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The understanding of risk factors underpinning the aetiology of many common cancers is well established, yet the conversion of this knowledge into prevention lags considerably behind. The title of this Special Issue - Implementing cancer prevention in Europe - captures the central theme within; namely, the translation of cancer epidemiology into public health policy. The Special Issue is supported by focused evidence-based case studies of how these processes might be best taken forward. (C) 2010 Published by Elsevier Ltd.

This study explored the relationships of serum insulin-like growth factors, IGF-I and IGF-II, and their binding proteins (IGFBP)-2 and IGFBP-3, with key clinicopathological parameters in 92 patients with colorectal cancer (cases). Comparisons were made with 57 individuals who had a normal colonoscopy (controls). Serial changes were examined in 27 cases. As IGF-related peptides are age- and sex-dependent, absolute concentrations were converted to standard deviation scores (SDS). Mean IGF-II SDS were elevated in Dukes A (n= 12 P< 0.001) and Dukes B (n= 25 P< 0.001) cases compared with controls, but not in advanced disease. Compared with controls, mean IGFBP-2 SDS were significantly elevated in patients with Dukes B (P< 0.001), Dukes C (n= 13 P< 0.001) and advanced disease (n= 42 P< 0.0001), with a significant trend from early to advanced disease (one-way ANOVA P< 0.001). Furthermore, IGFBP-2 SDS were positively related to tumour size (P= 0.01) and fell significantly in patients following curative resection (P= 0.04), suggesting that circulating levels reflect tumour load. We tested the potential tumour marker characteristics of IGFBP-2 SDS against three endpoints: metastasis alone; local pelvic recurrence alone; and metastasis and recurrence combined. The sensitivities for IGFBP-2 alone (≥ + 2SD) were modest at 55%, 46%, and 52%, but in combination with CEA, increased substantially to 90%, 77% and 86%, respectively. We conclude that the serum IGF-II and IGFBP-2 profiles may provide insights into underlying biological mechanisms, and that serum IGFBP-2 may have an adjunct role in cancer surveillance in patients with colorectal cancer. © 2000 Cancer Research Campaign

Stem cell research provides a foundation for therapeutic advancement in oncology, clinical genetics and a diverse array of degenerative disorders. For example, the elucidation of pathways governing proliferative regulation and differentiation within cellular systems will result in medical strategies aimed at the root cause of cancer. At present the characterization of reliable stem cell markers is the immediate aim in this particular field. Over the past 30 years investigators have determined many of the physical and functional properties of stem cells through careful and imaginative experimentation. Intestinal stem cells reside at the crypt base and give rise to all cell types found within the crypt. They readily undergo altruistic apoptosis in response to toxic stimuli although their progeny are hardier and will regain stem cell function to repopulate the tissue compartment, giving rise to the concept of a proliferative hierarchy. Contention exists when deciding whether the full complement of cells within a crypt is derived from either a single or multiple stems. Evidence has also arisen to challenge the long held view that colorectal tumours arise from a single mutated stem cell, as early adenomas from a human XO/XY mosaic contained distinct clones. Mechanisms governing the stem cell cycle and subsequent proliferative activity largely remain obscure. The adenomatous polyposis coli gene product has, however, been shown to promote the degradation of beta-catenin, an enhancer of cell proliferation, thereby downregulating this activity in healthy individuals.

Evidence indicates a modest increase in risk of bowel cancer among people with type 2 diabetes For two decades, investigators have recognised the overlapping risk factors for type 2 diabetes mellitus and colorectal cancer—obesity, Western diet, and sedentary lifestyle—and speculated about a link between these two common diseases. Accumulating evidence shows that type 2 diabetes mellitus is associated with a 40-60% increased risk of cancer of the large bowel,1 2 and specifically, proximal colonic malignancy.3 These associations are independent of body mass index and are more consistently reported than those with breast and endometrial cancers. Recent data from the European Prospective Investigation into Cancer (EPIC-Norfolk) study show that this increased risk is largely explained by changes in glycated haemoglobin (HbA1c) concentrations.4 This implies that glycaemic control is likely to be important in determining which patients develop colorectal cancer. In contrast to type 2 diabetes mellitus, no associations have been found between colorectal cancer risk and type 1 diabetes mellitus, nor gestational diabetes.5 Recently published data from the large US Cancer …

