced AEs not directly related to the single-use duodenoscope, namely 2 post-ERCP pancreatitis (PEP), 1 cholangitis and 1 bleeding. CONCLUSIONS: Single-use duodenoscope is effective, reliable and safe even in technically challenging procedures with a non-inferiority to reusable duodenoscope, making these devices a viable alternative to standard reusable equipment.

Small bowel lesions in patients with iron deficiency anaemia without overt bleeding: a multicentre study.

The diagnostic work-up in iron deficiency anaemia (IDA) patients can be challenging when bleedings or malabsorption are not clinically manifest. Lesions on the small bowel mucosa may cause IDA. We evaluated the prevalence of lesions on the small bowel mucosa detected at Videocapsule Endoscopy (VCE) in IDA patients following negative upper and lower endoscopies. Clinical and endoscopic data collected in 5 centres were retrieved. Lesions with a high bleeding potential (P2) were computed, and predictive factors investigated at multivariate analysis. By considering data of 230 patients, the endoscopic examination detected a total of 96 (41.7%; 95% CI: 35.4-48.1) P2 lesions on the small bowel mucosa, including 4 (1.7%) cancers. The use of non-steroidal anti-inflammatory drugs was found to be the only associated factor at both univariate (OR: 5.7, 95% CI: 2.4-13.4; P <0.001) and multivariate (OR: 2.8; 95% CI: 1.7-3.9, P <0.01) analyses. Present study showed that evaluation of small bowel mucosa with VCE allows to disclose a potential cause of IDA in near half patients. The cooperation between haematologists and gastroenterologists in the diagnostic work-up may be useful.

Cold-snare endoscopic resection of non-ampullary duodenal adenomas: Systematic review and pooled-analysis.

BACKGROUND: Mirroring the experience with colonic resections, cold snare-based techniques have been recently proposed for non-ampullary duodenal lesions to reduce the risk of adverse events (AEs). As the duodenal wall is thinner and more vascularized than in the colon, electrocautery-related AEs are relevant issues in this setting. AIMS: We performed a systematic review with pooled-analysis to evaluate the efficacy and safety of this technique. METHODS: Electronic databases (Medline, Scopus, EMBASE) were searched up to January 2023. Full articles including patients with duodenal lesions resected by cold-snare technique were eligible. The adverse events (i.e., bleeding, perforation, stricture), complete resection, and recurrence rates were pooled using a random model. RESULTS: Eleven studies were eligible, providing data on 3137 lesions removed from 233 patients. The overall AE rate for cold snaring was 0.25% (95% CI, 0.19%-0.69%). Among the three studies comparing cold- and hot-snare approaches, procedure-related bleeding rate was significantly lower with cold approach (OR 1.21, 0.51-2.85; p = 0.66). The complete resection rate was 99.40% (95% CI, 98.60%-100%), with a residual/recurrence rate of 12.95% (95% CI, 4.75%-21.16%). On univariate meta-regression, lesion size significantly affected both the adverse events and recurrence risk. CONCLUSION: Cold-snare resection appears effective and extremely safe for resecting non-ampullary duodenal lesions.

Comparative diagnostic yield of different endoscopic techniques for tissue sampling of upper gastrointestinal subepithelial lesions: a network meta-analysis.

BACKGROUND: There is limited evidence on the comparative diagnostic performance of endoscopic tissue sampling techniques for subepithelial lesions. We performed a systematic review with network meta-analysis to compare these techniques. METHODS: A systematic literature review was conducted for randomized controlled trials (RCTs) comparing the sample adequacy and diagnostic accuracy of bite-on-bite biopsy, mucosal incision-assisted biopsy (MIAB), endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), and EUS-guided fine-needle biopsy (FNB). Results were expressed as relative risk (RR) and 95%CI. RESULTS: Eight RCTs were identified. EUS-FNB was significantly superior to EUS-FNA in terms of sample adequacy (RR 1.20 [95%CI 1.05-1.45]), whereas none of the other techniques significantly outperformed EUS-FNA. Additionally, bite-on-bite biopsy was significantly inferior to EUS-FNB (RR 0.55 [95%CI 0.33-0.98]). Overall, EUS-FNB appeared to be the best technique (surface under cumulative ranking [SUCRA] score 0.90) followed by MIAB (SUCRA 0.83), whereas bite-on-bite biopsy showed the poorest performance. When considering lesions <20 mm, MIAB, but not EUS-FNB, showed significantly higher accuracy rates compared with EUS-FNA (RR 1.68 [95%CI 1.02-2.88]). Overall, MIAB ranked as the best intervention for lesions <20 mm (SUCRA score 0.86 for adequacy and 0.91 for accuracy), with EUS-FNB only slightly superior to EUS-FNA. When rapid on-site cytological evaluation (ROSE) was available, no difference between EUS-FNB, EUS-FNA, and MIAB was observed. CONCLUSION: EUS-FNB and MIAB appeared to provide better performance, whereas bite-on-bite sampling was significantly inferior to the other techniques. MIAB seemed to be the best option for smaller lesions, whereas EUS-FNA remained competitive when ROSE was available.

