Design, development, testing at ISO standards and in vivo feasibility study of a novel polymeric heart valve prosthesis.

Clinically available prosthetic heart valves are life-saving, but imperfect: mechanical valves requiring anticoagulation therapy, whilst bioprosthetic valves have limited durability. Polymer valves offer the prospect of good durability without the need for anticoagulation. We report the design and development of a polymeric heart valve, its bench-testing at ISO standards, and preliminary extra-vivo and in vivo short-term feasibility. Prototypes were manufactured by injection moulding of styrenic block copolymers to achieve anisotropic mechanical properties. Design was by finite element stress-strain modelling, which has been reported previously, combined with feedback from bench and surgery-based testing using various combinations of materials, valve geometry and processing conditions. Bench testing was according to ISO 5840:2015 standards using an in vitro cardiovascular hydrodynamic testing system and an accelerated fatigue tester. Bench comparisons were made with a best-in-class bio-prosthesis. Preliminary clinical feasibility evaluations included extra-vivo and short-term (1-24 hours) in vivo testing in a sheep model. The optimised final prototype met the requirements of ISO standards with hydrodynamic performance equivalent to the best-in-class bioprosthesis. Bench durability of greater than 1.2 billion cycles (30 years equivalent) was achieved (still ongoing). Extra-vivo sequential testing (n = 8) allowed refinement of external diameter, 3D shape, a low profile, flexibility, suturability, and testing of compatibility to magnetic resonance imaging and clinical sterilisation. In vivo short-term (1-24 hours) feasibility (n = 3) confirmed good suturability, no mechanical failure, no trans-valvular regurgitation, competitive trans-valvular gradients, and good biocompatibility at histopathology. We have developed and tested at ISO standards a novel prosthetic heart valve featuring competitive bench-based hydrodynamics and durability, well beyond the ISO requirements and comparable to a best-in-class bioprosthesis. In vivo short-term feasibility testing confirmed preliminary safety, functionality and biocompatibility, supporting progression to a long-term efficacy trial.

Repeat EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis.

BACKGROUND AND AIMS: EUS-guided FNA (EUS-FNA) is the criterion standard for the diagnosis of solid pancreatic lesions. Several studies assessed the role of repeat EUS-FNA (rEUS-FNA) after an inconclusive examination. Our aim was to evaluate the pooled diagnostic accuracy of rEUS-FNA after a nondiagnostic result. METHODS: We conducted systematic research on electronic databases (Medline, PubMed, EMBASE) and a meta-analysis to obtain pooled sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio. A summary receiver operating characteristic curve was used to calculate area under the curve. Subgroup analysis was used to assess the role of rapid on-site evaluation (ROSE). RESULTS: Twelve studies (505 patients) were included. Sensitivity was 77% (66%-86%), specificity 98% (78%-100%), and positive and negative predictive values 99% (98%-100%) and 61 (60%-63%), respectively. At 73% of disease prevalence (pretest probability), positive rEUS-FNA increased the disease probability to 99%, whereas a negative result decreased the disease probability to 39%. The sensitivity was 83% (64%-93%) and specificity 98% (80%-100%) when ROSE was available and 65% (57%-73%) and 94% (31%-100%) when not available. The number needed to diagnose was 1.2 (1.1-2.3) and 1.7 (1.4-8.3) in ROSE-positive and ROSE-negative cases, respectively. The number of correctly diagnosed cases increased from 6 (1-7) to 8 (4-9) of 10 patients without and with ROSE, respectively. CONCLUSIONS: This study objectively substantiated the added value of rEUS-FNA for the diagnosis of solid pancreatic masses in cases of a previous nondiagnostic or inconclusive result. Moreover, our data suggested that ROSE may be beneficial in this setting, because it increased the proportion of definitive diagnoses.

Contrast-enhanced endoscopic ultrasound for the differential diagnosis between benign and malignant lymph nodes: a meta-analysis.

