Endoscopic ultrasound-guided biopsies vs surgical specimens for establishing patient-derived pancreatic cancer organoids: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Patient-Derived Tumor Organoids (PDTOs) is a promising new disease model in pancreatic cancer for use in personalized medicine, but overall success rate (SR) of establishing these cultures from endoscopic ultrasound-guided biopsies is unknown. METHODS: We searched relevant databases publications reporting SR of PDTO establishment from pancreatic cancer. The primary outcome was SR stratified on tissue acquisition method (EUS-guided biopsies, percutaneous biopsies, and surgical specimens). RESULTS: We identified 24 studies including 1,053 attempts at establishing PDTOs. Overall SR was 63% (95% CI: 54%-72%). Pooled SR of PDTO establishment from EUS-guided biopsies, percutaneous biopsies, and surgical specimens were 60% (95% CI: 43-76%), 36% (95% CI: 14-61%) and 62% (95% CI: 48-75%), respectively and did not differ significantly (p = 0.1975). CONCLUSION: The SR of PDTO establishment from EUS-guided biopsies is comparable to surgical specimens. Both techniques are suitable for tissue acquisition for PDTOs in clinical and research settings.

Performance of EUS-FNA and EUS-B-FNA for the diagnosis of left adrenal glands metastases in patients with lung cancer: A systematic review and meta-analysis.

OBJECTIVES: For diagnosing left adrenal gland metastasis in lung cancer, clinical guidelines recommend to perform EUS, but EUS-B (EUS using an EBUS-scope) is increasingly being used. We evaluated the diagnostic performance of both procedures. MATERIALS AND METHODS: We did a systematic review (PROSPERO, CRD42023416205) and searched MEDLINE and EMBASE on 04-July-2023 for studies evaluating EUS and/or EUS-B in diagnosing left adrenal gland metastases in adults with (suspected) lung cancer. Outcomes were: (1) ability to visualize the left adrenal gland, (2) ability to sample (in those with successful visualization and in whom sampling was attempted), (3) ability to obtain adequate material (in those with successful sampling), (4) malignancy detection rate (in those with successful sampling), and (5) remaining risk of malignancy (in those with a negative EUS(-B)-FNA and undergoing a reference standard). We performed random-effects meta-analyses. RESULTS: We included 19 studies (EUS: n = 11, EUS-B: n = 6, both: n = 2), covering 1712 patients. All studies had high (n = 18) or unclear (n = 1) risk of bias (QUADAS-2). Average ability to visualize the left adrenal gland was 0.94 (95 %CI 0.82-0.98; n = 7 studies). Average ability to sample was 1.00 (95 %CI 0.99-1.00; n = 9). Average ability to obtain adequate material was 0.96 (95 %CI 0.93-0.98; n = 18). Average malignancy detection rate was 0.42 (95 %CI 0.34-0.49; n = 18). Remaining risk of malignancy was 0.07 (95 %CI 0.04-0.12; n = 8). Ability to visualize was slightly higher for EUS (0.99; 95 %CI 0.90-1.00) than EUS-B (0.84; 95 %CI 0.70-0.92; p = 0.025), but the other performance characteristics were similar. No major complications were reported. CONCLUSION: Both EUS and EUS-B have good performance and are safe for left adrenal gland analysis in patients with lung cancer, but the number of high-quality studies is limited and further well-constructed prospective studies are needed.

Tissue amount and diagnostic yield of a novel franseen EUS-FNB and a standard EUS-FNA needle-A randomized controlled study in solid pancreatic lesions.

