Biomarkers for early detection of colon cancer.

There is an increasing demand for biomarkers in colon cancer for risk assessment, early detection, prognosis, and surrogate end points. A number of biomarkers have been identified for early detection of colon cancer, although the risk factors have not been identified extensively. The major advances in understanding colorectal cancer include the identification and the involvement of APC, p53, and Ki-ras in the development and progression of the disease, the identification of the aberrant crypt foci as an early preinvasive lesion, and its relation to the development of cancer. Detecting malignant neoplasms in the early stages offers clinical advantages; therefore, the National Cancer Institute has established an Early Detection Research NETWORK: The emphasis of the network is on translational research and collaboration among scientists.     

DNA methylation biomarker candidates for early detection of colon cancer

Promoter CpG island hypermethylation of tumor suppressor genes is a common hallmark of all human cancers. Many researchers have been looking for potential epigenetic therapeutic targets in cancer using gene expression profiling with DNA microarray approaches. Our recent genome-wide platform of CpG island hypermethylation and gene expression in colorectal cancer (CRC) cell lines revealed that FBN2 and TCERG1L gene silencing is associated with DNA hypermethylation of a CpG island in the promoter region. In this study, promoter DNA hypermethylation of FBN2 and TCERG1L in CRC occurs as an early and cancer-specific event in colorectal cancer. Both genes showed high frequency of methylation in colon cancer cell lines (>80% for both of genes), adenomas (77% for FBN2, 90% for TCERG1L, n = 39), and carcinomas (86% for FBN2, 99% for TCERG1L, n = 124). Bisulfite sequencing confirmed cancer-specific methylation of FBN2 and TCERG1L of promoters in colon cancer cell line and cancers but not in normal colon. Methylation of FBN2 and TCERG1L is accompanied by downregulation in cell lines and in primary tumors as described in the Oncomine™ website. Together, our results suggest that gene silencing of FBN2 and TCERG1L is associated with promoter DNA hypermethylation in CRC tumors and may be excellent biomarkers for the early detection of CRC.     

Mass screening for the early detection of colon cancer in patients with endometrial cancer

A mass screening has been performed for the early detection of colon cancer by evaluating Hemocult II slides of blood relatives of patients with endometrial cancer. Though the defect of this screening is that the subject of the investigation, which was undertaken in all parts of Japan, is restricted, one case of colon cancer, two cases of colon polyposis, two cases of hemorrhoids, and one case of colon diverticulum have been uncovered by this screening. The rate of discovery of colon cancer proved to be 0.45%, a rate that is higher than seen in usual screening method. It has been concluded that blood relatives of patients with endometrial cancer should be screened, since they represent a high risk group for developing colon cancer.     

F-FLT-PET for detection of rectal cancer

Purpose: This pilot study was undertaken to examine the ability of ¹⁸F-3′-fluoro-3′-deoxy-l-thymidine positron emission tomography (¹⁸F-FLT-PET)to detect rectal cancer, to identify pathologic lymph nodes and to determine the accuracy of tumour length estimation in comparison with computer tomography (CT). Methods: Nine patients with biopsy proven rectal cancer underwent CT and ¹⁸F-FLT-PET scanning prior to short-term pre-operative radiotherapy (5 × 5 Gy). Within 10 days after the start of radiotherapy a surgical resection was performed. Tumour lengths and regional lymph node visualisation on both imaging modalities were compared with pathology findings. Results: All tumours were visible on CT. ¹⁸F-FLT-PET visualised 7 out of 9 tumours (78%). The pathology-based tumours lengths correlated better with CT as compared to FLT-PET(r = 0.91, p < 0.01). ¹⁸F-FLT-PET was not able to visualise pathologic lymph nodes. However, CT identified all patients with pathologic lymph nodes. Conclusion: Primary rectal cancer can be visualised by ¹⁸F-FLT-PET in the majority of cases but not in all. However, ¹⁸F-FLT-PET was not able to identify pathologic lymph nodes. Therefore, we conclude that ¹⁸F-FLT-PET has limited value for the detection of pathologic lymph nodes and tumour delineation in rectal cancer.     

