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.

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.

Preliminary experience with a new robotic technique to facilitate distal pancreatectomy with spleen preservation: left lateral approach in right lateral decubitus position.

Spleen-preserving distal pancreatectomy (SP-DP), for patients with benign or small low-grade malignant tumors of the body or tail of the pancreas, is the ideal procedure although it is technically demanding. The robotic da Vinci system has been introduced to overcome these technical challenges and reduce operative risks. We report our experience of a new variation in surgical technique: the left lateral approach robotic spleen-preserving distal pancreatectomy (RSP-DP) in right lateral decubitus position. We performed this new variant of SP-DP, in five patients, using the da Vinci Xi system. Technical and clinical feasibility are described. The mean age and body mass index were 53.4 years and 31.4 kg/m2, respectively. The mean total operative time was 323 min. The estimated mean blood loss was 240 ml. In all patients, the spleen could be preserved. In four patients, the splenic vessels were also preserved. One patient required a Warshaw technique due to significant fibrosis attached to the splenic vein. The postoperative period of all patients was uneventful except the presence of biochemical leak (BL) in two patients that only required maintenance of the drainage at home. The mean length of hospital stay was 6 days after surgery. The left lateral approach robotic SP-DP in right lateral decubitus position is a feasible and safe procedure for distal benign or small low-grade malignant tumors of the left pancreas. The right lateral decubitus position associated to robotic surgery can facilitate this complex procedure, especially when splenic vessels preservation is indicated, with a lower risk of conversion and shortening of the learning curve.

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.

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 .

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.

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.

Immediate Oral Refeeding in Patients With Mild and Moderate Acute Pancreatitis: A Multicenter, Randomized Controlled Trial (PADI trial).

OBJECTIVE: To establish the optimal time to start oral refeeding in mild and moderate acute pancreatitis (AP) to reduce hospital length-of-stay (LOS) and complications. SUMMARY BACKGROUND DATA: Oral diet is essential in mild and moderate AP. The greatest benefits are obtained if refeeding starts early; however, the definition of "early" remains controversial. METHODS: This multicenter, randomized, controlled trial (NCT03829085) included patients with a diagnosis of mild or moderate AP admitted consecutively to 4 hospitals from 2017 to 2019. Patients were randomized into 2 treatment groups: immediate oral refeeding (IORF) and conventional oral refeeding (CORF). The IORF group (low-fat-solid diet initiated immediately after hospital admission) was compared to CORF group (progressive oral diet was restarted when clinical and laboratory parameters had improved) in terms of LOS (primary endpoint), pain relapse, diet intolerance, complications, and, hospital costs. RESULTS: One hundred and thirty one patients were included for randomization. The mean LOS for the IORF and CORF groups was 3.4 (SD ± 1.7) and 8.8 (SD ± 7.9) days, respectively (P < 0.001). In the CORF group alone, pain relapse rate was 16%. There were fewer complications (8% vs 26%) and health costs were twice as low, with a savings of 1325.7€/patient in the IORF than CORF group. CONCLUSIONS: IORF is safe and feasible in mild and moderate AP, resulting in significantly shorter LOS and cost savings, without causing adverse effects or complications.

The effect of preoperative chemotherapy on liver regeneration after portal vein embolization/ligation or liver resection in patients with colorectal liver metastasis: a systematic review protocol.

