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BACKGROUND: High intra-hepatic fat (IHF) content is associated with insulin resistance, visceral adiposity, and increased morbidity and mortality following liver resection. However, in clinical practice, IHF is assessed indirectly by pre-operative imaging [for example, chemical-shift magnetic resonance (CS-MR)]. We used the opportunity in patients undergoing liver resection to quantify IHF by digital histology (D-IHF) and relate this to CT-derived anthropometrics, insulin-related serum biomarkers, and IHF estimated by CS-MR. METHODS: A reproducible method for quantification of D-IHF using 7 histology slides (inter- and intra-rater concordance: 0.97 and 0.98) was developed. In 35 patients undergoing resection for colorectal cancer metastases, we measured: CT-derived subcutaneous and visceral adipose tissue volumes, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), fasting serum adiponectin, leptin and fetuin-A. We estimated relative IHF using CS-MR and developed prediction models for IHF using a factor-clustered approach. RESULTS: The multivariate linear regression models showed that D-IHF was best predicted by HOMA-IR (Beta coefficient(per doubling): 2.410, 95% CI: 1.093, 5.313) and adiponectin (ß(per doubling): 0.197, 95% CI: 0.058, 0.667), but not by anthropometrics. MR-derived IHF correlated with D-IHF (rho: 0.626; p = 0.0001), but levels of agreement deviated in upper range values (CS-MR over-estimated IHF: regression versus zero, p = 0.009); this could be adjusted for by a correction factor (CF: 0.7816). CONCLUSIONS: Our findings show IHF is associated with measures of insulin resistance, but not measures of visceral adiposity. CS-MR over-estimated IHF in the upper range. Larger studies are indicated to test whether a correction of imaging-derived IHF estimates is valid.

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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.

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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.

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AIMS: To evaluate the role of the Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM), the Portsmouth variant (p-POSSUM) and the Glasgow Prognostic Score (GPS) in predicting outcome after pancreatic surgery with reference to the International Study Group of Pancreatic Surgery (ISGPS) definitions of post-pancreatectomy complications. METHODS: All consecutive patients undergoing major pancreatic resection over a 32- month period were included. POSSUM, p-POSSUM and GPS score were calculated for each patient and correlated against the observed mortality and morbidity using the ISGPS definitions. RESULTS: The observed:expected ratios for POSSUM mortality, POSSUM morbidity and p-POSSUM mortality were 0.24 (p < 0.0001), 0.86 (p < 0.0001) and 0.79 (p = 0.09), respectively. POSSUM had a 'poor fit' with respect to predicting morbidity (χ(2) = 16.4, 8 d.f., p = 0.04). Multifactorial regression analysis revealed the GPS as an independent predictor of post-operative outcome (GPS 1, p = 0.03, OR 2.99, 95% CI 1.4-7.9, and GPS 2, p = 0.02, OR 4.3, 95% CI 1.8-15.5). CONCLUSION: POSSUM has a limited role as an outcome score in pancreatic resection. The GPS may be a novel alternative to POSSUM as a pre-operative predictor of outcome.

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AIMS: To determine the efficacy of radiation dose escalation and to examine organ motion during conformal radiotherapy for locally advanced pancreatic cancer. MATERIALS AND METHODS: Thirty-nine patients who were consecutively treated with chemoradiotherapy were studied. Fifteen patients, treated from 1993 to 1997, received 50 Gy in 20 fractions (group I). Twenty-four patients, treated from 1997 to 2003, received an escalated dose of 55 Gy in 25 fractions (group II). Intra-fraction pancreatic tumour motion was assessed in three patients using megavoltage movies during radiation delivery to track implanted radio-opaque markers. RESULTS: Improved survival rates were seen in latterly treated group II patients (P=0.083), who received escalated radiotherapy to smaller treatment volumes due to advances in verification. Worse toxicity effects (World Health Organization grade 3-4) were reported by some patients (<10%), but treatment compliance was similar in both groups, indicating equivalent tolerance. Substantial intra-fraction tumour displacement due to respiratory motion was observed: this was greatest in the superior/inferior (mean=6.6 mm) and anterior/posterior (mean=4.75 mm) directions. Lateral displacements were small (<2 mm). CONCLUSIONS: Dose escalation is feasible in pancreatic cancer, particularly when combined with a reduction in irradiated volume, and enhanced efficacy is indicated. Large, globally applied margins to compensate for pancreatic tumour motion during radiotherapy may be inappropriate. Strategies to reduce respiratory motion, and/or the application of image-guided techniques that incorporate individual patients' respiratory motion into radiotherapy planning and delivery, will probably improve pancreatic radiotherapy.

