Overexpression of the Nek2 kinase in colorectal cancer correlates with beta-catenin relocalization and shortened cancer-specific survival.

The serine/threonine kinase Nek2 (NIMA-related kinase 2) regulates centrosome separation and mitotic progression, with overexpression causing induction of aneuploidy in vitro. Overexpression may also enable tumour progression through effects upon Akt signalling, cell adhesion markers and the Wnt pathway. The objective of this study was to examine Nek2 protein expression in colorectal cancer (CRC). Nek2 protein expression was examined in a panel of CRC cell lines using Western blotting and immunofluorescence microscopy. Nek2 and beta-catenin expression were examined by immunohistochemistry in a series of resected CRC, as well as their matched lymph node and liver metastases, and correlated with clinicopathological characteristics. Nek2 protein expression in all CRC lines examined was higher than in the immortalised colonocyte line HCEC. Nek2 overexpression was present in 86.4% of resected CRC and was significantly associated with advancing AJCC tumour stage and shortened cancer-specific survival. Elevated Nek2 expression was maintained within all matched metastases from overexpressing primary tumours. Nek2 overexpression was significantly associated with lower tumour membranous beta-catenin expression and higher cytoplasmic and nuclear beta-catenin accumulation. These data support a role for Nek2 in CRC progression and confirm potential for Nek2 inhibition as a therapeutic avenue in CRC.

Staging laparoscopy for hilar cholangiocarcinoma in 100 patients.

PURPOSE: Accurate preoperative radiological staging of hilar cholangiocarcinoma remains difficult, and a number of patients are found to have irresectable advanced tumours or occult metastases at exploration. Staging laparoscopy can improve the detection of irresectable disease, avoiding unnecessary laparotomy. This study examines the role of staging laparoscopy in hilar cholangiocarcinoma, with a focus on yield over different time periods and identification of preoperative factors increasing the risk of irresectable disease. METHODS: Retrospective case note review of all patients undergoing staging laparoscopy for radiologically resectable hilar cholangiocarcinoma, identified from the hepatobiliary multidisciplinary team database, was performed. RESULTS: One hundred consecutive patients underwent staging laparoscopy between 1998 and 2011. Of these, 34 patients were found to be irresectable due to metastatic disease, and 11, due to extensive local disease. Fifty patients proceeded to exploratory laparotomy following staging laparoscopy, and 36 % (18/50) of whom were found to have irresectable disease: 12 patients due to advanced local disease and 6 patients due to metastases. The overall yield of laparoscopy was 45 %, and the accuracy was 71 %. There was no significant difference in age, preoperative bilirubin, neutrophil/lymphocyte ratio, Ca19-9 levels or T stage between patients with resectable disease and with irresectable disease on laparoscopy. There was also no change in the yield of laparoscopy over time, despite advances in radiological imaging. CONCLUSION: In this series, staging laparoscopy avoided unnecessary laparotomy in 45 % of patients with radiologically resectable hilar cholangiocarcinoma. No factor was able to predict positive yield, and therefore, all patients with potentially resectable hilar cholangiocarcinoma should undergo staging laparoscopy.

Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo.

The aims of this study were to determine potency of oxaliplatin in combination with curcumin in oxaliplatin-resistant cell lines in vitro and to evaluate the efficacy of a novel curcumin formulation (Meriva®) alone and in combination with oxaliplatin in colorectal tumor-bearing mice, exploring relevant pharmacodynamic markers in vivo. Oxaliplatin-resistant HCT116 p53wt and p53(-/-) cell lines were generated, and the effects of oxaliplatin in combination with curcumin on resistance- and proliferation-associated proteins investigated. Eighty nude mice were implanted with HCT116 p53wt colorectal cancer cells before randomization into the following treatment groups: control; Meriva only; oxaliplatin only; Meriva + oxaliplatin. Tumor volume was assessed, as was the expression of Ki-67, cleaved caspase-3 and Notch-1. Curcumin in combination with oxaliplatin was able to decrease proliferative capacity of oxaliplatin-resistant p53 wildtype and p53(-/-) cell lines more effectively than oxaliplatin alone. It also decreased markers associated with proliferation. After 21 days of treatment in the xenograft model, the order of efficacy was combination > Meriva > oxaliplatin > control. The decrease in tumor volume when compared to vehicle-treated animals was 53, 35 and 16%, respectively. Ki-67 and Notch-1 immunoreactivity was decreased by the combination when compared to vehicle-treated animals, with cleaved caspase-3 rising by 4.4-fold. Meriva did not adversely affect the DNA-platinating ability of oxaliplatin. Curcumin enhanced the cytotoxicity of oxaliplatin in models of oxaliplatin resistance in vitro. In vivo, Meriva greatly enhanced oxaliplatin efficacy, without affecting the mode of action of oxaliplatin. Addition of formulated curcumin to oxaliplatin-based chemotherapy regimens has the potential for clinical benefit.

