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D G Bostwick

Publications and source records attributed to D G Bostwick.

At least 73 records · Page 4Linked to original sources
PubMed1999

Overexpression of the EphA2 tyrosine kinase in prostate cancer.

BACKGROUND: Molecules that are highly expressed by human prostate cancers may serve as therapeutically relevant targets or tumor markers. Tyrosine kinases are frequently overexpressed in metastatic tumor cells and this prompted us to screen for tyrosine kinases that are overexpressed in prostate cancer cells. METHODS: Expression levels of the EphA2 receptor tyrosine kinase were determined by Western blot analysis in canine and human prostate cancer cell lines and in immortalized and transformed variants of 267B1 prostatic epithelial cells. EphA2 levels in benign human prostate and prostate cancers were also determined in formalin-fixed, paraffin-embedded tissues using immunohistochemical staining. RESULTS: Metastatic prostate cancer cells overexpressed EphA2 by 10-100 fold as compared with non-invasive prostatic epithelial cells. EphA2 immunoreactivity in vivo was also significantly greater in human prostate cancers as compared with benign prostate epithelium. CONCLUSIONS: The EphA2 receptor tyrosine kinase is differentially expressed in human and canine prostate cancer cell lines and overexpressed in human prostate cancers as compared with benign prostate tissues. Metastasis-derived canine prostate carcinoma cell lines overexpress EphA2 and may provide pre-clinical models to further evaluate the role of EphA2 in prostate carcinogenesis. Further investigations are needed to determine the utility of EphA2 as a tumor marker and a novel target in human prostate cancer.

Animals↗
PubMed1999

Urothelial papilloma of the bladder. Clinical and biologic implications.

BACKGROUND: An international consensus has been reached regarding diagnostic criteria for papilloma of the urinary bladder. However, the incidences of recurrence and progression in patients with urothelial papilloma are uncertain. METHODS: The population for this study consisted of 52 patients who were diagnosed with urothelial papilloma of the bladder at the Mayo Clinic between 1914 and 1998. All histologic slides were reviewed and fulfilled the diagnostic criteria of urothelial papilloma from the 1998 World Health Organization/International Society of Urological Pathology classification system. No patients had previous or coexistent urothelial carcinoma, and none were treated after biopsy. RESULTS: The mean patient age at diagnosis was 57 years (range, 22-89 years). The male-to-female ratio was 1.9:1. The mean follow-up was 9.8 years (range, 0.1-58 years). Four patients developed recurrent papilloma (mean interval from diagnosis to recurrence, 3.3 years); 1 other patient developed papillary neoplasm of low malignant potential (Ta WHO Grade 1 papillary urothelial carcinoma) 6 years after the initial diagnosis of papilloma. None of these patients developed dysplasia, carcinoma in situ, or invasive urothelial carcinoma or died of bladder cancer. CONCLUSIONS: Patients with urothelial papilloma have a low incidence of recurrence and rarely, if ever, develop urothelial carcinoma.

Adult↗
PubMed1999

Papillary urothelial neoplasms of low malignant potential. Clinical and biologic implications.

BACKGROUND: Knowledge of the long term outcomes of patients with papillary urothelial neoplasms of low malignant potential (LMP) is limited. METHODS: The authors studied 112 consecutive patients who were diagnosed with papillary urothelial neoplasms of LMP (formerly Ta, World Health Organization Grade 1 of 3 papillary urothelial carcinoma) at the Mayo Clinic between 1958 and 1963. All histologic slides were reviewed and fulfilled the diagnostic criteria of the 1998 World Health Organization/International Society of Urological Pathology classification system. RESULTS: Patient age at diagnosis ranged from 33 to 99 years (mean, 65 years). The male-to-female ratio was 3:1. The mean follow-up was 12.8 years (range, 0.1-35 years; median, 11.7 years). Twelve patients had biopsy-proven, noninvasive urothelial carcinoma; 17 patients had cystoscopically detected recurrences (all were treated by fulguration without biopsy); and 4 patients developed invasive urothelial carcinoma (including 2 with muscle-invasive carcinoma). Twelve (75%) of 16 patients with biopsy-proven recurrence or progression had cancer dedifferentiation, which resulted in a diagnosis of higher grade cancer than was indicated on initial biopsies. The mean interval from initial diagnosis to development of invasive carcinoma was 13.3 years (range, 10-14 years). Three patients died of bladder cancer. CONCLUSIONS: Patients with papillary urothelial neoplasms of LMP have increased risks of local recurrence, progression, and death from bladder carcinoma. Long term clinical follow-up may be indicated for patient management.