INTRODUCTION: Liver resection (LR) in patients with liver metastasis from colorectal cancer remains the only curative treatment. Perioperative chemotherapy improves prognosis of these patients. However, there are concerns regarding the effect of preoperative chemotherapy on liver regeneration, which is a key event in avoiding liver failure after LR. The primary objective of this systematic review is to assess the effect of neoadjuvant chemotherapy on liver regeneration after (LR) or portal vein embolization (PVE) in patients with liver metastasis from colorectal cancer. The secondary objectives are to evaluate the impact of the type of chemotherapy, number of cycles, and time between end of treatment and procedure (LR or PVE) and to investigate whether there is an association between degree of hypertrophy and postoperative liver failure. METHODS: This meta-analysis will include studies reporting liver regeneration rates in patients submitted to LR or PVE. Pubmed, Scopus, Web of Science, Embase, and Cochrane databases will be searched. Only studies comparing neoadjuvant vs no chemotherapy, or comparing chemotherapy characteristics (bevacizumab administration, number of cycles, and time from finishing chemotherapy until intervention), will be included. We will select studies from 1990 to present. Two researchers will individually screen the identified records, according to a list of inclusion and exclusion criteria. Primary outcome will be future liver remnant regeneration rate. Bias of the studies will be evaluated with the ROBINS-I tool, and 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 qualitative systematic review will be performed. DISCUSSION: The results of this systematic review may help to better identify the patients affected by liver metastasis that could present low regeneration rates after neoadjuvant chemotherapy. These patients are at risk to develop liver failure after extended hepatectomies and therefore are not good candidates for such aggressive procedures. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42020178481 (July 5, 2020).

Clinical Classification and Severity Scoring Systems in Chronic Pancreatitis: A Systematic Review.

INTRODUCTION: Chronic pancreatitis (CP) is characterised by pain, functional deficits, nutritional and mechanical complications. Frequently managed in out-patient settings, the clinical course is unpredictable and requires multi-disciplinary care. There remains substantial variation in management. In contrast to acute pancreatitis, there are no globally accepted classification or severity scores to predict the disease course or compare interventions. We conducted a systematic review to determine the scope and clinical use of existing scoring systems. METHODS: A systematic search was developed with a medical librarian using the Embase, Medline and Cochrane databases. Original articles and conference abstracts describing an original or modified classification or scoring system in CP that stratified patients into clinical and/or severity categories were included. To assess clinical application/validation, studies using all or part of a score as a stratification tool to measure another parameter or outcome were selected. Studies reporting on diagnosis or aetiology only were excluded. Four authors performed the search in independent pairs and conflicts were resolved by a fifth author using CovidenceTM systematic review software. RESULTS: Following screening 6,652 titles and 235 full-text reviews, 48 papers were analysed. Eleven described original scores and 6 described modifications of published scores. Many were comprehensive but limited in capturing the full spectrum of disease. In 31 studies, a score was used to categorise patients to compare or correlate various outcome measures. Exocrine and endocrine dysfunction and pain were included in 6, 5, and 4 scoring systems, respectively. No score included other nutrition parameters, such as bone health, malnutrition, or nutrient deficiency. Only one score has been objectively validated prospectively and independently for monitoring clinical progression and prognosis, but this had been applied to an in-patient population. CONCLUSION: Available systems and scores do not reflect recent advances and guidelines in CP and are not commonly used. A practical clinical classification and scoring system, validated prospectively for prognostication would be useful for the meaningful analysis in observational and interventional studies in CP.

Single-stage approach for the management of choledocolithiasis with concomitant cholelithiasis. Implementation of a protocol in a secondary hospital.

BACKGROUND: Current evidence shows that single-stage treatment of concomitant choledocholithiasis and cholelithiasis is as effective and safe as two-stage treatment. However, several studies suggest that single-stage approach requires shorter hospitalization time and is more cost-effective than the two-stage approach, even though it requires considerable training. This study aimed to evaluate the implementation of a protocol for managing concomitant choledocholithiasis and cholelithiasis using single-stage treatment. METHODS: A prospective cohort study of patients diagnosed with cholelithiasis and choledocholithiasis who were treated with the single-stage treatment - transcystic instrumentation, choledocotomy or intraoperative endoscopic retrograde cholangiopancreatography (ERCP) - between September 2010 and June 2017 was assessed. The primary outcomes were complications, hospital stay, operative time and recurrence rate. RESULTS: 164 patients were enrolled. 141 (86%) were operated laparoscopically. Preoperatively diagnosed stones were not found by intraoperative imaging or disappeared after "flushing" in 38 patients (23.2%). Surgical approach was transcystic in 45 patients (27.41%), choledochotomy in 74 (45.1%), intraoperative ERCP in 4 (2.4%), and bilioenteric derivation in 3 (1.8%). Mean hospitalization stay was 4.4 days. Mean operative time was 166 min 27 patients (16.5%) had complications and 1 patient was exitus (0.6%). Recurrence rate was 1.2%. CONCLUSIONS: Single-stage approach is a safe and effective management option for concomitant cholelithiasis and choledocolithiasis. Furthermore, a significant number of common bile duct stones pass spontaneously to duodenum or can benefit from a transcystic approach, with presumable low morbidity and cost-efficiency.

