Prognosis and Circumferential Margin in Patients with Resected Hilar Cholangiocarcinoma.

BACKGROUND: Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear. METHODS: Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006-2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern. RESULTS: Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33-80). The median follow-up was 21.7 months (range 0.3-92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P < 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P > 0.05). CONCLUSION: Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.

Multicentre validation of a clinical prognostic score integrating the systemic inflammatory response to the host for patients treated with curative-intent for colorectal liver metastases: The Liverpool score.

BACKGROUND: This study aimed to create a new prognostic score integrating the systemic inflammatory response to predict survival in patients treated with curative intent for colorectal liver metastases (CLM). METHODS: We identified independent prognostic factors in patients who underwent liver surgery for CLM in a tertiary centre in the United Kingdom (UK) between 2010 and 2015. A pre- and a postoperative score (Liverpool score) were created by combining these factors to stratify patients into different risk groups. These new scores were validated in an international cohort of 219 patients from China and France. RESULTS: Multivariate cox regression analysis of the 364 patients of the UK cohort identified 6 preoperative and 1 postoperative prognostic factors for overall survival (OS): American society of anaesthesiologists (ASA) score, location and node status of the primary tumour, number and size of CLM, neutrophil-to-lymphocyte ratio (NLR) and resection margin. Both pre- and postoperative scores can be calculated with an online calculator at https://jscalc.io/calc/PXatrmjfrEFpYy2t. Using the pre-operative model on the UK cohort, median OS was 61.22 (50.23, not reached) months in the low-risk group (n = 162) and 30.36 (23.68, 35.95) months in the high-risk group (n = 162, p < 0.0001). The same difference was observed in the validation cohort. The Liverpool score outperformed previously published scoring system with a c-index of 0.619 pre-operatively and of 0.637 post-operatively. CONCLUSION: We developed a new prognostic score based on clinicopathologic characteristics including the site of the primary tumour location and on measurement of the systemic inflammatory response which could help to tailor patients' management.

Reshaping the critical role of surgeons in oncology research.

Surgery remains a mainstay in the treatment of most solid cancers. Surgeons have always engaged in various forms of high-quality cancer research to optimize outcomes for their patients, for example, contributing to clinical research and outcomes research as well as health education and public health policy. Over the past decade, however, concerns have been raised about a global decline in the number of surgeons performing basic science research alongside clinical activity - so-called surgeon scientists. Herein, we describe some of the unique obstacles faced by contemporary trainee and practising surgeons engaged in research, as well as providing a perspective on the implications of the diminishing prominence of the surgeon scientist. Finally, we offer some thoughts on potential strategies and future directions for surgical engagement in oncology research to increase the number of research-active surgeons.

Preoperative Leucocyte-Based Inflammatory Scores in Patients with Colorectal Liver Metastases: Can We Count on Them?

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) have been identified as potential prognostic factors for overall survival (OS) in primary colorectal cancer, and there is a growing interest in their use in colorectal liver metastases (CLMs). However, optimal cut-off values for these ratios have not been defined by making comparison between series difficult. This study aimed to confirm the prognostic value of inflammatory scores in patients undergoing resection for CLM. METHODS: We retrospectively analysed data from 376 consecutive patients who underwent liver surgery for CLM between June 2010 and August 2015. We assessed the reproducibility of previously published ratios and determined new cut-off values using the Cut-off Finder web-based tool. Relations between cut-off values and OS were analysed with Kaplan-Meier log-rank survival analysis and multivariate Cox models. RESULTS: Three hundred and forty-three patients had full preoperative blood tests for calculation of NLR, PLR and LMR. The number of cut-off values which showed a significant discrimination for OS was 49/249 (19.7%) for NLR, 28/316 (8.9%) for PLR and 22/214 (10.3%) for LMR, all with a scattered nonlinear distribution. CONCLUSIONS: This study showed that inflammatory scores expressed as ratios do not seem to be consistently reliable prognostic markers in patients with resectable CLM.

Changing outlook for colorectal liver metastasis resection in the elderly.

