Resected Colorectal Cancer Patients Research Articles

GPR48, a poor prognostic factor, promotes tumor metastasis and activates β-catenin/TCF signaling in colorectal cancer

G-protein-coupled receptor 48 (GPR48) is an orphan receptor belonging to the G-protein-coupled receptors family, which plays an important role in the development of various organs and cancer development and progression such as gastric cancer and colorectal cancer (CRC). However, the prognostic value of GPR48 expression in patients with CRC has not been reported. In this study, we observed that GPR48 was overexpressed in primary CRC and metastatic lymph nodes and closely correlated with tumor invasion and metastasis. Multivariate analysis indicated that high GPR48 expression was a poor prognostic factor for overall survival in CRC patients. In vitro and in vivo assays demonstrated that enforced expression of GPR48 contributed to enhance migration and invasion of cancer cells and tumor metastasis. In addition, we found that GPR48 increased nuclear β-catenin accumulation, T-cell factor 4 (TCF4) transcription activity, and expression of its target genes including Cyclin D1 and c-Myc in CRC cells. Correlation analysis showed that GPR48 expression in CRC tissues was positively associated with β-catenin expression. Upregulation of GPR48 resulted in increased phosphorylation of glycogen synthase kinase 3β, Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) in CRC cells, while inhibition of PI3K/Akt and mitogen-activated protein kinase /ERK1/2 pathways was sufficient to abolish the effect of GPR48 on β-catenin/TCF signaling. Taken together, GPR48 could serve as both a prognostic biomarker and a therapeutic target for resectable CRC patients.

Prognostic associations of preoperative plasma levels of fibrinogen and D-dimer after curative resection in patients with colorectal cancer

To explore the associations of preoperative plasma levels of fibrinogen and D-dimer with clinicopathologic parameters and overall survival in colorectal cancer patients after curative resection. From January 2002 to December 2003, a total of 341 colorectal cancer patients underwent curative resection. And their relevant clinical data were reviewed. The median age was 58 years (range: 23 - 90 years) and the median follow-up period was 64 months (range: 5 - 89 months). The preoperative plasma levels of fibrinogen and D-dimer were examined, the correlation of clinicopathologic findings and overall survival was analyzed. A Log-rank test was used for univariate analysis and a Cox regression model for multivariate analysis. The preoperative plasma levels of fibrinogen and D-dimer were (3.7 ± 0.7) g/L and (0.49 ± 0.18) mg/L respectively. Elevated plasma levels of fibrinogen were associated with advanced tumor stage (P = 0.008), venous invasion (P = 0.006), postoperative distant metastases (P < 0.01) and lymph node involvement (P = 0.001), but not with histologic grade (P = 0.232), and invasion depth (P = 0.253). The overall survival is 64.5% (220/341). Elevated plasma levels of D-dimer were associated with advanced tumor stage (P = 0.013), invasion depth (P = 0.007) and lymph node involvement (P = 0.001), but not with histologic grade (P = 0.082), venous invasion (P = 0.746) or postoperative distant metastases (P = 0.131). Multivariate analysis showed that preoperative plasma levels of fibrinogen (P = 0.029), histologic grade (P = 0.001), and lymph node involvement (P = 0.001) were independent prognostic factors. High preoperative plasma levels of fibrinogen and D-dimer are associated with clinicopathologic parameters. And a high preoperative plasma level of fibrinogen is associated with distant metastases and poor prognosis after curative resection in colorectal cancer patients.

Tumor cancer stem cell genetic profile as predictor of relapse in stage II and III radically resected colon cancer patients.

