Biomedical subjects

Leslie A Mangold

Publications and source records attributed to Leslie A Mangold.

At least 19 recordsLinked to original sources

PubMed2006

Clinical and pathologic outcome after radical prostatectomy for prostate cancer patients with a preoperative Gleason sum of 8 to 10.

BACKGROUND: Men with a biopsy Gleason sum of 8 to 10 are considered high-risk. The current study sought to identify whether there was a subset of men with high biopsy Gleason sums who would have a good pathologic and biochemical outcome with surgical monotherapy. To increase the generalizability of the findings, data were used from patients treated at 2 very different practice settings: a tertiary care referral center (Johns Hopkins Hospital) and multiple equal-access medical centers (Shared Equal Access Regional Cancer Hospital [SEARCH] Database). METHODS: The data were retrospectively reviewed from men with biopsy Gleason sums 8 to 10 treated by radical prostatectomy at the Johns Hopkins Hospital (n = 220, 3.8% of total cohort) and within the SEARCH Database (n = 149, 7.7% of total cohort). The preoperative clinical characteristics predicting unfavorable pathologic disease (nonorgan-confined and/or positive surgical margins) and time to biochemical recurrence were determined using logistic regression and Cox proportional hazards analysis, respectively. RESULTS: Favorable pathologic outcome (organ-confined and negative surgical margins) was observed in 21% of the men in the Johns Hopkins cohort and 41% from the SEARCH cohort. On multivariate analysis, higher serum prostate-specific antigen (PSA) was the only variable that significantly predicted an unfavorable pathologic outcome from both the Johns Hopkins (P = .047) and SEARCH cohorts (P = .002). The 5-year and 10-year estimated biochemical-free survival rates in the Johns Hopkins cohort were 40% (95% confidence interval [CI], 33-48%) and 27% (95% CI, 18-36%), respectively, and 32% (95% CI, 22-42%) and 28% (95% CI, 18-38%) in the SEARCH cohort, respectively. Among men with favorable pathologic findings, the 5- and 10-year estimated biochemical-free survival rates in the Johns Hopkins cohort were 79% (95% CI, 62-89%) and 50% (95% CI, 25-71%), respectively, and 49% (95% CI, 32-65%) and 49% (95% CI, 32-65%) in the SEARCH cohort, respectively. No single preoperative variable significantly predicted the risk of biochemical progression in both the SEARCH or Johns Hopkins cohorts. CONCLUSIONS: The majority of men with a biopsy Gleason sum of >or=8, regardless of where the patient is treated, had unfavorable pathologic disease and experienced a biochemical progression after radical prostatectomy. Even among men with organ-confined disease and negative surgical margins or pathologic Gleason sum <8, at least half of the men experienced a PSA recurrence. Patients with biopsy Gleason sum 8 to 10 cancers are good candidates for multimodal therapy. Whereas multimodal therapy has often meant radiation plus hormonal therapy, newer possibilities for multimodal therapy exist such as surgery with neoadjuvant or adjuvant chemohormonal therapy or surgery with adjuvant radiation.

Aged↗

PubMed2006

Pathological outcomes and biochemical progression in men with T1c prostate cancer undergoing radical prostatectomy with prostate specific antigen 2.6 to 4.0 vs 4.1 to 6.0 ng/ml.

