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AIM: Pseudomyxoma peritonei (PMP) is a rare neoplasm of the appendix, which if untreated disseminates throughout the abdominal cavity and generates considerable morbidity. Since 2002 in the UK, patients with PMP have been managed via two nationally commissioned centres. We evaluated referrals and treatment pathways over time at the Manchester centre.METHOD: Data from all patients referred with suspected PMP were prospectively collected (2002-2015). Definitive treatment was cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC). Disease burden was quantified using the Peritoneal Cancer Index (PCI: score 0-39) and complete cytoreduction (CC) defined by scores of 0/1. Novel treatment algorithms were developed for patients with low-grade appendiceal mucinous neoplasm (LAMN) localised to the peri-appendiceal tissue.RESULTS: 817 patients with confirmed PMP were referred increasing from 11 in 2002 to 103 in 2015. Disease burden was high with mean PCI of 31 in the first quartile (Q1), levelling-off to 15,15,17 thereafter (p = 0.002). The proportion of CC0/1 increased from 67% in Q1 to 77% Q2 and 74% Q3/4. Where complete cytoreduction was achieved, 5 and 10-year overall survival was 77% and 66%. The proportion of patients referred with localised LAMN increased over time reaching 25% each year since 2010 (Ptrend CONCLUSION: The establishment of a national treatment centre was associated with an initial presentation of patients with advanced disease. The programme has demonstrated a clear trend over time towards earlier referral and adoption of minimal invasive techniques for localised disease. This article is protected by copyright. All rights reserved.

OBJECTIVE: Microvessel density (MVD) has been studied as a prognostic marker in human cancers. Quantification of lymphatic vessel density (LVD) is now possible by using new antibodies. Expression of the lymphangiogenic growth factors, VEGF-C and VEGF-D, is associated with poorer clinicopathological outcomes in various tumours. The aim of this study was to quantify LVD and MVD in colorectal cancer, determine the relationship between LVD, MVD and clinicopathological variables and examine the relationship between LVD and tumour expression of VEGF-C and VEGF-D. METHOD: Thirty primary colorectal cancers were immunostained for CD34, lymph vessel endothelial hyaluronan receptor-1 (LYVE-1), VEGF-A and VEGF-D using standard techniques. LVD and MVD were determined by Chalkley grid counting. Tumours were assessed for the presence or absence of LYVE-1 positive lymphatics at different areas within the tumour and the tumour was scored for VEGF-C and VEGF-D immunostaining intensity at the invading tumour edge. Non-parametric tests were used for statistical analysis and a P-value of

BACKGROUND: Patients with acromegaly are at moderately increased risk of developing colorectal cancer and may be considered for screening colonoscopy. In turn, large bowel dimensions may be increased in these patients, factors that predict for increased risk of serious complications such as perforation. OBJECTIVE: To evaluate this risk potential, we measured large bowel length and loop complexity using magnetic endoscopic imaging (MEI). DESIGN: Case-control study in 25 unselected patients with acromegaly (mean age 56 years) vs. 41 nonacromegalic controls (mean age 60 years) undergoing screening colonoscopy. MEASUREMENTS: MEI parameters were determined and age- and sex-adjusted mean differences calculated. The dependency of total large bowel length on various demographic and disease-related factors (e.g. GH exposure, IGF-I and IGFBP-3 concentrations) was assessed using regression techniques. RESULTS: Total large bowel length was increased by 20%[95% confidence interval (CI) 9-31%] in patients with acromegaly compared with controls (unadjusted and adjusted; P-values < 0.001). Acromegaly was also associated with increased time taken to reach the caecum (P = 0.01) and increased pelvic loop complexities (5/25 vs. 1/41, Fisher's exact test: P = 0.03). Total large bowel length was predicted by age at colonoscopy (P = 0.003) and patient height (P = 0.03), but not by surrogate biochemical markers of disease activity. CONCLUSIONS: Acromegaly is associated with increased large bowel length and loop complexity making colonoscopy technically challenging, and theoretically increasing the risk of serious complications. Patients need to be counselled accordingly, and appropriate resources with experienced staff allocated.