429 Background: Although disease stage is the most relevant factor influencing treatment choice in locally advanced radically resected colon cancer, it is not uncommon to observe disease relapse in patients with apparent low risk stage that are usually excluded from an adjuvant therapy. On the contrary we also know that some patients with high risk stage are not likely to relapse, independently from medical treatment received. Preclinical data suggested that cancer stem cells may influence the biological behaviour of many solid tumours including colorectal cancer, we then tested a panel of genetic markers of stemness in resected Dukes stage B and C colorectal cancer patients in order to define a prognostic profile. Methods: We performed k-means unsupervised clustering (K=2) using the mRNA expression data of 66 genes. The algorithm divided the patients into two groups (A and B). Most patients clustered in a manner consistent with relapse free survival, defined as the time between primary surgery and first radiological sign of metastatic involvement or patients death, whichever came first. Results: A total of 62 patients were analysed (36, 58% stage II and 26, 41% stage III), 36 (58%) patients relapsed during the follow-up period (range 1.63-86.5 months). Respectively 12 (19%) and 50 (81%) patients were allocated into group A and B. A significantly different median relapse-free survival was observed between the 2 groups (22.18 vs 42.85 months, p=0.0296). Interestingly, even if group A had a worse outcome in terms of risk of relapse, an higher proportion of stage II patients could be found in this group (83%) when compared with the group B (52%). Among tested genes, those with the highest capability in determining allocation into one of the two groups were CD44, ALCAM, DTX2, HSPA9, CCNA2, PDX1, MYST1, COL1A1 and ABCG2. Conclusions: This analysis supports the idea that, other than (or maybe more than) stage, biological variables, such as expression levels of colon cancer stem cell genes, may be relevant in determining an increased risk of relapse in resected colorectal cancer patients. Our findings may also be relevant for new treatment strategies targeting tumour stem cells genetic profile.

Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant Folfox IV

Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40 % of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration. One hundred sixty-nine completely resected colorectal cancer patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcaemia, hypomagnesaemia, hypoalbuminaemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, vitamin B(12) deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded. Incidence of neuropathy was found to be higher in patients with pre-treatment anaemia (p = 0.001), hypoalbuminaemia (p = 0.01) and hypomagnesaemia (p = 0.001) as well in those with habit to alcohol consumption (p = 0.003). Neuropathy durations were conversely associated with age, being longer in younger patients (p = 0.03), and again with hypoalbuminaemia (p = 0.04) and hypomagnesaemia (p = 0.002). No correlation was found with gender, hypocalcaemia, diabetes and CRF. The correlation between vitamin B(12) and folate levels and the development of neurotoxicity were not analysed because of the high number of missing data in the population. Age, anaemia, hypoalbuminaemia, hypomagnesaemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin-induced neuropathy.

215P - Cancer Stem Cell Genetic Profile as Predictor of Relapse in Radically Resected Colorectal Cancer

ABSTRACT Although disease stage is the most relevant factor influencing treatment choice in locally advanced radically resected colorectal cancer, it is not uncommon to observe disease relapse in patients with apparent low risk stage that are usually excluded from an adjuvant therapy. On the contrary we also know that some patients with high risk stage are not likely to relapse independently from medical treatment received. Preclinical data suggested that cancer stem cells may influence the biological behaviour of many solid tumours including colorectal cancer. We tested a panel of genetic markers of stemness in resected Dukes stage B and C colorectal cancer and their impact on prognosis. We performed k-means unsupervised clustering (K = 2) using the mRNA expression data of 66 genes. The algorithm divided the patients into two groups (A and B) and most of the patients clustered in a manner consistent with relapse free survival, defined as the time between primary surgery and first radiological sign of metastatic involvement or patients death, whichever came first. A total of 62 patients were analysed (46, 74% stage II and 16, 26% stage III), 36 (58%) patients relapsed during the follow-up period (range 1.63-86.5 months). Respectively 12 (19%) and 50 (81%) patients were allocated into group A and B. A significantly different median relapse-free survival was observed between the 2 groups (22.18 vs 42.85 months, p = 0.0296). Interestingly enough, even if group A had a worse outcome in terms of risk of relapse, an higher percentage of stage II patients could be found in this group (83%) when compared with the group B (52%). Among of all genes tested, those with the higher “weight” in determining allocation into one of the two groups were CD44, ALCAM, DTX2, HSPA9, CCNA2, PDX1, MYST1, COL1A1 and ABCG2. This analysis supports the idea that, other than (or maybe more than) stage, biological variables, such as expression levels of colon cancer stem cell genes, may be relevant in determining an increased risk of relapse in resected colorectal cancer patients. Disclosure All authors have declared no conflicts of interest.

