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  Table of Contents  
Year : 2016  |  Volume : 53  |  Issue : 4  |  Page : 548-551

The role of COX-2 and Ki-67 over-expression in the prediction of pathologic response of rectal cancer to neoadjuvant chemoradiation therapy

1 Department of Pathology, Ghaem Hospital, Mashhad, Iran
2 Department of Surgical Oncology Research Center, Imam Reza Hospital; Cancer Research Center, Omid Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3 Cancer Research Center, Omid Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Date of Web Publication21-Apr-2017

Correspondence Address:
A Taghizadeh Kermani
Department of Surgical Oncology Research Center, Imam Reza Hospital; Cancer Research Center, Omid Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.204770

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 » Abstract 

BACKGROUND: The response to neoadjuvant chemoradiotherapy (CRT) is not the same among all cases with advanced rectal cancer. AIMS: This study investigated the association between over-expression of the two molecular markers (Cyclooxygenase-2 [COX-2] and Ki-67) and tumor response to neoadjuvant therapy. MATERIALS AND METHODS: In a retrospective cohort study, 55 patients with stage II-III rectal carcinoma were enrolled. All patients were treated with neoadjuvant therapy (45-50.4 Gy plus Capecitabine) between 2002 and 2009 in our institute. The pretreatment specimens were immunohistochemistry (IHC) stained for COX-2 and Ki-67 markers. The tumor response to neoadjuvant treatment was evaluated using a 5-point tumor regression grade (TRG) system. The induced inflammation and necrosis after CRT were also investigated. Statistical analysis was performed using SPSS version 11.5 and statistical significance was determined at P < 0.05. RESULTS: The pathologic response to neoadjuvant treatment from complete response as (TRG = 1) through no response as (TRG = 5) was found in 10 (22.2%), 8 (17%), 6 (13.3%), 16 (35.6%), and 5 (11.1%) cases. In comparison with poor responders (TRG: 4, 5), patients with good response to neoadjuvant treatment (TRG: 1, 2) were associated with lower pretreatment mean COX-2 staining extent (72.9% vs. 22.8%, P < 0.001) as well as lower mean Ki-67 staining extent (70.7% vs. 28.5%, P < 0.001). High COX-2 staining and high Ki-67 index were significantly associated with more inflammation. CONCLUSIONS: Over-expression of COX-2 and high Ki-67 index were associated with a poorer response to neoadjuvant CRT. These markers might be helpful to define those patients with rectal carcinoma who benefit more from neoadjuvant treatments.

Keywords: Cyclooxygenase-2, Ki-67 antigen, neoadjuvant therapy, rectal cancers, regression

How to cite this article:
Jafarian A, Kermani A T, Esmaeili J, Roshan N, Seilanian-Toosi M, Omidi A, Shahri M K. The role of COX-2 and Ki-67 over-expression in the prediction of pathologic response of rectal cancer to neoadjuvant chemoradiation therapy. Indian J Cancer 2016;53:548-51

How to cite this URL:
Jafarian A, Kermani A T, Esmaeili J, Roshan N, Seilanian-Toosi M, Omidi A, Shahri M K. The role of COX-2 and Ki-67 over-expression in the prediction of pathologic response of rectal cancer to neoadjuvant chemoradiation therapy. Indian J Cancer [serial online] 2016 [cited 2020 May 30];53:548-51. Available from:

 » Introduction Top

Preoperative chemoradiotherapy (CRT) followed by surgical resection is the standard of care in locally advanced rectal cancer. This approach not only increases the possibility of curative resection but also decreases local recurrence and improves survival.[1],[2]

Nowadays, 10-30% of patients with rectal carcinoma treated with neoadjuvant CRT achieve complete pathological response. Results from a number of studies have revealed the association between good pathological response to CRT and favorable prognosis.[3],[4] In addition to intrinsic biology of tumor, there are several factors that influence the efficacy of neoadjuvant therapy including radiation dose, chemotherapy regimen, and the interval between completing preoperative CRT and surgical resection.[5],[6],[7],[8] Presently, there is no definite histological characteristic to predict which cases are responsive to CRT before commencing the treatment. Defining the predictive factors would help us to detect a subset of patients with low chance for satisfactory response to common CRT treatments. This group of patients could be appropriate for alternative or experimental protocols.