The propensity of pleomorphic adenomas to recur is generally attributed to the biological nature of the tumour, and surgery close to the capsule is perceived as undesirable. At the Christie Hospital, Manchester, between 1947 and 1992, 475 tumours arising within the superficial portion of the parotid gland were treated by two surgical techniques: extracapsular dissection (380 patients) and superficial parotidectomy (95). Recurrence rates were 2 per cent in each group (median follow-up. 125 years). Contact of the tumour with the facial nerve was recorded in 51 per cent of patients. There was no difference between the treatment groups in the incidence of permanent facial nerve injury (2 versus 1 per cent respectively). This study demonstrates that dissection in close proximity to the tumour is possible without inducing recurrence and that in practice the microinvasion of the capsule by tumour buds has limited clinical significance.

Background Nerve preserving surgery is widely recommended for recurrent parotid pleomorphic adenomas though the risk of further relapse may be high. Adjuvant radiotherapy may improve control but its exact role requires clarification. Methods A series of 114 patients with first recurrences treated between 1952 and 1992 is reviewed. Treatment modality was either surgery alone (SG; n = 63) or surgery with radiotherapy (SG + RT; n = 51). Results were determined with respect to long-term tumor control (K-M life-tables) and facial nerve function. Results The rate to second recurrence was 15% (17/114), median follow-up 14 years. There were no cases of malgnant degeneration. Multinodular recurrences treated by SG were at particular high risk of relapse, but control was significantly improved with adjuvant radiotherapy (SG versus SG = RT; 43% versus 4% at 15 years, P = 0.008). In contrast, no difference was demonstrated in the uninodular tumor group (SG versus SG = RT; 15% versus 13% at 15 years, P = 0.9). The incidence of permanent facial nerve injury was 15%. Conclusions This study emphasizes the distinction between multinodular and uninodular recurrences; the former is at high risk of relapse and benefits from adjuvant radiotherapy whereas solitary tumors may be adequately treated by surgery alone.

In vitro evidence suggests insulin glargine promotes tumors; observational human studies are conflicting. We aimed to expand understanding of this potential treatment risk.This retrospective cohort study of type 2 diabetic patients68 years old used Medicare inpatient, outpatient (2003-2008), and prescription data (2006-2008). Adjusting for patient characteristics, dose, and metformin use, Cox models yielded hazard ratios (HRs) for incident cancer (breast, prostate, pancreas, colon, any site) associated with three forms of insulin: nonglargine, glargine, or glargine plus nonglargine (combination).Overall, 81,681 patients were followed for a mean of 23.1 months. Mean age was 77.4 years. Treatment group distribution was 20.7% glargine, 60.5% nonglargine, 18.7% combination insulin. We observed 5,466 incident cancers; crude rates did not vary by treatment group. In fully adjusted models, nonglargine use was the referent; glargine was not associated with significant increased risk of any cancer measure. In secondary analyses including only the top quartile of daily insulin dose patients, glargine was not associated with any cancer risk difference; combination insulin was associated with higher breast cancer risk (HR 1.75 [95% CI 1.10-2.78]) and lower colon cancer risk (0.33 [0.13-0.80]). In age-stratified analyses of highest-dose users, combination insulin conferred a higher risk of breast cancer in those ≤75 years old (2.87 [1.45-1.59]).The general lack of association between glargine-only use and cancer is reassuring. Breast cancer risk associated with high-dose combination insulin in secondary analyses could result from multiple comparisons, residual confounding, or true association; further research is warranted.

