Defining the role of corticotropin releasing factor binding protein in alcohol consumption.

The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the binding protein (CRFBP), and has been implicated in alcohol use disorder (AUD). Therefore, identification of the exact contribution of each protein that mediates CRF effects is necessary to design effective therapeutic strategies for AUD. A series of in vitro/in vivo experiments across different species were performed to define the biological discrete role of CRFBP in AUD. First, to establish the CRFBP role in receptor signaling, we developed a novel chimeric cell-based assay and showed that CFRBP full length can stably be expressed on the plasma membrane. We discovered that only CRFBP(10 kD) fragment is able to potentiate CRF-intracellular Ca2+ release. We provide evidence that CRHBP gene loss increased ethanol consumption in mice. Then, we demonstrate that selective reduction of CRHBP expression in the center nucleus of the amygdala (CeA) decreases ethanol consumption in ethanol-dependent rats. CRFBP amygdalar downregulation, however, does not attenuate yohimbine-induced ethanol self-administration. This effect was associated with decreased hemodynamic brain activity in the CRFBP-downregulated CeA and increased hemodynamic activity in the caudate putamen during yohimbine administration. Finally, in alcohol-dependent patients, genetic variants related to the CRFBP(10 kD) fragment were associated with greater risk for alcoholism and anxiety, while other genetic variants were associated with reduced risk for anxiety. Taken together, our data provide evidence that CRFBP may possess both inhibitory and excitatory roles and may represent a novel pharmacological target for the treatment of AUD.

Leptin levels are reduced by intravenous ghrelin administration and correlated with cue-induced alcohol craving.

Increasing evidence supports the role of appetite-regulating pathways, including ghrelin and leptin, in alcoholism. This study tested the hypothesis that intravenous exogenous ghrelin administration acutely decreases endogenous serum leptin levels, and that changes in leptin levels negatively correlate with alcohol craving. This was a double-blind, placebo-controlled human laboratory study. Non-treatment-seeking, alcohol-dependent, heavy drinkers (n=45) were randomized to receive intravenous ghrelin or placebo, followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol trial cues. There was a main effect for intravenous ghrelin administration, compared with placebo, in reducing serum leptin levels (P<0.01). Post hoc analysis showed significant differences in serum leptin levels at the alcohol trial (P<0.05) that persisted at the end of the experiment (P<0.05). By contrast, there were no significant differences in serum leptin levels at the juice trial (P=not significant (NS)). The change of serum leptin level at the alcohol trial correlated with the increase in alcohol urge (P<0.05), whereas urge to drink juice was not correlated with the leptin change at the juice trial (P=NS). These findings provide preliminary evidence of ghrelin-leptin cross-talk in alcoholic individuals and suggest that their relationship may have a role in alcohol craving.

D-cycloserine to enhance extinction of cue-elicited craving for alcohol: a translational approach.

Cue-elicited craving for alcohol is well established but extinction-based treatment to extinguish this response has generated only modest positive outcomes in clinical trials. Basic and clinical research suggests that D-cycloserine (DCS) enhances extinction to fear cues under certain conditions. However, it remains unclear whether DCS would also accelerate extinction of cue-elicited craving for alcohol. The goal of the current study was to examine whether, compared with placebo (PBO), DCS enhanced extinction of cue-elicited craving among treatment-seeking individuals with alcohol use disorders (AUDs). Participants were administered DCS (50 mg) or PBO 1 h before an alcohol extinction paradigm in a simulated bar environment on two occasions. The extinction procedures occurred 1 week apart and were fully integrated into outpatient treatment. Subjective craving for alcohol was the primary variable of interest. Follow-up cue reactivity sessions were conducted 1 week and 3 weeks later to ascertain persisting DCS effects. Drinking outcomes and tolerability were also examined. DCS was associated with augmented reductions in alcohol craving to alcohol cues during the first extinction session and these effects persisted through all subsequent sessions, suggesting facilitation of extinction. Participants in the DCS condition reported significant short-term reductions in drinking, although these did not persist to follow-up, and found the medication highly tolerable. These findings provide evidence that DCS enhances extinction of cue-elicited craving for alcohol in individuals with AUDs in the context of outpatient treatment. The potential clinical utility of DCS is discussed, including methodological considerations and context-dependent learning.

