Danil V. Makarov

Biomarkers for prostate cancer

The development of biomarkers for prostate cancer screening, detection, and prognostication has revolutionized the management of this disease. Prostate-specific antigen (PSA) is a useful, though not specific, biomarker for detecting prostate cancer. We review the literature on prostate cancer biomarkers, including serum markers (PAP, tPSA, fPSA, proPSA, PSAD, PSAV, PSADT, EPCA, and EPCA-2), tissue markers (AMACR, methylated GSTP1, and the TMPRSS2-ETS gene rearrangement), and a urine marker (DD3PCA3/UPM-3). Future research should focus on validation of already existing biomarkers and the discovery of new markers to identify men with aggressive prostate cancer.

Comparison of WHO/ISUP and WHO classification of noninvasive papillary urothelial neoplasms for risk of progression

OBJECTIVES To investigate the relation of the World Health Organization/International Society of Urological Pathology (WHO/ISUP) system for bladder neoplasia to prognosis. METHODS A total of 134 patients with pTa bladder tumors were identified. We excluded cases with prior or concurrent carcinoma in situ or invasion (pT1 or pT2). Progression was defined as a tumor recurrence with either lamina propria (pT1) or muscularis propria (pT2) invasion or carcinoma in situ. Age at diagnosis, sex, tumor size, multifocality, and grade (WHO, WHO/ISUP) were entered into a Cox multivariate analysis to predict progression. RESULTS The distribution of WHO papilloma, WHO G1, WHO G2, and WHO G3 was 5.2%, 31.3%, 59%, and 4.5%, respectively. The distribution of WHO/ISUP papilloma, tumors of low malignant potential, low-grade carcinomas, and high-grade carcinomas was 2.2%, 21.6%, 13%, and 21.6%, respectively. The mean and median follow-up was 56.2 and 50 months, respectively. The 90-month actuarial risk of progression for WHO papilloma, G1, G2, and G3 was 0%, 11%, 24%, and 60%, respectively. The corresponding progression rate for WHO/ISUP papilloma, tumors of low malignant potential, low-grade carcinoma, and high-grade carcinoma was 0%, 8%, 13%, and 51%, respectively. In separate analyses, WHO grade (P = 0.003) and tumor size (P = 0.03), as well as WHO/ISUP (P = 0.002) and tumor size (P = 0.04), independently predicted progression. CONCLUSIONS WHO G3 has a more rapid progression rate and a slightly worse long-term progression rate compared with WHO/ISUP high-grade carcinoma. However, although only 4.5% of tumors were WHO G3, we were able to classify 21.6% as WHO/ISUP high-grade carcinoma with a poor prognosis. Use of the WHO/ISUP system allows urologists to more closely follow a larger group of patients at high risk of progression.

Immortal time bias: a frequently unrecognized threat to validity in the evaluation of postoperative radiotherapy.

PURPOSE To evaluate the influence of immortal time bias on observational cohort studies of postoperative radiotherapy (PORT) and the effectiveness of sequential landmark analysis to account for this bias. METHODS AND MATERIALS First, we reviewed previous studies of the Surveillance, Epidemiology, and End Results (SEER) database to determine how frequently this bias was considered. Second, we used SEER to select three tumor types (glioblastoma multiforme, Stage IA-IVM0 gastric adenocarcinoma, and Stage II-III rectal carcinoma) for which prospective trials demonstrated an improvement in survival associated with PORT. For each tumor type, we calculated conditional survivals and adjusted hazard ratios of PORT vs. postoperative observation cohorts while restricting the sample at sequential monthly landmarks. RESULTS Sixty-two percent of previous SEER publications evaluating PORT failed to use a landmark analysis. As expected, delivery of PORT for all three tumor types was associated with improved survival, with the largest associated benefit favoring PORT when all patients were included regardless of survival. Preselecting a cohort with a longer minimum survival sequentially diminished the apparent benefit of PORT. CONCLUSIONS Although the majority of previous SEER articles do not correct for it, immortal time bias leads to altered estimates of PORT effectiveness, which are very sensitive to landmark selection. We suggest the routine use of sequential landmark analysis to account for this bias.