Bilirubin levels predict malignancy in patients with obstructive jaundice.

BACKGROUND: Differentiating between benign and malignant causes of obstructive jaundice can be challenging, even with the advanced imaging and endoscopic techniques currently available. In patients with obstructive jaundice, the predictive accuracy of bilirubin levels at presentation was examined in order to determine whether such data could be used to differentiate between malignant and benign disease. METHODS: A total of 1,026 patients with obstructive jaundice were identified. Patients were divided into benign and malignant groups. The benign patients were subgrouped into those with choledocholithiasis and those with inflammatory strictures of the biliary tree. Bilirubin levels at presentation and other demographic data were obtained from case records. RESULTS: Area under the curve (AUC) values for bilirubin as a predictor of malignancy were highly significant for all benign presentations and for those with benign biliary strictures (AUC: 0.8 for both groups; P < 0.001). A bilirubin level > 100 µmol/l was determined to provide the optimum sensitivity and specificity for malignancy in all patients and in those without choledocholithiasis (71.9% and 86.9%, 71.9% and 88.0%, respectively). The application of a bilirubin level > 250 µmol/l achieved specificities of 97.1% and 98.0% in each subgroup of patients, respectively. CONCLUSIONS: In patients with obstructive jaundice, bilirubin levels in isolation represent an important tool for discriminating between benign and malignant underlying causes.

Preoperative early warning scores can predict in-hospital mortality and critical care admission following emergency surgery.

BACKGROUND: EWS is frequently used to monitor acute admissions requiring emergency surgery. This study examined preoperative early warning scoring (EWS) and its ability to predict mortality and critical care admission. Postoperative EWS was also evaluated as a predictor of mortality. METHODS: Preoperative EWS, age, physiologic and operative severity (POSSUM) scores, ASA grade, and serology were compared in 280 patients undergoing emergency surgery. RESULTS: Two hundred eighty patients were identified with a mortality of 15%. Among the physiological scoring systems, ASA grade and POSSUM scores were the best predictors of mortality (AUC values of 0.81). EWS, APACHE II, and age were the next best predictors (AUC values of 0.70). Postoperative APACHE II and EWS both predicted mortality. EWS on day 2 postoperatively was the best overall predictor of mortality of all the variables studied (AUC value of 0.83). Survival between patients with "improving or stable" EWS and those with "deteriorating or failing to improve" EWS was also found to be significantly different (P < 0.001). In addition, both EWS on admission and EWS 1 h preoperatively were found to predict critical care requirement postoperatively (AUC value of 0.78). CONCLUSIONS: EWS can predict the need for critical care admission and mortality following emergency surgery. In particular, the progression of EWS preoperatively, that is, whether scores improve or deteriorate, is a highly significant factor in predicting survival following emergency surgery. These findings support the use of EWS in monitoring the acute surgical patient.

A review of factors predicting perioperative death and early outcome in hepatopancreaticobiliary cancer surgery.

OBJECTIVES: In the context of comparisons of surgical outcomes, risk adjustment is the retrospective adjustment of a provider's or a surgeon's results for case mix and/or hospital volume. It allows accurate, meaningful inter-provider comparison. It is therefore an essential component of any audit and quality improvement process. The aim of this study was to review the literature to identify those factors known to affect prognosis in hepatobiliary and pancreatic cancer surgery. METHODS: PubMed was used to identify studies assessing risk in patients undergoing resection surgery, rather than bypass surgery, for hepatobiliary and pancreatic cancer. RESULTS: In total, 63 and 68 papers, pertaining to 24 609 and 63 654 patients who underwent hepatic or pancreatic resection for malignancy, respectively, were identified. Overall, 22 generic preoperative factors predicting outcome on multivariate analysis, including demographics, blood results, preoperative biliary drainage and co-morbidities, were identified, with tumour characteristics proving disease-specific factors. Operative duration, transfusion, operative extent, vascular resection and additional intra-abdominal procedures were also found to be predictive of early outcome. CONCLUSIONS: The development of a risk adjustment model will allow for the identification of those factors with most influence on early outcome and will thus identify potential targets for preoperative optimization and allow for the development of a multicentre risk prediction model.