Adult↗
PubMed1999

Expression of cyclooxygenase-2 (COX-2) in human invasive transitional cell carcinoma (TCC) of the urinary bladder.

Cyclooxygenase (COX)-inhibiting drugs have antitumor activity in canine and rodent models of urinary bladder cancer. Two isoenzymes of COX have been identified, COX-1 and COX-2. The purpose of this study was to characterize COX-1 and COX-2 expression in human invasive transitional cell carcinoma of the urinary bladder by immunohistochemistry and Western blot analysis. COX-2 was not expressed in normal urinary bladder samples but was detected in 25 of 29 (86%) invasive transitional cell carcinomas of the urinary bladder and in 6 of 8 (75%) cases of carcinoma in situ. These results indicate that COX-2 may play a role in bladder cancer in humans and support further study of COX-2 inhibitors as potential antitumor agents in human bladder cancer.

Aged↗
PubMed1999

Correlation of margin status and extraprostatic extension with progression of prostate carcinoma.

BACKGROUND: The correlation of surgical margins and extraprostatic extension (EPE) with progression is uncertain with regard to prostate carcinoma patients treated by radical prostatectomy. The objective of this study was to define factors predictive of cancer progression; emphasis was placed on surgical margins and their relation to extraprostatic extension. METHODS: The study group consisted of 377 patients who were treated by radical retropubic prostatectomy and bilateral pelvic lymphadenectomy at the Mayo Clinic between 1986 and 1993. All specimens were totally embedded and whole-mounted. Patients ranged in age from 41 to 79 years (mean, 65 years). Those with seminal vesicle invasion or lymph node metastasis and those treated preoperatively with radiation or androgen deprivation were excluded. Final pathologic T classifications were pT2a (41 patients), pT2b (237), and pT3a (99). Progression was defined as biochemical failure (prostate specific antigen [PSA] >0.2 ng/mL), clinical or biopsy-proven local recurrence, or distant metastasis. The mean follow-up was 5.8 years (range, 0.2-11.4 years). Seventy-nine patients who received adjuvant treatment within 3 months after surgery were excluded from survival analysis. RESULTS: The overall margin positivity rate was 29%. Seventy-two patients (19%) had only positive surgical margins without evidence of EPE ("surgical incision"), 53 (14%) had only EPE, 37 (10%) had both, and 215 (57%) had neither. Positive margins were correlated with the finding of EPE (P = 0.003). Progression free survival rates at 5 and 10 years were 88% and 67%, respectively. In univariate analysis, preoperative PSA concentration, positive surgical margins, Gleason grade, cancer volume, and DNA ploidy were significant in predicting progression (P values, <0.001, <0.001, 0.01, 0.007, and <0.001, respectively). In multivariate analysis, margin status and DNA ploidy were independent predictors of progression (relative risk for margin status, 1.9; 95% confidence interval [CI], 1.1-3.4; P = 0.03; relative risk for DNA ploidy, 5.1; 95% CI, 2.4-10.9; P<0.001). Among patients with positive margins, 5-year progression free survival was 78% for those with negative EPE and 55% for those with positive EPE. CONCLUSIONS: Surgical margin status and DNA ploidy were independent predictors of progression after radical prostatectomy. To improve cancer control, adjuvant therapy may be considered for patients with positive surgical margins or nondiploid cancer.

Adult↗
PubMed1999

Substaging of T1 bladder carcinoma based on the depth of invasion as measured by micrometer: A new proposal.

