The stromal part of adenocarcinomas of the oesophagus: does it conceal targets for therapy?

OBJECTIVE: To evaluate the prognostic value of the tumour stroma ratio (TSR) in resected adenocarcinoma of the oesophagus. BACKGROUND: In the literature, a refinement of oesophageal cancer staging has been proposed. Recently, TSR has been identified as a histological characteristic of the tumour itself that proved to be a strong predictor for survival in colorectal cancer. METHODS: In our cancer registry database, we identified 93 consecutive patients who underwent resection for oesophageal adenocarcinoma between 1990 and 2004 in two hospitals in our region. Using a predefined histopathological protocol, TSR was determined on the original haematoxylin-eosin (H&E) tissue sections of oesophagectomy specimens by two independent investigators. RESULTS: With a cut-off value of 50% tumour/stroma, patients were classified as TSR high (n=60) or TSR low (n=33). There were no significant differences in patient, tumour and treatment characteristics between the two groups, except for M status (M1a) and radicality of resection. The (disease-free) survival in the TSR high group was significantly better than in the TSR low group. By multivariate analysis, TSR was identified as a highly significant prognostic factor for overall survival (HR 2.0; P=0.010), independent of depth of tumour invasion, nodal status, lymph node ratio, extracapsular involvement, TNM stage, histological grade and radicality of resection. CONCLUSION: TSR is a new and practicable prognostic tumour characteristic for oesophageal adenocarcinoma that can discriminate patients with a poor outcome from those with a better outcome.

Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients.

BACKGROUND: For stage I-II colon cancer a significant number (5-25%) of patients has recurrent disease within 5 years. There is need to identify these high-risk patients as they might benefit from additional treatment. Stroma-tissue surrounding the cancer cells plays an important role in the tumor behavior. The proportion of intra-tumor stroma was evaluated for the identification of high-risk patients. In addition, protein expression of markers involved in pathways related to stroma production and epithelial-to-mesenchymal transition (EMT) was analyzed: beta-catenin, TGF-beta-R2 and SMAD4. METHODS: In a retrospective study of 135 patients with stage I-II colon cancer, the amount of stroma was estimated on routine haematoxylin-eosin stained histological sections. Sections were also immunohistochemically stained for beta-catenin, TGF-beta-R2 and SMAD4. RESULTS: Of 135 analyzed patients 34 (25.2%) showed a high proportion of stroma (stroma-high) and 101 (74.8%) a low proportion (stroma-low). Significant differences in overall-survival and disease-free-survival were observed between the two groups, with stroma-high patients showing poor survival (OS p<0.001, HZ 2.73, CI 1.73-4.30; DFS p<0.001, HZ 2.43, CI 1.55-3.82). A high-risk group was identified with stroma-high and SMAD4 loss (OS p=0.008, HZ 7.98, CI 4.12-15.44, DFS p=0.005, HZ 6.57, CI 3.43-12.56); 12 of 14 (85.7%) patients died within 3 years. In a logistic-regression analysis a high proportion of stroma and SMAD4 loss were strongly related (HZ 5.42, CI 2.13-13.82, p<0.001). CONCLUSIONS: Conventional haematoxylin-eosin stained tumor slides contain more prognostic information than previously fathomed. This can be unleashed by assessing the tumor-stroma ratio. The combination of analyzing the tumor-stroma ratio and staining for SMAD4 results in an independent parameter for confident prediction of clinical outcome.