Background and Objectives: Several types of needles are available for EUS-guided tissue sampling of pancreatic lesions. Whereas fine-needle aspiration (FNA) needles typically provide cytological samples, fine-needle biopsy (FNB) needles are designed to obtain microcores with preserved tissue architecture. The aim of this study was to compare tissue amount and diagnostic yield between a modified Franseen-type FNB needle (TopGain; Medi-Globe GmbH, Grassau, Germany) and a standard FNA needle. Methods: We performed a prospective, multicenter randomized controlled study between June 2020 and September 2021, including patients with a solid pancreatic lesion referred for EUS-guided tissue sampling at 3 centers in Denmark. The patients were randomized 1:1 to either FNA needle or the novel FNB needle. Primary outcomes included the number of obtained tissue microcores and total and diagnostic tissue area. Results: Sixty-four patients were included. The median number of tissue microcores procured per pass was significantly higher in the FNB group compared with FNA (3 vs. 2, P < 0.001). Similarly, the mean total tissue area (2.74 vs. 0.44 mm2, P < 0.001) and mean diagnostic tissue area (1.74 vs. 0.28 mm2, P < 0.001) were more than 6-fold larger in the FNB samples compared with FNA. The median number of passes needed for a diagnostic sample was 1 for the FNB needle and 2 for FNA needle (P = 0.12). The novel FNB needle provided a higher percentage of samples of excellent quality (P = 0.002). Conclusions: The novel Franseen-type FNB needle seems to be significantly superior to a conventional FNA needle. The results of this study underline excellent performance of crown-cut needles.

Validation of a Novel EUS-FNB-Derived Organoid Co-Culture System for Drug Screening in Patients with Pancreatic Cancer.

Cancer-associated fibroblasts (CAFs) have been shown to impact the chemosensitivity of patient-derived tumor organoids (PDTOs). However, the published literature comparing PDTO response to clinical outcome does not include CAFs in the models. Here, a co-culture model was created using PDTOs and CAFs derived from endoscopic ultrasound-guided fine-needle biopsies (EUS-FNBs) for potential use in drug screening applications. Co-cultures were established, and growth was compared to monocultures using image metrics and a commercially available assay. We were able to establish and expand validated malignant PDTOs from 19.2% of adenocarcinomas from EUS-FNBs. CAFs could be established from 25% of the samples. The viability of PDTOs in the mixed cell co-culture could be isolated using image metrics. The addition of CAFs promoted PDTO growth in half of the established co-cultures. These results show that co-cultures can be established from tiny amounts of tissue provided by EUS-FNB. An increased growth of PDTOs was shown in co-cultures, suggesting that the present setup successfully models CAF-PDTO interaction. Furthermore, we demonstrated that standard validation techniques may be insufficient to detect contamination with normal cells in PDTO cultures established from primary tumor core biopsies.

Endoscopic Ultrasound-guided Radiofrequency Ablation Versus Surgical Resection for Treatment of Pancreatic Insulinoma.

BACKGROUND & AIMS: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is emerging as a safe and effective treatment for pancreatic neuroendocrine tumors. We aimed to compare EUS-RFA and surgical resection for the treatment of pancreatic insulinoma (PI). METHODS: Patients with sporadic PI who underwent EUS-RFA at 23 centers or surgical resection at 8 high-volume pancreatic surgery institutions between 2014 and 2022 were retrospectively identified and outcomes compared using a propensity-matching analysis. Primary outcome was safety. Secondary outcomes were clinical efficacy, hospital stay, and recurrence rate after EUS-RFA. RESULTS: Using propensity score matching, 89 patients were allocated in each group (1:1), and were evenly distributed in terms of age, sex, Charlson comorbidity index, American Society of Anesthesiologists score, body mass index, distance between lesion and main pancreatic duct, lesion site, size, and grade. Adverse event (AE) rate was 18.0% and 61.8% after EUS-RFA and surgery, respectively (P < .001). No severe AEs were observed in the EUS-RFA group compared with 15.7% after surgery (P < .0001). Clinical efficacy was 100% after surgery and 95.5% after EUS-RFA (P = .160). However, the mean duration of follow-up time was shorter in the EUS-RFA group (median, 23 months; interquartile range, 14-31 months vs 37 months; interquartile range, 17.5-67 months in the surgical group; P < .0001). Hospital stay was significantly longer in the surgical group (11.1 ± 9.7 vs 3.0 ± 2.5 days in the EUS-RFA group; P < .0001). Fifteen lesions (16.9%) recurred after EUS-RFA and underwent a successful repeat EUS-RFA (11 patients) or surgical resection (4 patients). CONCLUSION: EUS-RFA is safer than surgery and highly effective for the treatment of PI. If confirmed in a randomized study, EUS-RFA treatment can become first-line therapy for sporadic PI.

