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In view of safety concerns surrounding the use of pharmaceuticals such as nonsteroidal anti-inflammatory drugs and tamoxifen as cancer chemopreventive agents, potentially innocuous phytochemicals derived from the diet are considered attractive alternatives. However, results from cancer chemoprevention trials of dietary agents have been disappointing to date, as promising activities observed in rodent models and cells in vitro have not translated into clinical success. This may be partly due to the development process for these agents, which is complex for a number of reasons; the definitive end point, inhibition of carcinogenesis, requires large numbers of individuals followed-up over many years. Furthermore, whereas biomarkers are frequently used as surrogate efficacy end points to expedite the process, biomarker assessment and validation has proven difficult because dietary agents exert multiple actions with an unknown hierarchy of biological importance. These factors have made determining the dose for clinical investigation extremely challenging, and at present, there are no defined strategies for rationally identifying the most appropriate doses. In this commentary, the complexities involved in the development of dietary chemoprevention agents are discussed, and a tentative route towards selection of the optimal clinical dose is proposed. The approach highlights the need to conduct long-term preclinical studies with realistic concentrations that are achievable in human tissues and the importance of efficacy biomarkers that are intrinsically linked to the key mechanisms of action. A more logical design of studies should increase the likelihood that the encouraging preclinical results observed for many phytochemicals translate into tangible clinical benefit.

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

Supplementary Figure 1 from Development of Dietary Phytochemical Chemopreventive Agents: Biomarkers and Choice of Dose for Early Clinical Trials

Supplementary Tables 1-5, Methods from Development of Dietary Phytochemical Chemopreventive Agents: Biomarkers and Choice of Dose for Early Clinical Trials

Perspective on this Article from Pilot Study of Oral Anthocyanins for Colorectal Cancer Chemoprevention

Supplementary Table 2 from Development of Dietary Phytochemical Chemopreventive Agents: Biomarkers and Choice of Dose for Early Clinical Trials

Background The dietary polyphenol resveratrol prevents various malignancies in preclinical models, including prostate cancer. Despite attempts to translate findings to humans, gaps remain in understanding pharmacokinetic-pharmacodynamic relations and how tissue concentrations affect efficacy. Such information is necessary for dose selection and is particularly important given the low bioavailability of resveratrol. Objectives This study aimed to determine concentrations of resveratrol in prostate tissue of men after a dietary-achievable (5 mg) or pharmacological (1 g) dose. We then examined whether clinically relevant concentrations of resveratrol/its metabolites had direct anticancer activity in prostate cell lines. Methods A window trial was performed in which patients were allocated to 5 mg or 1 g resveratrol daily, or no intervention, before prostate biopsy. Patients (10/group) ingested resveratrol capsules for 7–14 d before biopsy, with the last dose [14C]-labeled, allowing detection of resveratrol species in prostate tissue using accelerator MS. Cellular uptake and antiproliferative properties of resveratrol/metabolites were assessed in cancer and nonmalignant cell cultures using HPLC with UV detection and cell counting, respectively. Results [14C]-Resveratrol species were detectable in prostate tissue of all patients analyzed, with mean ± SD concentrations of 0.08 ± 0.04 compared with 22.1 ± 8.2 pmol/mg tissue for the 5 mg and the 1 g dose, respectively. However, total [14C]-resveratrol equivalents in prostate were lower than we previously reported in plasma and colorectum after identical doses. Furthermore, resveratrol was undetectable in prostate tissue; instead, sulfate and glucuronide metabolites dominated. Although resveratrol reduced prostate cell numbers in vitro over 7 d, the concentrations required (≥10 µM) exceeded the plasma maximum concentration. Resveratrol mono-sulfates and glucuronides failed to consistently inhibit cell growth, partly due to poor cellular uptake. Conclusions Low tissue concentrations of resveratrol species, coupled with weak antiproliferative activity of its conjugates, suggest daily doses of ≤1 g may not have direct effects on human prostate. This trial was registered at clinicaltrialsregister.eu as EudraCT 2007-002131-91.

Background: The Notch pathway is frequently activated in cancer. Pathway inhibition by g-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. Methods: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000mgm-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour. Results: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. Conclusions: Gemcitabine and a g-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.

Background: Marine-derived ω-3 fatty acids (ω-3FAs) have proven antitumor activity in vivo and in vitro and improve quality of life (QOL) in clinical cancer studies. These changes may be mediated by reduction in circulating proangiogenic and proinflammatory factors. In this first study of intravenous ω-3FAs as a therapy in cancer patients, we aimed to assess if it could augment the antitumor activity of gemcitabine in patients with advanced pancreatic cancer and improve QOL. Materials and Methods: Patients were administered gemcitabine 1000 mg/m3 weekly followed by up to 100 g (200 mg/mL) of ω-3 rich lipid emulsion for 3 weeks followed by a rest week. This was continued for up to 6 cycles, progression, unacceptable toxicity, patient request, or death. The primary outcome measure was objective response rate, with secondary outcome measures of overall and progression free survival, QOL scores, and adverse events. Results: Fifty patients were recruited. Response rate was 14.3% and disease control rate was 85...

BACKGROUND: Pancreatic adenocarcinoma (PAC) is a devastating condition, with the majority of patients presenting with metastatic or locally advanced disease. In these patients their disease is classified as advanced pancreatic cancer (APC), which is incurable and associated with survivals generally of a few months. The overall survival (OS) for pancreatic cancer has not changed significantly in the past forty years with multiple trials demonstrating disappointing results. Immune modulatory cells particularly myeloid derived suppressor cells (MDSCs) and T regulatory cells (Tregs) are important mediators in PAC. Omega 3 fatty acids (ω-3FAs) have been shown to have anti-inflammatory properties and there is now evidence demonstrating the benefit of ω-3FAs in PAC. METHODS: This was a single-center cohort study investigating intravenous ω-3FAs and gemcitabine chemotherapy versus gemcitabine therapy only in patients with APC. Here, we investigated levels of MDSCs and Tregs and examined how these changes correlated with survival. RESULTS: Eighteen trial and nine control patients were recruited. There was a significant benefit in progression-free survival (PFS) in trial compared to control patients (P=0.0003). Median survival in trial patients was 5.65 months compared to 1.8 months in control patients. There was no significant benefit in OS in trial compared to control patients (P=0.13). Median survival in trial patients was 7 months compared to 2.9 months in control patients. MDSCs were significantly decreased in trial patients (P=0.0001) but not control patients. Conversely Tregs were significantly increased in control patients (P=0.005) but not in trial patients. CONCLUSIONS: Administration of ω-3FAs with gemcitabine chemotherapy in APC results in a significant decrease of MDSCs and stability of Tregs. This may be secondary to the reduction of pro-inflammatory mediators. A phase three randomized trial is justified to further examine these effects.

