Adenomas as a risk factor in familial colorectal cancer: implications for screening and surveillance in the UK.

Colorectal cancer (CRC) develops from normal epithelium, through dysplastic adenoma to invasive carcinoma. In addition to familial adenomatous polyposis and Lynch syndrome, approximately 10-35% of CRCs are familial in nature. CRC screening and surveillance programmes are based on an understanding of the natural history of polyps and rely on the ability to remove premalignant lesions endoscopically before they are capable of developing invasion. There are, however, significant differences in these guidelines between the UK and the USA in relation to the weight attributed to a family history of polyps. Here, using publicly available national data sets, we show that these differences in guidelines unexpectedly generate inadequate screening recommendations for second-degree relatives of patients with CRC in the UK. We validate our simple mathematical modelling of the clinical problem on a regional data set as well as previously published study data to demonstrate the correct interpretation. We further discuss the implications of a family history of adenoma formation in the current climate of the Bowel Cancer Screening Programme and suggest a re-evaluation of the UK guidelines in the light of this developing issue.

The impact of a dedicated multidisciplinary team on the management of early rectal cancer.

AIM: Local excision of early rectal cancer (ERCa) offers comparable survival and reduced operative morbidity compared with radical surgery, yet it risks an adverse oncological outcome if performed in the wrong setting. This retrospective review considers the impact of the introduction of a specialist early rectal cancer multidisciplinary team (ERCa MDT) on the investigation and management of ERCa. METHOD: A retrospective comparative cohort study was undertaken. Patients with a final diagnosis of pT1 rectal cancer at our unit were identified for two 12-month periods before and after the introduction of the specialist ERCa MDT. Data on investigations and therapeutic interventions were compared. RESULTS: Nineteen patients from 2006 and 24 from 2011 were included. In 2006, 12 patients underwent MRI and four transrectal ultrasound (TRUS) examination, while in 2011, 18 and 20, respectively, received MRI and TRUS. In 2006 four patients underwent incidental ERCa polypectomy, with all having a positive resection margin leading to anterior resection. In 2011 only one case with a positive margin following extended endoscopic mucosal resection was identified. Definitive local excision without subsequent resection occurred in two patients in 2006 and in 16 in 2011. CONCLUSION: The study demonstrates an improvement in preoperative ERCa staging, a reduction in margin positivity and an increase in the use of local excision following the implementation of a specialist ERCa MDT. The increased detection of rectal neoplasms through screening and surveillance programmes requires further investigation and management. A specialist ERCa MDT will improve management and should be available to all practitioners involved with patients with ERCa.

Systematic analysis of missed colorectal cancer cases and common pitfalls in diagnosis.

BACKGROUND: Missed colorectal cancer on endoscopic or radiological investigations may delay diagnosis and impact outcome. This study audits incidence of previous investigations in patients with colorectal cancer, considers outcome in 'missed' cancer cases and examines the diagnostic pathway in the derived case series to identify common pitfalls in diagnosis. METHODS: Patients diagnosed with colorectal cancer in 2011 at a single National Health Service (NHS) Trust were reviewed. Incidence of endoscopic and radiological investigations in the 3 years preceding diagnosis and outcome data were collected. Cases of prior investigation not leading to diagnosis were considered 'missed' cancers and survival compared with 'detected' cases. The diagnostic pathway in each 'missed' case was reviewed. RESULTS: 395 colorectal cancer cases were studied. Eighteen (4.6%) patients underwent previous investigation including colonoscopy (n=4), flexible sigmoidoscopy (n=5), barium enema (n=5) and diagnostic abdominal CT scan (n=12), median 708 days prior to diagnosis. Previous investigation predicted reduced overall and disease-free survival (HR 2.07, p=0.04 and HR 2.66, p<0.0001), after age and gender adjustment. Ten different categories termed 'pitfalls' were derived from analysis of the diagnostic pathway. These included CT scanning for abdominal pain without further investigation (n=7), rectosigmoid cancer following a previous diagnosis of diverticular disease (n=4) and incomplete diagnostic investigations without adequate follow-up (n=3). CONCLUSIONS: A proportion of patients diagnosed with colorectal cancer have previously been investigated for gastrointestinal symptoms and survival appears reduced in these patients. Regular audit and analysis of previous investigations can identify common pitfalls in diagnosis, which should be used to inform training and improve practice.

