Non-metastatic Colorectal Carcinoma Research Articles

Defining early recurrence in patients with resected primary colorectal carcinoma and its respective risk factors

PurposeThere is no evidence-based definition of early recurrence following resection of colorectal cancer. The purpose of this study is to define a point that discriminates between early and late recurrence in patients who have undergone colorectal cancer resection with curative intent and to analyze associated risk factors.MethodsA retrospective single-center cohort study was performed at a university hospital recognized as a comprehensive cancer center, specializing in colorectal cancer surgery. Patient data were retrieved from a prospectively maintained institutional database. Included patients underwent resection for primary, non-metastatic colorectal carcinomas with curative intent between 1995 and 2010. Aims of the study were (1) to define the optimal cut-off point of recurrence-free survival based on overall survival using a minimum p value approach and (2) to identify patterns of initial recurrence and putative risk factors for early recurrence using regression models.ResultsRecurrence was diagnosed in 412 of 1893 patients. Statistical analysis suggested that a recurrence-free survival of 16 months could be used to distinguish between early and late recurrence based on overall survival (p < 0.001). Independent risk factors for early recurrence included advanced pT categories (pT3,4/ypT3,4) and positive lymph node status (pN+/ypN+). Early recurrence was independent of site of recurrence and was associated with worse prognosis.ConclusionsRecurrence of colorectal carcinoma within 16 months after primary treatment should be labeled as “early.” Tumor categories pT3,4/ypT3,4 and positive lymph node status pN+/ypN+ are predictive of early recurrence.

Realtime qRT-PCR Expression of P53, KRAS, and human Telomerase genes in circulating tumor cells, as potential biomarkers for early detection of sporadic colorectal cancer

Objectives: The objectives of present study were to investigate the potential use of mRNA of P53, KRAS, and human telomerase genes in circulating tumor cells as biomarkers for early detection of sporadic cases of colorectal cancer. Background: Inspite of colorectal cancer is a curable disease if detected early; it is still the third leading cause of death from cancer. There is an ultimate need for implementing an accurate and noninvasive screening method. The recent advances in molecular genetics have showed that the genes of P53, KRAS and human telomerase play major roles in development of colorectal cancer. Therefore the study of their expression in blood samples might be used as a mean for early detection of sporadic colorectal carcinoma cases. Methods: A case control pilot study in which 20 patients with non-metastatic colorectal carcinoma in Duke’s stages (A – C, TNM from 0 – III) and 20 healthy controls were enrolled. Expression of studied genes and the housekeeping gene Glyceraldehyde-3 phosphate dehydrogenase were determined using quantitative reverse transcriptase polymerase chain reaction. The study was performed in duplicate taking 1µg of total RNA from each sample. Results: The results showed significant overexpression of mRNAs of studies genes in samples taken from cases of proved colorectal carcinoma compared to that of controls group with a statistically significant P- value of ​

Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer

ABSTRACT Tertiary lymphoid structures (TLS) are associated with favorable outcome in non-metastatic colorectal carcinoma (nmCRC), but the dynamics of TLS maturation and its association with effective anti-tumor immune surveillance in nmCRC are unclear. Here, we hypothesized that not only the number of TLS but also their composition harbors information on recurrence risk in nmCRC. In a comprehensive molecular, tissue, laboratory, and clinical analysis of 109 patients with stage II/III nmCRC, we assessed TLS numbers and degree of maturation in surgical specimens by multi-parameter immunofluorescence of follicular dendritic cell (FDC) and germinal center (GC) markers. TLS formed in most tumors and were significantly more prevalent in highly-microsatellite-instable (MSI-H) and/or BRAF-mutant nmCRC. We could distinguish three sequential TLS maturation stages which were characterized by increasing prevalence of FDCs and mature B-cells: [1] Early TLS, composed of dense lymphocytic aggregates without FDCs, [2] Primary follicle-like TLS, having FDCs but no GC reaction, and [3] Secondary follicle-like TLS, having an active GC reaction. A simple integrated TLS immunoscore reflecting these parameters identified a large subgroup of nmCRC patients with a very low risk of recurrence independently of clinical co-variables such as ECOG performance status, age, stage, and adjuvant chemotherapy. We conclude that (1) mismatch repair and BRAF mutation status are associated with the formation of TLS in nmCRC, (2) TLS formation in nmCRC follows sequential maturation steps, culminating in germinal center formation, and (3) this maturation process harbors important prognostic information on the risk of disease recurrence.

