Breast cancer liver metastases: systematic review and time to event meta-analysis with comparison between available treatments.

INTRODUCTION: The current gold standard treatment for breast cancer liver metastases (BCLM) is systemic chemotherapy and/or hormonal therapy. Nonetheless, greater consideration has been given to local therapeutic strategies in recent years. We sought to compare survival outcomes for available systemic and local treatments for BCLM, specifically surgical resection and radiofrequency ablation. METHODS: A review of the PubMed (MEDLINE), Embase and Cochrane Library databases was conducted. Data from included studies were extracted and subjected to time-to-event data synthesis, algorithmically reconstructing individual patient-level data from published Kaplan-Meier survival curves. FINDINGS: A total of 54 studies were included, comprising data for 5,430 patients (surgery, n=2,063; ablation, n=305; chemotherapy, n=3,062). Analysis of the reconstructed data demonstrated survival rates at 1, 3 and 5 years of 90%, 65.9% and 53%, respectively, for the surgical group, 83%, 49% and 35% for the ablation group and 53%, 24% and 14% for the chemotherapy group (p<0.0001). CONCLUSION: Local therapeutic interventions such as liver resection and radiofrequency ablation are effective treatments for BCLM, particularly in patients with metastatic disease localised to the liver. Although the data from this review support surgical resection for BCLM, further prospective studies for managing oligometastatic breast cancer disease are required.

Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC. METHODS: This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred. RESULTS: There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63). CONCLUSIONS: The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.

Graduated Compression Stockings as an Adjunct to Low Dose Low Molecular Weight Heparin in Venous Thromboembolism Prevention in Surgery: A Multicentre Randomised Controlled Trial.

BACKGROUND: The evidence base upon which current global venous thromboembolism (VTE) prevention recommendations have been made is not optimal. The cost of purchasing and applying graduated compression stockings (GCS) in surgical patients is considerable and has been estimated at £63.1 million per year in England alone. OBJECTIVE: The aim was to determine whether low dose low molecular weight heparin (LMWH) alone is non-inferior to a combination of GCS and low dose LMWH for the prevention of VTE. METHODS: The randomised controlled Graduated compression as an Adjunct to Pharmacoprophylaxis in Surgery (GAPS) Trial (ISRCTN 13911492) will randomise adult elective surgical patients identified as being at moderate and high risk of VTE to receive either the current "standard" combined thromboprophylactic LMWH with GCS mechanical thromboprophylaxis, or thromboprophylactic LMWH pharmacoprophylaxis alone. To show non-inferiority (3.5% non-inferiority margin) for the primary endpoint of all VTE within 90 days, 2236 patients are required. Recruitment will be from seven UK centres. Secondary outcomes include quality of life, compliance with stockings and LMWH, overall mortality, and GCS or LMWH related complications (including bleeding). Recruitment commenced in April 2016 with the seven UK centres coming "on-line" in a staggered fashion. Recruitment will be over a total of 18 months. The GAPS trial is funded by the National Institute for Health Research Health Technology Assessment in the UK (14/140/61).

Novel xylan-controlled delivery of therapeutic proteins to inflamed colon by the human anaerobic commensal bacterium.

INTRODUCTION: Growth factors such as keratinocyte growth factor-2 (KGF-2) and transforming growth factor-beta (TGF-ß) are important immunoregulatory and epithelial growth factors. They are also potential therapeutic proteins for inflammatory bowel disease. However, owing to protein instability in the upper gastrointestinal tract, it is difficult to achieve therapeutic levels of these proteins in the injured colon when given orally. Furthermore, the short half-life necessitates repeated dosage with large amounts of the growth factor, which may have dangerous side effects, hence the importance of temporal and spatial control of growth factor delivery. METHODS: The human commensal gut bacterium, Bacteroides ovatus, was genetically engineered to produce human KGF-2 or TGF-ß1 (BO-KGF or BO-TGF) in a regulated manner in response to the dietary polysaccharide, xylan. The successful application of BO-KGF or BO-TGF in the prevention of dextran sodium sulphate induced murine colitis is presented here. RESULTS: This novel drug delivery system had a significant prophylactic effect, limiting the development of intestinal inflammation both clinically and histopathologically. The ability to regulate heterologous protein production by B ovatus using xylan is both unique and an important safety feature of this drug delivery system. CONCLUSIONS: The use of genetically engineered B ovatus for the controlled and localised delivery of epithelial growth promoting and immunomodulatory proteins has potential clinical applications for the treatment of various diseases targeting the colon.