Adjuvant therapy decisions based on magnetic resonance imaging of extramural venous invasion and other prognostic factors in colorectal cancer.

INTRODUCTION: There remains a lack of high quality randomised trial evidence for the use of adjuvant chemotherapy in stage II rectal cancer, particularly in the presence of high risk features such as extramural venous invasion (EMVI). The aim of this study was to explore this issue through a survey of colorectal surgeons and gastrointestinal oncologists. METHODS: An electronic survey was sent to a group of colorectal surgeons who were members of the Association of Coloproctology of Great Britain and Ireland. The survey was also sent to a group of gastrointestinal oncologists through the Pelican Cancer Foundation. Reminder emails were sent at 4 and 12 weeks. RESULTS: A total of 142 surgeons (54% response rate) and 99 oncologists (68% response rate) responded to the survey. The majority in both groups of clinicians thought EMVI was an important consideration in adjuvant treatment decision making and commented routinely on this in their multidisciplinary team meeting. Although both would consider treating patients on the basis of EMVI detected by magnetic resonance imaging, oncologists were more selective. Both surgeons and oncologists were prepared to offer patients with EMVI adjuvant chemotherapy but there was lack of consensus on the benefit. CONCLUSIONS: This survey reinforces the evolution in thinking with regard to adjuvant therapy in stage II disease. Factors such as EMVI should be given due consideration and the prognostic information we offer patients must be more accurate. Historical data may not accurately reflect today's practice and it may be time to consider an appropriately designed trial to address this contentious issue.

EMVI-positive stage II rectal cancer has similar clinical outcomes as stage III disease following pre-operative chemoradiotherapy.

BACKGROUND: Stage II rectal cancers comprise a heterogeneous group, and there is significant variability in practise with regards to adjuvant chemotherapy; the survival benefit of chemotherapy is perceived to be <4% in these patients. However, in recent years, the emergence of additional prognostic factors such as extramural venous invasion (EMVI) suggests that there may be sub-stratification of stage II tumours and, further, we may be under-estimating the benefit adjuvant chemotherapy provides in high-risk patients. This study examined the outcomes of patients with stage II and III rectal cancer to determine whether EMVI status influences disease-free survival (DFS). PATIENTS AND METHODS: An analysis of a prospectively maintained database was conducted of patients presenting with rectal cancer between 2006 and 2012. All patients underwent curative surgery and had no evidence of metastases at presentation. Clinicopathological factors were compared between stage II and III disease. The primary end point was 3-year DFS; univariate and multivariate analysis was carried out using Cox proportional hazards regression models; hazard ratios (HR) with 95% confidence intervals (CIs) were calculated. RESULTS: Four hundred and seventy-eight patients were included: 233 stage II; 245 stage III. The prevalence of EMVI was 34.9%; 57 stage II patients (24.5%) and 110 stage III patients (44.9%). On multivariate analysis, only EMVI status was a significant factor for DFS. The adjusted HR for EMVI either alone or in combination with nodal involvement was 2.08 (95% CI 1.10-2.95) and 2.74 (95% CI 1.66-4.52), respectively. CONCLUSION: EMVI is an independently poor prognostic factor for DFS for both stage II and stage III rectal cancer. These results demonstrate that there is risk-stratification within stage II tumours which affects prognosis. When discussing the use of adjuvant chemotherapy with patients that have EMVI-positive stage II tumours, these results provide evidence for a similarly increased risk of distant failure as stage III disease without venous invasion.

Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy.