Beclin 1 and LC3 as predictive biomarkers for metastatic colorectal carcinoma.

Autophagy is a highly conserved self-destructive process that disassembles dysfunctional or unnecessary cellular components. It plays an important role in cancer metastasis, which is of particular interest considering metastatic disease is the major cause of colorectal carcinoma (CRC) related mortality. Here, we investigated the immunohistochemical expression of autophagy-related protein Beclin 1 and Microtubule-associated protein 1A/1B-light chain 3 (LC3) within surgical CRC specimens, first in a training cohort (205 patients), then in an inner validation cohort (160 patients) and an independent cohort (161 patients). The expressions of Beclin 1 and LC3 were lower in metastatic CRC compared with non-metastatic CRC. Furthermore, we developed an autophagy-based classifier for metastatic prediction. This classifier, including Beclin 1, LC3 and carcinoembryonic antigen (CEA) level, resulted in 82.9% sensitivity and 89.8% specificity for metastatic detection in the training cohort. In the independent cohort, it achieved 77.9% sensitivity and 90.3% specificity in predicting the metastasis of CRC. These results suggested that low expression of Beclin 1 and LC3 contributed to a more aggressive cancer cell phenotype, and our autophagy-based classifier was a reliable tool for metastatic prediction in CRC.

The expression profiles of the galectin gene family in colorectal adenocarcinomas

We aim to investigate the expression profiles of galectin family genes (galectins-1, 2, 3, 4, 7, 8, 9, 10, and 11) in colorectal carcinomas. Messenger RNA (mRNA) expression of galectin family members (1, 2, 3, 4, 7, 8, 9, 10, and 12) was analyzed by real-time polymerase chain reaction in colorectal tissues from 201 patients (54 noncancer colorectal tissues, 49 adenomas, and 98 adenocarcinomas). Galectin-1 and galectin-3 protein expressions were determined by immunohistochemistry. In general, high galectin mRNA expression was noted in colorectal carcinomas in early stages of their pathogenesis. Significant differences in galectins-2, 3, 7, 8, and 10 mRNA expression were associated with pathologic stages (P<.05). Increased prevalence of galectins-2, 7, 8, and 10 mRNA overexpression was noted in nonmetastatic colorectal carcinomas (P<.05). Galectin-1 and galectin-3 proteins were present in the nucleus and cytoplasm of the colorectal tissues and expressed significantly higher in colorectal carcinomas when compared to colorectal adenomas (61% and 95%, respectively). Patients with colorectal carcinoma with high levels of galectin-3 mRNA and protein expression showed better prognosis (P=.052). To conclude, many novel correlations between the deregulation of galectin family genes and various clinicopathological features in colorectal adenocarcinoma were noted. Overexpression of galectins at the mRNA level and proteins were predominant in earlier stages of colorectal carcinomas. These altered expression patterns of galectin genes suggest the multifunctional role of galectin genes in the regulation of colorectal cancer development, progression, and metastasis.

