Perioperative outcomes for benign hysterectomy among women with thrombocytopenia.

OBJECTIVE: To determine whether mild or moderate thrombocytopenia is associated with postoperative complications after benign hysterectomy. METHODS: A retrospective study of data from women who underwent benign hysterectomy included in the American College of Surgeons National Surgical Quality Improvement Project Database. The data were stratified by normal platelet count, mild thrombocytopenia (100-149 × 103 platelets/µl), and moderate thrombocytopenia (50-99 × 103 platelets/µl). Multivariable logistic regression was used to determine the relationship between mild or moderate thrombocytopenia and the main outcome measures. RESULTS: Moderate thrombocytopenia was associated with an increased risk of perioperative transfusion (adjusted odds ratio [aOR], 2.87; 95% confidence interval [CI], 1.96-4.21) and reoperation (aOR, 4.03; 95% CI, 1.94-17.33), but mild thrombocytopenia was not. There was an increased risk of infection among women with both mild (aOR, 1.38; 95% CI, 1.12-1.69) and moderate (aOR, 2.00; 95% CI,1.23-3.22) thrombocytopenia. There was no association between either mild or moderate thrombocytopenia and readmission, prolonged hospital stay, or longer surgical time. CONCLUSION: Thrombocytopenia was found to be associated with increased infectious morbidity after hysterectomy, and moderate thrombocytopenia was associated with an increased risk of perioperative transfusion and reoperation.

Evaluation of 30-day complication rates following vaginal anterior compartment repair with and without graft augmentation in a propensity score matched cohort.

OBJECTIVE: To determine if graft augmentation with anterior colporrhaphy (AC+G) is associated with higher complication rates compared to native tissue repair (AC). MATERIALS AND METHODS: Retrospective cohort study using data from the ACS-NSQIP database between 2010 and 2017. CPT codes were used to identify women undergoing AC+G and AC. Propensity scores for the likelihood of undergoing AC+G were calculated and were used to match to women undergoing native tissue repair at a ratio of 1:2. The primary outcome was the composite complication rate. Descriptive statistics are reported as means with standard deviations for parametric data and as medians and interquartile ranges for non-parametric data. Pairwise comparisons were performed using Fisher's exact test, Wilcoxon rank-sum and Student's t test as appropriate. Multivariable logistic regression was then used to adjust for confounders to identify statistically significant factors associated with the likelihood of experiencing a complication after prolapse repair. RESULTS: 582 women met inclusion criteria for AC+G and were matched with 1164 women undergoing AC. There were no differences in preoperative characteristics between groups. There was no difference in the composite complication rate, (10.8% vs. 8.5%, p = 0.13) between groups. Dependent functional status (aOR 4.31, 95% CI 1.96-13.58) was the strongest predictor of the likelihood of a complication: other significant predictors were operating time greater than 20 min (aOR 1.68, 95% CI 1.19-2.38) and ASA class greater than 2 (aOR 1.44, 95% CI 1.01-2.05). CONCLUSION: There is no increase in 30-day complication rates in women undergoing AC+G compared to a matched cohort of those undergoing AC alone.

Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication.

Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies.

Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography.

Combined inhibition of ribonucleotide reductase and deoxycytidine kinase (dCK) in multiple cancer cell lines depletes deoxycytidine triphosphate pools leading to DNA replication stress, cell cycle arrest, and apoptosis. Evidence implicating dCK in cancer cell proliferation and survival stimulated our interest in developing small molecule dCK inhibitors. Following a high throughput screen of a diverse chemical library, a structure-activity relationship study was carried out. Positron Emission Tomography (PET) using (18)F-L-1-(2'-deoxy-2'-FluoroArabinofuranosyl) Cytosine ((18)F-L-FAC), a dCK-specific substrate, was used to rapidly rank lead compounds based on their ability to inhibit dCK activity in vivo. Evaluation of a subset of the most potent compounds in cell culture (IC50 = ∼1-12 nM) using the (18)F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy.