Recurrence In Colorectal Cancer Patients Research Articles

Postoperative Detection of Circulating Tumor Cells Predicts Tumor Recurrence in Colorectal Cancer Patients

IntroductionCirculating tumor cells are thought to play a crucial role in the development of distant metastases. Their detection in the blood of colorectal cancer patients may be linked to poor outcome, but current evidence is controversial. Materials and MethodsPre- and postoperative flow cytometric analysis of blood samples was carried out in 76 colorectal cancer patients undergoing surgical resection. The EpCAM/CD326 epithelial surface antigen was used to identify circulating tumor cells. ResultsFifty-four (71 %) patients showed circulating tumor cells preoperatively, and all metastatic patients showed high levels of circulating tumor cells. Surgical resection resulted in a significant decrease in the levels of circulating tumor cells. Among 69 patients undergoing radical surgery, 16 had high postoperative levels of circulating tumor cells, and 12 (75 %) experienced tumor recurrence. High postoperative level of circulating tumor cells was the only independent variable related to cancer relapse. In patients without circulating tumor cells, the progression-free survival rate increased from 16 to 86 %, with a reduction in the risk of tumor relapse greater than 90 %. ConclusionsHigh postoperative levels of circulating tumor cells accurately predicted tumor recurrence, suggesting that assessment of circulating tumor cells could optimize tailored management of colorectal cancer patients.

Association between c-Met expression and tumor recurrence in colorectal cancer patients after liver resection.

3559 Background: c-Met is a receptor for hepatocyte growth factor that has been implicated in the pathogenesis and growth of a wide variety of human malignancies, including colorectal cancer (CRC). The aim of the present study was to clarify the correlation between c-Met protein expression in the primary lesion and relapse-free survival (RFS) in patients who had undergone curative hepatectomy for colorectal metastases. Methods: Between January 2004 and December 2009, formalin-fixed paraffin-embedded sections of surgical specimens from 108 CRC patients who had undergone hepatectomy were obtained at a single center. We performed immunohistochemical staining to detect c-Met expression. c-Met expression levels were scored dependent on staining intensity; 0, negative; 1, weak; 2, moderate; 3, strong. We defined scores 0 and 1 as c-Met-low, and scores 2 and 3 as c-Met-high. The Kaplan-Meier method and Cox proportional hazards model were used to investigate relationships between c-Met expression, patient characteristics, and RFS. Results: We identified 65 males and 43 females with a median age of 62 years. A total of 53% of patients underwent simultaneous resection of primary and metastatic liver lesions, and the others underwent metachronous resection. High levels of c-Met expression (c-Met-high) in the primary tumor were observed in 52% of patients. There were no differences in terms of size or number of metastatic liver lesions between the c-Met-low patients and the c-Met-high patients. RFS was significantly shorter in the c-Met-high patients (9.7 months) than that in the c-Met-low patients (21.1 months) in primary tumors (p=0.013). Multivariate analyses demonstrated that c-Met-high (hazards ratio [HR], 1.73; 95% confidence interval [95% CI], 1.08-2.79 for c-Met-high vs. c-Met-low) and hepatic resection for synchronous disease (HR, 2.17; 95% CI, 1.36-3.46 for synchronous vs. metachronous resection) were associated with worse RFS. Conclusions: High levels of c-Met expression in the primary tumor were associated with shorter RFS after hepatic metastasectomy.

Abstract 4690: Combined analysis of Aldh1, Survivin and EpCAM expression, representing important hallmarks of cancer, predicts clinical prognosis in colorectal cancer.

Abstract Background: Current treatment of colorectal cancer patients is solely based on TNM stage. Biomarkers to further refine this staging system are warranted. Tumor aggressiveness might be related to the number of cancer hallmarks possessed by a tumor. Expression level of a specific biomarker may represent gain of those cancer hallmarks represented by this marker. Combining such biomarkers might add to needed discriminative value and biological- and clinical significance. We therefore investigated combined expression of Aldh1, Survivin and EpCAM, which together reflect the main cancer hallmarks, in relation to clinical outcome of colorectal cancer patients. Methods: Immunohistochemistry was performed using a tumor tissue micro array of colorectal cancer patients (N=410). Percentage of cells positive for individual markers was scored. Patients were divided into groups based on median expression. Individual markers and their combination were assessed for associations with overall survival, disease specific survival and recurrence free survival. Complete covariate- and marker expression data were available for 249 patients (study cohort) for uni- and multivariate survival analysis, performed with automated stepwise backward Cox regression. Results: In single marker analyses, increased expression of Aldh1 and Survivin, and decreased expression of EpCAM was associated with poor clinical outcome in colorectal cancer, and designated clinically unfavorable marker expression. Based on these results, the three biomarkers were combined into four groups (groups 0, I, II and III). Group number represented the number of markers that showed unfavorable expression in the tumor. Reference group 0 contained patients with favorable marker expression for all markers. Group I, group II and group III contained patients with unfavorable marker expression of respectively one, two or three of the markers. No correlation with clinicopathological parameters was found. Combined expression of all three markers (Group I / Group II / Group III, compared to Group 0) was shown to be a strong independent prognostic factor of tumor recurrence rates and patient survival in the multivariate analyses: overall survival (HR= 1.33 / 2.05 / 5.39, P< 0.001), disease specific survival (HR= 2.39 / 4.54 / 12.18, P< 0.001) and recurrence free survival (HR= 2.35 / 5.18 / 12.90, P< 0.001). Increase in group number was associated with higher hazard ratios, indicating that gain of cancer hallmarks was associated with more aggressive tumors. Discussion: Our data demonstrated that combined expression level of Aldh1, Survivin and EpCAM, together representing the main cancer hallmarks, reflected tumor aggressiveness and hence predicted survival and recurrence in colorectal cancer patients. Including the analysis of these biomarkers may therefore complement the current TNM staging system. Citation Format: Inès Goossens-Beumer, Eliane Zeestraten, Anne Benard, Tim Christen, Marlies Reimers, Rob Keijzer, Gerrit-Jan Liefers, Hans Morreau, Hein Putter, Cornelis van de Velde, Peter Kuppen. Combined analysis of Aldh1, Survivin and EpCAM expression, representing important hallmarks of cancer, predicts clinical prognosis in colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4690. doi:10.1158/1538-7445.AM2013-4690

Use of FDG-PET or PET/CT to detect recurrent colorectal cancer in patients with elevated CEA: a systematic review and meta-analysis

The purpose of the present study was to conduct a systematic review and meta-analysis of the published literature to assess the diagnostic performance of FDG-PET or PET/CT in the detection of recurrent colorectal cancer (CRC) rising in patients with elevated CEA. The authors conducted a systematic MEDLINE search of published articles. Two reviewers independently assessed the methodological quality of each study. We estimated pooled sensitivity and specificity and positive and negative likelihood ratios, and summary receiver-operating characteristic curves in the detection of recurrent CRC in patients with elevated CEA. Eleven studies with a total of 510 patients met the inclusion criteria. One hundred and six patients (106/510 = 20.8%) had true-negative FDG-PET (PET/CT) results in detection of recurrent CRC when rising CEA. The pooled estimates of sensitivity and specificity and positive and negative likelihood ratios of FDG-PET in the detection of tumor recurrence in CRC patients with elevated CEA were 90.3% (95% CI, 85.5-94.0%), 80.0% (95% CI, 67.0-89.6%), 2.88 (95% CI, 1.37-6.07), and 0.12 (95% CI, 0.07-0.20), respectively. The pooled estimates of sensitivity and specificity and positive and negative likelihood ratios of FDG-PET/CT in the detection of tumor recurrence in CRC patients with elevated CEA were 94.1% (95% CI, 89.4-97.1%), 77.2% (95% CI, 66.4-85.9%), 4.70 (95% CI, 0.82-12.13), and 0.06 (95% CI, 0.03-0.13), respectively. Whole-body FDG-PET and PET/CT are valuable imaging tools for the assessment of patients with suspected CRC tumor recurrence based on the increase of CEA.

Micro-RNA-21 (miR21) expression in colorectal cancer (CRC) as a predictor for fluoropyrimidine-based adjuvant chemotherapy.

408 Background: Fluoropyrimidine-based adjuvant chemotherapy is a standard treatment option for patients with high risk II or stage III CRC. It is, however, unclear if a subset of patients will benefit from chemotherapy more than others. MiR21, a small non-coding RNA, has been associated with promotion of tumor cell growth and metastasis. To assess the effect of miR21 on chemotherapy, we analyzed the association of miR21 expression with clinical outcomes and known prognostic factors. Methods: MicroRNA detection was performed by in situ hybridization on a CRC tissue microarray containing specimens from 130 cases (stage I, 21 patients; II: 44; III: 33; IV: 32). MiR21 expression was graded as negative (no staining in all tissue cores), low (0-10% staining), moderate (20-40%) and strong (50-100%), and was analyzed with stage, grade, expression of VEGF, Ki67, LEF1, OPN and MSH2 by immunohistochemistry. Cox proportional hazards regression analysis was performed to assess the association of miR21 expression with 10-year recurrence-free survival in the subgroup of 77 stage II or III patients. Results: In all, miR21 expression had moderate positive correlation with genes associated with tissue proliferation and invasion, including Ki67 (Spearman's r=0.42, p<0.001), VEGF (r=0.32, p<0.001) and OPN (r=0.32, p<0.001), and weak correlation with LEF1 (r=0.22, p=0.012) and MSH 2 (r=0.18, p=0.039). In the subgroup of 36 patients treated with adjuvant therapy, low or negative miR21 expression (≤10%, n=15) was associated with increased recurrence (HR =3.5; p=0.05). In the multivariate Cox regression model including stage, grade and LEF1 expression, the association of low or negative miR21 with cancer recurrence remained significant along with grade and LEF1. Ki67 was excluded from the multivariate model because of significant association with miR21 (r=0.44, p=0.007) in the analyzed group. Conclusions: Our results suggest that low miRNA21 expression is associated with increased risk for recurrence in CRC patients received adjuvant chemotherapy. Further investigation of miR21 in randomized studies is warranted to establish its role as a predictor for CRC in the setting of adjuvant therapy.

Serum Carcinoembryonic Antigen for Recurrence in Colorectal Cancer Patients

See Article on Page 156-160 Carcinoembryonic antigen (CEA) is secreted by most colorectal cancers, and the CEA level reflects the burden of the tumor present. An elevated preoperative CEA level is a poor prognostic factor for colorectal cancer [1], and the prognosis is better in those patients whose elevated preoperative CEA level is normalized postoperatively. Although an elevated postoperative CEA level is not specific for recurrent colorectal cancer, a rising CEA level on serial examinations and a new solid mass on imaging studies are diagnostic of metastatic disease. The role of CEA in patients following definitive management of colorectal cancer has been evaluated, and the American Society of Clinical Oncology recommended that postoperative serum CEA tests be performed every 3 months in patients with stage II or III disease for up to 3 years after diagnosis [2]. Postoperative serum CEA surveillance was more useful when patients had high preoperative serum CEA levels [3]. When the elevated postoperative serum CEA in stage III (71.9%) was higher than that in stage II colorectal cancer patients (41.8%), the incidence of recurrence was low [4]. The 18F-fluorodeoxyglucose positron emission tomography/computed tomography (CT) has an additional role in patients with isolated elevated CEA levels or positive contrast enhanced CT findings without accompanying CEA elevation [5]. Although the CEA is not an ideal tumor marker, the preoperative and the postoperative CEA levels are useful and cost effective for determining a prognosis and for predicting recurrence in colorectal cancer patients.