Multiple studies on some molecular markers have been conducted to evaluate their effect on tumor response to CRT; however, their role in predicting tumor response and survival has remained controversial. Cyclooxygenase-2 (COX-2) is an important mediator of tumor invasion and metastasis.[9] This enzyme catalyzes the conversion of arachidonic acid to prostaglandins.[10] After exposure to radiation, neoplastic cells produce prostaglandins by means of COX-2, which can be used as survival factors against radiation-induced cell death, resulting in resistance to treatment.[11] According to some recent studies, incorporation of selective inhibitors of COX-2 to radiation therapy might increase the sensitivity of tumors to radiation by blocking prostaglandin release.[9],[11]

Ki-67 is an antigen linked to a nuclear non-histone protein expressed during G1, G2, M, and S proliferative phases of cell cycle. This antigen shows a good correlation with mitotic activity and can be used as a cellular proliferation marker.[12] It has been shown that the degree of positive reaction to Ki-67 is in coherence with the clinical stage of the tumor. The most studied examples include brain, breast, and prostate cancers.[13]

We studied the association of COX-2 and Ki-67 immunoreactivity with the response to neoadjuvant CRT in a group of patients with rectal carcinoma.

 » Materials and Methods Top

In this retrospective cohort study, we selected patients with Stage II-III rectal carcinoma who were treated with the following protocol between 2002 and 2009 at oncology and pathology departments affiliated to our institution. The cases received whole pelvic radiation dose of 4500-5040 cGy in 25 to 28 fractions concurrent with Capecitabine (Xeloda) 825-850 mg/m 2/dose twice daily. Mesorectal resection was performed 4-6 weeks following completion of neoadjuvant treatment. The patients continued on adjuvant chemotherapy typically using FOLFOX 4 regimen for 6 months.

Pretreatment (neoadjuvant chemoradiation) specimens were obtained by endoscopy.

All stages were performed according to the Novacostra lyophilized mouse monoclonal antibody COX-2 instructions (NCL-COX-2, Leica Biosystem Newcastle, UK). Deparaffinized and rehydrated sections were placed in 0.5% hydrogen peroxidase for 10 minutes to block endogenous peroxidase activity. Antigen retrieval was performed by immersing the slides in boiling unmasking solution (0.01 M citrate buffer, pH 6.0) for 1 min in a pressure cooker, followed by their immediate placing into a bath of tap water and washing in tris-buffered saline (TBS) (pH 7.6) for 1.5 min. Non-specific binding of the primary antibody was prevented with incubation of the specimens in diluted normal serum for 10 min. Specimens were incubated with the primary antibody for 30 min before being incubated in a biotin-avidin secondary antibody and in the avidin biotin complex (ABC) reagent, followed by washing in TBS buffer for 2.5 min. The antibody binding was detected with diaminobenzidine (DAB). The sections were lightly counterstained with hematoxylin and then dehydrated through a graded series of alcohols and xylene before being mounted under a coverslip. Positive and negative controls were respectively provided by normal colonic mucosa and omission of the primary antibody.

The extent of staining was scored 0 to 3 according to the percentage of immunoreactive cells per 1000 cells in 10 high power fields (×40) of light microscopy [Table 1] and [Figure 1].
Table 1: Staining extent scoring system

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Figure 1: COX-2 IHC staining in a case of rectal cancer showing moderate immunoreactivity in 50% of tumoral cells

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Endoscopic tissue (before chemoradiation) slides were deparaffinized and rehydrated by using xylene and a series of graded alcohols. The sections were treated with heat prior to IHC staining. The target retrieval procedure included immersion of slides in a pre-heated buffer solution (code S1699, Dako Cytomation, Copenhagen, Denmark) and incubation at 95-99°C for 20 minutes. Non-specific binding of primary antibody was prevented by incubation with a blocking serum for 10 min. Primary antibody (N1633) was applied for 10 min at room temperature. Next, sections were lightly counterstained in hematoxylin, dehydrated, and mounted under a coverslip. Positive and negative controls were provided by a lymph node tissue and omission of the primary antibody, respectively. A proliferation index was ascribed to each section, by counting the percentage of reactive cells per 1000 cells in 10 high power fields (×40) of light microscopy [Figure 2]. High proliferation index was regarded as Ki-67 greater than 40%.
Figure 2: Ki-67 IHC staining in a case of rectal cancer showing immunoreactivity in 94% of tumoral cells. The right inferior corner shows Ki-.67 negative non tumoral glands

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At least three microscopic slides obtained from each surgical sample were examined. The response to treatment was evaluated as the Tumor Regression Grade (TRG) 1 to 5 according to Mandard's method that is based on the proportion of neoplastic tissue to fibrous tissue [Table 2]. The patients are clinically classified as good (TRG = 1 or 2), moderate (TRG = 3), and poor (TRG = 4 and 5) responders.
Table 2: Mandard's classification

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In addition, the extent of tumor necrosis was evaluated as the percentage of necrotic tissue per total tumor volume. Inflammation was divided into three groups; mild, moderate, and severe.


