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Clinical Cancer Research Vol. 11, 3784-3789, May 15, 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Cyclooxygenase-2 Overexpression Is Associated with a Poor Outcome in Resected Ampullary Cancer Patients

Daniele Santini1, Bruno Vincenzi1, Giuseppe Tonini1, Susanna Scarpa2, Fortunata Vasaturo2, Carolina Malacrino2, Fabio Vecchio3, Domenico Borzomati1, Sergio Valeri1, Roberto Coppola1, Paolo Magistrelli3, Gennaro Nuzzo3 and Aurelio Picciocchi3

Authors' Affiliations: 1 University Campus Bio-Medico; 2 Department of Experimental Medicine and Pathology, University "La Sapienza"; and 3 Catholic University of the Sacred Heart, Rome, Italy

Requests for reprints: Giuseppe Tonini, Campus Bio-Medico University, Via Emilio Longoni, 83, 00155 Rome, Italy. Phone: 39-06-22541853; Fax: 39-06-22541520; E-mail: g.tonini{at}unicampus.it.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: To identify potential prognostic molecular factors in ampullary adenocarcinoma that could be of significant importance. To this end, we examined the possible prognostic significance of cyclooxygenase-2 (Cox-2) and Survivin expression and the apoptotic index in a cohort of uniformly treated patients with ampullary cancer treated with radical surgical excision.

Experimental Design: The entry criteria were that the patients have a pathologic diagnosis of ampullary cancer which had been resected. Expression analysis for Cox-2 and Survivin was done by immunohistochemical staining. Apoptotic cells were identified by the terminal deoxyribonucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) method.

Results: Thirty-nine tumor specimens from resected ampullary adenocarcinoma patients were included. By univariate analysis, overall survival was affected by Cox-2 expression and TUNEL staining (respectively, P = 0.0003 and 0.03). Survivin expression did not influence the overall survival in our patient population (P = 0.123). Patients' clinicopathologic features (gender, age, and T and N factors) did not influence outcome. In multivariate Cox regression analysis, Cox-2 expression (relative risk, 4.330; P = 0.005) was the only variable that significantly affected overall survival.

Conclusions: The results of the present article provide, for the first time, evidence that Cox-2 expression, but not Survivin expression, may represent a significant prognostic factor after surgical resection in patients affected by cancer of the ampulla of Vater. Further studies are required to determine whether Cox-2 inhibitors may be useful for the therapy or prevention of ampullary carcinoma.

Key Words: cancer of the ampulla • Cox-2 • Survivin • apoptosis • survival

Periampullary neoplasms (usually including extrahepatic bile ducts, pancreatic head, and ampulla of Vater cancers) are significant health problems worldwide and their management represents great challenges for the hepatobiliary specialist. Carcinoma of the ampulla of Vater is a relatively uncommon neoplasm, which accounts for ~6% to 7% of periampullary tumors and 0.2% of gastrointestinal tract malignancies (1), with age-standardized incidence rates of 3.8 per 1,000,000 inhabitants in men and 2.7 per 1,000,000 inhabitants in women (2). Five-year relative survival rates vary from 72.8% in tumor-node-metastasis stage I cancers to 6.6% in tumor-node-metastasis stage IV cancers. Most studies report a 5-year survival in 30% to 50% of resected patients (3, 4). The identification of independent prognostic factors in ampullary tumors has been limited by small numbers of tumor samples and a lack of pathologic review. Furthermore, independently from tumor-node-metastasis stage, any cancer stage includes both long-term survivors and short-term survivors. Literature still show few data on the role of clinical, histopathologic, and molecular factors in predicting length of survival. More specifically, there are only some interesting data that report on the role of allelic loss (loss of heterozygosity) of chromosomes 5q, 17p, and 18q as molecular significant prognostic markers for ampullary cancer patients (5–7). Achille et al. (5) reported that chromosome 5 allelic losses signify early events in tumors of the papilla of Vater. Moreover, Scarpa et al. (6) evaluated the prognostic role of loss of heterozygosity on chromosomes 17p and 18q in a cohort of 53 ampullary cancers. The authors, by the use of multivariate analysis, showed that chromosome 17p status is an independent prognostic factor in ampullary cancers at the same stage. Finally, Moore et al. (7) analyzed, by genomewide allelotyping on DNA obtained from frozen tissue, a total of 2,976 microsatellites. The resulting allelotype revealed that distinctive chromosomal alterations are present in ampulla of Vater cancers.

