Clinical Application of Liquid Biopsy in Pancreatic Cancer: A Narrative Review.

Pancreatic ductal adenocarcinoma contributes significantly to global cancer-related deaths, featuring only a 10% survival rate over five years. The quest for novel tumor markers is critical to facilitate early diagnosis and tailor treatment strategies for this disease, which is key to improving patient outcomes. In pancreatic ductal adenocarcinoma, these markers have been demonstrated to play a crucial role in early identification, continuous monitoring, and prediction of its prognosis and have led to better patient outcomes. Nowadays, biopsy specimens serve to ascertain diagnosis and determine tumor type. However, liquid biopsies present distinct advantages over conventional biopsy techniques. They offer a noninvasive, easily administered procedure, delivering insights into the tumor's status and facilitating real-time monitoring. Liquid biopsies encompass a variety of elements, such as circulating tumor cells, circulating tumor DNA, extracellular vesicles, microRNAs, circulating RNA, tumor platelets, and tumor endothelial cells. This review aims to provide an overview of the clinical applications of liquid biopsy as a technique in the management of pancreatic cancer.

Early Management of Severe Biliary Infection in the Era of the Tokyo Guidelines.

Sepsis of biliary origin is increasing worldwide and has become one of the leading causes of emergency department admissions. The presence of multi-resistant bacteria (MRB) is increasing, and mortality rates may reach 20%. This review focuses on the changes induced by the Tokyo guidelines and new concepts related to the early treatment of severe biliary disease. If cholecystitis or cholangitis is suspected, ultrasound is the imaging test of choice. Appropriate empirical antibiotic treatment should be initiated promptly, and selection should be performed while bearing in mind the severity and risk factors for MRB. In acute cholecystitis, laparoscopic cholecystectomy is the main therapeutic intervention. In patients not suitable for surgery, percutaneous cholecystostomy is a valid alternative for controlling the infection. Treatment of severe acute cholangitis is based on endoscopic or transhepatic bile duct drainage and antibiotic therapy. Endoscopic ultrasound and other new endoscopic techniques have been added to the arsenal as novel alternatives in high-risk patients. However, biliary infections remain serious conditions that can lead to sepsis and death. The introduction of internationally accepted guidelines, based on clinical presentation, laboratory tests, and imaging, provides a framework for their rapid diagnosis and treatment. Prompt assessment of patient severity, timely initiation of antimicrobials, and early control of the source of infection are essential to reduce morbidity and mortality rates.

Development of a clinical score to estimate pancreatitis-related hospital admissions in patients with a new diagnosis of chronic pancreatitis: the trinity score.

BACKGROUND: The clinical course of chronic pancreatitis is unpredictable and there is no globally accepted score to predict the disease course. We developed a clinical score to estimate pancreatitis-related hospitalisation in patients with newly diagnosed chronic pancreatitis. METHODS: We conducted a retrospective cohort study using two clinical chronic pancreatitis databases held in tertiary referral centres in Dublin, Ireland, and in Tarragona, Spain. Individuals diagnosed with chronic pancreatitis between 2007 and 2014 were eligible for inclusion. Candidate predictors included aetiology, body mass index, exocrine dysfunction, smoking and alcohol history. We used multivariable logistic regression to develop the model. RESULTS: We analysed data from 154 patients with newly diagnosed chronic pancreatitis. Of these, 105 patients (68%) had at least one hospital admission for pancreatitis-related reasons in the 6 years following diagnosis. Aetiology of chronic pancreatitis, body mass index, use of pain medications and gender were found to be predictive of more pancreatic-related hospital admissions. These predictors were used to develop a clinical score which showed acceptable discrimination (area under the ROC curve = 0.70). DISCUSSION: We developed a clinical score based on easily accessible clinical parameters to predict pancreatitis-related hospitalisation in patients with newly diagnosed chronic pancreatitis.

Comparison between Comprehensive Complication Index (CCI®) and Clavien-Dindo Classification for laparoscopic single-stage treatment of choledocholithiasis with concomitant cholelithiasis.