BACKGROUND: A significant number of T1 bladder carcinoma patients are understaged by transurethral resection of the bladder (TURB), indicating a substantial need for more accurate staging. METHODS: The authors studied 55 patients with T1 bladder carcinoma detected by TURB at the Mayo Clinic between December 1979 and July 1984. The mean age of the patients was 66 years (range, 50-78 years). All patients were treated by cystectomy. The median interval from TURB to cystectomy was 10 days. Grading was performed according to the 1998 World Health Organization/International Society of Urologic Pathology grading system. The 1997 TNM classification was used for pathologic staging. In addition, the depth of invasion was measured from the mucosal basement membrane by micrometer. Receiver operating characteristic (ROC) analysis was used to evaluate the usefulness of depth of invasion as a marker for advanced stage bladder carcinoma (>/= T2). RESULTS: The final pathologic stages were Ta (2 patients), T1 (10 patients), T2a (9 patients), T2b (13 patients), T3 (11 patients), and T4 (10 patients) at cystectomy. There was a significant correlation between the depth of invasion at TURB and the final pathologic stage (Spearman correlation coefficient = 0.63; P < 0.001). The overall accuracy for the prediction of advanced stage (>/= T2) bladder carcinoma as measured by the area under the ROC curve was 0.89 (standard error, 0.05). Using 1.5 mm as a threshold (with >1.5 mm indicating advanced stage disease), the sensitivity, specificity, and positive and negative predictive values were 81%, 83%, 95%, and 56%, respectively. Histologic grade at the time of TURB also was associated significantly with final pathologic stage at cystectomy (P = 0.03) whereas stratification of patients according to invasion above or below the muscularis mucosae at TURB was not a significant predictor of final pathologic stage. CONCLUSIONS: The results of the current study show that substaging of T1 bladder carcinoma according to the depth of invasion (as measured by micrometer) provides significant prognostic information. Therefore the authors recommend that it be reported in specimens obtained by TURB.

Adult↗
PubMed1999

Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma.

BACKGROUND: Chromosome 8 alterations, including loss of 8p21-22 and gain of 8q24, are commonly observed in prostate carcinoma. We examined whether these alterations are associated with poor prognosis in prostate cancer. METHODS: We used dual-probe fluorescence in situ hybridization and DNA probes for 8p22 (lipoprotein lipase gene), centromere 8 (8cen), and 8q24 (c-myc gene) to determine the corresponding copy numbers in tumor samples from 144 patients with high-grade, advanced (stage III) prostate carcinoma. Cox models were used for multivariate analysis of systemic progression or patient death from prostate cancer. All statistical tests are two-sided. RESULTS: We classified the 8p22, 8cen, and c-myc copy number as normal, loss, and gain. An additional increase (AI) category of c-myc relative to the centromere copy number (i.e., overrepresentation and amplification of c-myc) was also used. Alterations of 8p22 were not statistically significantly associated with either systemic progression or patient death. Alterations of c-myc were associated with both systemic progression (P =.024) and patient death (P =.039); AI of c-myc showed the poorest outcome. We also evaluated the prognostic relevance of the combined 8p22-8cen-c-myc loci anomaly pattern for the following six patterns: normal-normal-normal, loss-any 8cen-normal, loss-gain-gain, gain-gain-gain, non-loss-any 8cen-AI, and loss-any 8cen-AI, where any 8cen is normal, loss, or gain of the chromosome 8 centromere. Patients with the loss-any 8cen-AI pattern had earlier systemic progression (P =.009) and earlier cause-specific death (P =.013) than did patients with other patterns. Multivariate analyses demonstrated that the loss-any 8cen-AI pattern was an independent risk factor for systemic progression (P<.001) and cause-specific death (P =.002). CONCLUSIONS: Genetic alterations of chromosome 8 appear to accumulate in parallel with the progression of prostate carcinomas. AI of the c-myc gene, especially with loss of 8p22, appears to be associated with poor patient prognosis.

Centromere↗
PubMed1999

Dedifferentiation in the metastatic progression of prostate carcinoma.

