Dynamic changes of alkaline phosphatase are strongly associated with PSA-decline and predict best clinical benefit earlier than PSA-changes under therapy with abiraterone acetate in bone metastatic castration resistant prostate cancer.

BACKGROUND: Significant progress in treatment of metastatic castration resistant prostate cancer (mCRPC) has been made. Biomarkers to tailor therapy are scarce. To facilitate decision-making we evaluated dynamic changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and prostate specific antigen (PSA) under therapy with Abiraterone. METHODS: Men with bone mCRPC (bmCRPC) on Abiraterone 12/2009-01/2014 were analyzed. Dynamic ALP-, LDH- and PSA-changes were analyzed as predictors of best clinical benefit and overall survival (OS) with logistic-regression, Cox-regression and Kaplan-Meier-analysis. RESULTS: Thirty-nine pre- and 45 post-chemotherapy patients with a median follow up of 14.0 months were analyzed. ALP-Bouncing can be observed very early during therapy with Abiraterone. ALP-Bouncing is defined as rapidly rising ALP-levels independent of baseline ALP during the first 2-4 weeks of Abiraterone-therapy with subsequent equally marked decline to pretreatment levels or better within 8 weeks of therapy, preceding potentially delayed PSA-decline. In univariate analysis failure of PSA-reduction ≥ 50% and failure of ALP-Bouncing were the strongest predictors of progressive disease (p = 0.003 and 0.021). Rising ALP at 12 weeks, no PSA-reduction ≥ 50% and no ALP-Bouncing were strongest predictors of poor OS, (all p < 0.001). Kaplan-Meier-analysis showed worse OS for rising ALP at 12 weeks, no PSA-reduction ≥ 50% and no ALP-Bouncing (p < 0.001). In subgroup-analysis of oligosymptomatic patients all parameters remained significant predictors of poor OS, with no PSA-reduction ≥ 50% and rising ALP at 12 weeks being the strongest (p < 0.001). In multivariate analysis PSA-reduction ≥ 50% remained an independent predictor of OS for the whole cohort and for the oligosymptomatic subgroup (both p = 0.014). No patient with ALP-Bouncing had PD for best clinical benefit. Patients with rising ALP at 12 weeks had no further benefit of Abiraterone. CONCLUSIONS: Dynamic changes of ALP, LDH and PSA during Abiraterone-therapy are associated with best clinical benefit and OS in bmCRPC. ALP-Bouncing occurring earlier than PSA-changes as well as prior to equivocal imaging results and rising ALP at 12 weeks under Abiraterone may help to decide whether to discontinue Abiraterone. An external validation of these findings on a prospective cohort is planned.

Preoperative Serum Prostate-Specific Antigen Levels Vary According to the Topographical Distribution of Prostate Cancer in Prostatectomy Specimens.

OBJECTIVE: To evaluate whether the spatial distribution of prostate cancer (PCa) influences the concentration of prostate-specific antigen (PSA). METHODS: An observational prospective study was performed in 775 consecutive men with preoperative PSA levels ≤20 ng/mL who underwent radical prostatectomy for organ-confined PCa. We evaluated prostate specimens using a cMDX-based map model of the prostate and determined the prostate volume, number of cancer foci, relative tumor volume, Gleason score, zone of origin, localization, and pathologic stage after stratification according to PSA levels categorized into 3 groups: <4 ng/mL, 4-10 ng/mL, and 10.1-20 ng/mL. The distribution of 5254 PCa foci was analyzed after stratification according to PSA levels and visualized on heat maps. A logistic regression analysis was performed to assess the odds ratios of PSA levels for the presence of PCa in 16 regions. RESULTS: PCa with PSA <4 ng/mL was predominantly localized to the apical part and the peripheral zone of the prostate. PCa with a PSA level 10.1-20 ng/mL (16.4% of cases) was observed more frequently in the anterior part and the base of the prostate than PCa with a PSA level <4 or 4-10 ng/mL (6% and 10%, respectively). CONCLUSION: Preoperative PSA levels vary according to the spatial distribution of PCa in radical prostatectomy specimens. The probability of anterior PCa is increased with higher PSA serum levels. Regions of interest harboring the PCa can be defined according to preoperative PSA and prostate volume. These findings are useful to optimize the focal therapy or to adjust the radiation fields.

Prostate cancers detected on repeat prostate biopsies show spatial distributions that differ from those detected on the initial biopsies.

OBJECTIVE: To evaluate the spatial distribution of prostate cancer detected at a single positive biopsy (PBx) and a repeat PBx (rPBx). PATIENTS AND METHODS: We evaluated 533 consecutive men diagnosed with prostate cancer who underwent radical prostatectomy using a clinical map document based on XML (cMDX©)-based map model of the prostate. We determined the number of cancer foci, relative tumour volume, Gleason score, zone of origin, localisation, and pathological stage after stratification according to the number of PBx sessions (PBx vs rPBx). The distribution of 3966 prostate cancer foci was analysed and visualised on heat maps. The colour gradient of the heat map was reduced to six colours representing the frequency classification of prostate cancer using an image posterisation effect. Additionally, the spatial distribution of organ-confined prostate cancer between PBx and rPBx was evaluated. RESULTS: Prostate cancer diagnosed on PBx was mostly localised to the apical portion and the peripheral zone of the prostate. Prostate cancer diagnosed on rPBx was more frequently found in the anterior portion and the base of the prostate. Organ-confined prostate cancer foci were mostly localised in the dorsolateral zone of the prostate in men at PBx, whereas men at rPBx had more prostate cancer foci in the anterior portion. CONCLUSIONS: The spatial distribution of prostate cancer with rPBx differs significantly from the spatial distribution of prostate cancer with PBx. The whole anterior portion of the prostate should be considered by rPBx.

