Lymph nodes, tumor deposits, and TNM: are we getting better?

PURPOSE: New editions of the TNM staging system for colorectal cancer have been subject to extensive criticism. In the current study, we evaluate each edition of TNM and analyze stage migration caused by the different versions. PATIENTS AND METHODS: Two independent test populations were used: participants derived from a randomized surgical trial from the United Kingdom (n = 455) and patients from a population-based series from Sweden (n = 505). All slides from these patient cases were reviewed with special attention for the presence of tumor deposits. Tumor deposits were classified according to the fifth, sixth, and seventh editions of TNM and correlated with prognosis. RESULTS: Every change in edition of TNM led to a stage migration of between 33% and 64% in patients with tumor deposits. Reproducibility was best in the fifth edition of TNM. The prognostic value of the seventh edition was best only when all tumor deposits irrespective of size or contour were included as lymph nodes. The prognostic value of the fifth edition was better than that of the sixth. CONCLUSION: We demonstrate there is a place for tumor deposits in the staging of patients with colorectal cancer. However, many questions remain about their definition and the reproducibility and use of this category in special situations, such as after neoadjuvant treatment. These should be the subject of additional research before use as a factor in TNM staging. This work demonstrates the necessity of testing modifications before their introduction.

Randomized trial of laparoscopic-assisted resection of colorectal carcinoma: 3-year results of the UK MRC CLASICC Trial Group.

PURPOSE: The aim of the current study is to report the long-term outcomes after laparoscopic-assisted surgery compared with conventional open surgery within the context of the UK MRC CLASICC trial. Results from randomized trials have indicated that laparoscopic surgery for colon cancer is as effective as open surgery in the short term. Few data are available on rectal cancer, and long-term data on survival and recurrence are now required. METHODS: The United Kingdom Medical Research Council Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (UK MRC CLASICC; clinical trials number ISRCTN 74883561) trial study comparing conventional versus laparoscopic-assisted surgery in patients with cancer of the colon and rectum. The randomization ratio was 2:1 in favor of laparoscopic surgery. Long-term outcomes (3-year overall survival [OS], disease-free survival [DFS], local recurrence, and quality of life [QoL]) have now been determined on an intention-to-treat basis. RESULTS: Seven hundred ninety-four patients were recruited (526 laparoscopic and 268 open). Overall, there were no differences in the long-term outcomes. The differences in survival rates were OS of 1.8% (95% CI, -5.2% to 8.8%; P = .55), DFS of -1.4% (95% CI, -9.5% to 6.7%; P = .70), local recurrence of -0.8% (95% CI, -5.7% to 4.2%; P = .76), and QoL (P > .01 for all scales). Higher positivity of the circumferential resection margin was reported after laparoscopic anterior resection (AR), but it did not translate into an increased incidence of local recurrence. CONCLUSION: Successful laparoscopic-assisted surgery for colon cancer is as effective as open surgery in terms of oncological outcomes and preservation of QoL. Long-term outcomes for patients with rectal cancer were similar in those undergoing abdominoperineal resection and AR, and support the continued use of laparoscopic surgery in these patients.

Carcinoma of the body of pancreas in evolution: an aggressive disease affecting younger patients?

CONTEXT: Pancreatic body carcinoma has a poor prognosis with advanced disease at presentation. Recent experience at multidisciplinary team (MDT) meetings suggests increasing prevalence. OBJECTIVE: Our aim was to determine if introduction of MDT meetings has affected the natural history of this disease. DESIGN: Retrospective diagnostic and survival data were collected from 1995 to 2006 at two large teaching hospitals, and divided into pre- and post 2003 groups (based on MDT introduction). PARTICIPANTS: Thirty-one patients with pancreatic body carcinoma (median age at diagnosis 72 years; range 43-87 years). RESULTS: Commonest symptoms at presentation were abdominal pain and weight loss. Eight patients (25.8%) were diagnosed pre MDT (median age 71.5 years, range: 60-87 years) and 23 patients (74.2%) were diagnosed post MDT (median age 67 years, range: 43-85 years; P=0.299 vs. pre MDT). There was a significantly (P=0.024) greater prevalence of more advanced tumours post MDT (stage IV: 15/23, 65.2%) than pre MDT (stage IV: 2/8, 25.0%). Neither tumour markers nor liver biochemistry differentiated tumour stage. Best supportive care was offered to 16 patients (51.6%) while 12 patients (38.7%) were suitable for chemotherapy: 2 out of 8 pre MDT (25.0%) and 10 out of 23 (43.5%) post MDT (P=0.433). For stage III tumours, post MDT patients tended to be younger (median 59 years vs. 74.5 years, P=0.042). Survival was not significantly increased after MDT introduction but chemotherapy offered significant survival benefit on multivariate analysis (P=0.042; hazard ratio: 0.39, 95% CI: 0.16-0.97). CONCLUSION: The trend is towards increased prevalence of pancreatic body cancer and more advanced disease at presentation. Chemotherapy was associated with a survival benefit, although the introduction of the MDT has not significantly altered disease management.