Celecoxib inhibits growth of tumors in a syngeneic rat liver metastases model for colorectal cancer.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of colorectal cancer in cyclooxygenase-2 (COX-2) overexpressing colorectal cancers. The present study was designed to evaluate the inhibitory effects of the COX-2 inhibitor celecoxib on the growth of colorectal cancer liver metastases in a syngeneic rat model, CC531. MATERIALS AND METHODS: The effects of celecoxib on cell viability in vitro were evaluated by treatment of CC531 tumor cell cultures with celecoxib. In vivo, Wag/Rij rats were inoculated with CC531 tumor cells at two sites in the liver and treated with celecoxib starting one week before, or directly after tumor inoculation. Control rats were inoculated without treatment. Three weeks after tumor inoculation rats were sacrificed. Tumor size, immune cell infiltration, caspase-3 activity, PGE(2) and celecoxib levels were determined. RESULTS: CC531 tumors did not show COX-2 expression. Tumor growth was significantly inhibited by celecoxib treatment in a dose dependent manner. Immune cell infiltration was decreased after celecoxib treatment, indicating that the immune system was not involved in preventing tumor growth. Tumor caspase-3 levels were only significantly increased if treatment was started before tumor inoculation. Celecoxib serum concentration starting at 0.84 microg/ml significantly inhibited the outgrowth of CC531 liver tumors. In contrast, in vitro concentrations of celecoxib of at least 12 microg/ml were needed to affect tumor cell viability. CONCLUSION: These results suggest that the inhibitory effects of celecoxib on tumor growth are not by direct cytotoxicity, but by creating an unfavorable environment for tumor growth.

The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage.

BACKGROUND: Tumor staging insufficiently discriminates between colon cancer patients with poor and better prognosis. We have evaluated, for the primary tumor, if the carcinoma-percentage (CP), as a derivative from the carcinoma-stromal ratio, can be applied as a candidate marker to identify patients for adjuvant therapy. METHODS: In a retrospective study of 63 patients with colon cancer (stage I-III, 1990-2001) the carcinoma-percentage of the primary tumor was estimated on routine H&E stained histological sections. Additionally these findings were validated in a second independent study of 59 patients (stage I-III, 1980-1992). (None of the patients had received preoperative chemo- or radiation therapy nor adjuvant chemotherapy.) RESULTS: Of 122 analyzed patients 33 (27.0%) had a low CP and 89 (73.0%) a high CP. The analysis of mean survival revealed: overall-survival (OS) 2.13 years, disease-free- survival (DFS) 1.51 years for CP-low and OS 7.36 years, DFS 6.89 years for CP-high. Five-year survival rates for CP-low versus CP-high were respectively for OS: 15.2% and 73.0% and for DFS: 12.1% and 67.4%. High levels of significance were found (OS p<0.0001, DFS p<0.0001) with hazard ratio's of 3.73 and 4.18. In a multivariate Cox regression analysis, CP remained an independent variable when adjusted for either stage or for tumor status and lymph-node status (OS p<0.001, OS p<0.001). CONCLUSIONS: The carcinoma-percentage in primary colon cancer is a factor to discriminate between patients with a poor and a better outcome of disease. This parameter is already available upon routine histological investigation and can, in addition to the TNM classification, be a candidate marker to further stratify into more individual risk groups.

Factors influencing the local failure rate of radiofrequency ablation of colorectal liver metastases.

BACKGROUND: The prognosis of patients with colorectal cancer is poor, especially when there is distant metastatic disease. Local ablation of tumor by radiofrequency ablation (RFA) has emerged as a safe and effective new treatment modality, but its long-term efficacy may be hindered by renewed local tumor growth at the site of RFA. The objectives of this study were to identify risk factors for local RFA failure and to define exclusion criteria for RFA treatment of colorectal liver metastases. METHODS: A total of 199 lesions in 87 patients were ablated with RFA. Factors influencing local failure rates were identified and compared with data from the literature. RESULTS: The local failure rate was 47.2%, and the average time to local disease progression was 6.5 months. Factors that significantly correlated with increased failure rates were metachronous occurrence of liver metastases, large mean lesion size, and central tumor location. CONCLUSIONS: Because accurate electrode placement is pivotal in achieving adequate tumor necrosis, RFA should not be performed percutaneously when electrode placement is impaired. We suggest that lesions >5 cm and lesions located near great vessels or adjacent organs should be treated with open RFA, thus allowing vascular inflow occlusion and complete mobilization of the liver. Lesions that are difficult to reach by electrodes should be approached by an open procedure.