BACKGROUND: This study sought to evaluate the impact of the advancements in clinical care, obtained over the last 20 years, for patients aged 70 and older undergoing liver resection for colorectal liver metastases (CRLM). METHODS: Consecutive patients age 70 or older who underwent liver resection for CRLM at Aintree University Hospital (Liverpool, UK) between May 2008 and May 2015 were compared to a dataset of consecutive patients, meeting the same criteria, between 1990 and 2007. An enhanced recovery programme after surgery (ERAS) combined with cardiopulmonary exercise testing (CPET) was introduced in January 2008. RESULTS: The proportion of patients over 70 years undergoing liver resection for CRLM increased over the study period (6% in 1990, 16.3% in 2000, 26.5% in 2005 and 25.8% in 2007). The patients in the later group were more often treated with neoadjuvant chemotherapy (58 vs 34, p = 0.006) and underwent parenchymal sparing surgery, resulting in fewer major hepatectomies (51 vs 111, p < 0.001) and less perioperative morbidity (49 vs 70, p = 0.043) and mortality (3 vs 9, p = 0.229). Although there was shorter disease free survival (DFS) in the later group (DFS at 1, 3 and 5 years was 52.1%, 31.6%, 29% vs. 71.8%, 49.1%, 44.0%)(p < 0.01), similar overall survival (OS) was achieved (OS at 1, 3 and 5 years was 85.4%, 51.6%, 32.8% vs. 81.7%, 42.1%, 27.3%)(p = 0.21). CONCLUSIONS: This study demonstrates that, with modern management (ERAS, CPET, neoadjuvant chemotherapy and parenchymal sparing surgery), a greater number of patients with CRLM, over the age of seventy, can undergo liver resection, with improved perioperative outcomes.

Clinical outcome after resection of early-stage hilar cholangiocarcinoma.

BACKGROUND: Liver transplantation in patients with unresectable early-stage (<3 cm, node negative) hilar cholangiocarcinoma has been recently reported to be associated with longer survival compared to liver resection and therefore suggested as potential treatment option also in resectable disease. Here, we investigated the outcome of resection in early-stage tumours as the standard of care in an experienced European centre. METHODS: Patients with de novo resectable hilar cholangiocarcinomas who underwent liver resection between mid-2009 and December 2017 were classified as early-stage (<3 cm and node negative) or later-stage tumours (≥3 cm and/or node positive), and were investigated with respect to clinical outcome. RESULTS: Fifty-six patients were analyzed of whom 17 had early-stage tumours and 39 had later-stage tumours. The sex ratio (m:f) was 30:26. The median age was 65 years (range 33-80). The median follow-up was 17.0 months (range 0.7-92.4). 5-year overall survival (OS) rates were 82% in patients with early-stage tumours and 23% in patients with later-stage tumours, respectively. Median OS was 89.9 months and 27.6 months, respectively (HR 0.25 (95% CI 0.08-0.84), P = 0.024). CONCLUSIONS: In an experienced European centre, 5-year survival rates after liver resection for early-stage hilar cholangiocarcinoma are comparable with reported outcomes after transplantation. The results of this study question the value of liver transplantation in this setting, especially with respect to the shortage of transplantable organs worldwide.

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.

Optimal perioperative care in peri-hilar cholangiocarcinoma resection.

Surgical resection remains the only proven curative treatment for peri-hilar cholangiocarcinoma. Despite recent advances in liver surgery techniques and perioperative care, resection for peri-hilar cholangiocarcinoma remains associated with significant morbidity and mortality. Considerable variation in the perioperative management of these patients exists. Optimal perioperative management has the potential to deliver improved outcomes. This article seeks to summarize the evidence underpinning best practice in the perioperative care of patients undergoing resection of peri-hilar cholangiocarcinoma. The authors also seek to identify areas where research efforts and future clinical trials should be targeted.

Hepatectomy for octogenarians with colorectal liver metastasis in the era of enhanced recovery.

BACKGROUND: Concern exists regarding the use of hepatectomy to treat colorectal liver metastasis (CRLM) in octogenarians due to prior studies suggesting elevated morbidity and mortality. Cardiopulmonary exercise testing (CPET) within pre-operative assessment and enhanced recovery after surgery (ERAS) have both been shown to be associated with low morbidity and mortality in patients undergoing hepatectomy. This study sought to compare the outcomes of octogenarians with patients aged 70-79 undergoing hepatectomy for CRLM, within a center utilizing both CPET and ERAS. METHODS: Consecutive patients age 70 or older who underwent hepatectomy for CRLM at Aintree University Hospital (Liverpool,UK), between May 2008 and May 2015 were identified from a prospectively maintained cancer database. Data were extracted and comparisons drawn. RESULTS: 127 patients aged 70-79 years and 34 octogenarians underwent respectively 137 and 35 hepatectomy for CRLM. There was no difference in hospital stay (6 days), morbidity and mortality between the groups. OS at 1, 3 and 5 years were 86.7%, 55% and 35.8% for those aged 70-79 compared to 79.4%, 37.3% and 20.4% for the octogenarians (p=0.127). DFS at 1,3 and 5 years was 52.5%, 31.7% and 31.7% for 70-79 group compared to 46.2%, 31.5% and 16.8% for the octogenarians (p=0.838). On multivariate analysis major hepatectomy was associated with an increased risk of post-operative complications, inferior OS and DFS. Chronological age was not a predictor of postoperative complications, poorer OS or DFS. CONCLUSIONS: Appropriately selected octogenarians can have similar postoperative outcomes to patients aged 70-79 when undergoing hepatectomy for CRLM using ERAS combined with CPET. This study advocates using CPET and ERAS in the selection and management of octogenarian patients with CRLM undergoing hepatectomy.

