David J Sherlock

Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial.

BACKGROUND The liver is the most frequent site for metastases of colorectal cancer, which is the second largest contributor to cancer deaths in Europe. We did a randomised trial to compare an intrahepatic arterial (IHA) fluorouracil and folinic acid regimen with the standard intravenous de Gramont fluorouracil and folinic acid regimen for patients with adenocarcinoma of the colon or rectum, with metastases confined to the liver. METHODS We randomly allocated 290 patients from 16 centres to receive either intravenous chemotherapy (folinic acid 200 mg/m2, fluorouracil bolus 400 mg2 and 22-h infusion 600 mg/m2, day 1 and 2, repeated every 14 days), or IHA chemotherapy designed to be equitoxic (folinic acid 200 mg/m2, fluorouracil 400 mg/m2 over 15 mins and 22-h infusion 1600 mg/m2, day 1 and 2, repeated every 14 days). The primary endpoint was overall survival, and analysis was by intention to treat. FINDINGS 50 (37%) patients allocated to IHA did not start their treatment, and another 39 (29%) had to stop before receiving six cycles of treatment because of catheter failure. The IHA group received a median of two cycles (0-6), compared with 8.5 (6-12) for the intravenous group. 45 (51%) IHA patients who did not start or did not receive six cycles switched to intravenous treatment. In both groups, grade 3 or 4 toxicity was uncommon. Median overall survival was 14.7 months for the IHA group and 14.8 months for the intravenous group (hazard ratio 1.04 [95% CI 0.80-1.33], log-rank test p=0.79). Similarly, there was no significant difference in progression-free survival. INTERPRETATION Our results showed no evidence of an advantage in progression-free survival or overall survival for the IHA group; thus continued use of this regimen cannot be recommended outside of a clinical trial.

Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy

Vascular endothelial growth factor-C (VEGF-C) and VEGF-D are members of the VEGF family of cytokines and have angiogenic and lymphangiogenic actions. In gastric adenocarcinoma, VEGF-C mRNA and tissue protein expression correlate with lymphatic invasion, lymph node metastasis and in some reports, venous invasion and reduced 5-year survival. Patients with gastric adenocarcinomas containing high levels of VEGF-C expression have significantly reduced 5-year survival rates, and VEGF-C expression is an independent prognostic risk factor for death. The role of VEGF-C in oesophageal squamous and colorectal cancer and VEGF-D in colorectal cancer is not clear, with conflicting reports in the published literature. In order to exploit potential therapeutic applications, further research is necessary to define the precise roles of these cytokines in health and disease.

Lymphatic vessel density, microvessel density and lymphangiogenic growth factor expression in colorectal cancer.

Objective  Microvessel density (MVD) has been studied as a prognostic marker in human cancers. Quantification of lymphatic vessel density (LVD) is now possible by using new antibodies. Expression of the lymphangiogenic growth factors, VEGF‐C and VEGF‐D, is associated with poorer clinicopathological outcomes in various tumours. The aim of this study was to quantify LVD and MVD in colorectal cancer, determine the relationship between LVD, MVD and clinicopathological variables and examine the relationship between LVD and tumour expression of VEGF‐C and VEGF‐D.

Excess adiposity and survival in patients with colorectal cancer: a systematic review.

Excess adiposity is an established risk factor for incident colorectal cancer (CRC) but whether this association extrapolates to poorer survival is unclear. We undertook a systematic review to examine relationships between measures of adiposity and survival in patients with CRC. For distinction, we included pre‐diagnosis exposure and CRC‐related mortality. We performed dose‐response meta‐analyses and assessed study quality using eight domains of bias. Six study categories were identified based on (i) timing of adiposity measurement relative to survival analysis time zero and (ii) clinical setting. Several types of adiposity measurements were reported; body mass index (BMI) was the commonest. For pre‐diagnosis cohorts, baseline BMI negatively impacted on CRC‐related mortality in men only (risk estimate per 5 kg m−2 = 1.19, 95% confidence intervals: 1.14–1.25). The other groups were pre‐diagnosis BMI but diagnosis as time zero; population‐based cohorts; treatment cohorts; observational analyses within adjuvant chemotherapy trials; patients with metastatic CRC – each had several biases (e.g. treatment selection, reverse causality) and sources of confounding (e.g. chemotherapy ‘capping’). Overall, there was insufficient evidence for a strong link between adiposity and survival. These findings demonstrate an important principle: an established link between an exposure (here, adiposity) and increased cancer incidence does not necessarily extrapolate into an inferior post‐treatment outcome.

An MVA-based vaccine targeting the oncofetal antigen 5T4 in patients undergoing surgical resection of colorectal cancer liver metastases.

