Ashley R. Dennison

Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients.

ObjectiveCurrently, there is considerable controversy about the place of transplantation in the treatment of hepatocellular carcinoma (HCC). This study compared resection to transplantation in cirrhotic patients with HCC in order to determine reasonable indications of each treatment. Summary Background DataThe usual procedure is to resect when feasible and to transplant in other cases. MethodsThree-year survival with and without recurrence was analyzed in 60 patients who underwent resection and 60 who underwent transplantation. Several prognostic factors, such as size, number of nodules, portal thrombus, and histologic form, were studied. ResultsIn terms of overall survival rates, resection and transplantation yield the same results (50% vs. 47%, respectively, at 3 years). For transplantation, however, the rate for survival without recurrence is better than that for resection (46% vs. 27%, respectively; p < 0.05). In the case of small uninodular or binodular tumors (> 3 cm), transplantation has much better results than resection (survival without recurrence, 83% vs. 18%, respectively; p < 0.001). However, it seems that a group of patients with high risk of recurrence after transplantation can be determined (diffuse form, more than two nodules > 3 cm, or presence of portal thrombus). ConclusionsThe best indication for transplantation seems to be patients with small and uninodular or binodular tumors; until now, these patients were considered to be the best candidates for resection. Patients undergoing transplantation for unresectable, large, multinodular or diffuse tumors seem to represent bad indications for transplantation. These results could help define reasonable indications for transplantation in an era with a shortage of liver grafts.

The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential.

Omega-3 fatty acid (omega-3 FA) consumption has long been associated with a lower incidence of colon, breast and prostate cancers in many human populations. Human trials have demonstrated omega-3 FA to have profound anti-inflammatory effects in those with cancer. In vitro and small animal studies have yielded a strong body of evidence establishing omega-3 FA as having anti-inflammatory, anti-apoptotic, anti-proliferative and anti-angiogenic effects. This review explores the evidence and the mechanisms by which omega-3 FA may act as angiogenesis inhibitors and identifies opportunities for original research trialling omega-3 FAs as anti-cancer agents in humans. The conclusions drawn from this review suggest that omega-3 FAs in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found principally in oily fish have potent anti-angiogenic effects inhibiting production of many important angiogenic mediators namely; Vascular Endothelial Growth Factor (VEGF), Platelet-Derived Growth Factor (PDGF), Platelet-Derived Endothelial Cell Growth Factor (PDECGF), cyclo-oxygenase 2 (COX-2), prostaglandin-E2 (PGE2), nitric oxide, Nuclear Factor Kappa Beta (NFKB), matrix metalloproteinases and beta-catenin.

Improvements in survival by aggressive resections of hilar cholangiocarcinoma.

The operative management of hilar Cholangiocarcinoma has evolved because of advances in diagnostic imaging that have permitted improved patient selection, and refinements in operative techniques that have lowered operative mortality rates. Over a 4-year period, 48 patients with hilar Cholangiocarcinoma were managed. Twenty-seven patients were treated by palliative measures. Preoperative investigation identified 29 patients who were judged fit for operation without proven irresectability by radiologic studies, and 21 of the 29 patients had tumor removal (72%). Twenty-three operative procedures were performed: local excision (n = 12) (two had subsequent hepatic resection), and hepatic resection primarily (n = 9). Eight patients had complications (35%), and one patient died (4.3%). The mean actuarial survival after local excision is 36 months, and after hepatic resection, 32 months. Palliation as assessed by personal interview was excellent for more than 75% of the months of survival. A combination of careful patient selection and complete radiologic assessment will allow an increased proportion of patients to be resected by complex operative procedures with low mortality rate, acceptable morbidity rate, and an increase in survival with an improved quality of life.

Pilot Study of Oral Silibinin, a Putative Chemopreventive Agent, in Colorectal Cancer Patients: Silibinin Levels in Plasma, Colorectum, and Liver and Their Pharmacodynamic Consequences

Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I. Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M1dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 μmol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141 nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M1dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.

Segmental nature of the porcine liver and its potential as a model for experimental partial hepatectomy

In‐depth knowledge of pig liver anatomy allows potential research into segmental liver resections and hepatic regeneration, as well as liver transplantation techniques. The segmental anatomy, however, remains largely unknown. This study aimed to delineate the segmental anatomy of the porcine liver in comparison with that of the human.

Pancreatectomy with islet autotransplantation for the treatment of severe chronic pancreatitis: the first 40 patients at the leicester general hospital.

Background. Surgical resection of the pancreas is considered a final resort in the treatment of chronic pancreatitis. However, the opportunity to perform an islet autotransplant at the same time provides the potential to prevent the onset of diabetes. Methods. Pancreatectomy together with islet autotransplantation has been offered in our center since 1994. A total of 40 patients have now undergone this procedure. The follow‐up times range from 6 months to 7 years. The data presented here include the annual postoperative oral glucose tolerance test and glycosylated hemoglobin (HbA1c) results, together with insulin and opiate requirements. Results. Nineteen male and 21 female patients (median age 44, range 21‐65) have been transplanted. Pancreatitis was related to alcohol in 45% and was idiopathic in 40%. A median of 130,108 (24,332‐1, 165,538) islet equivalent (IEQ) were transplanted, which related to 2,020 (320‐23,311) IEQ per kilogram of body weight. At 2 years posttransplant, 18 patients had a median HbA1c of 6.6% (5.2‐19.3%), fasting C‐peptide of 0.66 ng/mL (0.26‐2.65 ng/mL), and required a median of 12 (0‐45) units of insulin per day. At 6 years, these figures were 8% (6.1‐11.1%), 1.68 ng/mL (0.9‐2.78 ng/ml) and 43 U/day (6‐86 U/day), respectively. The majority of patients no longer require opiate analgesia, 68% have been able to return to work, and one patient has had a baby. Conclusions. Islet autotransplantation offers a valuable addition to surgical resection of the pancreas, as a treatment for chronic pancreatitis; and even in cases in which insulin independence is not achieved, the potential beneficial effects of C‐peptide make the procedure worthwhile.