Systematic review and meta-analysis on the effect of obesity on recurrence after laparoscopic anti-reflux surgery.

BACKGROUND & AIMS: Laparoscopic anti-reflux surgery (LARS) aims to provide relief from gastroesophageal reflux disease (GORD). With increase in the prevalence of obesity, there is a concurrent increase in obese patients requiring LARS. In addition to being a more technically difficult procedure, there is conflicting evidence regarding the effectiveness of LARS in obese patients. We performed a systematic review and meta-analysis to compare the outcomes of LARS in obese versus non-obese patients. METHODS: Articles on the effects of obesity on LARS were identified from Ovid Medline, EMBASE and the Cochrane Library databases up to 30th of November 2016. Two independent searches were conducted. Data were extracted independently by two researchers. The primary outcome was recurrence, whilst the secondary outcome was operative time. Pooled data were statistically analysed using forest and funnel plots. RESULTS: Twelve studies (3346 patients) met the inclusion criteria, with 923 patients in the obese group and 2423 patients in the non-obese group. Based on a random effects model, there was a risk ratio of 1.36 (95% CI 1.08-1.72, p = 0.009), if studies reporting recurrence objectively are analysed risk ratio of 1.53 (95% CI 1.01-2.32, p = 0.05) showing 53% increased risk of recurrence for obese patients. Using a random effects model, the difference in operative time was 13.94 min (95% confidence interval (CI) 9.33-18.55, p < 0.0001), showing an increased operative time for obese patients. CONCLUSION: A meta-analysis of 12 studies showed that there was greater recurrence of GORD symptoms and longer operative time relating to LARS in obese patients compared to non-obese patients.

The potential role of gut microbiota in pancreatic disease: A systematic review.

BACKGROUND: Several studies have suggested a link between microbiota imbalance and some gastrointestinal, inflammatory and neoplastic diseases. However, the role in pancreatic diseases remain unclear. To evaluate the available evidence for pancreatic diseases, we undertook a systematic review. METHODS: OVID Medline (1946-2017), EMBASE (1980-2017) and the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3, 2017) were searched for studies on microbiota in pancreatic disease. We also searched the reference lists of retrieved papers, and conference proceedings. We excluded animal studies, reviews, and case reports. RESULTS: A total of 2833 articles were retrieved. After screening and applying the exclusion criteria, 10 studies were included. Three studies showed lower levels of Bifidobacterium or Lactobacillus and higher levels of Enterobacteriaceae in chronic pancreatitis. Two of these studies were uncontrolled, and the third (controlled) study which compared patients with endocrine and exocrine insufficiency, reported that Bacteroidetes levels were lower in those patients without diabetes, while Bifidobacteria levels were higher in those without exocrine insufficiency. Only one study investigated acute pancreatitis, showing higher levels of Enterococcus and lower levels of Bifidobacterium versus healthy participants. There was an overall association between pancreatic cancer and lower levels of Neisseria elongate, Streptococcus mitis and higher levels of Porphyromonas gingivalis and Granulicatella adiacens. CONCLUSIONS: Current evidence suggests a possible link between microbiota imbalance and pancreatic cancer. Regarding acute and chronic pancreatitis, data are scarce, dysbiosis appears to be present in both conditions. However, further investigation is required to confirm these findings and to explore therapeutic possibilities.