Background The differential diagnosis between benign and malignant lymph nodes (LNs) is crucial for patient management and clinical outcome. The use of contrast-enhanced endoscopic ultrasound (EUS) has been evaluated in several studies with diverse results. The aim of this meta-analysis was to evaluate the pooled diagnostic accuracy of contrast-enhanced EUS (CE-EUS) and contrast-enhanced harmonic EUS (CH-EUS) in this setting. Methods A systematic electronic search was performed, including all original papers dealing with assessment of the nature of the LNs using CE-EUS or CH-EUS. A meta-analysis was performed to obtain pooled sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio. The Summary Receiver Operating Characteristic (ROC) Curve method was used to calculate the area under the curve. Statistical analysis was carried out using Meta-Disc V.1.4, Stata V.12.0 and Review Manager V.5.2. Results Among 210 pertinent studies, four (336 patients) were included in the analysis. The pooled sensitivity was 82.1 % (75.1 - 87.7 %) and pooled specificity was 90.7 % (85.9 - 94.3 %) with significant heterogeneity found in sensitivity; the positive-likelihood ratio (LR) was 7.77 (5.09 - 11.85) and the negative-LR was 0.15 (0.05 - 0.46); the pooled diagnostic odds ratio (DOR) was 54 (15 - 190). Subgroup analysis including studies performed using CH-EUS (two studies, 177 LNs) showed a pooled sensitivity of 87.7 % (77.0 - 93.9 %) and a pooled specificity of 91.8 % (84.5 % - 96.4 %) with no significant heterogeneity; the pooled positive-LR was 9.51 (4.95 - 18.28) and the pooled negative-LR was 0.14 (0.06 - 0.35); pooled DOR was 68.42 (15.5 - 301.4). Conclusions From these data, CE-EUS is not recommended due to inadequate sensitivity. On the other hand, CH-EUS studies showed optimal accuracy (pooled sensitivity 87.7 % and specificity 91.8 %), comparable to elastography and even EUS-guided fine needle aspiration (EUS-FNA), suggesting a role in the diagnostic algorithm.

Evaluation of a new slim radial echoendoscope: A better option for an aging population.

BACKGROUND AND OBJECTIVES: The radial echoendoscope is still widely used for the investigation of abnormalities in the gastrointestinal wall and for stone detection in the extrahepatic biliary tree. Due to aging patient population, EUS is frequently performed in fragile and elderly individuals. We aimed to compare the maneuverability and image quality of a new thin radial echoendoscope to the current one. PATIENTS AND METHODS: This evaluation was conducted at a referral academic EUS center. The new radial echoendoscope has a thinner shaft and distal tube and a shorter bending section compared to the previous one. Patients referred for diagnostic EUS with a radial echoendoscope were enrolled. Indications included pancreaticobiliary disease, esophagogastric abnormalities, and neoplasms and rectal cancer staging. RESULTS: We enrolled 177 patients (122 pancreaticobiliary, 48 esophagogastric, and 7 rectal cases). Overall, the new echoendoscope performed better than the previous model in terms of maneuverability during esophageal intubation and transition from the duodenal bulb to the second portion. On the other hand, pylorus traversing was comparable to the current radial echoendoscope. No loss in image quality was appreciated at predefined stations (esophagus, stomach, and duodenum) compared to the current model. On the other hand, image penetration depth in tissue harmonic mode was significantly improved with the new echoendoscope. CONCLUSIONS: A new thinner radial echoendoscope showed improved maneuverability compared to the existing version. Image quality was also improved thanks to increased penetration depth in the tissue harmonic mode. We speculate that this new echoendoscope may allow for safer and faster EUS examination, which may prove useful in an aging patient population.

EUS liver assessment using contrast agents and elastography.

Transabdominal-US is the first-line imaging modality used to assess the whole liver parenchyma and vascularization; EUS assessment of the liver is incomplete and is not sufficient to rule out the presence of focal liver lesions. On the other hand, due the high diagnostic yield in detecting very small (< 1 cm) lesions, EUS is considered complementary to radiological imaging techniques for the investigation of liver parenchyma. Scarce data are available regarding the investigation of liver parenchyma using both EUS-elastography (EUS-E) and CH-EUS. The aim of this review is to evaluate the clinical role of image enhancement techniques, namely EUS-E and contrast harmonic-EUS (CH-EUS), for the evaluation liver diseases. Despite a potential interest for the application of EUS-E in the assessment of liver diseases, available evidence relegates this technique only to research areas, such as the differential diagnosis between benign and malignant focal liver lesions and the quantification of liver fibrosis in diffuse parenchymal diseases. With the future introduction of EUS shear-wave elastography, interesting data can be obtained for the assessment of liver fibrosis during real-time EUS evaluation. The usefulness of CH-EUS for the evaluation of liver disease is limited by the intrinsic EUS ability to explore only the left lobe and a small part of the right lobe. CH-EUS could be used to increase the diagnostic ability of EUS for the detection and characterization of small lesions and for guiding tissue sampling. Targeting EUS-guided treatments with either EUS-E or CH-EUS might represent potential future applications.

Basics in Endoscopic Ultrasound Part 2: EUS-guided Sampling and Therapeutic Applications.