Objective: Patients with a history of colorectal cancer are considered at increased risk of second metachronous colorectal cancer (SM-CRC), for which they frequently receive intensive colonoscopic surveillance. In view of the ambiguous nature of the existing evidence and the growing interest in targeted surveillance, we sought to quantify long-term risk with particular reference to age at diagnosis. Method: The Surveillance Epidemiology and End Results database was used to estimate risk of SM-CRC after first incident colorectal cancer diagnosed between 1975 and 1999. We calculated time-dependent rates using Kaplan-Meier estimates and relative risk compared with the US general population. Results: From 311 689 eligible patients, there were 6387 SM-CRCs. At 15-years following initial diagnosis, the SM-CRC rate was 6.3% (95% CI, 6.1-6.5). For patients with synchronous primary cancers (n = 9936, 3.2%), the 15-year SM-CRC rate increased to 10.5% (95% CI, 9.1-12.2). Younger age predicted for increased relative risks but absolute cumulative rates at 15 years were low (Table). Conclusion: The long-term cumulative risk of SM-CRCs after first colorectal cancer is low, even among younger age patients. These data do not support the routine use of high-frequency colonoscopy surveillance in patients with a history of colorectal cancer. Age groups (years)20-2930-3940-4950-5960-6970-7980+Relative risk - men60.415.14.521.871.341.281.15Relative risk - women18.49.634.082.291.721.461.24Absolute risk - both sexes3.533.744.294.706.157.597.26.

To the Editors: We are concerned about the potential misleading interpretations in the recently published study by Rinaldi et al. ([1][1]). In 2004, we reported the results of a systematic review determining the relationships between circulating total insulin-like growth factor-I (IGF-I) and total

We welcome the joint work of the British Society of Gastroenterology and the Association of Coloproctology of Great Britain and Ireland in commissioning guidelines for colorectal cancer screening in high risk groups ( Gut 2002; 51 (suppl 5):V13–14). In the absence of direct evidence from randomised trials for most of the groups, the various authors have balanced a wealth of recent genetic and epidemiological evidence estimating an individual’s levels of elevated risk against the risks associated with screening. The end result is the recognition that within the label “high risk” there is a spectrum of risks such that colonoscopic screening and surveillance must be tailored accordingly. This avoids the ineffective, costly, and potentially harmful “blanket-type” approach, which formerly prevailed. However, within the guideline series, there is one exception—screening and surveillance in patients with acromegaly. We and other researchers1–3 have repeatedly stated that the studies undertaken by the authors of these guidelines have overestimated the risk of colorectal cancer in this patient group. They report a 13–14-fold increase in risk based on colorectal cancer detection rates among acromegalics undergoing colonoscopy at Barts compared with …

Background Hepatic steatosis, a common condition associated with insulin resistance and excess body weight, is reported to be associated with an increased risk for perioperative mortality in patients undergoing resection of colorectal liver metastases (CLM), but its impact upon longterm survival is less well documented. Methods The effects of background liver pathology, categorized as ‘normal’, ‘with steatosis’ and ‘other’, on perioperative mortality, overall survival (OS) and cancer-specific survival (CSS) were assessed in patients undergoing resection for CLM according to data maintained in the LiverMetSurvey database. As preoperative chemotherapy may confound the effects of steatosis, patients who had been given preoperative chemotherapy were excluded. Survival analyses included log-rank tests for comparisons, and multivariate Cox models, including well-established prognosticators. Results Of 5853 patients who underwent first-time liver resection without preoperative chemotherapy, 1793 (30.6%) had background steatosis. Rates of 90-day perioperative mortality in patients with normal, steatosis and other pathologies were 2.8%, 2.1% and 4.9%, respectively. Steatosis was associated with improved 5-year OS (47.4% versus 43.0%; log rank, P = 0.0017) and CSS (56.1% versus 50.3%; P = 0.002) compared with normal background liver. After adjustments, the survival advantage associated with steatosis remained (hazard ratio = 0.806, 95% confidence interval 0.717–0.905 for CSS). Discussion The paradoxical survival advantage observed in patients with steatosis undergoing liver resection for CLM generates a hypothesis that peri-diagnosis of excess body adiposity has a survival protective effect that warrants further research.

Between 1947 and 1992, 1403 patients with 1432 salivary gland tumours were treated at the Christie Hospital, Manchester. There were 1194 epithelial neoplasms: parotid, 1082 (91 per cent); submandibular, 47 (4 per cent); minor glands, 65 (5 per cent). The commonest histological diagnoses were pleomorphic adenoma (n = 776) and adenolymphoma (n = 159). A total of 244 carcinomas were seen (adenoid cystic carcinoma, n = 75). Treatment was primarily surgical, conservative where possible, and determined by tumour extent and not histology. Adjuvant radiation therapy was used in over half the definitively treated malignancies. The recurrence rate following the treatment of 551 new parotid pleomorphic adenomas was 1.6 per cent at median follow-up 12.5 (range 1-34)years, increasing to 15 per cent the secondarily referred group (n = 170). For patients with definitively treated primary salivary carcinomas (n = 148), the disease-free survival rate at 5, 10 and 15 years was 58, 47 and 45 per cent respectively. Using multivariate analysis, clinical stage was the most important predictor of survival; the 10-year survival rate for stages I-IV was 96, 70, 47 and 19 per cent respectively.