PURPOSE: Recent studies have suggested that the cut point for recommending prostate biopsy among men with a normal digital rectal examination should be greater than 2.5 ng/ml as opposed to the more traditional greater than 4.0 ng/ml. We compared outcomes between men with clinical stage T1c disease undergoing radical prostatectomy who had a low vs slightly increased prostate specific antigen. MATERIALS AND METHODS: The study population consisted of 2,896 men treated with radical prostatectomy between 1985 and 2004 at a tertiary care referral center with clinical stage T1c disease and a pre-biopsy prostate specific antigen between 2.6 and 6.0 ng/ml. Using multivariate analysis we evaluated the association between pre-biopsy prostate specific antigen 2.6 to 4.0 ng/ml (784) vs 4.1 to 6.0 ng/ml (2,112), and pathological outcomes and biochemical progression. RESULTS: After adjusting for multiple clinical and pathological characteristics, lower preoperative serum prostate specific antigen values were associated with decreased odds of Gleason score 7 or greater in the surgical specimen (p = 0.004), positive surgical margins (p = 0.02) and extraprostatic extension (p = 0.001). There was no significant association between these preoperative prostate specific antigen groups and odds of seminal vesicle invasion (p = 0.47) or lymph node metastasis (p = 0.90). Among the 1,534 men with followup information available there was a trend for increased risk of biochemical progression associated with a higher preoperative prostate specific antigen, although this trend did not reach statistical significance (relative risk 1.48, 95% CI 0.69-3.19, p = 0.31). CONCLUSIONS: In the current study of men with clinical stage T1c treated with radical prostatectomy a lower preoperative prostate specific antigen was associated with significantly more favorable pathological findings. Whether this degree of improved outcomes justifies the limitations associated with decreasing the prostate specific antigen cut point (eg increased biopsies performed and diagnosis of insignificant cancers) remains to be determined.

Disease Progression↗

PubMed2006

Time to prostate specific antigen recurrence after radical prostatectomy and risk of prostate cancer specific mortality.

PURPOSE: In patients treated with radical prostatectomy who have biochemical recurrence we have previously reported that time from surgery to biochemical recurrence and postoperative prostate specific antigen doubling time are significantly related to the risk of prostate cancer death. We performed a more thorough examination of the association of time from surgery to biochemical recurrence and the risk of prostate cancer death. MATERIALS AND METHODS: We retrospectively studied the records of 379 patients treated with radical prostatectomy between 1982 and 2000 who had had biochemical recurrence. We examined the association of time from surgery to prostate specific antigen recurrence and prostate specific antigen doubling time, and the risk of prostate cancer death using the Spearman correlation and Cox proportional hazards regression, respectively. RESULTS: Longer time from surgery to prostate specific antigen recurrence was associated with a slower prostate specific antigen doubling time (Spearman r = 0.36, p < 0.001) and a decreased risk of prostate cancer death (RR 0.76, 95% CI 0.66 to 0.88, p < 0.001). The 15-year actuarial prostate cancer specific survival rate after biochemical recurrence in patients with recurrence at 3 years or less was 41% (95% CI 29 to 53) compared to 87% (95% CI 75 to 93) in patients with recurrence more than 3 years after radical prostatectomy. On multivariate analysis a shorter time from surgery to prostate specific antigen recurrence was associated with an increased risk of prostate cancer death (3 or less vs more than 3 years, RR 2.70, 95% CI 1.37 to 5.31, p = 0.004). CONCLUSIONS: Earlier prostate specific antigen recurrence is associated with an increased risk of prostate cancer death. These data suggest that perhaps time to prostate specific antigen recurrence may be a reasonable intermediate end point in patients treated with radical prostatectomy, although this must be validated in other studies.

Aged↗

PubMed2006

Relationship between primary Gleason pattern on needle biopsy and clinicopathologic outcomes among men with Gleason score 7 adenocarcinoma of the prostate.

OBJECTIVES: To examine the relationship among needle biopsy primary grade, prostatectomy grade, and postprostatectomy biochemical recurrence among men with Gleason score 7 disease. METHODS: We identified 320 men with Gleason score 7 tumors on prostate biopsy treated with radical prostatectomy between 1991 and 2001 by a single surgeon. None of these patients had received neoadjuvant or adjuvant hormonal therapy or radiotherapy. The chi-square test and Kaplan-Meier method were used to evaluate the correlation among biopsy Gleason score, prostatectomy Gleason score, and biochemical recurrence. RESULTS: A total of 252 (79%) and 68 (21%) men had primary Gleason pattern 3 and 4 identified on needle biopsy, respectively. Of the patients with Gleason pattern 3 + 4 tumors on biopsy, 24% were upgraded to primary pattern 4 or more on final pathologic analysis. Of the patients with Gleason pattern 4 + 3 tumors on biopsy, 47% were downgraded to primary pattern 3 or less on final pathologic analysis. The actuarial risk of biochemical prostate-specific antigen recurrence was significantly lower among patients with Gleason pattern 4 + 3 on biopsy, if the prostatectomy Gleason score was downgraded to 3 + 4 or less (P = 0.03). CONCLUSIONS: Approximately 47% of men with a diagnosis of Gleason pattern 4 + 3 on needle biopsy are downgraded at radical prostatectomy and will have biochemical prostate-specific antigen recurrence-free outcomes similar to patients originally diagnosed with Gleason pattern 3 + 4 adenocarcinoma. This group of patients may benefit from definitive treatment such as radical prostatectomy for management of their disease.