This study received approval from ethics committee of our institution.


All cases were studied by two pathologists in a single blind method, and in cases of discrepancy the average of the scores was used. Data was analyzed using SPSS Software (v.11.5), statistical test ANOVA was done, and P < 0.05 was considered statistically significant.

 » Results Top

Forty-five patients including 27 males (60%) and 18 females (40%) with the mean age of 52 years (range; 18-87) were studied. The pathological responses to neoadjuvant therapy according to Mandard's classification were as follows; 10 (22.2%) TRG = 1, 8 (17.8%) TRG = 2, 6 (13.3%) TRG = 3, 16 (35.6%) TRG = 4, and 5 (11.1%) TRG = 5. Fifteen cases (33.3%) showed necrosis in more than 50% of the tumor volume. The degree of inflammation in postsurgical specimens was mild in 15 cases (33.3%), moderate in 22 cases (48.9%), and severe in 8 cases (17.8%).

Reactivity to COX-2 was observed in 95.6% of cases with various extent and intensities. The median COX-2 staining extent was 58% (range; 0-96%). The staining scores were as follows: 0 in 7 (15.7%), 1 in 8 (17.8%), 2 in 9 (20%), and 3 in 21 cases (46.7%). According to [Table 3], from 18 patients with good response to neoadjuvant therapy, no cases showed extensive COX-2 staining extent (score: 3) in pretreatment specimens. Meanwhile, 19 out of 21 poor responders (90.4%) revealed extensive COX-2 staining extent (P < 0.001). The mean COX-2 staining extent was also significantly lower in good responders as compared with poor responders (22.8% ± 19.5% vs. 72.9% ± 16%, P < 0.001).
Table 3: The correlation between COX-2 staining score and tumor response to neoadjuvant therapy

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The degree of inflammation in post-surgical specimens correlated well with the mean COX-2 staining extent in pretreatment biopsies. The mean COX-2 staining extent in cases with mild, moderate, and severe inflammation was 23.4%, 58.6%, and 70.2%, respectively (P < 0.01, ANOVA).

The mean COX-2 immunoreactivity extent in pre-CRT biopsies was significantly higher in cases with post-CRT biopsies showing >50% necrosis than those with <50% necrosis (68.2% ± 18.8% vs. 39.3% ± 29.7%, P < 0.01).

The median Ki-67 staining extent was 47% (range, 3-94%); 27 (60%) cases revealed high proliferation index (Ki-67 > 40%). As illustrated in [Table 4], in comparison with patients with good response to CRT, the proportion of patients with high Ki-67 proliferation index was significantly higher among poor responders (27.8% vs. 85.7%, P = 0.001). The mean Ki-67 staining extent among good (TRG: 1, 2) and poor responders (TRG: 4, 5) was 28.5% ± 14.6% and 70.7% ± 27.7% respectively (P < 0.001). These results revealed that patients whose pretreatment biopsies showed high Ki-67 proliferation index were less likely responsive to CRT.
Table 4: The correlation between Ki-67 proliferation index and tumor response to neoadjuvant therapy

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The mean Ki-67 staining extent in pre-treatment biopsies in patients with mild, moderate, and severe inflammation in their post-CRT samples equaled 33.8%, 51.4%, and 74.3%, respectively (P < 0.01) demonstrating an association between high Ki-67 proliferation index and more severe inflammation following CRT.

The mean pre-treatment Ki-67 staining extent was relatively higher in those having more than 50% necrosis in their post-CRT specimens than cases with less than 50% necrosis (63% ± 34.9% vs. 42.9% ± 28.8%); however, the difference did not reach statistical significance (P = 0.07, ANOVA).

 » Discussion Top

Considering the high rate of locoregional recurrence in patients with Stage II and Stage III rectal carcinoma treated by surgery alone, combined modality approaches with incorporation of radiotherapy and chemotherapy are strongly recommended. Approximately 70.2% of the patients with rectal cancers who are treated only with surgery may develop local recurrence, regional lymph node involvement, or distant metastasis.[13],[14] Neoadjuvant therapy can cause tumor regression and provide improved local control and increased survival.[15],[16],[17] However, the degree of tumor response to treatment is not the same in all patients. Molecular factors should contribute to the variability seen in responses to CRT. COX-2 and Ki-67 antigen are among several markers, which have been studied for this purpose.[3],[4]

