Cost effectiveness analysis of intensive versus conventional follow up after curative resection for colorectal cancer

Objective To determine the cost effectiveness of intensive follow up compared with conventional follow up in patients with colorectal cancer.Design Incremental cost effectiveness analysis recognising differences in follow up strategies, based on effectiveness data from a meta-analysis of five randomised trials.Setting United Kingdom.Main outcome measures Taking a health service perspective, estimated incremental costs effectiveness ratios for each life year gained for five trials and four trials designed for early detection of extramural recurrences (targeted surveillance).Results Based on five year follow up, the numbers of life years gained by intensive follow up were 0.73 for the five trial model and 0.82 for the four trial model. For the five trials, the adjusted net (extra) cost for each patient was £2479 (€3550; $4288) and for each life year gained was £3402, substantially lower than the current threshold of NHS cost acceptability (£30 000). The corresponding values for the four trial model were £2529 and £3077, suggesting that targeted surveillance is more cost effective. The main predictor of incremental cost effectiveness ratios was surveillance costs rather than treatment costs. Judged against the NHS threshold of cost acceptability, the predicted incremental cost threshold was ninefold and the effectiveness threshold was 3%.Conclusions Based on the available data and current costs, intensive follow up after curative resection for colorectal cancer is economically justified and should be normal practice. There is a continuing need to evaluate the efficacy of specific surveillance tools: this study forms the basis for economic evaluations in such trials.     

肿瘤特异性抗原(MAGE)在肿瘤免疫治疗中的作用

目前,已经发现肿瘤特异性抗原Mage基因家族有55个成员,其中MageA、B和C三个亚家族在各种组织来源的恶性肿瘤中特异性表达,正常组织(睾丸除外)均不表达。所以,Mage抗原作为肿瘤的特异性标志,在肿瘤的检测和免疫治疗方面具有很大的应用潜力。本文介绍了Mage家族的基因定位,Mage蛋白的特性,Mage基因的作用。同时,总结了近年来Mage基因家族在临床方面的应用研究结果。     

Differential expression of miRNAs in colorectal cancer: comparison of paired tumor tissue and adjacent normal mucosa using high-throughput sequencing

We present the results of a global study of dysregulated miRNAs in paired samples of normal mucosa and tumor from eight patients with colorectal cancer. Although there is existing data of miRNA contribution to colorectal tumorigenesis, these studies are typically small to medium scale studies of cell lines or non-paired tumor samples. The present study is to our knowledge unique in two respects. Firstly, the normal and adjacent tumor tissue samples are paired, thus taking into account the baseline differences between individuals when testing for differential expression. Secondly, we use high-throughput sequencing, thus enabling a comprehensive survey of all miRNAs expressed in the tissues. We use Illumina sequencing technology to perform sequencing and two different tools to statistically test for differences in read counts per gene between samples: edgeR when using the pair information and DESeq when ignoring this information, i.e., treating tumor and normal samples as independent groups. We identify 37 miRNAs that are significantly dysregulated in both statistical approaches, 19 down-regulated and 18 up-regulated. Some of these miRNAs are previously published as potential regulators in colorectal adenocarcinomas such as miR-1, miR-96 and miR-145. Our comprehensive survey of differentially expressed miRNAs thus confirms some existing findings. We have also discovered 16 dysregulated miRNAs, which to our knowledge have not previously been associated with colorectal carcinogenesis: the following significantly down-regulated miR-490-3p, -628-3p/-5p, -1297, -3151, -3163, -3622a-5p, -3656 and the up-regulated miR-105, -549, -1269, -1827, -3144-3p, -3177, -3180-3p, -4326. Although the study is preliminary with only eight patients included, we believe the results add to the present knowledge on miRNA dysregulation in colorectal carcinogenesis. As such the results would serve as a robust training set for validation of potential biomarkers in a larger cohort study. Finally, we also present data supporting the hypothesis that there are differences in miRNA expression between adenocarcinomas and neuroendocrine tumors of the colon.     