Introduction Survival in metastatic colorectal cancer is worse than expected in the United Kingdom. Real-world data are needed to better understand UK-specific treatment practices that may explain this. Patients and Methods The Avastin ColORectal Non-interventional (ACORN) study is a multicenter, prospective, UK-based, observational, phase 4 study ( ClinicalTrials.gov , NCT01506167 ) that recruited patients with metastatic colorectal cancer scheduled to receive bevacizumab in combination with first-line chemotherapy as part of routine clinical practice. Primary end points included progression-free survival, overall survival (OS), serious adverse events (AEs), and grade 3 to 5 bevacizumab-related AEs. Results A total of 714 patients were recruited between August 30, 2012, and February 4, 2014. Median follow-up was 16.4 months. Median first-line chemotherapy duration was 5.6 months, with capecitabine/oxaliplatin (265 [37.1%]) being the most common regimen. Median total chemotherapy duration was 8.1 months and did not vary by geographic location in the UK. Median progression-free survival (95% confidence interval) was 8.7 (8.2-9.1) months, and median OS was 17.8 (16.1-19.3) months. There was no significant difference in efficacy by chemotherapy regimen administered. Ninety-nine patients (13.9%) received bevacizumab after disease progression. The safety profile of bevacizumab was consistent with previous studies. Conclusion ACORN provided evidence that there were no clear differences observed in outcomes between bevacizumab with capecitabine-based chemotherapy and fluorouracil-based regimens, and confirmed the safety profile of bevacizumab in a real-world UK-based population. The lower-than-expected OS is likely due to the short total chemotherapy duration, less frequent use of bevacizumab after disease progression, and higher rates of in-situ primary tumors.

Summary Background & aims Omega-3 rich fatty acids (n-3FA) have powerful anti-inflammatory and anti-neoplastic properties. Previous studies have investigated plasma and cellular uptake of oral and parenteral n-3FA regimens. These have shown that n-3FA undergo rapid uptake into cells which is sustained for the length of the treatment course. The aim of this study was to investigate long-term uptake of prolonged, regular treatment courses of parenteral n-3FA which has not been previously reported. Methods As part of a phase II single-arm trial, patients with advanced pancreatic cancer were treated with gemcitabine plus parenteral n-3FA rich lipid emulsion (up to 100 g) each week for three consecutive weeks with a subsequent rest week. This was repeated for up to six months in total for each patient. Pre-treatment serum and erythrocyte cell membrane (ECM) pellet samples were obtained each week for the entire treatment course of each patient. Post-treatment samples were obtained for the first two cycles only to assess rapid uptake. Fatty acid methyl esters (FAME) were produced and analysed using gas chromatography. FAME proportions as a total of sample lipid composition for each class were plotted and the results analysed using a linear regression coefficient model. Results There was rapid and significant uptake of EPA and DHA FAME into plasma Non-Esterified Fatty Acids (NEFA) and EPA into ECM pellets in post-treatment samples (median increase of 1.06%, 0.65% and 0.05% respectively). There was significant reduction in n-6 fatty acid FAMEs and DHA in ECM pellets (decrease of 0.31% and 0.8% respectively- p = 0.031 for all). There was significant sustained uptake of EPA and DHA FAME into ECM pellets over the cohort's pooled treatment course with corresponding reduction in the n-6:n-3 ratio. Conclusions Prolonged regular parenteral n-3FA administration results in rapid and sustained cellular uptake. This regimen is appropriate for therapies aimed at increasing n-3FA content of cellular membranes and reduction of the n-6:n-3 ratio.

Lung cancer is responsible for over one million deaths worldwide each year. Smoking cessation for lung cancer prevention remains key, but it is increasingly acknowledged that prevention strategies also need to focus on high-risk groups, including ex-smokers, and patients who have undergone resection of a primary tumor. Models for chemoprevention of lung cancer often present conflicting results, making rational design of lung cancer chemoprevention trials challenging. There has been much focus on use of dietary bioactive compounds in lung cancer prevention strategies, primarily due to their favorable toxicity profile and long history of use within the human populace. One such compound is curcumin, derived from the spice turmeric. This review summarizes and stratifies preclinical evidence for chemopreventive efficacy of curcumin in models of lung cancer, and adjudges the weight of evidence for use of curcumin in lung cancer chemoprevention strategies.

SUMMARY Colon cancer is the third most common cancer worldwide. Sigmoidoscopy and colonoscopy, with the removal of rectal and colon polyps, are proven strategies for the prevention of colon cancer, and testing for fecal occult blood helps to identify subjects suitable for endoscopy. Evidence that low-dose aspirin is associated with a substantial reduction in colon cancer risk and reduces the number and growth of colon polyps is accumulating from randomized trials and observational studies. Advantages and disadvantages of endoscopy and aspirin prophylaxis are discussed extensively in this review. The reduction in cancer incidence by the two approaches together is considerably enhanced as they complement each other. Expenditure could become more cost effective if the two were promoted together.

