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.

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 .

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).

Evolution Under Normothermic Machine Perfusion of Type 2 Donation After Cardiac Death Livers Discarded as Nontransplantable.

BACKGROUND: Type 2 donation after cardiac death (DCD) represents an underused source of grafts for liver transplantation. In our center, normothermic regional perfusion and strict selection criteria have led to acceptable postoperative results after transplanting type 2 DCD livers. However, many of these grafts are still discarded before transplantation. We believe that the suitability of these organs may be improved by adding normothermic machine perfusion (NMP) to our current procedure. MATERIALS AND METHODS: A total of 5 type 2 DCD livers discarded for transplantation were submitted to normothermic regional perfusion and 12 h of NMP. The macroscopic aspect of the liver, vascular and bile flows, and pH were continuously monitored. Serial perfusate analyses and liver biopsies were performed. After NMP, the microscopic appearance of the liver parenchyma and the bile ducts was analyzed. RESULTS: All the grafts showed hemodynamic stability during the NMP. The alanine aminotransferase peak during NMP correlated with the warm ischemia time (Pearson correlation of 0.933, p 0.021). After an initial period of acidosis, the grafts were generally able to spontaneously correct pH and lactate levels without the need for additional bicarbonate. Livers with favorable bile duct histology generally started bile production earlier and registered higher bile flows. CONCLUSIONS: NMP represents a feasible procedure for use with type 2 DCD livers. The pH and lactate correction and the bile flows appear to be significant factors associated with graft viability. However, these favorable results should be confirmed in a clinical transplant setting.

Trasplante hepático con injerto de donante en asistolia tipo 2 con perfusión regional normotérmica y máquina de perfusión normotérmica / Liver transplantation from type II donation after cardiac death donor with normothermic regional perfusion and normothermic machine perfusion

INTRODUCCIÓN: Hoy en día, el desequilibrio entre el número de donantes y los pacientes en lista de espera para trasplante hepático (TH) hace necesaria la utilización de órganos con criterios expandidos, como los de donación en asistolia tipo 2. MÉTODOS: Presentamos el primer TH realizado mediante un protocolo de perfusión regional normotérmica y máquina de perfusión normotérmica para un injerto de donación en asistolia tipo 2 inicialmente descartado para TH. RESULTADOS: Tras una evolución favorable en máquina de perfusión normotérmica (mejoría del aspecto macroscópico del injerto, control del equilibrio ácido-base y producción de bilis), el TH se realizó sin incidencias. Después de 3 meses la evolución del paciente y del injerto son correctas, sin signos de colangiopatía isquémica en la colangiografía trans-Kehr. CONCLUSIONES: La supervivencia del injerto y del receptor invitan al optimismo. Sin embargo, son necesarios más casos con el objetivo de verificar la eficacia clínica del nuevo protocolo

BACKGROUND: The current imbalance between donor supply and patients on the waiting list for liver transplantation (LT) is significant. To resolve this situation, marginal organs, such as those from type 2 donation after cardiac death (DCD2), are being considered. METHODS: In the present article, we present the first LT with a new protocol consisting in normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) for a type 2 DCD graft initially rejected for LT. RESULTS: After a favorable evolution with NMP (improved macroscopic appearance of the graft, acid-base equilibrium control and bile production), the transplantation was performed without major incidents. The evolution of the graft and patient were favorable. After 3 months, cholangiography showed no signs of ischemic cholangiopathy. CONCLUSIONS: Three-month patient and graft survival are encouraging, but more cases are needed to test the clinical efficacy of the new protocol

Expansion of the hepatocellular carcinoma Milan criteria in liver transplantation: Future directions.

Milan criteria are currently the benchmark related to liver transplantation (LT) for hepatocellular carcinoma. However, several groups have proposed different expanded criteria with acceptable results. In this article, we review the current status of LT beyond the Milan criteria in three different scenarios-expanded criteria with cadaveric LT, downstaging to Milan criteria before LT, and expansion in the context of adult living donor LT. The review focuses on three main questions: what would the impact of the expansion beyond Milan criteria be on the patients on the waiting list; whether the dichotomous criteria (yes/no) currently used are appropriate for LT or continuous survival estimations, such as the one of "Metroticket" and whether it should enter into the clinical practice; and, whether the use of living donor LT in the context of expansion beyond Milan criteria is justified.

Liver transplantation from type II donation after cardiac death donor with normothermic regional perfusion and normothermic machine perfusion. / Trasplante hepático con injerto de donante en asistolia tipo 2 con perfusión regional normotérmica y máquina de perfusión normotérmica.

