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The combination of DNA ploidy and automatically estimated stroma fraction has been shown to correlate with recurrence and cancer death in colorectal cancer. We aimed to extend this observation and evaluate the prognostic importance of this combined marker in prostate cancer. DNA ploidy status was determined by image cytometry and the stroma fraction was estimated automatically on hematoxylin and eosin stained sections in three tumor samples from each patient to account for tumor heterogeneity. The optimal threshold for low (≤56%) and high (>56%) stroma fraction was identified in a discovery cohort (n = 253). The combined marker was validated in an independent patient cohort (n = 259) with biochemical recurrence as endpoint. The combined marker predicted biochemical recurrence independently in the validation cohort. Multivariable analysis showed that the highest risk of recurrence was observed for patients with samples that had both non‐diploid ploidy status and a high stroma fraction (hazard ratio: 2.51, 95% confidence interval: 1.18–5.34). In conclusion, we suggest the combination of DNA ploidy and automatically estimated stroma fraction as a prognostic marker for the risk stratification of prostate cancer patients. It may also be a potential generic marker as concurrent results have been described in colorectal cancer. What's new? The stroma that surrounds tumor cells can have significant effects on tumor growth and behavior. Another hallmark of cancer is aneuploidy caused by genomic instability, which offers an important prognostic marker in several cancer types. In this study, the authors found that combining these two markers—stromal fraction and DNA ploidy—provided a significant predictor of biochemical recurrence in prostate cancer. The low cost, high throughput, and accuracy of digital analysis using this combined method thus promise to provide improved prognostic biomarkers in prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The high degree of genomic diversity in cancer represents a challenge for identifying objective prognostic markers. We aimed to examine the extent of tumour heterogeneity and its effect on the evaluation of a selected prognostic marker using prostate cancer as a model.Methods: We assessed Gleason Score (GS), DNA ploidy status and phosphatase and tensin homologue (PTEN) expression in radical prostatectomy specimens (RP) from 304 patients followed for a median of 10 years (interquartile range 6-12). GS was assessed for every tumour-containing block and DNA ploidy for a median of four samples for each RP. In a subgroup of 40 patients we assessed DNA ploidy and PTEN status in every tumour-containing block. In 102 patients assigned to active surveillance (AS), GS and DNA ploidy were studied in needle biopsies.Results: Extensive heterogeneity was observed for GS (89% of the patients) and DNA ploidy (40% of the patients) in the cohort, and DNA ploidy (60% of the patients) and PTEN expression (75% of the patients) in the subgroup. DNA ploidy was a significant prognostic marker when heterogeneity was taken into consideration. In the AS cohort we found heterogeneity in GS (24%) and in DNA ploidy (25%) specimens.Conclusions: Multi-sample analysis should be performed to support clinical treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Pathological evaluations give the best prognostic markers for prostate cancer patients after radical prostatectomy, but the observer variance is substantial. These risk assessments should be supported and supplemented by objective methods for identifying patients at increased risk of recurrence. Markers of epigenetic aberrations have shown promising results in several cancer types and can be assessed by automatic analysis of chromatin organisation in tumour cell nuclei.Methods: A consecutive series of 317 prostate cancer patients treated with radical prostatectomy at a national hospital between 1987 and 2005 were followed for a median of 10 years (interquartile range, 7-14). On average three tumour block samples from each patient were included to account for tumour heterogeneity. We developed a novel marker, termed Nucleotyping, based on automatic assessment of disordered chromatin organisation, and validated its ability to predict recurrence after radical prostatectomy.Results: Nucleotyping predicted recurrence with a hazard ratio (HR) of 3.3 (95% confidence interval (CI), 2.1-5.1). With adjustment for clinical and pathological characteristics, the HR was 2.5 (95% CI, 1.5-4.1). An updated stratification into three risk groups significantly improved the concordance with patient outcome compared with a state-of-the-art risk-stratification tool (P<0.001). The prognostic impact was most evident for the patients who were high-risk by clinical and pathological characteristics and for patients with Gleason score 7.Conclusion: A novel assessment of epigenetic aberrations was capable of improving risk stratification after radical prostatectomy. [ABSTRACT FROM AUTHOR]

The unfolded protein response ( UPR) is a homeostatic mechanism to maintain endoplasmic reticulum ( ER) function. The UPR is activated by various physiological conditions as well as in disease states, such as cancer. As androgens regulate secretion and development of the normal prostate and drive prostate cancer ( PCa) growth, they may affect UPR pathways. Here, we show that the canonical UPR pathways are directly and divergently regulated by androgens in PCa cells, through the androgen receptor ( AR), which is critical for PCa survival. AR bound to gene regulatory sites and activated the IRE1α branch, but simultaneously inhibited PERK signaling. Inhibition of the IRE1α arm profoundly reduced PCa cell growth in vitro as well as tumor formation in preclinical models of PCa in vivo. Consistently, AR and UPR gene expression were correlated in human PCa, and spliced XBP-1 expression was significantly upregulated in cancer compared with normal prostate. These data establish a genetic switch orchestrated by AR that divergently regulates the UPR pathways and suggest that targeting IRE1α signaling may have therapeutic utility in PCa. [ABSTRACT FROM AUTHOR]