BACKGROUND: Dedifferentiation is a distinctive feature of cancer progression. Detailed histologic analysis of primary prostate carcinoma and synchronous lymph node metastases may improve our understanding of the complex process of cancer progression and metastasis. METHODS: The authors studied 242 regional lymph node positive prostate carcinoma patients who underwent radical prostatectomy and bilateral lymphadenectomy between 1987 and 1992 at the Mayo Clinic. Patients ranged in age from 47-79 years (median, 66 years). The median follow-up was 6.1 years. Gleason scores of lymph node metastases and primary tumors were compared and correlated with systemic disease progression. Histologic dedifferentiation was defined as a higher Gleason grade in the lymph node metastases than in the primary tumor. Systemic disease progression was defined as the presence of distant metastases documented by biopsies, abdominal computed tomography, plain radiograph, or bone scan. RESULTS: The 5-year systemic progression free survival (PFS) rate was 90%. The Gleason score in the lymph node metastases was higher than in the primary tumor in 45% of patients, lower in 12% of patients, and matched exactly in 43% of patients. The 5-year PFS was significantly different between patients with histologic dedifferentiation (88% +/- 3) and those without dedifferentiation (94% +/- 2) (P = 0.04). Adjusting for the Gleason grade of the primary tumor and total lymph node tumor volume, the relative risk for disease progression associated with dedifferentiation was 1.8 (95% confidence interval, 0.7-4.7; P = 0.25). CONCLUSIONS: The findings of the current study demonstrate the morphologic heterogeneity of metastases from prostate carcinoma. There is a trend toward histologic dedifferentiation when prostate carcinoma metastasizes to regional lymph nodes. This dedifferentiation, although univariately significant, was not associated with disease progression when adjusted for lymph node tumor volume.

Aged↗
PubMed1999

Hemangioma of the urinary bladder.

BACKGROUND: Hemangioma of the urinary bladder is rare and the long term outcome of patients is unknown. METHODS: The authors evaluated the clinical and pathologic findings in 19 patients with a vesical hemangioma. All patients were treated at the Mayo Clinic between 1932-1998 and had histologic confirmation of the diagnosis. Hemangioma was classified into cavernous, capillary, or arteriovenous types based on conventional criteria from other sites. Clinical information was obtained from chart review. The mean follow-up of the patients was 6.9 years (range, 0.3-25 years). RESULTS: The mean patient age at the time of diagnosis was 58 years (range, 19-76 years) and the male-to-female ratio was 3.7:1. Patients typically presented with macroscopic hematuria and endoscopic findings usually were nonspecific. The diagnosis of hemangioma was suspected in 3 patients (16%) prior to biopsy. There was a predilection for the posterior and lateral walls and the tumor usually was small (range, 0.2-3 cm; median, 0.7 cm) and solitary. The histologic types of hemangioma were cavernous (15 cases), capillary (2 cases), and arteriovenous (2 cases). All patients were treated with biopsy with or without fulguration, except for one patient who was treated with a partial cystectomy. No patients developed a recurrence during a mean follow-up of 6.9 years. CONCLUSIONS: Patients with hemangioma of the urinary bladder have a favorable outcome. Biopsy and fulguration are effective for hemangioma of the bladder when the lesion is small.

Adult↗
PubMed1999

Neurofibroma of the urinary bladder.