Fatty liver disease as a predictor of local recurrence following resection of colorectal liver metastases.

BACKGROUND: Obesity and tissue adiposity constitute a risk factor for several cancers. Whether tissue adiposity increases the risk of cancer recurrence after curative resection is not clear. The present study analysed the influence of hepatic steatosis on recurrence following resection of colorectal liver metastases. METHODS: A prospective cohort of patients who had primary resection of colorectal liver metastases in two major hepatobiliary units between 1987 and 2010 was studied. Hepatic steatosis was assessed in non-cancerous resected liver tissue. Patients were divided into two groups based on the presence of hepatic steatosis. The association between hepatic steatosis and local recurrence was analysed, adjusting for relevant patient, pathological and surgical factors using Cox regression and propensity score case-match analysis. RESULTS: A total of 2715 patients were included. The cumulative local (liver) disease-free survival rate was significantly better in the group without steatosis (hazard ratio (HR) 1·32, 95 per cent confidence interval 1·16 to 1·51; P < 0·001). On multivariable analysis, hepatic steatosis was an independent risk factor for local liver recurrence (HR 1·28, 1·11 to 1·47; P = 0·005). After one-to-one matching of cases (steatotic, 902) with controls (non-steatotic, 902), local (liver) disease-free survival remained significantly better in the group without steatosis (HR 1·27, 1·09 to 1·48; P = 0·002). Patients with steatosis had a greater risk of developing postoperative liver failure (P = 0·001). CONCLUSION: Hepatic steatosis was an independent predictor of local hepatic recurrence following resection with curative intent of colorectal liver metastases.

Intermittent Pringle manoeuvre is not associated with adverse long-term prognosis after resection for colorectal liver metastases.

BACKGROUND: Intermittent clamping of the porta hepatis, or the intermittent Pringle manoeuvre (IPM), is often used to control inflow during parenchymal liver transection. The aim of this study was to determine whether IPM is associated with an adverse long-term outcome after liver resection for colorectal liver metastasis (CRLM). METHODS: All patients undergoing resection for CRLM in 1993-2006, for whom data on IPM were recorded, were included in the study. A total of 563 patients was available for analysis. RESULTS: IPM was performed in 289 (51.3 per cent) of the patients. The duration of IPM ranged from 2 to 104 (median 22) min. There were no differences in clinicopathological features or postoperative morbidity between patients who had an IPM and those who did not. The median survival of patients undergoing IPM was 55.7 months compared with 48.9 months in those not having an IPM (P = 0.406). There was no difference in median disease-free survival between the two groups (22.1 versus 19.9 months respectively; P = 0.199). CONCLUSION: IPM is not associated with an adverse long-term prognosis in patients undergoing liver resection for CRLM.

Surgeon's awareness of the synchronous liver metastases during colorectal cancer resection may affect outcome.

AIM: There is conflicting evidence about the importance of synchronous metastases upon tumor outcome. The aim of this study is to identify the effect of finding synchronous colorectal liver metastases on the performance of the surgeon whilst operating on primary colorectal cancer. METHODS: Patients with completed colorectal cancer data who underwent liver resection for colorectal metastases between 1993 and 2001 were included. Two hundred seventy patients were categorised according to the site of the primary tumour (colon or rectum) and knowledge of the presence of liver metastases by the colorectal surgeon (SA=surgeon aware, n=112, SNA=surgeon not aware, n=158). The number of retrieved lymph nodes and colorectal resection margin involvement were used as surgical performance indicators. Survival and local recurrence rate were monitored. RESULTS: The SA group had a higher rate of colorectal circumferential resection margin involvement, the local and intra-abdominal recurrence rate was also significantly higher in this group (p<0.001). CONCLUSIONS: Awareness of the presence of liver metastases by the operating surgeon is an independent predictor of intra abdominal extra hepatic recurrence of colorectal cancer following potentially curative hepatic resection. This is related to an increased rate of primary colorectal resection margin involvement.