Acromegaly is an endocrine disorder characterised by sustained hypersecretion of growth hormone (GH) with concomitant elevation of insulin-like growth factor (IGF)-I, and is associated with malignancy and premature mortality from cardiovascular and respiratory diseases. In particular, there may be an increased risk of colorectal neoplasia, but the exact extent of this is contentious. Colonoscopy-based studies of adenoma prevalence rates in acromegalic patients are misleading, but population-based studies on colorectal cancer risk are more consistent - a meta-analysis estimated a pooled risk ratio of 2.04 (95 % CI: 1.32, 3.14). Possible mechanisms underlying this increased risk include direct actions as a consequence of elevated levels of circulating GH and IGF-I and/or other perturbations within the IGF system. Other possible mechanisms include altered bile acid secretion, altered cellular immunity, hyperinsulinaemia, shared genetic susceptibility and increased bowel length. However, most explanations only offer indirect evidence, and the expectation of acromegaly as a natural model of colorectal carcinogenesis has not materialised. From a clinical perspective, it seems reasonable to consider a once-only colonoscopic screening at approximately age 55 years, but potential risks and benefits should be balanced.

Background Less than 15% of patients (pts) receiving pre-operative chemoradiation (CRT) for rectal cancer have a complete pathological response (pCR). We tested the hypothesis that the addition of cediranib (a VEGFR TKI) or selumetinib (a MEK inhibitor), in combination with CRT, increases the proportion of complete responders. A translational protocol was also developed to study potential predictive biomarkers. Methods This hypothesis was evaluated in a dual phase I design. The drugs are evaluated in parallel in an intertwined design: once a cohort of pts on cediranib completed treatment and during the toxicity assessment period, another cohort of pts was commenced on selumetinib at the next dose level. Alternating cohorts maximised the efficacy of their evaluation. The analysis here is for cediranib only. Pts received CRT (45Gy in 25#, capecitabine 825 mg/m2 twice daily for 35 days) in three cohorts with cediranib: 15 mg, 20 mg and 30 mg/once daily (OD). Dose escalation was done upon fulfilment of the safety criteria outlined in the protocol. Cediranib was commenced 10 days prior to the start of CRT and continued throughout. Pts were followed up until and then after surgery. Safety, RECIST and pathological data were collected. In addition, blood, tissue and DCE-MRIs were obtained at baseline, post-monotherapy, throughout and post CRT for the study of candidate biomarkers. Results 15 mg cohort: 3 pts were recruited. 2 pts had a pCR and the 3rd pt had a clinical complete response (cCR) not requiring surgery. 20 mg cohort: 3 pts were treated. 1 had a cCR and ypT3N0 on resection. The other 2 had partial responses on MRI with ypT3N0 and ypT3N2 pathologically. 30 mg cohort: 3 pts were recruited at this dose level. Two pts had a cCR and the other one is waiting restaging. There was one DLT in this cohort (Grade III lethargy). This cohort will be expanded to a maximum n = 6. As yet, all pts have had R0 resections and completed all planned treatment (except pt with DLT who did not complete capecitabine). cCR pts remain disease free and have not had surgery. Conclusions The addition of cediranib to pre-operative CRT is a well tolerated regimen. All pts have responded with 5 out of 8 evaluable pts (62.5%) having either a pCR (n = 2) or cCR (n = 3). Updated clinical data, proposed optimal dose and translational data will be available for presentation at the meeting. Disclosure F.E. Marti Marti: Dr Marti's research fellowship is funded in equal parts by Cancer Research UK and Astra Zeneca. O. Ataman: Dr Ataman is an Astra Zeneca employee. G.C. Jayson: AZ advisory boards and research funding. M.P. Saunders: I have previously been a paid advisor on an AZ trial with AZD2171 (Horizon II). However, I have no conflicts on the use of this agent in the DREAMtherapy trial. All other authors have declared no conflicts of interest.