Validation of clinical prognostic scores for patients treated with curative-intent for recurrent colorectal liver metastases.

BACKGROUND: Scoring systems were developed to stratify patients with colorectal liver metastases considered for liver resection into different risk groups. Such scores have never been evaluated in recurrent liver metastases. The aim of this study was to evaluate whether these scores are applicable to patients with recurrent colorectal liver metastases and treated with curative intent. METHODS: We retrospectively analyzed data from 375 consecutive patients who underwent liver surgery for colorectal liver metastases between June 2010 and August 2015. Seventy-three patients developed liver-limited recurrence treated with curative intent. The predictive value of 6 scores (Fong, Sofocleous, Nagashima, Nordlinger, Konopke, and the Basingstoke index) was assessed in this set of patients. RESULTS: Median follow-up was 36.2 months. Overall survival and progression-free survival were 33.6 and 5.6 months, respectively. When scores were applied for OS, none showed a significant stratification between patients, although Nagashima's score showed a significant difference in overall survival between patients from the low-risk group and those from the intermediate- and high-risk groups (40.8 vs 30.5 months, P = 0.039). For PFS, only Fong's score showed a statistically significant stratification (6.6 vs 4.7 months, P = 0.027). CONCLUSION: Scoring systems are of limited-value in stratifying patients operated on for recurrent colorectal liver metastases.

Influence of the primary tumour location in patients undergoing surgery for colorectal liver metastases.

BACKGROUND: The prognosis of patients undergoing liver resection for colorectal liver metastases (CLM) seems to be altered when the primary tumour is right-sided. However, data are lacking and conflicting. We aimed to evaluate the influence of the primary tumour location on oncologic outcomes following such surgery. METHODS: We retrospectively analysed prospectively collected data from 376 consecutive patients who underwent liver surgery for CLM between June 2010 and August 2015. We compared the outcomes of patients with right colon tumours and those with left colorectal tumours. The splenic flexure was used as the cut-off point to determine the anatomic primary site. RESULTS: Among the 364 patients eligible, 74 (20.3%) had a right-sided primary tumour. These patients were older, had a poorer American Society of Anaesthesiologists status and had fewer node-positive primary tumours. The CLM characteristics were similar between both groups. Median PFS was not significantly different between the two groups at 9.9 months, as well as the pattern of recurrence. Median OS was shorter for patients with right-sided primary tumour (34.6 versus 45.3 months, p = 0.035). Similar results were observed when patients with rectal tumour were excluded from analysis (34.6 vs. 47.5 months, p = 0.007). Primary tumour site was an independent prognosis factor in multivariate analysis. CONCLUSION: Right-sided location of the primary tumour is associated with worse OS after surgery for CLM, but seems to have no influence on PFS, and on the pattern of recurrence.

Curative-intent treatment of recurrent colorectal liver metastases: A comparison between ablation and resection.

BACKGROUND: Liver-limited recurrence after resection of colorectal liver metastases is a frequent occurrence, and can in some cases be treated with curative intent. Although surgical re-resection remains standard of care, there is growing interest in the role of ablation in this setting. The aim of this study was to compare the outcomes after curative-intent ablation and resection in patients with recurrent colorectal liver metastases. METHODS: We retrospectively analysed data from 366 consecutive patients who underwent liver resection for colorectal liver metastases between June 2010 and August 2015. Sixty-four developed liver-limited recurrence which was treated with curative intent, thirty-three (51.6%) by ablation and 31 (48.4%) by repeat resection. RESULTS: Patient groups were well matched, with surgically resected patients showing higher pre-operative carcinoembryonic antigen levels and larger metastases. There were fewer post-operative complications and shorter length of stay in the ablation group (p < 0.02). After a median follow-up of 36.2 months, median overall survival was the same for both the resected and ablated groups at 33.3 months. Median progression-free survival was longer for patients treated with surgery (10.2 months) compared to ablation (4.3 months) (p = 0.002). CONCLUSIONS: Ablation or resection for liver-limited recurrence after surgery for colorectal liver metastases is associated with improved overall survival compared with systemic chemotherapy alone, and should always be considered for patients with resectable liver recurrence. Although ablation seemed to be associated with a shorter progression-free survival, post-procedure morbidity was significantly lower. The choice between ablation and resection should therefore be made on a personalised basis.