ALDH+ tumor-initiating cells exhibiting gain in NOTCH1 gene copy number have enhanced regrowth sensitivity to a γ-secretase inhibitor and irinotecan in colorectal cancer

The Notch signaling pathway has been shown to be upregulated in colorectal cancer (CRC) and important for the self-renewal of cancer stem cells. In this study, we evaluated the efficacy of PF-03084014, a γ-secretase inhibitor, in combination with irinotecan to identify the effects of treatment on tumor recurrence and the tumor-initiating population in our CRC preclinical explant model. The combination of PF-03084014 and irinotecan had the greatest effect at reducing tumor growth on four CRC tumors when compared with treatment with PF-03084014 or irinotecan alone. The combination significantly reduced tumor recurrence in two CRC explants (CRC001 and CRC036) after treatment was discontinued. Both of these tumors exhibited elevated baseline levels of Notch pathway activation as well as an increase in NOTCH1 gene copy number when compared with the two CRC explants (CRC026 and CRC027) where tumors reappeared quickly after termination of treatment. Isolation and injection of aldehyde dehydrogenase (ALDH+ and ALDH−) cells in an in vivo explant model demonstrated that the ALDH+ cell population were tumorigenic. Evaluation of the ALDH+ cells after 28 days of treatment showed that the combination reduced the ALDH+ population in the tumors that did not regrow. Furthermore, ALDH+ cells from CRC001 and CRC027 were injected in vivo and treated immediately for 28 days. Two months after treatment, tumors were evident in the combination treatment group for CRC027 but not for CRC036. These results indicate the combination of PF-03084014 and irinotecan may be effective in reducing tumor recurrence in CRC patients whose tumors exhibit elevated levels of the Notch pathway.

Accuracy of monitoring serum carcinoembryonic antigen levels in postoperative stage III colorectal cancer patients is limited to only the first postoperative year

The aim of the present study was to determine the accuracy of yearly postoperative monitoring of serum tumor markers to either detect or rule out recurrence in colorectal cancer patients. A total of 127 colorectal cancer patients who underwent curative surgery were enrolled. The serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were assayed, and radiological examinations were performed routinely for 5 years after surgery or until recurrence was detected. Yearly recurrence rates (number of recurrences/number of patients assessed in a given year), sensitivities, specificities, and likelihood ratios were calculated. Post-test probabilities were calculated from these values. Recurrences tended to show almost the same frequencies in the first and second year after surgery (20 of 127 patients and 18 of 107 patients, respectively). However, the post-test probability of recurrence in patients with positive and negative serum CEA levels was significantly lower in the second year than in the first year (test positive: 40.0% and 76.0%; test negative: 9.3% and 0.5%, respectively). Measuring CEA can help to identify patients likely to demonstrate recurrence with high accuracy only within the first year after surgery. Another examination, such as imaging, is therefore necessary for monitoring patients at 2 or more years after surgery.

Carcinoembryonic antigen level of draining venous blood as a predictor of recurrence in colorectal cancer patient

PurposeWe designed this study to evaluate the efficacy of carcinoembryonic antigen in draining venous blood (vCEA) as a predictor of recurrence.MethodsDraining venous and supplying arterial bloods were collected separately during the operation of 82 colorectal cancer patients without distant metastasis from September 2004 to December 2006. Carcinoembryonic antigen was measured and assessed for the efficacy as a prognostic factor of recurrence using receiver operating characteristic (ROC) and Kaplan-Meier curves.ResultsvCEA is a statistically significant factor that predicts recurrence (P = 0.032) and the optimal cut-off value for vCEA from ROC curve is 8.0 ng/mL. The recurrence-free survival between patients with vCEA levels >8 ng/mL and ≤8 ng/mL significantly differed (P < 0.001). The significance of vCEA as a predictor of recurrence gets higher when limited to patients without lymph node metastasis. The proper cut-off value for vCEA is 4.0 ng/mL if confined to patients without lymph node metastasis. The recurrence-free survival between the patients of vCEA levels >4 ng/mL and ≤4 ng/mL significantly differed (P < 0.001). Multivariate analysis revealed vCEA is an independent prognostic factor in patients without lymph node metastasis.ConclusionvCEA is an independent prognostic factor of recurrence in colorectal cancer patients especially in patients without lymph node metastases.

