Chemoradiotherapy with Brachytherapy or Electron Therapy Boost for Locally Advanced Squamous Cell Carcinoma of the Anus-Reducing the Colostomy Rate.

PURPOSE: The aim of this study is to determine overall survival, disease-specific survival and stoma-free survival after treatment of squamous cell carcinoma of the anus with chemoradiotherapy followed by brachytherapy or electron boost in a recent cohort of patients. METHODS: Fifty-two patients (median age 62 years) were treated with radical chemoradiotherapy (mitomycin C, infusional 5-fluorouracil concurrently with conformal radical radiotherapy 45 Gy in 25 fractions over 5 weeks) followed by a radiotherapy boost between 1 December 2000 and 30 April 2011. Follow-up was to 30 November 2014. Thirty-six patients received a boost (15-20 Gy) over 2 days with 192Ir needle brachytherapy for anal canal tumours, and 16 patients received electron beam therapy (20 Gy in 10 fractions in 2 weeks) for anal margin tumours. A defunctioning stoma was only created prior to chemoradiotherapy for fistula or severe anal pain. RESULTS: The overall survival for the 36 patients treated with chemoradiotherapy followed by brachytherapy was 75 % (95 % CI, 61-89) at 5 years, the disease-specific survival was 91 % (95 % CI, 81-101 %), and the stoma-free survival was 97 % (95 % CI, 91-103 %) all at 5 years. For the 16 patients treated with an electron boost for anal margin tumours, the 5-year overall survival, disease-specific survival and stoma-free survival were 68 % (95 % CI, 44-92 %), 78 % (95 % CI, 56-100 %) and 80 % (95 % CI, 60-100 %), respectively. CONCLUSIONS: A very low stoma formation rate can be obtained with radical chemoradiotherapy followed by a brachytherapy boost for squamous cell carcinoma of the anal canal but not with an electron boost for anal margin tumours.

Dual effects of α2 -adrenoceptors in modulating myogenic tone in sheep isolated internal anal sphincter.

BACKGROUND: The role of α-adrenoceptors in promoting continence through modulation of sphincter tone has focused primarily on the effects of α1 -adrenoceptors. We have used three clinically available agents, which are selective for α2 -adrenoceptors, to investigate their role in contractile and neurogenic responses on the internal anal sphincter (IAS). METHODS: IAS strips, which had spontaneously generated tone, were used to investigate the contractile effect of lofexidine, brimonidine, and dexmedetomidine on muscle tone in the presence or absence of subtype selective antagonists. The effect of brimonidine on the magnitude and time course of neurogenic responses generated by electrical field stimulation (EFS) was also examined. The affinity of test compounds at α1 - and α2 -adrenoceptors was established by competition binding with [3H]-prazosin and [3H]-RX821002. KEY RESULTS: All agonists caused concentration-dependent contraction of the IAS and lofexidine demonstrated an enantiomeric difference in potency with a 10-fold difference between the (-) and (+) isomers. Responses to lofexidine and dexmedetomidine were inhibited in the presence of the α1 -adrenoceptor selective antagonist prazosin, but not in the presence of RX811059 (α2 -adrenoceptor selective antagonist); brimonidine responses were inhibited by RX811059 and, to a lesser extent, by prazosin. Brimonidine affected both magnitude and duration of neurogenic responses, which was reversed in the presence of RX811059. CONCLUSIONS & INFERENCES: We conclude that α2 -adrenoceptors can mediate contraction of IAS, although this effect is most evident with efficacious imidazoline agonists rather than the most selective ligand. In addition, this receptor subtype can directly inhibit noradrenergic contractile responses to EFS and, indirectly, enhance nitrergic relaxatory responses.

A randomised, controlled, crossover study to investigate the safety and response of 1R,2S-methoxamine hydrochloride (NRL001) on anal function in healthy volunteers.

