Five-year follow-up of the Medical Research Council CLASICC trial of laparoscopically assisted versus open surgery for colorectal cancer.

INTRODUCTION: The UK Medical Research Council CLASICC trial assessed the safety and efficacy of laparoscopically assisted surgery in comparison with open surgery for colorectal cancer. The results of the 5-year follow-up analysis are presented. METHODS: Five-year outcomes were analysed and included overall and disease-free survival, and local, distant and wound/port-site recurrences. Two exploratory analyses were performed to evaluate the effect of age (70 years or less, or more than 70 years) on overall survival between the two groups, and the effect of the learning curve. RESULTS: No differences were found between laparoscopically assisted and open surgery in terms of overall survival, disease-free survival, and local and distant recurrence. Wound/port-site recurrence rates in the laparoscopic arm remained stable at 2.4 per cent. Conversion to open operation was associated with significantly worse overall but not disease-free survival, which was most marked in the early follow-up period. The effect of surgery did not differ between the age groups, and surgical experience did not impact on the 5-year results. CONCLUSION: The 5-year analyses confirm the oncological safety of laparoscopic surgery for both colonic and rectal cancer. The use of laparoscopic surgery to maximize short-term outcomes does not compromise the long-term oncological results. REGISTRATION NUMBER: ISRCTN74883561 (http://www.controlled-trials.com).

Adhesions and incisional hernias following laparoscopic versus open surgery for colorectal cancer in the CLASICC trial.

BACKGROUND: This study investigated adhesive intestinal obstruction (AIO) and incisional hernia (IH) in patients undergoing laparoscopically assisted and open surgery for colorectal cancer. METHODS: In a case-note review of patients randomized to the Medical Research Council's Conventional versus Laparoscopic-Assisted Surgery In Colorectal Cancer (CLASICC) trial, primary and key secondary endpoints were AIO and IH admission rates respectively. RESULTS: Of 411 patients, 11 were admitted for AIO: four (3.1 per cent) of 131 patients in the open arm of the trial versus seven (2.5 per cent) of 280 in the laparoscopic arm (difference 0.6 (95 per cent confidence interval (c.i.) - 2.9 to 4.0) per cent). Thirty-six patients developed IH: 12 (9.2 per cent) after open versus 24 (8.6 per cent) after laparoscopic surgery (difference 0.6 (95 per cent c.i. - 5.3 to 6.5) per cent). Results by actual procedure showed higher AIO and IH rates in the 24.5 per cent of patients who converted from laparoscopic to open surgery (AIO: 2.3, 2.0 and 6 per cent; IH: 8.6, 7.4 and 11 per cent-for open, laparoscopic and converted operations respectively). CONCLUSION: Although this study has not confirmed that laparoscopic surgery reduces rates of AIO and IH after colorectal cancer surgery, trends suggest that a reduction in conversion to open surgery and elimination of port-site hernias may produce such an effect. Registration number for CLASICC trial: ISRCTN74883561 (http://www.controlled-trials.com).

Identification of Raman spectroscopic markers for the characterization of normal and adenocarcinomatous colonic tissues.

Raman spectroscopy has been recognised as a valuable analytical tool in biological and medical research. This technique allows probing molecular vibrations of samples without external labels or extensive preparation. This non-destructive optical technique can provide rapid and objective and reproducible measurements of sample biochemistry and identify variations that occur between healthy and diseased tissues. In fact, biochemical changes within tissue may either initiate disease or occur as a result of the disease process. The qualitative analysis of such changes provides important clues in the search for a specific diagnosis and the quantitative analysis of biochemical abnormalities is important in measuring the extent of the disease process, designing therapy and evaluating the efficacy of treatment. In this paper, we discuss one medical application of near-infrared Raman microspectroscopic imaging as a diagnostic tool to investigate, ex vivo, the changes between normal and adenocarcinomatous human colonic tissues. Multivariate statistical analysis was applied on these measured data to identify the molecular composition and distribution of lipids, proteins, mucus and collagens in normal and malignant tissue. Unsupervised hierarchical cluster analysis shows two unsupervised distinct clusters that were assigned to normal and adenocarcinomatous in accordance with conventional histopathological examination. The spectral images allowed good correlation between pseudo-color Raman and histopathological features.