BACKGROUND: Neurofibroma of the urinary bladder is rare. Only isolated case reports have appeared. Information regarding the long term follow-up of patients with neurofibroma is limited. METHODS: The authors studied 4 cases of neurofibroma of the bladder diagnosed at Mayo Clinic from 1965 through 1990. Immunostains for S-100 protein, neurofilament protein, epithelial membrane antigen (EMA), cytokeratin (CAM 5.2; AE 1/3), Type IV collagen, MIB-1, and p53 protein were performed in all cases, as was Alcian blue at pH 2.5. The mean follow-up was 9.6 years (range, 2-18 years). RESULTS: The mean age at diagnosis was 17 years (range, 7-28 years); the male-to-female ratio was 1:1. All four patients exhibited physical stigmata of neurofibromatosis type 1. Clinical presentations included hematuria (one patient), irritative symptoms (two patients), and pelvic mass (one patient). Long term urinary complications included bladder atony (two patients), neurogenic bladder (one patient), and recurrent urinary tract infection with hematuria (one patient). Subsequently, two patients underwent partial cystectomy and one a complete cystectomy. Involvement of the bladder was generalized in all four cases. Three tumors were transmural, showing a diffuse and plexiform pattern of growth; in the fourth case, a superficial biopsy showed only diffuse submucosal growth with conspicuous pseudo-Meissnerian corpuscle formation. An Alcian blue positive, variably collagenized matrix was present in all cases. Tumor cells displayed immunoreactivity for S-100 protein and Type IV collagen in all cases. Neurofilament protein positive axons were evident in three cases; all other immunostains were negative. The mean MIB-1 labeling index was 3.2% (range, 0.9-7.3%). No malignant transformation was observed during a mean follow-up of 9.6 years. CONCLUSIONS: Neurofibroma of the bladder presents early in life, is of the plexiform type with a diffuse component, and usually occurs in the setting of generalized neurofibromatosis type 1 rather than as isolated visceral neurofibromatosis. Malignant transformation did not occur in any of these 4 patients during a mean follow-up time of 9.6 years.

Adolescent↗
PubMed1999

Tumor size predicts the survival of patients with pathologic stage T2 bladder carcinoma: a critical evaluation of the depth of muscle invasion.

BACKGROUND: Accurate examination of radical cystectomy specimens is critical for stratifying patients into prognostically important groups and determining the need for adjuvant treatment. Evidence has accumulated that cancers invading the superficial muscle wall (T2a) behave similarly to those invading the deep muscle wall (T2b). Quantitative analysis of the depth of invasion in relation to patient outcome is needed. METHODS: The authors systematically evaluated the depth of invasion by micrometer measurement and its relation to the survival of 64 patients with bladder carcinoma pathologic classification as pT2 who had long term follow-up after radical cystectomy. Numerous clinical and pathologic variables were analyzed with univariate and multivariate Cox proportional hazards models. The mean age of patients was 64 years, and their mean follow-up was 8.3 years. RESULTS: There was no significant difference in clinical outcome between patients with T2a carcinoma and those with T2b. Lymph node metastasis and tumor size were each significantly associated with distant metastasis free and cancer specific survival. Ten-year distant metastasis free and cancer specific survival were 100% and 94%, respectively, for patients with tumors <3 cm (P = 0.006) and 68% and 73%, respectively, for patients with tumors > or = 3 cm (P = 0.005). After adjustment for lymph node status, tumor size maintained significance in predicting distant metastasis free survival (risk ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.009) and cancer specific survival (risk ratio, 1.5; 95% confidence interval, 1.1-1.9; P = 0.01). Age was associated with recurrence free survival and all-cause survival. None of the other variables, including gender, vascular invasion, presence of carcinoma in situ, pathologic classification (T2a vs. T2b), depth of invasion, depth of muscle invasion, ratio of depth of invasion to bladder wall thickness, and percentage of muscle wall invasion, were significantly associated with patient outcome. CONCLUSIONS: The findings of this study indicate that the subclassification of T2 bladder carcinoma by depth of muscle invasion is of no prognostic value; conversely, tumor size, an easily measured factor, is predictive of distant metastasis free and cancer specific survival.

Adult↗
PubMed1999

The radial distance of extraprostatic extension of prostate carcinoma: implications for prostate brachytherapy.