There is a need for a better understanding of the biology of ampullary adenocarcinoma, the identification of potential prognostic factors, and clinically relevant molecular targets for therapy. Among the regulators of apoptosis, interest has recently focused on Survivin, a novel, bifunctional member of the inhibitors of apoptosis (IAP) gene family that counteracts cell death and controls mitotic progression. Survivin is a member of the IAP family (endogenous caspase inhibitors), has an antiapoptotic function, and is expressed during human fetal development, but is not detectable in normal adult tissues, except for in the thymus and placenta (8–10). Survivin is expressed in most malignant cells, including those of pancreatic, gastric, colonic, lung, breast, prostatic, and bladder cancers, neuroblastomas, and lymphomas (11–18). The prognostic role of Survivin in human cancer is still a debatable matter; most data obtained from these studies suggest that Survivin expression in cancer seems to be associated with unfavorable clinicopathologic variables such as poor prognosis with progressive diseases and shorter patient survival rates (11, 12, 14–17). However, it must be pointed out that recent publications report a possible favorable prognostic role of the nuclear expression of Survivin in several cancers such as osteosarcoma (19), breast (16) and gastric (20) cancer, as well as in pediatric ependymomas and choroid plexus tumors (21). At the moment there is no study of the prognostic role of Survivin in ampullary carcinoma in literature. Cyclooxygenase (Cox) is a rate-limiting enzyme involved in the conversion of arachidonic acid to H2-prostaglandin, the precursor of several molecules including prostaglandins, prostacyclins, and thromboxanes. Two Cox genes, Cox-1 and Cox-2, have been identified. Cox-1 is constitutively expressed in many tissues and is involved in several physiologic functions including the cytoprotection of the stomach, vasodilation in the kidney, and the production of a proaggregatory prostanoid, thromboxane, by the platelets. On the other hand, Cox-2 is an inducible gene originally found to be induced by an inflammation or by a variety of other stimuli, such as mitogens, cytokines, and growth factors (22, 23). Recent studies have stressed the potential role of Cox-2 in carcinogenesis. During recent years, the induction of Cox-2 has been reported in colorectal, gastric, breast, esophagus, and lung carcinomas (24–28). There is also strong evidence that Cox-2 overexpression is inversely correlated with the prognosis of several cancers as breast, gastric, lung, cervical, ovarian cancers, and mesothelioma (29–34). Moreover, overexpression of Cox-2 has recently been found in various histologic types of pancreatic carcinomas and so suggests that Cox-2 inhibitors could potentially be effective in countering the development and/or progression of human pancreatic carcinoma (35–37). Only Kim et al. (38) have investigated the prognostic role of Cox-2 overexpression in ampullary cancer but have not defined its correlation with survival or other clinicopathologic factors. Little is known about the expression and the prognostic role of Cox-2 and Survivin in human ampullary carcinoma. This study is the first in the literature to examine the possible prognostic significance of the expression of Survivin and Cox-2 in relation to the modulation of the apoptotic pathway in a homogeneous cohort of radically resected ampullary cancer patients.


   Patients and Methods
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 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Clinical data and tumor specimen acquisition. All patients were consecutively treated at the Catholic University School of Medicine of Rome and at the University Campus Bio-Medico of Rome from January 1986 to April 2003. All patients underwent surgical resection for tumors of ampullary origin and only patients with no residual disease were considered suitable for the study. All patients were staged before surgery by thorax, abdomen, and pelvis computerized tomography scans, by liver palpation and, when indicated, by intraoperative ultrasound of the liver with an aim of excluding the presence of distant metastases. Data on clinical variables, including sex, age, preoperative assessment of disease state, and type of operative procedure, were gathered retrospectively from patient records. Pathologic findings (tumor size and spread and lymph node status) were obtained from the pathologists' original reports. In addition to the original pathology reports, microscopic findings (tumor type, degree of differentiation, and tumor-node-metastasis classification) were reassessed by our pathologists. Tumors were classified in accordance with the International Union Against Cancer variables (39). Survival was defined as from the date of initial surgery to the date of death or the last contact. Follow-up data were available for all included patients.