Endoscopic management of benign biliary strictures: Looking for the best stent to place.

Benign biliary strictures (BBS) might occur due to different pancreaticobiliary conditions. The etiology and location of biliary strictures are responsible of a wide array of clinical manifestations. The endoscopic approach endoscopic retrograde cholangiopancreatography represents the first-line treatment for BBS, considering interventional radiology and surgery when endoscopic treatment fails or it is not suitable. The purpose of this review is to provide an overview of possible endoscopic treatments for the optimal management of this subset of patients.

LETHE: A Digital Intervention for Cognitive Decline.

Dementia is the main cause of disability in elderly populations. It has been shown that the risk factors of dementia are a mixture of pathological, lifestyle and heritable factors, with some of those being provably modifiable. Early diagnosis of dementia and approaches to slow down its evolution are currently the most prominent management methodologies due to lack of a cure. For that reason, a plethora of home-based assistive technologies for dementia management do exist, with most of them focusing on the improvement of memory and thinking. The main objective of LETHE is prevention in the whole spectrum of cognitive decline in the elderly population at risk reaching from asymptomatic to subjective or mild cognitive impairment to prodromal Dementia. LETHE will provide a Big Data collection platform and analysis system, that will allow prevention, personalized risk detection and intervention on cognitive decline. Through the subsequent 2-year clinical trial, the LETHE system, as well as the respective knowledge gained will be evaluated and validated. The scope of the current paper is to introduce the LETHE study and its respective novel platform as a holistic approach to multidomain lifestyle intervention trial studies. The present work depicts the architectural perspective and extends beyond state-of-the-art guidelines and approaches to health management systems and cloud platform development.Clinical Relevance - Patient Management Systems as well as lifestyle management platforms have significant clinical relevance as they allow for remote and continuous monitoring of patients' health status. LETHE aims to improve patient outcomes by providing predictive models for cognitive decline and patient adherence to the multimodal lifestyle intervention, enabling prompt and appropriate medical decisions.

Endoscopic Biliary Drainage in Surgically Altered Anatomy.

Endoscopic retrograde cholangiopancreatography (ERCP) is considered the preferred method for managing biliary obstructions. However, the prevalence of surgically modified anatomies often poses challenges, making the standard side-viewing duodenoscope unable to reach the papilla in most cases. The increasing instances of surgically altered anatomies (SAAs) result from higher rates of bariatric procedures and surgical interventions for pancreatic malignancies. Conventional ERCP with a side-viewing endoscope remains effective when there is continuity between the stomach and duodenum. Nonetheless, percutaneous transhepatic biliary drainage (PTBD) or surgery has historically been used as an alternative for biliary drainage in malignant or benign conditions. The evolving landscape has seen various endoscopic approaches tailored to anatomical variations. Innovative methodologies such as cap-assisted forward-viewing endoscopy and enteroscopy have enabled the performance of ERCP. Despite their utilization, procedural complexities, prolonged durations, and accessibility challenges have emerged. As a result, there is a growing interest in novel enteroscopy and endoscopic ultrasound (EUS) techniques to ensure the overall success of endoscopic biliary drainage. Notably, EUS has revolutionized this domain, particularly through several techniques detailed in the review. The rendezvous approach has been pivotal in this field. The antegrade approach, involving biliary tree puncturing, allows for the validation and treatment of strictures in an antegrade fashion. The EUS-transmural approach involves connecting a tract of the biliary system with the GI tract lumen. Moreover, the EUS-directed transgastric ERCP (EDGE) procedure, combining EUS and ERCP, presents a promising solution after gastric bypass. These advancements hold promise for expanding the horizons of comprehensive and successful biliary drainage interventions, laying the groundwork for further advancements in endoscopic procedures.

Updates on the Management of Ampullary Neoplastic Lesions.