In this open-label, intra-patient phase I/II trial, bortezomib was replaced with carfilzomib (escalated from 20 to 45 mg/m(2) on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle) for multiple myeloma (MM) patients who progressed while on or within 12 weeks of receiving a bortezomib-containing combination regimen. Study objectives included determination of the maximum tolerated dose (MTD), overall response rate (ORR), clinical benefit rate (CBR), time to progression, time to response, duration of response, progression-free survival and overall survival (OS). Of 38 registered patients, 37 were treated and evaluable for efficacy and safety. Thirty-one carfilzomib-based regimens using 14 different drug combinations were tested. One regimen (carfilzomib (45 mg/m(2)), ascorbic acid (1000 mg) and cyclophosphamide (2.2 mg/kg)) reached MTD. ORR and CBR were 43.2 and 62.2%, respectively. Median progression-free survival, time to progression and OS were 8.3, 9.9 and 15.8 months, respectively. Hematologic adverse events (AEs; ⩾grade 3) included lymphopenia (35.1%), thrombocytopenia (24.3%), anemia (10.8%) and neutropenia (10.8%). Nonhematologic AEs (⩾grade 3) included fever (5.4%) and hypokalemia (5.4%). These results demonstrate that replacing bortezomib with carfilzomib is safe and can be effective for MM patients failing bortezomib-containing combination regimens. This trial was registered at http://www.clinicaltrials.gov (#NCT01365559).

Mucinous carcinoma of the rectum: a distinct clinicopathological entity.

PURPOSE: The definition of mucinous tumours relies on quantification of the amount of mucus produced by neoplastic cells within the rectum. This has changed over the years to include varying degrees of mucin production. The inconsistency of diagnosis has led to conflicting reports in the literature regarding clinical outcomes and treatment response. A universally accepted definition and improved imaging and surgical techniques in the last decade are now challenging the traditional view of these tumours. The aim of this review was to present the current evidence on the clinicopathological characteristics of mucinous tumours of the rectum. METHODS: A systematic review was conducted using Preferred Reporting for Systematic Reviews and Meta-Analyses guidelines. A literature search was performed using the Ovid SP to search both EMBASE and MEDLINE databases, Google Scholar and PubMed to find all studies relating to mucinous carcinoma of the rectum. The search dates were between 1 January 1965 and 1 March 2013. RESULTS: Mucinous tumours comprise 5-20 % of all rectal cancers and commonly present at a more advanced stage and in younger patients. They are readily identified on MRI, and the diagnosis is confirmed on histological analysis, demonstrating more than 50 % of extracellular mucin within the tumour complex. They carry an overall worse prognosis compared to adenocarcinoma of the same stage. The response to oncological treatment remains controversial. CONCLUSION: Mucinous tumours of the rectum are less well understood than non-mucinous adenocarcinoma. This is due to the inconsistent histopathological definitions of the past making comparison of clinical outcome data difficult. They remain challenging to treat and are associated with a poor prognosis. A universally accepted definition and the role of imaging techniques such as MRI to accurately detect mucinous tumours are likely to lead to a better understanding of these cancers.

Adjuvant chemotherapy improves overall survival after TME surgery in mucinous carcinoma of the rectum.

INTRODUCTION: Mucinous tumours of the rectum are characterised by an abundance of extracellular mucin within the tumour complex. They are known to have a poor prognosis compared to non-mucinous adenocarcinomas. The effect of adjuvant chemotherapy on the survival outcomes of patients with mucinous cancer remains unclear. This study evaluated the 5-year overall survival of patients with mucinous rectal cancer following optimal TME surgery to determine whether adjuvant chemotherapy conferred a survival benefit. METHODS: An analysis of a prospectively-maintained database was conducted of patients presenting with mucinous rectal cancer between 2000 and 2010. Patients with mucinous tumours were identified from final pathology reports of the surgical resection specimens. The primary outcome was 5-year overall survival; univariate and multivariate analysis was performed using Cox proportional hazards regression models. RESULTS: A total of 191 patients were included for analysis with mean age of presentation 64.6 years (36-88 ± 11). On the fully adjusted multivariate model, EMVI status (HR 1.853, 95% CI 1.081-3.175) and not being given adjuvant chemotherapy (HR 2.888, 95% CI 1.801-4.633) were significant for disease recurrence. The 5-year overall survival for patients that had undergone adjuvant chemotherapy was 66.1% compared with 35.2% (Mantel Cox log-rank test - p < 0.0001). CONCLUSION: This study demonstrates that adjuvant chemotherapy is an independent factor for improvement in overall survival in patients with mucinous adenocarcinoma. Therefore, patients who have undergone TME surgery for mucinous carcinoma of the rectum should be offered adjuvant chemotherapy even in the absence of other high-risk features for poor outcomes.