Endoluminal radiofrequency ablation of malignant biliary obstruction.

This case report describes the first Danish case of endoluminal radiofrequency ablation (RFA) of malignant biliary obstruction due to a Klatskin tumour in a 59-year-old male undergoing neoadjuvant therapy. The treatment was interrupted several times due to recurrent occlusions of the bile duct stents. The patient was offered endoluminal RFA of the central bile ducts in order to reduce his tumour burden and possibly achieve longer stent patency, so the palliative therapy could be resumed. The procedure was performed successfully without any adverse events achieving access to previously occluded left hepatic duct.

Prognostic Value of Combined Hematological/Biochemical Indexes and Tumor Clinicopathologic Features in Colorectal Cancer Patients-A Pilot Single Center Study.

Colorectal cancer (CRC) is a significant public health problem. There is increasing evidence that the host's immune response and nutritional status play a role in the development and progression of cancer. The aim of our study was to examine the prognostic value of clinical markers/indexes of inflammation, nutritional and pathohistological status in relation to overall survival and disease free-survival in CRC. The total number of CRC patients included in the study was 111 and they underwent laboratory analyses within a week before surgery. Detailed pathohistological analysis and laboratory parameters were part of the standard hospital pre-operative procedure. Medical data were collected from archived hospital data. Data on the exact date of death were obtained by inspecting the death registers for the territory of the Republic of Serbia. All parameters were analyzed in relation to the overall survival and survival period without disease relapse. The follow-up median was 42 (24-48) months. The patients with the III, IV and V degrees of the Clavien-Dindo classification had 2.609 (HR: 2.609; 95% CI: 1.437-4.737; p = 0.002) times higher risk of death. The modified Glasgow prognostic score (mGPS) 2 and higher lymph node ratio carried a 2.188 (HR: 2.188; 95% CI: 1.413-3.387; p < 0.001) and 6.862 (HR: 6.862; 95% CI: 1.635-28.808; p = 0.009) times higher risk of death in the postoperative period, respectively; the risk was 3.089 times higher (HR: 3.089; 95% CI: 1.447-6.593; p = 0.004) in patients with verified tumor deposits. The patients with tumor deposits had 1.888 (HR: 1.888; 95% CI: 1024-3481; p = 0.042) and 3.049 (HR: 3.049; 95% CI: 1.206-7.706; p = 0.018) times higher risk of disease recurrence, respectively. The emphasized peritumoral lymphocyte response reduced the risk of recurrence by 61% (HR: 0.391; 95% CI: 0.196-0.780; p = 0.005). Standard perioperative laboratory and pathohistological parameters, which do not present any additional cost for the health system, may provide information on the CRC patient outcome and lay the groundwork for a larger prospective examination.

Targeted next-generation sequencing of EUS-guided through-the-needle-biopsy sampling from pancreatic cystic lesions.

BACKGROUND AND AIMS: Recent advances have introduced molecular subtyping of pancreatic cystic lesions (PCLs) as a possible amendment to the diagnostic algorithm. The study evaluated the feasibility and diagnostic accuracy of molecular analysis and subtyping of PCLs using the recently introduced EUS-guided through-the-needle-biopsy (TTNB) sampling. METHODS: We prospectively included 101 patients in the study who presented with PCLs >15 mm in the largest cross-section. EUS-guided TTNB samples were obtained by a micro-biopsy forceps introduced through a 19-gauge needle. The TTNB samples were analyzed by next-generation sequencing (NGS) for point mutations in tumor suppressors and oncogenes using a 51-gene customized hotspot panel. Sensitivity and specificity were calculated with the histologic diagnosis as reference. RESULTS: After initial microscopic evaluation of the samples, 91 patients had residual TTNB samples available for NGS. Of these, 49 harbored mutations, most frequently in KRAS and GNAS, reflecting an excess frequency of intraductal papillary mucinous neoplasms (IPMNs) in the study population. A sensitivity and specificity of 83.7% (95% confidence interval [CI], 70.3-92.7) and 81.8% (95% CI, 48.2-97.7), respectively, were demonstrated for the diagnosis of a mucinous cyst and 87.2% (95% CI, 74.2-95.2) and 84.6% (95% CI, 54.5-98.1) for the diagnosis of an IPMN. CONCLUSIONS: Thus, molecular analysis of TTNB samples by NGS has high sensitivity and specificity for diagnosing mucinous cysts and IPMNs. Although the procedure comes with a risk of adverse events of 9.9%, TTNB samples are a robust alternative to cyst fluid for a combined histologic and molecular diagnosis of PCLs. (Clinical trial registration number: NCT03578445.).

