PITX1 Is a Regulator of TERT Expression in Prostate Cancer with Prognostic Power.

The current risk stratification in prostate cancer (PCa) is frequently insufficient to adequately predict disease development and outcome. One hallmark of cancer is telomere maintenance. For telomere maintenance, PCa cells exclusively employ telomerase, making it essential for this cancer entity. However, TERT, the catalytic protein component of the reverse transcriptase telomerase, itself does not suit as a prognostic marker for prostate cancer as it is rather low expressed. We investigated if, instead of TERT, transcription factors regulating TERT may suit as prognostic markers. To identify transcription factors regulating TERT, we developed and applied a new gene regulatory modeling strategy to a comprehensive transcriptome dataset of 445 primary PCa. Six transcription factors were predicted as TERT regulators, and most prominently, the developmental morphogenic factor PITX1. PITX1 expression positively correlated with telomere staining intensity in PCa tumor samples. Functional assays and chromatin immune-precipitation showed that PITX1 activates TERT expression in PCa cells. Clinically, we observed that PITX1 is an excellent prognostic marker, as concluded from an analysis of more than 15,000 PCa samples. PITX1 expression in tumor samples associated with (i) increased Ki67 expression indicating increased tumor growth, (ii) a worse prognosis, and (iii) correlated with telomere length.

VPRBP Functions Downstream of the Androgen Receptor and OGT to Restrict p53 Activation in Prostate Cancer.

Androgen receptor (AR) is a major driver of prostate cancer initiation and progression. O-GlcNAc transferase (OGT), the enzyme that catalyzes the covalent addition of UDP-N-acetylglucosamine (UDP-GlcNAc) to serine and threonine residues of proteins, is often highly expressed in prostate cancer with its expression correlated with high Gleason score. In this study, we have identified an AR and OGT coregulated factor, Vpr (HIV-1) binding protein (VPRBP) also known as DDB1 and CUL4 Associated Factor 1 (DCAF1). We show that VPRBP is regulated by the AR at the transcript level, and stabilized by OGT at the protein level. VPRBP knockdown in prostate cancer cells led to a significant decrease in cell proliferation, p53 stabilization, nucleolar fragmentation, and increased p53 recruitment to the chromatin. In human prostate tumor samples, VPRBP protein overexpression correlated with AR amplification, OGT overexpression, a shorter time to postoperative biochemical progression and poor clinical outcome. In clinical transcriptomic data, VPRBP expression was positively correlated with the AR and also with AR activity gene signatures. IMPLICATIONS: In conclusion, we have shown that VPRBP/DCAF1 promotes prostate cancer cell proliferation by restraining p53 activation under the influence of the AR and OGT.

Overexpression of the TRIM24 E3 Ubiquitin Ligase is Linked to Genetic Instability and Predicts Unfavorable Prognosis in Prostate Cancer.

Tripartite motif containing 24 (TRIM24) is a multifunctional protein involved in p53 degradation, chromatin binding, and transcriptional modulation of nuclear receptors. Emerging research has revealed that upregulation of TRIM24 in numerous tumor types is linked to poor prognosis, attributing an important role to TRIM24 in tumor biology. In order to better understand the role of TRIM24 in prostate cancer, we analyzed its immunohistochemical expression on a tissue microarray containing >17,000 prostate cancer specimens. TRIM24 immunostaining was detectable in 61% of 15,321 interpretable cancers, including low expression in 46% and high expression in 15% of cases. TRIM24 upregulation was associated with high Gleason grade, advanced pathologic tumor stage, lymph node metastasis, higher preoperative prostate-specific antigen level, increased cell proliferation as well as increased genomic instability, and predicted prognosis independent of clinicopathologic parameters available at the time of the initial biopsy (all P<0.0001). TRIM24 upregulation provides additional prognostic information in prostate cancer, particularly in patients with low Gleason grade tumors who may be eligible for active surveillance strategies, suggesting promising potential for TRIM24 in the routine diagnostic work-up of these patients.

Increased Cytoplasmic CD138 Expression Is Associated with Aggressive Characteristics in Prostate Cancer and Is an Independent Predictor for Biochemical Recurrence.