Extramural venous invasion is a potential imaging predictive biomarker of neoadjuvant treatment in rectal cancer.

BACKGROUND: Extramural venous invasion (EMVI) is a poor prognostic factor in rectal cancer and identified on magnetic resonance imaging (MRI) (mrEMVI). The clinical relevance of improvement in mrEMVI following neoadjuvant therapy is unknown. This study aimed to demonstrate that regression of mrEMVI following neoadjuvant chemoradiotherapy (CRT) results in improved outcomes and mrEMVI can be used as an imaging biomarker. METHODS: Retrospective analysis of prospectively collected data was conducted examining the staging and post-treatment MRIs of patients who had presented with EMVI-positive rectal cancer. All patients had undergone neoadjuvant CRT and curative surgery. Changes in mrEMVI were graded with a new MRI-based TRG scale-mr-vTRG; and related to disease-free survival (DFS). The study fulfilled Reporting Recommendations for Tumour Marker Prognostic Studies criteria for biomarkers. RESULTS: Sixty-two patients were included. Thirty-five patients showed more than 50% fibrosis of mrEMVI (mr-vTRG 1-3); 3-year DFS 87.8% and 9% recurrence. Twenty-seven patients showed less than 50% fibrosis (mr-vTRG 4-5); 3-year DFS 45.8% with 44% recurrence - P<0.0001. On multivariate Cox-regression, only mr-vTRG 4-5 increased risk of disease recurrence - HR=5.748. CONCLUSION: Patients in whom there has been a significant response of EMVI to CRT show improved DFS. Those patients with poor response should be considered for intensive treatment. As an imaging biomarker in rectal cancer, mrEMVI can be used.

Predictors of cognitive recovery after cardiac surgery.

BACKGROUND: Postoperative neurocognitive decline occurs frequently. Although predictors of cognitive injury have been well examined, factors that modulate recovery have not. We sought to determine the predictors of cognitive recovery after initial injury following cardiac surgery. METHODS: Two hundred eighty-one patients previously enrolled in cognitive studies who experienced cognitive decline 6 weeks after cardiac surgery were retrospectively evaluated. Eligible patients completed a battery of neurocognitive measures and quality-of-life assessments at baseline, 6 weeks, and 1 year after surgery. Factor analysis was conducted to calculate the cognitive index (CI), a unified, continuous measure of cognitive function. Cognitive recovery was defined as 1-year CI greater than baseline CI. Potential predictors of cognitive recovery including patient characteristics, quality-of-life factors, comorbidities, medications, and intraoperative variables were assessed with multivariable regression modeling; P<0.05 was considered significant. RESULTS: Of the 229 patients in our final data set, 103 (45%) demonstrated cognitive recovery after initial decline in CI at 6 weeks. Multivariable analyses revealed that more education (odds ratio [OR] 1.332 [1.131-1.569], P<0.001), baseline CI (OR 0.987 [0.976-0.998], P=0.02), less decline in CI at 6 weeks (OR 1.044 [1.014-1.075], P=0.004), and greater activities of daily living at 6 weeks (OR 0.891 [0.810-0.981], P=0.02) were significant predictors of cognitive recovery. CONCLUSION: Cognitive recovery occurred in approximately one half of the cardiac surgical patients experiencing early decline. The association between cognitive recovery and Instrumental Activities of Daily Living scores at 6 weeks merits further investigation as it is the only potentially modifiable predictor of recovery.

A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma.

