Åsmund A. Fretland

Margin status after laparoscopic resection of colorectal liver metastases: does a narrow resection margin have an influence on survival and local recurrence?

OBJECTIVES Recent studies of margin-related recurrence have raised questions on the necessity of ensuring wide resection margins in the resection of colorectal liver metastases. The aim of the current study was to determine whether resection margins of 10 mm provide a survival benefit over narrower resection margins. METHODS A total of 425 laparoscopic liver resections were carried out in 351 procedures performed in 317 patients between August 1998 and April 2012. Primary laparoscopic liver resections for colorectal metastases were included in the study. Two-stage resections, procedures accompanied by concomitant liver ablations and one case of perioperative mortality were excluded. A total of 155 eligible patients were classified into four groups according to resection margin width: Group 1, margins of < 1 mm [n = 33, including 17 patients with positive margins (Group 1a)]; Group 2, margins of 1 mm to < 3 mm (n = 31); Group 3, margins of ≥ 3 mm to <10 mm (n = 55), and Group 4, margins of ≥ 10 mm (n = 36). Perioperative and survival data were compared across the groups. Median follow-up was 31 months (range: 2-136 months). RESULTS Perioperative outcomes were similar in all groups. Unfavourable intraoperative incidents occurred in 9.7% of procedures (including 3.2% of conversions). Postoperative complications developed in 11.0% of patients. Recurrence in the resection bed developed in three (1.9%) patients, including two (6.1%) patients in Group 1. Rates of actuarial 5-year overall, disease-free and recurrence-free survival were 49%, 41% and 33%, respectively. Median survival was 65 months. Margin status had no significant impact on patient survival. The Basingstoke Predictive Index (BPI) generally underestimated survival. This underestimation was especially marked in Group 1 when postoperative BPI was applied. CONCLUSIONS Patients with margins of <1 mm achieved survival comparable with that in patients with margins of ≥ 10 mm. When modern surgical equipment that generates an additional coagulation zone is applied, the association between resection margin and survival may not be apparent. Further studies in this field are required. Postoperative BPI, which includes margin status among the core factors predicting postoperative survival, seems to be less precise than preoperative BPI.

Laparoscopic Versus Open Resection for Colorectal Liver Metastases: The OSLO-COMET Randomized Controlled Trial.

Objective: To perform the first randomized controlled trial to compare laparoscopic and open liver resection. Summary Background Data: Laparoscopic liver resection is increasingly used for the surgical treatment of liver tumors. However, high-level evidence to conclude that laparoscopic liver resection is superior to open liver resection is lacking. Methods: Explanatory, assessor-blinded, single center, randomized superiority trial recruiting patients from Oslo University Hospital, Oslo, Norway from February 2012 to January 2016. A total of 280 patients with resectable liver metastases from colorectal cancer were randomly assigned to undergo laparoscopic (n = 133) or open (n = 147) parenchyma-sparing liver resection. The primary outcome was postoperative complications within 30 days (Accordion grade 2 or higher). Secondary outcomes included cost-effectiveness, postoperative hospital stay, blood loss, operation time, and resection margins. Results: The postoperative complication rate was 19% in the laparoscopic-surgery group and 31% in the open-surgery group (12 percentage points difference [95% confidence interval 1.67–21.8; P = 0.021]). The postoperative hospital stay was shorter for laparoscopic surgery (53 vs 96 hours, P < 0.001), whereas there were no differences in blood loss, operation time, and resection margins. Mortality at 90 days did not differ significantly from the laparoscopic group (0 patients) to the open group (1 patient). In a 4-month perspective, the costs were equal, whereas patients in the laparoscopic-surgery group gained 0.011 quality-adjusted life years compared to patients in the open-surgery group (P = 0.001). Conclusions: In patients undergoing parenchyma-sparing liver resection for colorectal metastases, laparoscopic surgery was associated with significantly less postoperative complications compared to open surgery. Laparoscopic resection was cost-effective compared to open resection with a 67% probability. The rate of free resection margins was the same in both groups. Our results support the continued implementation of laparoscopic liver resection.