FOLFIRI plus bevacizumab (B) as neoadjuvant treatment for potentially resectable colorectal cancer patients (pts) with liver metastasis: A phase II trial.

e14130 Background: Irinotecan-based chemotherapy plus B was shown to be effective and safe in both first- and second-line treatment for metastatic colorectal cancer (mCRC) pts.We designed this trial to assess whether the combination of FOLFIRI + B given to untreated, potentially resectable mCRC pts was feasible and active. Methods: Phase II, single arm trial with 1-year progression-free rate (PFR) as primary end-point. A sample size of 39 pts was calculated to detect a 70% ± 12% 1-year PFR. The treatment was FOLFIRI q2w (irinotecan 180 mg/m2, leucovorin 200 mg/m2, 5FU 2400 mg/m2 iv in 46 hrs) plus B 5mg/kg q2w. Last cycle before surgery was without B. Potentially resectable, untreated mCRC pts, with liver as unique site of metastases, were eligible. Normal organ function and no contraindications to B were required. Pts were reevaluated for surgery after 6 cycles. PET-Scan were performed at baseline and at the second cycle. Results: Overall 39 pts were enrolled. Median age was 58 (range 30-75), male/female were 24/15. Twenty seven pts (69.2%; 95%CI 52.4% – 83.0%) were progression-free at 1-year. Thirty seven pts (94.9%) underwent surgery. One complete and 22 partial responses were observed (response rate 59.0%; 95% CI 42.1% – 74.4%); 5 pts had disease progression (4 resectable and 1 unresectable). Early PET-scan was assessed according PERCIST criteria [Wahl RL, J Nucl Med 2009] in 29 pts and showed metabolic response (SUV-max decrease &gt; 30%) in 17 (58.6%; 95% CI: 38.9%- 76.5%).Severe toxicity includes grade 3 neutropenia (3 pts, 7.7%) and grade 3 diarrhea (1 pt, 2.6%). Other toxicities include grade 1-2 diarrhea (15.4%), grade 2 nausea (7.8%), grade 2 leucopenia (5.1%), grade 2 asthenia (5.1%), grade 1 anemia (2.6%), grade 2 thrombosis (2.6%). Overall, 16 pts out of 37 experienced surgical complications (43.2%; 95%CI 27.1% - 60.5%): biliary leak (11 pts, 29.7%), biliary fistula (1 pt, 2.7%), other complications (4 pts, 10.8%). All complications were reversible. No peri-operative bleeding was observed. Conclusions: The trial yielded its primary aim and shows that FOLFIRI plus B is feasible and active as neo-adjuvant treatment in patients with resectable liver metastases of CRC.

The use of multiple molecular markers as predictors of the clinical prognosis of patients with colorectal cancer

Serum carcinoembryonic antigen (CEA) is most commonly used as a prognostic biomarker for evaluating curatively resected colorectal cancer (CRC) patients, but it has a low sensitivity and specificity. The aim of this study was to evaluate potential genetic markers in CRC patients using membrane array. Fifty CRC patients were enrolled and mRNA expression in their tissues were analyzed using membrane array analysis. Seven genes were analyzed in this study, including ATP2A2, GLUT1, MMP13, MAGE-A2, MAGE-A7, MAGE-A8, and MAGE-A12. Correlations between the results of the membrane array and the clinicopathological features of these CRC patients were then evaluated. The results show that the overexpression of any three or four of these seven genes is correlated with tumor invasion depth, lymphatic invasion, advanced stage, and postoperative recurrence (all p < 0.005). Furthermore, the expression of any four genes was more significantly correlated with clinicopathological characteristics than the expression of only two or three genes. The combination of multiple molecular markers and the membrane array method might be useful for predicting postoperative relapse in CRC patients.

Evaluation of the necessity of primary tumor resection for synchronous metastatic colorectal cancer.

592 Background: Recent advances in chemotherapy have improved survival in patients with metastatic colorectal cancer. Resection of primary tumor for patients with metastatic colorectal cancer remains controversial. Primary tumor with obstruction or bleeding may be recommended to resection pior to chemotherapy. In contrast, it should be considered potential complications associated with resection of primary tumor and disadvantage of the delay in chemotherapy. Here, we evaluate the needs of primary tumor resection for colorectal cancer patients with synchronous metastases. Methods: A retrospective analysis of patients with synchronous metastatic colorectal cancer treated at Kumamoto University Hospital between April, 2005 and December, 2009 was performed. We compared the survival of resected patients and non-resected patients. Results: 104 patients were identified. Sixty-four and 40 patients were included in the resected group and the non-resected group respectively. The mean follow-up time was 16.1 months. Median age was 61.9 and 64.3 years respectively. The non-resected group was more likely to have right-sided tumors (resected: 28%, non-resected: 43%). The number of patient with metastatic disease limited to the liver was similar in both group(resected: 48%, non-resected: 50%). In the resected group, 12 patients (18%) developed postoperative complications. In the nonresected group, 5 patients (12.5%) required creation of a diverting colostomy during the course of their treatment due to obstruction, and 2 patients (5%) required emergency surgical treatment for intestinal perforation due to the primary tumor. No significant difference in survival was observed between the groups, (logrank P=0.33). Median survival period was not significantly different (resected: 27.3 months, non-resected: 21.5 months, P=0.43). Conclusions: We concluded that it was not necessary to resect the primary lesion in patients with synchronous metastatic colorectal cancer when obstruction or bleeding was not found in primary lesions.

