The obliterated ureteric orifice: a nightmare for the pelvic surgeon or a routine-job for the endo-urologist? Case report of a standardized endoscopic approach.

We present the endoscopic management of two cases of complete ureteric occlusion at vesico-ureteral junction (VUJ) level following iatrogenic injury. Case 1 is a 60-year-old man who developed bilateral ureteric injury at the level of the VUJ following robot-assisted radical prostatectomy (RARP) for Gleason 3 + 4 = 7 T2bN0 prostate cancer. Case 2 is an 81-year-old man with history of recurrent G2pTa transitional cell carcinoma of the bladder originally diagnosed in 2005 and history of radical radiotherapy for prostate cancer. At his most recent transurethral resection of bladder tumour, the left ureteric orifice was not visualized. We describe step-by-step our technique in restoring continuity of the ureter with minimally invasive endoscopic approach, resulting in excellent long-term upper tract drainage for our patients. To our knowledge, combined utilization of a Collins knife to incise the area around the ureteric orifice to unearth them is not reported. We aim to report our technique and its outcomes.

Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells.

Acute myeloid leukaemia (AML) cells often up-regulate pro-survival members of the BCL-2 protein family, such as BCL-2 and MCL-1, to avoid apoptosis. Venetoclax (ABT-199) targets BCL-2 and has shown promising efficacy in AML but over-expression of MCL-1 can cause resistance. A co-operative approach, targeting both BCL-2 and MCL-1 may therefore prove beneficial. This study investigated the potential synergistic relationship between Venetoclax and the MCL-1 inhibitor S63845 in AML cells. We treated MV4-11 cells and primary AML samples for 4 hours with Venetoclax, S63845 or the combination. We used a short-term flow cytometric technique to assess synergy using cytochrome C release as a read out of response. The combination of Venetoclax and S63845 produced a synergistic apoptotic response in MV4-11 cells and primary samples, including the leukaemia re-populating leukaemic stem cell (LSC) population, in 92% of the samples. Known molecular biomarkers of response to BCL-2 and MCL-1 targeting agents were corroborated, and augmented, with the short-term functional assay. The assay also predicted potential biomarkers of response to the combination of BCL-2 and MCL-1 targeting agents. Primary samples with an IDH2_140 mutation were more sensitive to Venetoclax as a single agent whereas samples with a FLT3-ITD mutation were more resistant. This resistance could be reversed when combined with S63845. All FLT3-ITD and NPM1 mutated samples were sensitive to the combination of drugs. We report that co-operatively targeting BCL-2 and MCL-1 may be beneficial in AML and a short-term in vitro assay can identify patients who might best respond to this combination.