BACKGROUND: Extraprostatic extension (EPE) is an unfavorable prognostic factor in patients with prostate carcinoma. Prior studies have reported the linear extent of EPE measured circumferentially along the edge of the prostate. In this study, the authors defined and evaluated a novel measure of EPE in a large series of radical prostatectomy specimens. These results have important clinical implications in the management of localized prostate carcinoma by brachytherapy and other modalities. METHODS: The authors reviewed the preoperative records and biopsy findings from 376 patients who underwent radical retropubic prostatectomy between September 1991 and June 1993. Whole mount radical prostatectomy specimens were examined, and the location of EPE for each specimen was recorded. The radial EPE distance was measured perpendicular to the edge of the prostate. For specimens with multiple EPE sites, the maximum radial EPE distance was recorded. Established eligibility criteria for prostate brachytherapy were evaluated using these results, with emphasis placed on achieving adequate radiation dose coverage 3-5 mm beyond the capsule or the edge of the prostate. RESULTS: EPE was identified in 105 of 376 specimens (28%) at 248 sites. The radial EPE distance in these specimens had a mean of 0.8 mm (range, 0.04-4.4 mm) and a median of 0.5 mm. Of these 105 patients, the median and mean preoperative prostate specific antigen (PSA) concentrations were 11.8 ng/mL and 17.9 ng/mL, respectively. The mean and range of the Gleason score and prostate volume for all specimens were 6.3 (range, 3-9) and 39 cc (range, 8-294 cc), respectively. In 107 patients who met the selection criteria for prostate brachytherapy eligibility of a PSA level < 10 ng/mL, Gleason score < 7, and gland volume < 60 cc, the maximum and mean radial EPE distances were 0.6 mm and 0.03 mm, respectively. CONCLUSIONS: The radial distance of EPE is an important measure that influences treatment strategies for patients with localized prostate carcinoma. Currently described criteria for the treatment of early stage prostate carcinoma by brachytherapy alone appear satisfactory to ensure effective radiation dose coverage of EPE of prostate tumors. Treating the prostate with a 3-5 mm margin by brachytherapy would encompass all known tumor in approximately 99% of the specimens examined in this study.

Aged↗
PubMed1999

p53 alteration in regional lymph node metastases from prostate carcinoma: a marker for progression?

BACKGROUND: Alterations of the p53 tumor suppressor gene are associated with advanced stage prostate carcinoma. The biologic significance of p53 nuclear accumulation in prostate cancer patients with regional lymph node metastases is uncertain. METHODS: The authors investigated p53 alterations by immunohistochemistry in 220 lymph node positive patients who were treated with radical prostatectomy, bilateral pelvic lymphadenectomy, and androgen deprivation therapy between 1987-1992 at the Mayo Clinic. The mean follow-up was 6.3 years. Tumor volume of lymph node metastases was measured using the grid method. RESULTS: p53 immunoreactivity was detected in 109 of 211 primary tumors (52%) and 83 of 144 matched regional lymph node metastases (58%); this expression was strongly concordant (correlation coefficient 0.53; P = 0.0001). Overexpression of p53 protein in lymph node metastases was associated with distant metastasis free survival by univariate analysis (P = 0.03), but did not reach statistical significance by multivariate analysis (P = 0.07). Regional lymph node cancer volume was the single most important predictor of distant metastases after adjusting for Gleason score, DNA ploidy, and p53 expression. CONCLUSIONS: The findings of the current study suggest that assessment of biologic changes (including p53 alterations in regional lymph node metastases) could be of value in the assessment of the biologic aggressiveness of prostate carcinoma, whereas p53 expression in the primary tumor does not appear to influence patient outcome.

Aged↗
PubMed1999

Survival of patients with carcinoma in situ of the urinary bladder.

