Elevated Levels of Apoptosis Regulator Proteins P53 and BCL-2 are Independent Prognostic Biomarkers in Surgically Treated Clinically Localized Prostate Cancer

Purpose

The tumor suppressor gene (TSG) p53 and the proto-oncogene bcl-2 have been shown to be involved in the regulation of cell growth and apoptosis and have been implicated in hormone refractory prostate cancer (PC) and poor prognosis. The goal of this study was to determine the clinical utility of the presence of p53 and bcl-2 immunohistochemical (IHC) protein in the primary tumor as predictors of disease progression following radical prostatectomy (RP).

Materials and Methods

The expression of p53 and bcl-2 was evaluated in archival paraffin-embedded RP specimens from 175 patients followed from 1 to 9 years (mean = 4.6 years) and correlated with stage, grade, race and serologic (PSA) recurrence following surgery.

Results

Overexpression of bcl-2 was noted in 47 of 175 (26.9 percent) patients; these patients had a significantly higher 5-year failure rate than those who did not overexpress bcl-2 (67.0 percent versus 30.7 percent). Expression of p53 was noted in 114 of 175 (65.1 percent) patients with a 5-year failure rate of 51.1 percent compared with a 5-year failure rate of only 22 percent in p53 negative patients. When expression rates for p53 and bcl-2 were combined, the 5-year failure rate was 75.3 percent. Conversely, when both p53 and bcl-2 IHC staining were negative, the 5-year failure rate was 20.4 percent. Univariate Kaplan-Meier analysis showed a statistically significant difference between p53 and bcl-2 positive and negative patients (p less than 0.001). Multivariate Cox Regression Analysis with backward elimination controlling for age, race, stage and grade showed both p53 (p = .0185) and bcl-2 (p = .044) to be independent predictors of disease-free survival.

Conclusion

p53 and bcl-2 appear to be important biomarkers that predict recurrence in clinically localized PC after RP.     

Prognostic impact of HER-2/neu expression on squamous head and neck carcinomas

BACKGROUND: HER-2/neu gene amplification and protein overexpression have been identified in various solid tumors, but its prognostic relevance in head and neck squamous cell carcinoma (HNSCC) is still controversial. METHODS: The study investigated the expression of HER-2/neu oncoprotein in HNSCC and sought possible correlations to various clinicopathologic parameters. Expression of HER-2/neu oncoprotein was assessed in archival tumor tissues from 87 untreated HNSCC patients by immunohistochemical technique. Data were correlated with both the clinicopathologic parameters and patient survival. RESULTS: A high membranous HER-2/neu protein expression level was found in 39% of patients. Multivariate analysis indicated that HER-2/neu protein expression and pN lymph-node status were independent prognostic factors for disease-free survival. CONCLUSIONS: HER2/neu overexpression and its relationship with survival suggest that new therapeutic approaches targeting epidermal growth factor receptor (EGFR) family receptors could provide a new way of treating HNSCC patients with HER2/neu-positive neoplastic lesions.     

Microinvasive Breast Cancer: ER, PR, and HER-2/neu Status and Clinical Outcomes after Breast-Conserving Therapy or Mastectomy

Background

Contemporary clinical outcomes of microinvasive breast cancer (MIBC), defined as no focus >1 mm, are not well characterized. We document the immunophenotype, incidence of axillary metastases, and rate of recurrence in a well-defined case series.

Methods

We reviewed 83 consecutive patients with MIBC from 1997 to 2005. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2/neu) receptor status were assessed. The cumulative incidence of local recurrence (LR) and nodal/distant recurrence was calculated. Predictors of recurrence were identified and effect estimates determined.