Tumor percentage but not number of tumor foci predicts disease-free survival after radical prostatectomy especially in high-risk patients.

OBJECTIVE: To evaluate the predictive value of tumor volume (TV), tumor percentage (TP), and number of tumor foci (NF) in patients with prostate cancer. The prognostic relevance of TV, TP, and NF as predictors of biochemical recurrence (BCR) following radical prostatectomy (RPE) is controversial. PATIENTS AND METHODS: The cohort consisted of 758 referred subjects who underwent RPE between 2000 and 2005 at the University of Muenster. The mean time of follow-up was 62 months. TV, TP, and NF were estimated visually with the assistance of a pathologic mapping grid for embedded whole-mount RPE specimens. In addition, TV and TP were assessed in a categorized fashion by using quartiles as cutoff points. Subgroup analyses for high- and low-risk patients using univariate and multivariate Cox proportional hazard analyses for BCR were performed. RESULTS: TV, TP, and NF were strongly related to tumor stage, Gleason score, surgical margin status, and preoperative prostate-specific antigen (PSA). In univariate analysis, all pathologic parameters including TV, TP, and NF were predictive for BCR. In multivariate analysis, only TP, tumor stage, and PSA level were independent predictors. In subgroup analysis, TP was an independent predictor for BCR in the high-risk group but not in the low-risk group. CONCLUSIONS: TP, but not TV or NF, was found to be an independent predictor for BCR in patients after RPE. TP seems to be more relevant in high-risk patients (i.e., any of the following: > pT2, Gleason score > 6, or PSA > 20 ng/ml).

The presence of positive surgical margins in patients with organ-confined prostate cancer results in biochemical recurrence at a similar rate to that in patients with extracapsular extension and PSA ≤ 10 ng/ml.

PURPOSES: We investigated whether patients with organ-confined prostate cancer (PCa) and positive surgical margins (SMs) had a similar biochemical recurrence (BCR) risk compared with patients with pT3a and preoperative prostate-specific antigen (PSA) levels ≤ 10ng/ml. Furthermore, we examined the effects of incorporating SM status, Gleason score (Gls), and preoperative PSA level into the discrimination accuracy of the current tumor node metastasis-staging system. MATERIALS AND METHODS: We analyzed 863 PCa patients treated with radical prostatectomy from 1999 to 2008. Only individuals with pT2N0 or pT3N0, without neoadjuvant or adjuvant therapy, were included. We performed chi-square automatic interaction detection analysis to generate a classification model for predicting BCR by analyzing interactions between age at surgery, SM status, Gls, PSA, and tumor stage, tumor volume and relative tumor volume. Cox regression analyses tested the relationship between SM status and BCR rate after stratification according to T-stage and the novel classification. The predictive and discrimination accuracy of the current T-stage and of the classification model was quantified with time-dependent receiver operating characteristics and integrated discrimination improvement. The topographical association between extracapsular extension of PCa and positive SM was analyzed in patients with pT3aR1 using a computational reconstruction diagram of the prostate. RESULTS: The chi-square automatic interaction detection analysis found interactions among pT Stage, SM status, PSA and Gls and generated a classification model for BCR prediction: pT2R0, pT2R1, pT3a PSA ≤ 10 ng/ml, pT3a PSA>10 ng/ml and pT3b. Men with pT2R1 had a shorter time to BCR compared with men with pT3a-PSA ≤ 10 ng/ml (P<0.0001). Gls≥7a was correlated with a poorer BCR rate than Gls≤7a in men with pT2R1 or pT3a PSA ≤ 10 ng/ml (P = 0.012). The rank order (highest to lowest) for the risk of developing BCR was pT3b>pT2R1/pT3a-PSA>10 ng/ml>pT2R1/pT3a PSA ≤ 10 ng/ml>pT2R0 (P<0.0001). Discrimination accuracy gains were observed when PCa was stratified according to the novel classification (P<0.0001). A topographical association between extracapsular extension and positive SM was found in patients with pT3aR1 (P = 0.01). CONCLUSION: Patients with pT2R1 develop a similar BCR risk to that of patients with pT3a PSA ≤ 10 ng/ml. Gls≥7b is associated with a high BCR risk in these patient groups. Including SM status, PSA, and Gls in pT stage appears to improve prognostic stratification in patients with PCa.

High-grade prostatic intraepithelial neoplasia (HGPIN) and topographical distribution in 1,374 prostatectomy specimens: existence of HGPIN near prostate cancer.