Effect of type of resection on outcome of hepatic resection for colorectal metastases.

BACKGROUND: Non-anatomical liver resections have become more common in the management of colorectal liver metastases. This study examined survival and patterns of recurrence following surgery for colorectal liver metastases. METHODS: Data were collected prospectively on all patients who had hepatic surgery for colorectal liver metastases at St James' University Hospital, Leeds between 1993 and May 2003, and analysed with respect to type of resection. RESULTS: A total of 96 patients underwent non-anatomical liver resection, 280 patients had an anatomical resection, and 108 patients had a combined procedure. There was no significant difference in overall survival between the anatomical and non-anatomical groups (hazard ratio 1.14 (95 per cent confidence interval 0.60 to 2.17); P = 0.691). Intrahepatic recurrence was significantly less common in the anatomical group, whereas morbidity and mortality rates were lower in the non-anatomical group. On multivariable analysis, multiple metastases and poorer primary T stage predicted poorer overall survival and a positive resection margin predicted poorer disease-free survival. CONCLUSION: Non-anatomical resection can be performed with lower rates of surgical morbidity and mortality than anatomical resection, and does not disadvantage the patient in terms of overall survival.

C-reactive protein as a predictor of prognosis following curative resection for colorectal liver metastases.

There is increasing evidence that systemic inflammatory response has a positive correlation with a poorer outcome in patients undergoing resection for solid tumours. The aim of this study was to analyse the impact of an elevated C-reactive protein (CRP), an outcome following curative resection for colorectal liver metastases. One hundred and seventy patients who underwent curative resection for colorectal liver metastases were included in the study. Laboratory measurements of haemoglobin, white cell, platelets, albumin and CRP were taken on the day before surgery. Elevated CRP (>10 mg l(-1)) was present in 54 (31.8%) patients. The median survival of patients with an elevated CRP was 19 months (95% CI 7.5-31.2 months) compared to 42.8 months (95% CI 33.2-52.5 months) for those with a normal CRP, P=0.004. Similarly, when assessing disease-free survival, patients with an elevated CRP had poorer disease-free survival (median of 11.8 months (95% CI 6.4-17.3) compared to median of 15.1 months (95% CI 11.1-19.1)), P=0.043. The result of the study showed that an elevated preoperative CRP is a predictor of poor outcome in patients undergoing curative resection for colorectal liver metastases.

Outcome following repeat liver resection for colorectal liver metastases.

AIM: Our aim was to determine independent predictors of survival after second liver resection and to confirm whether the type of first resection influences survival after repeat resection. METHODS: Fifty-four patients who underwent a second liver resection for colorectal liver metastases were analyzed. To find independent predictors of survival, possible prognostic factors regarding the primary tumor, and the first and second resections were used in the Cox regression analysis. RESULTS: There were three postoperative deaths within 90 days of surgery. The 3- and 5-year overall survival rates were 53% and 46%, respectively. The size of the tumor (>50mm) (p=0.005), serum carcinoembryonic antigen level (>30microg/L) (p=0.002), and the presence of a positive surgical margin at the second resection (p=0.006) were independent predictors of poor survival following the second resection. The type of first resection was not associated with survival but was associated with the ability to achieve a histological negative surgical margin at the second liver resection (p=0.01). CONCLUSION: Three independent predictors of survival were identified. Major initial liver resection was associated with a reduced ability to achieve surgical clearance at the second resection. For colorectal liver metastases, major resection should only be performed if a negative margin cannot be achieved by minor resection.