Adenocarcinoma↗

PubMed2005

Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy.

CONTEXT: The natural history of biochemical recurrence after radical prostatectomy can be long but variable. Better risk assessment models are needed to identify men who are at high risk for prostate cancer death early and who may benefit from aggressive salvage treatment and to identify men who are at low risk for prostate cancer death and can be safely observed. OBJECTIVES: To define risk factors for prostate cancer death following radical prostatectomy and to develop tables to risk stratify for prostate cancer-specific survival. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of 379 men who had undergone radical prostatectomy at an urban tertiary care hospital between 1982 and 2000 and who had a biochemical recurrence and after biochemical failure had at least 2 prostate-specific antigen (PSA) values at least 3 months apart in order to calculate PSA doubling time (PSADT). The mean (SD) follow-up after surgery was 10.3 (4.7) years and median follow-up was 10 years (range, 1-20 years). MAIN OUTCOME MEASURE: Prostate cancer-specific mortality. RESULTS: Median survival had not been reached after 16 years of follow-up after biochemical recurrence. Prostate-specific doubling time (<3.0 vs 3.0-8.9 vs 9.0-14.9 vs > or =15.0 months), pathological Gleason score (< or =7 vs 8-10), and time from surgery to biochemical recurrence (< or =3 vs >3 years) were all significant risk factors for time to prostate-specific mortality. Using these 3 variables, tables were constructed to estimate the risk of prostate cancer-specific survival at year 15 after biochemical recurrence. CONCLUSION: Clinical parameters (PSADT, pathological Gleason score, and time from surgery to biochemical recurrence) can help risk stratify patients for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. These preliminary findings may serve as useful guides to patients and their physicians to identify patients at high risk for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy to enroll them in early aggressive treatment trials. In addition, these preliminary findings highlight that survival in low-risk patients can be quite prolonged.

Aged↗

PubMed2005

Preoperative serum DNA GSTP1 CpG island hypermethylation and the risk of early prostate-specific antigen recurrence following radical prostatectomy.

PURPOSE: Hypermethylation of the CpG island at the promoter region of the pi-class glutathione S-transferase gene (GSTP1) is the most common somatic genome abnormality in human prostate cancer. We evaluated circulating cell-free DNA GSTP1 CpG island hypermethylation as a prognostic biomarker in the serum of men with prostate cancer. EXPERIMENTAL DESIGN: Prostate cancer DNA GSTP1 CpG island hypermethylation was detected using a restriction endonuclease quantitative PCR technique. We analyzed preoperative serum from 85 men with clinically localized prostate cancer treated with radical prostatectomy and from 35 men with a negative prostate biopsy. We then assayed preoperative serum from a data set of 55 pairs of men with clinically localized prostate cancer treated with radical prostatectomy, matched for Gleason score, comprising 55 men suffering prostate-specific antigen (PSA) recurrence (median, 2 years) and 55 men who were free of disease at last follow-up (median, 3 years). The association of serum GSTP1 CpG island hypermethylation and PSA recurrence was determined. RESULTS: Circulating cell-free DNA with GSTP1 CpG island hypermethylation was not detected in the serum of men with a negative prostate biopsy but was detected in 12% of men with clinically localized disease and 28% of men with metastatic cancer (P = 0.003). In the matched data set, eight men (15%) who developed PSA recurrence were positive for DNA with GSTP1 CpG hypermethylation, whereas no patient who was free of disease was positive for GSTP1 CpG island hypermethylation (McNemar test, chi(2) = 6.1, P = 0.01). In a multivariable analysis that accounted for recognized prognostic factors, the presence of serum DNA with GTSP1 CpG island hypermethylation was the most significant predictor of PSA recurrence (hazard ratio, 4.4; 95% confidence interval, 2.2, 8.8; P < 0.001). CONCLUSION: Our study suggests that GSTP1 CpG island hypermethylation may be an important DNA-based prognostic serum biomarker for prostate cancer.