Syndecan-1 (CD138) is a transmembrane proteoglycan expressed in various normal and malignant tissues. It is of interest due to a possible prognostic effect in tumors and its role as a target for the antibody-drug conjugate indatuximab ravtansine. Here, we analyzed 17,747 prostate cancers by immunohistochemistry. Membranous and cytoplasmic CD138 staining was separately recorded. In normal prostate glands, CD138 staining was limited to basal cells. In cancers, membranous CD138 positivity was seen in 19.6% and cytoplasmic CD138 staining in 11.2% of 12,851 interpretable cases. A comparison with clinico-pathological features showed that cytoplasmic CD138 staining was more linked to unfavorable tumor features than membranous staining. Cytoplasmic CD138 immunostaining was associated with high tumor stage (p < 0.0001), high Gleason grade (p < 0.0001), nodal metastases (p < 0.0001), positive surgical margin (p < 0.0001), and biochemical recurrence (p < 0.0001). This also holds true for both V-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion positive and ERG fusion negative tumors although the cytoplasmic CD138 expression was markedly more frequent in ERG positive than in ERG negative tumors (p < 0.0001). Comparison with 11 previously analyzed chromosomal deletions identified a conspicuous association between cytoplasmic CD138 expression and 8p deletions (p < 0.0001) suggesting a possible functional interaction of CD138 with one or several 8p genes. Multivariate analysis revealed the cytoplasmic CD138 expression as an independent prognostic parameter in all cancers and in the ERG positive subgroup. In summary, our study indicates the cytoplasmic CD138 expression as a strong and independent predictor of poor prognosis in prostate cancer. Immunohistochemical measurement of CD138 protein may thus-perhaps in combination with other parameters-become clinically useful in the future.

Xenograft-derived mRNA/miR and protein interaction networks of systemic dissemination in human prostate cancer.

BACKGROUND: Distant metastasis formation is the major clinical problem in prostate cancer (PCa) and the underlying mechanisms remain poorly understood. Our aim was to identify novel molecules that functionally contribute to human PCa systemic dissemination based on unbiased approaches. METHODS: We compared mRNA, microRNA (miR) and protein expression levels in established human PCa xenograft tumours with high (PC-3), moderate (VCaP) or weak (DU-145) spontaneous micrometastatic potential. By focussing on those mRNAs, miRs and proteins that were differentially regulated among the xenograft groups and known to interact with each other we constructed dissemination-related mRNA/miR and protein/miR networks. Next, we clinically and functionally validated our findings. RESULTS: Besides known determinants of PCa progression and/or metastasis, our interaction networks include several novel candidates. We observed a clear role of epithelial-to-mesenchymal transition (EMT) pathways for PCa dissemination, which was additionally confirmed by an independent human PCa model (ARCAP-E/-M). Two converging nodes, CD46 (decreasing with metastatic potential) and DDX21 (increasing with metastatic potential), were used to test the clinical relevance of the networks. Intriguingly, both network nodes consistently added prognostic information for patients with PCa whereas CD46 loss predicted poor outcome independent of established parameters. Accordingly, depletion of CD46 in weakly metastatic PCa cells induced EMT-like properties in vitro and spontaneous micrometastasis formation in vivo. CONCLUSIONS: The clinical and functional relevance of the dissemination-related interaction networks shown here could be successfully validated by proof-of-principle experiments. Therefore, we suggest a direct pro-metastatic, clinically relevant role for the multiple novel candidates included in this study; these should be further exploited by future studies.

Up regulation of the Hippo signalling effector YAP1 is linked to early biochemical recurrence in prostate cancers.

The transcriptional coactivator YAP1 controls the balance between cell proliferation and apoptosis. YAP1 overexpression is linked to poor prognosis in many cancer types, yet its role in prostate cancer is unknown. Here, we applied YAP1 immunohistochemistry to a tissue microarray containing 17,747 clinical prostate cancer specimens. Cytoplasmic and nuclear YAP1 staining was seen in 81% and 63% of tumours. For both cytoplasmic and nuclear YAP1 staining, high levels were associated with advanced tumour stage, classical and quantitative Gleason grade, positive nodal stage, positive surgical margin, high KI67 labelling index, and early biochemical recurrence (p < 0.0001 each). The prognostic role of YAP1 staining was independent of established prognostic features in multivariate models (p < 0.001). Comparison with previously studied molecular markers identified associations between high YAP1 staining, TMPRSS2:ERG fusion (p < 0.0001), high androgen receptor (AR) expression (p < 0.0001), high Ki67 labelling index (p < 0.0001), and PTEN and 8p deletions (p < 0.0001 each). In conclusion, high YAP1 protein expression is an independent predictor of unfavourable disease course in prostate cancer. That cytoplasmic and nuclear YAP1 staining is equally linked to phenotype and prognosis fits well to a model where YAP1 activation during tumour progression includes up regulation, cytoplasmic accumulation and subsequent translocation to the nucleus.