Ampullary neoplastic lesions (ANLs) represent a rare cancer, accounting for about 0.6-0.8% of all gastrointestinal malignancies, and about 6-17% of periampullary tumors. They can be sporadic or occur in the setting of a hereditary predisposition syndrome, mainly familial adenomatous polyposis (FAP). Usually, noninvasive ANLs are asymptomatic and detected accidentally during esophagogastroduodenoscopy (EGD). When symptomatic, ANLs can manifest differently with jaundice, pain, pancreatitis, cholangitis, and melaena. Endoscopy with a side-viewing duodenoscopy, endoscopic ultrasound (EUS), and magnetic resonance cholangiopancreatography (MRCP) play a crucial role in the ANL evaluation, providing an accurate assessment of the size, location, and characteristics of the lesions, including the staging of the depth of tumor invasion into the surrounding tissues and the involvement of local lymph nodes. Endoscopic papillectomy (EP) has been recognized as an effective treatment for ANLs in selected patients, providing an alternative to traditional surgical methods. Originally, EP was recommended for benign lesions and patients unfit for surgery. However, advancements in endoscopic techniques have broadened its indications to comprise early ampullary carcinoma, giant laterally spreading lesions, and ANLs with intraductal extension. In this paper, we review the existing evidence on endoscopic diagnosis and treatment of ampullary neoplastic lesions.

Endoscopy Ultrasound-Guided Biliary Drainage Using Lumen Apposing Metal Stent in Malignant Biliary Obstruction.

This narrative review provides an overview of the application of endoscopic ultrasound-guided biliary drainage (EUS-BD), including EUS-guided gallbladder drainage (EUS-GBD), for the treatment of malignant biliary obstruction. EUS-BD has demonstrated excellent technical and clinical success rates, with lower rates of adverse events when compared with percutaneous trans-hepatic biliary drainage (PTBD). EUS-BD is currently the preferred alternative technique for biliary drainage (BD) in patients with distal malignant biliary obstruction (DMBO) after failed endoscopic retrograde cholangiopancreatography (ERCP). Particularly, this review will focus on EUS-BD performed with the use of lumen apposing metal stent (LAMS). The introduction of these innovative devices, followed by the advent of electrocautery-enhanced LAMS (EC-LAMS), gave the procedure a great technical implementation and a widespread application.

Concept learning in a probabilistic language-of-thought. How is it possible and what does it presuppose?

Where does a probabilistic language-of-thought (PLoT) come from? How can we learn new concepts based on probabilistic inferences operating on a PLoT? Here, I explore these questions, sketching a traditional circularity objection to LoT and canvassing various approaches to addressing it. I conclude that PLoT-based cognitive architectures can support genuine concept learning; but, currently, it is unclear that they enjoy more explanatory breadth in relation to concept learning than alternative architectures that do not posit any LoT.

Exploring a novel composite method using non-contrast EUS enhanced microvascular imaging and cyst fluid analysis to differentiate pancreatic cystic lesions.

BACKGROUND AND AIMS: Differentiating pancreatic cystic lesions (PCLs) remains a diagnostic challenge. The use of high-definition imaging modalities which detect tumor microvasculature have been described in solid lesions. We aim to evaluate the usefulness of cystic microvasculature when used in combination with cyst fluid biochemistry to differentiate PCLs. METHODS: We retrospectively analyzed 110 consecutive patients with PCLs from 2 Italian Hospitals who underwent EUS with H-Flow and EUS fine needle aspiration to obtain cystic fluid. The accuracy of fluid biomarkers was evaluated against morphological features on radiology and EUS. Gold standard for diagnosis was surgical resection. A clinical and radiological follow up was applied in those patients who were not resected because not surgical indication and no signs of malignancy were shown. RESULTS: Of 110 patients, 65 were diagnosed with a mucinous cyst, 41 with a non-mucinous cyst, and 4 with an undetermined cyst. Fluid analysis alone yielded 76.7% sensitivity, 56.7% specificity, 77.8 positive predictive value (PPV), 55.3 negative predictive value (NPV) and 56% accuracy in diagnosing pancreatic cysts alone. Our composite method yielded 97.3% sensitivity, 77.1% specificity, 90.1% PPV, 93.1% NPV, 73.2% accuracy. CONCLUSIONS: This new composite could be applied to the holistic approach of combining cyst morphology, vascularity, and fluid analysis alongside endoscopist expertise.

A Comprehensive Guide to Artificial Intelligence in Endoscopic Ultrasound.

BACKGROUND: Endoscopic Ultrasound (EUS) is widely used for the diagnosis of bilio-pancreatic and gastrointestinal (GI) tract diseases, for the evaluation of subepithelial lesions, and for sampling of lymph nodes and solid masses located next to the GI tract. The role of Artificial Intelligence in healthcare in growing. This review aimed to provide an overview of the current state of AI in EUS from imaging to pathological diagnosis and training. METHODS: AI algorithms can assist in lesion detection and characterization in EUS by analyzing EUS images and identifying suspicious areas that may require further clinical evaluation or biopsy sampling. Deep learning techniques, such as convolutional neural networks (CNNs), have shown great potential for tumor identification and subepithelial lesion (SEL) evaluation by extracting important features from EUS images and using them to classify or segment the images. RESULTS: AI models with new features can increase the accuracy of diagnoses, provide faster diagnoses, identify subtle differences in disease presentation that may be missed by human eyes, and provide more information and insights into disease pathology. CONCLUSIONS: The integration of AI in EUS images and biopsies has the potential to improve the diagnostic accuracy, leading to better patient outcomes and to a reduction in repeated procedures in case of non-diagnostic biopsies.