BACKGROUND: The current imbalance between donor supply and patients on the waiting list for liver transplantation (LT) is significant. To resolve this situation, marginal organs, such as those from type 2 donation after cardiac death (DCD2), are being considered. METHODS: In the present article, we present the first LT with a new protocol consisting in normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) for a type 2 DCD graft initially rejected for LT. RESULTS: After a favorable evolution with NMP (improved macroscopic appearance of the graft, acid-base equilibrium control and bile production), the transplantation was performed without major incidents. The evolution of the graft and patient were favorable. After 3 months, cholangiography showed no signs of ischemic cholangiopathy. CONCLUSIONS: Three-month patient and graft survival are encouraging, but more cases are needed to test the clinical efficacy of the new protocol.

Perfusión normotérmica ex vivo de injerto hepático procedente de donante en asistolia tipo 2 / Normothermic ex vivo liver perfusion from donors after type 2 cardiac arrest

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Beneficial Effect of a Resorbable Biliary Stent in Living Donor Liver Transplantation.

BACKGROUND: Living donor liver transplantation (LDLT) entails a significant number of bile duct complications. We aimed to diminish the biliary complication rate with the use of a resorbable biliary stent (RBS) during LDLT. The objective of this study is to describe the surgical techniques and the associated outcomes, especially in terms of safety, of RBS use in LDLT. METHODS: From 2011 to 2014, 12 LDLT recipients were enrolled in a clinical trial with the use of a specifically designed RBS. These patients were followed according to the clinical protocol. Specific complications derived from RBS as well as biliary complications were recorded. RESULTS: One patient underwent early retransplantation due to a small-for-size syndrome. None of the patients had a complication attributable to the placement, remaining in place, or degradation of the stent. Four of the remaining patients presented with a biliary complication: 1 (9.1%) with a biliary leak alone, 1 (9.1%) with a biliary stenosis alone, and 2 (18.2%) with both. However, none of the leaks could be directly attributed to the RBS. Patient and graft 1-year survival was 100 and 91.7%, respectively. CONCLUSION: The use of an RBS in LDLT is not associated with complications, and initial results regarding efficacy and safety are encouraging. The need for a larger and prospective study is warranted.

La máquina de perfusión normotérmica en el trasplante hepático con injertos provenientes de donación en asistolia / Normothermic perfusion machine in liver transplant with cardiac death donor grafts

La diferencia cada vez mayor entre el número de pacientes en espera para un trasplante hepático y el número de donantes disponibles ha generado un gran interés en la utilización de órganos «no ideales» como es el caso de los provenientes de donantes en asistolia. Sin embargo, la sensibilidad de estos hígados a la isquemia hace que su tasa de utilización sea baja y las tasas de complicaciones y retrasplante mayores que en el trasplante convencional. Las máquinas de perfusión normotérmica eXVIvo (MPN) surgen como una opción para intentar mantener la viabilidad de estos órganos e incluso mejorar su función. Esta revisión se centra en los resultados actuales obtenidos en el trasplante hepático con órganos provenientes de donantes en asistolia y el papel que puede tener la MPN en este campo

The increasing difference between the number of patients in waiting lists for liver transplantation and the number of available donors has generated a great interest in the use of non-ideal organs, like grafts obtained from cardiac death donors (DCD). However, the extreme sensibility to ischemia of these livers results in a low utilization rate and a high percentage of post-transplant complications and re-transplantation. Normothermic perfusion machines (NMP) emerged as an alternative that tries to maintain the viability of the organ and even to improve its function. This review focuses on current results of DCD liver transplantation and on the role that NMP may have in this field

Klatskin tumor: Diagnosis, preoperative evaluation and surgical considerations.

Hiliar cholangiocarcinoma is the most common type of cholangiocarcinoma, an represent around 10% of all hepatobiliary tumors. It is an aggressive malignancy, resectable in around 47% of the patients at diagnosis. Complete resection is the most effective and only potentially curative therapy, with a survival rate of less than 12 months in unresectable cases. Axial computerized tomography and magnetic resonance are the most useful image techniques to determine the surgical resectability. Clinically, jaundice and pruritus are the most common symptoms at diagnosis;preoperative biliary drainage is recommended using endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography. Surgery using extended liver resections with an en bloc resection of the liver with vascular reconstruction is the technique with the highest survival. Complete resection with histologically negative resection margins (R0), nodal involvement and metastases are the most important prognostic factors.

Normothermic perfusion machine in liver transplant with cardiac death donor grafts.

The increasing difference between the number of patients in waiting lists for liver transplantation and the number of available donors has generated a great interest in the use of non-ideal organs, like grafts obtained from cardiac death donors (DCD). However, the extreme sensibility to ischemia of these livers results in a low utilization rate and a high percentage of post-transplant complications and re-transplantation. Normothermic perfusion machines (NMP) emerged as an alternative that tries to maintain the viability of the organ and even to improve its function. This review focuses on current results of DCD liver transplantation and on the role that NMP may have in this field.

Reparación quirúrgica de falsa vía bilioduodenal tras colangiografia transparietohepática en paciente con estenosis biliar secundaria a colecistectomía / Surgical repair of a false bile-duct passage after percutaneous transhepatic cholangiography in a patient with biliary stenosis after cholecystectomy

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