Histology. The formalin-fixed, paraffin-embedded samples were sectioned at 5 µm and stained with H&E. The histologic diagnosis were reexamined by two independent pathologists. In addition, the most representative blocks of each patient were selected to be cut into new 5-µm-thick sections for immunohistochemical studies.

Immunohistochemistry and quantification of the immunoreactivity. Immunohistochemical studies were done on 5-mm sections by the streptavidin-biotin-peroxidase system using a commercial kit (UCS Diagnostic, West Logan, UT) in accordance with the instructions of the manufacturer. In brief, sections were deparaffinized and antigen retrieval was achieved by steaming slides for 35 minutes. Endogenous peroxidase was blocked using 3% H2O2 solution in PBS for 5 minutes. The following primary antibodies were used: rabbit polyclonal anti-Survivin (ABcam, Cambridge, United Kingdom), goat polyclonal anti–Cox-2 (Santa Cruz Biotechnologies, Santa Cruz, CA). Sections were counterstainded with hematoxylin and mounted. The primary antibody was replaced with rabbit or goat preimmune serum as a negative control for nonspecific staining. The stained sections were observed using a light microscope, and positivity was determined by cell staining. Antigens were then quantified according to the following two variables: (a) the number of positively stained cells and (b) the intensity of the staining, ranging from pale pink to dark orange.

The Cox-2 and Survivin positivities were graded on the basis of the intensity and the number of positive cells: 0, negative; +1, weak to moderate positive affecting less than 50% of the tumor area; +2, weak to moderate positive on the majority of the tumor or strong positive in the minority of the tumor; and +3, strong positive in the majority of the tumor area. The specimens with a grade of more than +1 were regarded as positive, and 0 grade as negative. These scorings were done in a blinded fashion.

Detection of apoptosis. Apoptotic cells were identified by the terminal deoxyribonucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) method. Dewaxed and rehydrated specimens were incubated in 40 µg/mL proteinase K for 1 hour at 37°C and were treated with 3% H2O2 in methanol for 30 minutes at room temperature. After adding an equilibration buffer for 5 minutes at room temperature, terminal deoxynucleotidyl transferase enzyme was pipetted onto the sections and incubated at 37°C for 2 hours. The reaction was stopped by incubating the sections in stop buffer for 30 minutes at 37°C. The biotinylated dUTP molecules incorporated into nuclear DNA were made visible by incubation with horseradish peroxidase–conjugated streptavidin (Dako, Glostrup, Denmark) diluted 1:100 at 37°C for 30 minutes in a moist chamber. After further rinsing of the sections in PBS thrice for 5 minutes, the peroxidase coloring reaction was done by immersing the sections for 5 minutes in 0.05 mol/L Tris-HCl buffer (pH 7.4), containing 30 mg/dL diaminobenzidine tetrahydrochloride, 65 mg/dL sodium azide, 10 mmol/L imidazole, and 0.005% H2O2. The nuclei were counterstained with 5% Mayer's hematoxylin buffered with 0.1 mol/L veronal acetate (pH 4.0) for 10 seconds. A specimen known to be positive for apoptotic cells was used as the positive control for subsequent staining. For the negative control, terminal deoxynucleotidyl transferase was replaced with distilled water. The sections were counterstained with hematoxylin. A total of 500 cells were counted in each specimen. The apoptotic index was defined as follows: apoptotic index (%) = 100 x apoptotic cells/total cells. We stratified tumor specimens according to TUNEL staining in <10% or >10% stained cells.

Statistical analysis. A univariate survival analysis for each prognostic variable on overall survival was estimated as by the Kaplan-Meier method (40). The terminal event was death, attributable to cancer or noncancer causes. The statistical significance of the differences in survival distribution among the prognostic groups was evaluated by the log-rank test (41). The Cox proportional hazards model was applied to the multivariate survival analysis (42). The prognostic variables on overall survival included age, gender, T and N factors, TUNEL staining, cytoplasmic Survivin expression, and cox-2 expression.