Effects of Intraperitoneal Chemotherapy with Mitomycin C on the Prevention of Peritoneal Recurrence in Colorectal Cancer Patients with Positive Peritoneal Lavage Cytology Findings

The detection of intraperitoneal free cancer cells in colorectal cancer (CRC) patients is associated with a poorer prognosis. The aim of this study was to investigate the effects of intraperitoneal chemotherapy (IPC) with mitomycin C (MMC) on preventing peritoneal recurrence in CRC patients with positive peritoneal lavage cytology findings. A total of 52 CRC patients who had no clinically confirmed peritoneal dissemination and whose status of peritoneal lavage cytology was positive were investigated. Conventional peritoneal lavage cytology was performed. Overall, 31 of the 52 patients (59.6%) were administered IPC with MMC. Before closure of the abdomen, 4 silicon catheters were inserted into peritoneal cavity. After closure, the perfusate (diluting 20 mg MMC with 500 ml saline) was instilled from the catheter, and all catheters were clumped. All catheters were opened 1 h later. The mean follow-up period was 83.1 months. According to univariate analyses of all 52 patients and the subgroup of 36 patients with stage II or III tumors, patients with IPC had a significantly better peritoneal recurrence-free survival and cancer-specific survival than patients who did not receive IPC (P < 0.005). In multivariate analysis, IPC remained an independent prognostic factor for peritoneal recurrence-free survival in all patients. It appears that IPC with MMC is an effective treatment to prevent peritoneal recurrence and prolong the cancer-specific survival in CRC patients without peritoneal dissemination, but who have positive peritoneal lavage cytology. It is necessary to verify the effectiveness of IPC with MMC in a prospective trial.

Serum p53 Antibody as Tumor Marker for Follow-Up of Colorectal Cancer After Curative Resection

No large-scale studies have examined the use of serial measurements of serum p53 antibodies (s-p53Abs) combined with carcinoembryonic antigen (CEA) measurements during the follow-up of colorectal cancer (CRC) patients after curative resection. A highly specific enzyme-linked immunosorbent assay was used to analyze s-p53Abs levels in 305 CRC patients before and after curative resection at a single institution. Agreement between recurrence and serial s-p53Ab and CEA measurements was evaluated by diagnostic accuracy odds ratio (DOR), kappa, and area under receiver operating characteristic curve (AUC). Among 305 patients, 76 (25%) patients had disease recurrence during follow-up. None of the 168 s-p53Ab seronegative patients (s-p53Ab < 10 U/microL) without recurrence had an abnormal s-p53Ab test during follow-up. Among the remaining low-level (10 U/microL <or= s-p53Ab <or= 76 U/microL, n = 103) and high-level (s-p53Ab titer > 76 U/microL, n = 34) seropositive patients, recurrence defined by s-p53Ab tests resulted in a DOR of 4.3 and infinity, a kappa of 0.35 and 1.00, and an AUC of 0.633 [95% confidence interval (CI), 0.495 to 0.772; P = 0.047], and 1.0 (95% CI, 1.000 to 1.000; P < 0.0001), respectively. Recurrence defined by CEA tests had an AUC of 0.781 (95% CI, 0.654 to 0.909) for low-level and 0.796 (95% CI, 0.611 to 0.982) for high-level seropositive patients. Agreement between clinical recurrence and serial s-p53Ab test was dependent upon preoperative s-p53Ab level. Serial s-p53Ab testing outperformed CEA testing when predicting clinical recurrence in colorectal cancer patients with an abnormal preoperative s-p53Ab level.

Preoperative Serum Vascular Endothelial Growth Factor-A Is a Marker for Subsequent Recurrence in Colorectal Cancer Patients