COX-2 enzyme is over-expressed in many malignant neoplasms including colorectal tumors. The association of COX-2 expression and response to CRT has been investigated in patients with laryngeal, cervical, and rectal cancers, which demonstrated that positive immunoreactivity of this marker is correlated with poor response to treatment and unfavorable prognosis.[18],[19],[20] The attempts to assess the possible predictive value of COX-2 in rectal cancer response to neoadjuvant therapy have yielded different results. A study by Debucquoy et al. showed that combined CRT was effective in down-regulation of COX-2 expression; however, no predictive value or prognostic role was revealed for this marker in rectal cancers.[15] In a research performed on 88 surgical specimens of rectal cancers treated only by radiotherapy, Bouzourene et al. showed that COX-2 expression was induced in majority of patients treated with radiation, which was correlated only with inflammation, not with survival or tumor response. However, positive COX-2 expression in post-operative specimens was associated with higher probability of local recurrence.[20] Meanwhile, Smith et al., in a study on 49 patients with rectal cancer, suggested that COX-2 over-expression assessed by IHC was associated with moderate or poor response. In the same study, apoptosis was evaluated by TUNEL staining and appeared to be in coherence with tumor response.[21] Min BS et al. found also that cases with locally advanced rectal cancer with COX-2 over-expression were more likely to have poor TRG (P = 0.003) and were less likely to attain histopathologic nodal down-staging compared with those with normal COX-2 expression.[22] Likewise, the results of our study showed that COX-2 over-expression was correlated with poorer response of rectal cancer to pre-operative CRT. It was also associated with post-CRT inflammation and necrosis. The results of some studies suggest that COX-2 inhibitors may enhance tumor radio-response through multiple mechanisms.[21],[22] Considering availability and low toxicity profile of COX-2 inhibitors, more investigations on their incorporation in standard CRT protocols are justified.

Excessive proliferation is a characteristic of neoplastic growths. Deregulation of growth signaling pathways leads to less dependency of tumors on growth factors and their less sensitivity to growth suppression signals.[23] Thus, the proliferation index may be important in predicting response of neoplasms to therapeutic regimens.[24] In the setting of colorectal cancers, the results regarding the correlation between proliferation index and tumor response have been unequivocal. While Debucquoy et al. in a study on morphological features and molecular markers in 95 cases of rectal cancers could not identify any predictive or prognostic value for Ki-67 expression,[15] Kikuchi found Ki-67 expression to be an independent predictive factor showing good correlation with tumor response to CRT.[25] Meanwhile, Jakob et al., in a trial on patients with advanced rectal carcinoma undergoing 5FU based neoadjuvant CRT, showed that patients with high tumor regression had lower Ki-67 index.[26] In compatible with the last study, our cases with rectal cancer showing high Ki-67 proliferation index were associated with poorer response to CRT as well as higher inflammation in post-surgical specimens. There was no significant correlation between Ki-67 over-expression and the extent of necrosis following CRT.

Finally, there are complex pathways involving in response to CRT;[27] therefore, in addition to these two markers, other factors such as P53 gene mutations [27] and P21 expression [28] play a significant role in this regard. Consequently, further investigation of other potential markers, which may affect the tumor response to CRT, is warranted.

 » Acknowledgments Top

The results described in this paper formed part of a thesis submitted by the third author for a postgraduate degree in pathology. The study was supported by the Vice Chancellor for Research of Mashhad University of Medical Sciences. We sincerely acknowledge Ms. M. Hassanpour for editing the manuscript.