P < 0.05 was regarded as statistically significant in two-tailed tests. SPSS software (version 10.00, SPSS, Chicago, IL) was used for statistical analysis.


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics. The cohort of patients (Table 1) consisted of 39 patients with pathologic diagnosis of ampullary cancer (20 men and 19 women) undergoing pancreaticoduodenectomy. The median age at diagnosis was 62.3 years (range 38-78). The main histopathologic tumor features are summarized in Table 1. The median duration of follow-up after surgery was 51 months (range 13-102). The median overall survival was 46 months (range 6-100) and the 1-, 3-, and 5-year overall survivals were 89.7%, 28.2% and 25.5%, respectively. After a median follow-up of 51 months, 24 patients (61.5%) are still alive without evidence of disease, 2 patients (5.1%) are alive with recurrence of disease, and 13 patients (33.4%) are dead (9 patients died of ampullary carcinoma). Adjuvant radiotherapy and/or chemotherapy for ampullary cancer was not routinely offered in the hospitals involved in the study.


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  		Table 1. Patient characteristics

 
Cox-2, Survivin, and TUNEL staining. Table 2 summarizes the results from the immunohistochemical analysis of 39 ampullary carcinoma specimens from radically resected patients. The expression analysis of Cox-2 revealed that in 24 of 39 (61.5%) specimens Cox-2 staining was positive (Fig. 1A). Cox-2 expression was always cytoplasmic. TUNEL staining was present in more than 10% of the observed cancer cells in 24 ampullary cancer specimens (61.5%; Fig. 1B). Moreover, the expression analysis of Survivin revealed that in 36 of 39 (92.3%) specimens no nuclear expression was recorded (data not shown), whereas in 16 (41.0%) specimens the cytoplasmic staining for Survivin was positive (Fig. 1C) and in the other 23 specimens (59.0%) the cytoplasmic staining was negative.


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  		Table 2. Immunohistochemical variables in ampullary adenocarcinoma patients

 


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  		Fig. 1. A, immunostaining of Cox-2 (magnification, x20). *, stromal tissue; **, tumoral tissue. B, TUNEL staining (magnification, x100). C, cytoplasmic immunostaining of Survivin (magnification, x20). *, stromal tissue; **, tumoral tissue.

 
Immunohistochemical and clinicopathologic variables and patient survival. To determine the prognostic effect of Survivin and Cox-2 protein expression and TUNEL staining in a univariate survival analysis, patients were stratified according to the dichotomized variables (criteria as stated above) in positive (Survivinpositive, cox-2positive, and TUNELhigh apoptotic index) versus negative (Survivinnegative, cox-2negative, and TUNELlow apoptotic index). The main clinicopathologic patient features (gender, age, and T and N factors) were included in the univariate analysis. By univariate analysis, overall survival was not influenced by the clinicopathologic patients' features (Table 3). Moreover, between the molecular factors analyzed, only Cox-2 expression and TUNEL staining seemed to influence overall survival. In particular, those patients with overexpression of Cox-2 showed a shorter overall survival (P = 0.0003) and those with high TUNEL staining showed a longer survival (P = 0.03; Table 3). The median survival time in patients with high Cox-2 expression was only 16 versus 73 months in those with low Cox-2 expression. The median survival time in patients with high apoptotic index, evaluated by TUNEL method, was 122 versus 44 months in those with low apoptotic index (Table 3). The Kaplan-Meier method was used to examine the effect of Survivin and Cox-2 overexpression and of high apoptotic index evaluated by TUNEL method on overall survival in patients radically resected for an ampullary cancer. The Kaplan-Meier survival plots for all patients showed a statistically significant association between either a low apoptotic index (Fig. 2) or low Cox-2 expression (Fig. 3) and better outcome (P = 0.03 and 0.0003, respectively), whereas Survivin levels (Fig. 4) did not significantly associate with clinical outcome (P = 0.123). The results of the multivariate survival analysis are given in Table 4. All variables that reached significance in the univariate survival analysis were incorporated in the multivariate analysis, with disease-related survival used as primary end point. In this model, only Cox-2 expression was defined as an independent prognostic factor. The calculated relative risk of death in ampullary cancer patients with high Cox-2 expression was significantly higher (relative risk, 4.330; P = 0.005). The other immunohistochemical variables associated with prognosis in univariate analysis (TUNEL staining) did not influence overall survival when evaluated by multivariate analysis as single prognostic factors (relative risk, 1.989; P = 0.201).