Evolution of Laparoscopic Liver Surgery from Innovation to Implementation to Mastery: Perioperative and Oncologic Outcomes of 2,238 Patients from 4 European Specialized Centers

BACKGROUND First seen as an innovation for select patients, laparoscopic liver resection (LLR) has evolved since its introduction, resulting in worldwide use. Despite this, it is still limited mainly to referral centers. The aim of this study was to evaluate a large cohort undergoing LLR from 2000 to 2015, focusing on the technical approaches, perioperative and oncologic outcomes, and evolution of practice over time. STUDY DESIGN The demographics and indications, intraoperative, perioperative, and oncologic outcomes of 2,238 patients were evaluated. Trends in practice and outcomes over time were assessed. RESULTS The percentage of LLR performed yearly has increased from 5% in 2000 to 43% in 2015. Pure laparoscopy was used in 98.3% of cases. Wedge resections were the most common operation; they were predominant at the beginning of LLR and then decreased and remained steady at approximately 53%. Major hepatectomies were initially uncommon, then increased and reached a stable level at approximately 16%. Overall, 410 patients underwent resection in the posterosuperior segments; these were more frequent with time, and the highest percentage was in 2015 (26%). Blood loss, operative time, and conversion rate improved significantly with time. The 5-year overall survival rates were 73% and 54% for hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM), respectively. The 5-year, recurrence-free survival rates were 50% and 37% for HCC and CRLM, respectively. CONCLUSIONS Since laparoscopy was introduced, a long implementation process has been necessary to allow for standardization and improvement in surgical care, mastery of the technique, and the ability to obtain good perioperative results with safe oncologic outcomes.

RAS Mutation Clinical Risk Score to Predict Survival After Resection of Colorectal Liver Metastases.

Objective: To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM). Background: The t-CS relies on the following factors: primary tumor nodal status, disease-free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS. Methods: Patients who underwent resection of CLM from 2005 through 2013 and had RAS mutation status and t-CS factors available were included. Multivariate analysis was used to identify prognostic factors to include in the m-CS. Log-rank survival analyses were used to compare the t-CS and the m-CS. The m-CS was validated in an international multicenter cohort of 608 patients. Results: A total of 564 patients were eligible for analysis. RAS mutation was detected in 205 (36.3%) of patients. On multivariate analysis, RAS mutation was associated with poor overall survival, as were positive primary tumor lymph node status and diameter of the largest liver metastasis >50 mm. Each factor was assigned 1 point to produce a m-CS. The m-CS accurately stratified patients by overall and recurrence-free survival in both the initial patient series and validation cohort, whereas the t-CS did not. Conclusions: Modifying the t-CS by replacing disease-free interval, number of metastases, and CEA level with RAS mutation status produced an m-CS that outperformed the t-CS. The m-CS is therefore a simple validated tool that predicts survival after resection of CLM.

Laparoscopic Surgery for Solid Pseudopapillary Tumor of the Pancreas

Background and Objectives: Solid pseudopapillary tumors of the pancreas are rare and occur most frequently in young women. They have an uncertain pathogenesis and unclear clinical behavior. Our aim was to evaluate the clinical presentation of solid pseudopapillary tumors and assess the efficacy of treatment with minimally invasive surgery. Methods: From March 1997 to February 2011, 13 of 273 patients who underwent laparoscopic procedures on the pancreas were found to have solid pseudopapillary tumors. There were 12 female patients and 1 male patient. The median age was 21 years (range, 15–77 years). Abdominal pain was the most common presenting symptom (n = 9). Tumors were incidentally found in 3 patients on computed tomography scans obtained for other reasons. Results: Enucleation of the tumor was performed in 4 patients, including 3 in whom the tumor was located in the head of the pancreas. Eight patients underwent distal pancreatectomy with splenectomy, whereas spleen-preserving distal pancreatectomy was performed in one case. The median tumor size was 6 cm (range, 1.5–11 cm), the median operative time was 197 minutes (range, 68–320 minutes), and the median blood loss was 50 mL (range, <50–750 mL). Distal resections were performed with a linear stapler. Four patients had postoperative complications. The median length of hospital stay was 5 days (range, 2–12 days). During a median follow-up period of 11 months (range, 3–121 months), no local recurrences or distant metastases were found. Conclusion: Laparoscopic resections and enucleations of solid pseudopapillary tumors of the pancreas can be performed safely and with adequate resection margins even if the tumors are located in the head of the organ.

The impact of laparoscopic versus open colorectal cancer surgery on subsequent laparoscopic resection of liver metastases: a multicenter study

BACKGROUND Laparoscopic liver surgery is expanding. Most laparoscopic liver resections for colorectal carcinoma metastases are performed subsequent to the resection of the colorectal primary, raising concerns about the feasibility and safety of advanced laparoscopic liver surgery in the context of an abdomen with possible postoperative adhesions. The aim was to compare the outcome of laparoscopic hepatectomy for colorectal metastases after open versus laparoscopic colorectal surgery. METHODS This observational, multicenter study reviewed 394 patients undergoing laparoscopic minor and major liver resection for colorectal carcinoma metastases. Main outcome measures were intraoperative unfavorable incidents and short-term results in patients who had previous open versus laparoscopic colorectal cancer surgery. RESULTS Three hundred six patients (78%) had prior open and 88 (22%) had prior laparoscopic colorectal resection. Laparoscopic major hepatectomies were undertaken in 63 (16%). Intraoperative unfavorable incidents during laparoscopic liver surgery were significantly higher among patients who had prior open colorectal surgery (26%) compared with the laparoscopic group (14%; P = .017). Positive resection margins and postoperative complications were not associated with the approach adopted for the resection of the primary cancer. On multivariate logistic regression analysis, intraoperative unfavorable incidents were associated significantly only with prior open colorectal surgery (odds ratio, 2.8; P = .006) and laparoscopic major hepatectomy (odds ratio, 2.4; P = .009). CONCLUSION Laparoscopic minor hepatectomy can be performed safely in patients who have undergone previous open colorectal surgery. Laparoscopic major hepatectomy after open colorectal surgery may be challenging. Careful risk assessment in the decision-making process is required not to compromise patient safety and to guarantee the expected benefits from the minimally invasive approach.

Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases

BACKGROUND Metastatic colorectal cancer (CRC) is associated with highly variable clinical outcome and response to therapy. The recently identified consensus molecular subtypes (CMS1-4) have prognostic and therapeutic implications in primary CRC, but whether these subtypes are valid for metastatic disease is unclear. We performed multi-level analyses of resectable CRC liver metastases (CLM) to identify molecular characteristics of metastatic disease and evaluate the clinical relevance. METHODS In this ancillary study to the Oslo-CoMet trial, CLM and tumor-adjacent liver tissue from 46 patients were analyzed by profiling mutations (targeted sequencing), genome-wide copy number alteration (CNAs), and gene expression. RESULTS Somatic mutations and CNAs detected in CLM were similar to reported primary CRC profiles, while CNA profiles of eight metastatic pairs suggested intra-patient divergence. A CMS classifier tool applied to gene expression data, revealed the cohort to be highly enriched for CMS2. Hierarchical clustering of genes with highly variable expression identified two subgroups separated by high or low expression of 55 genes with immune-related and metabolic functions. Importantly, induction of genes and pathways associated with immunogenic cell death (ICD) was identified in metastases exposed to neoadjuvant chemotherapy (NACT). CONCLUSIONS The uniform classification of CLM by CMS subtyping may indicate that novel class discovery approaches need to be explored to uncover clinically useful stratification of CLM. Detected gene expression signatures support the role of metabolism and chemotherapy in shaping the immune microenvironment of CLM. Furthermore, the results point to rational exploration of immune modulating strategies in CLM, particularly by exploiting NACT-induced ICD.Background Metastatic colorectal cancer (CRC) is associated with highly variable clinical outcome and response to therapy. The recently identified consensus molecular subtypes (CMS1-4) have prognostic and therapeutic implications in primary CRC, but whether these subtypes are valid for metastatic disease is unclear. We performed multi-level analyses of resectable CRC liver metastases (CLM) to identify molecular characteristics of metastatic disease and evaluate the clinical relevance. Methods In this ancillary study to the Oslo-CoMet trial, CLM and tumor-adjacent liver tissue from 46 patients were analyzed by profiling mutations (targeted sequencing), genome-wide copy number alteration (CNAs), and gene expression. Results Somatic mutations and CNAs detected in CLM were similar to reported primary CRC profiles, while CNA profiles of eight metastatic pairs suggested intra-patient divergence. A CMS classifier tool applied to gene expression data, revealed the cohort to be highly enriched for CMS2. Hierarchical clustering of genes with highly variable expression identified two subgroups separated by high or low expression of 55 genes with immune-related and metabolic functions. Importantly, induction of genes and pathways associated with immunogenic cell death (ICD) was identified in metastases exposed to neoadjuvant chemotherapy (NACT). Conclusions The uniform classification of CLM by CMS subtyping may indicate that novel class discovery approaches need to be explored to uncover clinically useful stratification of CLM. Detected gene expression signatures support the role of metabolism and chemotherapy in shaping the immune microenvironment of CLM. Furthermore, the results point to rational exploration of immune modulating strategies in CLM, particularly by exploiting NACT-induced ICD.