We investigated the use of a therapeutic vaccine, TroVax in patients undergoing surgical resection of colorectal cancer liver metastases. Systemic immunity generated by vaccination before and after resection of metastases was measured in addition to assessing safety and analyzing the function and phenotype of tumor-associated lymphocytes. Twenty patients were scheduled to receive 2 TroVax vaccinations at 2-week intervals preoperatively and 2 postoperatively; if immune responses were detected, 2 further vaccinations were offered. Blood was taken at trial entry and 2 weeks after each vaccination; tumor biopsies were collected at surgery. 5T4-specific cellular responses were assessed by lymphocyte proliferation and enzyme-linked immunosorbent spot, with antibody responses by enzyme-linked immunosorbent assay. Immunohistochemistry characterized the phenotype of tumor-infiltrating lymphocytes. Seventeen of 19 colorectal cancer patients showed 5T4 expression in the liver metastases or surrounding stroma and 18 mounted a 5T4-specific cellular and/or humoral response. In patients who received at least 4 vaccinations and potentially curative surgery (n=15), those with above median 5T4-specific proliferative responses or T-cell infiltration into the resected tumor showed significantly longer survival compared with those with below median responses. Seven of 8 patients who had preexisting proliferative responses to 5T4 were longer-term survivors; these patients showed significantly higher proliferative responses after vaccination than those who subsequently died. These data suggest that the magnitude of 5T4 proliferative responses and the density of CD3 cells in colorectal cancer liver metastases are associated with longer survival. These observations warrant more studies to identify the precise underlying mechanisms.

Intestinal Ciprofloxacin Efflux: The Role of Breast Cancer Resistance Protein (ABCG2)

Intestinal secretory movement of the fluoroquinolone antibiotic, ciprofloxacin, may limit its oral bioavailability. Active ATP-binding cassette (ABC) transporters such as breast cancer resistance protein (BCRP) have been implicated in ciprofloxacin transport. The aim of this study was to test the hypothesis that BCRP alone mediates intestinal ciprofloxacin secretion. The involvement of ABC transport proteins in ciprofloxacin secretory flux was investigated with the combined use of transfected cell lines [bcrp1/BCRP-Madin-Darby canine kidney II (MDCKII) and multidrug resistance-related protein 4 (MRP4)-human embryonic kidney (HEK) 293] and human intestinal Caco-2 cells, combined with pharmacological inhibition using 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6, 7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143), cyclosporine, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), and verapamil as ABC-selective inhibitors. In addition, the regional variation in secretory capacity was investigated using male Han Wistar rat intestine mounted in Ussing chambers, and the first indicative measurements of ciprofloxacin transport by ex vivo human jejunum were made. Active, Ko143-sensitive ciprofloxacin secretion was observed in bcrp1-MDCKII cell layers, but in low-passage (BCRP-expressing) Caco-2 cell layers only a 54% fraction was Ko143-sensitive. Ciprofloxacin accumulation was lower in MRP4-HEK293 cells than in the parent line, indicating that ciprofloxacin is also a substrate for this transporter. Ciprofloxacin secretion by Caco-2 cell layers was not inhibited by MK571. Secretory flux showed marked regional variability in the rat intestine, increasing from the duodenum to peak in the ileum. Ciprofloxacin secretion was present in human jejunum and was reduced by Ko143 but showed marked interindividual variability. Ciprofloxacin is a substrate for human and rodent BCRP. An additional pathway for ciprofloxacin secretion exists in Caco-2 cells, which is unlikely to be MRP(4)-mediated. BCRP is likely to be the dominant transport mechanism for ciprofloxacin efflux in both rat and human jejunum.

Eotaxin-2 and Colorectal Cancer: A Potential Target for Immune Therapy

Purpose: To study the production of chemokines by colorectal hepatic metastases. Experimental Design: Biopsies of resected colorectal hepatic metastases and nonneoplastic adjacent liver tissue were screened for chemokines using protein arrays and results were confirmed by ELISA and immunohistochemistry. Results: Two chemokines, eotaxin-2 and MCP-1, were found at elevated levels within the tumor biopsy compared with adjacent liver. The relative increase in expression from tumor was much higher for eotaxin-2 than MCP-1, with 10 of 25 donors having a >100-fold increase in expression compared with 0 of 24 donors for MCP-1. In a parallel analysis, eotaxin-2 was also found at elevated levels in the tumor region of primary colorectal cancer biopsies. Immunohistochemical staining indicated that carcinoembryonic antigen–positive tumor cells stained strongly for eotaxin-2, implicating these cells as the predominant source of the chemokine. In vitro studies confirmed that several colorectal tumor lines produce eotaxin-2 and that secretion of this chemokine could be depressed by IFN-γ and enhanced by the Th2-type cytokines interleukin-4 and interleukin-13. Jurkat T cells were engineered to express the receptor for eotaxin-2 (CCR3). These cells effectively migrated in response to eotaxin-2 protein, suggesting that immune cells gene modified to express a chemokine receptor may have improved abilities to home to tumor. Conclusions: Taken together, these observations confirm eotaxin-2 as a chemokine strongly associated with primary and metastatic tumors of colorectal origin. Furthermore, the importance of this result may be a useful tool in the development of targeted therapeutic approaches to colorectal tumors.