Resection of Liver Metastases in Colorectal Cancer in the Era of Expanding Systemic Therapy.

About 25% of patients with colorectal cancer develop liver metastases after resection of the primary tumor, and surgical resection of the metastases offers the only opportunity for long-term survival. However, only 20% of patients present with resectable disease. Deciding which patients should be offered surgery, and which should receive additional treatment in the form of perioperative chemotherapy, is complex. For the majority of patients who present with technically irresectable liver-limited disease, systemic downsizing chemotherapy offers the only opportunity to reach surgery and potential cure. Molecular analysis of tumor tissue is improving patient stratification, allowing more appropriate treatment selection, but is not yet a regular part of clinical practice. Decision making is limited by a lack of clear prospective evidence, and so multidisciplinary team assessment is essential to optimize outcomes.

Colorectal Liver Metastases: A Critical Review of State of the Art.

BACKGROUND: Over 50% of patients with colorectal cancer will develop liver metastases. Only a minority of patients present with technically resectable disease. Around 40% of those undergoing surgical resection are alive five years after their diagnosis compared with less than 1% for those with disseminated disease treated with systemic chemotherapy. Surgical resection remains the only possibility for long-term survival for these patients and great efforts have been made to increase the rates of resection whilst improving long-term outcomes. SUMMARY: This review considers current technical and oncological criteria for resection, as well as targeted approaches to stratify underlying tumor biology in order to better predict long-term benefit. The role of neoadjuvant and perioperative systemic chemotherapy is critically reviewed, with suggestions for patient stratification in order to identify those who are likely to derive the greatest benefit. The key role of multidisciplinary assessment and decision making for these complex patients is also discussed. KEY MESSAGES: Surgery remains the optimal treatment for colorectal liver metastases (CRLM). Despite the curative intent of surgical resection, the majority of patients develop recurrence. Surgical strategies should therefore be adopted to maximize the potential for repeat resections in the event of recurrence. Although a number of preoperative prognostic markers have been identified, none are absolute contraindications to resection. In order to reduce postoperative recurrence, neo-adjuvant chemotherapy is now the standard of care in a number of countries. The evidence base for this approach is contentious, and the potential benefit of such a strategy is likely to be greatest in patients with high oncological risk disease. Multidisciplinary care is essential to ensure the optimal management of these complex patients. In addition, all patients with CRLM should be discussed with specialist hepatobiliary surgeons.

The risk of malignancy in ultrasound detected gallbladder polyps: A systematic review.

INTRODUCTION: Gallbladder polyps (GBPs) are a common incidental finding on ultrasound (US) examination. The malignant potential of GBPs is debated, and there is limited guidance on surveillance. This systematic review sought to assess the natural history of ultrasonographically diagnosed GBPs and their malignant potential. METHODS: The keywords: "Gallbladder" AND ("polyp" OR "polypoid lesion") were used to conduct a search in four reference libraries to identify studies which examined the natural history of GBPs diagnosed by US. Twelve studies were eligible for inclusion in this review. RESULTS: Of the 5482 GBPs reported, malignant GBPs had an incidence of just 0.57%. True GBPs had an incidence of 0.60%. Sixty four patients of adenomatous and malignant polyps were reported. Only in one patient was a malignant GBP reported to be <6mm. Risk factors associated with increased risk of malignancy were GBP >6mm, single GBPs, symptomatic GBPs, age >60 years, Indian ethnicity, gallstones and cholecystitis. CONCLUSION: With the reported incidence of GBP malignancy at just 0.57%, a management approach based on risk assessment, clear surveillance planning, and multi disciplinary team (MDT) discussion should be adopted. The utilization of endoscopic ultrasound(EUS) should be Only considered on the grounds of its greater sensitivity and specificity when compared to US scans.