Laparoscopically assisted vs open colectomy for colon cancer: a meta-analysis.

OBJECTIVE: To perform a meta-analysis of trials randomizing patients with colon cancer to laparoscopically assisted or open colectomy to enhance the power in determining whether laparoscopic colectomy for cancer is oncologically safe. DATA SOURCES: The databases of the Barcelona, Clinical Outcomes of Surgical Therapy (COST), Colon Cancer Laparoscopic or Open Resection (COLOR), and Conventional vs Laparoscopic-Assisted Surgery in Patients With Colorectal Cancer (CLASICC) trials were the data sources for the study. STUDY SELECTION: Patients who had at least 3 years of complete follow-up data were selected. DATA EXTRACTION: Patients who had undergone curative surgery before March 1, 2000, were studied. Three-year disease-free survival and overall survival were the primary outcomes of this analysis. DATA SYNTHESIS: Of 1765 patients, 229 were excluded, leaving 796 patients in the laparoscopically assisted arm and 740 patients in the open arm for analysis. Three-year disease-free survival rates in the laparoscopically assisted and open arms were 75.8% and 75.3%, respectively (95% confidence interval [CI] of the difference, -5% to 4%). The associated common hazard ratio (laparoscopically assisted vs open surgery with adjustment for sex, age, and stage) was 0.99 (95% CI, 0.80-1.22; P = .92). The 3-year overall survival rate after laparoscopic surgery was 82.2% and after open surgery was 83.5% (95% CI of the difference, -3% to 5%). The associated hazard ratio was 1.07 (95% CI, 0.83-1.37; P = .61). Disease-free and overall survival rates for stages I, II, and III evaluated separately did not differ between the 2 treatments. CONCLUSION: Laparoscopically assisted colectomy for cancer is oncologically safe.

Solid pseudopapillary tumour of the pancreas: diverse presentation, outcome and histology.

CONTEXT: Solid pseudopapillary tumour of the pancreas is an uncommon tumour, which predominantly occurs in young females and is of unknown origin. CASE REPORT: We describe five cases with diverse clinical and/or histological features, including one unusually aggressive case resulting in early death. CONCLUSION: There is great variability in the presentation and clinical course of these tumours with further research needed to define their histogenesis and biological behaviour.

Endoscopic ultrasound guided transgastric stenting of traumatic pancreatic pseudocyst.

CONTEXT: Although there exists multiple modalities of managing traumatic pancreatic pseudocysts it remains a diagnostic and therapeutic challenge. We report herein a case that was successfully managed by endoscopic ultrasound guided transgastric stent placement. CASE REPORT: A 28-year-old female jockey presented with abdominal pain after being kicked by a horse. Computerised tomography and magnetic resonance imaging revealed pancreatitis which resolved with conservative treatment. She proceeded to develop a pancreatic pseudocyst demonstrated on a magnetic resonance cholangiopancreatogram. This was managed by transgastric placement of two double pigtail stents into the pseudocyst by endoscopic ultrasound guidance. Rapid recovery followed with the patient remaining well on follow up. CONCLUSIONS: EUS guided transgastric stent placement for drainage of pancreatic pseudocysts is recommended particularly if they are in close proximity to the stomach.

Solitary main pancreatic ductal calculus of possible biliary origin causing acute pancreatitis.