Adult↗

PubMed2005

Stronger association between obesity and biochemical progression after radical prostatectomy among men treated in the last 10 years.

BACKGROUND: Prior prospective cohort studies found that obesity was associated with increased risk of prostate cancer death. However, in the last 20 years dramatic changes in both the extent of obesity and prostate cancer screening and treatment have occurred. Whether the association between obesity and aggressive disease has changed as a result of these temporal changes is unclear. METHODS: The study population consisted of 2,832 men treated by anatomic radical retropubic prostatectomy between 1985 and 2004 by a single surgeon. We evaluated the associations of obesity (body mass index > or =30 kg/m(2))with tumor stage and grade using logistic regression and with biochemical progression using Cox proportional hazards regression. We examined whether these associations have changed over the last 20 years. RESULTS: On multivariable analysis, the strength of the positive association between obesity and high-grade disease increased over time whereas the strength of the positive association between obesity and positive surgical margins decreased over time. The strength of the positive association between obesity and extraprostatic extension fluctuated over time, although the strongest and only statistically significant association was among men treated since 2000. The association between obesity and biochemical progression was strongest among men treated since 1995 (relative risk, 1.90; 95% confidence interval, 1.09-3.30; P = 0.02). CONCLUSIONS: In the current study, with the exception of positive surgical margins, the positive association between obesity and high-grade disease, advanced stage, and biochemical progression after radical retropubic prostatectomy was in general strongest among men treated in the last 10 years. The reasons for these findings are not clear, although factors possibly related to prostate-specific antigen-based screening and/or other temporal changes in prostate cancer diagnosis and treatment may play a role.

Body Mass Index↗

PubMed2005

Serum leptin and pathological findings at the time of radical prostatectomy.

PURPOSE: Obesity has been associated with a higher risk of progression following radical prostatectomy (RP). Obese men have higher serum leptin, a hormone produced by adipocytes, which has also been shown to be an in vitro prostate cancer growth factor. We examined whether serum leptin correlates with advanced pathological findings at RP. MATERIALS AND METHODS: Preoperative serum from 225 men treated with RP between 1998 and 1999 was examined for serum leptin. Multivariate logistic regression analysis was used to determine whether serum leptin was predictive of extraprostatic extension (pT3a). RESULTS: Serum leptin highly correlated with body mass index (Spearman r = 0.602, p <0.001). Serum leptin was not associated with total or percent free prostate specific antigen (PSA), biopsy or prostatectomy Gleason score, age or height. On multivariate analysis with total and percent free PSA, clinical stage, age, biopsy Gleason score, body mass index, serum leptin, and height as variables considered for entry into the model, serum PSA (p = 0.009), clinical stage (p = 0.019) and serum percent free PSA (p = 0.041) were the only variables predictive of extraprostatic extension. Serum leptin was not significantly associated with pathological stage (pT3a). CONCLUSIONS: In the current study of predominantly white men with mainly low risk disease there was no statistically significant association between serum leptin and pathological stage (pT3a) at RP. In this cohort serum leptin was not a good biomarker for predicting advanced stage at RP.

Humans↗

PubMed2005

Obesity and risk of biochemical progression following radical prostatectomy at a tertiary care referral center.

PURPOSE: We have previously reported that obesity is an independent predictor of biochemical progression after radical prostatectomy (RP) in men treated by a single surgeon at our institution. We sought to validate or refute these findings using data on men treated by multiple other surgeons at our institution. MATERIALS AND METHODS: The study population consisted of 2,796 men treated with anatomical radical RP between 1988 and 2004 by 1 of 17 surgeons at our institution, a tertiary care referral center. We evaluated the association between body mass index (BMI), and adverse pathological features and biochemical progression. RESULTS: On multivariate analysis increased BMI was associated with high grade disease in the RP specimen (p = 0.03), positive surgical margins (p <0.001), extraprostatic extension (p <0.001) and lymph node metastasis (p = 0.01) but not with seminal vesicle invasion (p = 0.59). After multivariate adjustment for preoperative clinical characteristics increased BMI was significantly associated with an increased risk of biochemical progression (p <0.001), which was somewhat but not completely attenuated by further adjusting for RP specimen pathological features (p = 0.03). Adjustment for surgeon did not affect these results. CONCLUSIONS: In men undergoing RP increased BMI was associated with adverse pathological features and a greater risk of biochemical progression. These findings together with the results of several recently published series collectively provide strong evidence that obese men undergoing RP are more likely to have aggressive prostate cancer.