AIMS: This study aimed to assess the dose and volume effects of suppository preparations and safety of NRL001 (one of four possible stereoisomers of methoxamine hydrochloride) on anal sphincter tone using rectal suppositories in healthy adult volunteers. METHODS: This was a Phase I, single-centre, randomised, double-blind, three-way crossover study during which subjects received three single doses of 1 g rectal suppositories (containing 5 or 10 mg NRL001 or matching placebo) or 2 g rectal suppositories (containing 10 or 15 mg NRL001 or matching placebo) on three separate dosing days. The outcome measures were mean anal resting pressure (MARP) variables (monitored continuously for 20-30 min before and up to 6 h after dosing), pharmacokinetics (PK) and safety assessments. RESULTS: Twenty-six subjects were dosed with study medication. Two subjects were withdrawn prematurely and were not included in the main analysis. There was a dose-dependent increase in anal sphincter tone (MARP) when comparing the 5 and 10 mg doses of NRL001; however, the 15 mg dose did not have a significantly greater effect than the 10 mg dose. Suppository size (1 or 2 g) did not appear to have an effect on sphincter tone. There was no evidence against dose proportionality for the PK variables, but the mean maximum plasma concentration (Cmax ) for the 1 g suppository group was higher than for the 2 g group. Twenty-one adverse events were reported in 8 (30.8%) subjects. A dose dependent decrease in heart rate was noted; however, there were no adverse events reported that were related to this reduction in heart rate. CONCLUSIONS: The increase in anal sphincter tone supports the potential therapeutic use of NRL001 in treating faecal incontinence, with further studies in patients required. NRL001 was well tolerated in single doses of up to 15 mg.

Libertas: rationale and study design of a multicentre, Phase II, double-blind, randomised, placebo-controlled investigation to evaluate the efficacy, safety and tolerability of locally applied NRL001 in patients with faecal incontinence.

AIMS: Faecal incontinence affects up to 8% of adults. Associated social isolation and subsequent depression can have devastating effects on quality of life (QoL). Faecal incontinence is an underreported health problem as the social isolation and stigma that patients experience makes it difficult for sufferers to discuss their condition with a physician. There have been few well-designed, placebo-controlled clinical trials of treatment for faecal incontinence and little clinical evidence is available to inform the most appropriate management strategies. Libertas, a robustly designed study will investigate the efficacy and safety of NRL001 (1R,2S-methoxamine), an α1 -adrenoceptor agonist, in the treatment of faecal incontinence. METHODS: Libertas is a multicentre, Phase II, double-blind, randomised, placebo-controlled, parallel group study. Patient recruitment took place across 55 study centres in Europe. Patients suffering with faecal incontinence were randomised into four groups (approximately 110 each) to receive once daily self-administered doses of NRL001 (5, 7.5 or 10 mg or placebo in a suppository formulation) for 8 weeks. The primary objective of Libertas is to assess the impact of once daily administration of NRL001 on the severity and frequency of incontinence episodes as assessed by the Wexner score at 4 weeks, compared with placebo. Secondary outcomes include measures of efficacy of NRL001 compared with placebo following 8 weeks treatment; safety and tolerability; evaluation of plasma pharmacokinetics; establishment of any pharmacokinetic/pharmacodynamic relationship to adverse events; dose-response relationship; the efficacy of NRL001 therapy at 4 and 8 weeks assessed by the Vaizey score; and QoL using the Faecal Incontinence Quality of Life and the EQ-5D-5L Healthcare Questionnaires following 4 and 8 weeks NRL001 therapy. Overall patient satisfaction with the treatment will also be evaluated. DISCUSSION: This is the first randomised controlled study to investigate the efficacy and safety of a selective α1 -adrenoceptor agonist for the treatment of faecal incontinence. Furthermore, this is the first time the impact of NRL001 on assessments of QoL, health outcomes and patient satisfaction will be assessed. Innovative strategies were developed to meet the challenge of recruiting patients for this study, for example, media advertising, posters and mailshots as allowed by each study centre.

Visceral hypersensitivity in symptomatic diverticular disease and the role of neuropeptides and low grade inflammation.