PURPOSE: High-grade prostatic intraepithelial neoplasia (HGPIN) is believed to be a precursor of prostate cancer (PCa). This study evaluated whether HGPIN was located close to PCa in whole radical prostatectomy specimens (RPSs). MATERIALS AND METHODS: We evaluated 1,374 prostate specimens from 1999 to 2010 using a cMDX-based map model of the prostate. The distribution of 10,439 PCa foci was analyzed and visualized on a heat map. The color gradient of the heat map was reduced to six colors representing the frequency classification of the relative frequency of PCa using an image posterization effect. We defined 22 regions in the prostate according to the frequency of PCa occurrence. Seven hundred ninety RPSs containing 6,374 PCa foci and 4,502 HGPIN foci were evaluated. The topographical association between PCa and HGPIN in the RPSs was analyzed by estimating the frequencies of PCa and HGPIN in 22 regions. A logistic regression analysis was performed to assess the odds ratios of HGPIN for the presence of PCa in 22 regions. RESULTS: Fifty-eight percent of PCa specimens included HGPIN and had significantly more favorable Gleason scores, lower PSA levels and smaller relative tumor volumes than isolated PCa specimens. HGPIN (68%) and PCa (69%) were predominantly localized to the apical half of the prostate. HGPIN was mainly concentrated in the peripheral zone medial to regions with high PCa frequencies. Upon logistic regression analysis, HGPIN was a significant predictor of PCa co-existence in 11 regions. CONCLUSIONS: HGPIN was located adjacent to PCa in whole RPSs. PCa concomitant with HGPIN had more favorable pathologic features than isolated PCa.

CMDX©-based single source information system for simplified quality management and clinical research in prostate cancer.

BACKGROUND: Histopathological evaluation of prostatectomy specimens is crucial to decision-making and prediction of patient outcomes in prostate cancer (PCa). Topographical information regarding PCa extension and positive surgical margins (PSM) is essential for clinical routines, quality assessment, and research. However, local hospital information systems (HIS) often do not support the documentation of such information. Therefore, we investigated the feasibility of integrating a cMDX-based pathology report including topographical information into the clinical routine with the aims of obtaining data, performing analysis and generating heat maps in a timely manner, while avoiding data redundancy. METHODS: We analyzed the workflow of the histopathological evaluation documentation process. We then developed a concept for a pathology report based on a cMDX data model facilitating the topographical documentation of PCa and PSM; the cMDX SSIS is implemented within the HIS of University Hospital Muenster. We then generated a heat map of PCa extension and PSM using the data. Data quality was assessed by measuring the data completeness of reports for all cases, as well as the source-to-database error. We also conducted a prospective study to compare our proposed method with recent retrospective and paper-based studies according to the time required for data analysis. RESULTS: We identified 30 input fields that were applied to the cMDX-based data model and the electronic report was integrated into the clinical workflow. Between 2010 and 2011, a total of 259 reports were generated with 100% data completeness and a source-to-database error of 10.3 per 10,000 fields. These reports were directly reused for data analysis, and a heat map based on the data was generated. PCa was mostly localized in the peripheral zone of the prostate. The mean relative tumor volume was 16.6%. The most PSM were localized in the apical region of the prostate. In the retrospective study, 1623 paper-based reports were transferred to cMDX reports; this process took 15 ± 2 minutes per report. In a paper-based study, the analysis data preparation required 45 ± 5 minutes per report. CONCLUSIONS: cMDX SSIS can be integrated into the local HIS and provides clinical routine data and timely heat maps for quality assessment and research purposes.

Clinical map document based on XML (cMDX): document architecture with mapping feature for reporting and analysing prostate cancer in radical prostatectomy specimens.

BACKGROUND: The pathology report of radical prostatectomy specimens plays an important role in clinical decisions and the prognostic evaluation in Prostate Cancer (PCa). The anatomical schema is a helpful tool to document PCa extension for clinical and research purposes. To achieve electronic documentation and analysis, an appropriate documentation model for anatomical schemas is needed. For this purpose we developed cMDX. METHODS: The document architecture of cMDX was designed according to Open Packaging Conventions by separating the whole data into template data and patient data. Analogue custom XML elements were considered to harmonize the graphical representation (e.g. tumour extension) with the textual data (e.g. histological patterns). The graphical documentation was based on the four-layer visualization model that forms the interaction between different custom XML elements. Sensible personal data were encrypted with a 256-bit cryptographic algorithm to avoid misuse. In order to assess the clinical value, we retrospectively analysed the tumour extension in 255 patients after radical prostatectomy. RESULTS: The pathology report with cMDX can represent pathological findings of the prostate in schematic styles. Such reports can be integrated into the hospital information system. "cMDX" documents can be converted into different data formats like text, graphics and PDF. Supplementary tools like cMDX Editor and an analyser tool were implemented. The graphical analysis of 255 prostatectomy specimens showed that PCa were mostly localized in the peripheral zone (Mean: 73% ± 25). 54% of PCa showed a multifocal growth pattern. CONCLUSIONS: cMDX can be used for routine histopathological reporting of radical prostatectomy specimens and provide data for scientific analysis.