Posttranscriptional protein modification by SUMOylation plays an important role in tumor development and progression. In the current study we analyzed prevalence and prognostic impact of the de-SUMOylation enzyme SENP1 in prostate cancer. SENP1 expression was analyzed by immunohistochemistry on a tissue microarray containing more than 12,400 prostate cancer specimens. Results were compared to tumor phenotype, ERG status, genomic deletions of 3p, 5q, 6q and PTEN, and biochemical recurrence. SENP1 immunostaining was detectable in 34.5 % of 9,516 interpretable cancers and considered strong in 7.3 %, moderate in 14.9 % and weak in 12.3 % of cases. Strong SENP1 expression was linked to advanced pT stage (p < 0.0001), high Gleason grade (p < 0.0001), positive lymph node status (p = 0.0019), high pre-operative PSA levels (p = 0.0037), and PSA recurrence (p < 0.0001). SENP1 expression was strongly associated with positive ERG fusion status as determined by both in situ hybridization (FISH) and immunohistochemistry as well as with PTEN deletions. Detectable SENP1 immunostaining was found in 41 % of ERG positive and in 47 % of PTEN deleted cancers but in only 30 % of ERG negative and 30 % of PTEN non-deleted cancers (p < 0.0001 each). Deletions of 3p, 5q, and 6q were unrelated to SENP1 expression. Subset analyses revealed that the prognostic impact of SENP1 expression was solely driven by the subgroup of ERG positive, PTEN undeleted cancers. In this subgroup, the prognostic role of SENP1 expression was independent of the preoperative PSA level, tumor stage, Gleason grade, and the status of the resection margin. SENP1 expression has strong prognostic impact in a molecularly defined subset of cancers. This is per se not surprising as the biologic impact of each individual molecular event is likely to be dependent on its cellular environment. However, such findings challenge the concept of finding clinically relevant molecular signatures that are equally applicable to all prostate cancers.

(1) Background: Abdominal compartment syndrome (ACS) is a life-threatening situation and is associated with high mortality in the intensive care unit (ICU). Decompressive laparotomy represents the last therapeutic option. This cohort study aims to optimize the selection of ICU patients suffering from ACS who benefit from decompressive laparotomy. (2) Methods: All available data from adult patients treated at the 12 ICUs of a university hospital between 2011 and 2019 were included. Outcome parameters for patients with and without extracorporeal membrane oxygenation (ECMO) were compared. (3) Results: 207 ICU patients with ACS undergoing surgery were identified. Laparotomy resulted in immediate improvement of organ functions in 15% of patients, who then survived more frequently. The overall mortality rate in our cohort was 69%. The group of ECMO patients—including va- and vv-ECMO—showed significantly less organ function improvement and a higher mortality rate of 79% compared to a better postoperative improvement and a lower mortality rate of 62% in non-ECMO patients. (4) Conclusions: There are ICU patients who benefit from decompressive laparotomy—nevertheless, mortality is high. Non-ECMO patients have a better prognosis than ECMO patients. Our findings can support clinical decision-making on emergency surgery and the development of future guidelines.

Molecular prognostic markers are urgently needed in order to improve therapy decisions in prostate cancer. To better understand the requirements for biomarker studies, we re-analyzed prostate cancer tissue microarray immunohistochemistry (IHC) data from 39 prognosis markers in subsets of 50 – >10,000 tumors. We found a strong association between the “prognostic power” of individual markers and the number of tissues that should be minimally included in such studies. The prognostic relevance of more than 90% of the 39 IHC markers could be detected if ≥6400 tissue samples were analyzed. Studying markers of tissue quality, including immunohistochemistry of ets-related gene (ERG) and vimentin, and fluorescence in-situ hybridization analysis of human epidermal growth factor receptor 2 (HER2), we found that 18% of tissues in our tissue microarray (TMA) showed signs of reduced tissue preservation and limited immunoreactivity. Comparing the results of Kaplan-Meier survival analyses or associations to ERG immunohistochemistry in subsets of tumors with and without exclusion of these defective tissues did not reveal statistically relevant differences. In summary, our study demonstrates that TMA-based marker validation studies using biochemical recurrence as an endpoint require at least 6400 individual tissue samples for establishing statistically relevant associations between the expression of molecular markers and patient outcome if weak to moderate prognosticators should also be reliably identified.

Epigenetic reprogramming including altered transcription factor binding and altered patterns of chromatin and DNA modifications are now accepted as the hallmark of aggressive cancers. We show that global changes in chromatin structure and chromatin accessibility in prostate tumour tissue can define castrate-resistant prostate cancer and be used to inform the discovery of gene-level classifiers for therapy. In addition, we show that the androgen receptor overexpression alone, which is a hallmark of progression on its own, is a primary driver for chromatin relaxation, which can lead to promiscuous binding of other key transcription factors important to disease progression. We identify mediators of chromatin relaxation that can be used as disease biomarker and show that such mediators identify DNA stretches enriched in low p-value GWAS-significant disease/tissue-specific susceptibility loci. Presenting Author: Urbanucci Alfonso Urbanucci, Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forksningsparken, University of Oslo, Oslo, Norway and Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Email: alfonso.urbanucci@gmail.com