Expression and serum levels of the neural cell adhesion molecule L1-like protein (CHL1) in gastrointestinal stroma tumors (GIST) and its prognostic power.

INTRODUCTION: Diagnosis of gastrointestinal stroma tumors (GIST) is based on the histological evaluation of tissue specimens. Reliable systemic biomarkers are lacking. We investigated the local expression of the neural cell adhesion molecule L1-like protein (CHL1) in GIST and determined whether soluble CHL1 proteoforms could serve as systemic biomarkers. MATERIAL AND METHODS: Expression of CHL1 was analyzed in primary tumor specimens and metastases. 58 GIST specimens were immunohistochemically stained for CHL1 on a tissue microarray (TMA). Systemic CHL1 levels were measured in sera derived from 102 GIST patients and 91 healthy controls by ELISA. Results were statistically correlated with clinicopathological parameters. RESULTS: CHL1 expression was detected in GIST specimens. Reduced tissue expression was significantly associated with advanced UICC stages (p = 0.036) and unfavorable tumor localization (p = 0.001). CHL1 serum levels are significantly elevated in GIST patients (p < 0.010). Elevated CHL1 levels were significantly associated with larger tumors (p = 0.023), advanced UICC stage (p = 0.021), and an increased Fletcher score (p = 0.041). Moreover, patients with a higher CHL1 serum levels displayed a significantly shortened recurrence free survival independent of other clinicopathological variables. CONCLUSION: Local CHL1 expression and serum CHL1 levels show a reverse prognostic behavior, highlighting the relevance of proteolytic shedding of the molecule. The results of the study indicate a potential role of serum CHL1 as a diagnostic and prognostic marker in GIST.

Prognostic and diagnostic role of PSA immunohistochemistry: A tissue microarray study on 21,000 normal and cancerous tissues.

To assess the prognostic and diagnostic utility of PSA immunostaining, tissue microarrays containing 17,747 prostate cancers, 3,442 other tumors from 82 different (sub) types and 608 normal tissues were analyzed at two different antibody concentrations (1:100 and 1:800). In normal tissues, PSA expression was limited to prostate epithelial cells. In prostate cancers, PSA staining was seen in 99.9-100% (1:800-1:100) primary tumors, 98.7-99.7% of advanced recurrent cancers, in 84.6-91.4% castration resistant cancers, and in 7.7-18.8% of 16 small cell carcinomas. Among extraprostatic tumors, PSA stained positive in 0-3 (1:800-1:100) of 19 osteosarcomas, 1-2 of 34 ovarian cancers, 0-2 of 35 malignant mesotheliomas, 0-1 of 21 thyroid gland carcinomas and 0-1 of 26 large cell lung cancers. Reduced staining intensity and loss of apical staining were strongly linked to unfavorable tumor phenotype and poor prognosis (p < 0.0001 each). This was all the more the case if a combined "PSA pattern score" was built from staining intensity and pattern. The prognostic impact of the "PSA pattern score" was independent of established pre- and postoperative clinico-pathological prognostic features. In conclusion, PSA immunostaining is a strong prognostic parameter in prostate cancer and has high specificity for prostate cancer at a wide range of antibody dilutions.

Protein expression of close homologue of L1 (CHL1) is a marker for overall survival in non-small cell lung cancer (NSCLC).

BACKGROUND: The cell adhesion molecule close homologue of L1 (CHL1) is a potential tumour suppressor and was recently detected in non-small cell lung cancer (NSCLC) specimens. The expression pattern, prognostic, and functional role of CHL1 in NSCLCs is unknown. METHODS: We evaluated the protein expression of CHL1 by immunohistochemistry in 2161 NSCLC patients based on a tissue microarray. The results were correlated with clinical, histopathological, and patient survival data (Chi square test, t test, and log-rank test, respectively). A multivariate analysis (Cox regression) was performed to validate its impact on patients' survival. RESULTS: CHL1 was expressed in NSCLC patients and was significantly overexpressed in lung adenocarcinomas and squamous cell carcinomas compared to neuroendocrine and large cell carcinomas of the lung (p < 0.001). CHL1 expression was associated with the T stage in adenocarcinomas (p = 0.011) and with metastatic lymph node status and UICC stage in squamous cell carcinomas (p = 0.034 and p = 0.035, respectively). Increased CHL1 expression was associated with improved survival in univariate (p = 0.031) and multivariate analyses (odds ratio 0.797, 95% confidence interval 0.677-0.939, p = 0.007). CONCLUSION: The prognostic significance of CHL1 makes it a potential prognostic and therapeutic target and underlines its role as a tumour suppressor. Further validation studies and functional analyses are needed to investigate its potential role in tumourigenesis and dissemination.