CONTEXT: Pancreatic ductal calculi are most often associated with chronic pancreatitis. Radiological features of chronic pancreatitis are readily evident in the presence of these calculi. However, acute pancreatitis due to a solitary main pancreatic ductal calculus of biliary origin is rare. CASE REPORT: A 59-year-old man presented with a first episode of acute pancreatitis. Contrast enhanced computerized tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP) revealed a calculus in the main pancreatic duct in the head of the pancreas causing acute pancreatitis. There were no features suggestive of chronic pancreatitis on CT scanning. The episode acute pancreatitis was managed conservatively. ERCP extraction of the calculus failed as the stone was impacted in the main pancreatic duct resulting in severe acute pancreatitis. Once this resolved, a transduodenal exploration and extraction of the pancreatic ductal calculus was performed successfully. Crystallographic analysis revealed the composition of the calculus was different to that seen in chronic pancreatitis, but more in keeping with a calculus of biliary origin. This could be explained by migration of the biliary calculus via the common channel into the main pancreatic duct. Following the operation the patient made an uneventful recovery and was well at two-year follow up. CONCLUSION: Acute pancreatitis due to a solitary main pancreatic ductal calculus of biliary origin is rare. Failing endoscopic extraction, transduodenal exploration and extraction is a safe option after resolution of acute pancreatitis.

Diagnostic variation and outcome for high-grade gastric epithelial dysplasia.

HYPOTHESIS: High-grade dysplasia (HGD) of the gastric epithelium is associated with high prevalence of invasive carcinoma, and distinction by endoscopic biopsy is difficult. DESIGN: Cohort study, 1996 to 2003. SETTING: Tertiary care center. PATIENTS: Consecutive sample of 22 patients with initial diagnosis of gastric HGD by endoscopic biopsy. Biopsy specimens were separately reviewed by 3 experienced pathologists. Clinical management was individually decided. MAIN OUTCOME MEASURES: Strength of interpathologist agreement (kappa) and final pathological diagnosis. RESULTS: The diagnosis was revised to intramucosal carcinoma in 14% to 32% of patients or suspicious for invasive carcinoma in 23% to 41%. The strength of agreement between any 2 pathologists for distinguishing between dysplasia and invasive carcinoma was fair (kappa = 0.35-0.36). A diagnosis of intramucosal carcinoma or suspicious for invasive carcinoma by 2 pathologists correlated strongly with subsequent detection of invasive carcinoma. Three patients underwent gastrectomy for HGD, and invasive carcinoma was detected in all (2 patients, T1 N0; 1 patient, T2 N0). Six patients had invasive carcinoma on endoscopic surveillance at a median of 15 months (range, 3-34 months) after diagnosis of HGD and underwent endoscopic mucosal resection (2 patients, T1 NX), gastrectomy (2 patients, T1 N0), or no resection (2 patients). Another patient had metastatic gastric adenocarcinoma despite having a diagnosis of only HGD by endoscopy. Seven patients (32%) died of unrelated causes, without invasive carcinoma, at a median of 19 months (range, 1-38 months). Three patients were alive with persistent HGD at 26 to 61 months. Two patients had no dysplasia on follow-up. CONCLUSIONS: Experienced pathologists often disagreed in distinguishing invasive carcinoma from HGD in gastric biopsy specimens. One third of patients with gastric HGD died of causes unrelated to cancer. Invasive carcinoma was detected in 67% of the remainder.

Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial.

BACKGROUND: Laparoscopic-assisted surgery for colorectal cancer has been widely adopted without data from large-scale randomised trials to support its use. We compared short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer to predict long-term outcomes. METHODS: Between July, 1996, and July, 2002, we undertook a multicentre, randomised clinical trial in 794 patients with colorectal cancer from 27 UK centres. Patients were allocated to receive laparoscopic-assisted (n=526) or open surgery (n=268). Primary short-term endpoints were positivity rates of circumferential and longitudinal resection margins, proportion of Dukes' C2 tumours, and in-hospital mortality. Analysis was by intention to treat. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN74883561. FINDINGS: Six patients (two [open], four [laparoscopic]) had no surgery, and 23 had missing surgical data (nine, 14). 253 and 484 patients actually received open and laparoscopic-assisted treatment, respectively. 143 (29%) patients underwent conversion from laparoscopic to open surgery. Proportion of Dukes' C2 tumours did not differ between treatments (18 [7%] patients, open vs 34 [6%], laparoscopic; difference -0.3%, 95% CI -3.9 to 3.4%, p=0.89), and neither did in-hospital mortality (13 [5%] vs 21 [4%]; -0.9%, -3.9 to 2.2%, p=0.57). Apart from patients undergoing laparoscopic anterior resection for rectal cancer, rates of positive resection margins were similar between treatment groups. Patients with converted treatment had raised complication rates. INTERPRETATION: Laparoscopic-assisted surgery for cancer of the colon is as effective as open surgery in the short term and is likely to produce similar long-term outcomes. However, impaired short-term outcomes after laparoscopic-assisted anterior resection for cancer of the rectum do not yet justify its routine use.