Expression patterns of hypoxic markers at the invasive margin of colorectal cancers and liver metastases.

AIM: To understand the role of hypoxia in cancer progression of primary colorectal cancer and colorectal liver metastases. To look at associations of hypoxia with more aggressive phenotypes. METHODS: Archival tissue was retrieved from 55 patients and tissue micro arrays were constructed using tissue from the margin and the centre of the tumour. Hypoxia markers Hif-1alpha, Vegf, CA-9, VHL and Glut-1 were visualised using immunohistochemical detection and quantified using semi-quantitative analysis of the digitised images. Clinical details and outcome data were retrieved by case note review and collated with hypoxia markers data in a statistical database. RESULTS: Significantly increased expression of all markers were found at the tumour margin compared to the tumour centre, both in primary colorectal cancer (CRC) and liver metastases. Pushing margin CRC was associated with increased Vegf expression. Positive correlations were observed between Hif-1alpha and Vegf (p<0.001), and Hif-1alpha and VHL (p<0.001) in primary CRC, but no relationship was seen between Hif-1alpha and either Glut-1 or CA-9. A significant trend to worse disease-free survival was also noted with increased margin expression of Hif-1alpha (p<0.001) and VHL (p=0.02) in primary CRC, but not for any of the other markers. CONCLUSION: This study underlines the importance of the invasive margin in colorectal cancer biology. It is the area most responsive to hypoxic influences and its dependence on its ability to up-regulate Hif-1alpha has a significant impact on disease-free survival.

Laser microdissection expression profiling of marginal edges of colorectal tumours reveals evidence of increased lactate metabolism in the aggressive phenotype.

BACKGROUND: The morphology of the invasive margin in colorectal cancer can be described as either pushing or infiltrative. These phenotypes carry prognostic significance, particularly in node negative disease, and provide an excellent model for the study of invasive behaviour in vivo. METHODS: The marginal edges of 16 stage-matched tumours exhibiting these contrasting growth patterns were microdissected. The extracted mRNA was amplified and hybridised to a 9546 feature oligonucleotide array. Selected differentials were validated using real-time polymerase chain reaction and the protein product was interrogated by using immunohistochemistry. RESULTS: After stringent quality control and filtering of data generated, 39 genes were identified as being significantly differentially expressed between the two types of marginal edge. Several genes involved in cellular metabolism were identified as differentials including lactate dehydrogenase B (LDHB) and modulators of glucose transport. CONCLUSIONS: The LDH expression profile differs between the invasive phenotypes. A hypothesis is proposed in which altered metabolism is a cause of contrasting invasive behaviour independent of the hypoxia-inducible factor mediated hypoxic response, consistent with the Warburg phenomenon.

The role of hypoxia in recurrence following resection of Dukes' B colorectal cancer.

GOALS: Tumour hypoxia has been shown to be a predictor of early distant relapse in node-negative breast and cervical cancer. The purpose of the present study was to determine the role of hypoxia in predicting patients who are at high risk of disease recurrence in Dukes B colorectal cancers. MATERIALS AND METHODS: Archival tissue was retrieved from 52 patients who had undergone surgical resection for primary colorectal cancer. Tissue micro-arrays were constructed using tissue from the margin and the centre of the tumour. Hypoxia markers hypoxia-inducible factor (Hif)-1 alpha, vascular endothelial growth factor (VEGF), carbonic anhydrase (CA)-9 and glucose transporter (Glut)-1 were visualised using immunohistochemical detection and quantified using semi-quantitative analysis of the digitised images. Clinical details and outcome data were retrieved by case note review and collated with hypoxia markers data in a statistical database. RESULTS: Primary colorectal cancers with a high Hif-1 alpha expression tended to have a significantly worse disease-free survival (log rank p < 0.001) and overall survival (log rank p = 0.012). VEGF was also a significant predictor of disease recurrence in primary colorectal cancers (p = 0.015). Significant correlations were also noted between Hif-1 alpha and VEGF (Pearson's p = 0.009). Glut-1 and CA-9 did not show a similar pattern with no differences in the expression pattern and no correlation observed with any of the markers. Multivariate analysis of prognostic factors showed vascular invasion (p < 0.001) and Hif-1 alpha at the tumour margin (p < 0.001) to be independent predictors for the development of liver metastases. CONCLUSION: These results suggest an important role for Hif-1 alpha and VEGF in colorectal cancer progression, with both markers biological mechanisms directly interlinked through the hypoxic pathway. Identification of high-risk patients using the above factors will improve treatment strategies in node-negative disease and help improve patient outcome.