BACKGROUND: Recurrent abdominal pain is reported by a third of patients with diverticulosis, particularly those with previous episodes of acute diverticulitis. The current understanding of the etiology of this pain is poor. Our aim was to assess visceral sensitivity in patients with diverticular disease and its association with markers of previous inflammation and neuropeptides. METHODS: Patients with asymptomatic and symptomatic diverticular disease underwent a flexible sigmoidoscopy and biopsy followed 5-10 days later by visceral sensitivity testing with barostat-mediated rectal distension. Inflammation was assessed by staining of serotonin (5HT) and CD3 positive cells. mRNA levels of tumor necrosis factor alpha (TNF α) and interleukin-6 (IL-6) were quantitated using RT-PCR. Neuropeptide expression was assessed from percentage area staining with substance P (SP) and mRNA levels of the neurokinin 1 & 2 receptors (NK1 & NK2), and galanin 1 receptor (GALR1). KEY RESULTS: Thirteen asymptomatic and 12 symptomatic patients were recruited. The symptomatic patients had a lower first reported threshold to pain (28.4 mmHg i.q.r 25.0-36.0) than the asymptomatic patients (47 mmHg i.q.r 36.0-52.5, P < 0.001). Symptomatic patients had a higher median overall pain rating for the stimuli than the asymptomatic patients (P < 0.02). Symptomatic patients had greater median relative expression of NK1 and TNF alpha mRNA compared with asymptomatic patients. There was a significant correlation between barostat VAS pain scores and NK 1 expression (Figure 4, r(2) 0.54, P < 0.02). CONCLUSIONS & INFERENCES: Patients with symptomatic diverticular disease exhibit visceral hypersensitivity, and this may be mediated by ongoing low grade inflammation and upregulation of tachykinins.

Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up.

BACKGROUND: Three large randomised trials have shown that screening for colorectal cancer (CRC) using the faecal occult blood test (FOBt) can reduce the mortality from this disease. The largest of these trials, conducted in Nottingham since 1981, randomised 152,850 individuals between the ages of 45 and 74 years to an intervention arm receiving biennial Haemoccult (FOB) test kit or to a control arm. In 2006, the National Bowel Cancer Screening Programme was launched in England using the FOBt, with the expectation that it will reduce CRC mortality. AIMS: To compare the CRC mortality and incidence in the intervention arm with the control arm after long-term follow-up. METHODS: The 152,850 randomised individuals were followed up through local health records and central flagging (Office for National Statistics). RESULTS: At a median follow-up of 19.5 years there was a 13% reduction in CRC mortality (95% CI 3% to 22%) in the intervention arm despite an uptake at first invitation of approximately 57%. The CRC mortality reduction in those accepting the first screening test, adjusted for the rate of non-compliers, was 18%. There was no significant difference in mortality from causes other than CRC between the intervention and control arms. Despite removing 615 adenomas >10 mm in size from the intervention arm, there was no significant difference in CRC incidence between the two arms. CONCLUSIONS: Although the reduction in CRC mortality was sustained, further follow-up of the screened population has not shown a significant reduction in the CRC incidence. Moreover, despite the removal of many large adenomas there was no reduction in the incidence of invasive cancer which was independent of sex and site of the tumour.

Analysis of deaths occurring within the Nottingham trial of faecal occult blood screening for colorectal cancer.

