Laparoscopic supracervical hysterectomy for the larger uterus (>500 g): a case series and literature review.

BACKGROUND: In clinical practice, the current trend for surgical hysterectomy for the large uterus is by laparotomy, where vaginal hysterectomy is not feasible. The benefits of a laparoscopic approach to hysterectomy are well documented, but limited literature is available on laparoscopic hysterectomy in the larger uterus. A supracervical hysterectomy should be considered for women, where there is no contraindication to a residual cervix. OBJECTIVE: To compare surgical outcomes for laparoscopic supracervical hysterectomy (LSH) in the large uterus (equal or greater than 500 g) compared with normal (<500 g), results were compared to the limited literature on this topic. METHODS AND STUDY DESIGN: A retrospective review was undertaken of 207 women who underwent an LSH between 2005 and 2015 at Whipps Cross University hospital. The operative outcome of patients undergoing surgery, for uteri both greater than 500 g and less than 500 g, was analysed. Data included patient demographics, intra-operative details, and complications. A literature search was performed using keywords 'laparoscopic supracervical hysterectomy' and 'laparoscopic sub-total hysterectomy' which yielded six informative articles. RESULTS: In the study group of 207 patients, 67 had a large uterus (56 patients 500-1000 g, 11 patients >1000 g). The operation time and intra-operative blood loss were both greater in the larger uterus cohort (P < 0.0001 and P = 0.0021, respectively). The hospital stay and intra-operative complication rate were similar for the two study cohorts (six for the study, n = 207). Review of the literature revealed six relevant studies evaluating patients with uteri greater than 500 g. There was an agreement between all the studies that a larger uterus resulted in an increase in both intra-operative time and blood loss, but this did not translate to increase in hospital stay or intra-operative complications. CONCLUSION: The use of LSH for the larger uterus is feasible and safe due to the low level of operative complications as demonstrated in our study and following a review of the literature.

mTORC1 and DNA-PKcs as novel molecular determinants of sensitivity to Chk1 inhibition.

BACKGROUND: Chk1 inhibitors are currently under clinical evaluation as single agents and in combination with cytotoxic chemotherapy. Understanding determinants of sensitivity and novel combinations is critical for further clinical development. METHODS: Potentiation of mTOR inhibitor cytotoxicity by the Chk1 inhibitor V158411 was determined in p53 mutant colon cancer cells. DNA damage response, expression levels of repair proteins, cell cycle effects and the contribution of alternative DSB repair pathways were further evaluated by western blotting and high content analysis. RESULTS: mTOR inhibitors AZD8055, RAD-001, rapamycin and BEZ235 induced synergistic cytotoxicity with the Chk1 inhibitor V158411 in p53 mutant colon cancer cells. Reduced FANCD2, RAD51 and RPA70, core proteins in homologous recombination repair (HRR) and interstrand crosslink repair (ICLR), following inhibition of mTOR was associated with increased V158411 induced DSBs and caspase 3-independent cell death. Dual mTOR and Chk1 inhibition activated DNA-PKcs. Cells defective in DNA-PKcs exhibited increased resistance to V158411 with Chk1 expression closely correlated to DNA-PKcs expression in various types of cancer. CONCLUSIONS: Down regulation of proteins involved in HRR or ICLR by mTOR inhibitors is associated with increased sensitivity of human tumours to Chk1 inhibitors such as V158411. High levels of DNA-PKcs may be a potential biomarker to stratify patients to Chk1 inhibitor therapy alone or in combination with mTOR inhibitors.