Persistent acid and bile reflux in asymptomatic patients with Barrett esophagus receiving proton pump inhibitor therapy.

HYPOTHESIS: Symptom control does not reflect elimination of abnormal acid reflux or abnormal bile reflux in patients with long-segment Barrett esophagus receiving proton pump inhibitors (PPIs). DESIGN: Prospective survey. SETTING: University hospital. PATIENTS: Thirty-two patients with long-segment Barrett esophagus who were asymptomatic with PPIs. MAIN OUTCOME MEASURES: Twenty-four-hour ambulatory pH and bile reflux monitoring while continuing PPIs. RESULTS: Abnormal acid reflux (pH <4 for 11.9% [interquartile range, 6.8%-19.6%) of 24 hours] persisted in 15 patients (47%) who could not be distinguished from those with normal acid reflux (pH <4 for <4.5% of 24 hours) by any endoscopic, manometric, or therapeutic characteristic. Abnormal bile reflux (absorbance >0.14 for 8.7% [interquartile range, 3.9%-8.7%] of 24 hours) was detected in 11 (48%) of 23 patients, such that both normal bile reflux (absorbance >0.14 for <1.8% of 24 hours) and normal acid reflux were observed in only 8 patients (35%). There was no association between abnormal acid reflux and abnormal bile reflux. CONCLUSIONS: Despite symptom control with PPIs, both acid reflux and bile reflux were controlled in only one third of patients. Posttherapeutic monitoring of acid and bile reflux is recommended in future clinical trials of PPI treatment vs laparoscopic antireflux surgery.

Apoptotic and proliferative indexes in esophageal cancer: predictors of response to neoadjuvant therapy [corrected].

Altered expression of the genes that control apoptosis and proliferation may influence the response of cancer cells to cytotoxic agents. The primary aim of this study was to determine the role of the novel antiapoptotic and cell cycle gene, survivin, in apoptotsis and proliferation in esophageal cancer and to evaluate whether the survivin, p53, and bcl-2 status were able to predict a patient's response to neoadjuvant therapy. A total of 104 patients with esophageal tumors were studied. Tumor tissue was immunostained for survivin, p53, and bcl-2 proteins. Proliferative and apoptotic activity was measured using ki-67 immunohistochemical analysis and the TUNEL method, respectively. Forty-eight patients whose pretreatment biopsies were analyzed received neoadjuvant chemoradiation therapy or chemotherapy followed by surgery. Outcome was graded as a complete response, a partial response, or no response according to the results of histologic examination and CT imaging. Expression of survivin was found to correlate significantly with the proliferative index but not the apoptotic index. Patients who received neoadjuvant treatment were more likely to achieve a complete response if their tumors had high proliferative activity, and p53 positive tumors were more likely to contain residual tumor after treatment. In conclusion, survivin expression appears to foster proliferative activity in esophageal cancer, and tumors with a high proliferative index or a functioning p53 gene are more responsive to neoadjuvant chemoradiation therapy.

Apoptotic and proliferative indexes in esophageal cancer: Predictors of response to neoadjuvant therapy apoptosis and proliferation in esophageal cancer.