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  		Table 3. Univariate analysis of survival in radically operated ampullary adenocarcinoma patients

 


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  		Fig. 2. Kaplan-Meier survival curves for radically resected ampullary cancer patients: TUNEL staining (>10% versus <10%).

 


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  		Fig. 3. Kaplan-Meier survival curves for radically resected ampullary cancer patients: Cox-2 expression (Cox-2 positive versus Cox-2 negative).

 


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  		Fig. 4. Kaplan-Meier survival curves for radically resected ampullary cancer patients: cytoplasmatic Survivin expression (Survivin positive versus Survivin negative).

 

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  		Table 4. Multivariate analysis of survival in radically operated ampullary adenocarcinoma patients

 

   Discussion
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 Abstract
 Patients and Methods
 Results
 Discussion
References
 
There are few substantial data reporting significant prognostic markers for ampullary cancer patients. The influence of pathologic (tumor size, lymph node involvement, status of resection margins, and perineural invasion), surgical (aggressive surgical approach versus limited resection), and biological (p53, c-erbB2, bax-2, and apoptotic index) factors is inconclusive (43–47). An increasing interest is now focused on molecular markers to select patients with better prognosis and, therefore, in need of more aggressive treatments. For these reasons, for the first time in literature, we have attempted to characterize the expression, examining the possible prognostic significance, of Survivin and Cox-2 in a homogeneous cohort of patients with radically resected cancer of the ampulla of Vater. Only Kim et al. (38) have investigated the prognostic role of Cox-2 overexpression in ampullary cancer but failed to show any correlation with survival and other clinicopathologic factors. On the other hand, Sarela et al. (48) evaluated the expression of Survivin on 52 pancreatic and 12 ampullary adenocarcinomas. Although Survivin overexpression was pointed out in 83% of cases, survival was not influenced by the expression of this protein. Our cohort of ampullary carcinoma patients is well selected for radical surgery and well documented for clinicopathologic variables and for clinical and outcome data. According to the results of Sarela et al. (48), our study has shown that cytoplasmic expression of Survivin does not reach a prognostic role in ampullary cancer. On the other hand, for the first time in the literature, we report a statistically significant association between high Cox-2 expression and poor clinical outcome with the Kaplan-Meier survival plots. Furthermore, when variables affecting survival in the univariate survival analysis were incorporated in a multivariate analysis, only Cox-2 expression retained an independent prognostic significance. As a consequence, the calculated relative risk of death in ampullary cancer patients with high Cox-2 expression was significantly higher (relative risk, 4.330; P = 0.005). The recorded positive statistically significant correlation with survival suggests that, in ampullary carcinoma, Cox-2 plays a relevant role in determining the biological phenotype and the aggressiveness of tumor. The mechanisms by which Cox-2 is up-regulated and contributes to the poor prognosis of patients with carcinoma of the ampulla have not been elucidated to date. It is possible that cancer cells become intrinsically more active in expressing Cox-2 than do the nonneoplastic cells. Cox-2 expression has been linked to tumor invasion (49).

This data is supported by the observation that both lymph node metastasis and histologically detectable angioinvasion are correlated with increased expression of Cox-2 in several kinds of cancers (50, 51).