Results

Fifty-two patients (63 %) underwent breast-conserving therapy (BCT) and 31 (37 %) underwent mastectomy. Sixty-one percent had ER-positive disease and 49 % had HER-2/neu-positive disease. Three (4 %) of 68 patients with sentinel node mapping or axillary dissection had single node micrometastases, and none had macrometastases or multiple nodes involved. Median follow-up was 6.4 years, with 6 LRs, 2 regional nodal recurrences, and 2 concurrent local/distant recurrences. The 5-year cumulative incidence of recurrence (local, nodal, or distant) was 5.3 % (95 % confidence interval [CI] 2.0–13.4) for all patients, and among BCT patients, the 5-year cumulative incidence of LR was 4.2 % (95 % CI 0.7–12.7). HER-2/neu overexpression was not associated with recurrence (P = 0.46). Close/positive margins (≤2 mm) were significantly associated with an increased risk of LR after BCT or mastectomy (hazard ratio 8.8; 95 % CI 1.6–48.8; P = 0.003).

Conclusions

MIBC has a favorable prognosis, and HER-2/neu overexpression, although highly prevalent, is not significantly associated with recurrence. Axillary metastases at diagnosis are small and infrequent. The cumulative incidence of LR after BCT is acceptable; however, our data confirm that negative margins (>2 mm) are required for optimal BCT outcomes.     

A comparative analysis of core needle biopsy and final excision for breast cancer: histology and marker expression

Background

Core needle biopsy (CNB) is used increasingly not only to diagnose breast cancer, but to determine tumor histology, grade and marker expression, select neoadjuvant therapy, and predict sentinel lymph node status. Thus, we undertook this study to evaluate the accuracy of CNB as a predictor of breast cancer histology and marker expression.

Methods

We identified 209 Breast Cancer Registry cases with a preoperative CNB and reviewed all clinicopathologic data for accuracy. Statistical analysis was performed with statistical software.

Results

CNB unequivocally showed cancer in 93%. Exact tumor histology concordance was 86%. Ductal carcinoma in situ on CNB was upgraded to invasive cancer in 23%. Concordance was substantial for estrogen receptor expression (88%, κ = .71), but kappa values were less than .6 for tumor grade, mitotic rate, progesterone receptor (PR), Ki-67, HER-2/neu, and p53 expression.

Conclusions

Reliance on CNB grade and marker expression for critical decision making may be inadvisable. Further study is warranted to optimize breast cancer patient care.     

p53, bcl-2 and Retinoblastoma Proteins as Long-Term Prognostic Markers in Localized Carcinoma of the Prostate

Purpose

The accumulation of p53 and bcl-2 gene products as well as the loss of the retinoblastoma (Rb) gene product have been associated with prostate cancer progression. We assessed whether the levels of immunoreactivity for p53, Rb and bcl-2 are better long-term predictors of disease specific survival than conventional pathological parameters of the primary tumor, such as Gleason score, capsular penetration, seminal vesicle invasion, and percent tumor in the specimen, in patients with clinically localized prostate cancer treated with radical prostatectomy.

Materials and Methods

A total of 71 patients with clinical stages A1 to B2 adenocarcinoma of the prostate underwent radical prostatectomy after a negative metastatic evaluation. No neoadjuvant or adjuvant treatments were given and causes of death were recorded. Prostatectomy specimens were analyzed to determine the conventional pathological parameters, and p53, Rb and bcl-2 immunohistochemical staining. Univariate and multivariate analyses were done to determine the independent contributions of p53, Rb and bcl-2 in predicting survival.

Results

On multivariate analysis the independent factors predicting disease specific survival were p53 staining score (p <0.001) and Rb staining score (p <0.001). In patients with p53 immunoreactive tumors the 15-year disease specific survival was 38% compared to 87% for those with less immunoreactivity. Analysis of Rb immunoreactivity for 15-year disease specific survival yielded 92 and 66% high and low staining levels, respectively. Best subset analysis revealed that the combination of p53 score and Rb score yielded the best predictive value for disease specific survival.

Conclusions

p53 and Rb immunohistochemical staining scores were independent predictors of disease specific survival and were superior to conventional pathological prognostic factors of the primary tumor. These findings lay the groundwork for the prospective study of these markers in patients treated with radical prostatectomy.     