Age-related increase in colorectal cancer stem cells in macroscopically normal mucosa of patients with adenomas: A risk factor for colon cancer

It is becoming increasingly evident that cancer stem cells play a vital role in development and progression of cancers and relapse following chemotherapy. The present study examines the presence of cancer stem-like cells (CSC) in adenomatous polyps and in normal appearing colonic mucosa in humans during aging. The number of polyps was found to increase linearly with advancing age (r² = 0.92, p < 0.02). Immunohistochemical analysis revealed co-localization of CSC markers CD44 and CD166 in colonic polyps. Real-time RT-PCR analysis of normal appearing mucosa from subjects with adenomatous polyps showed an age-related rise in CSC as evidenced by the increased expression of CD44, CD166 and ESA. A similar phenomenon was also observed for EGFR. In addition, the expression each CSC marker was found to be about 2-fold higher in subjects with 3–4 polyps than those with 1–2 polyps. In conclusion, our results show that colon cancer stem-like cells are present in the premalignant adenomatous polyps as well in normal appearing colonic mucosa. Moreover, our observation of the age-related rise in CSC in macroscopically normal colonic mucosa suggests a predisposition of the organ to developing colorectal cancer.     

Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials

ObjectiveTo review the evidence from clinical trials of follow up of patients after curative resection for colorectal cancer.DesignSystematic review and meta-analysis of randomised controlled trials of intensive compared with control follow up.ResultsFive trials, which included 1342 patients, met the inclusion criteria. Intensive follow up was associated with a reduction in all cause mortality (combined risk ratio 0.81, 95% confidence interval 0.70 to 0.94, P=0.007). The effect was most pronounced in the four extramural detection trials that used computed tomography and frequent measurements of serum carcinoembryonic antigen (risk ratio 0.73, 0.60 to 0.89, P=0.002). Intensive follow up was associated with significantly earlier detection of all recurrences (difference in means 8.5 months, 7.6 to 9.4 months, P<0.001) and an increased detection rate for isolated local recurrences (risk ratio 1.61, 1.12 to 2.32, P=0.011).ConclusionsIntensive follow up after curative resection for colorectal cancer improves survival. Large trials are required to identify which components of intensive follow up are most beneficial.

What is already known on this topic

There is a lack of direct evidence that intensive follow up after initial curative treatment for colorectal cancer leads to increased survivalGuidelines are inconclusive and clinical practice varies widely

What this study adds

The cumulative analysis of available data supports the view that intensive follow up after curative resection for colorectal cancer improves survivalIf computed tomography and frequent measurements of serum carcinoembryonic antigen are used during follow up mortality related to cancer is reduced by 9-13%This survival benefit is partly attributable to the earlier detection of all recurrences, particularly the increased detection of isolated recurrent disease     

The expression of Lewisx on carcinoembryonic antigen (CEA)-related glycoproteins of normal and inflamed oesophageal squamous mucosa

Carcinoembryonic antigen (CEA)-related antigens were detected histologically in normal and inflamed oesophageal squamous mucosa using polyclonal anti-CEA antisera and monoclonal antibodies recognizing CEA or NCAs (non-specific cross-reacting antigens). Expression was limited to the surface of more mature squames. Immunoblotting of detergent extracts of oesophageal mucosa separated on polyacrylamide gels using polyclonal anti-CEA antisera showed a number of CEA-related proteins, of 195, 145, and 80 kDa. CEA-specific monoclonal antibodies recognized only the 195-kDa glycoprotein. The lower molecular weight species were recognized by anti-NCA antibody DD9 and a CD66 antibody. The carboyhydrate antigen Lewis^x (Le^x, CD15), previously shown to be a marker of mature squames, was present predominantly on a subpopulation of the 195-kDa antigen and was demonstrable on the higher molecular weight component of a doublet recognized by the CEA antibodies. Expression of Le^x carbohydrate antigens in inflamed oesophageal squamous mucosa was shown to be significantly reduced relative to the expression seen in normal tissue. A suprabasal layer of CEA-positive, Le^x-negative cells became apparent in inflamed tissue showing altered glycosylation of the CEA under these conditions. It is postulated that CEA plays a role in maintaining the integrity of the squamous mucosa.     