Other factors which showed to be involved in Cox-2–related pathways are induction of angiogenesis (52), suppression of apoptosis (53, 54), and suppression of antitumor immunity (55). The results of the present article provide evidence that Cox-2 may represent a significant prognostic factor in radically resected ampullary cancer patients. Knowledge of the factors with an independent prognostic power is crucial for the development and interpretation of prospective randomized trials in which patients are stratified according to these prognostic determinants. Preclinical animal model studies in several neoplasms have shown tumor reduction when animals are treated with either nonspecific or specific inhibitors of Cox-2 (56, 57). These studies propose that nonsteroidal anti-inflammatory drugs may act on multiple tumor-progression targets via both Cox-2–dependent and –independent pathways. The present study suggests a possible role of Cox-2 inhibitors in the prevention or therapy of ampullary carcinoma. Possible indications include adjuvant therapy for patients with radically resected ampullary carcinoma or for patients with metastatic or recurrent disease. Further studies aim to determine the utility of Cox-2 inhibitors in the treatment or prevention of ampullary carcinoma. In conclusion, our study seems to show that Cox-2 expression is a poor prognostic factor for patients with cancer of the ampulla of Vater and may represent a possible and appropriate target for novel targeted therapies.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/22/04; revised 1/17/05; accepted 2/15/05.