Two-week wait symptoms are prevalent in screened patients with a positive faecal occult blood test but do not predict cancer.

AIM: Lower gastrointestinal (LGI) symptoms are prevalent in patients screened for bowel cancer yet do not predict a finding of cancer. This study evaluates symptoms in patients with these characteristics against the 2-week wait (2ww) criteria to determine whether they predicted cancer in these patients. METHOD: A prospective cohort study was performed. Patients with a positive faecal occult blood (FOB) test attending our unit over a 7-month period were included. Data on symptom prevalence, frequency and duration were collected and assessed against the 2ww criteria. Associations between symptom prevalence and patient outcome were investigated using the χ(2) test. RESULTS: Three hundred and ninety-seven patients were included and 37 (9%) were found to have colorectal cancer (CRC). The prevalence of undefined LGI symptoms was 71% and appeared comparable between those with and without CRC (65 vs 72%, P = 0.385). 2ww symptoms were reported in 147 (37%), with 2ww change in bowel habit in 10% and 2ww rectal bleeding in 31%. 2ww symptom prevalence was similar in those with and without cancer (38 vs 37%, P = 0.915). No significant differences in overall 2ww prevalence or prevalence of individual 2ww symptoms were demonstrated between those with a normal colonoscopy or one showing cancer, polyps or other pathology. Twenty nine per cent of patients with 2ww symptoms had reported these to their GP. CONCLUSION: Undefined LGI symptoms are prevalent in FOB-positive patients but do not predict CRC. 2ww symptoms are also highly prevalent, yet similarly fail to predict cancer. Further efforts to increase public awareness of cancer symptoms are required, whilst false reassurance from a negative FOB result should be discouraged.

Invited Article: Indenter materials for high temperature nanoindentation.

As nanoindentation at high temperatures becomes increasingly popular, a review of indenter materials for usage at high temperatures is instructive for identifying appropriate indenter-sample materials combinations to prevent indenter loss or failure due to chemical reactions or wear during indentation. This is an important consideration for nanoindentation as extremely small volumes of reacted indenter material will have a significant effect on measurements. The high temperature hardness, elastic modulus, thermal properties, and chemical reactivities of diamond, boron carbide, silicon carbide, tungsten carbide, cubic boron nitride, and sapphire are discussed. Diamond and boron carbide show the best elevated temperature hardness, while tungsten carbide demonstrates the lowest chemical reactivity with the widest array of elements.

Elevated temperature, nano-mechanical testing in situ in the scanning electron microscope.

A general nano-mechanical test platform capable of performing variable temperature and variable strain rate testing in situ in the scanning electron microscope is described. A variety of test geometries are possible in combination with focused ion beam machining or other fabrication techniques: indentation, micro-compression, cantilever bending, and scratch testing. The system is intrinsically displacement-controlled, which allows it to function directly as a micro-scale thermomechanical test frame. Stable, elevated temperature indentation∕micro-compression requires the indenter tip and the sample to be in thermal equilibrium to prevent thermal displacement drift due to thermal expansion. This is achieved through independent heating and temperature monitoring of both the indenter tip and sample. Furthermore, the apex temperature of the indenter tip is calibrated, which allows it to act as a referenced surface temperature probe during contact. A full description of the system is provided, and the effects of indenter geometry and of radiation on imaging conditions are discussed. The stabilization time and temperature distribution throughout the system as a function of temperature is characterized. The advantages of temperature monitoring and thermal calibration of the indenter tip are illustrated, which include the possibility of local thermal conductivity measurement. Finally, validation results using nanoindentation on fused silica and micro-compression of [100] silicon micro-pillars as a function of temperature up to 500 °C are presented, and procedures and considerations taken for these measurements are discussed. A brittle to ductile transition from fracture to splitting then plastic deformation is directly observed in the SEM for silicon as a function of temperature.

Trans-anal rectoscopic ball diathermy (TARD) for radiotherapy-induced haemorrhagic telangiectasia: a safe and effective treatment.