Serum vascular endothelial growth factor-A has been associated with stage of disease and prognosis in colorectal cancer. In this study, the clinical usefulness of preoperative serum vascular endothelial growth factor-A concentrations in the long-term follow-up of colorectal cancer patients was evaluated. Serum vascular endothelial growth factor-A levels were determined by quantitative enzyme-linked immunosorbent assay in 93 patients prior to resection for colorectal cancer: node-negative (n = 41) and node-positive (n = 52). Median follow-up for patients without cancer death was 54 (interquartile range, 24-63.5) months. The median preoperative serum vascular endothelial growth factor-A level of these patients was 168 (interquartile range, 48-414) pg/ml. Seven patients had local recurrences with a median time of 6 (interquartile range, 4-12) months. Patients (n = 17) that developed metastasis had a median time of 17 (interquartile range, 7-42) months. Patients with local recurrence had significantly higher levels of serum vascular endothelial growth factor-A (P = 0.01). By classifying the patients into two groups, using the maximal chi-squared value of the Cox's regression based on our previous work, it was found that a serum vascular endothelial growth factor-A level >575 pg/ml is an independent prognostic factor for predicting tumor recurrence. Patients with colorectal cancer who have preoperative serum vascular endothelial growth factor-A levels >575 pg/ml are more likely to develop recurrence. Trials are warranted to investigate the efficacy of adjuvant therapy for this high-risk group.

Double primary malignancy in colorectal cancer patients—MSI is the useful marker for predicting double primary tumors

The incidence of double primary malignancies (DPM) is known to be higher in colorectal cancer patients than the general population. And, the role of microsatellite instability (MSI) in DPM has been previously studied. We evaluated the clinical features and association between MSI and colorectal cancer patients with DPM. From September 1994 to May 2004, we reviewed 2,301 colorectal cancer patients with regard to secondary primary malignancies. A subgroup analysis was performed for MSI after January 2003. One hundred forty-five patients (6.3%) had a DPM identified. In DPM group, 57 patients had a synchronous DPM (39.3%), and 88 patients had a metachronous malignancy (60.7%). Male gender (p<0.001) and colon cancer (p<0.001) were the factors related with the development of the DPM. Most of the second malignancies occurred within 3 years after the primary operation. The common second malignancies were stomach (58 patients, 40%) and lung (21 patients, 14.5%). In the subgroup analysis, there was a higher frequency of DPM in the MSI group when compared to the microsatellite stable group (p=0.021). The careful pre- and postoperative evaluation should be paid for detecting DPM as well as for detecting recurrence in colorectal cancer patients. The results of this study suggest that MSI might be a useful marker for the detection of DPM in colorectal cancer patients.

Expression of the hMLH1 gene is a possible predictor for the clinical response to 5-fluorouracil after a surgical resection in colorectal cancer

The loss of a DNA mismatch repair occurs in approximately 15% of sporadic colorectal cancer (CRC) and is usually caused by the lack of expression of the hMLH1 gene due to promoter methylation. Despite undergoing adjuvant 5-fluorouracil (5-FU) therapy after a curative surgical resection, some patients with advanced-stage CRC develop recurrence. In the present study, we investigated whether the hMLH1 mRNA expression or promoter methylation is a prognostic factor in CRC patients treated with adjuvant 5-FU. The hMLH1 mRNA expression levels were measured by quantitative reverse transcription PCR in cancer and normal epithelial cells that were obtained from 94 CRC patients using a laser capture microdissection. Then, the methylation status of the hMLH1 promoter in the CRC tissues was examined by methylation-specific PCR. The hMLH1 mRNA expression levels were significantly lower in the cancer cells than in the normal mucosa (p<0.01) and the hMLH1 mRNA expression levels in the cancer cells were significantly lower in the CRC tissues with methylated versus unmethylated hMLH1 (p<0.01) in the 94 patients. Among the 35 patients receiving adjuvant 5-FU, the disease-free survival rate was significantly better in the patients demonstrating a low hMLH1 mRNA expression in the cancer cells in comparison to that of the patients with a high hMLH1 mRNA expression (p<0.01). Moreover, a multivariate analysis revealed that hMLH1 mRNA expression was a significant independent prognostic factor for tumor recurrence in CRC patients treated with adjuvant 5-FU. However, hMLH1 methylation was not correlated with the survival in these 35 patients. These data suggest that the hMLH1 mRNA quantitation in colorectal cancer cells may be helpful for evaluating the prognosis of CRC patients receiving 5-FU-based adjuvant chemotherapy after a surgical resection.