Hepatic Resection Following Selective Internal Radiation Therapy for Colorectal Cancer Metastases in the FOXFIRE Clinical Trial: Clinical Outcomes and Distribution of Microspheres.

The FOXFIRE (5-Fluorouracil, OXaliplatin and Folinic acid ± Interventional Radio-Embolisation) clinical trial combined systemic chemotherapy (OxMdG: Oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radio-embolisation) using yttrium-90 resin microspheres in the first-line management for liver-dominant metastatic colorectal cancer (CRC). We report clinical outcomes for patients having hepatic resection after this novel combination therapy and an exploratory analysis of histopathology. Multi-Disciplinary Teams deemed all patients inoperable before trial registration and reassessed them during protocol therapy. Proportions were compared using Chi-squared tests and survival using Cox models. FOXFIRE randomised 182 participants to chemotherapy alone and 182 to chemotherapy with SIRT. There was no statistically significant difference in the resection rate between groups: Chemotherapy alone was 18%, (n = 33); SIRT combination was 21% (n = 38) (p = 0.508). There was no statistically significant difference between groups in the rate of liver surgery, nor in survival from time of resection (hazard ratio (HR) = 1.55; 95% confidence interval (CI) = 0.83-2.89). In the subgroup studied for histopathology, microsphere density was highest at the tumour periphery. Patients treated with SIRT plus chemotherapy displayed lower values of viable tumour in comparison to those treated with chemotherapy alone (p < 0.05). This study promotes the feasibility of hepatic resection following SIRT. Resin microspheres appear to preferentially distribute at the tumour periphery and may enhance tumour regression.

Ultrasound changes within the liver after total pancreatectomy and intrahepatic islet cell autotransplantation.

OBJECTIVE: Intrahepatic infusion is the most common method of islet autotransplantation. Structural and functional changes within the liver may result from a number of factors, including embolization of the terminal branches of the portal vein, the effects of high insulin concentration on surrounding hepatocytes or responses to the death of admixed exocrine tissue. Awareness of the potential changes in the appearance of the liver on ultrasonography (USS), together with an assessment of liver function, is important in the postoperative surveillance of these patients. METHODS: We retrospectively reviewed 83 patients who underwent total pancreatectomy between 1993 and 2006. Thirty-three patients had total pancreatectomy alone (control group) and 50 patients underwent total pancreatectomy and islet autotransplantation (islet group). The islets were infused into the left lobe of the liver through the middle colic or recannalated umbilical vein. All patients underwent USS as part of their hepaticojejunostomy surveillance (initially every 6 months and then yearly). RESULTS: "Echogenic nodularity" of the liver was observed in 25% of the islet group of patients and in none of the control group patients (P=0.03). These USS changes occurred from 6 to 12 months after islet autotransplantation and were not associated with any significant loss of liver function or increase in insulin requirements. The islet group had significantly less insulin requirement compared with the control group (P<0.01). CONCLUSION: Echogenicity with a nodular appearance is a common ultrasonographic finding in the liver after intrahepatic islet autotransplantation. These changes do not seem to adversely affect liver function or insulin requirement. Appreciating these changes is important to avoid misinterpretation or over-interpretation of postoperative USS images.

Survival following curative resection for pancreatic ductal adenocarcinoma. A systematic review of the literature.

CONTEXT: Patients with resectable pancreatic cancer comprise a small subgroup of the overall population with the disease from around 15 to 20%, with nearly all patients dying from their disease within 7 years of surgery. In the light of such bleak statistics, data regarding what factors may influence outcome, following attempted curative resection is essential in order to optimise the treatment options for patients. METHODS: This review analysed all English-language publications using PubMed and Web of Science databases for studies detailing outcomes following resection for pancreatic ductal adenocarcinoma from 1980 to the present day. MAIN OUTCOME MEASURES: The data examined from papers were post-operative mortality rates, median survival, yearly survival rates and other factors which may have influenced long-term survival; such as patient demographics, operative details and tumour characteristics (such as example tumour size, lymph node metastases and tumour differentiation). RESULTS: There has been significant improvement in post-operative mortality over the last decades with a modest improvement in long-term survival. With the exception of post-operative blood transfusion, tumour characteristics remain the only significant features influencing survival after pancreatic cancer surgery. Favourable prognostic factors include tumour size less than 2 cm, negative resection margin, lymph node negative tumours, well-differentiated tumours and absence of perineural or blood vessel invasion. CONCLUSION: In light of these data, it could be reasoned that tumour size, on cross-sectional imaging, might be employed as means of selecting the most appropriate candidates for surgery, in cases where the risks of resection are high.