Although gemcitabine remains current first-line chemotherapy for patients with advanced pancreatic cancer, median survival times have not improved significantly since its introduction 15 years ago. Of the phase III trials which have investigated alternative regimens to single-agent gemcitabine, most have used combination regimens as the investigational arm. Accurate data on median overall, progression-free survival and objective response rates is important, for two principle reasons: advising patients about their prognosis and when powering phase II trials and evaluating the results of single-armed trials. This study aims to pool results from published randomized trials to date. Twenty-one randomized phase III trials involving a total of 6348 patients were identified from 1997 to 2010. Only one trial investigating a novel agent in combination with gemcitabine showed a significantly prolonged median and progression-free survival compared with single-agent gemcitabine. Pooled median and progression-free survivals for the single-agent gemcitabine arm involving 3171 patients across all studies were 6.15 and 3.3 months, respectively. Length of survival for patients with advanced pancreatic cancer remains disappointing. Further trials of novel agents to complement or replace gemcitabine are indicated.

Many cancers contain cell subpopulations that display characteristics of stem cells. These cells are characterised by their ability to self-renew, form differentiated progeny and develop resistance to chemotherapeutic strategies. Cancer stem cells may utilise many of the same signalling pathways as normal stem cells including Wnt, Notch and Hedgehog. The dietary agent curcumin exerts a plethora of anti-carcinogenic effects both in vitro and in vivo, and can also inhibit many of the signalling pathways associated with stem cell biology. Emerging evidence suggests that curcumin can exert its anti-carcinogenic activity via targeting cancer stem cells through the disruption of stem cell signalling pathways. In this review we summarise the ability of curcumin to interfere with signalling pathways Wnt, Hedgehog, Notch, Signal Transducers and Activator (STAT) and interleukin-8, and report curcumin-induced changes in function and properties of cancer stem cells. We present evidence that the effects of curcumin on cancer stem cells mediate, or contribute to, its anti-carcinogenic activity.

Among the plethora of biochemical mechanisms engaged by resveratrol in preclinical systems, its anticarcinogenic effects represent some of the most convincing and intriguing. As outlined in this review, there is considerable interest in developing resveratrol for cancer prevention and treatment. The plasma pharmacokinetics of resveratrol in humans are now reasonably well defined, and studies have shown that repeated daily doses up to 1 g are safe and well tolerated, although gastrointestinal toxicity is observed at higher intakes. However, care is needed regarding underlying conditions in specific patient groups, and there is potential for drug interactions at doses greater than 1 gram. Little is known regarding the pharmacodynamic effects of resveratrol in humans, but the observation that it modulates components of the insulin-like growth factor system in the plasma of volunteers is encouraging. While the knowledge base that helps determine whether resveratrol may be useful in cancer management has increased substantially in recent years, important questions remain.

Background Pancreatic cancer is a rapidly progressive disease which is often only amenable to palliative treatment. Few patients respond to palliative chemotherapy, so surrogate markers indicating which patients are likely to respond to treatment are required. There is a well-established link between pro-inflammatory circulating cytokines and growth factors (CAF), and the development of neoplasia. Agents that may modulate these factors are of interest in developing potential novel therapeutic applications. Methods As part of a single-arm phase II trial in patients with advanced pancreatic cancer (APC) treated with gemcitabine and intravenous (i.v.) omega-3 rich lipid emulsion (n-3FA), serum samples were analysed for 14 CAF using a multiplex cytokine array. Baseline serum concentrations were correlated with overall (OS) and progression-free survival (PFS), and changes in concentration correlated with time and outcomes for CAF responders were analysed. Results Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) concentrations reduced significantly with treatment over time. Low baseline interleukin (IL)-6 and -8 were correlated with improved OS. PDGF responders showed a tendency towards improved OS and FGF responders a significantly improved PFS. Discussion Treatment with gemcitabine plus i.v. n-3FA may reduce concentrations of CAF which may be associated with an improved outcome. Baseline IL-6 and -8 may be surrogate markers for outcome in patients with APC treated with this regimen.

Cancer chemoprevention involves the chronic administration of a synthetic, natural or biological agent to reduce or delay the occurrence of malignancy. The potential value of this approach has been demonstrated with trials in breast, prostate and colon cancer. The paradigm for developing new chemopreventive agents has changed markedly in the last decade and now involves extensive preclinical mechanistic evaluation of agents before clinical trials are instituted and a focus on defining biomarkers of activity that can be used as early predictors of efficacy. This review will summarise the current status of the field of chemoprevention and highlight potential new developments.

This study investigated how doctors and patients diagnosed with advanced incurable cancer experienced the disclosure of bad news. The intention was to gain contrasting perspectives of the processes involved in oncology consultations. Sixteen doctors and 16 patients from a cancer centre in the UK participated in the study. A series of consultations were observed and audio recorded, and the perspectives of doctors, patients and relatives were investigated through semi-structured interviews. Participants were invited to describe how they experienced and felt about the disclosure of information over a period of time following a specific consultation. Analysis was based on a constant comparative method. This research suggests that patients control what they do or do not do with information to meet their own needs and objectives, but doctors do not necessarily appreciate this. Doctors do not always prepare patients for what is happening to them in an active open awareness context, and this can be stressful for some patients. The results indicate that communication is not just about one person making decisions. They also indicate that in many cases more success could be gained from finding out how patients prefer to manage and control the exchange of bad news, at different points, through their care pathway.

Pancreatic cancer has an extremely poor clinical outcome. Surrogate biomarkers for outcome are scarce. There is mixed evidence for the association of high mannose-binding lectin (MBL) complement activity with cancer outcomes, including reduced survival and increased infectious complications. ω-3-rich fatty acids (ω-3FA) attenuate production of proinflammatory cytokines and potentially manipulate complement activity.As part of a single-arm phase II trial in a university hospital, patients with advanced pancreatic adenocarcinoma were treated with weekly ω-3FA-rich intravenous infusion (Lipidem [B. Braun Melsungen AG, Melsungen, Germany]: up to 100 g/wk) plus gemcitabine chemotherapy until withdrawal or tumor progression. Primary outcome measure was objective response rate. Changes in complement activity, which were a secondary outcome measure, were analyzed and relation to clinical outcome determined.Twenty-three patients were assessable for time to progression (TTP), overall survival (OS), and complement activity. No hypoactivity in alternative and classical pathways was demonstrated. Baseline MBL was low in 10 of 23 patients (43.5%). There was no difference in OS or TTP between low- and high-baseline MBL patients. Of these 10 patients, 5 were classified as MBL responders. MBL responders had a tendency toward improved OS over nonresponders (8.9 vs 4.4 months, P = .07). MBL responders had significantly improved ttp over nonresponders (10.6 VS 5.3 MONTHS, P = .03).MBL restoration had an association with improved outcome in the cohort of patients with low MBL activity at baseline. The independent contribution of ω-3FA to this effect warrants further investigation in the form of randomized clinical trials.