Patient factors influencing conversion from laparoscopically assisted to open surgery for colorectal cancer.

BACKGROUND: Intraoperative conversion from laparoscopically assisted to open surgery for colorectal cancer is thought to be influenced by several patient factors. Analysis of the Conventional versus Laparoscopic-Assisted Surgery In Colorectal Cancer (CLASICC) Trial data aimed to identify these risk factors. METHODS: Of 488 laparoscopically assisted procedures attempted, 143 (29.3 per cent) were converted to open operation. Patient factors considered in multivariable analyses were age, sex, previous abdominal incisions, body mass index (BMI), tumour site, tumour diameter, pathological tumour (pT) and pathological node (pN) stage, extent of tumour spread from the muscularis propria, liver and peritoneal metastases, and American Society of Anesthesiologists (ASA) grade. As BMI was missing for 30.7 per cent of patients, two approaches were employed: one considered BMI as a possible risk factor and one did not. RESULTS: When BMI was taken into consideration, male sex (odds ratio (OR) 2.07; P = 0.020), BMI (OR 1.10; P = 0.006) and extent of tumour spread from the muscularis propria (OR 1.08; P < 0.001) were independent predictors of conversion. When BMI was not considered, extent of tumour spread (OR 1.07; P < 0.001) and male sex (OR 2.05; P = 0.004) were again identified, as were tumour site (OR 2.11; P = 0.005) and ASA grade (II versus I, OR 0.92; III versus I, OR 2.74; P = 0.012). CONCLUSION: Intraoperative conversion is more likely with larger BMI, in men, patients with rectal cancer, those graded ASA III or when there is greater local tumour spread.

The influence of invasive growth pattern and microvessel density on prognosis in colorectal cancer and colorectal liver metastases.

The nature of the invasive growth pattern and microvessel density (MVD) have been suggested to be predictors of prognosis in primary colorectal cancer (CRC) and colorectal liver metastases. The purpose of the present study was to determine whether these two histological features were interrelated and to assess their relative influence on disease recurrence and survival following surgical resection. Archival tissue was retrieved from 55 patients who had undergone surgical resection for primary CRC and matching liver metastases. The nature of the invasive margin was determined by haematoxylin and eosin (H&E) histochemistry. Microvessel density was visualised using immunohistochemical detection of CD31 antigen and quantified using image capture computer software. Clinical details and outcome data were retrieved by case note review and collated with invasive margin and MVD data in a statistical database. Primary CRCs with a pushing margin tended to form capsulated liver metastases (P<0.001) and had a significantly better disease-free survival than the infiltrative margin tumours (log rank P=0.01). Primary cancers with a high MVD tended to form high MVD liver metastases (P=0.007). Microvessel density was a significant predictor of disease recurrence in primary CRCs (P=0.006), but not liver metastases. These results suggest that primary CRCs and their liver metastases show common histological features. This may reflect common mechanisms underlying the tumour-host interaction.

[Ocular melanoma: immunohistochemical evaluation of the potentially predictive markers of prognosis. Preliminary results]. / Mélanome oculaire: évaluation immunohistochimique de marqueurs potentiellement prédictifs du pronostic. Résultats préliminaires.