Summary background In patients with acromegaly serum IGF-I is increasingly used as a marker of disease activity. As a result, the relationship between serum GH and IGF-I is of profound interest. Healthy females secrete three times more GH than males but have broadly similar serum IGF-I levels, and women with GH deficiency require 30–50% more exogenous GH to maintain the same serum IGF-I as GH-deficient men. In a selected cohort of patients with active acromegaly, studied off medical therapy using a single fasting serum GH and IGF-I measurement, we have reported previously that, for a given GH level, women have significantly lower circulating IGF-I. objective To evaluate the influence of age and gender on the relationship between serum GH and IGF-I in an unselected cohort of patients with acromegaly independent of disease control and medical therapy. methods Sixty (34 male) unselected patients with acromegaly (median age 51 years (range 24–81 years) attending a colonoscopy screening programme were studied. Forty-five had previously received pituitary radiotherapy. Patients had varying degrees of disease control and received medical therapy where appropriate. Mean serum GH was calculated from an eight-point day profile (n = 45) and values obtained during a 75-g oral glucose tolerance test (n = 15). Serum IGF-I, IGFBP-3 and acid-labile subunit were measured and the dependency of these factors on covariates such as log10 mean serum GH, sex, age and prior radiotherapy was assessed using regression techniques. results The median calculated GH value was 4·7 mU/l (range 1–104). A significant linear association was observed between serum IGF-I and log10 mean serum GH for the cohort (R = 0·5, P

Colorectal cancer develops through a multistage process recognizable at a histopathological level by progression from normal mucosa to invasive carcinoma (the adenoma-carcinoma sequence). For many years, it has been hypothesized that increased cell proliferation in the colonic crypt represents the earliest recognizable stage in this sequence. This perspective is now changing. While several human studies have reported increased crypt cell proliferation in samples from at-risk patients, there are many inconsistencies and paradoxes in their conclusions. In addition, it is appreciated that the process of apoptosis (programmed cell death) is vital for normal crypt homeostasis and its impairment may be an early event in the neoplastic process. It is now believed that aberrant crypt foci (ACFs) represent the earliest step in colorectal carcinogenesis. Two ACF types are identifiable: hypercellular and dysplastic. Increased proliferative activity may be seen in both, but the dysplastic entity is most relevant to carcinogenesis. Animal and human studies support the notion that ACFs grow by crypt fission leading to the formation of microadenomas. Adenomas are monoclonal expansions of an altered cell, but very early lesions may be polyclonal. There are outward and inward theories of polypoid growth, and evidence to support both mechanisms. The ACF assay has become a useful tool to detect carcinogens in animal studies but has been less frequently used in human studies. For future cancer chemopreventive and risk assessment studies in humans, the identification and quantification of ACFs should be considered a more effective intermediate marker of risk than the determination of crypt cell proliferation alone.

OBJECTIVE: Circulating insulin-like growth factor (IGF)-II and IGF binding protein-2 (IGFBP-2) are frequently altered, often in parallel, in numerous pathologies including neoplastic disease but little is known about their normal regulation. This study compared serum IGF-II and IGFBP-2 distributions between acromegalics and a large normal adult population to explore possible determinants. PATIENTS: Sixty acromegalic patients undergoing screening colonoscopy (age range 25-81 years); normative data from 306 healthy adults (age range 20-89 years). MEASUREMENTS: Serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were measured in healthy adults and acromegalics. Mean growth hormone (GH) levels were obtained for acromegalic patients. Differences were compared using t-tests (unadjusted) and multiple regression models (adjusted for age and gender). Correlations were expressed as Pearson's coefficient (r). RESULTS: For acromegalic patients, GH was significantly correlated with IGF-I (r = 0.50; P < 0.001) and IGFBP-3 (r = 0.29; P = 0.03) but not IGF-II or IGFBP-2. Contrary to expectations, mean IGF-II and IGFBP-2 levels were significantly raised in the acromegalics compared with normals [adjusted mean difference (95% CI) = 226 (181, 271) microg/l and 305 (200, 410) microg/l, respectively]. Ten acromegalic patients had colorectal neoplasia but their presence did not contribute to the elevations in serum IGF-II and IGFBP-2. The (IGF-I + IGF-II)/IGFBP-3 molar ratios were remarkably constant in both healthy adults and acromegalics, but the relationships of the ligands individually with IGFBP-3 were not linear: as IGFBP-3 increased, IGF-I also increased whereas IGF-II initially increased but then decreased. IGFBP-2 did not correlate with IGF-II, but molar concentration significantly correlated with the IGF-II/IGFBP-3 molar ratio (r = 0.40; P = 0.001). CONCLUSIONS: Serum IGF-II and IGFBP-2 levels were paradoxically elevated in acromegalics, independent of the presence of colorectal neoplasia. The (IGF-I + IGF-II)/IGFBP-3 molar ratio appears to be pivotal in determining IGF-II values, which, in turn, expressed as a ratio of IGFBP-3, is related to IGFBP-2. These observations offer new insights into the regulation of these peptides.

