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Indicators of colorectal cancer prognosis and response to preoperative radiotherapy
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal cancer is one of the three most common malignant diseases in Sweden, with about 5,000 new cases each year. Thirty-five percent of these are rectal cancer, for which local recurrence after surgery has been a serious problem. The five-year survival rate in colorectal cancer has improved from about 40% in 1960 to 55% in 1995. Adjuvant chemotherapy of colon cancer, preoperative radiotherapy and improved surgical techniques in rectal cancer have contributed to the improved  results. To select patients best suited for pre- or postoperative therapy, we need indicators of both prognosis and response to therapy.

Using antibodies against cytokeratin, we found that 39% of patients with colorectal carcinoma that had penetrated the muscularis propria but without lymph-node metastases by routine light microscopy, had got micrometastases. Survival among patients with micrometastases was not significantly different from that among patients without such metastases.

We also identified subsets of tumour-infiltrating mononuclear cells and studied their pattern of distribution in relation to regressive tumour areas and Dukes class. Our interpretation is that the subsets of tumourinfiltrating mononuclear cells change with advancing Dukes class, indicating gradual deterioration of the local immune control.

We also investigated the interaction between p53, Ki-67, apoptosis and the outcome in rectal cancer with and without short-term preoperative radiotherapy. The expression of nuclear p53 protein seemed to be a significant predictive factor for local treatment failure after preoperative radiotherapy. Low tumour cell proliferation measured with Ki-67 in the preoperative biopsy correlated with improved local control and disease-free survival after preoperative radiotherapy.

High apoptotic index was associated with improved local control of rectal cancer even without pre-operative radiotherapy, whereas local control of tumours with low and intermediate apoptotic index was significantly improved by preoperative radiotherapy.

In conclusion, micrometastases in regional lymph nodes are an interesting phenomenon but with limited prognostic value. The subsets of tumour-infiltrating mononuclear cells change with advancing Dukes class, and its seems that the local immune control is gradually broken down. In rectal cancer, p53 expression, tumour proliferation measured with Ki-67 and apoptotic index seem to be interesting indicators of rectal cancer prognosis and response to preoperative radiotherapy.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2000. , 53 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 626
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25542Local ID: 9989ISBN: 91-7219-583-5 (print)OAI: oai:DiVA.org:liu-25542DiVA: diva2:245872
Public defence
2000-05-12, Onkologens föreläsningssal, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-08-10Bibliographically approved
List of papers
1. Occurrence and prognostic importance of micrometastases in regional lymph nodes in Dukes' B colorectal carcinoma: an immunohistochemical study
Open this publication in new window or tab >>Occurrence and prognostic importance of micrometastases in regional lymph nodes in Dukes' B colorectal carcinoma: an immunohistochemical study
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1996 (English)In: European Journal of Surgery, ISSN 1102-4151, E-ISSN 1741-9271, Vol. 162, no 8, 637-642 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To evaluate the incidence and prognostic importance of micrometastatic disease in regional lymph nodes from Dukes' B colorectal carcinomas.

DESIGN: Retrospective study.

SETTING: University hospital, Sweden.

SUBJECTS: 100 patients operated on for primary colorectal carcinoma, classified as Dukes' B lesions.

INTERVENTIONS: The regional lymph nodes were re-examined immunohistochemically using monoclonal antibodies against cytokeratin.

OUTCOME MEASURES: Incidence and prognostic importance of micrometastases.

RESULTS: Micrometastases were found in 39% (39/100) of the patients. The number of positive cells in the lymph nodes examined varied from 1 to over 100. They appeared as single cells or small clusters of cells located within the capsule or in the peripheral sinus of the lymph node. At least three sections from each of three lymph nodes had to be examined to identify 95% of the patients with lymph node micrometastases. The outcome of the patients with micrometastases was not significantly different from that of patients with no epithelial cells in the lymph nodes.

CONCLUSION: Micrometastases in regional lymph nodes are a interesting phenomenon but clinically seem to be of only weak prognostic value.

