Candidate driver genes in focal chromosomal aberrations of stage II colon cancer.

Chromosomal instable colorectal cancer is marked by specific large chromosomal copy number aberrations. Recently, focal aberrations of 3 Mb or smaller have been identified as a common phenomenon in cancer. Inherent to their limited size, these aberrations harbour one or few genes. The aim of this study was to identify recurrent focal chromosomal aberrations and their candidate driver genes in a well-defined series of stage II colon cancers and assess their potential clinical relevance. High-resolution DNA copy number profiles were obtained from 38 formalin-fixed, paraffin-embedded colon cancer samples with matched normal mucosa as a reference using array comparative genomic hybridization. In total, 81 focal chromosomal aberrations were identified that harboured 177 genes. Statistical validation of focal aberrations and identification of candidate driver genes were performed by enrichment analysis and mapping copy number and mutation data of colorectal, breast, and pancreatic cancer and glioblastomas to loci of focal aberrations in stage II colon cancer. This analysis demonstrated a significant overlap with previously identified focal amplifications in colorectal cancer, but not with cancers from other sites. In contrast, focal deletions seemed less tumour type-specific since they also showed significant overlap with focal deletions of other sites. Focal deletions detected were significantly enriched for cancer genes and genes frequently mutated in colorectal cancer. The mRNA expression of these genes was significantly correlated with DNA copy number status, supporting the relevance of focal aberrations. Loss of 5q34 and gain of 13q22.1 were identified as independent prognostic factors of survival in this series of patients. In conclusion, focal chromosomal copy number aberrations in stage II colon cancer are enriched in cancer genes that contribute to and drive the process of colorectal cancer development. DNA copy number status of these genes correlates with mRNA expression and some are associated with clinical outcome.

Visceral Leishmaniasis presenting with intestinal failure: a case report and literature review.

We describe an unusual case of visceral Leishmaniasis affecting the gastrointestinal tract in a young immunocompetent patient whose only recent foreign travel was a trip to Mexico 9 months previously. She presented insidiously with diarrhoea, weight loss and developed subacute intestinal failure. Interestingly, she lacked most of the typical features of acute infection, including visceromegaly, fevers and hypergammaglobulinaemia. Atypical visceral involvement involving the gastrointestinal tract is well recognized in HIV coinfection, but very rare in immunocompetent patients. Repeated microscopy and culture of endoscopic biopsies failed to identify Leishmania parasites. Serological tests - direct agglutination test and anti-K39 antibody tests - were negative. This case highlights a very rare presentation of the condition with the absence of other visceral involvement and diagnosis being eventually made solely on polymerase chain reaction of rectal tissue, with a subsequent excellent response to therapy with intravenous liposomal amphotericin.

Identifying stage III colorectal cancer patients: the influence of the patient, surgeon, and pathologist.

PURPOSE: Nodal yields from resected colorectal cancers vary greatly. This study sought to determine what patient, tumor, and management factors influence the number of nodes retrieved and to determine if the extent of lymphadenectomy affects stage allocation and influences survival. PATIENTS AND METHODS: Retrospective study of the nodal yields of 7,062 surgically resected colorectal cancer patients for whom colorectal pathology minimum data sets had been collected. The percentage of patients diagnosed as stage III was compared across nodal yield categories. A threshold for an adequate lymphadenectomy was defined as retrieval of 12 nodes. Binary logistic regression was used to determine factors associated with obtaining an adequate lymphadenectomy. RESULTS: Median nodal yields increased over the study period from 7 (interquartile range [IQR], 4 to 11) in 1995 to 13 (IQR 8 to 19) in 2003. There was no difference in yield by cancer site or sex, but yields were lower in older patients. Yields increased with increasing local invasion and stage of tumor. The percentage of patients diagnosed as stage III increased as yields increased. Five-year survival was lower in those patients who did not have an adequate lymphadenectomy. Adequate lymphadenectomy was significantly more likely in patients with advanced tumors and when the surgery and pathology was undertaken by a specialist. Older patients were significantly less likely to receive an adequate lymphadenectomy. CONCLUSION: Variations in nodal yield are due to idiosyncratic patient and tumor characteristics and differences in the quality of surgery and pathology undertaken. Adequate lymphadenectomy is essential to ensure correct stage allocation and optimal survival.