Our aim was to assess changes in attitudes to autologous transfusion amongst surgeons over a 10-year period in response to scientific evidence, public awareness, published guidelines, management and the increasing cost of blood products. Surgeons across the north-west of England completed questionnaires on knowledge, experience and attitude towards autologous transfusion in 1990, 1994 and 1999. Main outcome measures were changes in knowledge, experience and utilization of autologous transfusion; perceived advantages of autologous transfusion, obstacles to its implementation in surgical practice and preferences for specific techniques (preoperative autologous donation, acute normovolaemic haemodilution, intraoperative and postoperative cell salvage). There has been little change in practice over 10 years. Many more surgeons were keen to employ autologous transfusion than were using it. Autologous transfusion was only used in general, orthopaedic and cardiothoracic surgery. Safety and patient preference were the main arguments for implementation and logistics the main obstacles. Autologous transfusion was used sporadically in surgical practice. Clinical trials are needed to guide clinicians in the choice of transfusion techniques.

We submit a video of the highlights of three cases of laparoscopic cytoreductive surgery and heated intra-peritoneal chemotherapy. These cases point to some of the challenges of laparoscopic cytoreductive surgery and logical variations such as natural orifice specimen extraction, performed in the third case. This article is protected by copyright. All rights reserved.

Objective: Advanced pelvic tumours require multidisciplinary care to improve outcome. This is an audit of one specialist unit's experience. Method: Consecutive patients referred from 2001 to 2005 for consideration of pelvic clearance were evaluated by retrospective review. Results: Of 100 patients assessed, 55 were considered unsuitable for surgery. Exclusions included unresectable pelvic side-wall disease (25), widespread disease (23) and severe co-morbidity (7). Forty-five patients were operated on; 22 had locally advanced disease, 14 had recurrence and nine had residual disease following previous surgery. The primary cancers were colorectal in 24, gynaecological in 10 and urogenital in 10; one patient had non-neoplastic disease. Preoperatively 39 (87%) had examination under anaesthetic (87%) and all had MR and CT imaging. Neoadjuvant radiotherapy and chemotherapy was given in 27 and 18 patients respectively. Following resection by a multi-speciality team, surgery was considered curative in 40 (90%) of cases as judged by a histologically negative margin. All patients received level 2 care postoperatively with only two requiring level 3 care. There was no 30-day mortality but there were 17 complications treated conservatively and five that required surgery. Conclusion: Advanced pelvic tumours require careful multidisciplinary assessment and treatment. This study shows that this can be performed safely with high levels of histological clearance of tumour.

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.

Objective: Adenocarcinoma of the perineum is unusual. This series of nine patients highlights the challenges of management. Method: Six male and three female patients aged 29–85 years presented to a single unit, five were T4 and three were T3 tumours. Results: Pain and swelling in the perineum and perianal tissues remote from the anal canal occurred in six patients whilst three patients had chronic perineal fistulae, two of whom had longstanding Crohn's disease. In eight patients a primary adenocarcinoma was identified. One patient with fistulating perineal Crohn's disease had multifocal mucinous adenocarcinoma without evidence of a gastrointestinal primary. Radical multimodality treatment including long course chemo-radiotherapy (CRT) and radical abdominoperineal resection was used in seven patients, four of whom required perineal reconstruction with myocutaneous flaps. Two patients had CRT without surgery (one unresectable and one refused surgery). Negative resection margins were achieved in six of seven patients. All seven patients undergoing resection were well palliated with relief of pain and currently four patients remain free of disease with only one patient developing further perineal disease remote from the surgical resection site. Conclusion: Perineal adenocarcinoma may be associated with an occult colorectal primary or chronic fistulae. Lower GI endoscopy and biopsies of non-healing mucous producing fistulae should be undertaken to establish the diagnosis. Radical surgery often achieves local disease control.

Objective: Wound dehiscence with nonhealing of the perineum is a significant morbidity associated with radical abdominoperineal resection (APR). Myocutaneous flaps have been used to facilitate primary wound healing. The purpose of this study is to evaluate the results of myocutaneous flap reconstruction of the perineum following radical APR. Method: The clinical records of patients who had myocutaneous flap reconstruction of the perineum between 2000 and 2005 were reviewed. Details of wound healing and complications related to the flaps were recorded. Results: Seventeen patients with a median age of 59 (range 29–77) years had primary reconstruction of the perineum with gracilis (10), rectus abdominis (6) and gluteal (1) myocutaneous flaps. Malignancy of the anus (12) and rectum (4) was the primary pathology and one patient had chronic perianal crohns fistulae. Eleven patients had preoperative radiotherapy in this group. Complete healing of the perineum was achieved in 16 (94.2%) of the 17 patients. There were eight (47%) minor wound dehiscence and two (11%) skin necrosis all of which healed completely and one (5.8%) total flap necrosis. Discussion: Myocutaneous flaps improve wound healing with only minor morbidity in majority of patients and should be considered routinely to close perineal defects following radical APR particularly in irradiated perineum.