BACKGROUND: Endoscopic ultrasound (EUS) has been used in the clinical arena for almost 35 years and it is now well-integrated in everyday hospital practice. METHOD: We conducted a systematic review of the available English-language articles. OBJECTIVE: The purpose of this review is to summarize the relevant applications of operative EUS. RESULTS: More than 5000 scientific papers published in the literature have demonstrated its high accuracy for the diagnosis and staging of a variety of benign and malignant conditions. The main indications of operative EUS, both diagnostic and therapeutic, are related to its ability to combine ultrasound imaging and safe and effective needle insertion into lesions originating from the gut wall and from organs nearby. In addition, technologic advancements of echoendoscopes with a therapeutic working-channel have allowed to perform several EUS-guided interventions, i.e. celiac plexus neurolysis, drainage of fluid collections, drainage of dilated biliary and pancreatic ducts, and vascular interventions.

Basics in Endoscopic Ultrasound Part 1: Diagnostic Indications and Tissue Sampling.

BACKGROUND: Endoscopic Ultrasound has been used in the clinical arena for almost 35 years and it is now well-integrated in everyday hospital practice. METHOD: We conducted a systematic review of the available English-language articles. OBJECTIVE: The purpose of this review is to summarize all the relevant indications to endoscopic ultrasound and analyze its relevant data in terms of accuracy and clinical outcomes. RESULTS: More than 5000 scientific papers published in the literature have demonstrated its high accuracy for the diagnosis and staging of a variety of benign and malignant conditions. Staging indications include gastroesophageal and rectal cancers. Diagnostic, staging and therapeutic indications include diseases of the pancreaticobiliary area. Finally, differential diagnosis of submucosal tumors represents another important indication to this technique.

Role of contrast harmonic-endoscopic ultrasound in pancreatic cystic lesions.

Incidental pancreatic cysts (PCs) are frequently encountered in the general population often in asymptomatic patients who undergo imaging tests to investigate unrelated conditions. The detection of a PC poses a significant clinical dilemma, as the differential diagnosis is quite broad ranging from benign to malignant conditions. Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) has been reported to be an accurate tool in the differential diagnosis; however, its sensitivity is suboptimal and false negative results do occur. Contrast harmonic EUS (CH-EUS) was demonstrated to be a useful tool to investigate pancreatic solid lesions to differentiate between benign and malignant ones. In the setting of PCs, CH-EUS could help identify areas of malignant growth inside the cystic cavities. Several studies have reported promising results showing malignant areas in PCs as hyperenhanced lesions. Confirmation of malignancy can then be obtained by FNA, which should be precisely targeted according to the findings of the contrast harmonic study.

Contrast enhancement and elastography in endoscopic ultrasound: an update of clinical applications in pancreatic diseases.

It is well established that endoscopic ultrasound (EUS) is fundamental in the characterization of many diseases concerning different organs, i.e. pancreaticobiliary diseases, gastrointestinal pathologic conditions, and lymph nodes of unknown origin. It is also well known that many factors can hamper the accuracy of EUS, i.e. biliary stents, chronic pancreatitis, poor operator's expertise. These factors can also lead to suboptimal accuracy when cytological confirmation through EUS-fine needle aspiration (EUS-FNA) is indicated. In recent years, new technological tools have rapidly increased their clinical impact improving the diagnostic power of EUS and EUS-FNA. Among these new tools, the most investigated and useful ones are represented by contrast harmonic-EUS (CH-EUS) and EUS-elastography (EUS-E). The purpose of this paper is to provide, through a review of the literature, an update of the applications of CH-EUS and EUS-E in the routine clinical practice in pancreatic diseases. We discussed the first reports and applications of these techniques in our previous review published in Minerva Medica. The applications of CH-EUS and EUS-E to the study of pancreatic diseases appear feasible and safe. The use of both techniques is very simple and does not require any relevant additional workload for the endoscopic personnel. CH-EUS is now considered an important and accurate tool in the diagnosis of solid pancreatic masses and in the differential diagnosis of pancreatic cystic lesions. CH-EUS targeted FNA is an active field of research. However the available studies show that CH-EUS increases FNA accuracy by a little extent, without statistical significance; moreover, CH-EUS FNA showed a trend toward being more efficient vs. simple EUS FNA (less needle passes and more abundance in cytological material) but this trend did not reach statistical significance. On the other hand, the clinical impact of EUS-E in terms of differential diagnosis of pancreatic masses is still under investigation. Chronic pancreatitis evaluation represents the most recent field of application of EUS-E that shows promising results.

Contrast Harmonic-Endoscopic Ultrasound Is Useful to Identify Neoplastic Features of Pancreatic Cysts (With Videos).