Radiofrequency ablation of pancreatic insulinomas.

Insulinomas are rare neoplasms which may cause significant symptoms and substantially reduce quality of life. In operable patients, the current treatment is primarily surgery with either enucleation or resection of all or parts of the gland. This treatment is associated with high morbidity and long convalescence. Endoscopic ultrasound-guided radiofrequency ablation is a new and minimally invasive treatment for patients with insulinomas. The purpose of this review is to draw attention to the method and to communicate our preliminary experience with this procedure in Denmark.

Predictors of adverse events after endoscopic ultrasound-guided through-the-needle biopsy of pancreatic cysts: a recursive partitioning analysis.

BACKGROUND AND STUDY AIMS : Endoscopic ultrasound-guided through-the-needle biopsy (TTNB) of pancreatic cystic lesions (PCLs) is associated with a non-negligible risk for adverse events (AEs). We aimed to identify the hierarchic interaction among independent predictors for TTNB-related AEs and to generate a prognostic model using recursive partitioning analysis (RPA). PATIENTS AND METHODS : Multicenter retrospective analysis of 506 patients with PCLs who underwent TTNB. RPA of predictors for AEs was performed and the model was validated by means of bootstrap resampling. RESULTS : Mean cysts size was 36.7 mm. Most common diagnoses were intraductal papillary mucinous neoplasm (IPMN, 45 %), serous cystadenoma (18.8 %), and mucinous cystadenoma (12.8 %). Fifty-eight (11.5 %) AEs were observed. At multivariate analysis, age (odds ratio [OR] 1.32, 1.09-2.14; p = 0.05), number of TTNB passes (OR from 2.17, 1.32-4.34 to OR 3.16, 2.03-6.34 with the increase of the number of passes), complete aspiration of the cyst (OR 0.56, 0.31-0.95; p = 0.02), and diagnosis of IPMN (OR 4.16, 2.27-7.69; p < 0.001) were found to be independent predictors of AEs, as confirmed by logistic regression and random forest analyses. RPA identified three risk classes: high-risk (IPMN sampled with multiple microforceps passes, 28 % AEs rate), low-risk (1.4 % AE rate, including patients < 64 years with other-than-IPMN diagnosis sampled with ≤ 2 microforceps passes and with complete aspiration of the cyst) and middle-risk class (6.1 % AEs rate, including the remaining patients). CONCLUSION : TTNB should be selectively used in the evaluation of patients with IPMN. The present model could be applied during patient selection as to optimize the benefit/risk of TTNB.