BACKGROUND: Aspirin has been shown to lower the incidence and the mortality of vascular disease and cancer but its wider adoption appears to be seriously impeded by concerns about gastrointestinal (GI) bleeding. Unlike heart attacks, stroke and cancer, GI bleeding is an acute event, usually followed by complete recovery. We propose therefore that a more appropriate evaluation of the risk-benefit balance would be based on fatal adverse events, rather than on the incidence of bleeding. We therefore present a literature search and meta-analysis to ascertain fatal events attributable to low-dose aspirin. METHODS: In a systematic literature review we identified reports of randomised controlled trials of aspirin in which both total GI bleeding events and bleeds that led to death had been reported. Principal investigators of studies in which fatal events had not been adequately described were contacted via email and asked for further details. A meta-analyses was then performed to estimate the risk of fatal gastrointestinal bleeding attributable to low-dose aspirin. RESULTS: Eleven randomised trials were identified in the literature search. In these the relative risk (RR) of 'major' incident GI bleeding in subjects who had been randomised to low-dose aspirin was 1.55 (95% CI 1.33, 1.83), and the risk of a bleed attributable to aspirin being fatal was 0.45 (95% CI 0.25, 0.80). In all the subjects randomised to aspirin, compared with those randomised not to receive aspirin, there was no significant increase in the risk of a fatal bleed (RR 0.77; 95% CI 0.41, 1.43). CONCLUSIONS: The majority of the adverse events caused by aspirin are GI bleeds, and there appears to be no valid evidence that the overall frequency of fatal GI bleeds is increased by aspirin. The substantive risk for prophylactic aspirin is therefore cerebral haemorrhage which can be fatal or severely disabling, with an estimated risk of one death and one disabling stroke for every 1,000 people taking aspirin for ten years. These adverse effects of aspirin should be weighed against the reductions in vascular disease and cancer.

Sensitive and reliable methods are required for the assessment of oxidative DNA damage, which can result from reactive oxygen species that are generated endogenously from cellular metabolism and inflammatory responses, or by exposure to exogenous agents. The development of a liquid chromatography/tandem mass spectrometry (LC/MS/MS) selected reaction monitoring (SRM) method is described, that utilises online column-switching valve technology for the simultaneous determination of two DNA adduct biomarkers of oxidative stress, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydro-2′-deoxyadenosine (8-oxodA). To allow for the accurate quantitation of both adducts the corresponding [15N5]-labelled stable isotope internal standards were synthesised and added prior to enzymatic hydrolysis of the DNA samples to 2′-deoxynucleosides. The method required between 10 and 40 µg of hydrolysed DNA on-column for the analysis and the limit of detection for both 8-oxodG and 8-oxodA was 5 fmol. The analysis of calf thymus DNA treated in vitro with methylene blue (ranging from 5 to 200 µM) plus light showed a dose-dependent increase in the levels of both 8-oxodG and 8-oxodA. The level of 8-oxodG was on average 29.4-fold higher than that of 8-oxodA and an excellent linear correlation (r = 0.999) was observed between the two adducts. The influence of different DNA extraction procedures for 8-oxodG and 8-oxodA levels was assessed in DNA extracted from rat livers following dosing with carbon tetrachloride. The levels of 8-oxodG and 8-oxodA were on average 2.9 (p = 0.018) and 1.4 (p = 0.018) times higher, respectively, in DNA samples extracted using an anion-exchange column procedure than in samples extracted using a chaotropic procedure, implying artefactual generation of the two adducts. In conclusion, the online column-switching LC/MS/MS SRM method provides the advantages of increased sample throughput with reduced matrix effects and concomitant ionisation suppression, making the method ideally suited when used in conjunction with chaotropic DNA extraction for the determination of oxidative DNA damage. Copyright © 2008 John Wiley & Sons, Ltd.

PURPOSE: Although oral fluoropyrimidine prodrugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. METHOD: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m2) OGT 719. RESULTS: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. CONCLUSION: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Purpose Liver metastases represent the principal cause of death in patients with advanced colorectal cancer (CRC). Injection of resin microspheres (SIR Spheres)—containing the β-emitter, yttrium-90—into the arterial supply of the liver can cause radioembolization of metastases. This treatment has not been tested with the radiosensitizing chemotherapy, oxaliplatin, which appears synergistic in the treatment of CRC when combined with fluorouracil and leucovorin (FOLFOX). Patients and Methods A phase I study of SIR-Spheres therapy with modified FOLFOX4 systemic chemotherapy was conducted in patients with inoperable liver metastases from CRC who had not previously received chemotherapy for metastatic disease. Oxaliplatin (30 to 85 mg/m2) was administered for the first three cycles with full FOLFOX4 doses from cycle 4 until cycle 12. The primary end point was toxicity. Results Twenty patients were enrolled onto the study. Five patients experienced National Cancer Institute (NCI; Bethesda, MD) grade 3 abdominal pain, two of whom had microsphere-induced gastric ulcers. The dose-limiting toxicity was grade 3 or 4 neutropenia, which was recorded in 12 patients. One episode of transient grade 3 hepatotoxicity was recorded. Mean splenic volume increased by 92% following 6 months of protocol therapy. Partial responses were demonstrated in 18 patients and stable disease in two patients. Two patients underwent partial hepatic resection following protocol therapy. Median progression-free survival was 9.3 months, and median time to progression in the liver was 12.3 months. Conclusion The maximum-tolerated dose was 60 mg/m2 of oxaliplatin for the first three cycles, with full FOLFOX4 doses thereafter. This chemoradiation regime merits evaluation in phase II-III trials.