PURPOSE: The Clavien-Dindo Classification (CDC) and the Comprehensive Complication Index (CCI®) are both widely used methods for reporting postoperative complications. Several studies have compared the CCI® with the CDC in evaluating postoperative complications of major abdominal surgery. However, there are no published reports comparing both indexes in single-stage laparoscopic common bile duct exploration with cholecystectomy (LCBDE) for the treatment of common bile duct stones. This study aimed to compare the accuracy of the CCI® and the CDC in evaluating the complications of LCBDE. METHODS: In total, 249 patients were included. Spearman's rank test was used to calculate the correlation coefficient between CCI® and CDC with length of postoperative stay (LOS), reoperation, readmission, and mortality rates. Student t-test and Fisher's exact test were used to study, if higher ASA, age, larger surgical time, history of previous abdominal surgery, preoperative ERCP, and intraoperative cholangitis finding were associated with higher CDC grade or higher CCI® score. RESULTS: Mean CCI® was 5.17 ± 12.8. CCI® ranges overlap among three CDC grades: II (20.90-36.20), IIIa (26.20-34.60), and IIIb (33.70-52.10). Age > 60 years, ASA ≥ III, and intraoperative cholangitis finding were associated with higher CCI® (p = 0.010, p = 0.044, and p = 0.031) but not with CDC ≥ IIIa (p = 0.158, p = 0.209, and p = 0.062). In patients with complications, LOS presented a significantly higher correlation with CCI® than with CDC (p = 0.044). CONCLUSION: In LCBDE, the CCI® assesses better the magnitude of postoperative complications in patients older than 60 years, with a high ASA as well as in those who present intraoperative cholangitis. In addition, the CCI® correlates better with LOS in patients with complications.

Impact of neoadjuvant chemotherapy on post-hepatectomy regeneration for patients with colorectal cancer liver metastasis - Systematic review and meta-analysis.

BACKGROUND: Today, there is still debate on the impact of neoadjuvant chemotherapy (NeoChem) on liver regeneration (LivReg). The objectives of this study were to assess the impact of NeoChem and its characteristics (addition of bevacizumab, number of cycles and time from end of NeoChem) on post-hepatectomy LivReg. MATERIAL & METHODS: Studies reporting LivReg in patients submitted to liver resection were included. Pubmed, Scopus, Web of Science, Embase, and Cochrane databases were searched. Only studies comparing NeoChem vs no chemotherapy or comparing chemotherapy characteristics from 1990 to present were included. Two researchers individually screened the identified records registered in a predesigned database. Primary outcome was future liver remnant regeneration rate (FLR3). Bias of the studies was evaluated with the ROBINS-I tool, and quality of evidence with the GRADE system. Data was presented as mean difference or standard mean difference. RESULTS: Eight studies with a total of 681 patients were selected. Seven were retrospective and one prospective comparative cohort studies. In patients submitted to major hepatectomy, NeoChem did not have an impact on LivReg (MD 3.12, 95% CI -2,12-8.36, p 0,24). Adding bevacizumab to standard NeoChem was associated with better FLR3 (SMD 0.45, 95% CI 0.19-0.71, p 0.0006). DISCUSSION: The main drawback of this review is the retrospective nature of the available studies. NeoChem does not have a negative impact on postoperative LivReg in patients submitted to liver resection. Regimens with bevacizumab seem to be associated with better postoperative LivReg rates when compared to standard NeoChem.

The Impact of Molecular Biology in the Seeding, Treatment Choices and Follow-Up of Colorectal Cancer Liver Metastases-A Narrative Review.

There is a clear association between the molecular profile of colorectal cancer liver metastases (CRCLM) and the degree to which aggressive progression of the disease impacts patient survival. However, much of our knowledge of the molecular behaviour of colorectal cancer cells comes from experimental studies with, as yet, limited application in clinical practice. In this article, we review the current advances in the understanding of the molecular behaviour of CRCLM and present possible future therapeutic applications. This review focuses on three important steps in CRCLM development, progression and treatment: (1) the dissemination of malignant cells from primary tumours and the seeding to metastatic sites; (2) the response to modern regimens of chemotherapy; and (3) the possibility of predicting early progression and recurrence patterns by molecular analysis in liquid biopsy.

Simultaneous Treatment of Complex Incisional Hernia and Stoma Reversal.