Low-doses of sequential-kinetic-activated interferon-γ enhance the ex vivo cytotoxicity of peripheral blood natural killer cells from patients with early-stage colorectal cancer. A preliminary study

Natural killer (NK) cells are innate immune-system lymphocytes capable of killing tumor cells. They secrete cytokines, including interferon (IFN)-γ, which participate in shaping the initial inflammatory and downstream adaptive immune responses. Its potent immunoregulatory action means that IFN-γ might be beneficial in cases of tumor rejection, but its severe side-effects limit clinical applications. This pilot study compared low-dose IFN-γ prepared by sequential-kinetic-activation (SKA), with standard-dose recombinant (r) IFN-γ, in terms of ex-vivo cytotoxic activity of peripheral blood (PB)-NK cells from colorectal carcinoma (CRC) patients. This was tested against the NK-sensitive K562 cell line and the less-sensitive human CRC Caco-2 and HT-29 cell lines. Twenty primitive non-metastatic CRC patients, five metastatic CRC patients, and thirteen healthy donors were enrolled. PB lymphocytes (PBL) were exposed to medium alone, SKA-IFN-γ (0.25fg/ml) or rIFN-γ (1ng/ml). NK-cell cytolytic activity was examined via short-term (51)Cr-release. Pretreatment of PBL from non-metastatic patients with SKA-IFN-γ caused a significant increase in NK-cell cytotoxicity, compared to those from normal donors, although less markedly than pretreatment with rIFN-γ against all three cell lines. In contrast, PBL from metastatic CRC patients displayed significantly decreased NK-cell activity and responsiveness to both rIFN-γ and SKA-IFN-γ treatments. These results demonstrate in principle the immunomodulatory capacity of low-dose SKA-IFN-γ, and might open the door to the possibility of generating a novel, safe, and feasible approach to enhancing NK-cell antitumor activity in early-stage CRC patients.

Comparative proteomic analysis identifies proteins associated with the development and progression of colorectal carcinoma

To better understand the mechanism underlying colorectal carcinoma (CRC) genesis or metastasis, and to search for potential markers for CRC prognosis, a comparative proteomic analysis was performed on CRC tissue. Proteins were extracted from normal colorectal mucosa, non-metastatic CRC (nmCRC) and metastatic CRC (mCRC) tissue samples. Protein profiling of each sample was performed by two-dimensional electrophoresis coupled with MALDI-TOF MS, followed by confirmation by Western blotting. Thirty-one proteins were found to be differentially expressed between normal mucosa, nmCRC and mCRC tissue. In 126 paraffin-embedded CRC samples, three differentially expressed proteins, identified as LASP-1, S100A9 and RhoGDI by proteomic analysis, were detected by immunohistochemical staining to determine the clinicopathological characteristics of these proteins in CRC. Increased expression levels of these proteins were found in CRC, especially mCRC, compared with normal mucosa. The results provide the basis for searching for potential markers for CRC genesis and metastasis, and also provide clues for elucidating the mechanism of CRC progression. The pattern changes identified have the potential to be used for the design of marker panels for assistance in diagnostic and therapeutic strategies in CRC.

Postoperative treatment with fermented mistletoe (Viscum album L.) extract stratified by therapy regimen in patients with primary non-metastatic colorectal carcinoma

20536 Background: The therapy with fermented mistletoe extract Iscador (ISC) is a frequently used supportive treatment in colorectal carcinoma patients in Germany and Switzerland to improve quality of life (QoL) and reduce conventional therapy (CONTH)-related adverse drug reactions (ADR). Methods: In a multicenter comparative observational cohort study the efficacy and safety of ISC in supportive care of patients with colorectal carcinoma in comparison with parallel control groups were evaluated. The patients received either CONTH, CONTH with ISC, ISC only or no therapy. Unselected standardized pseudonymized data from medical records that met the eligibility criteria were followed up until the last visit or death. The pre-specified endpoints were ADR, QoL and disease-free survival (DFS). All endpoints were adjusted to confounders. Results: 804 (429 ISC and 375 control) eligible patients from 26 centers were evaluated with a median follow up of 58 vs 51 months and a median ISC therapy duration of 52 months. Significant fewer ISC than control patients developed ADR by CONTH (p<0.001). Patients with supportive ISC showed a better QoL. Results of DFS-analysis (HR=hazard ratio): see Table 1 Severe ISC-related ADR or tumor enhancement were not observed. Conclusions: These results show reliable safety and clinically relevant, independent beneficial effect of supportive ISC treatment in reduction of ADR by CONTH, better QoL, and suggest a prolongation of DFS. Prospective trials are planned to confirm these data. Table 1. DFS analysis. No therapy = control (reference) No therapy ISC CONTH CONTH+ISC Patients% 22.5 24.9 24.5 28.1 HR 1 0.54 0.18 0.13 p value 1 0.005 <0.001 <0.001 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Society for Cancer Research, Switzerland