EUS-guided biopsy versus confocal laser endomicroscopy in patients with pancreatic cystic lesions: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Pancreatic cystic lesions (PCLs) are frequent incidental findings on cross-sectional imaging and represent a diagnostic challenge as different kinds of PCLs harbor a dissimilar risk of malignancy. Two diagnostic tools have recently been developed and introduced: through-the-needle biopsy (TTNB) and needle-based confocal laser endomicroscopy (nCLE). The aim of this meta-analysis was to compare the diagnostic yield and performance, as well as the safety profile of the two methods. METHODS: This meta-analysis was performed in accordance with the PRISMA statement. Medline, Embase, Web of Science, and Cochrane Library databases were searched for studies with five or more patients undergoing either endoscopic ultrasound (EUS)-TTNB or EUS-nCLE for a PCL. Reviews, case reports, editorials, conference abstracts, and studies on exclusively solid pancreatic lesions were excluded. Outcomes of interest were diagnostic yield and performance, safety, and technical success. RESULTS: Twenty studies with 1023 patients were included in the meta-analysis. Pooled diagnostic yield of EUS-nCLE was higher compared to EUS-TTNB (85% vs. 74%, P < 0.0001), while diagnostic performance was high and comparable for both methods (pooled sensitivity: 80% vs. 86% and pooled specificity: 80% vs. 83% for TTNB and nCLE, respectively, P > 0.05). Pooled estimate of total adverse event (AE) rate was 5% in the TTNB group and 3% in the nCLE group, P = 0.302. Technical success rates were high and comparable (94% and 99% for EUS-TTNB and nCLE, respectively; P = 0.07). CONCLUSION: EUS-TTNB and EUS-nCLE have a similar safety profile with a relatively low number of AEs. Technical success, sensitivity, and specificity are comparable; however, EUS-nCLE seems to have a slightly higher diagnostic yield.

[Workup and treatment of patients with obstructive cholestasis].

The causes of cholestasis range from intrinsic hepatocellular disease to extrahepatic mechanical obstruction of the bile tree. Gallstones are the most common cause of obstructive cholestasis, but it is not seldomly associated with malignant disease. A systematic approach to diagnosing cholestatic liver disease, including thorough patient history, clinical examination, lab-panels and proper use of imaging and treatment alternatives, starting from least invasive and most cost-effective, ensures efficient patient outcomes and minimises the risk of complications as summarised in this review.

Diagnostic accuracy of EUS-guided through-the-needle-biopsies and simultaneously obtained fine needle aspiration for cytology from pancreatic cysts: A systematic review and meta-analysis.

OBJECTIVES: To address the diagnostic accuracy of endoscopic ultrasound guided through-the-needle-biopsies (TTNBs) and simultaneously obtained cytology samples from pancreatic cysts compared to the final histopathological diagnosis of the surgical specimen, and to give an overview of ancillary tests performed on TTNBs. METHODS: A literature search was conducted in MEDLINE, Embase and Scopus. Studies were included in the meta-analysis, if they had data for TTNB, cytology and a surgical specimen of pancreatic cysts as reference standard. The assessment of the risk of bias and quality of the included studies was conducted using the modified QUADAS-2 tool. RESULTS: Ten studies with 99 patients were included in the meta-analysis. Data regarding study design and clinicopathological features were extracted systematically. For TTNB, pooled sensitivity was 0.86 (95 % CI 0.62-0.96), specificity 0.95 (95 % CI 0.79-0.99) and area under the curve (AUC) 0.86 for the diagnosis of a mucinous cyst and pooled sensitivity was 0.78 (95 % CI 0.61-0.89), specificity 0.99 (95 % CI 0.90-0.99) and AUC 0.92 for the diagnosis of a high-risk cyst. For a specific diagnosis, pooled sensitivity was 0.69 (95 % CI 0.50-0.83), specificity 0.47 (95 % CI 0.28-0.68) and AUC 0.49. For cytology performed simultaneously, pooled sensitivity was 0.46 (95 % CI 0.35-0.57), specificity 0.90 (95 % CI 0.46-0.99) and AUC 0.64 for the diagnosis of mucinous cysts, and pooled sensitivity was 0.38 (95 % CI 0.23-0.55), specificity 0.99 (95 % CI 0.90-0.99) and AUC 0.84 for the diagnosis of a high-risk cyst. For a specific diagnosis, pooled sensitivity was 0.29 (95 % CI 0.21-0.39), specificity 0.45 (95 % CI 0.25-0.66) and AUC 0.30. Furthermore, immunohistochemical stains can be useful to establish the specific cyst subtype. CONCLUSIONS: TTNBs have a higher sensitivity and specificity than cytology for the diagnosis of mucinous cyst and high- risk cysts of the pancreas.

Clinical impact of endoscopic ultrasound-guided through-the-needle microbiopsy in patients with pancreatic cysts.

