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.

Home care/outpatient versus hospital admission in mild acute pancreatitis: protocol of a multicentre, randomised controlled trial (PADI_2 trial).

INTRODUCTION: Acute pancreatitis (AP) is the third most common gastrointestinal disease resulting in hospital admission, with over 70% of AP admissions being mild cases. In the USA, it costs 2.5 billion dollars annually. The most common standard management of mild AP (MAP) still is hospital admission. Patients with MAP usually achieve complete recovery in less than a week and the severity predictor scales are reliable. The aim of this study will be to compare three different strategies for the management of MAP. METHODS/DESIGN: This is a randomised, controlled, three-arm multicentre trial. Patients with MAP will be randomly assigned to group A (outpatient), B (home care) or C (hospital admission). The primary endpoint of the trial will be the treatment failure rate of the outpatient/home care management for patients with MAP compared with that of hospitalised patients. The secondary endpoints will be pain relapse, diet intolerance, hospital readmission, hospital length of stay, need for intensive care unit admission, organ failure, complications, costs and patient satisfaction. The general feasibility, safety and quality checks required for high-quality evidence will be adhered to. ETHICS AND DISSEMINATION: The study (version 3.0, 10/2022) has been approved by the Scientific and Research Ethics Committee of the 'Institut d'Investigació Sanitaria Pere Virgili-IISPV' (093/2022). This study will provide evidence as to whether outpatient/home care is similar to usual management of AP. The conclusions of this study will be published in an open-access journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05360797).

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.

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.

EASY-APP: An artificial intelligence model and application for early and easy prediction of severity in acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a potentially severe or even fatal inflammation of the pancreas. Early identification of patients at high risk for developing a severe course of the disease is crucial for preventing organ failure and death. Most of the former predictive scores require many parameters or at least 24 h to predict the severity; therefore, the early therapeutic window is often missed. METHODS: The early achievable severity index (EASY) is a multicentre, multinational, prospective and observational study (ISRCTN10525246). The predictions were made using machine learning models. We used the scikit-learn, xgboost and catboost Python packages for modelling. We evaluated our models using fourfold cross-validation, and the receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC), and accuracy metrics were calculated on the union of the test sets of the cross-validation. The most critical factors and their contribution to the prediction were identified using a modern tool of explainable artificial intelligence called SHapley Additive exPlanations (SHAP). RESULTS: The prediction model was based on an international cohort of 1184 patients and a validation cohort of 3543 patients. The best performing model was an XGBoost classifier with an average AUC score of 0.81 ± 0.033 and an accuracy of 89.1%, and the model improved with experience. The six most influential features were the respiratory rate, body temperature, abdominal muscular reflex, gender, age and glucose level. Using the XGBoost machine learning algorithm for prediction, the SHAP values for the explanation and the bootstrapping method to estimate confidence, we developed a free and easy-to-use web application in the Streamlit Python-based framework (http://easy-app.org/). CONCLUSIONS: The EASY prediction score is a practical tool for identifying patients at high risk for severe AP within hours of hospital admission. The web application is available for clinicians and contributes to the improvement of the model.

The characteristics and prognostic role of acute abdominal on-admission pain in acute pancreatitis: A prospective cohort analysis of 1432 cases.

INTRODUCTION: Pain is the most common symptom in acute pancreatitis (AP) and is among the diagnostic criteria. Therefore, we aimed to characterize acute abdominal pain in AP. METHODS: The Hungarian Pancreatic Study Group prospectively collected multicentre clinical data on 1435 adult AP patients between 2012 and 2017. Pain was characterized by its intensity (mild or intense), duration prior to admission (hours), localization (nine regions of the abdomen) and type (sharp, dull or cramping). RESULTS: 97.3% of patients (n = 1394) had pain on admission. Of the initial population with acute abdominal pain, 727 patients answered questions about pain intensity, 1148 about pain type, 1134 about pain localization and 1202 about pain duration. Pain was mostly intense (70%, n = 511/727), characterized by cramping (61%, n = 705/1148), mostly starting less than 24 h prior to admission (56.7%, n = 682/1202). Interestingly, 50.9% of the patients (n = 577/1134) had atypical pain, which means pain other than epigastric or belt-like upper abdominal pain. We observed a higher proportion of peripancreatic fluid collection (19.5% vs. 11.0%; p = 0.009) and oedematous pancreas (8.4% vs. 3.1%; p = 0.016) with intense pain. Sharp pain was associated with AP severity (OR = 2.481 95% CI: 1.550-3.969) and increased mortality (OR = 2.263, 95% CI: 1.199-4.059) compared to other types. Longstanding pain (>72 h) on admission was not associated with outcomes. Pain characteristics showed little association with the patient's baseline characteristics. CONCLUSION: A comprehensive patient interview should include questions about pain characteristics, including pain type. Patients with sharp and intense pain might need special monitoring and tailored pain management. SIGNIFICANCE: Acute abdominal pain is the leading presenting symptom in acute pancreatitis; however, we currently lack specific guidelines for pain assessment and management. In our cohort analysis, intense and sharp pain on admission was associated with higher odds for severe AP and several systemic and local complications. Therefore, a comprehensive patient interview should include questions about pain characteristics and patients with intense and sharp pain might need closer monitoring.