Aged↗

PubMed2005

Association between serum adiponectin, and pathological stage and grade in men undergoing radical prostatectomy.

PURPOSE: Adiponectin is a polypeptide hormone produced by adipocytes that has anti-angiogenic properties. Circulating adiponectin is lower in obese men. Obesity has been associated with advanced stage and a higher risk of biochemical progression following radical prostatectomy (RP) in several series. We examined whether serum adiponectin is associated with advanced disease stage at RP. MATERIALS AND METHODS: Adiponectin was measured by enzyme-linked immunosorbent assay in the preoperative serum of 236 men treated with RP between 1998 and 1999. The odds ratio (OR) of advanced stage (pT3a or greater) and high grade disease (pathological Gleason sum 7 or greater) associated with quartiles of adiponectin were estimated using multivariate logistic regression models. RESULTS: Serum adiponectin weakly correlated inversely with body mass index (Spearman r = -0.22, p = 0.01). Serum adiponectin was not associated with cancer stage or grade. However, in normal weight men adiponectin was positively associated with high stage disease (OR 1.14, 95% CI 1.02 to 1.29, p = 0.03), although there was no statistically significant association with high grade disease (OR 1.05, 95% CI 0.94 to 1.18, p = 0.38). In overweight and obese men adiponectin was inversely associated with high grade disease (OR 0.94, 95% CI 0.87 to 1.01, p = 0.09), although there was no statistically significant association with high stage disease (OR 0.97, 95% CI 0.91 to 1.04, p = 0.43). Further adjustments for body mass index had little impact on any ORs. CONCLUSIONS: These data provide evidence to suggest that adiponectin may be related to prostate cancer aggressiveness, although the direction of the associations may depend on the extent of adiposity and on cancer grade.

Adiponectin↗

PubMed2005

The prostatic specific antigen era is alive and well: prostatic specific antigen and biochemical progression following radical prostatectomy.

PURPOSE: Prostate specific antigen (PSA) has been shown to predict the presence of prostate cancer on biopsy, pathological stage, and biochemical progression following primary therapy. A recent study found only a weak association between PSA and tumor volume in the radical prostatectomy (RP) specimen and concluded that the PSA era is over. We examined the association between PSA and clinical progression in men undergoing RP. MATERIALS AND METHODS: The study population consisted of 2,312 men treated with RP between 1992 and 2004 by a single surgeon. We evaluated the association between preoperative PSA and biochemical progression on multivariate analysis. RESULTS: Men with higher preoperative PSA concentrations had higher grade cancers in the biopsy and RP specimen, and more adverse pathological features. After adjusting for the clinical covariates of age, race, grade, stage, and year of surgery, preoperative PSA was significantly associated with the risk of biochemical progression. When only men with PSA less than 10 ng/ml were examined, PSA remained a significant predictor of biochemical progression on multivariate analysis (RR 1.30, 95% CI 1.18 to 1.44, p <0.001). For each 2-point increase in PSA, the risk of biochemical progression increased approximately 2-fold. CONCLUSIONS: Preoperative PSA was significantly associated with high grade disease and adverse pathological findings. After adjusting for clinical covariates, PSA was significantly associated with the risk of biochemical progression, even in men with PSA less than 10 ng/ml. Despite multiple limitations, PSA remains the best prostate cancer tumor marker available.

Disease Progression↗

PubMed2005

Obesity and capsular incision at the time of open retropubic radical prostatectomy.

