Anton M.F. Kalsbeek

Initial multicentre experience of 68gallium-PSMA PET/CT guided robot-assisted salvage lymphadenectomy: acceptable safety profile but oncological benefit appears limited

To evaluate the safety and short‐term oncological outcomes of 68gallium‐labelled prostate‐specific membrane antigen (68Ga‐PSMA) positron‐emission tomography (PET)/computed tomography (CT)‐directed robot‐assisted salvage node dissection (RASND) for prostate cancer oligometastatic nodal recurrence.

Focal irreversible electroporation as primary treatment for localized prostate cancer

To determine the safety, quality of life (QoL) and short‐term oncological outcomes of primary focal irreversible electroporation (IRE) for the treatment of localized prostate cancer (PCa), and to identify potential risk factors for oncological failure.

Mutational load of the mitochondrial genome predicts pathological features and biochemical recurrence in prostate cancer

Prostate cancer management is complicated by extreme disease heterogeneity, which is further limited by availability of prognostic biomarkers. Recognition of prostate cancer as a genetic disease has prompted a focus on the nuclear genome for biomarker discovery, with little attention given to the mitochondrial genome. While it is evident that mitochondrial DNA (mtDNA) mutations are acquired during prostate tumorigenesis, no study has evaluated the prognostic value of mtDNA variation. Here we used next-generation sequencing to interrogate the mitochondrial genomes from prostate tissue biopsies and matched blood of 115 men having undergone a radical prostatectomy for which there was a mean of 107 months clinical follow-up. We identified 74 unique prostate cancer specific somatic mtDNA variants in 50 patients, providing significant expansion to the growing catalog of prostate cancer mtDNA mutations. While no single variant or variant cluster showed recurrence across multiple patients, we observe a significant positive correlation between the total burden of acquired mtDNA variation and elevated Gleason Score at diagnosis and biochemical relapse. We add to accumulating evidence that total acquired genomic burden, rather than specific mtDNA mutations, has diagnostic value. This is the first study to demonstrate the prognostic potential of mtDNA mutational burden in prostate cancer.

Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer

Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra‐glandular as well as inter‐patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes.

Mitochondrial genome variation and prostate cancer: a review of the mutational landscape and application to clinical management.

Prostate cancer is a genetic disease. While next generation sequencing has allowed for the emergence of molecular taxonomy, classification is restricted to the nuclear genome. Mutations within the maternally inherited mitochondrial genome are known to impact cancer pathogenesis, as a result of disturbances in energy metabolism and apoptosis. With a higher mutation rate, limited repair and increased copy number compared to the nuclear genome, the clinical relevance of mitochondrial DNA (mtDNA) variation requires deeper exploration. Here we provide a systematic review of the landscape of prostate cancer associated mtDNA variation. While the jury is still out on the association between inherited mtDNA variation and prostate cancer risk, we collate a total of 749 uniquely reported prostate cancer associated somatic mutations. Support exists for number of somatic events, extent of heteroplasmy, and rate of recurrence of mtDNA mutations, increasing with disease aggression. While, the predicted pathogenic impact for recurrent prostate cancer associated mutations appears negligible, evidence exists for carcinogenic mutations impacting the cytochrome c oxidase complex and regulating metastasis through elevated reactive oxygen species production. Due to a lack of lethal cohort analyses, we provide additional unpublished data for metastatic disease. Discussing the advantages of mtDNA as a prostate cancer biomarker, we provide a review of current progress of including elevated mtDNA levels, of a large somatic deletion, acquired tRNAs mutations, heteroplasmy and total number of somatic events (mutational load). We confirm via meta-analysis a significant association between mtDNA mutational load and pathological staging at diagnosis or surgery (p < 0.0001).

Feasibility and safety of focal irreversible electroporation as salvage treatment for localized radio-recurrent prostate cancer

To evaluate the feasibility, safety, early quality‐of‐life (QoL) and oncological outcomes of salvage focal irreversible electroporation (IRE) for radio‐recurrent prostate cancer (PCa).

MP83-01 HIGH-GRADE PROSTATE CANCER HAS INCREASED MITOCHONDRIAL CONTENT

transcriptome analysis performed by NGS. NanoString nCounter miRNA assays were used to profile miRNAs, and results validated by qRT-PCR. Cell proliferation assay was performed to evaluate the proliferative effects of TNF-a. RESULTS: Primary SM and UE cells express TNF-a receptors TNFR1 and TNFR2 and respond to TNF-a treatment. NFKB2, RelB and TNFAIP3 showed a progressive timeand concentration-dependent upregulation, and responses were stronger in SM cells compared to UE. TNF-a treatment increased cell proliferation. MiRNA expression profiling identified 17 miRNAs altered in both SMC and UE cells. MiRNAs miR-146a-5p, -21-5p, -1260a, -183-5p, -22-3p, -199a-3p, -199b-3p were similarly regulated in patients and cell-based models. MiR-26b was significantly induced in UE and SMC, but down-regulated in BOO. There was a cell-type dependent difference in miRNA profiles, with SMC-specific miRNAs gown-regulated after TNF-a treatment, in accordance with the down-regulation of SM markers and loss of contractility in human patients. Transcriptome analysis of TNF-treated cells was carried out and expression levels of predicted targets of disease-relevant miRNAs identified. CONCLUSIONS: Our results confirm an important role of TNF-a in the regulation of BOO-specific miRNAs, and identify miRNAs linking TNF-a signaling and fibrosis. Modulation of expression levels of TNF-a-regulated miRNAs in cell-based models of human bladder using miRNA-overexpression and inhibition will elucidate their role in organ remodeling and lead to novel therapeutic approaches for BOO-induced LUTD.

MP53-10 ROBOT-ASSISTED SALVAGE NODE DISSECTION FOR OLIGOMETASTATIC NODAL DISEASE DETECTED BY 68GALLIUM-PSMA PET/CT: A MULTICENTRE RETROSPECTIVE SERIES

p<0.001. The median OS was 7.1, 9.1 and 7.4 y respectively (p<0.001). Multivariable Cox proportional hazards analysis assessing for predictors of OS showed improved survival in diabetics on metformin (HR 0.77, 95% CI 0.74-0.81; p<0.001) vs. diabetics not on metformin (HR 0.99, 95% CI 0.95-1.03; p1⁄40.5) with non-diabetics as referent group while controlling for age, co-morbidity, and Gleason score. Assessing for predictors of SRE revealed no association between metformin use (HR 0.99, 95% CI 0.92-1.07; p1⁄40.8) and SRE. Lastly, PC-specific survival was improved in diabetics on metformin (HR 0.72, 95% CI 0.67-0.78; p<0.001) and to a lesser extent diabetics not on metformin (HR 0.87, 95% CI 0.810.93; p<0.001) with non-diabetics as referent group. CONCLUSIONS: Metformin use in Veterans with advanced PC receiving ADT is associated with improved OS and cancer-specific survival. Improved outcomes for PC patients receiving metformin should be evaluated in a prospective clinical trial.