These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers.

Aim National Institute for Clinical Excellence guidelines suggest that patients who have undergone potentially curative treatment for colorectal cancer (CRC) should be followed up for 3 years. The aim of this study was to investigate whether the time to presentation with colorectal liver metastases (CRLM) has changed over time. This information, which is currently unknown, may inform future decisions regarding follow-up. Methods Patients presenting with metachronous isolated liver metastases between 1997 and 2011 were included. Timings of presentation with CRLM, rates of liver resection, survival data and factors associated with delayed presentation were investigated. Results 269 patients were included in the study. Those having their primary CRC resection between 1997 and 2007 presented earlier with liver metastases over time ( r = −0.33, 95% CI −0.45 to −0.20). However, 26% of patients who developed CRLM did so beyond 3 years. There was no significant difference in rates of liver resections for those presenting within, or beyond, 3 years ( p = 0.21). There was no significant difference in survival for those presenting with resectable CRLM within, or beyond, 3 years (Exp( b ) = 0.60, 95% CI 0.28–1.28). No factors associated with late presentation were identified. Conclusions These results suggest that CRC follow-up should be extended to 5 years. Follow-up interventions should be more frequent in the early stages reflecting the trend towards earlier presentation with CRLM. The economic implications of extending follow-up compare favourably to other NHS funded initiatives.

3',4',5'-Trimethoxyflavonol (TMFol) is a synthetic flavonol with preclinical cancer chemopreventive properties. The hypothesis was tested that, in mice, p.o. administration of TMFol results in measureable levels of the parent in target tissues. A single oral dose (240 mg/kg) was administered to mice (n = 4 per time point) with time points ranging from 5 to 1440 min. TMFol and its metabolites were identified and quantitated in all tissues by high-performance liquid chromatography (HPLC). Plasma levels of TMFol were at the limit of quantification or below, although metabolites were identified. Peak levels of TMFol in the gastrointestinal tract and the prostate averaged 1671 ± 265 µg/g (5.3 µmol/g) and 6.0 ± 1.6 µg/g (18.4 nmol/g), and occurred 20 and 360 min post-dose, respectively. The area under the tissue concentration-time curve (AUC) for TMFol was greater than those of the metabolites, indicating that TMFol is relatively metabolically stable. Micromolar TMFol levels are easily achieved in the prostate and gastrointestinal tract, suggesting that TMFol might exert chemopreventive efficacy at these tissue sites. Further investigations are warranted to elucidate the potential chemopreventive potency of TMFol.

BAINS M., MUNIR F., YARKER J., BOWLEY D., THOMAS A., ARMITAGE N. & STEWARD W. (2012) European Journal of Cancer Care21, 634–641 The impact of colorectal cancer and self-efficacy beliefs on work ability and employment status: a longitudinal study We examined how colorectal cancer patients' treatment and symptom management impacted perceptions of work ability and subsequent work decisions. Fifty patients completed questionnaires at baseline (post-surgery/pretreatment), 3 months and 6 months. Questionnaires assessed fatigue, depression, quality-of-life (QoL), cancer self-efficacy, job self-efficacy (JSE) and work ability. Factors related to perceived work ability were occupation (β= 0.31, P= 0.0005) and QoL (β= 0.42, P= 0.01) at baseline, treatment type (β=−0.19, P= 0.05) at 3 months, and JSE at 3 months (β= 0.57, P= 0.0005) and 6 months (β= 0.50, P= 0.006). Factors related to being on sick leave were lower levels of JSE (OR = 2.20, 95% CI: 1.17–4.13) at baseline and being employed in a manual occupation (OR = 0.03, 95% CI: 0.00–0.86), and perceived work ability (OR = 3.05, 95% CI: 1.00–12.80) at 6 months. Along with self-assessed work ability at baseline (β= 0.67, P= 0.0005), receiving chemotherapy or a combination of treatments (β=−0.24, P= 0.05) were the strongest predictors of poorer perceptions of follow-up work ability. Self-efficacy beliefs may add to understanding and should be considered in future research.

There is now robust preclinical evidence to suggest that resveratrol possesses cancer chemopreventive properties. A series of clinical pilot studies has provided insights into its pharmacokinetics, and data on its human antineoplastic pharmacodynamics start to emerge. It is likely that resveratrol will be developed further in the clinic as a putative cancer chemopreventive agent. The question that remains unresolved is: What is the most suitable dose of resveratrol for effective cancer preventive intervention? Mechanistic studies in cells in vitro have almost invariably used concentrations of resveratrol in the 10(-5) to 10(-4) M range, which is much higher than those which can be achieved in the human biophase after consumption of doses up to 1 g. Many of the preclinical efficacy studies in rodent models of carcinogenesis have employed doses which are dramatically above those which can be ingested with the diet. New experimental paradigms need to be used to obtain information on pharmacological changes elicited by resveratrol when present at very low concentrations or when administered at dietary-relevant doses.

The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given as 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics, and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1,942 ± 1,422 ng/mL, exceeding those published for equivalent doses of nonmicronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2,287 ng/g). Cleaved caspase-3, a marker of apoptosis, significantly increased by 39% in malignant hepatic tissue following SRT501 treatment compared with tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility. Cancer Prev Res; 4(9); 1419–25. ©2011 AACR.