Potentially functional genetic variants in KDR gene as prognostic markers in patients with resected colorectal cancer

Angiogenesis plays a key role in the development and treatment response of various tumors. The signaling transductions mediated by the binding of vascular endothelial growth factor (VEGF) to its receptor KDR (kinase insert domain receptor) is the most important pathway in tumor angiogenesis. Single nucleotide polymorphisms (SNPs) in VEGF have been extensively implicated in the etiology and treatment outcome of colorectal cancer (CRC). However, no study has been reported evaluating the role of KDR SNPs in CRC prognosis. We herein assessed the association between four potentially functional KDR SNPs and tumor recurrence in a Chinese population with 408 surgically resected CRC patients. The most significant SNP was for rs10013228 located in the KDR gene promoter. Compared with the homozygous wild-type genotype, the variant-containing genotypes of this SNP were significantly associated with a reduced recurrence risk with a hazard ratio (HR) of 0.53 (95% confidence interval [CI] 0.30-0.95, P = 0.032). Moreover, a borderline significant association was noted for another promoter SNP, rs2071559, with an HR of 0.67 (95% CI 0.42-1.07, P = 0.092). In stratified analysis, the associations of both SNPs were more prominent in patients receiving chemotherapy (HR = 0.47, 95% CI 0.23-0.94, P = 0.033 for rs10013228 and HR = 0.55, 95% CI 0.32-0.95, P = 0.032 for rs2071559). Further analysis revealed a protective effect on patient recurrence by chemotherapy (HR = 0.56, 95% CI 0.32-1.01, P = 0.046), which was more evident in patients with the variant-containing genotypes of each of the two SNPs (HR = 0.09, 95% CI 0.02-0.55, P = 0.009 for rs10013228 and HR = 0.39, 95% CI 0.18-0.86, P = 0.020 for rs2071559). Collectively, our findings suggest SNPs in the KDR gene modulate CRC recurrence, especially in those receiving chemotherapy.

Short-term Outcomes of Laparoscopic Colonic Resection in Colorectal Cancer Patients Older than 80 Years of Age

Purpose : The safety and feasibility of laparoscopic colonic resection in elderly colorectal cancer patients remains to be verified. The aim of this study was to determine the safety and feasibility of laparoscopic colonic resection compared to open colonic resection for colorectal cancer in patients older than 80 years of age. Methods : One hundred ninety two patients older than 80 years of age underwent curative resection for colorectal cancer. Twenty-four (12.4%) patients who had been operated by laparoscopic surgery were compared with 168 (87.6%) patients who had undergone open colonic resection. Results : The mean age of the 192 patients was 81.9 years. The postoperative complication and mortality were 17.1% and 1.5%, respectively. The preoperative clinical parameters were similar between the two groups. The surgery time was longer in the laparoscopic group, but not significantly. The intraoperative blood loss was less in the laparoscopic group (p=0.025). The major postoperative complications in the laparoscopic group and the open groups were significantly different (0% vs 19.0%, p=0.018). There was no postoperative mortality in the laparoscopic group, but 3 cases (1.7%) of mortality were seen in the open group (p=0.594). Conclusion : Laparoscopic colonic resection in elderly colorectal cancer patients is safe and feasible. Therefore, laparoscopic colonic resection can be recommended as an alternative treatment for colorectal cancer in patients over 80 years of age.