Prognostic value of HER-2/neu and p53 expression in node-positive breast cancer. HER-2/neu effect on adjuvant tamoxifen treatment

HER-2/neu and p53 expression, conventional clinical and pathologic prognostic factors, were evaluated in a retrospective series of 283 node-positive breast cancer patients. Overexpression was determined by immunohistochemistry in formalin-fixed paraffin-embedded tissue blocks. Twenty one percent were HER-2/neu positive and 40% p53 positive. HER-2/neu expression was related to axillary lymph node metastasis (P=0.014), inflammatory infiltrates (P=0.004), and the absence of oestrogen (ER) (P=0.0026) and progesterone (P=0.01) receptors (PR). p53 expression was related to lymph node involvement (P=0.03), necrosis (P=0.036), absence of ER (P=0.028) and PR (P=0.065). p53 was not associated with outcome. HER-2/neu was an unfavourable prognostic factor for disease-free (DFS) (P=0.05) and overall survival (OS) (P=0.02) in univariate analysis. Multivariate analysis showed that the number of involved axillary nodes (P<0.00001), age (P=0.004), grade (P=0.04), and PR (P=0.04) were independent predictors for OS. ER-positive patients treated with adjuvant tamoxifen had shorter DFS and OS when they were HER-2/neu positive.     

Prognostic Value of Ki-67 for Recurrence and Progression of Superficial Bladder Cancer

Purpose

We retrospectively reviewed 104 cases of superficial bladder cancer to ascertain whether the Ki-67 labeling index predicts recurrence and progression.

Materials and Methods

Archival specimens from superficial bladder cancer cases were immunostained with Ki-67.

Results

The recurrence rate was significantly higher in cases with a Ki-67 labeling index of 5.35 or greater than in those with a value less than 5.35 (p <0.001). The recurrence rate at 2 years was 70% in cases with a Ki-67 labeling index of 5.35 or greater and 22% in those with an index less than 5.35 (p <0.001). Using multivariate analysis the index predicted recurrence of bladder cancer (p <0.005). Median Ki-67 labeling index in cases with progression was significantly higher than in those without progression (p <0.01).

Conclusions

The Ki-67 labeling index is an independent predictive factor for recurrence of superficial bladder cancer.     

Strong Correlation of Basement Membrane Degradation With P53 Inactivation and/or MDM2 Overexpression in Superficial Urothelial Carcinomas

Purposes

We investigated the relationships between the degradation of basement membrane underlying superficial urothelial carcinomas, including carcinoma in situ and the functional p53 loss caused by inactivation of p53 and the overexpression of mdm2 oncoprotein.

Materials and Methods

Nuclear accumulations of p53 and mdm2 were examined immunohistochemically for 60 transitional cell carcinomas (primary lesions) and 13 accompanying (concomitant) carcinoma in situ lesions. Degradation of the basement membrane was defined as the reduction or total loss of type IV collagen expression. Whether there was up-regulation of MMP-1, MMP-2, and MMP-9 was analyzed immunohistochemically.

Results

The frequency of the degradation of basement membrane underlying grade 1 pTa tumors was 0%, grade 2-3 pTa tumors 57.1%, and primary CIS lesions 83.3%. Nuclear over-accumulation of p53 was found in 48.3% and of mdm2 in 23.3% of the primary tumors. In pTa-pT1 carcinomas, nuclear staining of p53, mdm2, or both was highly correlated with degradation of the basement membrane underlying carcinomas (p = 0.00002). In the CIS lesions, the association of p53 nuclear staining with the destruction of type IV collagen expression was of borderline significance (p = 0.03). When mdm2 overexpression was considered as a molecular abnormality together with p53 inactivation, the correlation with the degradation of the basement membrane was highly significant (p = 0.00006). Moreover, the functional p53 loss was strongly associated with the up-regulation of matrix metalloproteinases (MMPs) (p = 0.0005). This finding was well correlated with the strong association of basement membrane degradation with up-regulation of MMPs (p = 0.000004).