The involvement of the sLe-a selectin ligand in the extravasation of human colorectal carcinoma cells

The extravasation of tumor cells is a pivotal stage in the formation of hematogenous metastasis. An interaction of selectins expressed on endothelial cells and selectin ligands expressed by tumor cells has been implicated to play a role in extravasation. In the present study we used a human–mouse model to prove the hypothesis that the selectin ligand sialyl Lewis-a (sLe-a) is indeed involved in the in vivo extravasation of colorectal carcinoma (CRC) cells. The results indicated that highly metastatic CRC cells expressing high levels of sLe-a extravasate more efficiently than non-metastatic CRC cells expressing low levels of sLe-a. It was also demonstrated that down regulating the expression levels of sLe-a in CRC cells by genetic manipulations, significantly reduced CRC extravasation. Non-specific effects of these manipulations were ruled out. The results of this study indicate that the arrest and adhesion of CRC cells, and possibly of other types of cancer cells as well, to endothelium depend on the expression of the selectin ligand sLe-a by the tumor cells.

Treatment with a fermented mistletoe (Viscum album L.) extract as part of long-term supportive care in patients with primary non-metastatic colorectal carcinoma

Treatment with a fermented mistletoe (Viscum album L.) extract as part of long-term supportive care in patients with primary non-metastatic colorectal carcinoma

Treatment with standardized mistletoe extract (Viscum album L.) Iscador® as a part of long-term supportive care in patients with primary non-metastatic colorectal carcinoma

Aims: Mistletoe therapy is a frequently used supportive treatment in cancer patients to improve quality of life and baseline therapy induced adverse events.

Evaluation of risk of liver metastasis in colorectal adenocarcinoma based on the combination of risk factors including CD10 expression: Multivariate analysis of clinicopathological and immunohistochemical factors

Evaluation of the relationship between clinicopathological and immunohistochemical risk factors for liver metastasis, including CD10 expression, is meaningful in colorectal carcinoma (CRC). The purpose of the present study was to clarify what kind of risk factors are significant and independent factors for the development of liver metastasis in CRC. Sixty cases of advanced CRC with synchronous liver metastasis and sixty cases of advanced CRC without liver metastasis at least 5 years after resection of the primary CRC were randomly selected. We analysed the clinicopathological factors and the expression of four biological factors, CD44, transforming growth factor alpha (TGF-alpha), vascular endothelial growth factor (VEGF) and CD10, by immunohistochemistry. Univariate analysis revealed that the incidence of vascular invasion, the incidence of lymph node metastasis and the expression of CD44, TGF-alpha, VEGF and CD10 were all significantly higher in the cases of CRC with liver metastasis than in cases of non-metastatic CRC. Logistic regression analysis showed that lymph node metastasis, the expression of CD10 and the expression of VEGF were significant factors and independent of the other variables. If all three markers are positive, the probability of liver metastasis becomes 92.7%. In this study, lymph node metastasis, CD10 and VEGF were all found to be significant risk factors for the development of liver metastasis in the cases of CRC. These risk factors according to multivariate analysis are candidate markers for predicting the development of liver metastasis.