An unusual case of concurrent insulinoma and nesidioblastosis.

CONTEXT: Endogenous hyperinsulinaemic hypoglycaemia in adults is most commonly caused by an insulinoma. Adult nesidioblastosis is rarely reported. To the best of our knowledge the presence of both insulinoma and nesidioblastosis has not been reported before. CASE REPORT: We report a case of a 35-year-old female presenting with neuroglycaemic symptoms. A supervised 72-hour fast confirmed hypoglycaemia in the presence of hyperinsulinaemia. Thorough pre-operative biochemical and radiological investigations, including selective splenic, superior mesenteric and portal venous sampling inferred a tentative diagnosis of adult nesidioblastosis. However, a grossly elevated insulin level within the splenic vein on a second set of venous sampling produced a high index of suspicion for the presence of an insulinoma. At surgical exploration both an insulinoma and nesidioblastosis were identified and confirmed by histological examination. CONCLUSION: We report an even rarer entity of concurrent insulinoma and nesidioblastosis.

Prognostic molecular markers in hepatocellular carcinoma: a systematic review.

Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and its incidence is rising. Surgery, including transplantation, remains the only potentially curative modality for HCC, yet recurrence rates are high and long-term survival poor. The ability to predict individual recurrence risk and subsequently prognosis would help guide surgical and chemotherapeutic treatment. As understanding of hepatocarcinogenesis has increased, the myriad of genetic and molecular events that drive the hepatocarcinogenic disease process, including angiogenesis, invasion and metastasis, have been identified. This systematic review examines the evidence from published manuscripts reporting the prognostic potential of molecular biomarkers in hepatocellular carcinoma. In summary, a number of molecular biomarkers with prognostic significance have been identified in hepatocellular carcinoma. Not only might these molecules allow more accurate prediction of prognosis for patients with HCC, but they may also provide targets for potential therapeutic agents.

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 micromol/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.

Quantitation of silibinin, a putative cancer chemopreventive agent derived from milk thistle (Silybum marianum), in human plasma by high-performance liquid chromatography and identification of possible metabolites.

Silibinin has recently received attention as a potential cancer chemopreventive agent because of its antiproliferative and anticarcinogenic effects. A simple and specific reversed-phase high-performance liquid chromatography method was developed and validated for the quantitation of silibinin in human plasma. Sample preparation involved simple protein precipitation, and separation was achieved on a Waters Atlantis C18 column with flow rate of 1.0 mL/min at 40 degrees C and UV detection at 290 nm. Silibinin was detected as two peaks corresponding to trans-diastereoisomers. The peak area was linear over the investigated concentration range (0-5000 ng/mL). The limits of detection were 2 and 1 ng/mL for the two diastereoisomers (d1 and d2), with a recovery of 53-58%. This method was utilized to detect silibinin in plasma of colorectal patients after 7 days of treatment with silipide (silibinin formulated with phosphatidyl choline).

Early warning scores predict outcome in acute pancreatitis.

The Early Warning Score (EWS) is a widely used general scoring system to monitor patient progress with a varying score of 0-20 in critically unwell patients. This study evaluated the EWS system compared with other established scoring systems in patients with acute pancreatitis. EWS scores were compared with APACHE scores, Imrie scores, computed tomography grading scores, and Ranson criteria for 110 admissions with acute pancreatitis. A favorable outcome was considered to be survival without intensive therapy unit admission or surgery. Nonsurvivors, necrosectomy, and critical care admission were considered adverse outcomes. EWS was the best predictor of adverse outcome in the first 24 hours of admission (receiver operating curve, 0.768). The most accurate predictor of mortality overall was EWS on day 3 of admission (receiver operating curve, 0.920). EWS correlated with duration of intensive therapy unit stay and number of ventilated days (P < 0.05) and selected those who went on to develop pancreas-specific complications such as pseudocyst or ascites. EWS of 3 or above is an indicator of adverse outcome in patients with acute pancreatitis. EWS can accurately and reliably select both patients with severe acute pancreatitis and those at risk of local complications.