Our previous studies have shown that lowering the dose of pegylated liposomal doxorubicin (PLD) and bortezomib in combination with intravenous dexamethasone on a longer 4-week cycle maintained efficacy and improved tolerability in both previously untreated and relapsed/refractory (R/R) multiple myeloma (MM) patients. Lenalidomide has shown efficacy in combination with bortezomib and dexamethasone but this combination has been poorly tolerated. We conducted this phase 2 study (clinicaltrials.gov identifier: NCT01160484) to evaluate whether a longer 4-week schedule using modified doses and schedules of IV dexamethasone (40 mg), bortezomib (1.0 mg/m(2)) and PLD (4.0 mg/m(2)) administered on days 1, 4, 8, and 11 with lenalidomide 10 mg daily on days 1-14 (DVD-R) would be effective and tolerated for patients with R/R MM. A total of 40 heavily pretreated patients were enrolled and 84.6% showed clinical benefit (complete response, 20.5%; very good partial response, 10.3%; partial response, 17.9%; minimal response, 35.9%) to the combination regimen. An additional 10.3% showed stable disease and 5.1% progressed while on study. The regimen was well tolerated, with a low incidence of adverse events such as fatigue (40%), thrombocytopenia (35%), neutropenia (35%), anemia (30%), peripheral neuropathy (25%) and pneumonia (15%). Thus, the DVD-R regimen is well tolerated and produces high response rates for patients with R/R MM.

Baclofen promotes alcohol abstinence in alcohol dependent cirrhotic patients with hepatitis C virus (HCV) infection.

Hepatitis C virus (HCV) and alcoholic liver disease (ALD), either alone or in combination, count for more than two thirds of all liver diseases in the Western world. There is no safe level of drinking in HCV-infected patients and the most effective goal for these patients is total abstinence. Baclofen, a GABA(B) receptor agonist, represents a promising pharmacotherapy for alcohol dependence (AD). Previously, we performed a randomized clinical trial (RCT), which demonstrated the safety and efficacy of baclofen in patients affected by AD and cirrhosis. The goal of this post-hoc analysis was to explore baclofen's effect in a subgroup of alcohol-dependent HCV-infected cirrhotic patients. Any patient with HCV infection was selected for this analysis. Among the 84 subjects randomized in the main trial, 24 alcohol-dependent cirrhotic patients had a HCV infection; 12 received baclofen 10mg t.i.d. and 12 received placebo for 12-weeks. With respect to the placebo group (3/12, 25.0%), a significantly higher number of patients who achieved and maintained total alcohol abstinence was found in the baclofen group (10/12, 83.3%; p=0.0123). Furthermore, in the baclofen group, compared to placebo, there was a significantly higher increase in albumin values from baseline (p=0.0132) and a trend toward a significant reduction in INR levels from baseline (p=0.0716). In conclusion, baclofen was safe and significantly more effective than placebo in promoting alcohol abstinence, and improving some Liver Function Tests (LFTs) (i.e. albumin, INR) in alcohol-dependent HCV-infected cirrhotic patients. Baclofen may represent a clinically relevant alcohol pharmacotherapy for these patients.

The impact of the two-week wait referral pathway on rectal cancer survival.

AIM: The aim of this study was to compare the outcome of patients with rectal cancer referred through the two-week wait (TWW) system with those identified by routine referral pathways (non-TWW). METHOD: A prospective study was carried out of 125 consecutive patients diagnosed with rectal cancer between January 2000 and December 2005 (6 years) in one district general hospital. Data were recorded prospectively in a local clinicopathological registry. The patients were divided into two groups: group 1 (TWW) and group 2 (routine referral pathway). RESULTS: Fifty-two (41%) of the 125 patients were diagnosed through the TWW (group 1). There was no significant difference in patient demographics, including baseline tumour characteristics, between the two groups. There was no difference in preoperative or postoperative T stage between the two groups (P = 0.63). There was no significant difference in circumferential margin positivity (five of 52 in group 1 vs four of 73 in group 2; P = 0.52) or local recurrence rates (P = 0.37). The 5-year all-cause mortality was 49% for group 1 and 52% for group 2 (P = 0.3). The overall disease-free survival was similar in the two groups (1521 days for group 1 vs 1591 days for group 1, P = 0.29). CONCLUSION: Referral under the TWW strategy does not translate into improved survival in rectal cancer.

MRI for detection of extramural vascular invasion in rectal cancer.