Missing colorectal liver metastases: the surgical challenge.

BACKGROUND: New chemotherapy schemes have allowed for a better radiological response of unresectable colorectal liver metastases, leading to an interesting scenario known as a complete radiological response. The aim of this study was to review the current management of missing liver metastases (MLM) from the liver surgeon's point of view. METHODS: A systematic search was conducted on all publications of PubMed and Embase between 2003 and 2018. Meta-analysis was performed on MLM resected/unresected. Residual tumor or regrowth and relapse-free survival were used as evaluation indices. RESULTS: After literature search, 18 original articles were included for analysis. The predictive factors for MLM are type and duration of chemotherapy and size and number of lesions. Magnetic resonance is the most sensitive preoperative technique. Regarding clinical management, liver surgery is deemed the fundamental pillar in the therapeutic strategy of these patients. Meta-analysis due to data heterogeneity was inconclusive. CONCLUSIONS: Depending on the clinical context, MLM monitoring appears to be a valid therapeutic alternative. Nevertheless, prospective randomized clinical studies are needed.

Evidence for diagnosis of early chronic pancreatitis after three episodes of acute pancreatitis: a cross-sectional multicentre international study with experimental animal model.

Chronic pancreatitis (CP) is an end-stage disease with no specific therapy; therefore, an early diagnosis is of crucial importance. In this study, data from 1315 and 318 patients were analysed from acute pancreatitis (AP) and CP registries, respectively. The population from the AP registry was divided into AP (n = 983), recurrent AP (RAP, n = 270) and CP (n = 62) groups. The prevalence of CP in combination with AP, RAP2, RAP3, RAP4 and RAP5 + was 0%, 1%, 16%, 50% and 47%, respectively, suggesting that three or more episodes of AP is a strong risk factor for CP. Laboratory, imaging and clinical biomarkers highlighted that patients with RAP3 + do not show a significant difference between RAPs and CP. Data from CP registries showed 98% of patients had at least one AP and the average number of episodes was four. We mimicked the human RAPs in a mouse model and found that three or more episodes of AP cause early chronic-like morphological changes in the pancreas. We concluded that three or more attacks of AP with no morphological changes to the pancreas could be considered as early CP (ECP).The new diagnostic criteria for ECP allow the majority of CP patients to be diagnosed earlier. They can be used in hospitals with no additional costs in healthcare.

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.

Amiloidosis de colon y clínica de oclusión intestinal / Amyloidosis of the colon and clinical features of intestinal obstruction

No disponible

Tratamiento quirúrgico de los tumores neuroendocrinos no funcionantes de páncreas basado en 3 escenarios clínicos / Surgical treatment of non-functioning pancreatic neuroendocrine tumours based on three clinical scenarios

INTRODUCCIÓN: El tratamiento de los tumores neuroendocrinos pancreáticos no funcionantes (TNEPNF) es la resección en caso de enfermedad localizada o metástasis hepáticas resecables. Existe controversia en metástasis hepáticas irresecables. MÉTODOS: Analizamos los datos perioperatorios y de supervivencia de 63 pacientes resecados por TNEPNF entre 1993 y 2012, dividiéndolos en 3 escenarios: A, resección pancreática (44 pacientes); B, resección pancreática y hepática por metástasis hepáticas sincrónicas (12 pacientes), y C, resección pancreática en presencia de metástasis hepáticas irresecables (6 pacientes). Se estudiaron factores pronósticos de supervivencia y recidiva. RESULTADOS: Las cirugías más frecuentes fueron, pancreatectomía corporocaudal (51%) y duodenopancreatectomía cefálica (38%). El 44% de los pacientes requirieron una cirugía asociada, resecando sincrónicamente páncreas e hígado en 9. Dos pacientes recibieron un trasplante hepático durante el seguimiento. Según la clasificación de la OMS, se distribuyeron en G1: 10 (16%), G2: 45 (71%) y G3: 8 (13%). La morbimortalidad postoperatoria fue del 49 y del 1,6%, respectivamente. Al cierre del estudio, 43 (68%) seguían vivos, con una supervivencia actuarial media de 9,6 años. La clasificación de la OMS y la recidiva fueron factores de riesgo de mortalidad en el estudio multivariante. La supervivencia actuarial mediana por escenarios fue de 131 meses (A), 102 meses (B) y 75 meses (C), sin diferencias estadísticamente significativas. CONCLUSIONES: El tratamiento del TNEPNF sin enfermedad a distancia es la resección. Las metástasis hepáticas resecables en los tumores bien diferenciados deben resecarse. La resección del tumor pancreático con metástasis hepáticas sincrónicas irresecables debe considerarse en TNEPNF bien diferenciados. El grado de clasificación de la OMS y la recidiva son factores de riesgo de mortalidad a largo plazo