Guidelines 2000 for colon and rectal cancer surgery

BACKGROUND: Oncologic resection techniques affect outcome for colon cancer and rectal cancer, but standardized guidelines have not been adopted. The National Cancer Institute sponsored a panel of experts to systematically review current literature and to draft guidelines that provide uniform definitions, principles, and practices. METHODS: Methods were similar to those described by the American Society of Clinical Oncology in developing practice guidelines. Experts representing oncology and surgery met to review current literature on oncologic resection techniques for level of evidence (I-V, where I is the best evidence and V is the least compelling) and grade of recommendation (A-D, where A is based on the best evidence and D is based on the weakest evidence). Initial guidelines were drafted, reviewed, and accepted by consensus. RESULTS: For the following seven factors, the level of evidence was II, III, or IV, and the findings were generally consistent (grade B): anatomic definition of colon versus rectum, tumor-node-metastasis staging, radial margins, adjuvant R0 stage, inadvertent rectal perforation, distal and proximal rectal margins, and en bloc resection of adherent tumors. For another seven factors, the level of evidence was II, III, or IV, but findings were inconsistent (grade C): laparoscopic colectomy; colon lymphadenectomy; level of proximal vessel ligation, mesorectal excision, and extended lateral pelvic lymph node dissection (all three for rectal cancer); no-touch technique; and bowel washout. For the other four factors, there was little or no systematic empirical evidence (grade D): abdominal exploration, oophorectomy, extent of colon resection, and total length of rectum resected. CONCLUSIONS: The panel reports surgical guidelines and definitions based on the best available evidence. The availability of more standardized information in the future should allow for more grade A recommendations.     

Comparison of risk factors for colon and rectal cancer

Predictors of colorectal cancer have been extensively studied with some evidence suggesting that risk factors vary by subsite. Using data from 2 prospective cohort studies, we examined established risk factors to determine whether they were differentially associated with colon and rectal cancer. Our study population included 87,733 women from the Nurses' Health Study (NHS) and 46,632 men from the Health Professionals Follow Up Study (HPFS). Exposure information was collected via biennial questionnaires (dietary variables were collected every 4 years). During the follow-up period (NHS: 1980 to May 31, 2000; HPFS: 1986 to January 31, 2000), we identified 1,139 cases of colon cancer and 339 cases of rectal cancer. We used pooled logistic regression to estimate multivariate relative risks for the 2 outcomes separately and then used polytomous logistic regression to compare these estimates. In the combined cohort, age, gender, family history of colon or rectal cancer, height, body mass index, physical activity, folate, intake of beef, pork or lamb as a main dish, intake of processed meat and alcohol were significantly associated with colon cancer risk. However, only age and sex were associated with rectal cancer. In a stepwise polytomous logistic regression procedure, family history and physical activity were associated with statistically significant different relative risks of colon and rectal cancer. Our findings support previous suggestions that family history and physical activity are not strong contributors to the etiology of rectal cancer. Future investigations of colon or rectal cancer should take into consideration risk factor differences by subsite.     

BAGE hypomethylation, a new epigenetic biomarker for colon cancer detection.

Early detection of colorectal cancer is a decisive step in the successful and complete cure of the disease. Epigenetic markers, in particular, those based on aberrant DNA methylation, can be used to diagnose cancer. B melanoma antigens (BAGE) are a family of genes and truncated genes located in the heterochromatic regions of several human chromosomes. Our previous work showed that BAGE loci (i.e., genes and truncated genes) were hypermethylated in normal tissues and hypomethylated in 98% of human cancers. In the present study, we analyzed DNA methylation of the BAGE loci in 54 colon cancers and in neighboring histopathologic normal tissue samples. Using a combined bisulfite restriction assay, we showed that BAGE loci were hypomethylated in 81% of carcinoma samples. Colon cancer could be diagnosed with 94% specificity, 83% sensitivity, and 89% accuracy. No correlation was found between DNA methylation of BAGE loci and age, gender of patients, nor with the tumor stage or site. Based on the hypothesis that during neoplastic transformation, hypomethylation occurs in juxtacentromeric CpG islands, we suggest that other genes located in the heterochromatic compartment should be tested. These new markers enrich the list of currently studied epigenetic alterations in colon cancer and could be associated with hypermethylation markers to develop reliable diagnostic tests.     

An analysis of immunocomplexes for the detection of the early stages of colon cancer

A radioimmunoassay was developed for the detection of the early stages of colon cancer by analysis of immune complexes (IC) with a specific polyclonal antibody. Human colon cancer cells were grown in a capillary culture system to provide unaltered antigens for the development of a specific antibody. The antibody was labeled with iodine 125 (125I) and used to analyze the antigen component of IC removed from whole serum. The assay was positive in 50% and 88% of known Dukes' A and Dukes' B colon cancer patients, respectively. It was also positive for only 25% of Dukes' C and 14% of Dukes' D patients, possibly because of the decreased quantity of specific IC found in the late stages of colon cancer. A blind study of patients referred for colonoscopy compared pathology diagnosis with the test results. The assay was positive for one patient with a polypoid adenocarcinoma (Dukes' B) and one with a villous adenoma and negative for 38 patients with benign polyps and 43 with no polyps. The assay was negative for all patients with stomach cancer and inflammatory bowel diseases and positive for about 10% of the patients with pancreas or breast cancer. The results of this preliminary investigation suggest that this radioimmunoassay may be useful for the detection of the early stages of colon cancer.     