AIM: Rectal bleeding may occur late after radiotherapy for prostate or bladder cancer, particularly when given by external beam, due to radiotherapy-induced haemorrhagic telangiectasia (RIHT). We present the results of trans-anal rectoscopic ball diathermy (TARD) for RIHT. METHOD: Data were collected from patients who received TARD for RIHT. The diagnosis was made during endoscopic examination. Treatment involved discretely spaced spot monopolar diathermy coagulation of the rectal mucosa to the affected areas. RESULTS: Thirteen patients [median age 76 (69-80) years] underwent TARD for RIHT between 2005 and 2008. All presented late with rectal bleeding following radiotherapy for prostate or bladder cancer. Eight were treated as a day case, four remained in hospital for one night and one was hospitalized for 2 days. There was no mortality. Eleven patients achieved excellent symptomatic control requiring no further treatment at a median follow-up of 20 (3-36) months. One patient underwent further TARD for recurrence. One patient complained of severe anorectal pain of no obvious cause and one developed constipation. CONCLUSION: Trans-anal rectoscopic ball diathermy (TARD) is a safe and effective treatment for patients with rectal bleeding due to RIHT.

Repeat 2-week wait referrals for colorectal cancer.

AIM: The inappropriate use of the '2-week wait' pathway for suspected colorectal cancer (CRC2ww) may overload urgent clinics and delay the assessment and investigation of other patients. Those who have been previously referred and investigated for suspected colorectal cancer may present one group that does not warrant repeat urgent referral. This paper aims to identify the incidence and diagnostic yield of repeat CRC2ww referrals. METHOD: All CRC2ww patients referred to our unit over a 4-year period were identified retrospectively. Referral indication, outcome and instances of repeat referral were identified from multidisciplinary team, endoscopy and imaging databases. RESULTS: In all, 2735 CRC2ww referrals were made over the study period. Of these, 122 were repeated CRC2ww referrals, with the incidence increasing from 2% in 2008 to 6% in 2010 (P = 0.0006). The median time to repeat referral was 1070 days. After initial referral 267 cancers were detected, including 212 colorectal cancers. The diagnostic yield was lower but not significantly so after repeated referral (six cancers) compared with initial referral (5%vs 10%, P = 0.07). CONCLUSION: The incidence of repeat referral is low but the diagnostic yield is not insignificant. Exclusion of these patients from urgent assessment and investigation will not significantly reduce workload and may risk missing some patients with cancer.

Does the incidence of unexpected malignancy in 'benign' rectal neoplasms undergoing trans-anal endoscopic microsurgery vary according to lesion morphology?

AIM: Mucosectomy by trans-anal endoscopic microsurgery (TEMS) allows safe and effective excision of benign rectal lesions. Preoperative endoscopic, clinical and ultrasonographic assessment aims to select benign lesions whilst avoiding inappropriate mucosectomy in lesions with malignancy. This study examines the relationship between lesion morphology and accurate benign preoperative classification of rectal lesions undergoing TEMS. METHOD: Primary lesions preoperatively assessed as benign were identified from a prospective TEMS database. Operative specimen morphology was independently classified by two blinded investigators, using photographs, into flat-sessile, exophytic or mixed morphology. The accuracy of the preoperative assessment by rectal ultrasonography was compared with the results of histological examination of the excised specimen (χ(2) and Fisher's exact tests). RESULTS: Of 167 lesions with adequate data, the morphological classification showed 60 flat-sessile, 56 mixed morphology and 51 exophytic tumours, of which 5, 7 and 9, respectively, contained unexpected malignancy (P=0.48). Accurate preoperative assessment of a lesion as benign occurred in 89% of flat-sessile and mixed morphology (n=55 and 49, respectively) and in 70% of exophytic lesions (n=36) (P=0.01). Only the exophytic group contained patients in whom preoperative endoscopic and ultrasonographic staging could not be confidently made (uTx). Histology demonstrated six of the seven uTx cases to be benign. CONCLUSION: In this study exophytic polyps were less likely to be accurately classified as benign using preoperative ultrasonography/endoscopy when compared with flat-sessile or mixed morphology polyps.

Prevalence and significance of anaemia in patients receiving long-course neoadjuvant chemoradiotherapy for rectal carcinoma.