OBJECTIVE: Extramural vascular invasion is a pathologic feature predictive of distant relapse and poor survival among patients with colorectal cancer. This article illustrates the use of high-spatial-resolution MRI to identify extramural vascular invasion. CONCLUSION: Objective MRI features that correlate with histopathologic findings can be identified and used to evaluate extramural vascular invasion on preoperative images. The MRI extramural vascular invasion score provides additional staging information, which is important when selective neoadjuvant therapy is being considered.

Management of complex pelvic floor disorders in a multidisciplinary pelvic floor clinic.

OBJECTIVE: To identify symptom clusters, management strategies and survey patient satisfaction in our combined multidisciplinary pelvic floor clinic (PFC). METHOD: Retrospective cohort study, patient satisfaction questionnaire. SAMPLE: Secondary and tertiary referrals with complex pelvic floor disorders. MAIN OUTCOME MEASURES: symptom clusters and treatment received; patient satisfaction. RESULTS: A total of 113 new cases over a 3-year period. There were two main symptom clusters: (i) obstructed defaecation with rectoceles (n = 55); of these, 23 had abdominal sacrocolpopexy with rectopexy, six had transvaginal rectocele repairs; and (ii) of the 33 with double incontinence, 10 had anal sphincter repairs, five had tension-free vaginal tapes and two had colposuspensions. Patient satisfaction audit: 73% found the care to be excellent/good, 12% satisfactory and 6% unsatisfactory. CONCLUSION: Combined PFCs led to a more pragmatic approach in treating patients' symptoms. Combined surgery was undertaken in one-fourth of patients and is associated with cost savings and a single recuperation period. Overall, patients rated this service very highly.

Prognostic significance of magnetic resonance imaging-detected extramural vascular invasion in rectal cancer.

BACKGROUND: Extramural vascular invasion (EMVI) is a poor prognostic feature in colorectal cancer. The accuracy of magnetic resonance imaging (MRI) in detecting EMVI and predicting relapse-free survival (RFS) was compared retrospectively with the histological reference standard. METHODS: Preoperative magnetic resonance images from patients diagnosed with rectal and sigmoid cancer were reviewed and an MRI-EMVI score (range 0 to 4) was assigned. Comparison was made with histology and clinical outcome. RESULTS: Some 142 patients with a median follow-up of 3.3 (range 0.9-5.7) years were reviewed. Histological EMVI was reported in a quarter of patients. The sensitivity and specificity of MRI detection of EMVI in 94 patients undergoing primary surgery were 62 and 88 per cent respectively. On univariable analysis, RFS at 3 years was 35 per cent for patients with an MRI-EMVI score of 3-4, compared with 74 per cent for those with a score of 0-2 (P < 0.001), similar to values in patients with positive and negative histological EMVI status respectively (34 versus 73.7 per cent; P < 0.001). CONCLUSION: High MRI-EMVI scores may help in predicting disease relapse.

The Relationship Between MR Demonstration of Extramural Venous Invasion and Nodal Disease in Rectal Cancer.

PURPOSE: To investigate the relationship between extramural venous invasion (EMVI) detected at T2-weighted MRI and nodal disease rectal cancer compared with histopathology. MATERIALS AND METHODS: The MR imaging of 79 consecutive patients with rectal cancer who underwent primary rectal surgery without neoadjuvant treatment were reviewed. MR images were scored by an expert radiologist for the presence and degree of EMVI using a five point scale blinded to pathological findings. Receiver operating characteristic curve analyses were performed to determine the sensitivity and specificity of MRI scoring in predicting EMVI and nodal disease at histopathology. RESULTS: Compared with histology, an MR score of >2 was found to have 100% sensitivity (95% CI: 77%-100%) and 89% specificity (95% CI: 79%-96%) in identifying EMVI involving veins >3 mm in diameter. An EMVI score of >2 was had a sensitivity of 56% (95% CI: 30%-80%) and specificity of 81% (95% CI: 69%-90%) for identifying patients with stage N2 disease. CONCLUSIONS: EMVI score of >2 on T2-weighted MR imaging has a high sensitivity and specificity for histopathologically proven extramural venous invasion involving venules ≥3 mm in diameter. However, EMVI scores have only moderate sensitivity in the predicting nodal involvement.

Accuracy of CT prediction of poor prognostic features in colonic cancer.

