Critical appraisal of surgical margins according to KRAS status in liver resection for colorectal liver metastases: Should surgical strategy be influenced by tumor biology?

BACKGROUND: KRAS mutation is a negative prognostic factor for colorectal liver metastases. Several studies have investigated the resection margins according to KRAS status, with conflicting results. The aim of the study was to assess the oncologic outcomes of R0 and R1 resections for colorectal liver metastases according to KRAS status. METHODS: All patients who underwent resection for colorectal liver metastases between 2010 and 2015 with available KRAS status were enrolled in this multicentric international cohort study. Logistic regression models were used to investigate the outcomes of R0 and R1 colorectal liver metastases resections according to KRAS status: wild type versus mutated. The primary outcomes were overall survival and disease-free survival. RESULTS: The analysis included 593 patients. KRAS mutation was associated with shorter overall survival (40 vs 60 months; P = .0012) and disease-free survival (15 vs 21 months; P = .003). In KRAS-mutated tumors, the resection margin did not influence oncologic outcomes. In multivariable analysis, the only predictor of disease-free survival and overall survival was primary tumor location (P = .03 and P = .03, respectively). In KRAS wild-type tumors, R0 resection was associated with prolonged overall survival (74 vs 45 months, P < .001) and disease-free survival (30 vs 17 months, P < .001). The multivariable model confirmed that R0 resection margin was associated with prolonged overall survival (hazard ratio = 1.43, 95% confidence interval: 1.01-2.03) and disease-free survival (hazard ratio = 1.42; 95% confidence interval: 1.06-1.91). CONCLUSIONS: KRAS-mutated colorectal liver metastases showed more aggressive tumor biology with inferior overall survival and disease-free survival after liver resection. Although R0 resection was not associated with improved oncologic outcomes in the KRAS-mutated tumors group, it seems to be of paramount importance for achieving prolonged long-term survival in KRAS wild-type tumors.

Radiofrequency-assisted transection of the pancreas versus stapler in distal pancreatectomy: study protocol for a multicentric randomised clinical trial (TRANSPAIRE).

INTRODUCTION: To date, no pancreatic stump closure technique has been shown to be superior to any other in distal pancreatectomy. Although several studies have shown a trend towards better results in transection using a radiofrequency device (radiofrequency-assisted transection (RFT)), no randomised trial for this purpose has been performed to date. Therefore, we designed a randomised clinical trial, with the hypothesis that this technique used in distal pancreatectomies is superior in reducing clinically relevant postoperative pancreatic fistula (CR-POPF) than mechanical closures. METHODS AND ANALYSIS: TRANSPAIRE is a multicentre randomised controlled trial conducted in seven Spanish pancreatic centres that includes 112 patients undergoing elective distal pancreatectomy for any indication who will be randomly assigned to RFT or classic stapler transections (control group) in a ratio of 1:1. The primary outcome is the CR-POPF percentage. Sample size is calculated with the following assumptions: 5% one-sided significance level (α), 80% power (1-ß), expected POPF in control group of 32%, expected POPF in RFT group of 10% and a clinically relevant difference of 22%. Secondary outcomes include postoperative results, complications, radiological evaluation of the pancreatic stump, metabolomic profile of postoperative peritoneal fluid, survival and quality of life. Follow-ups will be carried out in the external consultation at 1, 6 and 12 months postoperatively. ETHICS AND DISSEMINATION: TRANSPAIRE has been approved by the CEIM-PSMAR Ethics Committee. This project is being carried out in accordance with national and international guidelines, the basic principles of protection of human rights and dignity established in the Declaration of Helsinki (64th General Assembly, Fortaleza, Brazil, October 2013), and in accordance with regulations in studies with biological samples, Law 14/2007 on Biomedical Research will be followed. We have defined a dissemination strategy, whose main objective is the participation of stakeholders and the transfer of knowledge to support the exploitation of activities. REGISTRATION DETAILS: ClinicalTrials.gov Registry (NCT04402346).

Long-Term Outcomes of Perioperative Versus Neoadjuvant Chemotherapy for Resectable Colorectal Liver Metastases: An International Multicentre Propensity-Score Matched Analysis with Stratification by Contemporary Risk-Scoring.