BACKGROUND: To the authors' knowledge, the long term follow-up of patients with carcinoma in situ of the urinary bladder is limited. METHODS: The authors studied 138 patients diagnosed with urothelial carcinoma in situ of the bladder at the Mayo Clinic between 1972-1979. All the histologic slides were reviewed and fulfilled the diagnostic criteria for carcinoma in situ according to the newly proposed World Health Organization and International Society of Urologic Pathology classification system. None of these patients had previous or coexisting invasive urothelial carcinoma at the time of diagnosis. Cox proportional hazards models were used to determine the prognostic significance of numerous clinical and pathologic findings using progression free, cancer specific, and all-cause survival as the endpoints for analysis. Progression was defined as the development of invasive carcinoma, distant metastases, or death from bladder carcinoma. RESULTS: The patients ages at the time of diagnosis ranged from 32-90 years (mean, 65.6 years). The male to female ratio was 7:1. Carcinoma in situ usually was multifocal (50%) with a predilection for the trigone, lateral wall, and dome. The mean follow-up after surgery was 11.0 years (range, 0.7-25 years). Actuarial progression free, cancer specific, and all-cause survival rates were 63%, 79%, and 55%, respectively, at 10 years, and 59%, 74%, and 40%, respectively, at 15 years. The mean interval from the time of diagnosis to cancer progression was 5 years. Patient age at diagnosis was significant in predicting progression free (P = 0.01) and all-cause survival (P = 0.002). Cystectomy performed within 3 months after the initial diagnosis was associated with improved all-cause survival (P = 0.03). After controlling for age, there was no difference in survival between patients who received immediate cystectomy and those did not (P = 0.16). CONCLUSIONS: Patients with carcinoma in situ of the bladder are at significant risk of cancer progression and death from bladder carcinoma. Cystectomy does not appear to offer a significant survival advantage in patients with carcinoma in situ of the bladder after adjusting for age.

Adult↗
PubMed1999

Allelic imbalance in the clonal evolution of prostate carcinoma.

BACKGROUND: To understand better the genetic basis of the clonal evolution of prostate carcinoma, the authors analyzed the pattern of allelic loss in 25 matched primary and metastatic prostate tumors. METHODS: Twenty-five cases were selected from the surgical pathology files of the Mayo Clinic from patients who had undergone radical retropubic prostatectomy and bilateral lymphadenectomy between 1987-1991. All patients had regional lymph node metastases at the time of surgery. DNA samples for the analysis of allelic loss pattern were prepared from primary tumors and matched synchronous lymph node metastases by tissue microdissection. The oligonucleotide primer pairs for the microsatellite DNA markers were D8S133, D8S136, D8S137, ANK1 on chromosome 8p12-21, LPLTET on chromosome 8p22, and D17S855 (intragenic to the BRCA1 gene) on chromosome 17q21. One case was not informative at any of the loci tested and was excluded from further analysis. RESULTS: The overall frequency of allelic imbalance was 79% in primary tumors and 88% in paired metastases. Of 24 informative cases, 14 patients (58%) showed the same pattern of allelic loss or retention in matched primary and metastatic tumors at all marker locus; discordant allelic loss was observed in the remaining 10 patients (42%). Four patients showed loss of the same allele at one or more marker loci in both primary and metastatic tumors, but discordant allelic loss was observed at other marker loci. Five patients showed allelic loss in at least one genetic marker in the metastatic tumor but not in its matched primary tumor. Five patients displayed loss of one allele at one or more marker loci in a primary tumor but not in the matched metastases. There was no significant difference in the frequency of allelic imbalance between primary and metastatic tumors at any marker analyzed (P>0.05). CONCLUSIONS: These data suggest that different patterns of allelic deletion may be acquired during cancer progression to metastases. The differences in genetic composition between primary prostate carcinoma and its metastases may be related to intrinsic cancer heterogeneity, overall genetic instability, and clonal divergence.

Aged↗
PubMed1999

Predictors of cancer progression in T1a prostate adenocarcinoma.