BACKGROUND: The limited data on the utility of endoscopic ultrasound (EUS)-guided through-the-needle biopsies (TTNBs) in patients with pancreatic cystic lesions (PCLs) originate mainly from retrospective studies. Our aim was to determine the clinical impact of TTNBs, their added diagnostic value, and the adverse event rate in a prospective setting. METHODS: This was a prospective, single-center, open-label controlled study. Between February 2018 and August 2019, consecutive patients presenting with a PCL of 15 mm or more and referred for EUS were included. Primary outcome was a change in clinical management of PCLs following TTNB compared with cross-sectional imaging and cytology. Adverse events were defined according to the ASGE lexicon. RESULTS: 101 patients were included. TTNBs led to a change in clinical management in 11.9 % of cases (n = 12). Of these, 10 had serous cysts and surveillance was discontinued, while one of the remaining two cases underwent surgery following diagnosis of a mucinous cystic neoplasm. The diagnostic yield of TTNBs for a specific cyst diagnosis was higher compared with FNA cytology (69.3 % vs. 20.8 %, respectively; P < 0.001). The adverse event rate was 9.9 % (n = 10; 95 % confidence interval 5.4 % - 17.3 %), with the most common event being acute pancreatitis (n = 9). Four of the observed adverse events were severe, including one fatal outcome. CONCLUSIONS: TTNBs resulted in a change of clinical management in about one in every 10 patients; however, the associated adverse event risk was substantial. Further studies are warranted to elucidate in which subgroups of patients the clinical benefit outweighs the risks.

Diagnostic performance of current guidelines and postoperative outcome following surgical treatment of cystic pancreatic lesions - a 10-year single center experience.

OBJECTIVE: Pancreatic cystic lesions (PCLs) are diagnostically challenging and there are currently several different guidelines. The aim of this study was to compare diagnostic performance of the most widely utilized International Association of Pancreatology (IAP) guidelines and the recent evidence-based European guidelines and to report on postoperative outcomes following surgical treatment of PCLs. METHODS: This is a retrospective single-center study of patients undergoing surgery due to a PCL between 2010 and 2019. Primary outcome was a comparison of diagnostic performance between IAP and European guidelines, measured in area under the receiver operating characteristic curve (AUC). Other outcomes included diagnostic performance of different risk features, 30-day postoperative mortality and major morbidity, final diagnosis, and overall survival. RESULTS: We identified 137 patients, three of whom did not undergo curative surgery due to metastatic disease. Overall, there was no difference in the performance of the two guidelines with AUC values ranging from 0.572-0.610 and 0.607-0.621 for IAP and European guidelines respectively. Postoperative 30-day mortality and major morbidity were 0% (95% CI 0.0-2.7%) and 37.3% (95% CI 29.1-46.1%), respectively. More than half of the resected lesions (52.6%) were low-grade dysplastic or non-neoplastic. CONCLUSIONS: Overall, the IAP and the European guidelines performed equally, although European guidelines had a slightly higher mean specificity. Pancreatic surgery is associated with high major morbidity, and there is a need for new diagnostic tools and strategies in order to decrease the amount of overtreatment in patients with PCL.

EUS-guided through-the-needle microbiopsy of pancreatic cysts: Technical aspects (with video).

Pancreatic cystic lesions are frequently encountered and diagnostically challenging as some of the cysts may have malignant potential (mucinous) while others are completely benign (serous). EUS-guided through-the-needle biopsy (EUS-TTNB) of the cyst wall has recently been introduced as an alternative to cyst fluid cytology. Several studies have shown that microbiopsies outperform cytology in terms of distinction between mucinous and nonmucinous lesions, but also in determining the specific cyst diagnosis. However, little is known about the technical aspects of tissue sampling with TTNB. Herein, we summarize our experience with the procedure in a tertiary referral center and discuss indications, technical aspects, and safety of the procedure. Most adverse events (AEs) associated with the procedure are mild, but there is emerging evidence that the rate of postprocedural pancreatitis is higher compared to standard fine-needle aspiration. The added diagnostic yield should therefore be placed in perspective with an increased risk of AEs. Prospective studies are warranted to fully identify which patient groups could benefit from EUS-TTNB.