BACKGROUND: There is still debate regarding the principal role and ideal timing of perioperative chemotherapy (CTx) for patients with upfront resectable colorectal liver metastases (CRLM). This study assesses long-term oncological outcomes in patients receiving neoadjuvant CTx only versus those receiving neoadjuvant combined with adjuvant therapy (perioperative CTx). METHODS: International multicentre retrospective analysis of patients with CRLM undergoing liver resection between 2010 and 2015. Characteristics and outcomes were compared before and after propensity score matching (PSM). Primary endpoints were long-term oncological outcomes, such as recurrence-free survival (RFS) and overall survival (OS). Furthermore, stratification by the tumour burden score (TBS) was applied. RESULTS: Of 967 patients undergoing hepatectomy, 252 were analysed, with a median follow-up of 45 months. The unmatched comparison revealed a bias towards patients with neoadjuvant CTx presenting with more high-risk patients (p = 0.045) and experiencing increased postoperative complications ≥Clavien-Dindo III (20.9% vs. 8%, p = 0.003). Multivariable analysis showed that perioperative CTx was associated with significantly improved RFS (hazard ratio [HR] 0.579, 95% confidence interval [CI] 0.420-0.800, p = 0.001) and OS (HR 0.579, 95% CI 0.403-0.834, p = 0.003). After PSM (n = 180 patients), the two groups were comparable regarding baseline characteristics. The perioperative CTx group presented with a significantly prolonged RFS (HR 0.53, 95% CI 0.37-0.76, p = 0.007) and OS (HR 0.58, 95% CI 0.38-0.87, p = 0.010) in both low and high TBS patients. CONCLUSIONS: When patients after resection of CRLM are able to tolerate additional postoperative CTx, a perioperative strategy demonstrates increased RFS and OS in comparison with neoadjuvant CTx only in both low and high-risk situations.

Liver resection in elderly patients with extensive CRLM: Are we offering an adequate treatment? A propensity score matched analysis.

BACKGROUND: Data on the management of elderly patients with extensive colorectal liver metastases (CRLM) are scarce and conflicting. This study assesses differences in management and long-term oncological outcomes between older and younger patients with CRLM and a high Tumour Burden Score (TBS). METHODS: International multicentre retrospective study on patients with CRLM and a category 3 TBS, submitted to liver resection. Patients were divided into two groups according to their age (younger and older than 75) and were compared using propensity score matching (PSM) analysis and multivariable regression models. Differences in management and oncological outcomes including recurrence-free survival (RFS) and overall survival (OS) were assessed. RESULTS: The study included 386 patients, median follow-up was 48 months. The unmatched comparison revealed a higher ASA score (p = 0.035), less synchronous CRLM (47% vs 68%, p = 0.003), a lower median number of lesions (1 vs 3, p = 0.004) and less perioperative chemotherapy (CTx) (66% vs 88%, p < 0.001) in the elderly group. Despite the absence of CTx being an independent predictor of decreased RFS and OS (HR 0.760, p = 0.044 and HR 0.719, p = 0.049, respectively), the elderly group still received less CTx (OR 0.317, p = 0.001) than the younger group. After PSM (n = 100 patients), the two groups were comparable, however, CTx administration was still significantly lower in the elderly group. CONCLUSION: Liver resection should be considered in patients aged 75 and older, even if they present with extensive liver disease. Despite CTx being associated with improved oncological outcomes, a large percentage of elderly patients with CRLM are undertreated.

¿Qué aporta la imagen tridimensional preoperatoria en la cirugía pancreática compleja? / What does preoperative three-dimensional image contribute to complex pancreatic surgery?

La posibilidad de modelización de imágenes diagnósticas en tres dimensiones (3D) en cirugía pancreática es una novedad que nos aporta múltiples ventajas. Una mejor visualización de las estructuras nos permite una planificación de la técnica quirúrgica más precisa y nos facilita la realización de la cirugía en casos complejos. Presentamos el caso de un paciente diagnosticado de un adenocarcinoma de cabeza de páncreas borderline para ilustrar las ventajas de la modelización 3D en cirugía pancreática compleja. La ayuda de la tecnología 3D nos permitió planificar de manera óptima la intervención facilitando la resección quirúrgica. El uso de esta herramienta podría traducirse en: menor tiempo operatorio, menores complicaciones intraoperatorias o un aumento de las resecciones R0. La usabilidad del programa utilizado en nuestro caso, ágil e intuitivo, fue una ventaja añadida. (AU)

The possibility of modelling diagnostic images in three dimensions (3D) in pancreatic surgery is a novelty that provides us multiple advantages. A better visualization of the structures allows us a more accurate planning of the surgical technique and makes it easier the surgery in complex cases. We present the case study of a borderline pancreatic head adenocarcinoma patient to illustrate the advantages of 3D modelling in complex pancreatic surgery. The help of 3D technology allowed us to optimally plan the intervention and facilitate surgical resection. The use of this tool could translate into: shorter operative time, fewer intraoperative complications or an increase in R0 resections. The usability of the program used in our case, agile and intuitive, was an added advantage. (AU)

What does preoperative three-dimensional image contribute to complex pancreatic surgery?