Rapid genetic diagnosis with transcription-reverse transcription concerted reaction system for peritoneal recurrence and survival in colorectal cancer patients

The prediction of peritoneal recurrence in colorectal cancer patients is required for improvement of prognosis. In this study, we focused on establishing a novel rapid RNA direct amplification system with transcription-reverse transcription concerted reaction (TRC) to detect carcinoembryonic antigen (CEA) mRNA in peritoneal washings, and its usefulness as a prophylactic tool for peritoneal recurrence and survival in patients with colorectal cancer. Peritoneal washes were obtained from 161 patients with colorectal cancer during laparotomy. CEA mRNA and porphobilinogen deaminase (PBGD) mRNA levels of peritoneal washes were detected using the TRC method. Genetic detection in the CEA mRNA of peritoneal washes by TRC showed a significant correlation to the depth of invasion, lymphatic invasion, venous invasion, lymph node metastasis, peritoneal dissemination and stage. The overall survival and peritoneal recurrence-free survival rates of CEA mRNA-positive patients were significantly poorer than those of marker gene-negative patients. CEA mRNA levels in peritoneal washes were a significant independent prognostic factor for overall survival and peritoneal recurrence-free survival. In conclusion, our study demonstrated that the detection of CEA mRNA in peritoneal washings by TRC is a useful, rapid genetic diagnosis for the prediction of peritoneal recurrence and survival in patients with colorectal cancer.

Comparative analysis of intraperitoneal minimal free cancer cells between colorectal and gastric cancer patients using quantitative RT-PCR: possible reason for rare peritoneal recurrence in colorectal cancer

Peritoneal recurrence has a much lower incidence in colorectal cancer (CRC) patients than gastric cancer (GC) patients. The aim of this study is to clarify the reason for the rare peritoneal recurrence in CRC as compared with GC. The incidence and the abundance of free tumor cells in the peritoneal lavages from 102 CRC and 126 GC patients who underwent curative surgery were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) with carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) as genetic markers. Prognostic significance of CEA and CK20 mRNA was also compared between CRC and GC after 2 years of follow-up by Kaplan-Meyer method with overall and peritoneal recurrence-free survival as endpoints. Positivity rate and average values of CEA and CK20 mRNA in peritoneal lavages of CRC patients, which are correlated to the depth of tumor invasion (pT category), were essentially the same as those of GC cases. Overall survival was significantly (marginally) worse in CEA mRNA (CK20 mRNA)-positive CRC patients than negatives like GC. However, peritoneal recurrence-free survival was not different between CEA (CK20) mRNA-positive and -negative CRC patients, in quite contrast to GC cases. Multivariate analysis showed that CEA mRNA was an independent prognostic factor for overall survival in GC patients, but not in CRC patients. These results suggest that the rare peritoneal recurrence in CRC patients is not due to the low incidence or the small number of intraperitoneal free cancer cells, but more likely reflects due to the low-peritoneal metastatic potential of CRC cells.

Quantitative evaluation of vimentin expression in tumour stroma of colorectal cancer

Recent studies have identified vimentin, a type III intermediate filament, among genes differentially expressed in tumours with more invasive features, suggesting an association between vimentin and tumour progression. The aim of this study, was to investigate whether vimentin expression in colon cancer tissue is of clinical relevance. We performed immunostaining in 142 colorectal cancer (CRC) samples and quantified the amount of vimentin expression using computer-assisted image analysis. Vimentin expression in the tumour stroma of CRC was associated with shorter survival. Overall survival in the high vimentin expression group was 71.2% compared with 90.4% in the low-expression group (P=0.002), whereas disease-free survival for the high-expression group was 62.7% compared with 86.7% for the low-expression group (P=0.001). Furthermore, the prognostic power of vimentin for disease recurrence was maintained in both stage II and III CRC. Multivariate analysis suggested that vimentin was a better prognostic indicator for disease recurrence (risk ratio=3.5) than the widely used lymph node status (risk ratio=2.2). Vimentin expression in the tumour stroma may reflect a higher malignant potential of the tumour and may be a useful predictive marker for disease recurrence in CRC patients.