Conclusions

Degradation of basement membranes underlying superficial carcinomas or CIS of the urothelium was significantly related to p53 inactivation, mdm2 overexpression, or both. The expression status of mdm2 should provide better information about the progression of superficial urothelial carcinomas than the status of p53 alone.     

Relationship of p53 and bcl-2 to Prognosis in Muscle-Invasive Transitional Cell Carcinoma of the Bladder

Purpose

We examined the presence of the p53 and Bcl-2 oncoproteins, as detected by immunohistochemistry, in muscle-invasive bladder cancer and correlated this with survival.

Materials and Methods

Formalin-fixed cystectomy specimens from 41 consecutive patients with mean follow-up of 52 months were used. Five patients were either lost to follow-up or died of other diseases and were not included in the survival evaluation.

Results

Eighteen of 36 patients died of metastatic transitional cell carcinoma. p53 immunostaining was found in 61 percent of patients. In 21 of 23 this staining was homogeneous, with more than 75 percent of cancer cells staining using a DO-1/DO-7 antibody cocktail. p53 staining was not correlated with stage (p greater than 0.25) or grade (p less than 0.10) in these invasive cancer specimens. Contrary to recent studies p53 immunostaining was not correlated with disease-specific survival. Bcl-2 immunostaining was found in 28 percent of patients and was not correlated with grade (p greater than 0.25) or disease-specific survival. No combination of p53 and Bcl-2 staining gave added predictive information.

Conclusions

Cytoplasmic Bcl-2 is found in a small percentage of these cancers and does not correlate with prognosis. Further, p53 molecular overexpression is detected in the majority of muscle-invasive bladder tumors as a field defect. However, in patients undergoing cystectomy, it does not correlate with prognosis.     

Detection of C-ERBB-2 Amplification in Transitional Cell Bladder Carcinoma Using Competitive PCR Technique

Purpose

We used competitive PCR to verify retrospectively the prognostic significance of c-erbB-2 oncogene amplification in transitional cell bladder carcinomas as a predictive index of patient survival with a maximum follow-up of nine years, and to investigate the variations of c-erbB-2 amplification during bladder carcinoma recurrence and/or progression from superficial to more invasive states.

Materials and Methods

Oncogene amplification was determined by an accurate and sensitive procedure based on competitive PCR. Measurements were performed in DNA extracted from fresh cancers or from formalin-fixed, paraffin-embedded tumor samples.

Results

The overall mean incidence of c-erbB-2 oncogene amplification was 26 percent (24/92), with a significant relationship with tumor grade (p less than 0.001). We did not find any statistical difference in survival probability between subjects with (20 percent) or without (30 percent) oncogene amplification. During tumor progression we observed a limited increase of tumors carrying oncogene amplification (2 of 20) whereas the mean degree of amplification was not affected.

Conclusions

c-erbB-2 amplification seems to be a genetic event related to the degree of bladder tumor differentiation. However the presence and/or the degree of this genetic alteration do not seem predictive of tumor progression, recurrence and survival probability, at least in patients with advanced transitional cell bladder carcinoma. These data seem to indicate that the amplification of c-erbB-2 in bladder carcinoma could be considered as an epiphenomenon, present in a subset of tumors but apparently not related to the clinical outcome.     

EXPRESSION OF BCL-2 AND BCL-X IN BLADDER CANCER

Purpose

TP53 and RB1 gene mutations in bladder transitional cell carcinoma (TCC) are correlated with grade, stage, recurrence, and survival and may correlate with tumor cell apoptotic potential. Overexpression of the bcl-2 and bcl-X anti-apoptotic genes has been correlated with poor prognosis and chemotherapy resistance in other systems. Similar studies have not been performed in TCC. We thus sought to determine expression of bcl-2 and bcl-X in TCC and correlate these with stage, survival and abnormal pRb or p53 expression.

Materials and Methods

Forty-two TCC samples (19 Ta and 23 locally advanced tumors) and normal urothelial controls were examined. Immunohistochemistry for p53, pRb, bcl-2 and bcl-X was performed on an automated system using indirect streptavidin biotin/horseradish peroxidase staining. Western immunoblot analysis was performed on bladder cancer cell lines to further characterize bcl-X expression. Recurrence-free and disease-specific survival were retrospectively determined. Kaplan-Meier survival curves were compared using the log rank test, and correlation of abnormal staining with stage and p53 or pRb status was determined using Fisher's exact test.