探讨屎肠球菌的VanA调控人正常结直肠黏膜细胞FHC凋亡的机制

目的 探讨屎肠球菌的万古霉素替考拉宁A型抗性蛋白/D-丙氨酸-D-丙氨酸连接酶（Vancomycin Teicoplanin A-type resistance protein D-alanine-D-alanine ligase,vanA）调控人正常结直肠黏膜细胞FHC凋亡的机制。方法 在人正常结直肠黏膜细胞FHC中使用屎肠球菌感染,Annxin-V染色检测细胞凋亡情况。使用屎肠球菌的VanA蛋白刺激,检测FHC细胞凋亡情况、ROS水平以及ROS标志蛋白MDA、GSH和SOD的表达水平。ROS抑制Acetylcysteine处理VanA刺激的FHC细胞后,检测细胞凋亡相关蛋白的表达水平。结果 屎肠球菌与人正常结直肠黏膜细胞FHC共培养后,人正常结直肠黏膜细胞FHC的凋亡水平明显升高（t=2.876,P=0.045 2）,并且VanA蛋白能促进FHC凋亡水平（t=5.579,P=0.005 1）,同时细胞凋亡相关蛋白CLEAVED-CAS9、BAK的表达量上升,BCL-2的表达量下降。屎肠球菌的VanA蛋白刺激后,发现正常结直肠黏膜细胞FHC的ROS水平上升（t=10.190,P=0.000 5）,ROS标志蛋白MDA（t=4.315,P=0.012 5）和SOD（t=5.751,P=0.004 5）的表达水平上升,GSH（t=5.225,P=0.006 4）的表达水平下降,但是,ROS抑制剂Acetylcysteine能够抑制这种现象。结论 屎肠球菌的VanA通过提高细胞内ROS水平来促进人正常结直肠黏膜细胞FHC凋亡。     

Analysis of proliferative activity in colorectal mucosa by immunohistochemical detection of proliferating cell nuclear antigen (PCNA)

Immunohistochemical detection of proliferating cell nuclear antigen (PCNA) has been suggested as a new approach for determinating proliferative activity in paraffin-embedded tissue. In a prospective study PCNA immunostaining was performed in 284 colorectal biopsies using monoclonal antibodies 19F4 (Ogata et al. 1987) and PC10 (Waseem and Lane 1990) and compared with the Ki67 method. From each site three biopsies were taken and a variety of fixation regimens for frozen and paraffin-embedded samples tested. For frozen biopsies methanol fixation at −20° C proved best. In paraffin sections PCNA could be detected after methacarn fixation as well as after controled fixation at 4° C in 4% paraformaldehyde for 1 h and in most biopsies routinely fixed with 10% formalin. However, the latter fixation regimens revealed additional PCNA-positive cells in the normal superficial colonic mucosal epithelium. Although the percentage of cells positive for PCNA was generally lower than for Ki67, the rates correlated in a highly significant fashion, both in frozen methanolfixed biopsies, and in paraformaldehyde-fixed paraffinembedded samples. PCNA immunohistochemistry revealed a similar proliferative activity in different parts of the large bowel. A higher proliferative activity was found in inflamed mucosa, adenomas, carcinomas and even in normal mucosa from patients with colorectal neoplasms. In routinely fixed biopies, the monoclonal antibody PC10 was superior to 19F4 because of considerably less background staining. However, in the routine material only a rough estimate of the proliferative activity was possible by PCNA immunohistochemistry using these antibodies, because unpredictable numbers of non-S-phase cells were also stained. Thus, it was concluded that reliable results are only obtainable after careful control of the fixation conditions. Taking this reservation into account, PCNA immunohistochemistry still represents a convenient method for measurements of proliferative activity in paraffin-embedded colorectal mucosa and can be applied using methanol-containing fixatives as well as after 4% paraformaldehyde fixation. Supported by a grant of the Werner and Klara Kreitz-Stiftung, Kiel to J.D.     