Gleason Score 7 Prostate Cancer on Needle Biopsy: Is the Prognostic Difference in Gleason Scores 4 3 and 3 4 Independent of the Number of Involved Cores?

PURPOSE We addressed whether Gleason score 3 + 4 = 7 and 4 + 3 = 7 cancers on needle biopsy behave differently and whether this behavior is independent of the number of cores involved by cancer. If it is not an independent predictor of prognosis, one may report Gleason score 7 cancer with the number of positive cores without regard to whether the primary pattern was 3 or 4. This practice would remove a source of poor interobserver reproducibility when grading prostate cancer on needle biopsy. MATERIALS AND METHODS We identified 537 patients with Gleason score 7 tumors on biopsy. The results of patient preoperative digital rectal examination, serum prostate specific antigen (PSA) measurement and age were used to predict 4 outcomes based on assessment of the corresponding radical prostatectomy specimens, including 1) pathological stage (organ confined, focal extraprostatic extension, nonfocal extraprostatic extension or seminal vesicle-lymph node involvement), 2) organ confinement (yes/no), 3) Gleason score and 4) surgical margin status (positive/negative) RESULTS Multivariate regression of postoperative Gleason score groups against all 5 input variables (3 + 4 versus 4 + 3, number of positive cores, PSA, age and digital rectal examination) yielded a statistically significant positive correlation with preoperative PSA (p <0.001) and preoperative Gleason scores of 4 + 3 versus 3 + 4 on biopsy (p <0.001). Pathological stage correlated with preoperative PSA (p <0.001), Gleason score 4 + 3 disease (p = 0.016), positive digital rectal examination (p <0.001) and 3 or more positive cores (p = 0.016). Positive surgical margins were predicted only by preoperative PSA (p = 0.001). CONCLUSIONS Because the biological behavior of biopsy Gleason score 3 + 4 or 4 + 3 of Gleason score 7 cancer differs regardless of the number of cores involved, future nomograms predicting pathological stage would benefit from examining 3 + 4 and 4 + 3 disease separately.

The association between diffusion of the surgical robot and radical prostatectomy rates.

BackgroundDespite its expense and controversy surrounding its benefit, the surgical robot has been widely adopted for the treatment of prostate cancer. ObjectivesTo determine the relationship between surgical robot acquisition and changes in volume of radical prostatectomy (RP) at the regional and hospital levels. Research DesignRetrospective cohort study. SubjectsMen undergoing RP for prostate cancer at nonfederal, community hospitals located in the states of Arizona, Florida, Maryland, North Carolina, New York, New Jersey, and Washington. MeasuresChange in number of RPs at the regional and hospital levels before (2001) and after (2005) dissemination of the surgical robot. ResultsCombining data from the Healthcare Cost and Utilization Project State Inpatient Databases 2001 and 2005 with the 2005 American Hospital Association Survey and publicly available data on robot acquisition, we identified 554 hospitals in 71 hospital referral regions (HRR). The total RPs decreased from 14,801 to 14,420 during the study period. Thirty six (51%) HRRs had at least 1 hospital with a surgical robot by 2005; 67 (12%) hospitals acquired at least 1 surgical robot. Adjusted, clustered generalized estimating equations analysis demonstrated that HRRs with greater numbers ofhospitals acquiring robots had higher increases in RPs than HRRsacquiring none (mean changes in RPs for HRRs with 9, 4, 3, 2, 1, and 0 are 414.9, 189.6, 106.6, 14.7, −11.3, and −41.2; P<0.0001). Hospitals acquiring surgical robots increased RPs by amean of 29.1 per year, while those without robots experienced a mean change of −4.8, P<0.0001. ConclusionsSurgical robot acquisition is associated with increased numbers of RPs at the regional and hospital levels. Policy makers must recognize the intimate association between technology diffusion and procedure utilization when approving costly new medical devices with unproven benefit.

p300 (Histone acetyltransferase) biomarker predicts prostate cancer biochemical recurrence and correlates with changes in epithelia nuclear size and shape

p300 impacts the transcription of several genes involved in key pathways critical to PCa progression. Therefore, we evaluated the prognostic value of p300 expression and its correlation with nuclear alterations seen in tumor cells in men with long‐term follow‐up after radical prostatectomy (RP).