Purpose: The simultaneous repair of incisional hernias (IH) and the reconstruction of the intestinal transit may pose a challenge for many surgeons. Collaboration between units specialized in abdominal wall and colorectal surgery can favor simultaneous treatment. Methods: Descriptive study of patients undergoing simultaneous surgery of complex IH repair and intestinal transit reconstruction from the start of treatment in a joint team. All interventions were performed electively and with the collaboration of surgeons experts in abdominal wall and colorectal surgery. Results: 23 patients are included. 11 end colostomies, 1 loop colostomy, 6 end ileostomies and 5 loop ileostomies. Seven (30%) patients presented with a medial laparotomy incisional hernia, 3 (13%) with a parastomal incisional hernia, and 13 (56%) with a medial and parastomal incisional hernia. Closure of the hernial defect was achieved in 100% of cases, and reconstruction of the intestinal tract was achieved in 22 (95%). Component separation was required in 17 patients (74%), which were 11 (48%) posterior and 6 (26%) anterior. In-hospital morbidity was 9%, and only two patients presented Clavien-Dindo morbidity > III when requiring reoperation, one due to hemorrhage of the surgical bed and another due to dehiscence of the coloproctostomy. The mean follow-up was 11 months, with 20 (87%) patients having no complications. Mesh had to be removed in one patient with anastomotic dehiscence, no mesh had to be removed due to surgical site infection.

Circulating pyruvate is a potent prognostic marker for critical COVID-19 outcomes.

Background: Coronavirus-19 (COVID-19) disease is driven by an unchecked immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus which alters host mitochondrial-associated mechanisms. Compromised mitochondrial health results in abnormal reprogramming of glucose metabolism, which can disrupt extracellular signalling. We hypothesized that examining mitochondrial energy-related signalling metabolites implicated in host immune response to SARS-CoV-2 infection would provide potential biomarkers for predicting the risk of severe COVID-19 illness. Methods: We used a semi-targeted serum metabolomics approach in 273 patients with different severity grades of COVID-19 recruited at the acute phase of the infection to determine the relative abundance of tricarboxylic acid (Krebs) cycle-related metabolites with known extracellular signaling properties (pyruvate, lactate, succinate and α-ketoglutarate). Abundance levels of energy-related metabolites were evaluated in a validation cohort (n=398) using quantitative fluorimetric assays. Results: Increased levels of four energy-related metabolites (pyruvate, lactate, a-ketoglutarate and succinate) were found in critically ill COVID-19 patients using semi-targeted and targeted approaches (p<0.05). The combined strategy proposed herein enabled us to establish that circulating pyruvate levels (p<0.001) together with body mass index (p=0.025), C-reactive protein (p=0.039), D-Dimer (p<0.001) and creatinine (p=0.043) levels, are independent predictors of critical COVID-19. Furthermore, classification and regression tree (CART) analysis provided a cut-off value of pyruvate in serum (24.54 µM; p<0.001) as an early criterion to accurately classify patients with critical outcomes. Conclusion: Our findings support the link between COVID-19 pathogenesis and immunometabolic dysregulation, and show that fluorometric quantification of circulating pyruvate is a cost-effective clinical decision support tool to improve patient stratification and prognosis prediction.

Lipoprotein Profile in Immunological Non-Responders PLHIV after Antiretroviral Therapy Initiation.

Nuclear magnetic resonance (NMR)-based advanced lipoprotein tests have demonstrated that LDL and HDL particle numbers (LDL-P and HDL-P) are more powerful cardiovascular (CV) risk biomarkers than conventional cholesterol markers. Of interest, in people living with HIV (PLHIV), predictors of preclinical atherosclerosis and vascular dysfunction may be associated with impaired immune function. We previously stated that immunological non-responders (INR) were at higher CV risk than immunological responders (IR) before starting antiretroviral therapy (ART). Using Liposcale® tests, we characterized the lipoprotein profile from the same cohort of PLHIV at month 12 and month 36 after starting ART, intending to explore what happened with these indicators of CV risk during viral suppression. ART initiation dissipates the differences in lipoprotein-based CV risk markers between INR and IR, and only an increase in the number of HDL-P was found in INR + IR when compared to controls (p = 0.047). Interestingly, CD4+ T-cell counts negatively correlated with medium HDL-P concentrations at month 12 in all individuals (ρ = -0.335, p = 0.003). Longitudinal analyses showed an important increase in LDL-P and HDL-P at month 36 when compared to baseline values in both IR and INR. A proper balance between a proatherogenic and atherogenic environment may be related to the reconstitution of CD4+ T-cell count in PLHIV.