INTRODUCTION: The treatment of patients with non-functioning pancreatic neuroendocrine tumours (NFPNET) is resection in locally pancreatic disease, or with resectable liver metastases. There is controversy about unresectable liver disease. METHODS: We analysed the perioperative data and survival outcome of 63 patients who underwent resection of NFPNET between 1993 and 2012. They were divided into 3 scenarios: A, pancreatic resection (44 patients); B, pancreatic and liver resection in synchronous resectable liver metastases (12 patients); and C, pancreatic resection in synchronous unresectable liver metastases (6 patients). The prognostic factors for survival and recurrence were studied. RESULTS: Distal pancreatectomy (51%) and pancreaticoduodenectomy (38%) were more frequently performed. Associated surgery was required in 44% of patients, including synchronous liver resections in 9 patients. Two patients received a liver transplant during follow-up. According to the WHO classification they were distributed into G1: 10 (16%), G2: 45 (71%), and G3: 8 (13%). The median hospital stay was 11 days. Postoperative morbidity and mortality were 49% and 1.6%, respectively. At the closure of the study, 43 (68%) patients were still alive, with a mean actuarial survival of 9.6 years. The WHO classification and tumour recurrence were risk factors of mortality in the multivariate analysis. The median actuarial survival by scenarios was 131 months (A), 102 months (B), and 75 months (C) without statistically significant differences. CONCLUSIONS: Surgical resection is the treatment for NFPNET without distant disease. Resectable liver metastases in well-differentiated tumours must be resected. The resection of the pancreatic tumour with unresectable synchronous liver metastasis must be considered in well-differentiated NFPNET. The WHO classification grade and recurrence are risk factors of long-term mortality

Surgical treatment of non-functioning pancreatic neuroendocrine tumours based on three clinical scenarios. / Tratamiento quirúrgico de los tumores neuroendocrinos no funcionantes de páncreas basado en 3 escenarios clínicos.

INTRODUCTION: The treatment of patients with non-functioning pancreatic neuroendocrine tumours (NFPNET) is resection in locally pancreatic disease, or with resectable liver metastases. There is controversy about unresectable liver disease. METHODS: We analysed the perioperative data and survival outcome of 63 patients who underwent resection of NFPNET between 1993 and 2012. They were divided into 3 scenarios: A, pancreatic resection (44patients); B, pancreatic and liver resection in synchronous resectable liver metastases (12patients); and C, pancreatic resection in synchronous unresectable liver metastases (6patients). The prognostic factors for survival and recurrence were studied. RESULTS: Distal pancreatectomy (51%) and pancreaticoduodenectomy (38%) were more frequently performed. Associated surgery was required in 44% of patients, including synchronous liver resections in 9patients. Two patients received a liver transplant during follow-up. According to the WHO classification they were distributed into G1: 10 (16%), G2: 45 (71%), and G3: 8 (13%). The median hospital stay was 11days. Postoperative morbidity and mortality were 49% and 1.6%, respectively. At the closure of the study, 43 (68%) patients were still alive, with a mean actuarial survival of 9.6years. The WHO classification and tumour recurrence were risk factors of mortality in the multivariate analysis. The median actuarial survival by scenarios was 131months (A), 102months (B), and 75months (C) without statistically significant differences. CONCLUSIONS: Surgical resection is the treatment for NFPNET without distant disease. Resectable liver metastases in well-differentiated tumours must be resected. The resection of the pancreatic tumour with unresectable synchronous liver metastasis must be considered in well-differentiated NFPNET. The WHO classification grade and recurrence are risk factors of long-term mortality.