Results

Bcl-2 was expressed in less than 1% of normal urothelial cells, but moderate expression of bcl-x was found in all normal urothelial samples. Only 7.0% of TCC samples (1/19 Ta and 2/23 locally advanced tumors) demonstrated bcl-2 overexpression. Bcl-X overexpression was observed in 45.2% of TCC (8/19 Ta and 11/23 locally advanced tumors). Western blot analysis also revealed that both the long (29 kDa) anti-apoptotic form and short (19 kDa) pro-apoptotic form were overexpressed in bladder cancer cell lines and normal human urothelial cells. Bcl-X overexpression was weakly correlated with normal p53 expression (p = 0.06). There were no correlations of bcl-2 and bcl-X overexpression with abnormal p53, pRb, or tumor stage. There were no differences in recurrence-free or overall survival in patients with abnormal bcl-X staining.

Conclusions

Bcl-2 overexpression is rare in TCC. Bcl-X overexpression is common, likely reflecting its expression pattern in normal urothelium, but is not correlated with stage or abnormal p53 or pRb staining. Within the power limitations of this small study, bcl-X overexpression is not correlated with recurrence or survival.     

A Randomized Prospective Study Comparing Long-Term Intravesical Instillations of Mitomycin C and Bacillus Calmette-Guerin in Patients with Superficial Bladder Carcinoma

Purpose

We compared the efficacy and toxicity of long-term mitomycin C versus bacillus Calmette-Guerin (BCG) instillation in patients at high risk for recurrence and progression of superficial bladder carcinoma.

Materials and Methods

Our randomized comparison study included 261 patients with primary dysplasia, or stage Tis, stage T1, grade 3 and multiple recurrent stage Ta/T1, grade 1 or 2 disease. Mitomycin C (40 mg.) or Pasteur strain BCG (120 mg.) was instilled weekly for 6 weeks, then monthly for up to 1 year and every 3 months during year 2.

Results

After a median followup of 39 months 49 percent of the patients given BCG and 34 percent given mitomycin C were disease-free (p less than 0.03), compared to 48 and 35 percent, respectively, of those with stage Ta or T1 disease, and 54 and 33 percent, respectively, of those with dysplasia or stage Tis tumor. Tumor progressed in 13 percent of patients, with no statistically significant difference observed regarding progression between the mitomycin C and BCG groups. Side effects were more common after BCG instillation, with 5 cases of severe side effects compared to 1 in the mitomycin C group. Treatment was stopped due to toxicity in 10 percent of the patients.

Conclusions

The majority of patients tolerated long-term intravesical therapy well. BCG instillation was hampered by more frequent side effects. BCG was superior regarding recurrence prophylaxis, since patients given BCG had fewer recurrences and a significantly longer time to treatment failure compared to those treated with mitomycin C. No statistically significant difference was observed regarding progression.     

Coexistent Loss of the Expressions of BRCA1 and p53 Predicts Poor Prognosis in Triple-Negative Breast Cancer

Background

To investigate the prognostic significance of altered breast cancer susceptibility gene 1 (BRCA1) and p53 expression in triple-negative breast cancer (TNBC).

Methods

Immunohistochemical expression of BRCA1 and p53 was examined in the tumor tissues of 465 TNBC cases and relations were sought with clinicopathological features and patient survival.

Results

Loss of BRCA1 expression was found in 29.5% (137/465) of TNBCs. Positive expression of p53 was observed in 49.9% (232/465). Patients with loss of BRCA1 expression had a tendency to have higher rate of lymph node metastasis (p = 0.075). An association between p53 expression and high histological grade was observed (p = 0.039). TNBC patients with loss of BRCA1 expression had a tendency to have poorer overall survival (OS) than those positive for BRCA1 (p = 0.09). TNBC patients with positive p53 expression showed better OS than those with p53 negativity (p = 0.001). In terms of combined expression patterns, significantly poorer overall survival (OS) was observed for BRCA1-negative/p53-negative TNBCs and best OS for BRCA1-positive/p53-positive TNBCs (p = 0.005).