Keyword
colorectal carcinoma, regional lymph node micrometastases, anti-cytokeratin antibodies
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79591 (URN)8891622 (PubMedID)
Available from: 2012-08-10 Created: 2012-08-10 Last updated: 2017-12-07Bibliographically approved
2. Infiltration of mononuclear inflammatory cells into primary colorectal carcinomas: an immunohistological analysis
Open this publication in new window or tab >>Infiltration of mononuclear inflammatory cells into primary colorectal carcinomas: an immunohistological analysis
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1997 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 75, no 3, 374-380 p.Article in journal (Refereed) Published
Abstract [en]

Local immunoregulation mediated by mononuclear tumour-infiltrating cells is considered of importance for tumour progression of colorectal cancer, although the balance between immunosuppressor and cytotoxic activities is unclear. Colorectal cancers from 26 patients were investigated using a panel of monoclonal antibodies in order to identify subsets of mononuclear inflammatory cells and to study their pattern of distribution in relation to tumour stage and cytotoxic immune reactivity against the tumour. In all but five tumours, mononuclear cells, lymphocytes or monocytes were present in fairly large numbers, particularly in the stroma. The infiltration of CD4+ mononuclear cells predominated over the CD8+ subset. Infiltration near the tumour cells was found in four cancers only. Stromal infiltration of CD11c+ macrophages was found in all but eight tumours. Small regressive areas, in which the histological architecture of the tumours was broken down, were found in 17 tumours with intense or moderate infiltration by CD4+ lymphocytes or CD11c+ macrophages. Probably this destruction of tumour tissue was caused by cytotoxic activity of the tumour-infiltrating mononuclear cells. In Dukes' class A and B tumours, CD4+ lymphocytes predominated over CD4+ cells with macrophage morphology, but the latter were increasingly found in Dukes' class C and D disease. The occurrence of MHC II-positive macrophages and lymphocytes in different Dukes' classes was similar to that of CD4+ cells. In contrast to this, CD11c+ and CD11a+ cells were more frequent in Dukes' A and B class tumours compared with Dukes' C and D. Four out of nine tumours of the latter stages showed a poor inflammatory reaction. The interpretation of our results is that the subsets of tumour-infiltrating mononuclear cells change with advancing Dukes' class and that the local immune control is gradually broken down in progressive tumour growth, even if some cytotoxic activity is still present.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79592 (URN)9020482 (PubMedID)
Available from: 2012-08-10 Created: 2012-08-10 Last updated: 2017-12-07Bibliographically approved
3. p53 status: an indicator for the effect of preoperative radiotherapy of rectal cancer.
Open this publication in new window or tab >>p53 status: an indicator for the effect of preoperative radiotherapy of rectal cancer.
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1999 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 51, no 2, 169-174 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Rectal carcinoma is a common malignancy, with a history of high local recurrence rates following surgery. In recent years. preoperative radiotherapy and refined surgical technique have improved local control rates.

AIM: To investigate the relationship between expression of nuclear p53 protein and the outcome in rectal carcinoma, with and without short-term preoperative radiotherapy.

MATERIAL: Specimens from 163 patients from the Southeast Swedish Health Care region included in the Swedish rectal cancer trial between 1987-1990.

METHOD: New sections from the paraffin blocks of the preoperative biopsy and the surgical specimen were examined immunohistochemically using a p53 antibody (PAb 1801).

RESULT: Expression of nuclear p53 protein was seen in 41% of the tumours. The p53 negative patients treated with preoperative radiotherapy had a significant reduction of local failure compared with the non-irradiated p53 negative patients (P = 0.0008). In contrast, p53 positive patients showed no benefit from preoperative radiotherapy. The interaction between p53 status and the benefit of radiotherapy was statistically significant (P = 0.018).