Epidermal growth factor receptor expression in stage II-III colon carcinoma: A preliminary study

9718 Background: Epidermal growth factor receptor (EGFR) is a protoncogen that is found overexpressed in colorectal carcinomas (CRC) and it correlates with a worse prognosis. The aim was to describe EGFR overexpression patterns in non-metastatic CRC and to correlate these data with follow-up. Methods: We analyzed a series of 56 CRC. Inclusion criteria were: a) resected primary adenocarcinoma; b) curative surgery; c) pT3 N0–2 M0 without progression during the first 6 months post surgery; d) minimum follow-up over 3 years. EGFR overexpression was analyzed by immunohistochemistry (IHC) using the Dako PharmaDx kit (Glostrup, Denmark). As positive control the Dako slides and a bloc cell of A431-AAM cells were used. Presence of cytoplasmic and membrane patterns (intensity 1(+), 2(+) and 3(+)) were evaluated as well as the percentage of positive cells. Statistical analysis: association between qualitative variables was analyzed by Fisher's exact test. Disease-free and overall survival distributions were estimated by the Kaplan-Meier method and were analyzed with the log rank test. All P values are from two-sided statistical tests. Results: Characteristics of the patients (pts) were as follows: mean age: 68,4 years (range: 28–91); sex: 24 male and 32 female; location: 19 right colon and 37 left colon; follow-up: 44 pts alive without disease (78,5%), 9 died of disease (16,5%) and 3 died of other causes (5%). 10 pts had metastasis in the follow-up. IHC: Forty-two cases were positive (75%) and were classified as follows: 17 with >50% of positive cells (30%), 7 with 25–50% of positive cells (13%) and 18 cases with < 25% of positive cells. Patterns of staining were cytoplasmic predominance in 27 cases (48%) and 15 with membrane predominance (27%): 4 with intensity 1(+), 9 with 2(+) and 2 with 3(+). Only those patients with tumors harboring membrane positivity 2(+) and 3(+) had more probability to present metastasis (p= 0.067). Conclusions: EGFR overexpression evaluated as a membrane pattern with 2(+) and 3(+) intensity is related with metastatic development in colon carcinoma. Suported by a grant of C.I.R. Hospital de Sabadell. Consorci Sanitari Parc Taulí. Sabadell. Spain No significant financial relationships to disclose.

Correlation of N-myc downstream-regulated gene 1 overexpression with progressive growth of colorectal neoplasm

To study the function of N-myc downstream-regulated gene 1 (NDRG1) in colorectal carcinogenesis and its correlation with tumor lymph node metastasis. NDRG1 was detected at its protein level by immunohistochemistry (IHC) and image analysis (IA), and NDRG1 mRNA was detected by in situ hybridization (ISH) in formalin-fixed and paraffin-embedded sections with a total of 190 specimens including 38 normal colorectal mucosae, 31 colorectal adenomas, 45 non-metastatic colorectal carcinomas (CRCs), 38 metastatic primary CRC and subsequently regional lymph nodes respectively. At the same time, the correlations of NDRG1 with sex, age of patients and histological types of colorectal carcinomas were observed. NDRG1 proteins were gradually increased in colorectal carcinogenesis (P<0.05 or P<0.01). There was a significant difference in the expression of NDRG1 between non-metastatic and metastatic CRCs (P<0.05), and the correlation was positive (P<0.01, r(s)=0.329). However, there was no obvious difference in the expression of NDRG1 between the primary sites of CRCs and that in the metastatic sites of corresponding regional lymph nodes, nor was there an apparent difference in sex, age, and histological types. The expression of NDRG1 mRNA was generally in concordance with that of NDRG1 protein. NDRG1 gene may play an important role in colorectal carcinogenesis. In addition, NDRG1 may be a putative tumor metastasis promoter gene and is regarded as one of the molecular biological markers that can forecast early metastasis of CRCs. NDRG1 gene in the metastatic sites of regional lymph nodes may preserve its expression characteristics in the primary sites of CRCs to some extent. The expression of NDRG1 is not affected by sex, age and histological types. The role of NDRG1 in tumor metastatic process can be demonstrated by in vivo and in vitro.