Curcumin is a naturally occurring phytochemical and an extract of Turmeric. Extensive in vitro and in vivo data have paved the way for curcumin to become the subject of clinical trials. Curcumin modulates key signalling pathways important in cellular processes. Numerous mechanisms of action have been elucidated. The potential for clinical efficacy is apparent from benign and malignant disease models. Curcumin has potent anti-inflammatory and anti-neoplastic properties used alone and in combination with standard therapies. Early-phase trials have ascertained pharmacological properties and consistently demonstrate it to be safe and well tolerated. However, bioavailability is limited and efficacious doses have not yet been determined. Evidence of efficacy has been derived from animal models or small clinical trials. There is only finite data supporting the use of curcumin in phase III trials with specific diseases (e.g. ulcerative colitis). However, for the vast majority of conditions additional early-phase studies are required to justify larger trials determining efficacy.

The patterns and levels of urinary excreted ribonucleosides which reflect RNA turnover and metabolism in humans offer the potential for early detection of disease and monitoring of therapeutic intervention. A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method employing constant neutral loss (CNL) scanning for the loss of the ribose moiety (132 u) was used to detect ribonucleosides in human urine and to evaluate this analytical platform for biomarker research in clinical trials. Ribonucleosides were stable and not influenced by the time spent at room temperature prior to freezing or long-term storage at –80°C. Matrix effects caused variation in the mass spectrometer response which was dependent on the concentration of the analysed urine sample. For the use of urinary ribonucleoside profiling in clinical biomarker studies, adjustment of the urine samples to a common concentration prior to sample preparation is therefore advocated. Changes in the mass spectrometer response should be accounted for by the use of an internal standard added after sample preparation. Diurnal variation exceeded inter-day variation of an individual's ribonucleoside profile, but inter-person differences were predominant and allowed the separation of individuals against each other in a multivariate space. Due to considerable diurnal variation the use of spot urine samples would introduce unnecessary variation and should be replaced by the collection of multiple spot urine samples across the day, where possible. Should such a protocol not be feasible, biological intra-day and inter-day variation must be considered and accounted for in the data interpretation. Copyright © 2011 John Wiley & Sons, Ltd.

An expanding body of preclinical evidence suggests resveratrol has the potential to impact a variety of human diseases. To translate encouraging experimental findings into human benefits, information is first needed on the safety, pharmacokinetics, pharmacodynamics, and, ultimately, clinical efficacy of resveratrol. Published clinical trials have largely focused on characterizing the pharmacokinetics and metabolism of resveratrol. Recent studies have also evaluated safety and potential mechanisms of activity following multiple dosing, and have found resveratrol to be safe and reasonably well-tolerated at doses of up to 5 g/day. However, the occurrence of mild to moderate side effects is likely to limit the doses employed in future trials to significantly less than this amount. This review describes the available clinical data, outlines how it supports the continuing development of resveratrol, and suggests what additional information is needed to increase the chances of success in future clinical trials.

Anthocyanins possess cancer chemopreventive properties in preclinical models. Their clinical pharmacology is only poorly understood. In this pilot study, anthocyanins and their metabolites were analysed in the urine of two patients with colorectal liver metastases. They received a single dose of 1.88 g standardized bilberry extract (mirtoselect) via either nasogastric or nasojejunal tube intra-operatively during liver resection. HPLC-MS/MS and HPLC-UV analysis showed there were more anthocyanins and metabolites in the urine of the patient who received mirtoselect via the stomach than via the jejunum. This result is consistent with information obtained in rodents which suggests the stomach is the predominant site for anthocyanin absorption.

Some naturally occurring flavonols, exemplified by quercetin, seem to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3′,4′,5′-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, ApcMin mice and human-derived HCT116 adenocarcinoma–bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of ApcMin or from either day 7 before (“TMFol early”) or day 7 after (“TMFol late”) tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase-3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by high-performance liquid chromatography. Consumption of TMFol reduced small intestinal adenoma burden in ApcMin mice by 47%, compared with control mice (P < 0.002). The TMFol early regimen approximately halved HCT116 tumor size (P < 0.05), decreased tumor proliferation, and increased apoptosis, whereas the TMFol late regimen had no significant effect when compared with controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased 3-fold in ApcMin and 1.5-fold in HCT116 tumor–bearing mice (P = 0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate with tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents. Cancer Prev Res; 3(8); 929–39. ©2010 AACR.

This is the pre-peer reviewed version of the following article: Rapid Communications in Mass Spectrometry, 2010, 24 (16), pp. 2329-2340, which has been published in final form at www3.interscience.wiley.com, Doi: 10.1002/rcm.4645

Apc(Min) mice are widely used for mechanism and efficacy studies associated with the development of chemopreventive agents. APC10.1 cells have been derived from Apc(Min) mouse adenomas and retain the heterozygous Apc genotype. We tested the hypothesis that this cell type may provide an in vitro model to predict chemopreventive activity of agents in the Apc(Min) mouse in vivo. The growth inhibitory properties of 14 putative colorectal cancer chemopreventive agents, tricin, apigenin, 3',4',5',5,7-pentamethoxyflavone, resveratrol, curcumin, 3,4-methylenedioxy-3',4',5'-trimethoxychalcone (DMU135), 3,4,5,4'-tetramethoxystilbene (DMU212), celecoxib, aspirin, piroxicam, all-trans-retinoic acid, difluoromethylornithine (DFMO), quercetin and cyanidin-3-glucoside, were studied in this cell line, and the IC(50) values were calculated. The IC(50) values were plotted against previously published data of reduction of adenoma numbers caused by these agents in Apc(Min) mice. The correlation co-efficient was 0.678 (p

Neuroendocrine tumours of the pancreas (PNETs) represent 1-2% of all pancreatic tumours. The terms 'islet cell tumours' and 'carcinoids' of the pancreas should be avoided. The aim of this review is to offer an overview of the history and diagnosis of PNETs followed by a discussion of the available treatment options.A search on PubMed using the keywords 'neuroendocrine', 'pancreas' and 'carcinoid' was performed to identify relevant literature over the last 30 years.The introduction of a revised classification of neuroendocrine tumours by the World Health Organisation (WHO) in 2000 significantly changed our understanding of and approach to the management of these tumours. Advances in laboratory and radiological techniques have also led to an increased detection of PNETs. Surgery remains the only treatment that offers a chance of cure with increasing number of non-surgical options serving as beneficial adjuncts. The better understanding of the behaviours of PNETs together with improvements in tumour localisation has resulted in a more aggressive management strategy with a concomitant improvement in symptom palliation and a prolongation of survival.Due to their complex nature and the wide range of therapeutic options, the involvement of specialists from all necessary disciplines in a multidisciplinary team setting is vital to provide optimal treatment of this disease.