PURPOSE: The goal of radical prostatectomy (RP) is complete removal of the intact prostate. Obese men can represent a technical challenge. However, to our knowledge objective data linking obesity with technically inferior surgery are lacking. Therefore, we examined the association between body mass index (BMI) and capsular incision at RP as a surrogate of a poor technical operation in men treated for prostate cancer by several high volume surgeons at a center of excellence. MATERIALS AND METHODS: The study population consisted of 7,027 men treated with anatomical retropubic RP between 1996 and 2004 by 7 high volume surgeons. We evaluated the association between BMI and capsular incision using logistic regression, adjusting for clinical and pathological variables, and for the surgeon. RESULTS: Overall capsular incision was noted in 4.6% of all RP specimens. After adjustment for preoperative prostate specific antigen, patient race, height, year of surgery, clinical stage, pathological Gleason sum, prostate weight, extraprostatic extension and seminal vesicle invasion increased BMI was associated with increased odds of capsular incision (p trend = 0.005). After further adjustment for surgeon mild obesity was associated with 30% increased odds of capsular incision (OR 1.30, 95% CI 0.92 to 1.83), while moderate and severe obesity was associated with 57% increased odds of capsular incision (OR 1.57, 95% CI 0.82 to 3.00) relative to normal weight men (p trend = 0.06). CONCLUSIONS: In a study of more than 7,000 men treated by 7 experienced surgeons BMI was positively related to capsular incision. This suggests that open retropubic RP is technically more difficult in obese men, which results in a greater likelihood of a less than technically ideal operation. Although this may be predicted to have a negative impact on disease-free survival outcomes in obese men, it is unlikely to alone explain the worse outcomes in obese men noted in previous RP series.

Aged↗

PubMed2004

Characteristics of insignificant clinical T1c prostate tumors. A contemporary analysis.

BACKGROUND: The authors examined the cases of men who had undergone radical prostatectomy for low-volume clinical T1c prostate carcinoma that was judged to be 'insignificant' on the basis of previously established preoperative clinicopathologic parameters. Pathologic findings subsequently were analyzed for correlations with extent of disease in an attempt to validate the contemporary usefulness of existing parameters for predicting the 'significance' of prostate tumors. METHODS: A series of 237 men who had undergone radical prostatectomy for T1c disease between December 2000 and August 2003 was evaluated. Insignificant prostate carcinoma as assessed on biopsy was defined according to the 1994 Epstein criteria, which were as follows: prostate-specific antigen density < 0.15 ng/mL, Gleason score < or = 6, fewer than 3 cores containing prostate carcinoma, and < or = 50% involvement of any core with prostate carcinoma. Postsurgical pathologic findings were analyzed for potential correlations with the Epstein criteria. RESULTS: According to the Epstein needle biopsy criteria, organ-confined prostate carcinoma was detected in 91.6% of all patients, whereas the remaining 8.4% of patients were found to have non-organ-confined disease. Comparison of pathologic findings and Epstein biopsy criteria revealed that alteration of the original criteria did not improve the detection of non-organ-confined prostate carcinoma. CONCLUSIONS: The findings made in the current study suggest that the majority of patients with T1c prostate carcinoma have insignificant disease. Furthermore, it was found that the Epstein criteria for identifying insignificant prostate carcinoma remained a useful tool in the making of treatment-related decisions.

Adult↗

PubMed2004

Trefoil factor 3 overexpression in prostatic carcinoma: prognostic importance using tissue microarrays.

BACKGROUND: Human intestinal trefoil factor 3 (TFF3) is a member of a family of polypeptides encoded by a cluster of genes on chromosome 21. Through gene expression profiling studies TFF3 mRNA has been found to be overexpressed in prostate cancer. METHODS: We used immunochemistry on tissue microarrays and software tools, collectively referred to as TMAJ, for online assessment of staining to analyze samples from 294 primary tumors and 61 metastatic lesions. RESULTS: Applying a cutoff of 20% of cells staining as positive, the frequency of staining was 18.8% in normal (51 of 272) and 47.0% in primary tumors (126 of 268), P < 0.0001, Wilcoxon rank sum). Expression of TFF3 in metastatic prostate cancer was similar to that in primary tumors. TFF3 expression was not associated with time to biochemical recurrence, development of distant metastasis, or death due to prostate cancer. Scoring data derived from visual estimation of expression correlated highly with semi-automated image analysis using the Automated Cellular Imaging System (ACIS) from Chromavision, Inc. CONCLUSIONS: These studies validate that TFF3 is overexpressed at the protein level in a subset of primary and metastatic prostate cancers, show the first use of the TMAJ database, and demonstrate the ability to semi-automatically scan and score immunohistochemically stained tissue microarray slides.

