Intratumoural heterogeneity (ITH) is a major cause of cancer-associated lethality. Extensive genomic ITH has previously been reported in clear cell renal cell carcinoma (ccRCC). Here we address the question whether ITH increases with malignant progression and can hence be exploited as a prognostic marker. Unexpectedly, precision quantitative image analysis reveals that the degree of functional ITH is virtually identical between primary ccRCCs of the lowest stage and advanced, metastatic tumours. Functional ITH was found to show a stage-independent topological pattern with peak proliferative and signalling activities almost exclusively in the tumour periphery. Exome sequencing of matching peripheral and central primary tumour specimens reveals various region-specific mutations. However, these mutations cannot directly explain the zonal pattern suggesting a role of microenvironmental factors in shaping functional ITH. In conclusion, our results indicate that ITH is an early and general characteristic of malignant growth rather than a consequence of malignant progression.

BackgroundRetzius-sparing robot-assisted laparoscopic radical prostatectomy (rsRARP) allows entire prostatectomy procedure via the pouch of Douglas. In low- and intermediate-risk prostate cancer (PCa) there is level 1 evidence that the Retzius-sparing approach impacts early continence recovery. Since specific data on aggressive and locally advanced cancer is lacking and avoiding rsRARP is presently suggested, we investigated urinary and sexual recovery, perioperative complications and early oncologic outcomes after rsRARP in this particular cohort.MethodsProspectively collected data of 50 consecutive men (median age 66 years) with high-risk PCa who underwent rsRARP in a single institution was analysed retrospectively. The follow-up for all patients was 12 months after surgery.Results3 vs. 12 months after surgery, 82% vs. 98% of men used no pad or one safety pad and 50% vs. 72% used no pad. 89% of patients did not observe a decline of continence if postoperative radiotherapy was carried out.Considering the 17 preoperatively potent patients who underwent bi- or unilateral nerve-sparing surgery, 41% reported their first sexual intercourse within 1 year after rsRARP.84% of patients had ≥pT3a disease and 42% positive surgical margins. A lymphadenectomy was done in 94% of patients with a median lymph node removal of 15 and lymph node metastasis in 13%.34% underwent adjuvant radiotherapy and 22% adjuvant androgen deprivation therapy (ADT). 1-year recurrence-free survival was 96%, including 25% of patients on adjuvant or salvage ADT.ConclusionsRsRARP in high-risk PCa is feasible and results in excellent continence rates, even after postoperative radiotherapy. The potency rates are promising but need further clarification in larger cohorts. Reliable oncologic outcomes require longterm follow-up and are awaited.