Whilst imaging of poor prognostic features in rectal cancers has assisted pre-operative treatment stratification, such features have yet to be evaluated in colonic cancers. This study aims to develop criteria for identifying poor prognostic features in colonic tumours and assess the accuracy of CT prediction against histopathology. Criteria were developed for predicting T-stage and N-stage, the presence of extramural vascular invasion and involvement of the retroperitoneal surgical margin (RSM). These criteria were tested on 33 patients with colonic cancer who underwent pre-operative high-resolution CT of their tumour. Two radiologists (Obs 1 and Obs 2) identified independently these poor prognostic features and the results were compared with the final histopathological results. Histological agreement and interobserver variation were calculated using the kappa test. Accuracy of CT prediction of tumour extension beyond muscularis propria was 82% (Obs 1) and 70% (Obs 2). Correct prediction of RSM involvement was 76% (95% confidence interval (CI): 57.8-88.9%) and 79% (95%CI: 61.1-91%) for Obs1 and Obs 2, respectively, with significant agreement between observers (kappa = 0.455, p = 0.050). Prognosis was correctly predicted using CT in 82% (95%CI: 61.5-81.2%) (Obs1) and 85% (95%CI: 68.1-94.9%) (Obs2) with moderate agreement (kappa = 0.459, kappa = 0.527, respectively) with histology. In conclusion, CT has potential as the imaging modality of choice in the pre-operative prediction of poor prognostic features in colonic cancers and could play a role in future treatment stratification.

Preoperative computed tomography staging of nonmetastatic colon cancer predicts outcome: implications for clinical trials.

Colon cancer patients routinely undergo preoperative computed tomography (CT) scanning, but local staging is thought to be inaccurate. We aimed to determine if clinical outcome could be predicted from radiological features of the primary tumour. Consecutive patients at one hospital undergoing primary resection for colon cancer during 2000-2004 were included. Patients with visible metastases were excluded. Preoperative CT scans were reviewed independently by two radiologists blinded to histological stage and outcome. Images of the primary tumour were evaluated according to conventional TNM criteria and patients were stratified into 'good' or 'poor' prognosis groups. Comparison was made between prognostic group and actual clinical outcome. Hundred and twenty-six preoperative CT scans were reviewed. T-stage and nodal status was correctly predicted in only 60 and 62%, respectively. However, inter-observer agreement for prognostic group was 79% (kappa=0.59) and 3-year relapse-free survival was 71 and 43% for the CT-predicted 'good' and 'poor' groups, respectively (P<0.0066). This compared favourably with 75 vs 43% for histology-predicted prognostic groups. Computed tomography is a robust method for stratifying patients preoperatively, with similar accuracy to histopathology for predicting outcome. Recognition of poor prognosis tumours preoperatively may permit investigation into the future use of neo-adjuvant therapy in colon cancer.

Predictive poor prognostic factors in colonic carcinoma.

INTRODUCTION: Five-year survival in rectal cancer has been steadily improving since the introduction of neoadjuvant chemoradiation and total mesorectal excision surgery. In contrast, 5-year survival rates and management of colonic carcinoma remain relatively unchanged. This study aims to identify poor prognostic factors in colonic cancer patients that could potentially be predicted pre-operatively to identify a subset of patients amenable to neoadjuvant treatment strategies. METHODS: Database compilation of all operable rectal and colonic cancer patients presenting to a single district general hospital over 5 years. Data were documented on presentation and site of tumour, TNM staging, differentiation and extramural venous invasion. RESULTS: There was no significant difference in 4-year survival between rectal (57.5%) and right (57%) or left sided (52.5%) colonic cancers (p=0.4689). On multivariate analysis, N2-stage, T4-stage and emergency presentation were identified as independent prognostic factors. On univariate analysis, in addition to the above factors, presence of venous invasion (p=0.001) and poor differentiation (p=0.0003) of tumour also predicted for poor 5-year survival. CONCLUSION: T4-stage and N2-stage and extramural venous invasion are poor prognostic factors that could be identified pre-operatively with suitably accurate imaging. Such patients could then be considered for a pre-operative treatment strategy.