 » References Top

Janjan NA, Crane C, Feig BW, Cleary K, Dubrow R, Curley S, et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol 2001;24:107-12.  Back to cited text no. 1
Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-46.  Back to cited text no. 2
Vecchio FM, Valentini V, Minsky BD, Padula GD, Venkatraman ES, Balducci M, et al. The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer. Int J Radiat Oncol Biol Phys 2005;62:752-60.  Back to cited text no. 3
Ruo L, Tickoo S, Klimstra DS, Minsky BD, Saltz L, Mazumdar M, et al. Long-term prognostic significance of extent of rectal cancer response to preoperative radiation and chemotherapy. Ann Surg 2002;236:75-81.  Back to cited text no. 4
Gerard JP, Chapet O, Nemoz C, Hartweig J, Romestaing P, Coquard R, et al. Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: The lyon R96-02 randomized trial. J Clin Oncol 2004;22:2404-9.  Back to cited text no. 5
Klautke G, Feyerherd P, Ludwig K, Prall F, Foitzik T, Fietkau R. Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer. Br J Cancer 2005;92:1215-20.  Back to cited text no. 6
De Paoli A, Chiara S, Luppi G, Friso ML, Beretta GD, Del Prete S, et al. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: A multicentric phase II study. Ann Oncol 2006;17:246-51.  Back to cited text no. 7
Francois Y, Nemoz CJ, Baulieux J, Vignal J, Grandjean J, Partensky Ch, et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: The Lyon R90-01 randomized trial. J Clin Oncol 1999;17:2396.  Back to cited text no. 8
Gasparini G, Longo R, Sarmiento R, Morabito A. Inhibitors of cyclo-oxygenase 2: A new class of anticancer agents? Lancet Oncol 2003;4:605-15.  Back to cited text no. 9
Davis TW, O'Neal JM, Pagel MD, Zweifel BS, Mehta PP, Heuvelman DM, et al. Synergy between celecoxib and radiotherapy results from inhibition of cyclooxygenase-2-derived prostaglandin e2, a survival factor for tumor and associated vasculature. Cancer Res 2004;64:279-85.  Back to cited text no. 10
Brown DC, Gatter KC. Monoclonal antibody k-i67. Its use in histopathology. Histopathology 1990;17:489-503.  Back to cited text no. 11
Gerdes J, Schwab U, Lemke H, Stein H. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer 1983;31:13-20.  Back to cited text no. 12
Tiefenbacher U, Wenz F. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. Strahlenther Onkol 2001;177:682-4.  Back to cited text no. 13
Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 1997;336:980-7.  Back to cited text no. 14
Debucquoy A, Libbrecht L, Roobrouck V, Goethals L, McBride W, Haustermans K. Morphological features and molecular markers in rectal cancer from 95 patients included in the European Organisation for Research and Treatment of Cancer 22921 trial: Prognostic value and effects of preoperative radio (chemo) therapy. Eur J Cancer 2008;44:791-7.  Back to cited text no. 15
Coucke PA, Notter M, Stamm B, Matter M, Fasolini F, Schlumpf R, et al. Preoperative hyper-fractionated accelerated radiotherapy (HART) in locally advanced rectal cancer (LARC) immediately followed by surgery. A prospective phase II trial. Radiother Oncol 2006;79:52-8.  Back to cited text no. 16
Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-40.  Back to cited text no. 17
Nix P, Lind M, Greenman J, Stafford N, Cawkwell L. Expression of Cox-2 protein in radioresistant laryngeal cancer. Ann Oncol 2004;15:797-801.  Back to cited text no. 18
Kim YB, Kim GE, Pyo HR, Cho NH, Keum KC, Lee CG, et al. Differential cyclooxygenase-2 expression in squamous cell carcinoma and adenocarcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 2004;60:822-9.  Back to cited text no. 19
Smith FM, Reynolds JV, Kay EW, Crotty P, Murphy JO, Hollywood D, et al. COX-2 overexpression in pretreatment biopsies predicts response of rectal cancers to neoadjuvant radiochemotherapy. Int J Radiat Oncol Biol Phys 2006;64:466-72.  Back to cited text no. 20
Bouzourene H, Yan P, Sandmeier D, Zouhair A, Matter M, Vuilleumier H, et al. The role of COX-2 in rectal cancer treated with preoperative radiotherapy. Virchows Arch 2008;452:499-505.  Back to cited text no. 21
Min BS, Choi YJ, Pyo HR, Kim H, Seong J, Chung HC, et al. Cyclooxygenase-2 expression in pretreatment biopsy as a predictor of tumor responses after preoperative chemoradiation in rectal cancer. Arch Surg 2008;143:1091-7.  Back to cited text no. 22
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.  Back to cited text no. 23
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 1984;133:1710-5.  Back to cited text no. 24
Kikuchi M, Mikami T, Sato T, Tokuyama W, Araki K, Watanabe M, et al. High Ki67, Bax, and thymidylate synthase expression well correlates with response to chemoradiation therapy in locally advanced rectal cancers: Proposal of a logistic model for prediction. Br J Cancer 2009;101:116-23.  Back to cited text no. 25
Hanna E, Shrieve DC, Ratanatharathorn V, Xia X, Breau R, Suen J, et al. A novel alternative approach for prediction of radiation response of squamous cell carcinoma of head and neck. Cancer Res 2001;61:2376-80.  Back to cited text no. 26
Rebischung C, Gérard JP, Gayet J, Thomas G, Hamelin R, Laurent-Puig P. Prognostic value of P53 mutations in rectal carcinoma. Int J Cancer 2002;100:131-5.  Back to cited text no. 27
Rau B, Sturm I, Lage H, Berger S, Schneider U, Hauptmann S, et al. Dynamic expression profile of p21WAF1/CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy. J Clin Oncol 2003;21:3391-401.  Back to cited text no. 28


  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]

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