The possibility of modelling diagnostic images in three dimensions (3D) in pancreatic surgery is a novelty that provides us multiple advantages. A better visualization of the structures allows us a more accurate planning of the surgical technique and makes it easier the surgery in complex cases. We present the case study of a borderline pancreatic head adenocarcinoma patient to illustrate the advantages of 3D modelling in complex pancreatic surgery. The help of 3D technology allowed us to optimally plan the intervention and facilitate surgical resection. The use of this tool could translate into: shorter operative time, fewer intraoperative complications or an increase in R0 resections. The usability of the program used in our case, agile and intuitive, was an added advantage.

Perioperative chemotherapy versus surgery alone for resectable colorectal liver metastases: an international multicentre propensity score matched analysis on long-term outcomes according to established prognostic risk scores.

BACKGROUND: There is still uncertainty regarding the role of perioperative chemotherapy (CTx) in patients with resectable colorectal liver metastases (CRLM), especially in those with a low-risk of recurrence. METHODS: Multicentre retrospective analysis of patients with CRLM undergoing liver resection between 2010-2015. Patients were divided into two groups according to whether they received perioperative CTx or not and were compared using propensity score matching (PSM) analysis. Then, they were stratified according to prognostic risk scores, including: Clinical Risk Score (CRS), Tumour Burden Score (TBS) and Genetic And Morphological Evaluation (GAME) score. RESULTS: The study included 967 patients with a median follow-up of 68 months. After PSM analysis, patients with perioperative CTx presented prolonged overall survival (OS) in comparison with the surgery alone group (82.8 vs 52.5 months, p = 0.017). On multivariable analysis perioperative CTx was an independent predictor of increased OS (HR 0.705, 95%CI 0.705-0.516, p = 0.029). The benefits of perioperative CTx on survival were confirmed in patients with CRS and TBS scores ≤2 (p = 0.022 and p = 0.020, respectively) and in patients with a GAME score ≤1 (p = 0.006). CONCLUSION: Perioperative CTx demonstrated an increase in OS in patients with CRLM. Patients with a low-risk of recurrence seem to benefit from systemic treatment.

Non-arbitrary minimum threshold of yearly performed pancreatoduodenectomies: National multicentric study.

BACKGROUND: Annual hospital volume of pancreatoduodenectomies could influence postoperative outcomes. The aim of this study is to establish with a non-arbitrary method the minimum threshold of yearly performed pancreatoduodenectomies in order to improve several postoperative quality outcomes. METHOD: Prospective follow-up of patients submitted to pancreatoduodenectomy in participating hospitals during 1 year. The influence of hospital volume on quality outcomes was analyzed by univariable and multivariable models. The minimum threshold of yearly performed pancreatoduodenectomies to improve outcomes was established by Akaike's information criteria. RESULTS: Data from 877 patients operated in 74 hospitals were analyzed. Of 12 quality outcomes, 9 were influenced by hospital pancreatoduodenectomy volume on multivariable analysis. To decrease the risk of complications and the risk of retrieving an insufficient number of lymph nodes at least 31 pancreatoduodenectomies per year should be performed. To decrease the risk of prolonged length of stay, postoperative death, and affected surgical margins, at least 37, 6, and 14 pancreatoduodenectomies per year should be performed, respectively. CONCLUSION: Several postoperative quality outcomes are influenced by the number of yearly performed pancreatoduodenectomies and could be improved by establishing a minimum threshold of procedures. Number of procedures needed to improve quality outcomes has been established by a non-arbitrary method.

What does preoperative three-dimensional image contribute to complex pancreatic surgery? / ¿Qué aporta la imagen tridimensional preoperatoria en la cirugía pancreática compleja?

The possibility of modelling diagnostic images in three dimensions (3D) in pancreatic surgery is a novelty that provides us multiple advantages. A better visualization of the structures allows us a more accurate planning of the surgical technique and makes it easier the surgery in complex cases. We present the case study of a borderline pancreatic head adenocarcinoma patient to illustrate the advantages of 3D modelling in complex pancreatic surgery. The help of 3D technology allowed us to optimally plan the intervention and facilitate surgical resection. The use of this tool could translate into: shorter operative time, fewer intraoperative complications or an increase in R0 resections. The usability of the program used in our case, agile and intuitive, was an added advantage.