AIM: The study aimed to assess the prevalence and significance of anaemia during long-course neoadjuvant radiotherapy for rectal cancer at our centre. METHOD: Hospital coding and a prospective oncology database were used to identify all patients undergoing long-course neoadjuvant radiotherapy for rectal cancer at our centre between 2004 and 2009. A retrospective review of computerized records was used to extract individual patient data. Anaemia was defined as a haemoglobin level of < 11.5 g/dl for women and of < 13 g/dl for men. Downstaging was assessed by comparing radiological stage (rTNM) with histological stage (ypTNM). Tumour regression after radiotherapy was assessed using the Rectal Cancer Regression Group (RCRG) scores of 1-3. The results were analysed using Gnu PSPP statistical software. RESULTS: There were 70 patients (51 men) of median age 66 (interquartile range 60-72.75) years. Of these, 24 were anaemic. Two (3%) had no haemoglobin level recorded and were excluded. Forty-two per cent of anaemic patients demonstrated mural (T) downstaging compared with 68% of nonanaemic patients (P = 0.03). There was no difference in nodal downstaging between the groups. The RCRG scores showed more tumour regression in nonanaemic patients than in anaemic patients, as follows: RCRG 1, 59%vs 30%; RCRG 2, 11%vs 17%; and RCRG 3, 38%vs 46% (P < 0.001). CONCLUSION: The prevalence of anaemia in patients undergoing long-course neoadjuvant radiotherapy was 35%. Anaemia during long-course neoadjuvant radiotherapy was associated with significant reductions in tumour downstaging and regression.

Slipping through the bowel cancer screening programme.

AIM: Colorectal cancer is common and a leading cause of cancer death. Faecal occult blood screening has been shown to reduce mortality. The aim of this study was to identify patients in Gloucestershire with a new diagnosis of colorectal cancer who had previously been screened via the Bowel Cancer Screening Programme (BCSP). METHOD: Between 2006 and 2009, 1030 patients were diagnosed with colorectal cancer. Of these 237 (23%) had been invited to be screened via the BCSP. Their clinical notes were analysed. RESULTS: Fifty-seven (24%) of the 237 patients had previously had a negative faecal occult blood result. Thirty-three (14%) had their cancer discovered as part of the BCSP. Seventy (30%) had already been diagnosed with colorectal cancer prior to invitation, 62 (26%) did not respond to the invitation, nine (4%) were registered outside Gloucestershire and had therefore not been invited, and three (3%) had died before the invitation. Of the 57 patients with a negative faecal occult blood test, 47 (83%) had colorectal cancer staged Dukes B or C, and 34 (60%) had a rectal or sigmoid cancer. CONCLUSION: Patients will present with colorectal cancer despite having been invited to participate in the BCSP, with many having received a negative faecal occult blood test. This could be considered a high false negative rate.

Laparo-endoscopic resection for extensive and inaccessible colorectal polyps: a feasible and safe procedure.

INTRODUCTION: Polypectomy at colonoscopy may be difficult or dangerous. In such instances colonic resection may be indicated. Novel combined laparoscopic-endoscopic procedures have the potential to allow safe extensive extramucosal resection, thus avoiding resection. Laparoscopic colon mobilisation provides a more favourable orientation for endoscopic mucosal resection and facilitates identification of possible perforation sites with immediate laparoscopic repair or resection if necessary. This study aimed to assess the efficacy and safety of laparo-endoscopic resection (LER) of colonic polyps. PATIENTS AND METHODS: Data were collected prospectively on consecutive patients undergoing LER. The mode of presentation, referral pattern, lesion site and size, hospital stay, procedural details, complications, histology and further treatment were recorded. RESULTS: A total of 13 patients underwent attempted LER (16 polyps in total) and this was completed for 10, with a median hospital stay of 2 days. Five polyps were removed whole and eight piecemeal. Excision was clinically complete in all cases. Three procedures were converted to colonic resection. One lesion appeared malignant, indicating a conversion to laparoscopic right hemicolectomy. Two polyps were not amenable to LER and resection was performed. One patient underwent subsequent colonic resection based on the histological findings. There were no perforations or serious complications. CONCLUSIONS: LER is a safe and effective treatment for large and inaccessible colonic polyps that would otherwise be treated by colonic resection.

Factors influencing selection for a day-case or 23-h stay procedure in transanal endoscopic microsurgery.