Glycogen accumulation in adipocyte precursors from elderly and obese subjects triggers inflammation via SIRT1/6 signaling.

Dysfunctional adipocyte precursors have emerged as key determinants for obesity- and aging-related inflammation, but the mechanistic basis remains poorly understood. Here, we explored the dysfunctional adipose tissue of elderly and obese individuals focusing on the metabolic and inflammatory state of human adipose-derived mesenchymal stromal cells (hASCs), and on sirtuins, which link metabolism and inflammation. Both obesity and aging impaired the differentiation potential of hASCs but had a different impact on their proliferative capacity. hASCs from elderly individuals (≥65 years) showed an upregulation of glycolysis-related genes, which was accompanied by increased lactate secretion and glycogen storage, a phenotype that was exaggerated by obesity. Multiplex protein profiling revealed that the metabolic switch to glycogenesis was associated with a pro-inflammatory secretome concomitant with a decrease in the protein expression of SIRT1 and SIRT6. siRNA-mediated knockdown of SIRT1 and SIRT6 in hASCs from lean adults increased the expression of pro-inflammatory and glycolysis-related markers, and enforced glycogen deposition by overexpression of protein targeting to glycogen (PTG) led to a downregulation of SIRT1/6 protein levels, mimicking the inflammatory state of hASCs from elderly subjects. Overall, our data point to a glycogen-SIRT1/6 signaling axis as a driver of age-related inflammation in adipocyte precursors.

Near infrared indocyanine green fluorescent cholangiography versus intraoperative cholangiography to improve safety in laparoscopic cholecystectomy for gallstone disease-a systematic review protocol.

BACKGROUND: Laparoscopic cholecystectomy has become the standard surgical approach in the treatment of cholelithiasis. Diverse surgical techniques and different imaging modalities have been described to evaluate the biliary anatomy and prevent or early detect bile duct injuries. X-ray intraoperative cholangiography (IOC) and near infrared indocyanine green fluorescent cholangiography (NIR-ICG) are safe and feasible techniques to assess biliary anatomy. The aim of this systematic review will be to evaluate if NIR-ICG can visualize extrahepatic biliary anatomy more efficiently and safer than IOC in minimally invasive cholecystectomy for gallstone disease. METHODS: Literature search will be performed via MEDLINE (PubMed), Embase, Scopus, the Cochrane Central Register of Controlled Trials, and Web of Science Core Collection from 2009 to present. All randomized controlled clinical trials and prospective non-randomized controlled trials which report on comparison of NIR-ICG versus IOC will be included. All patients over 18 years old who require elective or urgent minimally invasive cholecystectomy (undergoing NIR-ICG during this procedure) due to gallstone disease both acute and chronic will be included. Since BDI has a low incidence, the primary outcome will be the ability to visualize extrahepatic biliary anatomy and the time to obtain relevant images of these structures. Two researchers will individually screen the identified records, according to a list of inclusion and exclusion criteria. Bias of the studies will be evaluated with the Newcastle-Ottawa score for non-randomized studies and with The Cochrane Risk of Bias Tool for randomized controlled trials. Quality of evidence for all outcomes will be determined with the GRADE system. The data will be registered in a predesigned database. If selected studies are sufficiently homogeneous, we will perform a meta-analysis of reported results. In the event of a substantial heterogeneity, a narrative synthesis will be provided. Subgroup analysis will be used to investigate possible sources of heterogeneity. DISCUSSION: Understanding the benefits of this technique is critical to ensuring policymakers can make informed decisions as to where preventive efforts should be focused regarding specific imaging techniques. If ICG is proven to be faster and non-invasive, its routine use could be encouraged. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020177991 .

Multi-institutional expert update on the use of laparoscopic bile duct exploration in the management of choledocholithiasis: Lesson learned from 3950 procedures.