Profiling tumor-associated autoantibodies for the detection of colon cancer.

PURPOSE: The purpose of the present study was to screen the autoantibody signature of colon cancers to develop serum markers for colon cancer detection. EXPERIMENTAL DESIGN: A phage cDNA expression library of colon cancer was built. The library was sequentially screened by a pool of 10 colon cancer sera, goat antihuman IgG, and a pool of two healthy sera to identify phage-expressed antigens recognized by tumor-associated antibodies. The clones picked out by these screening were subjected to a training set with 24 colon cancer sera and 24 healthy sera. The antigen combination, which got the most satisfactory classification, was tested by an independent set of 24 colon cancer sera with equal number of sera from normal donors. The carcinoembryonic antigen (CEA) level of these sera was detected for the additional classification analysis with or without the antigen combination. RESULTS: A cDNA expression library consisting of 2 x 10(6) primary clones was prepared. After three turns of screening, 24 antigens recognized by tumor-associated antibodies were picked out for serum marker identification. The training set showed that a six-marker combination got the most satisfactory classification in a logistic regression model; leave-one-out validation achieved 91.7% sensitivity and 91.7% specificity. In a testing set with this marker panel, we correctly predicted 85% of the samples. Although according to CEA level alone, we correctly predicted 75% of the samples with 42% of cancer patients misclassified. When CEA was combined with the six markers, the sensitivity and specificity increased to 91.7% and 95.8%, respectively. The six antigen sequences in the phage display system are relatively short peptides. Only two of them showed homology to known protein sequences. CONCLUSIONS: Autoantibodies against phage-expressed antigens derived from colon cancer tissues could be used as serum markers for the detection of colon cancer.     

Surgical treatment of colon and rectal cancer

There are many indications for surgical intervention in the current treatment of cancer of the colon and rectum. The hallmark of surgical therapy remains en bloc resection of the primary tumor, accompanied by removal of the mesenteric lymph nodes. Surgical resection is also the principal and most successful treatment for local recurrences and isolated metastases. Although the application of minimally invasive techniques is growing in all aspects of surgery and is accepted in the treatment of benign lesions of the colon, laparoscopic resection for colorectal cancer cannot be recommended apart from randomized, controlled trials. Similarly, the role of sentinel lymph node biopsy in the surgical treatment of colorectal cancer remains to be defined. Various surgical modalities have been developed for the treatment of unresectable colorectal cancer metastatic to the liver. Further studies should help to elucidate the exact role of these therapies in the treatment of this common clinical problem. In summary, surgical treatment plays an important role in multiple aspects of the care of the patient with colorectal cancer.     

Diagnostic markers for early detection of ovarian cancer.

PURPOSE: Early detection would significantly decrease the mortality rate of ovarian cancer. In this study, we characterize and validate the combination of six serum biomarkers that discriminate between disease-free and ovarian cancer patients with high efficiency. EXPERIMENTAL DESIGN: We analyzed 362 healthy controls and 156 newly diagnosed ovarian cancer patients. Concentrations of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125 were determined using a multiplex, bead-based, immunoassay system. All six markers were evaluated in a training set (181 samples from the control group and 113 samples from OC patients) and a test set (181 sample control group and 43 ovarian cancer). RESULTS: Multiplex and ELISA exhibited the same pattern of expression for all the biomarkers. None of the biomarkers by themselves were good enough to differentiate healthy versus cancer cells. However, the combination of the six markers provided a better differentiation than CA-125. Four models with <2% classification error in training sets all had significant improvement (sensitivity 84%-98% at specificity 95%) over CA-125 (sensitivity 72% at specificity 95%) in the test set. The chosen model correctly classified 221 out of 224 specimens in the test set, with a classification accuracy of 98.7%. CONCLUSIONS: We describe the first blood biomarker test with a sensitivity of 95.3% and a specificity of 99.4% for the detection of ovarian cancer. Six markers provided a significant improvement over CA-125 alone for ovarian cancer detection. Validation was performed with a blinded cohort. This novel multiplex platform has the potential for efficient screening in patients who are at high risk for ovarian cancer.     

直肠癌的局部切除术

早期直肠癌的局部切除术同经腹部的切除术相比具有手术风险低、手术创伤小、术后无性功能和泌尿功能的障碍等多项优点，并能最大程度上予以保留肛门。但由于手术指征掌握不同、手术入路和手术方法各异，导致最终手术疗效上的差别悬殊。因此严格掌握手术指征，选择适当的手术路径和技术，保证局部切除的根治性是早期直肠癌局部切除术取得优良疗效的关键。