Conclusions

Combined expression patterns of BRCA1 and p53 could serve as useful prognostic markers in TNBC.

     

p53 Protein and Gene Alterations in Pathological Stage C Prostate Carcinoma

Purpose

We determined the extent of p53 immunoreactivity in pathological stage C prostate cancer as well as its correlation to tumor grade, substage, recurrence and proliferation rate. To define better the temporal relationship of p53 nuclear reactivity in prostate cancer p53 immunoreactivity was evaluated in all associated prostatic intraepithelial neoplasia lesions.

Materials and Methods

Using immunohistochemistry p53 status and proliferation rate were determined in 96 tumors from patients with pathological stage C prostate cancer. Single strand conformational polymorphism in exons 5 to 8 was used in a subset of specimens to assess the association of p53 nuclear accumulation with mutations in the p53 gene.

Results

p53 Nuclear reactivity was demonstrated in 10 tumors (10.4%), including 6 with high and 4 with low level nuclear reactivity. Of the tumors 86 (89.6%) had no evidence of p53 immunoreactivity. Each of the 6 tumors with high level p53 reactivity had associated areas of prostatic intraepithelial neoplasia that also showed p53 nuclear reactivity. Furthermore, pathological stage C substage (C1, 2 or 3) was significantly associated with p53 nuclear reactivity (p = 0.04). Proliferation rates were correlated with p53 nuclear reactivity (p = 0.09), while there was no association with tumor grade or recurrence. p53 Gene alterations were noted in 2 of the 3 p53 positive tumors versus no alterations in the p53 gene of 3 p53 negative tumors.

Conclusions

p53 Nuclear accumulation is uncommon in pathological stage C prostate cancer and its presence in premalignant prostatic intraepithelial neoplasia lesions suggests that it may be an early event in a subset of prostate cancers.     

Prognostic values of p53 and HER-2/neu coexpression in invasive bladder cancer in Taiwan

OBJECTIVES: To explore the clinical significance of p53 and HER-2/neu coexpression by immunohistochemistry in patients with invasive bladder cancer in Taiwan. METHODS: Paraffin-embedded tumor blocks were obtained from 67 patients with invasive bladder cancer subjected to radical cystectomy, bilateral lymph node dissection, and urinary diversion with or without systemic chemotherapy. Two observers (N.H.C. and T.S.T.), blinded to clinical outcome, reviewed the immunohistochemical staining for p53 (PAb1801) and HER-2/neu (Ab-17). The results were analyzed for progression-free survival and patient survival. RESULTS: Positive staining for p53 and HER-2/neu was found in 30 (44.8%) and 39 (58.2%) patients. In contrast to HER-2/neu, p53 expression was significantly associated with tumor grade and pathologic stage (p = 0.040 and 0.004, respectively), and tended to be related to the nodal status (p = 0.080). Most importantly, coexpression of p53 and HER-2/neu significantly correlated with nodal metastases (p = 0.020). Univariate and multivariate analysis revealed p53 and nodal status as two independent prognostic factors. Additionally, patients with p53 and HER-2/neu coexpression had the shortest time to relapse and overall survival, irrespective of whether adjuvant chemotherapy was given or not (p = 0.005 and 0.030). CONCLUSIONS: In invasive bladder cancer, p53 was an important prognostic factor since its expression correlated with tumor grade and stage, even nodal status, whereas HER-2/neu did not show prognostic significance. Tumors with p53 and HER-2/neu coexpression were associated with nodal metastases, probably resulting in decreased progression-free survival. Although some basic studies provide some important supports, studies including larger patient cohorts would still be required to prove the hypothesis that p53 and HER-2/neu-coexpressing tumors have a worse prognosis and are more resistant to a cisplatin-based multidrug regimen.     