   References
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 Abstract
 Patients and Methods
 Results
 Discussion
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  1. Brennan MF. Surgical management of peripancreatic cancer. In: Bland KI, Karakousis CP, Copeland EM, editors. Atlas of Surgical Oncology. Philadelphia: WB Saunders Company; 1995. p. 473–85.
  2. Benhamiche AM, Jouve JL, Manfredi S, Prost P, Isambert N, Faivre J. Cancer of the ampulla of Vater: results of a 20-year population-based study. Eur J Gastroenterol Hepatol 2000;12:75–9.[Medline]
  3. Trede M, Schwall G, Saeger HD. Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality. Ann Surg 1990;211:447–58.[Medline]
  4. Howe JR, Klimstra DS, Moccia RD, Conlon KC, Brennan MF. Factors predictive of survival in ampullary carcinoma. Ann Surg 1998;228:87–94.[CrossRef][Medline]
  5. Achille A, Baron A, Zamboni G, Di Pace C, Orlandini S, Scarpa A. Chromosome 5 allelic losses are early events in tumours of the papilla of Vater and occur at sites similar to those of gastric cancer. Br J Cancer 1998;78:1653–60.[Medline]
  6. Scarpa A, Di Pace C, Talamini G, et al. Cancer of the ampulla of Vater: chromosome 17p allelic loss is associated with poor prognosis. Gut 2000;4446:842–8.
  7. Moore PS, Missiaglia E, Beghelli S, et al. Allelotype of ampulla of Vater cancer: highly frequent involvement of chromosome 11. J Cancer Res Clin Oncol 2004;11130:339–45.[CrossRef]
  8. Ambrosini G, Adida C, Altieri DC. A novel antiapoptosis gene, Survivin, expressed in cancer and lymphoma. Nat Med 1997;3:917–21.[CrossRef][Medline]
  9. Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitotic spindle checkpoint by Survivin. Nature 1998;396:580–4.[CrossRef][Medline]
  10. Adida C, Crotty PL, McGrath J, Berrebi D, Diebold J, Altieri DC. Developmentally regulated expression of the novel cancer anti-apoptosis gene Survivin in human and mouse differentiation. Am J Pathol 1998;52:43–9.
  11. Adida C, Berrebi D, Peuchmaur M, Reyes-Mugica M, Altieri DC. Anti-apoptosis gene, Survivin, and prognosis of neuroblastoma. Lancet 1998;351:882–3.[CrossRef][Medline]
  12. Kawasaki H, Altieri DC, Lu CD, Toyoda M, Tenjo T, Tanigawa N. Inhibition of apoptosis by Surviving predicts shorter survival rates in colorectal cancer. Cancer Res 1998;58:5071–4.[Abstract/Free Full Text]
  13. Lu CD, Altieri DC, Tanigawa N. Expression of a novel antiapoptosis gene, Survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res 1998;58:1808–12.[Abstract/Free Full Text]
  14. Swana HS, Grossman D, Anthony JN, Weiss RM, Altieri DC. Tumor content of the antiapoptosis molecule Survivin and recurrence of bladder cancer. N Engl J Med 1999;341:452–3.[Free Full Text]
  15. Hofmann HS, Simm A, Hammer A, Silber RE, Bartling B. Expression of inhibitors of apoptosis (IAP) proteins in non-small cell human lung cancer. J Cancer Res Clin Oncol 2002;128:554–60.[CrossRef][Medline]
  16. Kennedy SM, O'Driscoll L, Purcell R, et al. Prognostic importance of Survivin in breast cancer. Br J Cancer 2003;88:1077–83.[CrossRef][Medline]
  17. Schlette EJ, Medeiros LJ, Goy A, Lai R, Rassidakis GZ. Survivin expression predicts poorer prognosis in anaplastic large-cell lymphoma. J Clin Oncol 2004;22:1682–8.[Abstract/Free Full Text]
  18. Sarela AI, Verbeke CS, Ramsdale J, Davies CL, Markham AF, Guillou PJ. Expression of Survivin, a novel inhibitor of apoptosis and cell cycle regulatory protein, in pancreatic adenocarcinoma. Br J Cancer 2002;86:886–92.[CrossRef][Medline]
  19. Trieb K, Lehner R, Stulnig T, Sulzbacher I, Shroyer KR. Survivin expression in human osteosarcoma is a marker for survival. Eur J Surg Oncol 2003;29:379–82.[CrossRef][Medline]
  20. Okada E, Murai Y, Matsui K, et al. Survivin expression in tumor cell nuclei is predictive of a favorable prognosis in gastric cancer patients. Cancer Lett 2001;163:109–16.[CrossRef][Medline]
  21. Altura RA, Olshefski RS, Jiang Y, Boue DR. Nuclear expression of Survivin in paediatric ependymomas and choroid plexus tumours correlates with morphologic tumour grade. Br J Cancer 2003;89:1743–9.[CrossRef][Medline]
  22. Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A 1992;89:7384–8.[Abstract/Free Full Text]
  23. Jones DA, Carlton DP, McIntyre TM, Zimmerman GA, Prescott SM. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem 1993;268:9049–54.[Abstract/Free Full Text]
  24. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994;107:1183–8.[Medline]
  25. Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res 1997;57:1276–80.[Abstract/Free Full Text]
  26. Hwang D, Scollard D, Byrne J, Levine E. Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst 1998;90:455–60.[Abstract/Free Full Text]
  27. Wilson KT, Fu S, Ramanujam KS, Meltzer SJ. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett's esophagus and associated adenocarcinomas. Cancer Res 1998;58:2929–34.[Abstract/Free Full Text]
  28. Hida T, Yatabe Y, Achiwa H, et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 1998;58:3761–4.[Abstract/Free Full Text]
  29. Denkert C, Winzer KJ, Muller BM, et al. Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer 2003;97:2978–87.[CrossRef][Medline]