Expression of thrombospondin-1 in resected colorectal liver metastases predicts poor prognosis.

PURPOSE: The aim of this study was to examine the expression and prognostic relevance of thrombospondin-1 (TSP-1) in tumor biopsies taken from a consecutive series of liver resections done at the University Hospitals of Leicester and the Royal Liverpool Hospital. EXPERIMENTAL DESIGN: Patients having undergone a liver resection for colorectal liver metastases at our institutions between 1993 and 1999 inclusive were eligible. Inclusion criteria were curative intent, sufficient tumor biopsy, and patient follow-up data. One hundred eighty-two patients were considered in this study. Standard immunohistochemical techniques were used to study the expression of TSP-1 in 5-microm tumor sections from paraffin-embedded tissue blocks. TSP-1 was correlated with survival using the Kaplan-Meier method and log-rank test for univariate analysis and the Cox proportional hazard model for multivariate analysis. RESULTS: One hundred eighty-two patients (male, n = 122 and female, n = 60) ages between 25 and 81 years (mean, 61 years) were included. TSP-1 was expressed around blood vessels (n = 45, 25%) or in the stroma (n = 59, 33%). No expression was detected in the remaining tumors. TSP-1 significantly correlated with poor survival on univariate (P = 0.01 for perivascular expression and P = 0.03 for stromal expression) and multivariate analysis (P = 0.01 for perivascular expression). CONCLUSION: TSP-1 is a negatively prognostic factor for survival in resected colorectal liver metastases.

Hypoxia and angiogenesis in pancreatic cancer.

BACKGROUND: Pancreatic cancer remains one of the most lethal of all solid tumours of the gastrointestinal tract. It is characterized by late diagnosis, aggressive local invasion, early metastasis and resistance to chemoradiotherapy. Increasing knowledge regarding the molecular events behind the growth and invasion of pancreatic cancer may lead to new targets for intervention. METHODS: A search of Pubmed and Medline databases was undertaken using the keywords pancreatic cancer, gastrointestinal cancer, hypoxia, angiogenesis and anti-angiogenesis therapy. RESULTS: Hypoxia is the driving force behind angiogenesis in pancreatic cancers. Research into angiogenesis has shown many different sites that can be targeted by agents such as tyrosine kinase inhibitors. CONCLUSION: Anti-angiogenic therapy could be an important adjunct to conventional chemotherapy treatment of gastrointestinal neoplasia.

Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences.

Curcumin, a constituent of the spice turmeric, has been shown to reduce the adenoma burden in rodent models of colorectal cancer accompanied by a reduction of levels of the oxidative DNA adduct 3-(2-deoxy-beta-di-erythro-pentafuranosyl)-pyr[1,2-alpha]-purin-10(3H)one (M(1)G) and of expression of the enzyme cyclooxygenase-2 (COX-2). We tested the hypothesis that pharmacologically active levels of curcumin can be achieved in the colorectum of humans as measured by effects on levels of M(1)G and COX-2 protein. Patients with colorectal cancer ingested curcumin capsules (3,600, 1,800, or 450 mg daily) for 7 days. Biopsy samples of normal and malignant colorectal tissue, respectively, were obtained at diagnosis and at 6 to 7 hours after the last dose of curcumin. Blood was taken 1 hour after the last dose of curcumin. Curcumin and its metabolites were detected and quantitated by high-performance liquid chromatography with detection by UV spectrophotometry or mass spectrometry. M(1)G levels and COX-2 protein expression were measured by immunoslot blot and Western blotting, respectively. The concentrations of curcumin in normal and malignant colorectal tissue of patients receiving 3,600 mg of curcumin were 12.7 +/- 5.7 and 7.7 +/- 1.8 nmol/g, respectively. Curcumin sulfate and curcumin glucuronide were identified in the tissue of these patients. Trace levels of curcumin were found in the peripheral circulation. M(1)G levels were 2.5-fold higher in malignant tissue as compared with normal tissue (P < 0.05 by ANOVA). Administration of curcumin (3,600 mg) decreased M(1)G levels from 4.8 +/- 2.9 adducts per 107 nucleotides in malignant colorectal tissue to 2.0 +/- 1.8 adducts per 107 nucleotides (P < 0.05 by ANOVA). COX-2 protein levels in malignant colorectal tissue were not affected by curcumin. The results suggest that a daily dose of 3.6 g curcumin achieves pharmacologically efficacious levels in the colorectum with negligible distribution of curcumin outside the gut.