Functional polymorphisms of circadian positive feedback regulation genes and clinical outcome of Chinese patients with resected colorectal cancer

Previous studies have demonstrated that circadian genes play a role in the development and progression of many cancers. This study aims to assess the effects of single nucleotide polymorphisms (SNPs) in circadian genes on recurrence and survival of colorectal cancer (CRC) patients. Nine functional SNPs in 3 genes (CLOCK, NPAS2, and BMAL1) on the circadian positive feedback loop were selected and genotyped using the Sequenom iPLEX genotyping system in a cohort of 411 resected Chinese CRC patients. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis. The authors identified 2 SNPs in the CLOCK gene to be significantly associated with CRC overall survival. SNP rs3749474 exhibited a significant association with survival of CRC patients in the additive model (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.37-0.81; P = .003). In addition, patients carrying the heterozygous variant of rs1801260 had significantly increased overall survival compared with those carrying homozygous wild-type genotype (HR, 0.31; 95% CI, 0.11-0.88; P = .03). Findings from functional assay provided further biological support for these significant associations. Stratified analysis found no modifying effect of chemotherapy on the prognostic significance of both SNPs. Moreover, we observed cumulative effects of these 2 SNPs on CRC overall survival (P for trend = .01). Compared with patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 2.92-fold increased risk of death (P = .03). The results suggest for the first time that CLOCK gene polymorphisms may serve as an independent prognostic marker for CRC patients.

Resected colorectal cancer patients: what is best form of follow-up treatment?

Resected colorectal cancer patients: what is best form of follow-up treatment?

Tumour CD133 mRNA expression and clinical outcome in surgically resected colorectal cancer patients

Background Human prominin-1 (CD133) is a novel pentaspan membrane protein which was originally classified as a marker of primitive haematopoietic and neural stem cells. Cancer stem cells have been isolated and expanded from leukaemia and several solid tumours, and have been associated with metastasis, chemoresistance and relapse. CD133 is recognised as a stem cell marker and is capable of identifying a tumour-initiating subpopulation in brain, colon, melanoma and other solid tumours. Methods We assessed CD133 mRNA expression levels by RT-QPCR in tumour and matched normal tissue from 64 stages I–III colorectal cancer (CRC) patients and correlated tumour CD133 levels with clinicopathological characteristics and clinical outcome. Results In four patients, CD133 mRNA was not expressed in tumour or in normal tissue. In the remaining 60 patients, expression levels were higher in tumour than in normal tissue ( p = 0.001). Higher levels of CD133 expression were associated with shorter relapse-free interval (RFI) ( p = 0.004) and overall survival (OS) ( p < 0.0001). In the multivariate analyses, CD133 levels emerged as a prognostic marker for RFI and OS. Conclusions We have observed longer RFI and OS in patients with lower levels of CD133, regardless of adjuvant treatment and other clinical characteristics. If these findings are confirmed in larger prospective studies, CD133 assessment may prove useful for new diagnostic and therapeutic procedures for CRC patients.

Exactitude of Relative Survival Compared with Cause-Specific Survival and Competing Risk Estimations Based on a Clinical Database of Patients with Colorectal Carcinoma

Relative survival estimates are widely used by cancer registries. They provide survival rates adjusted for causes of death other than cancer. They have rarely been used in clinical settings. When compared with cause-specific survival rates or competing risks analysis, their applicability is hardly known. This study compares these three outcome measures on the basis of a well-documented clinical database of patients with colorectal cancer. We selected a consecutive series of 1,791 histopathologically completely resected colorectal cancer patients without neoadjuvant therapy from a prospective database from 1981 through 2006. Median follow-up was 4.7 (range, 0-23) years with only 3.1% patients lost. Cause-specific and relative survival are reported as failure rates as is the cumulative incidence in the presence of competing risks. The analysis comprised 1,081 patients with colon cancer and 710 patients with rectal cancer. Stage distribution was as follows: Stage I, 480 patients; Stage II, 785 patients; Stage III, 472 patients; and Stage IV, 54 patients. The "cause-specific" failure rate, the "relative" failure rate, and the cumulative incidence in the presence of competing risks at five years (95% CI) for all patients were 21.1 (range, 19.0-23.4) %, 22.5 (range, 19.6-25.2) %, and 19.0 (range, 17.0-20.9) %, respectively. Because we could demonstrate almost identical failure rates, we consider relative survival to be a powerful tool in clinical settings in which a comprehensive follow-up is not possible. It is especially useful as a reference parameter for clinical audit.