Tratamiento quirúrgico de neoplasia mucinosa papilar intraductal de la vía biliar diagnosticada mediante SpyGlass(R) / No disponible

Presentamos el caso de un varón de 76 años con antecedente de colecistitis aguda intervenido mediante colecistectomía laparoscópica. Intraoperatoriamente, se evidenció una colecistitis crónica con conducto cístico engrosado. La anatomía patológica informó de displasia de alto grado que afectaba al borde distal del cístico. Ante los hallazgos, se practicó colangiopancreatografía retrógrada endoscópica (CPRE) con SpyGlass(R) con la cual se observó, adyacente a la unión del cístico-colédoco, lesión excrecente sugestiva de malignidad. Se decidió nueva intervención quirúrgica y se realizó una resección de vía biliar extrahepática con linfadenectomía del hilio hepático y hepaticoyeyunostomía. El informe anatomopatológico definitivo informó de neoplasia mucinosa papilar intraductal pancreatobiliar con displasia de alto grado con márgenes libres

No disponible

Surgical treatment of an intraductal papillary mucinous neoplasm of the biliary tract diagnosed by SpyGlass®.

We present the case of a 76-year-old male with a history of acute cholecystitis who underwent a scheduled laparoscopic cholecystectomy. Chronic cholecystitis with a thickened cystic duct was observed intraoperatively. The anatomic pathology report found high-grade dysplasia that affected the distal edge of the cystic duct. In view of these findings, an endoscopic retrograde cholangiopancreatography (ERCP) was performed with SpyGlass® and an excrescent lesion suggestive of malignancy adjacent to the cystic-common bile duct junction was observed. A resection of the extrahepatic bile duct was performed with lymphadenectomy of the hepatic hilum and hepaticojejunostomy in a subsequent procedure. The definitive pathology report confirmed pancreaticobiliary intraductal papillary mucinous neoplasia with high-grade dysplasia and free margins.

Neoadjuvant treatment for locally advanced unresectable and borderline resectable pancreatic cancer: oncological outcomes at a single academic centre.

INTRODUCTION: Pancreatic cancer (PC), even in the absence of metastatic disease, has a dismal prognosis. One-third of them are borderline resectable (BRPC) or locally advanced unresectable PC (LAUPC) at diagnosis. There are limited prospective data supporting the best approach on these tumours. Neoadjuvant chemotherapy (ChT) is being increasingly used in this setting. METHODS: This is a retrospective series of consecutive patients staged as BRPC or LAUPC after discussion in the multidisciplinary board (MDB) at an academic centre. All received neoadjuvant ChT, followed by chemoradiation (ChRT) in some cases, and those achieving enough downstaging had a curative-intent surgery. Descriptive data about patient's characteristics, neoadjuvant treatments, toxicities, curative resections, postoperative complications, pathology reports and adjuvant treatment were collected. Overall survival (OS) and progression-free survival was calculated with Kaplan-Meier method and log-rank test. RESULTS: Between August 2011 and July 2019, 49 patients fulfilled the inclusion criteria, and all of them received neoadjuvant ChT. Fluorouracil+folinic acid, irinotecan and oxaliplatin was the most frequently used scheme (77%). The most prevalent grade 3 or 4 toxicities were neutropenia (26.5%), neurotoxicity (12.2%), diarrhoea (8.2%) and nausea (8.2%). 18 patients (36.7%) received ChRT thereafter. In total, 22 patients (44,9%) became potentially resectable and 19 of them had an R0 or R1 pancreatic resection. One was found to be unresectable at surgery and two refused surgery. A vascular resection was required in 7 (35%). No postoperative deaths were observed. Postoperative ChT was given to 12 (66.7%) of resected patients. Median OS of the whole cohort was 24,9 months (95% CI 14.1 to 35.7), with 30.6 months for resected and 13.1 months for non-resected patients, respectively (p<0.001). CONCLUSION: A neoadjuvant approach in BRPC and LAUPC was well tolerated and allowed a curative resection in 38.8% of them with a potential improvement on OS.

Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice.

Pancreatic duct ligation (PDL) in the murine model has been described as an exocrine pancreatic atrophy-inducing procedure. However, its influence has scarcely been described on premalignant lesions. This study describes the histological changes of premalignant lesions and the gene expression in a well-defined model of pancreatic ductal adenocarcinoma by PDL. Selective ligation of the splenic lobe of the pancreas was performed in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice (PDL-Kras mice). Three experimental groups were evaluated: PDL group, controls and shams. The presence and number of premalignant lesions (PanIN 1-3 and Atypical Flat Lesions-AFL) in proximal (PP) and distal (DP) pancreas were studied for each group over time. Microarray analysis was performed to find differentially expressed genes (DEG) between PP and PD. Clinical human specimens after pancreaticoduodenectomy with ductal occlusion were also evaluated. PDL-Kras mice showed an intense pattern of atrophy in DP which was shrunk to a minimal portion of tissue. Mice in control and sham groups had a 7 and 10-time increase respectively of risk of high-grade PanIN 2 and 3 and AFL in their DP than PDL-Kras mice. Furthermore, PDL-Kras mice had significantly less PanIN 1 and 2 and AFL lesions in DP compared to PP. We identified 38 DEGs comparing PP and PD. Among them, several mapped to protein secretion and digestion while others such as Nupr1 have been previously associated with PanIN and PDAC. PDL in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice induces a decrease in the presence of premalignant lesions in the ligated DP. This could be a potential line of research of interest in some cancerous risk patients.