Validation of clinical risk scores for laparoscopic liver resections of colorectal liver metastases: A 10-year observed follow-up study

The aim of this study was to validate clinical risk scores in patients underwent laparoscopic resection of colorectal liver metastases (CLM) with 5 years follow‐up or more, and assess 5‐ and 10‐year actual survival in this group.

Survival after resection of colorectal liver metastases in octogenarians and sexagenarians compared to their respective age-matched national population

Background The aim of the current study was to investigate survival after resection of colorectal liver metastases (CLM) in octogenarians. The survival of octogenarian patients was compared to the survival of the national population of octogenarians and the survival of sexagenarians, the latter representing the average-age patient undergoing resection of CLM. Methods Octogenarian and sexagenarian were defined as person 80-89 and 60-69 years of age, respectively. Survival analyses of patients who underwent resection of CLM between 2002 and 2014 were performed. Data from Statistics Norway were used to estimate the survival of the age-matched national population of octogenarians (ageM-Octo) and the age-matched national population of sexagenarians (ageM-Sexa). Results During the study period, 59 octogenarians underwent resection of CLM. The majority of patients underwent a minor liver resection (n=50). In octogenarians, the 5-year survival was 32.5% and 66.3% [difference, 33.8 percentage points (pp)] in patients and ageM-Octo, respectively. The 10-year survival was 14.1% and 31.2% (difference, 17.1 pp) in patients and ageM-Octo, respectively. In sexagenarians, the 5-year survival was 50.9% and 96.2% (difference, 45.3 pp) in patients and ageM-Sexa, respectively. The 10-year survival was 35.7% and 90.3% (difference, 54.6 pp) in patients and ageM-Sexa, respectively. The 5-year cancer-specific survival and 5-year recurrence-free survival (RFS) after resection of CLM in octogenarians were 43.1% and 32.9%, respectively. Conclusions After resection of CLM, the survival was poorer in octogenarians than in sexagenarians. However, the difference between the survival curves of patients and their age-matched population was smaller in octogenarians. In practice, this finding may indicate a greater benefit of resection in the elderly than the survival rates alone would suggest.

Superior mesenteric artery syndrome: quality of life after laparoscopic duodenojejunostomy

In this study, we present results after laparoscopic duodenojejunostomy for five patients with protracted superior mesenteric artery syndrome. The procedure can be performed with minimal perioperative risk and very short postoperative stay. It provides significant postoperative symptom relief for many patients with typical presentation of the syndrome.