Endoscopic resection of non-ampullary duodenal adenomas: Is cold snaring the promised land?

Due to the high risk of morbidity and mortality associated with surgical resection in this tract, endoscopic resection (ER) has taken the place of surgical resection as the first line treatment for non-ampullary duodenal adenomas. However, due to the anatomical characteristics of this area, which enhance the risk of post-ER problems, ER in the duodenum is particularly difficult. Due to a lack of data, no ER technique for superficial non-ampullary duodenal epithelial tumours (SNADETs) has yet been backed by strong, high-quality evidence; yet, traditional hot snare-based techniques are still regarded as the standard treatment. Despite having a favourable efficiency profile, adverse events during duodenal hot snare polypectomy (HSP) and hot endoscopic mucosal resection, such as delayed bleeding and perforation, have been reported to be frequent. These events are primarily caused by electrocautery-induced damage. Thus, ER techniques with a better safety profile are needed to overcome these shortcomings. Cold snare polypectomy, which has already been shown as a safer, equally effective procedure compared to HSP for treatment of small colorectal polyps, is being increasingly evaluated as a potential therapeutic option for non-ampullary duodenal adenomas. The aim of this review is to report and discuss the early outcomes of the first experiences with cold snaring for SNADETs.

What Is "Cold" and What Is "Hot" in Mucosal Ablation for Barrett's Oesophagus-Related Dysplasia: A Practical Guide.

Over the last two decades, endoscopic eradication therapy has been established as the therapeutic strategy of choice for patients with Barrett's oesophagus-related dysplasia and early oesophageal adenocarcinoma. With a multimodal approach, ablative therapies have been highly effective in achieving remarkable eradication rates of metaplastic epithelium with an acceptable adverse event rate. Among ablative techniques, radiofrequency ablation is currently considered as the first-line option as its efficacy and safety are strongly supported by relevant data. Nevertheless, radiofrequency ablation is costly, and not universally available, or applicable to every situation. Moreover, primary failure and recurrence rates are not negligible. In the last few years, cryotherapy techniques and hybrid argon plasma coagulation have been increasingly assessed as potential novel ablative therapies. Preliminary data have been promising and suggest that they may even have a role as first-line options, alternatively to radiofrequency ablation. The aim of this review is to provide a practical guide for the ablation of Barrett's oesophagus, with emphasis on the different ablative options.

Diagnostic accuracy and safety of EUS-guided end-cutting fine-needle biopsy needles for tissue sampling of abdominal and mediastinal lymphadenopathies: a prospective multicenter series.

BACKGROUND AND AIMS: The role of the newer EUS fine-needle biopsy needles in lymphadenopathies (LAs) is still under evaluation. We aimed to evaluate the diagnostic accuracy and adverse event rate of EUS-guided fine-needle biopsy sampling (EUS-FNB) in diagnosing LAs. METHODS: From June 2015 to June 2022, all patients referred to 4 institutions for EUS-FNB of mediastinal and abdominal LAs were enrolled. Twenty-two-gauge Franseen tip or 25-gauge fork-tip needles were used. The criterion standard for positive results was surgery or imaging and clinical evolution over a follow-up of at least 1 year. RESULTS: One hundred consecutive patients were enrolled, consisting of those with a new diagnosis of LA (40%), presence of LA with a previous history of neoplasia (51%), or suspected lymphoproliferative disease (9%). EUS-FNB was technically feasible in all LA patients with 2 to 3 passes (mean, 2.62 ± .93). The overall sensitivity, positive predictive value, specificity, negative predictive value, and accuracy for EUS-FNB were 96.20%, 100%, 100%, 87.50%, and 97.00%, respectively. Histologic analysis was feasible in 89% of cases. Cytologic evaluation was performed in 67% of specimens. A statistical difference between the accuracy of the 22-gauge or 25-gauge needle (P = .63) was not found. A subanalysis on lymphoproliferative disease revealed a sensitivity and accuracy of 89.29% and 90.0%, respectively. No adverse events were recorded. CONCLUSIONS: EUS-FNB with new end-cutting needles is a valuable and safe method to diagnose LAs. The high quality of histologic cores and the good amount of tissue allowed a complete immunohistochemical analysis of metastatic LAs and precise subtyping of the lymphomas. (Clinical trial registration number: NCT02855151.).