Who to treat with adjuvant therapy in Dukes B/stage II colorectal cancer? The need for high quality pathology.

OBJECTIVE: To identify by routine pathology which Dukes B colorectal cancer patients may benefit from chemotherapy. METHOD: Retrospective study of the five year survival of colorectal cancer patients for whom colorectal pathology minimum datasets had been collected between 1997 and 2000 in the Yorkshire region of the UK. The study population consisted of 1625 Dukes B and 480 Dukes C patients who possessed one positive node treated between 1997 and 2000. The predictive ability of the Petersen prognostic model was investigated and survival of Dukes B patients with potentially high risk pathological features was compared to that of Dukes C patients with one positive node. RESULTS: Only 23.3% of patients had all the pathological variables required for the application of Petersen's index reported. The index offered a statistically significant survival difference of 24.3% and 30.3% between high and low risk colon (p<0.01) and rectal cancer patients (p<0.01). The size of these effects was smaller than predicted by the original model. Survival of Dukes B patients with any of the high risk pathological factors or low nodal yields was lower than that of Dukes C patients who possessed one positive node. CONCLUSION: Petersen's index discriminated between high and low risk Dukes B colorectal tumours, but inadequate pathological reporting diminished its ability to identify all high risk patients. The survival of patients with any high risk feature was lower than the threshold for adjuvant therapy of one lymph node positive Dukes C colorectal cancer. Chemotherapy may benefit patients with such features. Improving the quality of pathological reporting is vital if high risk patients are to be reliably identified.

Expression of DNA double-strand break repair proteins ATM and BRCA1 predicts survival in colorectal cancer.

PURPOSE: The double-strand break (DSB) is the major DNA lesion leading to chromosomal aberrations and faithful repair is crucial for maintaining genomic instability. Very little is known about the expression of DNA DSB repair proteins in colorectal cancer. To address this issue, we examined the expression pattern of DSB repair key proteins ATM, BRCA1, BRCA2, Ku70, and Ku80 and their putative role in patients survival in a large series of colorectal cancer. EXPERIMENTAL DESIGN: 342 sporadic colorectal cancer were subjected to immunohistochemistry by using specific antibodies for the various proteins investigated. Staining results were compared with clinicopathologic data, patient survival, as well as expression of mismatch repair proteins MLH1 and MSH2. RESULTS: The expression pattern of both ATM and BRCA1 predicted survival in all colorectal cancer patients as well as in the small subgroup of patients that received adjuvant therapy. Low expression of ATM and BRCA1 was associated with loss of MLH1 or MSH2 expression. CONCLUSIONS: This is the first study to show a relationship between the expression of DNA DSB repair proteins ATM and BRCA1 and survival in colorectal cancer patients. Studies in tumors from large randomized trials are now necessary to validate our pilot data and establish the clinical usefulness of the immunohistochemical assay in predicting response to a particular adjuvant therapy regimen. Furthermore, our results indicate a possible link between expression of DNA mismatch repair and DNA DSB repair proteins in sporadic colorectal cancer, which warrants further investigation.

Long-term hospital attendance of children and adults who have undergone removal of normal or inflamed appendices.

BACKGROUND: Early studies suggested that presentations with unexplained acute abdominal pain were associated with increased long-term rates of hospital attendance and self-harm, especially in women, but few studies were large enough for definitive findings. AIMS: To test the hypothesis that such presentations are followed by higher long-term utilisation rates of secondary health care even excluding further abdominal symptoms, and particularly for self-harm, than presentations with acute appendicitis. METHOD: New hospital attendance rates, liaison psychiatry attendances and self-harm attendances of patients with normal appendices at emergency appendicectomy were compared with those of appendicitis patients. RESULTS: Attendance rates of all kinds were significantly higher for normal appendix patients than for appendicitis patients, with equal strengths of finding for males and females. CONCLUSIONS: People with normal appendices at emergency appendicectomy show higher long-term rates of hospital attendance. This has implications for how these patients are best managed by health care systems.