Pro–Prostate-Specific Antigen Measurements in Serum and Tissue Are Associated with Treatment Necessity among Men Enrolled in Expectant Management for Prostate Cancer

Purpose: We assessed the association of quantitative clinical and pathologic information, including serum and tissue pro–prostate-specific antigen (proPSA) measurements, with outcomes among men with prostate cancer in an expectant management (active surveillance) program. Experimental Design: We identified 71 men enrolled in expectant management with frozen serum and tissue available from diagnosis: 39 subsequently developed unfavorable biopsies (Gleason score ≥7, ≥3 cores positive for cancer, >50% of any core involved with cancer), whereas 32 maintained favorable biopsies (median follow-up, 3.93 years). Serum total PSA, free PSA (fPSA), and [−2]proPSA were measured by the Beckman Coulter immunoassay. [−5/−7]proPSA was evaluated in cancer and benign-adjacent areas (BAA) by quantitative immunohistochemistry. Cox proportional hazards and Kaplan-Meier analyses were used to identify significant associations with unfavorable biopsy conversion. Results: The ratio [−2]proPSA/% fPSA in serum was significantly higher at diagnosis (0.87 ± 0.44 versus 0.65 ± 0.36 pg/mL; P = 0.02) in men developing unfavorable biopsies. [−5/−7]proPSA tissue staining was more intense (4104.09 ± 3033.50 versus 2418.06 ± 1606.04; P = 0.03) and comprised a greater fractional area (11.58 ± 7.08% versus 6.88 ± 5.20%; P = 0.01) in BAA of these men. Serum [−2]proPSA/% fPSA [hazard ratio, 2.53 (1.18-5.41); P = 0.02], BAA [−5/−7]proPSA % area [hazard ratio, 1.06 (1.01-1.12); P = 0.02] and BAA [−5/−7]proPSA stain intensity [hazard ratio, 1.000213 (1.000071-1.000354); P = 0.003] were significantly associated with unfavorable biopsy in Kaplan-Meier and Cox analyses. Serum [−2]proPSA/% fPSA significantly correlated with BAA [−5/−7]proPSA % area (ρ = 0.40; P = 0.002) and BAA [−5/−7]proPSA stain intensity (ρ = 0.33; P = 0.016). Conclusions: In a prospective cohort of men enrolled into expectant management for prostate cancer, serum and tissue levels of proPSA at diagnosis are associated with need for subsequent treatment. The increase in serum proPSA/% fPSA might be driven by increased proPSA production from “premalignant” cells in the prostate BAA. (Clin Cancer Res 2009;15(23):7316–21)

ProPSA and Diagnostic Biopsy Tissue DNA Content Combination Improves Accuracy to Predict Need for Prostate Cancer Treatment Among Men Enrolled in an Active Surveillance Program