The six transmembrane protein of prostate 2 ( STAMP2) is an androgen-regulated gene whose mRNA expression is increased in prostate cancer ( PCa). Here, we show that STAMP2 protein expression is increased in human PCa compared with benign prostate that is also correlated with tumor grade and treatment response. We also show that STAMP2 significantly increased reactive oxygen species ( ROS) in PCa cells through its iron reductase activity which also depleted NADPH levels. Knockdown of STAMP2 expression in PCa cells inhibited proliferation, colony formation, and anchorage-independent growth, and significantly increased apoptosis. Furthermore, STAMP2 effects were, at least in part, mediated by activating transcription factor 4 ( ATF4), whose expression is regulated by ROS. Consistent with in vitro findings, silencing STAMP2 significantly inhibited PCa xenograft growth in mice. Finally, therapeutic silencing of STAMP2 by systemically administered nanoliposomal si RNA profoundly inhibited tumor growth in two established preclinical PCa models in mice. These data suggest that STAMP2 is required for PCa progression and thus may serve as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Objective. The aims of this study were to establish 15-year postprostatectomy prostate cancer-specific mortality (PCSM), explore the time to prostate-specific antigen (PSA) relapse and identify clinically available prognostic factors. Material and methods. From 1987 to 2004, 309 men (median age 62 years, range 40-74 years) were prostatectomized for localized prostate cancer at a tertiary referral cancer centre. Slightly modified D'Amico risk groups were identified. PSA relapse was defined as PSA ≥ 4 μg/l before 2000, and thereafter as PSA > 0.2 μg/l. Radical prostatectomy (RP) 3-12 months after diagnosis represented 'deferred' RP. PCSM was assessed with competing risk modelling. The level of significance was set at p < 0.05. Results. After a median of 12 years, 41 men were dead from prostate cancer and 68 due to other causes [15-year PCSM 15%, 95% confidence interval (CI) 10-19%], with no significant difference in PCSM between the low- and intermediate-risk groups, and the 'conventional' high-risk group having 24% PCSM (95% CI 16-32%). PCSM was 33% (95% CI 20-46%) for men with two high-risk factors. The median time to PSA relapse ( n = 152) was 5 (range 0-17) years, with a median of 7 (range 0-17) years' survival thereafter. Deferral of RP for up to 1 year had no impact on PCSM for all patients combined. Conclusions. Approximately one in seven men with localized prostate cancer, prostatectomized before the PSA era, will die from the disease within the 15 years post-RP. Men with two high-risk criteria have a particularly poor prognosis. After PSA relapse the median survival is 7 years. The data on deferral of RP need confirmation, taking into account risk group allocation. [ABSTRACT FROM AUTHOR]

TCTP has been implicated in a plethora of important cellular processes related to cell growth, cell cycle progression, malignant transformation and inhibition of apoptosis. In addition to these intracellular functions, TCTP has extracellular functions and plays an important role in immune cells. TCTP expression was previously shown to be deregulated in prostate cancer, but its function in prostate cancer cells is largely unknown. Here we show that TCTP expression is regulated by androgens in LNCaP prostate cancer cells in vitro as well as human prostate cancer xenografts in vivo. Knockdown of TCTP reduced colony formation and increased apoptosis in LNCaP cells, implicating it as an important factor for prostate cancer cell growth. Global gene expression profiling in TCTP knockdown LNCaP cells showed that several interferon regulated genes are regulated by TCTP, suggesting that it may have a role in regulating immune function in prostate cancer. In addition, recombinant TCTP treatment increased colony formation in LNCaP cells suggesting that secreted TCTP may function as a proliferative factor in prostate cancer. These results suggest that TCTP may have a role in prostate cancer development. [ABSTRACT FROM AUTHOR]

Background: The clinical outcome for the individual prostate cancer patient is often difficult to predict, due to lack of reliable independent prognostic biomarkers. We tested DNA ploidy as a prognostic factor for clinical outcome in 186 patients treated with radical prostatectomy. Methods: DNA ploidy was measured using an automatic image cytometry system and correlated with preoperative PSA, age at surgery, Mostofi grade, surgical margins and Gleason score. Results: The mean follow up time after operation was 73.3 months (range 2–176 months). Of the 186 prostatectomies, 96 were identified as diploid, 61 as tetraploid and 29 as aneuploid. Twenty-three per cent, 36% and 62% of the diploid, tetraploid and aneuploid cases respectively, suffered from relapse during the observation time. DNA ploidy, Gleason score, Mostofi grading, surgical margins and preoperative PSA were all significant predictors of relapse in a univariate analysis. On multivariate analysis, only Gleason score and DNA ploidy proved to be independently predictors of disease recurrence. Furthermore, among the 68 cases identified with Gleason score 7, DNA ploidy was the only significant predictor of disease recurrence. Conclusions: Our data suggest that DNA ploidy should be included as an important additive prognostic factor for prostate cancer, especially for patients identified with Gleason score 7 tumours. [ABSTRACT FROM AUTHOR]