The actual management of colorectal liver metastases.

Colorectal cancer is one of the most frequent cancers in the world and between 50% and 60% of patients will develop colorectal liver metastases (CRLM) during the disease. There have been great improvements in the management of CRLM during the last decades. The combination of modern chemotherapeutic and biological systemic treatments with aggressive surgical resection strategies is currently the base for the treatment of patients considered unresectable until few years ago. Furthermore, several new treatments for the local control of CRLM have been developed and are now part of the arsenal of multidisciplinary teams for the treatment of these complex patients. The aim of this review was to summarize and update the management of CRLM, its controversies and relevant evidence.

Impact of type and severity of postoperative complications on long-term outcomes after colorectal liver metastases resection.

BACKGROUND AND OBJECTIVES: Postoperative complications (POCs) after hepatic resection for colorectal liver metastases (CRLM) adversely affect long-term survival. The aim of this study was to analyze the effect of POC etiology and severity on overall survival (OS) and disease-free survival (DFS). METHODS: A retrospective study of 254 consecutive hepatectomies for CRLM was performed. Univariate and multivariate analyses were performed to determine the effects of demographic, tumor-related and perioperative variables on OS and DFS. A 1:1 propensity score matching (PSM) was then used to compare patients with different POC etiology: infective (Inf-POC), noninfective (Non-inf POC), and no-complications (No-POC). RESULTS: Inf-POC, Non-inf POC, and No-POC patients represented 18.8%, 19.2%, and 62% of the sample, respectively. In univariate and multivariate analyses infectious POC were independent risk factors for decreased OS and DFS. After PSM, Inf-POC group presented decreased OS and DFS when compared with Non-inf POC (5-year OS 31.8% vs 51.6%; P = .05 and 5-year DFS 13.6% vs 31.9%; P = .04) and with No-POC (5-year OS 29.4% vs 58.7%; P = .03 and 5-year DFS 11.8% vs 39.7%; P = .03). There were no differences between Non-inf POC and No-POC patients. POC severity calculated using the Comprehensive Complications Index did not influence OS and DFS before and after PSM. CONCLUSION: The negative oncological impact of POCs after CRLM resection is determined by infective etiology not by severity.

Acute cholecystitis in elderly and high-risk surgical patients: is percutaneous cholecystostomy preferable to emergency cholecystectomy?

OBJECTIVE: To investigate whether percutaneous cholecystostomy (PC) for the treatment of acute calculous cholecystitis (ACC) has better results than emergency cholecystectomy (EC) in elderly and high-risk surgical patients. METHODS: Patients ≥ 70 years and/or ≥ ASA-PS 3 with ACC treated with PC or EC between 2005 and 2016 were retrospectively reviewed. Both techniques were compared regarding morbi-mortality, hospital stay, complications and readmissions. A subgroup analysis in higher risk patients (≥ 70 years plus ≥ ASA-PS 3) was also performed. A binary logistic regression analysis for outcome variables to calculate the OR was carried out. RESULTS: A total of 461 patients were included in the study. The results of PC were worse compared to EC: 30-day mortality (8.6 vs. 1.7%, OR 18.4), 90-day mortality (10.4 vs. 2.1%, OR 10.3), length of stay (days) (13.21 ± 8.2 vs. 7.48 ± 7.67, OR 8.7) and readmission rate (35.1 vs. 12.6%, OR 4.7). Complications were lower for PC (14 vs. 22.6%, OR 0.41), but there were no significant differences in the number of severe complications (Clavien-Dindo ≥ III). Higher-risk subgroup analysis (n = 193; PC = 128, EC = 65) showed similar results to the whole series. Patients with ACC for more than 3 days had more risk of severe complications in both groups (OR 2.26; OR 2.76). CONCLUSION: PC was associated with an increased risk of mortality at 30 and 90 days, more readmissions and longer hospital stay. Although PC presents a lower risk of complications, the percentage of severe complications (Clavien-Dindo ≥ III) does not show significant differences.