BACKGROUND: Transanal endoscopic microsurgery (TEMS) is an alternative to radical resection of the rectum for benign lesions and early rectal cancer. This study aimed to identify whether day-case TEMS is safe and which factors dictate patient suitability and length of stay (LOS). METHODS: Details of patients undergoing TEMS resection were retrieved from a tertiary referral prospective database. RESULTS: Of 96 patients, 46 (48 per cent) were day cases, 24 (25 per cent) had a 23-h stay and 26 (27 per cent) were inpatients. The frequency of day-case surgery increased significantly over the study interval (P = 0.050). Distance of the lesion from the anorectal junction, malignant potential and travel distance had no bearing on LOS. Older age (P = 0.004) and duration of surgery (P = 0.002) correlated significantly with increased LOS. Lesions covering one quadrant involved a significantly shorter stay than those covering two or more quadrants (P = 0.002). Maximum diameter (mean 5.7 cm) was strongly related to LOS (P = 0.009). Day-case and 23-h stay patients had a significantly higher proportion of lower-risk lesions (P = 0.001). CONCLUSION: High-volume day-case TEMS appears safe, even when long travel distances are involved. With advances in practice and procedural safety, traditional risk factors may not be as important as currently thought.

Genetically correlated effects of selective breeding for high and low methamphetamine consumption.

Improved prevention and treatment of drug addiction will require deeper understanding of genetic factors contributing to susceptibility to excessive drug use. Intravenous operant self-administration methods have greatly advanced understanding of behavioral traits related to addiction. However, these methods are not suitable for large-scale genetic experiments in mice. Selective breeding of mice can aggregate 'addiction alleles' in a model that has the potential to identify coordinated effects of multiple genes. We produced mouse lines that orally self-administer high (MAHDR) or low (MALDR) amounts of methamphetamine, representing the first demonstration of selective breeding for self-administration of any psychostimulant drug. Conditioned place preference and taste aversion results indicate that MAHDR mice are relatively more sensitive to the rewarding effects and less sensitive to the aversive effects of methamphetamine, compared to MALDR mice. These results validate the oral route of self-administration for investigation of the motivational effects of methamphetamine and provide a viable alternative to intravenous self-administration procedures. Gene expression results for a subset of genes relevant to addiction-related processes suggest differential regulation by methamphetamine of apoptosis and immune pathways in the nucleus accumbens of MAHDR and MALDR mice. In each line, methamphetamine reduced an allostatic state by bringing gene expression back toward 'normal' levels. Genes differentially expressed in the drug-naï ve state, including Slc6a4 (serotonin transporter), Htr3a (serotonin receptor 3A), Rela [nuclear factor kappaB (NFkappaB)] and Fos (cFos), represent candidates whose expression levels may predict methamphetamine consumption and susceptibility to methamphetamine reward and aversion.

Referral letters for 2-week wait suspected colorectal cancer do not allow a 'straight-to-test' pathway.

INTRODUCTION: Some clinicians have argued that 2-week wait suspected colorectal cancer patients can go 'straight-to-test' to facilitate time to diagnosis and treatment. The aim of this study was to evaluate whether the currently used referral letters are reliable enough to allow that pathway. PATIENTS AND METHODS: General practitioner (GP) letters referring patients under the Two Week-Wait Rule for suspected colorectal cancer were prospectively reviewed over a 6-month period. Three examining consultants were asked to outline the tests they would perform having only read the letter, and then again after a clinical consultation with the patient. The outcome of these tests was tracked. RESULTS: A total of 217 referral letters of patients referred under Two Week Wait Rule for suspected colorectal cancer were studied. Having just read the referral letter, the most frequently requested test was colonoscopy (148), then CT scan (48), barium enema (44), followed by gastroscopy (23) and flexible sigmoidoscopy in 15 patients (some patients would have had more than one test requested). After consultation with the patients, tests requested as guided by the GP letter were changed in 67 patients (31%), where 142 colonoscopies, 61 CT scans, 37 barium enemas, 23 flexible sigmoidoscopies and 19 gastroscopies were organised. The referral indication which had tests changed most often was definite palpable rectal mass (67%), while patients referred with definite palpable right-sided abdominal mass had their tests least often changed (9%). A total of 22 patients were found to have colorectal cancers (10%) and 30 patients were diagnosed with polyps (14%). Out of 142 colonoscopies performed, 19 (13%) showed some pathology beyond the sigmoid colon and of the 23 patients who had flexible sigmoidoscopy initially, only three went on to have colonoscopy subsequently. During the 6-month period of the study, only five breaches of the waiting time targets were recorded (1 to the 31-day target and 4 to the 62-day target). CONCLUSIONS: A significant number of patients would have had tests changed after a clinical consultation. However, only a small number required further investigations having had a consultation prior to their initial investigations. We conclude that 2-week wait suspected colorectal cancer patients should be seen in the clinic first and should not proceed 'straight-to-test'.