Biomarkers, Tumor↗

PubMed2004

Ability to predict metastasis based on pathology findings and alterations in nuclear structure of normal-appearing and cancer peripheral zone epithelium in the prostate.

PURPOSE: Malignant transformation in the prostate produces significant alterations in glandular architecture (Gleason grade) and nuclear structure that provide valuable prognostic information. Normal-appearing nuclei (NN) adjacent to cancer may also have altered functions in response to malignancy. We studied NN adjacent to peripheral zone (PZ) prostate cancer (PCa), as well as the PZ cancer nuclei (CaN) using quantitative image cytometry. The nuclear structure information was combined with routine pathological findings to predict metastatic PCa progression and/or death. EXPERIMENTAL DESIGN: Tissue microarrays of normal-appearing and cancer areas were prepared from 182 pathologist-selected paraffin blocks. Feulgen-stained CaN and NN were captured from the tissue microarrays using the AutoCyte Pathology Workstation. Multivariate logistic regression was used to calculate quantitative nuclear grade (QNG) solutions based on nuclear morphometric descriptors determined from NN and CaN. Multivariate logistic regression and Kaplan-Meier plots were also used to predict risk for distant metastasis and/or PCa-specific death using QNG solutions and routine pathology. RESULTS: The pathology model yielded an area under the receiver operator characteristic curve of 72.5%. The QNG-NN and QNG-CaN solutions yielded an area under the receiver operator characteristic curve of 81.6 and 79.9%, respectively, but used different sets of nuclear morphometric descriptors. Kaplan-Meier plots for the pathology variables, the QNG-NN and QNG-CaN solutions, were combined with pathology to defined three statistically significantly distinct risk groups for distant metastasis and/or death (P < 0.0001). CONCLUSIONS: Alterations in cancer or normal-appearing nuclei adjacent to peripheral zone cancer areas can predict PCa progression and/or death. The QNG-NN and QNG-CA solutions could be combined with pathology variables to improve the prediction of distant metastasis.

Adult↗

PubMed2004

Biopsy indication--a predictor of pathologic stage among men with preoperative serum PSA levels of 4.0 ng/mL or less and T1c disease.

OBJECTIVES: To determine the indications for biopsy among men with a prostate-specific antigen (PSA) level of 4 ng/mL or less and T1c disease and whether the reason for biopsy correlated with the final pathologic stage. It is not uncommon for men to undergo radical prostatectomy (RP) with a prostate-specific antigen (PSA) level of 4 ng/mL or less and T1c disease. METHODS: We examined the percentage of men with T1c disease and PSA level of 4.0 ng/mL or less undergoing RP over time. We identified 874 men with T1c prostate adenocarcinoma and PSA levels of 4 ng/mL or less who were treated with RP between 1994 and 2003. We excluded 72 patients who had received preoperative hormonal therapy and 86 patients for whom the reason for biopsy was unclear. The pathologic outcomes were compared between the various biopsy indication groups using analysis of variance. RESULTS: The percentage of men with T1c disease and a PSA level of 4.0 ng/mL or less has steadily increased from 0% before 1990 to 19% in 2003. Among men treated between 1994 and 2003, the most common indication for biopsy was a spike in the PSA level to greater than their reference level before biopsy (n = 471, 66%), although in all patients, the PSA level returned to 4 ng/mL or less before surgery. In 163 patients (35%), the PSA level remained elevated above the reference range and in the remaining 308 patients (65%), the PSA declined to a value below the reference range before surgery. The second most common indication for biopsy was an abnormal digital rectal examination by the referring/primary physician that, when repeated by the attending surgeon, was believed to be normal (n = 155, 22%). Abnormal PSA velocity accounted for biopsy in 68 patients (10%). Among patients with the three most common indications for biopsy, no statistically significant differences in the pathologic tumor characteristics between the groups were noted on the basis of the biopsy indication. CONCLUSIONS: One in five men undergoing RP at our institution today has T1c disease and a PSA value of 4.0 ng/mL or less. The most common indication for biopsy was an elevated PSA level above their reference range, although in most, the PSA had returned to a normal value before surgery. Regardless of the indication for biopsy, these men had favorable findings at RP. That 22% of patients underwent biopsy because of what was perceived to be an abnormal digital rectal examination underscores the need to continue to perform digital rectal examination along with PSA determination as a part of routine prostate cancer screening.