To optimize the indication for sentinel lymph node (SLN) biopsy according to tumour size in penile carcinoma. This was a retrospective analysis of 23 consecutive patients (median age 65 years; range 49–85 years) with primary penile carcinoma classified according to the TNM classification as stage T1–T3 who were identified as having SLNs in the groins. SLNs were detected by means of preoperative injection of a 99m Tc nanocolloid around the tumour and peroperative use of a gamma detector probe. The average tumour size was 2.9±1.3 cm. In 7/25 patients with penile carcinoma examined with the SLN method, metastases to inguinal lymph nodes could be demonstrated. Two out of three patients with primary penile carcinomas classified as T1 according to the TNM classification and tumours > 3&ThickSpace;cm in diameter had inguinal lymph node metastases. One of the patients had a micrometastasis, which was detected by means of immunohistochemical analysis. Seven out of eight patients with penile carcinomas > 3&ThickSpace;cm in diameter had lymph node metastases. We did not observe any major surgical complications associated with the SLN procedure. These data indicate that penile carcinomas with a diameter of >3&ThickSpace;cm should be investigated with SLN biopsy regardless of stage. However, multicentre studies are needed in order to obtain the appropriate number of patients. [ABSTRACT FROM AUTHOR]

Objective: To study the complication rate, local recurrence rate, and survival after total pelvic exenteration for primary advanced and recurrent rectal cancer. Design: Prospective study. Setting: Tertiary referral university hospital, Norway. Subjects: 25 patients who were operated on for primary advanced and 22 for recurrent rectal cancer since 1991; 42 men and 5 women, mean age 64 years (range 44-78). All had preoperative irradiation of 46-50 Gy. Main outcome measures: Incidence of major complications, and actuarial 5-year survival and local recurrence rate. Results: Twenty patients had R0 resection in the primary group versus seven in the recurrent group. No R2 resections were done in the primary group compared with four in the recurrent group. Half the primary cases (n = 13) had abdominoperineal resections. Hartmann's procedures were common in both groups (n = 8 in each). Postoperative mortality at 30 days was 4% (n = 2) and in-hospital 13% (n = 6). 18 patients had major complications and 12 were reoperated on. Overall 5-year actuarial survival for 43 patients without distant metastases was 28% - those with primary tumours 36%, and those with recurrent tumours 18% - similar to the figures for R0 and R1 resections. Actuarial local recurrence at 5 years for primary cancers was 18% compared with 68% for recurrent cancers, again nearly identical to the figures for R0/R1 operations (p = 0.008 and p = 0.03). Conclusion: Some patients with advanced rectal cancer either primary or recurrent may benefit from simultaneous en-bloc cystectomy. The higher postoperative morbidity and mortality indicate the need for well-defined indications for this procedure and the necessity for thorough preoperative staging. [ABSTRACT FROM AUTHOR]

Simple Summary: Molecular tissue-based prognostic biomarkers are anticipated to complement the current risk stratification systems in prostate cancer, but their manual assessment is subjective and time-consuming. Objective assessment of such biomarkers by machine learning-based methods could advance their adoption in a clinical workflow. PTEN and DNA ploidy status are well-studied biomarkers, which can provide clinically relevant information in prostate cancer at a low cost. Using a cohort of 253 patients who received radical prostatectomy, we developed a novel, fully-automated PTEN scoring in immunohistochemically-stained tissue slides, which could be used to assess PTEN status in a reliable and reproducible manner. In an independent validation cohort of 259 patients, automatically assessed PTEN status was significantly associated with time to biochemical recurrence after radical prostatectomy, and the combination of PTEN and DNA ploidy status further improved risk stratification. These results demonstrate the utility of machine learning in biomarker assessment. Machine learning (ML) is expected to improve biomarker assessment. Using convolution neural networks, we developed a fully-automated method for assessing PTEN protein status in immunohistochemically-stained slides using a radical prostatectomy (RP) cohort (n = 253). It was validated according to a predefined protocol in an independent RP cohort (n = 259), alone and by measuring its prognostic value in combination with DNA ploidy status determined by ML-based image cytometry. In the primary analysis, automatically assessed dichotomized PTEN status was associated with time to biochemical recurrence (TTBCR) (hazard ratio (HR) = 3.32, 95% CI 2.05 to 5.38). Patients with both non-diploid tumors and PTEN-low had an HR of 4.63 (95% CI 2.50 to 8.57), while patients with one of these characteristics had an HR of 1.94 (95% CI 1.15 to 3.30), compared to patients with diploid tumors and PTEN-high, in univariable analysis of TTBCR in the validation cohort. Automatic PTEN scoring was strongly predictive of the PTEN status assessed by human experts (area under the curve 0.987 (95% CI 0.968 to 0.994)). This suggests that PTEN status can be accurately assessed using ML, and that the combined marker of automatically assessed PTEN and DNA ploidy status may provide an objective supplement to the existing risk stratification factors in prostate cancer. [ABSTRACT FROM AUTHOR]