BACKGROUND: Recently there has been a growing interest in the laparoscopic management of common bile duct stones with gallbladder in situ (LBDE), which is favoring the expansion of this technique. Our study identified the standardization factors of LBDE and its implementation in the single-stage management of choledocholithiasis. METHODS: A retrospective multi-institutional study among 17 centers with proven experience in LBDE was performed. A cross-sectional survey consisting of a semi-structured pretested questionnaire was distributed covering the main aspects on the use of LBDE in the management of choledocholithiasis. RESULTS: A total of 3950 LBDEs were analyzed. The most frequent indication was jaundice (58.8%). LBDEs were performed after failed ERCP in 15.2%. The most common approach used was the transcystic (63.11%). The overall series failure rate of LBDE was 4% and the median rate for each center was 6% (IQR, 4.5-12.5). Median operative time ranged between 60-120 min (70.6%). Overall morbidity rate was 14.6%, with a postoperative bile leak and complications ≥3a rate of 4.5% and 2.5%, respectively. The operative time decreased with experience (P = .03) and length of hospital stay was longer in the presence of a biliary leak (P = .04). Current training of LBDE was defined as poor or very poor by 82.4%. CONCLUSION: Based on this multicenter survey, LBDE is a safe and effective approach when performed by experienced teams. The generalization of LBDE will be based on developing training programs.

Ischemic Conditioning in the Right Colon and Terminal Ileum: An Experimental Rat Model.

INTRODUCTION: Preoperative gastric ischemic conditioning (IC) improves the outcome of esophageal replacement gastroplasty and is associated with low morbidity. However, when the stomach cannot be used for esophageal replacement, a colonic replacement is required. The study aim was to assess the viability of right colon and terminal ileum IC in a rat model and the histological damage/recovery sequence and determine if neovascularization is a potential adaptive mechanism. METHODS: The study was conducted in Rattus norvegicus with ileocolic vascular ligation. Seven groups of animals were established (6 rats per group) with groups defined by the date of their post-IC euthanasia (+1, +3, +6, +10, +15, and +21 days). Comparisons were made with a sham group. Viability of the model was defined as <10% of transmural necrosis. The evaluation of histological damage used the Chiu score in hematoxylin and eosin sections of paraffin-embedded specimens with CD31 immunohistochemical assessment of neovascularization by the median of submucosal vessel counts in 5 high-magnification fields. RESULTS: Transmural colon necrosis occurred in 1/36 animals (2.78%) with no animal demonstrating transmural ileal necrosis. The maximum damage was observed in the colon on +1 day post-IC (average Chiu score 1.67, p = 0.015), whereas in the ileum, it was on days +1, +3, and +6 (average Chiu score 1.5, 1.3, and 1.17; p = 0.015, 0.002, and 0.015, respectively). In the +21-day group, histological recovery was complete in the colon in 4 (66.7%) of the 6 animals and in the ileum in 5 (83.3%) of 6 animals. There were no significant differences in quantitative neovascularization in any of the groups when compared with the sham group or when comparisons were made between groups. CONCLUSIONS: The tested animal model for IC of the colon and terminal ileum appeared to be feasible. Histological damage was maximal between the 1st and 3rd day following IC, but by day 21, recovery was complete in two-thirds of the rats. There was no evidence in this preliminary IC model that would suggest neovascularization as an adaptive mechanism.

Prevention of Incisional Hernia after Open Hepato-Pancreato-Biliary Surgery: A Systematic Review.

INTRODUCTION: Most hepato-pancreato-biliary (HPB) procedures are still performed through open approach. Incisional hernia (IH) is one of the most common complications after open surgery. To date, published data on IH after HPB surgery are scarce; therefore, the aim of this study was to assess the current evidence regarding incidence, risk factors, and prevention. METHODS: Medline/PubMed (1946-2020), EMBASE (1947-2020), and the Cochrane library (1995-2020) were searched for studies on IH in open HPB surgery. Animal studies, editorials, letters, reviews, comments, short case series and liver transplant, laparoscopic, or robotic procedures were excluded. The protocol was registered with PROSPERO (CRD42020163296). RESULTS: A total of 5,079 articles were retrieved. Eight studies were finally included for the analysis. The incidence of IH after HPB surgery ranges from 7.7% to 38.8%. The identified risk factors were body mass index, surgical site infection, ascites, Mercedes or reversed T incisions, and previous IH. Prophylactic mesh might be safe and effective. CONCLUSIONS: IH after open HPB surgery is still an important matter. Some of the risk factors are specific for the HPB operations and the incision type should be carefully considered. Randomized controlled trials are required to confirm the role of prophylactic mesh after HPB operations.