Estudio de minimización de costes hospitalarios en el tratamiento de la coledocolitiasis / Minimising hospital costs in the treatment of bile duct calculi: A comparison study

Introducción El tratamiento de la coledocolitiasis asociada a colelitiasis es controvertido. Los costes hospitalarios podrían ser un factor decisivo para elegir entre las distintas opciones terapéuticas. Objetivos Comparar la eficacia y los costes de 2 alternativas en el tratamiento de la coledocolitiasis: 1) Un-tiempo: colecistectomía y exploración de la vía biliar por laparoscopia y 2) Dos-tiempos: colangiopancreatografía retrógrada endoscópica y colecistectomía laparoscópica secuencial. Material y métodos Estudio observacional, retrospectivo de 49 pacientes con coledocolitiasis y vesícula in situ, tratados de forma consecutiva y simultánea durante 2 años, mediante una de las 2 estrategias. Se compararon las complicaciones postoperatorias, estancia, número de procedimientos por paciente, conversión a laparotomía, eficacia en la extracción de cálculos y costes hospitalarios. Resultados No hubo diferencias en cuanto a características clínicas y morbilidad de los pacientes. La estancia postoperatoria media para el grupo Un-tiempo fue menor que para el grupo Dos-tiempos. Tres pacientes del grupo Dos-tiempos requirieron conversión a laparotomía. La mediana de costes por paciente fue menor para la estrategia en Un-tiempo, representando un ahorro global de 37.173€ durante el período estudiado. Conclusiones Entre las 2 opciones terapéuticas, no se han encontrado diferencias significativas en cuanto a la eficacia, ni la morbimortalidad postoperatorias, pero sí desde el punto de vista de la estancia y los costes hospitalarios. El manejo de los pacientes con coledocolitiasis en un solo tiempo representó un ahorro de 3 días de estancia y 1.008€ por paciente (AU)

Introduction The treatment of bile duct calculi associated with cholelithiasis is controversial. The hospital costs could be a decisive factor in choosing between the different therapeutic options. Objectives To compare the effectiveness and costs of two options in the treatment of common bile duct calculi: 1) One-stage: Laparoscopic cholecystectomy and bile duct exploration, and 2) Two-stage: sequential endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy. Material and methods A retrospective, observational study was performed on 49 consecutive patients with bile duct calculi and gallbladder in situ, treated consecutively and simultaneously over a two year period. The post-operate complication, hospital stay, number of procedures per patient, conversion to laparotomy, efficacy of removing the calculi, and hospital costs. Results There were no differences as regards the patient clinical features or morbidity. The mean post-surgical hospital stay for the One-stage group was less than that in the Two-stage group. Three patients of the Two-stage group required conversion to laparotomy. The median costs per patient were less for the One-stage strategy, representing an overall saving of 37,173€ during the period studied. Conclusions No significant differences were found between the two treatment options as regards efficacy or post-surgical morbidity and mortality, but there were differences in hospital stay and costs. The management of patients with gallstones in one-stage surgery represents a saving of 3 days hospital stay and 1,008€ per patient (AU)

[Minimising hospital costs in the treatment of bile duct calculi: a comparison study]. / Estudio de minimización de costes hospitalarios en el tratamiento de la coledocolitiasis.

INTRODUCTION: The treatment of bile duct calculi associated with cholelithiasis is controversial. The hospital costs could be a decisive factor in choosing between the different therapeutic options. OBJECTIVES: To compare the effectiveness and costs of two options in the treatment of common bile duct calculi: 1) One-stage: Laparoscopic cholecystectomy and bile duct exploration, and 2) Two-stage: sequential endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy. MATERIAL AND METHODS: A retrospective, observational study was performed on 49 consecutive patients with bile duct calculi and gallbladder in situ, treated consecutively and simultaneously over a two year period. The post-operate complication, hospital stay, number of procedures per patient, conversion to laparotomy, efficacy of removing the calculi, and hospital costs. RESULTS: There were no differences as regards the patient clinical features or morbidity. The mean post-surgical hospital stay for the One-stage group was less than that in the Two-stage group. Three patients of the Two-stage group required conversion to laparotomy. The median costs per patient were less for the One-stage strategy, representing an overall saving of 37,173€ during the period studied. CONCLUSIONS: No significant differences were found between the two treatment options as regards efficacy or post-surgical morbidity and mortality, but there were differences in hospital stay and costs. The management of patients with gallstones in one-stage surgery represents a saving of 3 days hospital stay and 1,008€ per patient.