International multicentre prospective study on microwave ablation of liver tumours: preliminary results

BACKGROUND Microwave ablation (MWA) is increasingly utilized in the treatment of hepatic tumours. Promising single-centre reports have demonstrated its safety and efficacy, but this modality has not been studied in a prospective, multicentre study. METHODS Eighteen international centres recorded operative and perioperative data for patients undergoing MWA for tumours of any origin in a voluntary Internet-based database. All patients underwent operative MWA using a 2.45-GHz generator with a 5-mm antenna. RESULTS Of the 140 patients, 114 (81.4%) were treated with MWA alone and 26 (18.6%) were treated with MWA combined with resection. Multiple tumours were treated with MWA in 40.0% of patients. A total of 299 tumours were treated in these 140 patients. The median size of ablated lesions was 2.5 cm (range: 0.5-9.5 cm). Tumours were treated with a median of one application (range: 1-6 applications) for a median of 4 min (range: 0.5-30.0 min). A power setting of 100 W was used in 78.9% of cases. Major morbidity was 8.3% and in-hospital mortality was 1.9%. CONCLUSIONS These multi-institution data demonstrate rapid ablation time and low morbidity and mortality rates in patients undergoing operative MWA with a high rate of multiple ablations and concomitant hepatic resection. Longterm follow-up will be required to determine the efficacy of MWA relative to other forms of ablative therapy.

A comparison of diagnostic imaging modalities for colorectal liver metastases.

AIMS The aims of this study were to compare the diagnostic performance of CT scan, MR liver, PET-CT and intra-operative ultrasound (IOUS) for the detection of liver metastases against the histopathological findings, and to compare PET-CT with CT for the detection of distant disease in metastatic colorectal cancer patients eligible for surgical treatment. METHODS A prospective study was performed that measured concordance between the number and stage of metastatic lesions identified with various preoperative imaging modalities and histology of patients undergoing surgical treatment for CRLM. RESULTS Compared with histopathology, concordance for the number of metastatic liver lesions was moderate for CT scan (K = 0.477, 95% CI: 0.28-0.66), moderate for MR scan (K = 0.574, 95% CI: 0.39-0.75), good for FDG PET-CT (K = 0.703, 95% CI: 0.52-0.87) and very good for IOUS (K = 0.904, 95% CI: 0.81-0.99). Additional CRLM were identified intraoperatively in six patients (9.1%) with IOUS and in 7.5% of the cases surgical strategy was changed according to the new intraoperative findings. The diagnosis of intra abdominal lymph node metastatic disease was made with PET-CT only in nine patients (13.6%) DISCUSSION Our study supports the recent recommendations of the Oncosurg Multidisciplinary International Consensus regarding the importance of high quality CT and MR in the staging of CRLM but provides further evidence for the added value of PET-CT, especially in detecting extrahepatic intra-abdominal metastatic disease that may be amenable to potentially curative resection. Despite these advances in preoperative staging, there still remains a role for IOUS in detecting additional metastases at the time of surgery.

Complications arising in simple and polycystic liver cysts

Liver cysts are common, affecting 5%-10% of the population. Most are asymptomatic, however 5% of patients develop symptoms, sometimes due to complications and will require intervention. There is no consensus on their management because complications are so uncommon. The aim of this study was to perform a collected review of how a series of complications were managed at our institutions. Six different patients presenting with rare complications of liver cysts were obtained from Hepatobiliary Units in the United Kingdom and The Netherlands. History and radiological imaging were obtained from case notes and computerised radiology. As a result, 1 patient admitted with inferior vena cava obstruction was managed by cyst aspiration and lanreotide; 1 patient with common bile duct obstruction was first managed by endoscopic retrograde cholangiopancreatography and stenting, followed by open fenestration; 1 patient with ruptured cysts and significant medical co-morbidities was managed by percutaneous drainage; 1 patient with portal vein occlusion and varices was managed by open liver resection; 1 patient with infected cysts was treated with intravenous antibiotics and is awaiting liver transplantation. The final patient with a simple liver cyst mimicking a hydatid was managed by open liver resection. In conclusion, complications of cystic liver disease are rare, and we have demonstrated in this series that both operative and non-operative strategies have defined roles in management. The mainstays of treatment are either aspiration/sclerotherapy or, alternatively laparoscopic fenestration. Medical management with somatostatin analogues is a potentially new and exciting treatment option but requires further study.