Expression of adhesion molecules in hepatic metastases of colorectal carcinoma: relationship to primary tumours and prognosis after hepatic resection.

Adhesion molecules are closely involved in the development and growth of metastatic tumours. We examined the expression of two adhesion molecules in liver metastatic tumours originating from colorectal carcinomas and correlated the expression of E-cadherin (EC) and CD44 variant exon 6 (v6) in these tumours with prognosis after hepatic resection. We examined 39 primary colorectal and 44 liver metastatic tumours obtained from 39 patients and 30 non-metastatic colorectal carcinomas as controls. The expression of EC in primary colorectal carcinomas of the metastasis group was significantly lower than in the non-metastasis group (P < 0.05). The expression of EC was low in metastatic liver tumours. The expression of CD44v6 in primary colorectal carcinomas of the metastasis group was significantly higher than in the non-metastasis group (P < 0.01). Expression of CD44v6 was high in metastatic liver tumours. However, there was no correlation between the expression of EC and CD44v6 or between each of these molecules and clinicopathological features of primary and metastatic tumours. Negative expression of EC and CD44v6 was a poor prognostic factor for survival after hepatic resection. Our results indicate that the lack of expression of EC and CD44v6 in liver metastases of colorectal cancer is associated with poor survival after surgery.

Expression of multidrug resistance protein in metastatic colorectal carcinomas.

To clarify the relationship between multidrug resistance protein (MRP) and clinicopathologic features, the influence of adjuvant chemotherapy, and prognosis of patients who underwent resection of metastatic liver carcinomas originating from colorectal carcinomas, we examined the expression of MRP in tumor tissues by immunostaining. Specimens of 38 primary colorectal tumors and 44 metastatic liver tumors of colorectal origin were examined (metastatic group). We also examined 28 nonmetastatic colorectal carcinomas. The percentages of nonmetastatic tumors and of primary and metastatic tumors of the metastasis group that expressed MRP were similar. MRP expression in primary and metastatic tumors did not correlate with any clinicopathologic features. The use of adjuvant chemotherapy after operation for primary colorectal carcinomas was associated with increased MRP expression among metastatic liver tumors. Expression of MRP in the tumor did not influence the prognosis or survival rate after resection of primary or metastatic tumors. Our data suggest that MRP expression in metachronous liver metastases from colorectal carcinomas may be induced by administration of anticancer drugs but is not associated with clinicopathologic features of the tumor, liver metastasis, or prognosis.

Geographic and patient variation among Medicare beneficiaries in the use of follow‐up testing after surgery for nonmetastatic colorectal carcinoma

BACKGROUND There are a paucity of data supporting the routine use of follow-up testing to detect recurrent disease after potentially curative initial surgery in patients with nonmetastatic colorectal carcinoma. METHODS Using the population-based Surveillance, Epidemiology, and End Results (SEER) registry, all patients age ≥ 65 years with local or regional colorectal carcinoma who were diagnosed in 1991, underwent surgical resection, and survived at least 6 months after diagnosis were identified. All inpatient, hospital outpatient, and physician/supplier Medicare claims from 6 months after diagnosis through 1994 were examined for follow-up procedures of interest. Procedure use during follow-up was compared across patient groups using both bivariate and multivariate analyses. RESULTS A total of 5716 patients were identified, with 1.3% found to have developed subsequent primary tumors of the colon or rectum, and 74% surviving through 1994. One or more procedures of interest were performed in 88% of patients; the most commonly performed tests were liver enzymes, chest X-rays, colonoscopy, and computed tomography scans. Lower rates of testing generally were observed with older age groups, patients with fewer comorbidities, and patients who did not survive through the follow-up period. Among all procedures studied, there also was significant variation in the rates of testing across the 9 SEER areas, varying from 1.5-fold to 3.6-fold. The geographic variation persisted in multivariate models adjusting for potentially confounding factors. CONCLUSIONS The current study found significant variability in the use of follow-up procedures, with the most striking differences apparent across geographic regions. Further studies are needed to determine the underlying reasons for the disparities, as well as the impact of surveillance on patient outcomes. Cancer 1999;85:2124–31. © 1999 American Cancer Society.