Fraction of LOH on chromosome 17 and 18 (LOH-ratio) predicts colorectal cancer outcome

20114 Background: Identification of patients at high risk for recurrence remains a central issue in the treatment of colorectal cancer. Our goal was to identify predictive factors for recurrence in colorectal cancer patients. Methods: DNA from 84 colorectal cancers were analyzed for wide-ranging allelotyping. Using 27 microsatellite markers spanning every 10cM on chromosome 17 and 18, we defined the LOH-ratio as the proportion of markers which show LOH out of 27 markers. Tumors were grouped into two groups by the median value of LOH-ratio (0.19). Recurrence free survival was compared with Kaplan-Meier analysis and log rank statistic. The Cox proportional hazards regression model was used for both univariate and multivariate analysis of recurrence free survival. Results: Log rank statistic revealed that LOH-ratio, stage, lymph node metastasis significantly related to recurrence free survival. On univariate analysis, significant predictors of Recurrence free survival were LOH-ratio, lymph node metastasis, Dukes’ classification, and pathological type. On multivariate analysis, LOH-ratio (HR 3.1, p = 0.02) and lymph node metastasis (HR 5.2, p = 0.002) independently predicted for recurrence free survival. Conclusions: LOH-ratio and lymph node metastasis were the only independent predictors of recurrence free survival. Altogether with lymph node metastasis, LOH-ratio could help to improve postoperative surveillance and adjuvant therapy. No significant financial relationships to disclose.

Hepatic arterial infusion alternating with systemic chemotherapy in patients with non‐resectable hepatic metastases from colorectal cancer

Hepatic arterial infusion (HAI) chemotherapy has a number of limitations, including a low rate of complete response and frequent extrahepatic recurrence, in colorectal cancer patients with non-resectable hepatic metastases. Twenty-nine colorectal cancer patients with non-resectable hepatic metastases were consecutively enrolled for HAI alternating with systemic chemotherapy (HA + SC group). The protocol comprised six cycles of alternating HAI (5-FU + leucovorin for 14 days, and mitomycin C on the first day) and systemic chemotherapy (5-FU + leucovorin). Colorectal cancer patients with two or more hepatic metastases treated using hepatic resection and systemic chemotherapy (HR + SC group) were selected as a comparative group. Within the HA + SC group, complete response was achieved in eight patients (28%), whereas 13 patients (45%) showed progressive disease. Six of the eight patients with complete response lived for more than 38 months. Extrahepatic recurrences were more frequent in the HR + SC group than the HA + SC group (47 vs 21%, P = 0.024). The two groups did not differ with respect to overall and hepatic progression-free survival (P = 0.947 and 0.444, respectively), displaying median +/- SE values of 38 +/- 7 and 20 +/- 3 months in the HA + SC group, and 39 +/- 9 and 33 +/- 14 months in the HR + SC group, respectively. One patient in each group experienced toxic hepatitis, and sclerosing cholangitis occurred in one patient of the HA + SC group. Other complications were mostly grade 1 or 2. HAI alternating with systemic chemotherapy led to a promising response and hepatic progression-free survival, possibly reducing extrahepatic recurrence in colorectal cancer patients with non-resectable liver metastases.

FGD-PET in the follow-up of recurrent colorectal cancer.

The current methods of detection of recurrent colorectal cancer after surgical treatment are inaccurate using conventional imaging. This study set out to detect early recurrence by means of PET in patients treated surgically for colorectal cancer by curative resection. Thirty-one disease-free patients were recruited and underwent FDG-PET. The results were verified by clinical, surgical and radiological follow up and/or biopsy to evaluate the accuracy for detecting recurrence. PET detected 6 sites of increased activity in 5 patients. Three of these underwent surgery. One was false positive with no evident tumour and two underwent an hepatic resection with removal of a homental metastasis. The sensitivity was 100% and specificity 83.3%. Clinical management was altered in two cases (6.4%). This study demonstrates that PET is more accurate than conventional imaging for the evaluation of recurrence in colorectal cancer patients. FDG-PET should be considered in the follow-up of patients after treatment for colorectal cancer in addition to other imaging methods.