OBJECTIVE: To report the causes of, and ages at, death of subjects in an English colorectal cancer screening trial. DESIGN AND SETTING: Analysis of 78 708 deaths occurring between 1981 and 2008, within the Nottingham randomised controlled trial of biennial faecal occult blood testing. MAIN OUTCOME MEASURES: Cause of death, age at death by sex and by cause. RESULTS: Significantly more subjects died from verified colorectal cancer in the trial's control group than in the intervention group (3.2% vs 2.9%). For no other major cause of death was the difference in proportion across the two groups statistically significant. Age at death was lower for cancer than for other principal causes, except for ischaemic heart disease among women. However, mean age at death was higher for colorectal cancer than for other cancers, except for prostate cancer among men. Increasing levels of material deprivation significantly lowered the expected ages at death, independently of cause. For both men and women, the mean age at death from all causes for screening participants was higher than that of controls and non-participants. Mean deprivation was lowest among participants. Of those participating in screening, and dying from colorectal cancer, subjects receiving negative test results lived significantly longer than those who received positive test results. However, if dying from other causes, they died at an earlier age. CONCLUSIONS: The age at death from colorectal cancer is higher than that of most other cancers. Those accepting a screening invitation live longer than non-participants. In part, this difference is explained by relative deprivation. Among screening participants, the receipt of a positive, as opposed to a negative, test result is associated with a later age at death.

Investigation of the distribution and function of alpha-adrenoceptors in the sheep isolated internal anal sphincter.

BACKGROUND AND PURPOSE: We have investigated the distribution of alpha-adrenoceptors in sheep internal anal sphincter (IAS), as a model for the human tissue, and evaluated various imidazoline derivatives for potential treatment of faecal incontinence. EXPERIMENTAL APPROACH: Saturation and competition binding with (3)H-prazosin and (3)H-RX821002 were used to confirm the presence and density of alpha-adrenoceptors in sheep IAS, and the affinity of imidazoline compounds at these receptors. A combination of in vitro receptor autoradiography and immunohistochemistry was used to investigate the regional distribution of binding sites. Contractile activity of imidazoline-based compounds on sheep IAS was assessed by isometric tension recording. KEY RESULTS: Saturation binding confirmed the presence of both alpha(1)- and alpha(2)-adrenoceptors, and subsequent characterization with sub-type-selective agents, identified them as alpha(1A)- and alpha(2D)-adrenoceptor sub-types. Autoradiographic studies with (3)H-prazosin showed a positive association of alpha(1)-adrenoceptors with immunohistochemically identified smooth muscle fibres. Anti-alpha(1)-adrenoceptor immunohistochemistry revealed similar distributions of the receptor in sheep and human IAS. The imidazoline compounds caused concentration-dependent contractions of the anal sphincter, but the maximum responses were less than those elicited by l-erythro-methoxamine, a standard non-imidazoline alpha(1)-adrenoceptor agonist. Prazosin (selective alpha(1)-adrenoceptor antagonist) significantly reduced the magnitude of contraction to l-erythro-methoxamine at the highest concentration used. Both prazosin and RX811059 (a selective alpha(2)-adrenoceptor antagonist) reduced the potency (pEC(50)) of clonidine. CONCLUSIONS AND IMPLICATIONS: This study shows that both alpha(1)- and alpha(2)-adrenoceptors are expressed in the sheep IAS, and contribute (perhaps synergistically) to contractions elicited by various imidazoline derivatives. These agents may prove useful in the treatment of faecal incontinence.

CD24 shows early upregulation and nuclear expression but is not a prognostic marker in colorectal cancer.

BACKGROUND AND AIMS: The putative stem cell marker CD24 is a small, heavily glycosylated, cell surface molecule which was originally associated with tumour metastasis. Recently it has been reported to be upregulated and of prognostic importance in colorectal tumours. The study aims to study the prognostic value of CD24 in a large series of colorectal cancer (CRC). METHODS: CD24 protein expression was examined by immunohistochemistry. A total of 10 whole tissue sections (WTS) of adenoma and 345 CRCs arranged as tissue microarrays (TMAs) were evaluated. For comparison with non-neoplastic tissue, 10 WTS containing tumour with associated non-neoplastic tissue were also studied. RESULTS: None of the samples of normal tissue (adjacent to tumour) showed CD24 expression. In the tumours, CD24 expression was seen on the luminal surface of the cells, within the cytoplasm and, unexpectedly, also within the nucleus. Positive immunostaining was seen in 9/10 (90%) adenomas and 313/345 (91%) of CRCs. Weak statistical associations were found between CD24 expression and some clinicopathological features. In contrast to other published studies, however, the analysis did not show any association between CD24 expression and poor prognosis-if anything it was found that loss of CD24 expression appeared to be more related to poor outcome. CONCLUSION: Upregulation of CD24 is an early and common event during the development of CRC and it may be expressed in any cellular compartment, including the nucleus. CD24 is not, however, a good prognostic marker in CRC.