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Monthly intravenous pegylated liposomal doxorubicin (PLD) 50 mg m(-2), although well tolerated, showed almost no activity in this phase II study of 16 patients with advanced hepatocellular carcinoma with a response rate of 0%, stable disease 19%, median time to progression of 2.4 months, 1-year survival of 25% and median survival of 6.5 months.

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Despite improvements in treatment, the 5-year survival for metastatic colorectal cancer remains poor. Novel approaches such as gene immunotherapy are being investigated to improve treatment. Retroviral gene transfer methods have been shown to transduce primary human T lymphocytes effectively resulting in the expression of therapeutic genes. However, a number of defects have been identified in T lymphocytes isolated from patients bearing tumour, which may have critical implications for the development of gene-targeted T cells as an anticancer therapy. To address this issue, primary T lymphocytes were isolated from patients with advanced colorectal cancer and tested for their ability to be transduced and to express subsequently a chimeric immune receptor consisting of a single-chain antibody fragment antigen-binding moiety specific for carcinoembryonic antigen (CEA) fused to the T cell receptor (TCR) CD3zeta chain. In 10 out of 10 patients, T lymphocytes were transduced, expanded in the absence of selection and tested for functional activity against CEA-expressing tumour cells. In each case, functional-specific cytotoxic activity was observed. Negligible activity was found in control cultures. This study highlights the feasibility of patient-derived T lymphocytes as a source of immune cells for autologous gene immunotherapy approaches.

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BACKGROUND: This paper reports a 7-year experience of cryoablation for colorectal and non-colorectal liver metastases. METHODS: A retrospective review was undertaken of patients treated in two adjacent UK centres in the north-west of England. RESULTS: Over a 7-year period (1993-2000), 57 patients underwent cryotherapy for malignant hepatic tumours (41 colorectal, 16 non-colorectal). In the patients with colorectal metastases, preoperative carcinoembryonic antigen (CEA) levels fell significantly, from a mean of 444.1 to 6.22 micro g/l (P = 0.002). One patient died, two developed cryoshock and six had cardiorespiratory complications. All patients with colorectal metastases subsequently received 5-fluorouracil-based chemotherapy. The remaining 16 patients with non-colorectal tumours (seven neuroendocrine metastases, five hepatocellular carcinomas, three sarcomas, one cholangiocarcinoma) all received cryotherapy alone, with no major complications. The median survival for patients with non-colorectal metastases was 37 months, compared with 22 months for those with colorectal metastases (P = 0.005). CONCLUSION: Hepatic cryotherapy is effective and safe, as demonstrated by the significant reduction in postoperative CEA concentration and the low risk of complications. However, this initial short-term success was not reflected in 5-year survival rates. Cryotherapy for non-colorectal metastases had a greater long-term survival benefit and is a useful means of controlling symptoms.

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Primary malignant mesenchymal tumors of the liver are extremely rare. We report a case of a primary liposarcoma in the right hepatic lobe of a 50-year-old man. Sonography showed a poorly defined, lobulated, infiltrating echogenic tumor with shadowing. Within the tumor were hyperechoic and hypoechoic foci thought to represent areas of hemorrhage and necrosis. Color Doppler sonography showed the mass to be avascular. A low-attenuation mass of fat density was confirmed on CT. The resected tumor was reasonably well circumscribed, with demonstrable infiltration of the liver parenchyma. Histologic analysis showed liposarcoma with high-grade sarcomatous features.

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Because of its indolent course, high recurrence rate, and risk of malignant transformation, mucinous biliary papillomatosis is an important consideration in the differential diagnosis of bile duct obstruction. We report a case of mucinous biliary papillomatosis and review the sonographic and other imaging findings previously reported in the literature. On sonography, these tumors appear as nonshadowing intrabiliary masses that are clearly defined and associated with proximal biliary dilatation. They may be multiple and associated with mucoid sludge. The imaging findings reflect the macroscopic appearance of a doughy papilliferous tumor of a bile duct. Associated findings include cholelithiasis, choledocholithiasis, and gallbladder dysplasia.