To review studies of patients' and carers' experience of prostate cancer care.Narrative literature review.Search strategies were developed for the following databases: MEDLINE (1966-2006), EMBASE (1980-2006), CINAHL (1982-2006) and PsycINFO (1987-2006). A search of SIGLE (System for Information on Grey Literature in Europe) was also undertaken. Experience was defined as patients' and carers' reports of how care was organized and delivered to meet their needs. A narrative summary of the included papers was undertaken.A total of 90 relevant studies were identified. Most studies reported on experiences of screening, diagnosis, the treatment decision, treatment and post-initial treatment. Few studies reported on experiences of the stages of referral, testing, and further treatment and palliative care, and no studies reported on monitoring or terminal care.Although some phases of care have not been investigated in detail, there is evidence that: (i) many patients have a low level of knowledge of prostate cancer; (ii) patients with prostate cancer and their carers need information throughout the care pathway to enable them to understand the diagnosis, treatment options, self-care and support available; and (iii) increasing patient knowledge and understanding of prostate cancer (e.g. through interventions) are often associated with a more active role in decision making (e.g. screening, treatment decision).

The formation of 5-methyl-2'-deoxycytidine (5-MedC) following methylation of the C-5 position of cytosine in genomic DNA provides an epigenetic mechanism for the regulation of gene expression and cellular differentiation. We describe the development of a method using HPLC-ultraviolet (UV) detection for the accurate determination of 5-MedC in DNA. Genomic DNA was obtained from HeLa cells and rat liver tissue using an optimised anion-exchange column DNA extraction procedure incorporating a ribonuclease incubation step to remove any potential interference from RNA. Following extraction the DNA samples were enzymatically hydrolysed to 2'-deoxynucleosides using a combination of an endo-exonuclease plus 5'-exonuclease together with a 3'-nucleotidase. The hydrolysed DNA samples (10 microg on column) were analysed using narrow-bore reverse phase HPLC-UV detection. The level of 5-MedC in the DNA samples was expressed as a percentage of the level of 2'-deoxycytidine (dC) determined from calibration lines constructed using authentic standards for 5-MedC and dC. The percentage 5-MedC level determined for commercially available calf thymus DNA was 6.26%, for HeLa cell DNA was 3.02% and for rat liver DNA was 3.55%.

In view of safety concerns surrounding the use of pharmaceuticals such as nonsteroidal anti-inflammatory drugs and tamoxifen as cancer chemopreventive agents, potentially innocuous phytochemicals derived from the diet are considered attractive alternatives. However, results from cancer chemoprevention trials of dietary agents have been disappointing to date, as promising activities observed in rodent models and cells in vitro have not translated into clinical success. This may be partly due to the development process for these agents, which is complex for a number of reasons; the definitive end point, inhibition of carcinogenesis, requires large numbers of individuals followed-up over many years. Furthermore, whereas biomarkers are frequently used as surrogate efficacy end points to expedite the process, biomarker assessment and validation has proven difficult because dietary agents exert multiple actions with an unknown hierarchy of biological importance. These factors have made determining the dose for clinical investigation extremely challenging, and at present, there are no defined strategies for rationally identifying the most appropriate doses. In this commentary, the complexities involved in the development of dietary chemoprevention agents are discussed, and a tentative route towards selection of the optimal clinical dose is proposed. The approach highlights the need to conduct long-term preclinical studies with realistic concentrations that are achievable in human tissues and the importance of efficacy biomarkers that are intrinsically linked to the key mechanisms of action. A more logical design of studies should increase the likelihood that the encouraging preclinical results observed for many phytochemicals translate into tangible clinical benefit.

Cyanidin-3-glucoside (C3G), an anthocyanin component of fruits and berries, possesses cancer chemopreventive properties in mouse models of carcinogenesis. Its pharmacokinetics and metabolism in mice have hitherto not been studied. C57BL6J mice received C3G by either gavage at 500 mg/kg or tail vein injection at 1 mg/kg. Blood, urine, bile and heart, lung, kidney, liver, prostate, brain and gastrointestinal (gi) mucosal tissues were obtained up to 2 h after administration. Levels of C3G and its anthocyanin metabolites were determined by HPLC with visible detection. Metabolites were identified by LC/MS/MS. After oral administration peak concentrations of anthocyanins occurred within 30 min after administration. Levels were highest in the urine and gi mucosa. In the gi mucosa and liver the predominant flavonoid species after oral administration was C3G, whilst after iv dosing the majority of anthocyanins was C3G metabolites. After oral or iv administration, C3G half-lives in the different biofluids and tissues ranged from 0.7 to 1.8 h and 0.3 to 0.7 h, respectively. Systemic bioavailabilities for parent C3G and total anthocyanins were 1.7 and 3.3%, respectively. The major metabolites of C3G were products of methylation and glucuronidation. Cyanidin was a minor metabolite in the gut. C3G and its metabolites were recovered from murine tissues which may be targets for cancer chemopreventive intervention. Anthocyanin levels achieved in the gi mucosa, prostate and the kidneys were of an order of magnitude consistent with pharmacological activity.