CONCLUSION: Expression of nuclear p53 protein in rectal carcinoma seems to be a significant predictive factor for local treatment failure after preoperative radiotherapy. Further investigations are necessary to select patients for preoperative treatment based on analysis of the preoperative biopsies.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24826 (URN)10.1016/S0167-8140(99)00041-9 (DOI)10435809 (PubMedID)9223 (Local ID)9223 (Archive number)9223 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-08-10Bibliographically approved
4. Decreased tumor cell proliferation as an indicator of the effect of preoperative radiotherapy of rectal cancer
Open this publication in new window or tab >>Decreased tumor cell proliferation as an indicator of the effect of preoperative radiotherapy of rectal cancer
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2001 (English)In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, Vol. 50, no 3, 659-663 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Rectal cancer is a common malignancy, with significant local recurrence and death rates. Preoperative radiotherapy and refined surgical technique can improve local control rates and disease-free survival.

PURPOSE: To investigate the relationship between the tumor growth fraction in rectal cancer measured with Ki-67 and the outcome, with and without short-term preoperative radiotherapy.Method: Ki-67 (MIB-1) immunohistochemistry was used to measure tumor cell proliferation in the preoperative biopsy and the surgical specimen.

MATERIALS: Specimens from 152 patients from the Southeast Swedish Health Care region were included in the Swedish rectal cancer trial 1987-1990.

RESULTS: Tumors with low proliferation treated with preoperative radiotherapy had a significantly reduced recurrence rate. The influence on death from rectal cancer was shown only in the univariate analysis. Preoperative radiotherapy of tumors with high proliferation did not significantly improve local control and disease-free survival. The interaction between Ki-67 status and the benefit of radiotherapy was significant for the reduced recurrence rate (p = 0.03), with a trend toward improved disease-free survival (p = 0.08). In the surgery-alone group, Ki-67 staining did not significantly correlate with local recurrence or survival rates.

CONCLUSION: Many Ki-67 stained tumor cells in the preoperative biopsy predicts an increased treatment failure rate after preoperative radiotherapy of rectal cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24827 (URN)10.1016/S0360-3016(01)01515-2 (DOI)11395233 (PubMedID)9224 (Local ID)9224 (Archive number)9224 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-08-10Bibliographically approved
5. Apoptosis in rectal carcinoma: Prognosis and recurrence after preoperative radiotherapy
Open this publication in new window or tab >>Apoptosis in rectal carcinoma: Prognosis and recurrence after preoperative radiotherapy
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2001 (English)In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 91, no 10, 1870-1875 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Rectal carcinoma is common, with considerable local recurrence and death rates. Preoperative radiotherapy and refined surgical techniques can improve local control. The aim of this study was to investigate the interaction between apoptosis and the outcome of rectal carcinoma, with and without short-term preoperative radiotherapy.

METHODS: Specimens were from 162 patients from the Southeast Swedish Health Care region included in the Swedish Rectal Cancer Trial between 1987-1990. New sections from the paraffin blocks of the preoperative biopsies and the surgical specimens were examined for apoptosis using the terminal deoxynucleotidyl transferase mediated digoxigenin nick end labeling (TUNEL) method.

RESULTS: The mean percentage of apoptotic cells was 0.3% (0-4%) and 1.1% (0-14.5%) for the preoperative biopsy and the surgical specimen, respectively. The authors analyzed the surgical specimens from nonirradiated patients and divided them into three groups by apoptotic index (AI) as follows: 0%, 0-1%, and > 1%. A high AI was associated with a decreased local recurrence rate compared with an intermediate or a low AI (P = 0.024). There was no significant relation between AI and survival. There was a significant reduction in the local recurrence rate for irradiated patients compared with the nonirradiated in the low (P = 0.015) and intermediate (P = 0.038) AI groups. In the high AI group, there were few recurrences and no significant difference was observed between irradiated and nonirradiated patients. The relative risk of death from rectal carcinoma in Dukes A-C patients was not significantly decreased by radiotherapy, but, in the intermediate AI group, there was a trend (P = 0.08) in favor of the irradiated patients.

CONCLUSION: A high AI in rectal carcinoma indicated a decreased local recurrence rate.

Keyword
apoptosis, rectal carcinoma, radiotherapy, local failure, disease-free survival
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24825 (URN)10.1002/1097-0142(20010515)91:10<1870::AID-CNCR1208>3.0.CO;2-1 (DOI)9222 (Local ID)9222 (Archive number)9222 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-08-10Bibliographically approved

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