Spontaneous intramural esophageal hematoma.

We report the case of an 80-year-old woman who developed a spontaneous intramural esophageal hematoma and review the available literature. Spontaneous intramural esophageal hematoma (SIOH) is a rare but important condition. Because the cardinal symptom is severe chest pain, the condition is often initially misdiagnosed as an acute cardiac event or aortic dissection. Increased awareness of SIOH may prevent misdiagnosis on the basis of endoscopic and radiological appearances.

Percutaneous splanchnic nerve radiofrequency ablation for chronic abdominal pain.

BACKGROUND: Splanchnic nerve block is a useful alternative to coeliac plexus block in the management of patients with chronic upper abdominal pain. The predictable relationship of the splanchnic nerves to other structures allows for accurate needle placement and hence a low risk of iatrogenic damage. Radiofrequency ablation (RFA) uses a high frequency alternating current to heat tissues leading to thermal coagulation. It produces predictable and accurate lesions and hence is useful alternative to more conventional phenol and alcohol neurolytic methods. METHODS: The present study examined a series of 10 patients undergoing percutaneous RFA splanchnic nerve blockade for chronic pancreatitis. Pain levels, anxiety, quality of life, daily activity, mood and interpersonal relationships were all assessed pre- and postprocedure, using a visual analogue score. Median follow-up was 18 months (range: 12-24 months). Statistical analysis was undertaken using non-parametric Wilcoxon matched pair analysis, statistical significance was set at the 95% confidence intervals. RESULTS: Splanchnic nerve RFA not only led to a decrease in pain scores, opiate analgesia use and acute admissions for pain; but it also resulted in improvement of other parameters associated with long-term debilitating chronic pain, such as anxiety levels, daily activity, overall mood and general perception of health. There were no major complications. All changes observed were statistically significant. CONCLUSION: Although preliminary data regarding RFA ablation of splanchnic nerves are encouraging, further trials are also needed comparing percutaneous splanchnic nerve ablation with opioid analgesia and coeliac plexus blockade.

Combining curcumin (C3-complex, Sabinsa) with standard care FOLFOX chemotherapy in patients with inoperable colorectal cancer (CUFOX): study protocol for a randomised control trial.

BACKGROUND: The need for low toxicity adjuncts to standard care chemotherapy in inoperable colorectal cancer, with potential to improve outcomes and decrease the side-effect burden, is well recognised. Addition of the low toxicity diet-derived agent, curcumin (the active ingredient of turmeric), to standard oxaliplatin-based therapy has shown promise in numerous pre-clinical studies. METHODS/DESIGN: This study is the first to combine daily oral curcumin with standard care FOLFOX-based (5-fluorouracil, folinic acid and oxaliplatin) chemotherapy in colorectal cancer patients with inoperable liver metastases: the CUFOX trial. CUFOX comprises a Phase 1 dose-escalation study (3 + 3 + 3 design) to determine an acceptable target dose of curcumin with which to safely proceed to a Phase IIa open-labelled randomised controlled trial. Thirty three participants with histological or cytological confirmation of inoperable colorectal cancer will then be randomised to oxaliplatin-based chemotherapy with the addition of daily oral curcumin at the target dose determined in Phase I, or to standard care oxaliplatin-based chemotherapy alone (recruiting at a ratio of 2:1). DISCUSSION: Primary outcome measures will be the determination of a target dose which is both safe and tolerable for long-term administration to individuals in receipt of first-line oxaliplatin-based chemotherapy for inoperable colorectal cancer. Secondary outcome measures will include observation of any changes in neuropathic side-effects of chemotherapy, improvement to progression-free or overall survival and identification of putative efficacy biomarkers in plasma. The results will be disseminated via presentation at national and international conferences, via publication in appropriate peer-reviewed journals and via the Cancer Research UK/Department of Health Experimental Cancer Medicine Centre Network. This trial has full ethical and institutional approval, and commenced recruitment in February 2012. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01490996 , registered 7(th) December 2011), European Drug Regulating Authorities (EudraCT 2011-002289-19, registered 13(th) May 2011), UKCRN ID#10672.