Post inflammatory damage to the enteric nervous system in diverticular disease and its relationship to symptoms.

Some patients with colonic diverticula suffer recurrent abdominal pain and exhibit visceral hypersensitivity, though the mechanism is unclear. Prior diverticulitis increases the risk of being symptomatic while experimental colitis in animals increases expression of neuropeptides within the enteric nervous system (ENS) which may mediate visceral hypersensitivity. Our aim was to determine the expression of neuropeptides within the ENS in diverticulitis (study 1) and in patients with symptomatic disease (study 2). Study 1 - Nerves in colonic resection specimens with either acute diverticulitis (AD, n = 16) or chronic diverticulitis (CD, n = 16) were assessed for neuropeptide expression recording % area staining with protein gene product (PGP9.5), substance P (SP), neuropeptide K (NPK), pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP) and galanin. Study 2 - Seventeen symptomatic and 15 asymptomatic patients with colonic diverticula underwent flexible sigmoidoscopy and multiple peridiverticular mucosal biopsies. Study 1- Neural tissue, as assessed by PGP staining was increased to a similar degree in circular muscle in both AD and CD. The CD specimens showed significant increases in the immunoreactivity of SP, NPK and galanin in both mucosal and circular muscle layer compared with controls. Study 2 - Mucosal histology was normal and PGP9.5 staining was similar between groups however patients with symptomatic diverticular disease demonstrated significantly higher levels of SP, NPK, VIP, PACAP and galanin within the mucosal plexus. Patients with symptomatic diverticular disease exhibit increased neuropeptides in mucosal biopsies which may reflect resolved prior inflammation, as it parallels the changes seen in acute and chronic diverticulitis.

Hospital costs of colorectal cancer care.

OBJECTIVE: In a hospital based setting, identify factors which influence the cost of colorectal cancer care? DESIGN: Retrospective case note review SETTING: Nottingham, United Kingdom PARTICIPANTS: 227 patients treated for colorectal cancer METHODS: Retrospective review of the hospital records provided the primary data for the costing study and included all CRC related resource consumption over the study period. RESULTS: Of 700 people identified, 227 (32%) sets of hospital notes were reviewed. The median age of the study group was 70.3 (IQR 11.3) years and there were 128 (56%) males. At two years, there was a significant difference in costs between Dukes D cancers ( pound3641) and the other stages ( pound3776 Dukes A; pound4921 Dukes B). Using univariate and multivariate regression, the year of diagnosis, Dukes stage of disease, intensive nursing care, stoma requirements and recurrent disease all significantly affected the total cost of care. CONCLUSIONS: CRC remains costly with no significant difference in costs if diagnosed before compared to after 1992. Very early and very late stage cancers remain the least costly stage of cancers to treat. Other significant effectors of hospital costs were the site of cancer (rectal), intensive nursing care, recurrent disease and the need for a stoma.

Population screening for colorectal cancer: the implications of an ageing population.