BACKGROUND: The biologic behavior of T1a prostate adenocarcinoma is variable. A critical issue in the management of patients with T1a prostate adenocarcinoma is to distinguish those who will develop cancer progression from those who will not. Predictive factors that identify those at high risk of cancer progression are needed to stratify patients for treatment. In the current study the authors attempted to identify such predictors of cancer progression in a large series of untreated patients with lengthy follow-up. METHODS: The authors studied 102 patients who were diagnosed with T1a prostate adenocarcinoma (incidental tumor involving < or = 5% of the resected prostatic tissue) at the time they underwent transurethral resection of the prostate (TURP) at the Mayo Clinic between 1960-1970. None of these patients were treated. Patient ages ranged from 48-91 years (mean +/- standard deviation, 69 +/- 7 years). The average weight of the resected prostate tissue was 24 +/- 18 g (range, 3-115 g; median, 18 g). Tumor volume was measured by the grid method. Cox proportional hazards models were used to identify factors associated with cancer progression. Survival curves were estimated using the Kaplan-Meier method. RESULTS: Five-year and 10-year progression free survival rates were 93% and 87%, respectively. During the mean follow-up of 9.5 +/- 6.8 years (range, 0.3-31 years; median, 9.0 years), 14 patients developed clinical cancer progression, including 5 patients with systemic progression (1 with distant metastases and 4 who died of prostate adenocarcinoma). The interval from diagnosis to clinical cancer progression ranged from 1-23 years (mean, 7.3 years). The amount of resected prostate tissue (TURP weight) was associated with progression (P = 0.04). Patients with a TURP weight > or = 30 g had 100% progression free survival at 10 years compared with a progression free survival rate of 73% in patients with a TURP weight < 12 g. Gleason score, tumor volume, number of chips involved by tumor, number of tumor foci, and the presence of high grade prostatic intraepithelial neoplasia were not significant in predicting cancer progression. There was a trend toward a worse prognosis with the increasing number of chips involved by cancer (P = 0.16). Patients with < 3 chips involved by cancer had a 88% 10-year progression free survival rate compared with 73% in patients with > or = 3 chips involved by cancer. CONCLUSIONS: The clinical course of T1a prostate adenocarcinoma is variable. If left untreated, a small but significant proportion of patients are at risk for disease progression and death. However, the current study found that patients with a TURP weight > or = 30 g have an excellent prognosis and can be managed conservatively.

Adenocarcinoma↗
PubMed1999

p53 protein overexpression is associated with increased cell proliferation in patients with locally recurrent prostate carcinoma after radiation therapy.

BACKGROUND: The biologic changes in recurrent prostate carcinoma following radiation therapy are not fully understood. The authors sought to determine the level of p53 protein overexpression and its association with cellular proliferation (Ki-67 labeling index), glutathione S-transferase-pi (GST-pi) expression, and other clinical pathologic findings in patients with locally persistent prostate carcinoma after radiation therapy. METHODS: The authors investigated p53 nuclear accumulation, cellular proliferation activity (Ki-67 labeling index by digital image analysis), and GST-pi expression in 55 patients with persistent or recurrent prostate carcinoma after radiation therapy. All patients underwent salvage radical prostatectomy and bilateral pelvic lymphadenectomy following irradiation failure. The interval from radiation therapy to cancer recurrence ranged from 6 months to 17 years (mean, 3.8 years). Age at surgery ranged from 51 to 78 years (mean, 65 years). Mean follow-up after surgery was 5.7 years (range, 1-13 years). RESULTS: p53 protein overexpression was associated with increased cell proliferation (Spearman rank correlation coefficient = 0.29, P = 0.03). A substantial proportion (62%) of recurrent cancer also showed GST-pi immunoreactivity. No apparent correlation was observed between p53 protein overexpression, cellular proliferation (Ki-67 labeling index), or GST-pi expression and Gleason score, pathologic stage, DNA ploidy, or patient outcome. There was an inverse correlation between GST-pi expression and Gleason score (P = 0.06). The majority of prostate carcinomas (95%) were proliferative (mean Ki-67 labeling index, 7.0; range, 0-20), whereas concurrent prostatic intraepithelial neoplasia (PIN) had a lower Ki-67 labeling index (mean, 3.1; range, 0-11.5). Nineteen of 28 (68%) concurrent PIN demonstrated p53 immunoreactivity. A trend toward adverse clinical outcome was observed in patients with a higher Ki-67 labeling index in recurrent cancer. CONCLUSIONS: In this study cohort selected for salvage prostatectomy, recurrent cancers were biologically aggressive following radiation therapy. Whether this represents selective persistence and regrowth of prognostically unfavorable tumor clonogens or stepwise clonogenic progression is uncertain. Further investigation is needed to elucidate the correlation between p53 overexpression and the presence of other biologic changes after radiation therapy.

Aged↗