Expression of cyclooxygenase-2 in breast carcinogenesis and its relation to HER-2/neu and p53 protein expression in invasive ductal carcinoma

The purpose of this study was to evaluate cyclooxygenase-2 (COX-2) expression in the successive steps of breast carcinogenesis and to determine its correlation with HER-2/neu and p53 expression in invasive ductal carcinomas of the breast. Immunohistochemical staining with anti-COX-2 antibody was performed in normal breast tissue, usual hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Expression of COX-2 in invasive ductal carcinoma was correlated with immunohistochemical expression of HER-2/neu and p53 protein. COX-2 expression was found to be progressively elevated along the continuum from normal breast tissue to invasive ductal carcinoma (P<0.001). COX-2 expression significantly correlated with p53 and HER-2/neu protein expression (P<0.05 and P<0.001). On multivariate analysis, only TNM stage and elevated COX-2 expression correlated with survival. Our results suggest that COX-2 may be involved in the carcinogenesis of the breast and may be an independent prognostic indicator in patients with invasive ductal carcinoma. HER-2/neu and p53 are likely to be involved in the regulation of COX-2 expression in invasive ductal carcinomas of the breast.     

THE MOLECULAR CHARACTERISTICS OF BLADDER CANCER IN YOUNG PATIENTS

Purpose

The molecular characteristics of bladder cancer in children and young adults remain largely undefined. We sought to identify common molecular changes in bladder tumors in young patients using standard immunohistochemical and interphase cytogenetic methods.

Materials and Methods

We retrospectively evaluated 73 bladder tumors removed from patients younger than 30 years for the p53 tumor suppressor gene product using immunohitochemical techniques and numerical aberrations of chromosomes 9, 17, X and Y.

Results

Regardless of stage, immunohistochemical evidence of p53 gene product over expression was found in the majority of tumors studied. Numerical abberations (mosomy) of chromosome 9 were rare. Aneuploidy of chromosome 17 was common, particularly in carcinoma in situ and invasive bladder cancer.

Conclusions

These data suggest that immunohistochemical evidence of p53 gene product over expression is common in bladder cancer in young patients. Further prospective analysis of lesions in this population may help to establish a comprehensive molecular progression model for urothelial neoplasms.     

HER2 Expression in Carcinomas of the True Cardia (Siewert Type II Esophagogastric Junction Carcinoma)

Objectives

To evaluate the HER2 status in patients with Siewert type II esophagogastric junction carcinoma.

Background

Trastuzumab is now approved for use in the treatment of human epidermal growth factor receptor 2 (HER2)-positive unresectable metastatic gastric or esophagogastric junction (EGJ) carcinoma. Several studies have evaluated HER2 status in EGJ carcinoma, but none has addressed the implication of HER2 positivity in patients with Siewert type II EGJ carcinoma.

Methods

We retrospectively evaluated the frequency of HER2 positivity in a large single-center cohort of 208 patients with Siewert type II tumors. The relations between HER2 expression and the outcomes and other clinicopathologic features were examined.

Results

Overall, 18.2 % (38/208) of patients in our cohort had HER2-positive tumors. HER2 positivity was associated only with differentiated carcinomas. The 5-year overall survival (OS) rate was 58.7 %. The 5-year OS rates in the patient groups with HER2-negative and HER2-positive tumors were 61.2 and 48.5 %, respectively. There was no significant difference between the groups. Recurrence in the liver was observed in 23.7 % patients of the HER2-positive group and 7.6 % patients of the HER2-negative group. Multivariate analysis to identify the risk factors for liver recurrence revealed only HER2 positivity (p = 0.0155) as an independent predictive factor.

Conclusions

HER2 positivity is a powerful predictor of liver recurrence in patients with Siewert type II EGJ carcinoma. Use of trastuzumab in combination with chemotherapy in an adjuvant setting can be a potentially useful therapeutic strategy to prevent hepatic recurrence in patients with resectable EGJ adenocarcinoma showing HER2 overexpression.