Population screening for colorectal cancer (CRC) has recently commenced in the United Kingdom supported by the evidence of a number of randomised trials and pilot studies. Certain factors are known to influence screening cost-effectiveness (e.g. compliance), but it remains unclear whether an ageing population (i.e. demographic change) might also have an effect. The aim of this study was to simulate a population-based screening setting using a Markov model and assess the effect of increasing life expectancy on CRC screening cost-effectiveness. A Markov model was constructed that aimed, using a cohort simulation, to estimate the cost-effectiveness of CRC screening in an England and Wales population for two timescales: 2003 (early cohort) and 2033 (late cohort). Four model outcomes were calculated; screened and non-screened cohorts in 2003 and 2033. The screened cohort of men and women aged 60 years were offered biennial unhydrated faecal occult blood testing until the age of 69 years. Life expectancy was assumed to increase by 2.5 years per decade. There were 407 552 fewer people entering the model in the 2033 model due to a lower birth cohort, and population screening saw 30 345 fewer CRC-related deaths over the 50 years of the model. Screening the 2033 cohort cost pound 96 million with cost savings of pound 43 million in terms of detection and treatment and pound 28 million in palliative care costs. After 30 years of follow-up, the cost per life year saved was pound 1544. An identical screening programme in an early cohort (2003) saw a cost per life year saved of pound 1651. Population screening for CRC is costly but enables cost savings in certain areas and a considerable reduction in mortality from CRC. This Markov simulation suggests that the cost-effectiveness of population screening for CRC in the United Kingdom may actually be improved by rising life expectancies.

Prolonged elevation of galanin and tachykinin expression in mucosal and myenteric enteric nerves in trinitrobenzene sulphonic acid colitis.

Diverticulitis causes recurrent abdominal pain associated with increased mucosal expression of mucosal galanin and substance P (SP). We studied changes in mucosal and myenteric plexus neuropeptides in adult rats using a model of colonic inflammation, trinitrobenzenesulphonic acid colitis. We assessed the effects on the pan-neuronal markers protein gene product 9.5 (PGP9.5) and neurofilament protein, as well as specific neuropeptides at 1, 2, 3, 4, 6, 8, 10 and 14 weeks. Following the acute injury there was macroscopic resolution of inflammation but minor microscopic abnormalities persisted. Percent area stained of mucosal PGP9.5 fell initially but average levels on days 21 and 28 levels were significantly elevated (P < 0.001), returning to normal by day 42. Percent area staining of PGP9.5 in the muscle rose immediately and remained significantly elevated at 70 days (P < 0.001). SP, neuropeptide K and galanin followed a similar overall pattern. SP to PGP9.5 ratio was significantly increased in the muscle both acutely (days 1-28) and in the long term (days 70 and 98), whereas the galanin to PGP9.5 ratio was significantly increased in the mucosa throughout the study. Low-grade chronic inflammation after an acute initial insult causes a persistent increase in the expression of galanin in the mucosa and SP in muscle layer.

Treated Colorectal Cancer: What is the Cost to Primary Care?

BACKGROUND: Colorectal cancer is the second commonest cause of cancer death and the cost to primary care has not been estimated. AIM: To determine the direct primary care costs of colorectal cancer care. DESIGN: Retrospective case note review. SETTING: Nottingham, United Kingdom. METHODS: We identified people with colorectal cancer between 1995 and 1998, from computerised pathology records. Colorectal cancer related resources consumed in primary care, from hospital discharge to death, were identified from retrospective notes review. Outcome measures were costs incurred by the General Practitioner (GP) and the total cost to primary care. We used multiple linear regression to identify predictors of cost. RESULTS: Of 416 people identified from pathology records, the median age at primary operation of the 135 (33%) people we selected was 74.2 (IQR 14.4) years, 75 (56%) were male. The median GP cost was: Dukes A pound61.0 (IQR 516.2) and Dukes D pound936.2 (1196.2) p < 0.01. The geometric mean ratio found Dukes D cancers to be 10 times as costly as Dukes A. The median total cost was: Dukes A pound1038.3 (IQR 5090.6) and Dukes D pound1815.2 (2092.5) p = 0.06. Using multivariate analysis, Dukes stage was the most important predictor of GP costs. For total costs, the presence of a permanent stoma was the most predictive variable, followed by adjuvant therapy and advanced Dukes stage (Dukes C and D). CONCLUSIONS: Contrary to hospital based care costs, late stage disease (Dukes D) costs substantially more to general practice than any other stage. Stoma care products are the most costly prescribable item. Costs savings may be realised in primary care by screening detection of early stage colorectal cancers.