Effects of stem cells from inducible brown adipose tissue on diet-induced obesity in mice.

Adipose-derived mesenchymal stem cells (ASCs) are a promising option for the treatment of obesity and its metabolic co-morbidities. Despite the recent identification of brown adipose tissue (BAT) as a potential target in the management of obesity, the use of ASCs isolated from BAT as a therapy for patients with obesity has not yet been explored. Metabolic activation of BAT has been shown to have not only thermogenic effects, but it also triggers the secretion of factors that confer protection against obesity. Herein, we isolated and characterized ASCs from the visceral adipose tissue surrounding a pheochromocytoma (IB-hASCs), a model of inducible BAT in humans. We then compared the anti-obesity properties of IB-hASCs and human ASCs isolated from visceral white adipose tissue (W-hASCs) in a murine model of diet-induced obesity. We found that both ASC therapies mitigated the metabolic abnormalities of obesity to a similar extent, including reducing weight gain and improving glucose tolerance. However, infusion of IB-hASCs was superior to W-hASCs in suppressing lipogenic and inflammatory markers, as well as preserving insulin secretion. Our findings provide evidence for the metabolic benefits of visceral ASC infusion and support further studies on IB-hASCs as a therapeutic option for obesity-related comorbidities.

Single-incision versus four-port laparoscopic cholecystectomy in an ambulatory surgery setting: A prospective randomised double-blind controlled trial.

BACKGROUND: Single-incision laparoscopic cholecystectomy (SILC) can be done as a day-case procedure and may have advantages over conventional laparoscopic cholecystectomy (LC). We present the results of our study looking at post-operative pain and post-operative recovery time. METHODS: This was a single-institution randomised double-blind controlled trial. Seventy-three patients with symptomatic cholelithiasis were randomized to SILC (n = 37) or LC (n = 36). The primary endpoint was to compare post-operative pain. We also compared surgical time, procedural difficulty, adverse events, additional ports used and conversion rate, success of day surgery process, return to work, aesthetic satisfaction, quality of life and 4-year incisional hernia rate. RESULTS: In the SILC group, post-operative analgesic requirements were lower on day 7, there was an earlier return to work and cosmetic satisfaction was significantly higher. The SILC procedure presented a higher technical difficulty. Operative time, surgical complications, post-operative pain, success of the day-case process, return to normal activity, quality of life scores and incisional hernia rates were similar for both the procedures. CONCLUSIONS: SILC has advantages over LC in terms of late post-operative analgesic requirements and aesthetic results; however, it is technically harder to perform. There was no benefit in terms of day surgery outcomes.

Contemporary management of concomitant gallstones and common bile duct stones: a survey of Spanish surgeons.

BACKGROUND: Concomitant gallstones and common bile duct stones (CBDS) is a relatively frequent presentation. The optimal treatment remains controversial and the debate persists between two strategies. The one-stage approach: laparoscopic cholecystectomy with laparoscopic common bile duct exploration (LCBDE) has been shown to be equally safe and more cost-effective than the more traditional two-stage approach: endoscopic retrograde cholangiography followed by laparoscopic cholecystectomy (ERCP + LC). However, many surgeons worldwide still prefer the two-stage procedure. This survey evaluated contemporary management of CBDS in Spain and assessed the impact of surgeon and hospital factors on provision of LCBDE. METHODS: A 25-item, web-based anonymous survey was sent to general surgeons members of the Spanish Surgeons Association. Descriptive statistics were applied to summarize results. RESULTS: Responses from 305 surgeons across 173 Spanish hospitals were analyzed. ERCP is the initial approach for preoperatively suspected CBDS for 86% of surgeons. LCBDE is the preferred method for only 11% of surgeons and only 11% treat more than 10 cases per year. For CBDS discovered intraoperatively, 59% of respondents attempt extraction while 32% defer to a postoperative ERCP. The main reasons cited for not performing LCBDE were lack of equipment, training and timely availability of an ERCP proceduralist. Despite these barriers, most surgeons (84%) responded that LCBDE should be implemented in their departments. CONCLUSIONS: ERCP was the preferred approach for CBDS for the majority of respondents. There remains limited use of LCBDE despite many surgeons indicating it should be implemented. Focused planning and resourcing of both training and operational demands are required to facilitate adoption of LCBDE as option for patients.