Prognostic influence of multiple hepatic metastases from colorectal cancer.

AIMS: The aim of this study was to report the results of surgery for multiple colorectal liver metastases on patient outcome. METHODS: This was a review of 484 consecutive patients who underwent liver resection for colorectal liver metastases between 1993 and 2003. The cohort was divided into 2 groups, those with 1-3 metastases and those with "multiple" metastases, namely 4 or more lesions. The later group was subdivided into those with less than 8 ("several") or 8 or more ("numerous") separate lesions. MAIN OUTCOME MEASURES: the post-operative hospital stay was calculated and morbidity and mortality were assessed. RESULTS: On multivariate analysis the presence of multiple metastases was the only predictor for both poorer overall survival (p=0.007) and disease-free survival (p=0.031). However, when patients with multiple metastases are analysed in detail this survival disadvantage appears to be only present in patients with numerous (8 or more) lesions. CONCLUSION: Although patients with multiple metastases appear to have a poorer outcome, significant number of patients with multiple metastases survive to 5 years or more and should not be denied surgery. Patients with numerous (8 or more) metastases showed a poorer survival disadvantage. These patients need alternative treatment speculatives.

Resection margin in patients undergoing hepatectomy for colorectal liver metastasis: a critical appraisal of the 1cm rule.

AIM: We undertook this study to evaluate the influence of resection margin distance from metastases on survival and post-operative disease recurrence after hepatectomy for colorectal liver metastasis. METHODS: Between January 1993 and December 2001, 293 consecutive patients underwent primary liver resection for colorectal metastasis. Clinical, pathological and outcome data were analysed using a prospectively collected database. Cases were stratified into those with involved and non-involved resection margins. Different non-involved margin widths were analysed against survival, recurrence rate and pattern (hepatic, extra hepatic) of recurrence. RESULTS: The 1, 3, 5 and 10 years actuarial survival rates were 82, 58, 44 and 36%, respectively. The median survival was 46 months. The histological liver resection margin involvement was a significant predictor of survival and disease free survival after surgery. One, two, five and 10 millimetres disease free resection margin widths were found not to be significant in influencing patients' survival or recurrence rate. CONCLUSION: A positive hepatic resection margin was associated with a higher incidence of post-operative recurrence and lower survival rate. The width of the resection margin did not influence the post-operative recurrence rate or pattern of recurrence. The '1 cm rule' should be abandoned.

Hepatic resection for colorectal metastasis; time to challenge the accepted doctrine.

The selection of patients for resection of colorectal liver metastasis (CRLM) is based around a set of established rules and principles, some of which date back to and have changed little since the mid 1980's. In this paper the authors challenge this accepted doctrine and describe the criteria used for selection of patients for surgery in their own centre, criteria which permit the inclusion of many more patients for potentially curative surgery. They go on to describe methods used to increase resectability and discuss their own results achieved for the resection of CRLM.

Surgical pathological second opinion in thyroid malignancy: impact on patients' management and prognosis.

OBJECTIVES: To evaluate the effect of inter-institutional surgical pathology review of thyroid cancer on patients' treatment and prognosis. METHODS: All cases referred to the Institute of Pathology at Leeds for thyroid pathology review between January 2001 and March 2003 were included. The referring pathologists reports were compared to those produced in the MDT meeting by the expert pathologist. Whenever there was disagreement a third expert opinion was sought who was blinded for both diagnoses. Effects on management and prognosis were evaluated if there was disagreement. RESULTS: Of the 66 patients reviewed, 12 (18%) had a different pathological diagnosis (kappa=0.33). Two had their diagnosis changed from malignant to benign and a further two from benign to malignant. Eight patients had their prognosis downgraded and four upgraded after histopathological review. Five patients had their management affected by the new pathological diagnosis. CONCLUSION: A second opinion of surgical pathology for thyroid tumours can result in major therapeutic and prognostic modifications. All cases of suspected thyroid cancers should be reviewed in a multidisciplinary meeting supported by pathologist with experience in thyroid pathology.