Evaluation of the individual 50% inhibitory area under the concentration curve of 5-fluorouracil based on the collagen gel droplet embedded culture drug sensitivity test in colorectal cancer

We have previously reported the 5-fluorouracil (5-FU) sensitivity of cancer cells from colorectal cancer (CRC) patients using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) under multiple drug concentrations and contact durations. Moreover, the area under the concentration curve (AUC) and growth inhibition rate (IR) were combined, resulting in the AUC-IR curve, which was approximated to the logarithmic curve. In the present study, we used the AUC-IR curve to calculate the individualized AUCIR50, the AUC value that imparts 50% growth inhibition. Individual AUCIR50 was calculated in CRC patients, and its distribution was evaluated. The cumulative distribution of individual AUCIR50 was regressed over two lines (logarithmic scale). Among the 45 resectable CRC patients, those who achieved more than the individual AUCIR50 during post-operative 5-FU-based chemotherapy demonstrated a trend towards better disease-free survival compared to those who did not achieve AUCIR50. Of the Dukes' D patients (n=10), those who achieved more than twice the individual AUCIR50 during post-operative 5-FU-based chemotherapy demonstrated significantly better survival rates (p=0.05) than those who did not. In this study, the distribution of the individual AUCIR50 suggested that approximately 6% of patients demonstrated very low 5-FU sensitivity. Therefore, the individual AUCIR50 was useful in classifying good, intermediate and poor 5-FU response. Achievement of the individual AUCIR50 may be a prerequisite for individualized 5-FU-based adjuvant chemotherapy. As well, the early achievement of twice the individual AUCIR50 may indicate an improved prognosis in Dukes' D patients. The individual AUCIR50 using CD-DST is useful in determining the individualized chemotherapy of CRC patients, thus CD-DST has the potential to facilitate the establishment of individualized chemotherapy for CRC.

Bevacizumab-Related Surgical Site Complication Despite Primary Tumor Resection in Colorectal Cancer Patients

Combining conventional systemic chemotherapy with the angiogenesis inhibitor bevacizumab is now recommended as a first treatment for metastatic colorectal neoplasms. The risk for short-term postoperative complications related to bevacizumab has been assessed. Late postoperative complications related to bevacizumab have also been suggested by preliminary reports. We reviewed a cohort of 142 patients with previous surgery for primary colonic or rectal tumor and without evidence of local recurrence, receiving bevacizumab for metastatic disease. Four patients experienced a late surgical site complication related to bevacizumab. Common features were rectal location, low anastomosis, and preoperative irradiation. Combining these three factors, the risk of a bevacizumab-related complication was 4 in 27 (14.8%); if previous history of postoperative leakage was reported, the risk was raised to 2 in 4. No complications occurred in colonic location or the non-irradiated patients. The mechanism of these complications could be ischemic lesion in post-irradiated tissues involving anastomoses. We conclude that angiogenesis inhibitors should be carefully considered for patients having low colorectal anastomosis and previous irradiation.

Sialyl Lewis X Expression and Lymphatic Microvessel Density in Primary Tumors of Node-negative Colorectal Cancer Patients Predict Disease Recurrence

Up to 30% of curatively resected colorectal cancer patients with tumor-negative lymph nodes, show disease recurrence. We assessed whether these high-risk patients can be identified by examining primary tumors for the following blood and lymphatic vasculature markers: A) sialyl Lewis X (sLeX), vascular endothelial growth factor (VEGF)-C and VEGF-D expression; B) blood and lymphatic microvessel density (BMVD/LMVD); and C) the presence of blood and lymphatic vessel invasion. Thirty-six cases (disease recurrence within 5 years) and 72 controls (no disease recurrence for at least 5 years) were selected in a case-control design. Tumor sections were stained by antibodies CSLEX1 (sLeX), anti-VEGF-C, anti-VEGF-D, anti-CD31 (BMVD) or D2–40 (LMVD) to determine the parameters as mentioned above. A multivariate analysis showed sLeX expression and high LMVD (odds ratio 5.1, 95% confidence interval 1.3–20.0 and odds ratio 3.1, 95% confidence interval 1.0–10.0, respectively) to be independent factors predicting disease recurrence. Expression of sLeX correlated with liver metastases (P = 0.015). A high LMVD was related to regional intra-abdominal or intrapelvic metastases in lymph nodes and distant metastases other than in the liver and lungs such as peritoneum, bones, brain and adrenal glands (P = 0.004). A high BMVD in the invasive front correlated with lung metastases (P = 0.018). We show that high-risk node-negative colorectal cancer patients can be identified by primary tumor assessment for sLeX expression and LMVD. Our results are consistent with the notion that both lymphatic and hematogenous metastasis play a role in colorectal cancer.