Increased expression of I-region-associated antigen (Ia) on B cells after cross-linking of surface immunoglobulin

Both surface Ig (sIg) surface Ia (sIa) have been shown to have important roles in B lymphocyte activation. In order to investigate a possible relationship between these molecules, we studied the effects of cross-linking of sIg on the expression of sIa, as measured by fluorescence-activated cell sorter analysis of lymphoid cells stained with conventional anti-Ia anti-serum or with fluorescein-labeled anti-Ia antibodies. Exposure of cells for 24 hr in vitro to anti-delta, anti-mu, anti-kappa antibodies, or their F(ab')2 fragments induced a very dramatic increase in expression of sIa. Similarly, i.v. injection of anti-delta antibodies into adult mice induced a 2- to 3-fold increase in expression of B cell sIa on spleen, lymph node, and Peyer's patch lymphocytes. There was no increase under these conditions in expression of other B lymphocyte surface antigens, including H-2, 4B9, and 17C9. Furthermore, exposure of B lymphocytes to antibodies directed to B lymphocyte surface antigens other than sIg did not result in an increase in expression of sIa. The anti-Ig-induced increase in sIa expression appeared to be T independent, required cellular protein synthesis, and required more time to occur than did the cross-linking and removal of sIg. This increase in expression of sIa did not occur on B lymphocytes obtained from mice younger than 3 wk old. This increase in expression of sIa may reflect a proximal event in B lymphocyte activation that occurs after cross-linking of sIg by antigen and that may enhance subsequent cellular interactions involving B lymphocytes.     

Significant prolongation of disease-free period gained by oral polysaccharide K (PSK) administration after curative surgical operation of colorectal cancer

Summary To examine the clinical efficacy and the mechanism of action of polysaccharide K (PSK), a proteinbound polysaccharide extracted from a Basidiomycetes fungus, a randomized double-blind trial was performed by administering PSK to 56 patients and a placebo to another group of 55 patients after surgical operations on their colorectal cancers. The rate of patients in remission (or disease-free) was significantly higher in the PSK group than in the placebo group; the difference between both groups was statistically significant atP <0.05 by the logrank test. The survival rate of patients was also significantly (P <0.05) higher in the PSK group than in the control group. The most significant laboratory finding was that polymorphonuclear leukocytes from PSK-treated patients showed remarkable enhancement in their activities, such as random and/or chemotactic locomotion, and phagocytic activity, when compared with those in the control group. In conclusion, PSK was useful as a maintenance therapy for patients after their curative surgical operations for colorectal cancer. The beneficial effects were probably due to the activation of leukocyte functions as one of the many biological-response-modifying (activities induced by PSK).     

Immunoreactivity of normal rabbit serum with epinephrine (E) cells of the rat adrenal medulla after microwave antigen retrieval

Normal rabbit serum (NRS) produces intense staining of epinephrine (E) cells in microwave-heated sections of rat and mouse adrenal gland. This staining is not eliminated by liver adsorption, complement inactivation, high salt buffer, Triton X-100 or dilution in normal goat serum and bovine serum albumin (BSA), suggesting that it may result from specific antigen-antibody interactions. Western blots of adrenal medullary protein probed with NRS reveal several bands. The major band does not correspond to rat chromogranin A, which is a major constituent of E-cell secretory granules. The findings suggest that NRS may contain autoantibodies against a secreted rabbit E-cell protein with a homologous counterpart in rats and mice, and that this protein may be immunologically unmasked in situ by microwave heating. This phenomenon is a potential source of error in immunohistochemical studies of the adrenal medulla, and has potential biological significance in neuroimmunology.     