PURPOSE: To study the characteristics of certain biological parameters, many of which have been recently discovered, to assess their possible contribution to the prognosis of ocular melanoma. MATERIAL: and methods: 25 patients with ocular and orbital melanoma treated at the Reims Regional Hospital since 1993 were included in the retrospective study. The surgical specimens were put in formalin 10%, then in paraffin. Five proteins were analyzed retrospectively: topoisomerase I, topoisomerase IIalpha, ICBP90, Ki67, and P53 on 200 cells per case. RESULTS: Of the 25 tumors from 14 men and 11 women, 15 were iris and ciliary body melanomas and ten choroidal melanomas. Histopathologic analysis showed 12 spindle-cell-type melanomas, seven epithelioid-cell-type melanomas and six mixed-cell-type melanomas. The immunohistochemical study found a significant difference in distribution between the cellular types for the topoisomerase IIalpha and Ki67 antibodies. Eight patients had metastasis, six of whom died. The metastasis came from three mixed-cell-type melanomas, three epithelioid-cell-type melanomas, and two spindle-cell-type melanomas. On the other hand, six cases of sclera infiltration were discovered among these eight patients. CONCLUSION: Several prognostic factors seem to be involved in the progression of melanoma: sclera infiltration seems to be essential in our study. Its rate seems to increase with the tumor size and in epithelioid-cell-type melanomas. The correlation between the different immunomarkers and the appearance of metastasis has not yet been verified.

Short-term costs of conventional vs laparoscopic assisted surgery in patients with colorectal cancer (MRC CLASICC trial).

The short-term clinical results of the CLASICC trial indicated that clinical outcomes were similar between laparoscopic and open approaches. This study presents the short-term (3 month) cost analysis undertaken on a subset of patients entered into the CLASICC trial (682 of 794 patients). As expected the costs associated with the operation were higher in the 452 patients randomised to laparoscopic surgery (lap) compared with the 230 randomised to open procedure (open), Pounds 1703 vs Pounds 1386. This was partially offset by the other hospital (nontheatre) costs, which were lower in the lap group (Pounds 2930 vs Pounds 3176). The average cost to individuals for reoperations was higher in the lap group (Pounds 762 vs Pounds 553). Overall costs were slightly higher in the lap group (Pounds 6899 vs Pounds 6631), with mean difference of Pounds 268 (95%CI -689 to 1457). Sensitivity analysis made little difference to these results. The cost of rectal surgery was higher than for colon, for lap (Pounds 8259 vs Pounds 5586) and open procedures (Pounds 7820 vs Pounds 5503). The short-term cost analysis for the CLASICC trial indicates that the costs of either laparoscopic or open procedure were similar, lap surgery costing marginally more on average than open surgery.

Redefining the R1 resection in pancreatic cancer.

BACKGROUND: Resection margin (RM) status in pancreatic head adenocarcinoma is assessed histologically, but pathological examination is not standardized. The aim of this study was to assess the influence of standardized pathological examination on the reporting of RM status. METHODS: A standardized protocol (SP) for pancreaticoduodenectomy specimen examination, involving multicolour margin staining, axial slicing and extensive tissue sampling, was developed. R1 resection was defined as tumour within 1 mm of the RM. A prospective series reported according to this protocol (SP series, n = 54) was compared with a historical matched series in which a non-standardized protocol was used (NSP series, n = 48). RESULTS: Implementation of the SP resulted in a higher R1 rate overall, and for pancreatic (22 of 26 85 per cent) compared with ampullary (four of 15) and bile duct (six of 13) cancer. Sampling of the circumferential RM was more extensive in the SP series and correlated with RM status. RM involvement was often multifocal (14 of 32), affecting the posterior RM most frequently (21 of 32). Survival correlated with RM status for the entire SP series (P < 0.001), but not for the NSP series. There was a trend towards better median and actuarial 5-year survival after R0 resection in the SP pancreatic cancer subgroup. CONCLUSION: Standardized examination influences the reporting of RM status.

Mirizzi's syndrome--results from a large western experience.