Prediction of Mortality in Acute Pancreatitis: A Systematic Review of the Published Evidence

Objective: In this review, we focus on studies that examined such prognostic indices in relation to predicting a fatal outcome from pancreatitis. Summary Background Data: Acute pancreatitis (AP) is a common emergency, and early identification of high-risk patients can be difficult. For this reason, a plethora of different prognostic variables and scoring systems have been assessed to see if they can reliably predict the severity of pancreatitis and/or subsequent mortality. Methods: All studies that focused on AP, including retrospective series and prospective trials, were retrieved and analysed for factors that could influence mortality. Articles that analysed factors influencing the severity of the disease or the manifestation of disease-related complications were excluded. Results: 58 articles meeting the inclusion criteria were identified. Among the various factors investigated, APACHE II seemed to have the highest positive predictive value (69%). However, most prognostic variables and scores showed high negative predictive values but suboptimal values for positive predictive power. Conclusions: Despite the proliferation of scoring systems for grading AP, none are ideal for the prediction of mortality. With the exception of the APACHE II, the other scores and indexes do not have a high degree of sensitivity, specificity and predictive values.

Pilot Study of Oral Anthocyanins for Colorectal Cancer Chemoprevention

Naturally occurring anthocyanins possess colorectal cancer chemopreventive properties in rodent models. We investigated whether mirtocyan, an anthocyanin-rich standardized bilberry extract, causes pharmacodynamic changes consistent with chemopreventive efficacy and generates measurable levels of anthocyanins in blood, urine, and target tissue. Twenty-five colorectal cancer patients scheduled to undergo resection of primary tumor or liver metastases received mirtocyan 1.4, 2.8, or 5.6 grams (containing 0.5-2.0 grams anthocyanins) daily for 7 days before surgery. Bilberry anthocyanins were analyzed by high performance liquid chromatography (HPLC) with visible or mass spectrometric detection. Proliferation was determined by immunohistochemistry of Ki-67 in colorectal tumor. Concentrations of insulin-like growth factor (IGF)-I were measured in plasma. Mirtocyan anthocyanins and methyl and glucuronide metabolites were identified in plasma, colorectal tissue, and urine, but not in liver. Anthocyanin concentrations in plasma and urine were roughly dose-dependent, reaching ∼179 ng/gram in tumor tissue at the highest dose. In tumor tissue from all patients on mirtocyan, proliferation was decreased by 7% compared with preintervention values. The low dose caused a small but nonsignificant reduction in circulating IGF-I concentrations. In conclusion, repeated administration of bilberry anthocyanins exerts pharmacodynamic effects and generates concentrations of anthocyanins in humans resembling those seen in ApcMin mice, a model of FAP adenomas sensitive to the chemopreventive properties of anthocyanins. Studies of doses containing <0.5 gram bilberry anthocyanins are necessary to adjudge whether they may be appropriate for development as colorectal cancer chemopreventive agents.

Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function.

Total pancreatectomy is considered the final resort in the treatment of chronic pancreatitis; however, here we show that simultaneous islet autotransplantation can abrogate the onset of diabetes. Methods: In Leicester, 46 patients have now undergone total pancreatectomy with immediate islet auto transplant, and they have received a median of 2246 islet equivalent (IEQ)/kg body weight (range, 405-20,385 IEQ/kg body weight). Results: Twelve patients have shown periods of insulin independence, for a median of 16.5 months (range, 2-63 months), and 5 remain insulin independent. Over the 10 years of follow-up, there has been a notable increase in insulin requirement per kilogram per day, and percentage of glycosylated hemoglobin levels have increased significantly (r = 0.66, P = 0.01). However, 100% of patients tested were C-peptide positive at their most recent assessment, and high fasting and stimulated C-peptide values recorded at 10 years after transplantation, 1.44 (range, 1.09-1.8 ng/mL) and 2.86 ng/mL (range, 1.19-4.53 ng/mL), respectively, suggest significant graft function in the long term. In addition, median serum creatinine has increased very little after the operation (71 nmol/L [range, 49-125 nmol/L] atpreoperation vs 76.5 nmol/L [range 72-81 nmol/L] at year 10), suggesting no diabetic nephropathy. Conclusions: Although there is a notable decline in islet function after islet auto transplant, there is still evidence of significant long-term insulin secretion and possible protection against diabetic complications.Abbreviations: CP - chronic pancreatitis, HbA1c - glycosylated hemoglobin, IEQ - islet equivalent, OGTT - oral glucose tolerance test, TP - total pancreatectomy

Phytochemicals as potential chemopreventive and chemotherapeutic agents in hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and the incidence is rising. Surgery, including transplantation resection, is currently the most effective treatment for HCC; however, recurrence rates are high and long-term survival is poor. Identifying novel chemopreventive and chemotherapeutic agents and targeting them to patients at high risk of developing HCC or following curative treatment may go some way towards improving prognosis. This review examines current knowledge regarding the chemopreventive and chemotherapeutic potential of phytochemicals in heptocarcinogenesis. Both in-vitro and animal studies demonstrate that several phytochemicals, including curcumin, resveratrol, green tea catechins, oltipraz and silibinin, possess promising chemopreventive and chemotherapeutic properties. Despite this, very few clinical trials have been performed. Problems regarding validation of biomarkers, agent delivery, side effects and patient selection are barriers that need to be overcome to determine the potential of such agents in clinical practice.