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Biological and histological factors as predictors in rectal cancer patients: A study in a clinical trial of preoperative radiotherapy
Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL. Linköping University, Faculty of Health Sciences. (Colorectal cancer)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

With improved surgical techniques and preoperative radiotherapy (RT) the local recurrence rate in rectal cancer patients has been reduced, however the mortality rate is still high and there is a huge variation in the response to preoperative RT in patients with the same tumour stage. To improve patient’s survival, it is of great importance to identify good prognostic and predictive factors that help us to select the best suited patients for preoperative RT in the future.

For many years, studies of neoplastic transformation have mainly focused on tumour cells. In recent years, researchers have realised that the stroma around tumour cells and their extracellular matrix components also play an important role in tumour carcinogensesis.

The aim of this thesis was to investigate the biological factors, survivin and particularly interesting new cysteine-histidine rich protein (PINCH), histological factors, inflammatory infiltration, fibrosis, necrosis, mucinous content, angiogenesis and lymphangiogenesis as well as their relationships to preoperative RT and to clinical variables in rectal cancer patients who participated in a Swedish rectal cancer trial of preoperative RT.

In paper I, the expression of survivin and its relationship to preoperative RT and clinical factors were investigated in 98 primary rectal tumours and adjacent normal mucosa. In all patients, positive survivin expression was independently related to worse survival compared to negative survivin expression in a multivariate analysis.

In paper II, PINCH expression and its relationship to RT, clinical, histological and biological factors were investigated at the invasive margin and inner tumour area in 137 primary rectal tumours and in cell line of fibroblasts. In patients without RT, strong PINCH expression was independently related to worse survival in a multivariate analysis. No survival relationship was found in the patients with RT, and there was no difference in PINCH expression between the subgroups of non-RT and RT at the invasive margin/inner tumour area. In patients with RT, strong PINCH expression at the inner tumour area was related to a high level of lymphatic vessel density (LVD).

In paper III, the frequency of LVD/blood vessel density (BVD) was analysed at the periphery, the inner tumour area and the invasive margin of 138/140 primary rectal tumours and correlated to RT, clinical, histological and biological factors. In all patients, LVD at the periphery of the tumour was independently related to better survival compared to LVD at the inner tumour area/invasive margin. In all patients, a higher LVD at the periphery was related to negative (wild type) p53 expression.

In paper IV, the inflammatory infiltration, fibrosis, necrosis and mucinous content were studied in relation to RT, clinical and biological parameters in preoperative biopsies (n = 153) and in primary tumours (n = 148). In all patients and in the subgroups of non-RT and RT a higher grade of inflammatory infiltration was independently related to improved survival compared to weak inflammatory infiltration in a multivariate analysis.

In this thesis, survivin, PINCH, LVD and inflammatory infiltration are independent prognostic factors in rectal cancer patients who participated in a clinical trial of preoperative RT. This information may help us to improve patient’s survival by selecting the best suited patients for preoperative RT in the future.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 71 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1226
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-66207ISBN: 978-91-7393-234-9 (print)OAI: oai:DiVA.org:liu-66207DiVA: diva2:402423
Public defence
2011-03-25, Linden, Hälsouniversitetet, Ingång 65, Campus US, Linköpings univeristet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2011-07-05 Created: 2011-03-08 Last updated: 2011-12-05Bibliographically approved
List of papers
1. Survivin expression is an independent prognostic factor in rectal cancer patients with and without preoperative radiotherapy
Open this publication in new window or tab >>Survivin expression is an independent prognostic factor in rectal cancer patients with and without preoperative radiotherapy
2004 (English)In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 60, no 1, 149-155 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Survivin, as an inhibitor of apoptosis, is undetectable in normal tissues but expressed in tumors. Survivin expression in rectal cancer patients who have undergone preoperative radiotherapy (RT) alone has not been studied. We analyzed the relationships of survivin expression to RT, clinicopathologic variables, apoptosis, and p53 expression in rectal cancer patients who participated in a trial of preoperative RT. Methods and Materials: Survivin was immunohistochemically examined in 98 rectal tumors (74 had adjacent normal mucosa). Of 98 patients, 57 underwent surgery alone and 41 underwent RT before surgery. Results: Survivin positivity was related to worse survival, independent of Dukes' stage, local and distant recurrence, differentiation, gender, age, apoptosis, and p53 expression (p = 0.02). Survivin was not associated with survival in the patients without (p = 0.08) or with (p = 0.19) RT. After RT, survivin tended to be increased in adjacent normal mucosa (p = 0.057) but not in tumors (p = 0.71). Conclusion: Survivin was independently related to survival in rectal cancer patients who participated in a trial of preoperative RT, but not in either treatment group (surgery alone or surgery plus RT). Whether the effect of survivin on tumors is associated with RT and further related to patient survival needs to be investigated in a larger number of patients. (C) 2004 Elsevier Inc.

Keyword
radiotherapy, prognosis, rectal cancer, immunohistochemistry
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-46183 (URN)10.1016/j.ijorbp.2004.02.007 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13
2. PINCH is an independent prognostic factor in rectal cancer patients without preoperative radiotherapy: A study in a Swedish rectal cancer trial of preoperative radiotherapy
Open this publication in new window or tab >>PINCH is an independent prognostic factor in rectal cancer patients without preoperative radiotherapy: A study in a Swedish rectal cancer trial of preoperative radiotherapy
Show others...
2012 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, no 65Article in journal (Refereed) Published
Abstract [en]

Background and Purpose: The clinical significance between particularly interesting new cysteine-histidine rich protein (PINCH) expression and radiotherapy (RT) in tumours is not known. In this study, the expression of PINCH and its relationship to RT, clinical, pathological and biological factors were studied in rectal cancer patients.