BACKGROUND: This paper reports a series of patients with Mirizzi's syndrome (MS) who were managed at our institution over an 11-year (1994-2005) period. METHODS: Retrospective case note study of patients with a definitive or possible diagnosis of MS stated in radiology reports were identified using the hospital's radiology computer coding system. RESULTS: 33 patients were identified with a median age of diagnosis of 70 (35-90) years and male to female ratio of 15:18. Liver function tests were deranged in all patients. Pre-operative radiological diagnosis was achieved in 28 patients: ultrasound scan (n = 4), computer tomography (n = 3), magnetic resonance cholangiopancreatography (n = 10) and endoscopic retrograde cholangiopancreatography (n = 11). Five patients were diagnosed intra-operatively. Type I MS was reported in 27 patients. Laparoscopic cholecystectomy was attempted in 18 patients with 6 being converted to open cholecystectomy. Six patients had biliary stent insertion only and 3 were conservatively managed. Six patients had type II MS, 4 were treated with open cholecystectomy and Roux-en-Y hepaticojejunostomy, 1 underwent an open subtotal cholecystectomy with fistula closure and 1 had percutaneous biliary stent insertion only. The median follow-up period was 2 (1-7) months (n = 18). 10 patients are currently under follow-up. Overall morbidity was 27% (n = 8) and mortality was 7% (n = 2). CONCLUSION: Pre-operative diagnosis of MS can be achieved using MRCP. Laparoscopic cholecystectomy for type I MS is a safe option and type II MS can be treated with Roux-en-Y hepaticojejunostomy or subtotal cholecystectomy with fistula closure.

Bladder and sexual function following resection for rectal cancer in a randomized clinical trial of laparoscopic versus open technique.

BACKGROUND: Bladder and sexual dysfunction are recognized complications of mesorectal resection. Their incidence following laparoscopic surgery is unknown. METHODS: Bladder and sexual function were assessed in patients who had undergone laparoscopic rectal, open rectal or laparoscopic colonic resection as part of the UK Medical Research Council Conventional versus Laparoscopic-Assisted Surgery In Colorectal Cancer (CLASICC) trial, using the International Prostatic Symptom Score, the International Index of Erectile Function and the Female Sexual Function Index. Sexual and bladder function data from the European Organization for Research and Treatment of Cancer QLQ-CR38 collected in the CLASICC trial were used for comparison. RESULTS: Two hundred and forty-seven (71.2 per cent) of 347 patients completed questionnaires. Bladder function was similar after laparoscopic and open rectal operations for rectal cancer. Overall sexual function and erectile function tended to be worse in men after laparoscopic rectal surgery than after open rectal surgery (overall function: difference - 11.18 (95 per cent confidence interval (c.i.) -22.99 to 0.63), P = 0.063; erectile function: difference -5.84 (95 per cent c.i. -10.94 to -0.74), P = 0.068). Total mesorectal excision (TME) was more commonly performed in the laparoscopic rectal group than in the open rectal group. TME (odds ratio (OR) 6.38, P = 0.054) and conversion to open operation (OR 2.86, P = 0.041) were independent predictors of postoperative male sexual dysfunction. No differences were detected in female sexual function. CONCLUSION: Laparoscopic rectal resection did not adversely affect bladder function, but there was a trend towards worse male sexual function. This may be explained by the higher rate of TME in the laparoscopic rectal resection group.

Successful outcome following resection of a pancreatic liposarcoma with solitary metastasis.

Liposarcomas are rare soft tissue tumors, commonly affecting the lower limbs and less commonly the retroperitoneum. Although other organs can be affected, the pancreas is one of the rarest, and metastasis at presentation has never been reported. We describe the case of a 76-year-old gentleman presenting with abdominal pain and an abdominal mass. Imaging confirmed a primary tumor in the body and tail of the pancreas, with a metastatic deposit in the mesentery adjacent to the second part of the duodenum. Biopsy confirmed a liposarcoma, and subsequently a complete surgical excision was achieved. He then received adjuvant radiotherapy and has remained disease free for the next 26 mo.

Laparoscopic resection of colon Cancer: consensus of the European Association of Endoscopic Surgery (EAES).