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A modification of the technique of liver transplantation by the face-à-face venacavaplasty is described and the use in four patients reported. This technique enables livers with a small vena cava to be inserted in an anatomic fashion and should help increase the use of such grafts where disparity between vessel size exists.

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The shortage of paediatric liver donors has led to the use of reduced size hepatic allografts. Between July 1987 and July 1990, 30 reduced size orthotopic liver transplantations were performed in 24 children aged between 3 months and 7 years. All patients were in advanced chronic or acute liver failure and were considered unlikely to survive for long enough for a size-matched donor to become available. The most common indication was biliary atresia. The median intraoperative blood loss was 75 (range 13-1015) ml kg-1. Nine patients have died and seven have undergone retransplantation, four successfully. Seven patients had portal vein hypoplasia with a high graft failure rate due to ischaemic infarction. There was significant morbidity from biliary tract complications, leading to further operations in four cases. The 1-year actuarial survival rate was 62 per cent.

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Over a 10-year period from 1980, 46 patients with liver injuries were referred after primary admission to other hospitals. Previous surgery had been performed in 40 cases and the predominant reasons for referral were uncontrollable bleeding and postoperative sepsis with biliary leakage. Of 30 such cases, 19 were treated by liver resection; all were of a limited nature and no major hepatectomies were performed. Only two deaths occurred in these patients and this low mortality rate supports our conservative approach to liver trauma. Other reasons for referral were late biliary stenosis, complicated penetrating injury and intrahepatic haematoma. Three cases were referred with postoperative hepatic failure; two responded to resection of infected necrotic tissue and liver transplantation was attempted in the third. Injuries to liver segments 6 and 7 were those most frequently referred for assistance with bleeding, and all patients were safely transferred after intra-abdominal packing. This injury is particularly suitable for resection by segmentectomy rather than a formal hepatectomy, which has been associated with a high mortality rate in trauma cases. Further patients with intractable injuries might be salvaged by liver transplantation.

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Over 12 years, 22 patients with the Budd-Chiari syndrome were treated surgically. Eighteen underwent a mesenterico-caval shunt (MCS); two, a side-to-side portacaval shunt; one, a mesenterico-atrial shunt (MAS); and one, a liver transplantation (OLT). One patient died after operation from the precipitating condition, and two MCS grafts that thrombosed were restored. All 21 surviving patients remain well, free from ascites, and all shunts are patent after a mean follow-up of 5.6 +/- 1 years, five patients with more than 10 years' follow-up. This long-term survival achieved by portasystemic shunts suggests that they have a major role in the treatment of the Budd-Chiari syndrome. The authors prefer the mesenterico-caval shunt using a jugular graft. This ensures a total portasystemic shunt, avoids subhepatic surgery, and reduces the long-term risk of prosthetic graft thrombosis. The MAS was reserved for cases with complete caval thrombosis. Patients with significant degrees of caval compression were satisfactorily decompressed by MCS. In patients not promptly treated, the disease progresses to cirrhosis, and such patients must be evaluated for transplantation similarly to those with other hepatopathies.

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Malignant change occurring at the site of a stoma in two patients with proved Crohn's disease is described. Patients with ulcerative colitis have an increased risk of colonic malignancy and Crohn's disease is also associated with both small and large bowel carcinoma. Most previous reports of stomal carcinoma have been associated with ulcerative colitis although Crohn's disease seems to carry a greater risk of associated small bowel carcinomas. This is the first report of stomal carcinoma complicating Crohn's disease. Epithelial dysplasia is associated with gastrointestinal carcinomas in both ulcerative colitis and Crohn's disease and a dysplasia-carcinoma sequence has been suggested as the origin of these tumours. In both our patients with stomal adenocarcinoma, dysplasia was identified in adjacent tissues, which suggests a similar mechanism. Malignant change should be suspected if epithelial dysplasia is discovered in a biopsy specimen from the mucosa of an ileostomy in Crohn's disease, and this risk is increased if the dysplasia is of a high grade.

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The development of a malignant soft tissue tumour (malignant fibrous histiocytoma) in a surgical wound is reported. Although rare, this occurrence has important diagnostic implications and the management is discussed.

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