Visceral Obesity May Affect Oncologic Outcome in Patients with Colorectal Cancer

Obesity is closely related to the development of colorectal cancer as well as other metabolic complications. We investigated the prognostic significance of visceral obesity and body mass index (BMI) in 161 resectable colorectal cancer patients. Ratios of visceral fat area (VFA) to subcutaneous fat area (SFA) were measured from the digital images of patients' computed tomography taken before the surgery, and patients were divided into those with high and those with low VFA/SFA ratio according to the degree of proportional visceral adiposity, and into an overweight and a normal-weight group according to their preoperative BMI. The overweight group showed a borderline decrease in cumulative disease-free survival compared to the normal-weight group (P = 0.064). Patients with high VFA/SFA ratio (more than 50 percentiles) had significantly lower cumulative disease-free survival rate compared to patients with low VFA/SFA ratio (P = 0.008). BMI and visceral adiposity showed no influence on overall survival of patients. Increased visceral adiposity was a significant predictor of disease-free survival in patients with resectable colorectal cancer. The prognostic significance of visceral adiposity should further be determined in a larger set of patients.

The validity of the Royal College of Pathologists’ colorectal cancer minimum dataset within a population

Quality of colorectal cancer pathology reports is related to individual patient prognosis and future treatment options. This study sought to validate the prognostic utility of the Royal College of Pathologists minimum pathology dataset (MPD), regarded as the ‘gold standard’, within a population. Retrospective study of the survival of 5947 surgically resected colorectal cancer patients for whom an MPD had been collected. Variables were related to survival. The study population was representative of the Yorkshire colorectal cancer population. Survival was poorer in older patients and colonic tumours and improved over the study period. Local invasion, total number of lymph nodes retrieved, nodal stage, extramural vascular invasion, peritoneal involvement, distance of invasion beyond the muscularis propria, and in rectal cancers, circumferential resection margin involvement and distance to this margin were all validated as of prognostic significance within a population. Failure to report extramural vascular invasion, peritoneal involvement or circumferential resection margin status was associated with a worse survival than absence of the factor. All variables within the Royal College of Pathologists MPD are of prognostic significance. High-quality pathology reports are essential in providing accurate prognostic information and guiding optimal patient management.

Serum p53 antibodies is a postoperative predictive biomarker after curative resection in colorectal cancer patients

14567 Background: Because alternations of the p53 tumor suppressor gene are the most commonly observed and can occur early in the carcinogenic process, the accumulation of mutant p53 often leads to the production of p53 antibodies in the sera. The aim of this study is to evaluate the clinical usefullness as early detection marker and as a predictive biomarker of serum p53 antibodies in primary colorectal cancer. Methods: Serum samples are obtained before treatment and from time to time postoperatively and stored - 800C until assay. We employed the newly produced quantitative p53 antibodies ELISA Kit (MESACUP anti-p53 Test, MBL, Japan) to determine the presence of p53 antibodies in 311 patients with colorectal adenocarcinoma compared with the conventional two markers of CEA and CA19–9. Post operative clinical course and the long time survival were evaluated in sero-positive patients after resection. Results: The sensitivities of serum p53 antibodies, CEA and CA19–9 were 32.9%, 36.0% and 23.1%, almost equivalent to CEA and significantly higher than CA19–9. No obvious correlations were evident between the status of serum p53 antibodies and values of two markers, resulting in independent of the other markers. The sensitivity rate of CEA turned up as promotion of pathological stage, but the presence of serum p53 antibodies was more significantly associated with stage 0,I,II. One hundred-nine patients who showed preoperatively sero-positive patients were monitored for at least one year after resection. There was a significant correlation between operative curability and postoperative absence of serum p53 antibodies. Most of repeatedly positive patients treated as curative resection developed recurrence within one year in stageIIandIII. Repeatedly detected patients for serum p53 antibodies have a significantly poor prognosis compared with changed negative patients after curative resection in stageIIandIII. Conclusions: Serum p53 antibodies is easy and convenient, non- invasive, detectable many times and not necessary for surgical specimens for assay. Surveillance of p53 antibodies is rapid and readily facilitated test, which appears to be useful as a new tool for early diagnosis and as a postoperative predictive marker for colorectal cancer patients. No significant financial relationships to disclose.