Biopsy↗

PubMed2004

Clinical utility of proPSA and "benign" PSA when percent free PSA is less than 15%.

OBJECTIVES: To investigate the clinical utility of the subforms of free prostate-specific antigen (PSA), namely proPSA and "benign" PSA (BPSA), to improve cancer detection when the percent free PSA level is less than 15%. Percent free PSA, while maintaining sensitivity, has greatly improved the specificity of PSA for the early detection of prostate cancer. A low percent free PSA value indicates a greater risk of cancer, but only 30% to 50% of men with percent free PSA levels of less than 15% actually have cancer at biopsy. METHODS: Archived sera from 161 consecutive men who were prospectively enrolled in our Early Detection Research Network prostate cancer early detection biomarker program with a percent free PSA value of less than 15% were included in the study. Total PSA, free PSA, proPSA, and BPSA were measured for each sample. RESULTS: The mean total PSA was 6.1 ng/mL (range 1.8 to 24.0). The mean age of the study group was 62 +/- 7 years. Prostate cancer was detected in 66 (41%) of 161 men. The area under the curve-receiver operating characteristic for total and percent free PSA was 0.51 and 0.54, respectively. BPSA and proPSA/BPSA both improved cancer detection compared with percent free PSA alone; the improvement was statistically significant (P <0.001) . The area under the curve-receiver operating characteristic for proPSA/BPSA was 0.72, giving a sensitivity and specificity of 90% and 46%, respectively. CONCLUSIONS: The results of our preliminary studies have suggested that the ratio of proPSA and BPSA can distinguish cancer with greater accuracy when the percent free PSA value is very low (less than 15%), and may, therefore, provide better clinical utility in this lower range of percent free PSA.

Aged↗

PubMed2004

Detection of prostate cancer using serum proteomics pattern in a histologically confirmed population.

PURPOSE: We retrospectively identified a panel of serum proteins that can discriminate between men with prostate cancer (clinically organ confined) and men with benign prostate disease. MATERIALS AND METHODS: A contemporary set of 345 men who had an archival serum sample available were included in this study. The cancer group consisted of 246 men who underwent radical prostatectomy at the Johns Hopkins Hospital between March 1999 and April 2001. The noncancer group included 99 men with no histological evidence of prostate cancer on biopsy between April 1997 and April 2001 at the same institution. Serum proteomics mass spectra of these patients were generated using ProteinChip arrays and a ProteinChip Biomarker System II surface enhanced laser desorption/ionization time of flight mass spectrometer (Ciphergen Biosystems, Inc., Fremont, California). The cases and controls were randomly split into training and testing groups by a stratified sampling procedure. A combination of bioinformatics tools including ProPeak (3Z Informatics, Charleston, South Carolina) was used to reveal the optimal panel of biomarkers for maximum separation of the prostate cancer and the benign prostate disease cohorts. RESULTS: A panel of 3 proteins (PC-1, PC-2 and PC-3) was selected using the training data. Performance of each of the protein markers and a linear regression derived composite index (PC-com3) were evaluated on the testing data. The area under the curve for prostate specific antigen (PSA), PC-1, PC-2, PC-3 and PC-com3 was 0.542, 0.585, 0.600, 0.636 and 0.643, respectively. Improvement of PC-com3 compared to PSA is observed at specificity range 30% to 80%. At a selected specificity of 45% the sensitivity of PC-com3 is 76%, significantly better than the PSA sensitivity of 57% (p <0.0001). CONCLUSIONS: Serum proteomics patterns may potentially aid in the early detection of prostate cancer.

Diagnosis, Differential↗