BACKGROUND: The European Association of Endoscopic Surgery (EAES) initiated a consensus development conference on the laparoscopic resection of colon cancer during the annual congress in Lisbon, Portugal, in June 2002. METHODS: A systematic review of the current literature was combined with the opinions, of experts in the field of colon cancer surgery to formulate evidence-based statements and recommendations on the laparoscopic resection of colon cancer. RESULTS: Advanced age, obesity, and previous abdominal operations are not considered absolute contraindications for laparoscopic colon cancer surgery. The most common cause for conversion is the presence of bulky or invasive tumors. Laparoscopic operation takes longer to perform than the open counterpart, but the outcome is similar in terms of specimen size and pathological examination. Immediate postoperative morbidity and mortality are comparable for laparoscopic and open colonic cancer surgery. The laparoscopically operated patients had less postoperative pain, better-preserved pulmonary function, earlier restoration of gastrointestinal function, and an earlier discharge from the hospital. The postoperative stress response is lower after laparoscopic colectomy. The incidence of port site metastases is <1%. Survival after laparoscopic resection of colon cancer appears to be at least equal to survival after open resection. The costs of laparoscopic surgery for colon cancer are higher than those for open surgery. CONCLUSION: Laparoscopic resection of colon cancer is a safe and feasible procedure that improves short-term outcome. Results regarding the long-term survival of patients enrolled in large multicenter trials will determine its role in general surgery.

Interleukin 13 and inflammatory markers in human sepsis.

BACKGROUND: Interleukin (IL) 13 is an anti-inflammatory cytokine that reduces inflammatory cytokine production, and enhances monocyte survival and MHC class II and CD23 expression. The only report of IL-13 in human sepsis noted no increase in IL-13 concentration, in contrast to animal data. This study further examined the expression of IL-13 in relation to human sepsis. METHODS: In a prospective observational study of 31 patients (24 men) with sepsis or septic shock, high-sensitivity enzyme-linked immunoabsorbent assay (ELISA) was used to quantify levels of tumour necrosis factor (TNF) alpha on admission, and on days 1, 3, 5 and 7 thereafter. IL-13 and IL-2 were assayed by standard ELISA, and HLA-DR on CD14-positive monocytes was measured by flow cytometry. RESULTS: Twenty-three patients developed septic shock. Monocyte HLA-DR levels showed greater depression and a slower recovery in shocked than non-shocked patients. The serum IL-13 concentration was significantly higher in the shocked group from admission to day 3, but subsequently decreased to levels similar to those in the non-shocked group. IL-13 concentrations were higher in non-survivors. The TNF-alpha concentration was higher in those with septic shock than in those without. The TNF-alpha level correlated with IL-13 concentration (r(S) = 0.61, P = 0.002). The IL-13/TNF-alpha ratio was greater in patients with shock than those with sepsis only (P = 0.017). IL-2 was undetectable. CONCLUSION: In human sepsis and septic shock, IL-13 correlated with TNF-alpha expression, but its effect on HLA-DR class II molecules remains unclear.

Tumour-induced apoptosis in human mesothelial cells: a mechanism of peritoneal invasion by Fas Ligand/Fas interaction.

Gastrointestinal carcinomas frequently disseminate within the abdominal cavity to form secondary peritoneal metastases. Invasion of the peritoneal mesothelium is fundamental to this process, yet the underlying invasive mechanisms remain unclear. Preliminary in vitro work suggested that tumour cells can induce mesothelial apoptosis, representing a novel mechanism of peritoneal invasion. We examined the role of tumour cell-induced mesothelial apoptosis and explored the role of the death ligand/receptor system, Fas Ligand/Fas, as mediators of the apoptotic process. Cultured human mesothelial cells were used to establish in vitro co-culture models with the SW480 colonic cancer cell line. Tumour-induced mesothelial apoptosis was confirmed by phase-contrast microscopy and apoptotic detection assays. Human mesothelial cells and SW480 tumour cells constitutively expressed Fas and Fas Ligand mRNA and protein as determined by RT-PCR and confocal fluorescent microscopy. Stimulation of human mesothelial cells with anti-Fas monoclonal antibody or crosslinked soluble Fas Ligand-induced apoptosis, confirming the functional status of the Fas receptor. Pretreatment of SW480 cells with a blocking recombinant anti-Fas Ligand monoclonal antibody significantly reduced mesothelial apoptosis, indicating that tumour-induced mesothelial apoptosis may, in part, be mediated via a Fas-dependent mechanism. This represents a novel mechanism of mesothelial invasion and offers several new targets for therapeutic intervention.