Expression of Duffy antigen receptor for chemokines (DARC) is down-regulated in colorectal cancer

Abstract

Duffy antigen receptor for chemokines (DARC) is a silent chemokine receptor which selectively binds angiogenic chemokines without inducing conventional signaling responses. DARC has been reported to inhibit the development of multiple cancers through clearance of angiogenic chemokines. However, its role in colorectal cancer (CRC) remains unclear. We investigated the expression of DARC in CRC and explored correlation of DARC expression with clinical pathological features and microvessel density (MVD). The protein expression levels of DARC were detected by immunohistochemistry in 90 CRC and 64 paired unaffected tissues. The mRNA levels of DARC were detected by quantitative real-time PCR in 15 CRC and paired unaffected tissues. MVD in CRC was also assessed by immunohistochemistry of CD34. We found that the mRNA and protein expression levels of DARC were significantly lower in CRC than in the unaffected tissues (p?<?0.05). The DARC protein expression levels were positively correlated with DARC mRNA expression levels in both CRC (p?<?0.001) and unaffected tissues (p?<?0.001). We also found that DARC expression was significantly correlated with tumor differentiation (p?<?0.001), lymph node metastasis (p?<?0.01) and TNM stage (p?<?0.05). Moreover, we observed a strong negative relationship between DARC expression and MVD in CRC (p?<?0.001). We showed that DARC expression is down-regulated in CRC and associated with clinical pathological features and MVD of CRC. DARC might be involved in tumorigenesis, progression, angiogenesis, and metastasis of CRC.     

Roles of intestinal trefoil factor (ITF) in human colorectal cancer: ITF suppresses the growth of colorectal carcinoma cells

Intestinal trefoil factor (ITF) is a member of trefoil peptide family and is expressed almost exclusively in the goblet cells of small intestine and colon. Its expression is up-regulated by inflammatory and ulcerative conditions in the intestinal mucosa, and ITF has a role to maintain the mucosal integrity and repair the damaged mucosa. On the other hand, human colorectal carcinoma cells also express ITF peptide. In this review, we discussed the current views on the biological functions of ITF in the intestinal mucosa, and its suppressive effect on the growth of colorectal carcinoma cells.     

Characterization of proliferating cell nuclear antigen (PCNA) isoforms in normal and cancer cells: there is no cancer-associated form of PCNA

In order to clarify the status of PCNA in normal and transformed cells, we performed analysis of this protein by 2D-PAGE, Western blot and mass spectrometry. All the cell lines examined contained the major PCNA form (pI 4.57/30kDa), that is not post-translationally modified. In addition to the major form, two minor isoforms (pI 4.52/30kDa and pI 4.62/30kDa) were also detected in all the cell lines examined. However, the level of PCNA in cancer cells is 5-6 folds higher than those in primary and most of the immortalized cells. Taken together, the significant difference in PCNA status between cancer and normal cells is not at the post-translational modifications but in the overall levels of PCNA.     

The induction of Leu-1 antigen expression in human malignant and normal B cells by phorbol myristic acetate (PMA)

Malignant cells from five patients with B cell leukemia or lymphoma were cultured with phorbol myristic acetate (PMA). PMA was found to induce cell surface expression of the Leu-1 antigen in cells from three of the five patients. Using one- and two-color immunofluorescence staining and flow cytometry, we have shown simultaneous expression of the Leu-1 antigen with other B cell markers. Induction of Leu-1 antigen expression was not related to histologic subtype, in vitro secretion of immunoglobulin, or other clinical features. Biosynthetic labeling experiments showed that synthesis of Leu-1 antigen occurred and preceded expression of the antigen on the cell surface. PMA also induced the appearance of Leu-1 antigen-positive B cells in cultures of normal peripheral blood mononuclear cells. We propose that the Leu-1 antigen is expressed transiently during the differentiation of some B cells.