Altered expression of the genes that control apoptosis and proliferation may influence the response of cancer cells to cytotoxic agents. The primary aim of this study was to determine the role of the novel an-tiapoptotic and cell cycle gene, survivin, in apoptotsis and proliferation in esophageal cancer and to evaluate whether the survivin, p53, and bcl-2 status were able to predict a patient's response to neoadjuvant therapy. A total of 104 patients with esophageal tumors were studied. Tumor tissue was immunostained for survivin, p53, and bcl-2 proteins. Proliferative and apoptotic activity was measured using ki-67 immu-nohistochemical analysis and the TUNEL method, respectively. Forty-eight patients whose pretreat-ment biopsies were analyzed received neoadjuvant chemoradiation therapy or chemotherapy followed by surgery. Outcome was graded as a complete response, a partial response, or no response according to the results of histologic examination and CT imaging. Expression of survivin was found to correlate significantly with the proliferative index but not the apoptotic index. Patients who received neoadjuvant treatment were more likely to achieve a complete response if their tumors had high proliferative activity, and p53 positive tumors were more likely to contain residual tumor after treatment. In conclusion, survivin expression appears to foster proliferative activity in esophageal cancer, and tumors with a high proliferative index or a functioning p53 gene are more responsive to neoadjuvant chemoradiation therapy.

Interstitial cell cyclooxygenase-2 expression is associated with increased angiogenesis in human sporadic colorectal adenomas.

Cyclooxygenase (COX)-2 plays an important role in intestinal tumorigenesis and angiogenesis in animal models. In superficial areas of human sporadic colorectal adenomas, COX-2 is expressed predominantly by interstitial macrophages, in close proximity to microvessels. The aim of this study was to investigate the association between microvessel density (MVD) and COX-2 expression in human sporadic colorectal adenomas. Immunohistochemistry and immunofluorescence for CD31 and COX-2 were performed on a well-characterized series of human sporadic colorectal adenomas (n = 37). The mean MVD and COX-2 expression level (scored 0-3) in superficial and deep interstitial cells of adenomas were assessed by two independent observers. Superficial MVD was increased in COX-2-positive adenomas, compared with COX-2-negative adenomas (p = 0.037). There was a significant correlation between superficial MVD and increasing superficial interstitial cell COX-2 expression score (p = 0.048). COX-2-expressing interstitial cells aggregated in areas of high MVD. No relationship was evident between MVD and COX-2 expression in either deep interstitial cells or epithelial cells. Multivariate analysis demonstrated that only adenoma size (p = 0.005) was a significant independent predictor of MVD. COX-2 protein expression by superficial interstitial cells in human sporadic colorectal adenomas is associated with increased angiogenesis. Promotion of angiogenesis may play a role in the pro-tumourigenic activity of COX-2 during growth of human colorectal adenomas.

Analysis of cyclooxygenase expression in human colorectal adenomas.

INTRODUCTION: Evidence from rodent intestinal tumorigenesis models suggests that both cyclooxygenase-1 and cyclooxygenase-2 may play important roles in the development and progression of human sporadic colorectal adenomas. However, previous studies of cyclooxygenase isoform expression in human colorectal adenomas have produced conflicting data. Cyclooxygenase-1 expression has been poorly studied, and cyclooxygenase-2 positivity of adenomas has been variable depending on the detection technique used. It also remains unclear whether villous adenomas express cyclooxygenase-2. METHODS: Cyclooxygenase isoform expression in human sporadic colorectal adenomas was analyzed by reverse transcription-polymerase chain reaction, Western blot analysis, and immunohistochemistry. RESULTS: Variable cyclooxygenase-1 expression was detected in all adenomas (n = 9) by both reverse transcription-polymerase chain reaction and Western blot analysis. Cyclooxygenase-2 expression was detected in eight (89 percent) of nine adenomas by reverse transcription-polymerase chain reaction and immunohistochemistry. Cyclooxygenase-2 protein was not detected by Western blot analysis in any adenoma. Cyclooxygenase-2 was expressed by all histopathologic types of adenoma and localized predominantly to superficial interstitial cells, in which it was associated with increased adenoma size. CONCLUSION: Cyclooxygenase-1 is expressed at variable levels by all adenomas. Cyclooxygenase-2 is expressed by the majority of adenomas, including those of the villous type, at levels below the sensitivity of Western blot analysis.

Cancer of appendix as a presenting feature of Crohn's disease.

Appendiceal neoplasms are rare. Colonic malignancies, including appendiceal carcinomas, have been rarely reported in Crohn's disease patients. The involvement of the appendix in Crohn's disease is not often seen. We report an interesting case in which a caecal Crohn's disease patient presented for the first time with an appendiceal adenocarcinoma.