Centralization of Pancreatic Surgery in Europe.

BACKGROUND: The objective of this article is a review and an analysis of the current state of centralization of pancreatic surgery in Europe. Numerous recent publications demonstrate higher postoperative in-hospital mortality rates in low-volume clinics after pancreatic resection than previously assumed due to their not publishing significantly worse outcomes when compared to high-volume centres. Although the benefits of centralization of pancreatic surgery in high-volume centres have been demonstrated in many studies, numerous countries have so far failed to establish centralization in their respective health care systems. METHODS: A systematic literature search of the Medline database for studies concerning centralization of pancreatic surgery in Europe was conducted. The studies were reviewed independently for previously defined inclusion and exclusion criteria. We included 14 studies with a total of 117,634 patients. All data were extracted from or provided by health insurance company or governmental registry databases. RESULTS: Thirteen out of the 14 studies demonstrate an improvement in their respective outcome related to volume. Twelve studies showed a significantly lower postoperative mortality rate in the highest annual volume group in comparison to overall postoperative mortality rate in the whole patient cohort. CONCLUSION: As the available data indicate, most European countries have so far failed to establish centralization of pancreatic surgery to high-volume centres due to numerous reasons. Considering a plateau in survival rates of patients undergoing treatment for pancreatic cancer in Europe during the last 15 years, this review enforces the worldwide plea for centralization to lower post-operative mortality after pancreatic surgery.

Robotic cholecystectomy: first experience with the new Senhance robotic system.

This retrospective study was performed to evaluate the safety and feasibility of the new Senhance robotic system (Transenterix) for robotic cholecystectomy. Our series is the first experience with cholecystectomies utilizing this new platform. From May 2017 to August 2017, 20 robotic cholecystectomies were performed using the Senhance robotic system. Patients were between 23 years and 78 years of age, eligible for a laparoscopic procedure with general anesthesia, with no life-threatening co-morbidities that limited the subjects' life-expectancy to fewer than 12 months. A retrospective chart review was performed for a variety of pre-, peri- and postoperative data including, but not limited to patient demographics, intraoperative complications and postoperative complications. 9 male and 11 female patients were included in this study. Median age was 39.5 years (range 23-78); median BMI was 27.35 kg/m2 (range 22.8-48.3). Median docking time was 10 min (range 2-26), and median operative time was 71.5 min (range 34-197). Conversion to standard laparoscopy occurred in one case for lysis of extensive adhesions. There were no conversions to open technique. There were no intra- or post-operative complications noted. We report the first series of robotic cholecystectomies using the new Senhance system. Docking time and total operative time decreased significantly over the course of this series and did not plateau; console time did not change significantly. This study demonstrates the feasibility of utilizing this platform in performing minimally invasive cholecystectomies.

Robotic low anterior resection versus transanal total mesorectal excision in rectal cancer: A comparison of 115 cases.

BACKGROUND: Robotic low anterior resection (RLAR) and transanal total mesorectal excision (TaTME) are novel surgical techniques for resection of rectal cancer. To our knowledge, no data exist on direct comparison of these procedures in terms of oncological or functional parameters. METHODS: 60 RLAR and 55 TaTME for rectal cancer were compared in respect to patient characteristics, clinicopathological parameters, intraoperative and perioperative results and anatomopathological outcome. RESULTS: 62 surgeries addressed tumors of the lower third (53.9%). No intergroup differences in terms of patient characteristics and clinicopathological parameters were observed. Operating time did not differ between groups (p = 0.312), nor did the perioperative complication rate (p = 0.176). Circumferential resection margin was wider in the RLAR than in the TaTME group (p < 0.001), while no differences were found in the remaining oncological parameters. CONCLUSION: Our study shows comparable results for RLAR and TaTME in rectal cancer treatment. Both procedures should be considered equally feasible for low rectal cancer cases and as an alternative to conventional anterior resections (open or laparoscopic). Furthermore, both techniques allow excellent oncological outcome especially in patients with anatomical limitations.