Geographic and patient variation among Medicare beneficiaries in the use of follow-up testing after surgery for nonmetastatic colorectal carcinoma

There are a paucity of data supporting the routine use of follow-up testing to detect recurrent disease after potentially curative initial surgery in patients with nonmetastatic colorectal carcinoma. Using the population-based Surveillance, Epidemiology, and End Results (SEER) registry, all patients age > or =65 years with local or regional colorectal carcinoma who were diagnosed in 1991, underwent surgical resection, and survived at least 6 months after diagnosis were identified. All inpatient, hospital outpatient, and physician/supplier Medicare claims from 6 months after diagnosis through 1994 were examined for follow-up procedures of interest. Procedure use during follow-up was compared across patient groups using both bivariate and multivariate analyses. A total of 5716 patients were identified, with 1.3% found to have developed subsequent primary tumors of the colon or rectum, and 74% surviving through 1994. One or more procedures of interest were performed in 88% of patients; the most commonly performed tests were liver enzymes, chest X-rays, colonoscopy, and computed tomography scans. Lower rates of testing generally were observed with older age groups, patients with fewer comorbidities, and patients who did not survive through the follow-up period. Among all procedures studied, there also was significant variation in the rates of testing across the 9 SEER areas, varying from 1.5-fold to 3.6-fold. The geographic variation persisted in multivariate models adjusting for potentially confounding factors. The current study found significant variability in the use of follow-up procedures, with the most striking differences apparent across geographic regions. Further studies are needed to determine the underlying reasons for the disparities, as well as the impact of surveillance on patient outcomes.

Proliferation of hepatic metastases of colorectal carcinoma: relationship to primary tumours and prognosis after hepatic resection.

In this study, we determined the proliferation indices of liver metastatic tumours originating from colorectal carcinomas using Ki67 and argyrophil nucleolar organizer region associated proteins (AgNOR) stain. We examined the primary and metastatic tumours in 27 patients with liver metastasis and eight cases with non-metastatic colorectal carcinoma as a control.The number of AgNOR dots in metastatic tumours was significantly higher than in the respective primary tumours of the metastasis group or in non-metastatic colorectal carcinomas. The Ki67 labelling index was similar in all groups. The Ki67 labelling index and AgNOR counts did not correlate with each other. There was no significant relationship between proliferation indices and the duration of the disease-free period following hepatic resection for metastases or with prognosis after hepatectomy. We conclude that Ki67 and AgNOR are not useful indicators of prognosis in patients who undergo operation for liver metastasis of colorectal carcinomas.

Significance of angiogenic factors in liver metastatic tumors originating from colorectal cancers.

We examined the expression of vascular endothelial growth factor (VEGF) and microvessel counts expressed by CD34 staining in 39 patients with primary and 44 patients with metastatic liver tumors of metastatic colorectal carcinoma, and 29 patients with nonmetastatic colorectal carcinoma as control in order to determine their value in the evaluation of prognosis and recurrence after hepatectomy. Microvessel counts in primary colorectal carcinomas of the metastatic group were significantly higher than those in control (P<0.05). Neither factor correlated with any clinicopathological feature of primary or metastatic liver carcinomas. Higher microvessel counts in metastatic liver tumors tended to be associated with a shorter disease-free interval to second recurrence in the remaining liver (P = 0.069) and were significantly associated with poor prognosis after hepatectomy (P<0.05). We conclude that microvessel count is an important marker of liver metastasis and prognosis in patients with colorectal carcinoma treated with hepatectomy.