OBJECTIVES To assess a novel application of the Prostate Health Index (phi) and biopsy tissue DNA content in benign-adjacent and cancer areas to predict which patients would eventually require treatment of prostate cancer in the Proactive Surveillance cohort. METHODS We identified 71 men who had had serum and biopsy tissue from their diagnosis banked and available for the present study. Of the 71 patients, 39 had developed unfavorable biopsy findings and 32 had maintained favorable biopsy status during surveillance. The serum total prostate-specific antigen (tPSA), free PSA (fPSA) and [-2]proPSA were measured using the Beckman Coulter immunoassay. The DNA content measurements of Feulgen-stained biopsy sections were performed using the AutoCyte imaging system. RESULTS The ratio of phi was significantly greater (37.23 ± 15.76 vs 30.60 ± 12.28; P = .03) in men who ultimately had unfavorable biopsy findings. The serum phi ratio (P = .003), [-2]proPSA/%fPSA (P = .004), biopsy tissue DNA content (ie, benign-adjacent excess of optical density, P = .019; and cancer area standard deviation of optical density, P = .002) were significant predictors of unfavorable biopsy conversion on Cox regression analysis. However, phi and [-2]proPSA/%fPSA showed a highly significant correlation (rho = 0.927, P < .0001) and no difference in accuracy (c-index, 0.6247 vs 0.6158; P = .704) for unfavorable biopsy conversion prediction. Furthermore, phi and [-2]proPSA/%fPSA remained significant (P = .047 and P = .036, respectively) in the multivariate models and, combined with the biopsy tissue DNA content, showed improvement in the predictive accuracy (c-index, 0.6908 and 0.6884, respectively) for unfavorable biopsy conversion. CONCLUSIONS The Prostate Health Index to proPSA/%fPSA, combined with biopsy tissue DNA content, improved the accuracy to about 70% to predict unfavorable biopsy conversion at the annual surveillance biopsy examination among men enrolled in an Active Surveillance program.

Robotic Surgery Claims on United States Hospital Websites

Abstract: To examine the prevalence and content of robotic surgery information presented on websites of U.S. hospitals. We completed a systematic analysis of 400 randomly selected U.S. hospital websites in June of 2010. Data were collected on the presence and location of robotic surgery information on a hospitals website; use of images or text provided by the manufacturer; use of direct link to manufacturer website; statements of clinical superiority; statements of improved cancer outcome; mention of a comparison group for a statement; citation of supporting data and mention of specific risks. Forty‐one percent of hospital websites described robotic surgery. Among these, 37% percent presented robotic surgery on their homepage, 73% used manufacturer‐provided stock images or text, and 33% linked to a manufacturer website. Statements of clinical superiority were made on 86% of websites, with 32% describing improved cancer control, and 2% described a reference group. No hospital website mentioned risks. Materials provided by hospitals regarding the surgical robot overestimate benefits, largely ignore risks and are strongly influenced by the manufacturer.

Validation of the partin nomogram for prostate cancer in a national sample.

PURPOSE The Partin tables are a nomogram that is widely used to discriminate prostate cancer pathological stages, given common preoperative clinical characteristics. The nomogram is based on patients undergoing radical prostatectomy at The Johns Hopkins Medical Institutions. We validated the Partin tables in a large, population based sample. MATERIALS AND METHODS The National Cancer Institute Surveillance, Epidemiology and End Results database was used to identify patients treated from 2004 to 2005 who underwent radical prostatectomy. The 2007 Partin tables were used to estimate the prevalence of positive lymph nodes, seminal vesicle invasion, extraprostatic extension and organ confined disease in men with prostate cancer in the database using clinical stage, preoperative prostate specific antigen and Gleason score. The discriminative ability of the tables was explored by constructing ROC curves. RESULTS We identified 11,185 men who underwent radical prostatectomy for prostate cancer in 2004 to 2005. The Partin tables discriminated well between patient groups at risk for positive lymph nodes and seminal vesicle invasion (AUC 0.77 and 0.74, respectively). The discrimination of extraprostatic extension and organ confined disease was more limited (AUC 0.62 and 0.68, respectively). The AUC for positive lymph nodes was 0.78 in white men, 0.73 in black men and 0.83 in Asian/Pacific Islander men (p = 0.17). The AUC for positive lymph nodes in men 61 years old or younger was 0.80 vs 0.74 in men older than 61 years (p = 0.03). CONCLUSIONS The Partin tables showed excellent discrimination for seminal vesicle invasion and positive lymph nodes. Discrimination of extraprostatic extension and organ confined disease was more limited. The Partin tables performed best in young men.