OBJECTIVES: To evaluate the potential role of contrast harmonic endoscopic ultrasound (CH-EUS) in the differential diagnosis of pancreatic cysts and detection of malignancy. METHODS: Patients who underwent CH-EUS for evaluation of cyst wall, septae, and solid components of pancreatic cysts were included. The findings were compared to fine needle aspiration and surgery. RESULTS: Seventy-six patients were included. Serous and mucinous cysts were both hyperenhanced (86% and 89%, respectively; P = ns), whereas pseudocysts were hypoenhanced in 90% of the cases (P = 0.000004 vs serous cysts and P = 0.000005 vs mucinous cysts). Patients showing hyperenhanced solid components were finally diagnosed with malignancy (2 malignant intraductal papillary mucinous neoplasms, 2 cystic neuroendocrine tumors), in contrast to the patients with nonenhanced solid components who resulted to have either benign cysts with internal mucus clots (n = 10) or pseudocysts with internal debris (n = 8). CONCLUSIONS: CH-EUS allowed differentiation between pseudocysts and other pancreatic cysts but not mucinous versus serous cysts. Malignant vegetations inside pancreatic cystic lesions were clearly shown by CH-EUS as solid components with features of hyperenhancement, directing EUS-fine needle aspiration of potential neoplastic areas and avoiding puncture of debris and mucus plugs.

Performance of the forward-view echoendoscope for pancreaticobiliary examination in patients with status post-upper gastrointestinal surgery.

BACKGROUND AND OBJECTIVES: Failures of endoscopic ultrasound (EUS) imaging of the head of the pancreas (HOP) and the common bile duct (CBD) have been reported in up to 50% of patients with status postsurgery (e.g., Billroth II and Roux-en-Y). This is attributable to inability to intubate the afferent limb or the duodenum. Recently, a forward-view (FV) echoendoscope has become available. The frontal endoscopic and ultrasound field of view theoretically allow easier manipulation throughout the gastrointestinal tract compared to the traditional echoendoscopes. The aim of our study was to evaluate the safety and performance of the FV echoendoscope for the investigation of the biliary tree and the pancreas, including fine-needle aspiration (FNA), in patients with surgically altered upper gastrointestinal anatomy. PATIENTS AND METHODS: This was a retrospective evaluation of a prospectively maintained database. All EUS procedures were performed at our institution by one experienced endosonographer from March to September 2009 under conscious sedation. The FV echoendoscope was used for all procedures. RESULTS: Twenty-five (25) out of 37 presented status post-Billroth II and 12 out of 37 with status post-Roux-en-Y surgery. Overall, HOP and CBD were adequately visualized in 28 out of 37 (75.7%). All the failures occurred in the Roux-en-Y patients. EUS-FNA was successfully performed in 16 patients. No adverse events were observed. CONCLUSIONS: The FV echoendoscope proved to be safe and effective in reaching the periampullary area in patients with previous Billroth II, allowing complete exploration of the HOP and the CBD and performance of EUS-FNA. However, FV EUS was unsuccessful in the majority of patients with Roux-en-Y, which still remains a challenging condition.

Contrast harmonic endoscopic ultrasonography in the characterization of pancreatic metastases (with video).

OBJECTIVE: The differential diagnosis between primary pancreatic neoplasms versus pancreatic metastases (PM) is challenging. Endoscopic ultrasonography with fine-needle aspiration can be used to differentiate primary versus metastatic tumors although with a suboptimal accuracy. Recently, contrast harmonic EUS (CH-EUS) has been reported as an adjunct in the diagnosis of pancreatic neoplasms. We evaluated the potential role of CH-EUS in the differential diagnosis of PM. METHODS: This study is a retrospective analysis of a prospectively maintained database. Of the 266 patients, 4.1% were diagnosed with PM. Endoscopic ultrasonography with fine-needle aspiration and/or surgical pathology represented our criterion standard. RESULTS: The origins of PM were renal cancer (3 patients), colon cancer(2 patients), breast cancer (2 patients), ovarian cancer (1 patient), melanoma(1 patient), lymphoma (1 patient), and sarcoma (1 patient). All lesions appeared hypoechoic at standard EUS. At CH-EUS, of the 11 lesions, 6 appeared hypoenhancing (colon cancer, sarcoma, and breast and ovarian cancer), 4 were hyperenhancing (renal cancer and lymphoma),and 1 was isoenhancing (melanoma). CONCLUSIONS: In our population, standard EUS features of PM were unremarkable. At CH-EUS, most of the PM appeared hypoenhancing suggesting a possible malignant origin. However, a subset of PM showed hyperenhancing pattern. In the appropriate context, particularly when cancer history is present, CH-EUS may add to the differential diagnosis and potentially spare endoscopic ultrasonography with fine-needle aspiration.