Material and Methods: PINCH expression determined by immunohistochemistry was analysed at the invasive margin and inner tumour area in 137 primary rectal adenocarcinomas (72 cases without RT and 65 cases with RT). PINCH expression in colon fibroblast cell line (CCD-18 Co) was determined by Western blot.

Results: In patients without RT, strong PINCH expression at the invasive margin of primary tumours was related to worse survival, compared to patients with weak expression, independent of TNM stage and differentiation (p = 0.03). No survival relationship in patients with RT was observed (p = 0.64). Comparing the non-RT with RT subgroup, there was no difference in PINCH expression in primary tumours (invasive margin (p = 0.68)/inner tumour area (p = 0.49).

Conclusions: PINCH expression at the invasive margin was an independent prognostic factor in patients without RT. RT does not seem to directly affect the PINCH expression.

 

Place, publisher, year, edition, pages
BioMed Central, 2012
Keyword
PINCH, Radiotherapy, Prognosis, Rectal cancer, Immunohistochemistry
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-66104 (URN)10.1186/1471-2407-12-65 (DOI)000301425700001 ()
Note
funding agencies|Swedish Cancer Foundation||Swedish Research Council||Health Research Council in the South-East of Sweden||Available from: 2011-03-04 Created: 2011-03-03 Last updated: 2017-12-11Bibliographically approved
3. The location of lymphangiogenesis is an independent prognostic factor in rectal cancers with or without preoperative radiotherapy
Open this publication in new window or tab >>The location of lymphangiogenesis is an independent prognostic factor in rectal cancers with or without preoperative radiotherapy
Show others...
2010 (English)In: ANNALS OF ONCOLOGY, ISSN 0923-7534, Vol. 21, no 3, 512-517 p.Article in journal (Refereed) Published
Abstract [en]

Background: Lymphangiogenesis and angiogenesis are essential for tumour development and progression. The lymphatic vessel density (LVD) and blood vessel density (BVD) and their relationship to outcome have been studied extensively, however the clinical significance of the location of LVD/BVD in tumour is not known. In the present study, the location and degree of LVD/BVD and their relationship to preoperative radiotherapy (RT), clinicopathological, histopathological and biological factors were studied in rectal cancer patients participating in a Swedish clinical trial of preoperative RT. Patients and methods: The location and degree of LVD/BVD were analysed in primary tumours (n = 138/140) and in their subgroups of non-RT (n = 74) and RT (n = 64/66). Further, the degree of LVD/BVD was examined in the corresponding distant normal mucosa (n = 35/31) and adjacent normal mucosa (n = 72/91). All sections were immunohistochemically examined by using D2-40 and CD34 antibodies. Results: In the whole series of the patients, a higher LVD at the periphery was related to negative p53 expression (P = 0.03) and favourable survival independent of tumour-node-metastasis stage, differentiation and p53 expression (P = 0.03). LVD was increased in p53-negative tumours after RT (P = 0.01). Conclusion: LVD at the periphery of the tumour was an independent prognostic factor in rectal cancer patients.

Keyword
angiogenesis, lymphangiogenesis, prognosis, radiotherapy, rectal cancer
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54786 (URN)10.1093/annonc/mdp486 (DOI)000276045300012 ()
Note
This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Annals of Oncology following peer review. The definitive publisher-authenticated version: A Holmqvist, Jingfang Gao, Gunnar Adell, John Carstensen and Xiao-Feng Sun, The location of lymphangiogenesis is an independent prognostic factor in rectal cancers with or without preoperative radiotherapy, 2010, ANNALS OF ONCOLOGY, (21), 3, 512-517. is available at: http://dx.doi.org/10.1093/annonc/mdp486 Copyright: Oxford University Press http://www.oxfordjournals.org/ Available from: 2010-04-09 Created: 2010-04-09 Last updated: 2011-09-21
4. Inflammatory infiltration, fibrosis, necrosis and mucinous content in relation to clinicopathological and molecular factors in rectal cancers with or without preoperative radiotherapy.
Open this publication in new window or tab >>Inflammatory infiltration, fibrosis, necrosis and mucinous content in relation to clinicopathological and molecular factors in rectal cancers with or without preoperative radiotherapy.
2006 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 16, no 2, 321-327 p.Article in journal (Refereed) Published
Abstract [en]

The association between inflammatory infiltration, fibrosis, necrosis and mucinous content in rectal cancers, and their relationship to preoperative radiotherapy (RT) clinicopathological and biological factors (p53, apoptosis and Cox-2) is not fully characterised. We analysed these histopathological parameters and their relationships in rectal cancer patients who participated in a clinical trial of preoperative RT. One hundred and forty-eight preoperative biopsies and 153 surgically resected tumours were examined. Of the surgical specimens, 81 had surgery alone and 72 received RT before surgery. A higher grade of inflammatory infiltration was related to favourable survival in the whole group of patients (p=0.004, for multivariate analysis p=0.01) as well as in the subgroups of patients with (p=0.04) or without RT (p=0.01). After RT, tumours showed a decreased infiltration (p=0.0003) and increased necrosis (p=0.006), strong necrosis was related to favourable survival (p=0.046). Necrosis (p=0.054) and fibrosis (p=0.06) tended to be increased in p53-negative tumours after RT. Inflammatory infiltration was a strong prognostic factor in rectal cancer patients, regardless of RT. RT tended to induce necrosis and fibrosis in p53-negative tumours.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-36996 (URN)33270 (Local ID)33270 (Archive number)33270 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13

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