  30. Shi H, Xu JM, Hu NZ, Xie HJ. Prognostic significance of expression of cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma. World J Gastroenterol 2003;9:1421–6.[Medline]
  31. Khuri FR, Wu H, Lee JJ, et al. Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 2001;7:861–7.[Abstract/Free Full Text]
  32. Ferrandina G, Ranelletti FO, Legge F, et al. Prognostic role of the ratio between cyclooxygenase-2 in tumor and stroma compartments in cervical cancer. Clin Cancer Res 2004;10:3117–23.[Abstract/Free Full Text]
  33. Raspollini MR, Amunni G, Villanucci A, et al. Expression of inducible nitric oxide synthase and cyclooxygenase-2 in ovarian cancer: correlation with clinical outcome. Gynecol Oncol 2004;92:806–12.[CrossRef][Medline]
  34. Baldi A, Santini D, Vasaturo F, et al. Prognostic significance of cyclooxygenase-2 (Cox-2) and expression of cell cycle inhibitors p21 and p27 in human pleural malignant mesothelioma. Thorax 2004;59:428–33.[Abstract/Free Full Text]
  35. Okami J, Yamamoto H, Fujiwara Y, et al. Overexpression of Cyclooxygenase-2 in Carcinoma of the Pancreas. Clin Cancer Res 1999;5:2018–24.[Abstract/Free Full Text]
  36. Yip-Schneider MT, Barnard DS, Billings SD, et al. Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis 2000;2:139–46.
  37. Tucker ON, Dannenberg AJ, Yang EK, et al. Cyclooxygenase-2 Expression Is Up-Regulated in Human Pancreatic Cancer. Cancer Res 1999;59:987–90.[Abstract/Free Full Text]
  38. Kim HJ, Sohn TS, Lee KT, Lee JK, Paik SW, Rhee JC. Expression of cyclooxygenase-2 and its correlation with clinicopathologic factors of ampulla of vater cancer. J Korean Med Sci 2003;18:218–24.[Medline]
  39. Sobin LH, Wittekind C. TNM classification of malignant tumours: UICC International Union against Cancer. 5th ed. New York, NY: Wiley-Liss; 2002.
  40. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81.[CrossRef]
  41. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. Br J Cancer 1977;35:1–39.[Medline]
  42. Cox DR. Regression models and life tables. J R Stat Soc 1972;34:187–220.
  43. Todoroki T, Koike N, Morishita Y, et al. Patterns and predictors of failure after curative resections of carcinoma of the ampulla of Vater. Ann Surg Oncol 2003;10:1176–83.[Abstract/Free Full Text]
  44. Bakaeen FG, Murr MM, Sarr MG, et al. What prognostic factors are important in duodenal adenocarcinoma? Arch Surg 2000;135:635–41.[Abstract/Free Full Text]
  45. Howe JR, Klimstra DS, Moccia RD, Conlon KC, Brennan MF. Factors predictive of survival in ampullary carcinoma. Ann Surg 1998;228:87–94.
  46. Ajiki T, Kamigaki T, Hasegawa Y, et al. Proliferating cell nuclear antigen, p53, and c-erbB-2 expression in relation to clinicopathological variables and prognosis in cancer of the ampulla of Vater. Hepatogastroenterology 2001;48:1266–70.[Medline]
  47. Santini D, Tonini G, Vecchio FM, et al. Prognostic value of bax, bcl-2, p53 and TUNEL staining in patients with radically resected ampullary carcinoma. J Clin Pathol 2005;58:159–65.[Abstract/Free Full Text]
  48. Sarela AI, Verbeke CS, Ramsdale J, Davies CL, Markham AF, Guillou PJ. Expression of Survivin, a novel inhibitor of apoptosis and cell cycle regulatory protein, in pancreatic adenocarcinoma. Br J Cancer 2002;86:886–92.
  49. Shirahama T, Arima J, Akiba S, Sakakura C. Relation between cyclooxygenase-2 expression and tumor invasiveness and patient survival in transitional cell carcinoma of the urinary bladder. Cancer 2001;92:188–93.[CrossRef][Medline]
  50. Tatsuguchi A, Matsui K, Shinji Y, et al. Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue. Hum Pathol 2004;35:488–95.[CrossRef][Medline]
  51. Denkert C, Winzer KJ, Muller BM, et al. Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer 2003;97:2978–87.
  52. Davies G, Salter J, Hills M, Martin LA, Sacks N, Dowsett M. Correlation between cyclooxygenase-2 expression and angiogenesis in human breast cancer. Clin Cancer Res 2003;9:2651–6.[Abstract/Free Full Text]
  53. Moore BC, Simmons DL. Cox-2 inhibition, apoptosis, and chemoprevention by nonsteroidal anti-inflammatory drugs. Curr Med Chem 2000;7:1131–44.[Medline]
  54. Sun Y, Tang XM, Half E, Kuo MT, Sinicrope FA. Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells. Cancer Res 2002;62:6323–8.[Abstract/Free Full Text]
  55. Kojima M, Morisaki T, Uchiyama A, et al. Association of enhanced cyclooxygenase-2 expression with possible local immunosuppression in human colorectal carcinomas. Ann Surg Oncol 2001;8:458–65.[Abstract/Free Full Text]
  56. Yao M, Kargman S, Lam EC, et al. Inhibition of cyclooxygenase-2 by rofecoxib attenuates the growth and metastatic potential of colorectal carcinoma in mice. Cancer Res 2003;63:586–92.[Abstract/Free Full Text]
  57. Oshima M, Taketo MM. Cox selectivity and animal models for colon cancer. Curr Pharm Des 2002;8:1021–34.[CrossRef][Medline]



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B. Vincenzi, D. Santini, G. Perrone, A. Russo, V. Adamo, S. Rizzo, F. Castri, A. Antinori, R. Alloni, P. F. Crucitti, et al.
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