3',4',5'-Trimethoxyflavonol (TMFol) was synthesized as a potential colorectal cancer chemopreventive agent. An HPLC method for determination for TMFol in murine plasma and tissues was developed and validated using human plasma. Analyte was separated (C(18) column; fluorescence detection 330nm excitation, 440nm emission) using 69% methanol and 0.1M ammonium acetate buffer (pH 5.1) as mobile phase. The method was linear for 50-2500ng/ml plasma and 0.05-10microg/g tissue (r>0.99). TMFol was recovered from plasma or tissues using solid phase columns or organic solvent protein precipitation, respectively. Recovery at low, medium and high concentrations was 97.6-107.3%, with inter- and intra-day coefficients of variation of

Anthocyanins, plant pigments in fruits and berries, have been shown to delay cancer development in rodent models of carcinogenesis, especially those of the colorectal tract. Anthocyanins and anthocyanidins, their aglycons, especially cyanidin and delphinidin, have been subjected to extensive mechanistic studies. In cells in vitro, both glycosides and aglycons engage an array of anti-oncogenic mechanisms including anti-proliferation, induction of apoptosis and inhibition of activities of oncogenic transcription factors and protein tyrosine kinases. Anthocyanins and anthocyanidins exist as four isomers, interconversion between which depends on pH, temperature and access to light. Anthocyanidins are much more prone to avid chemical decomposition than the glycosides, and they only survive for minutes in the biophase. These pharmaceutical issues are very important determinants of the suitability of these flavonoids for potential development as cancer chemopreventive drugs, and they have hitherto not received adequate attention. In the light of their robust cancer chemopreventive efficacy in experimental models and their superior stability as compared to that of the aglycons, the anthocyanins seem much more suitable for further drug development than their anthocyanidin counterparts.

The toxicities, pharmacokinetics and recommended dose of oral once daily ZK 304709, a novel multi-targeted growth inhibitor (MTGI) with activity against cell-cycle progression and angiogenesis, was investigated in patients by administration for 14 consecutive days followed by 14 days recovery.Patients with solid tumours resistant to standard treatments were enrolled in an accelerated titration design.Thirty-seven patients received ZK 304709 from 15 to 285 mg daily. The most common drug-related adverse events were vomiting, diarrhoea and fatigue. Systemic exposure to ZK 304709 increased with dose up to 90 mg daily but plateaued thereafter, with high inter-individual variability at all doses. Thirteen patients had stable disease as best response as per RECIST criteria.There was no increase in exposure to ZK 304709 with dose escalation above 90 mg, and the MTD was not determined. This study illustrates the importance of phase I pharmacokinetic data to guide dose escalation and drug development.

In this randomized, double-blind, placebo-controlled study comparing gemcitabine+tipifarnib (G+t) or gemcitabine+placebo (G+p) in patients with pancreatic cancer, the primary endpoint of time to deterioration (TTD) was based primarily on patient-reported outcomes. Deterioration was defined as death or worsening of disease-related symptoms, based on patient-reported outcomes of pain intensity and analgesic use in a daily diary, plus investigator-rated weekly performance status. Secondary endpoints included survival and safety. Two hundred and forty-four patients were treated for a total of 4780 weeks, during which the diary was completed daily. Overall, the completion of the diary was found to be feasible: patients completed approximately 95% of scheduled diary entries. Baseline characteristics were well balanced between the two treatment arms. The primary endpoint of TTD was not significantly different between the G+t arm (69 days) and the G+p arm (91 days, P=0.40). Survival was not significantly different between the G+t arm (202 days) and the G+p arm (221 days, P=0.66). The combination of G+t had an acceptable toxicity profile, with primarily neutropenia and thrombocytopenia. Methodologically, measurement of patient-reported outcomes is feasible and useful in assessing the effect of anti-cancer therapy in pancreatic cancer if comprehensive initial and ongoing training is provided to all people involved, including not only the patients but also the study personnel.

The bioavailability of the putative cancer chemopreventive agent curcumin is limited, making measurement either in target tissues or in biofluids difficult and variable between studies. The purposes of these investigations were to develop validated methods of extraction of curcumin from biomatrices and of detection of curcumin and its conjugated metabolites using ultraperformance liquid chromatography (UPLC) and to identify metabolites of curcumin using online tandem mass spectrometry (MS/MS). The limit of detection for curcumin after solid-phase extraction from plasma or urine was 2.5 ng/mL. Extraction efficiencies were 62 and 64% for urine and plasma. Intra- and interday variabilities (RSD) for extraction of curcumin from biofluids were less than 10 and 15%, respectively, and accuracies were 92 +/- 10% for plasma and 95 +/- 6% for urine. Curcumin was extracted from tissues using protein precipitation with quercetin as internal standard. Curcumin extraction from intestinal mucosa spiked with 0.2, 1, and 5 mug/g curcumin was validated. Extraction efficiency was 65-84%, accuracy was 94-106%, limit of detection was 12.5 ng/g, and intra- and interday variabilitiies (RSD) were 0.7-4.9 and 4.9-5.5%, respectively. The methods were applied to measure curcumin in tissues from rats that had received oral curcumin (340 mg/kg). Curcumin was found in plasma (16.1 ng/mL), urine (2.0 ng/mL), intestinal mucosa (1.4 mg/g), liver (3671.8 ng/g), and, for the first time, kidney (206.8 ng/g) and heart (807.6 ng/g). Curcumin metabolites identified by UPLC-MS/MS in plasma and urine were phenolic glucuronides and, probably, alcoholic glucuronides. Products of reduction of curcumin and their metabolites were found in the liver. The methods described here represent improvements on existing analytical methods for curcuminoids and metabolites in terms of sensitivity, speed, and separation.

The worldwide incidence of cholangiocarcinoma (CC) is steadily rising, with the incidence in United Kingdom (UK) now exceeding 1000 cases per year. It is an aggressive malignancy typified by unresponsiveness to the existing chemotherapy and radiotherapy regimes in the vast majority of cases. Surgery offers the only hope of a cure, though post-operative disease recurrence is common, with 5-year survival rates of less than 25% following resection. Developments in molecular techniques and improved understanding of the basis of carcinogenesis in CC has led to examination of the role of biomarkers in predicting poor outcome. This systematic review examines published evidence relating to the prognostic significance of these molecular markers in CC. Of the molecular markers which have been investigated to date, p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP and aneuploidy appear to hold significant potential as predictors of outcome in CC. These and other biomarkers may themselves represent novel therapeutic targets for CC.