Heterogeneity of outcomes of endometrial cancer patients included in prospective clinical trials.

OBJECTIVE: To assess heterogeneity in five-year overall survival of patients with endometrial cancer using a large retrospective database with cohorts defined by recent prospective clinical trials. METHODS: The National Cancer Database was used to identify patients with endometrial cancer who underwent hysterectomy from 2004 to 2016. The reported inclusion criteria for GOG-249, PORTEC-3, and GOG-258 were used to define the respective cohorts. Five-year overall survival for each cohort was stratified by tumor characteristics and adjuvant therapy regimens. RESULTS: A total of 89,133 patients were identified who would have fulfilled the entry criteria to GOG-249, PORTEC-3, or GOG-258. When stratified by tumor characteristics, irrespective of adjuvant therapy, five-year overall survival ranged from 59.9%-81.7% for patients meeting GOG-249 inclusion criteria, 40.2%-81.8% for patients meeting PORTEC-3 inclusion criteria, and 17.5%-75.0% for those meeting GOG-258 inclusion criteria. Analysis of subgroups by adjuvant therapy regimen revealed significant improvement in five-year overall survival for chemoradiotherapy compared to chemotherapy or radiotherapy alone for endometroid stage III and stage IVA disease and for some stages of serous and clear cell histology. CONCLUSIONS: Recent prospective trials of adjuvant therapy for endometrial cancer have included heterogeneous cohorts of patients based on five-year overall survival rates when the populations are stratified by tumor characteristics. The variation in expected five-year overall survival for subsets of patients may result in underpowered studies or misleading results.

Carbonyl Reductase 1 Plays a Significant Role in Converting Doxorubicin to Cardiotoxic Doxorubicinol in Mouse Liver, but the Majority of the Doxorubicinol-Forming Activity Remains Unidentified.

Doxorubicin is a widely used cancer therapeutic, but its effectiveness is limited by cardiotoxic side effects. Evidence suggests cardiotoxicity is due not to doxorubicin, but rather its metabolite, doxorubicinol. Identification of the enzymes responsible for doxorubicinol formation is important in developing strategies to prevent cardiotoxicity. In this study, the contributions of three murine candidate enzymes to doxorubicinol formation were evaluated: carbonyl reductase (Cbr) 1, Cbr3, and thioredoxin reductase 1 (Tr1). Analyses with purified proteins revealed that all three enzymes catalyzed doxorubicin-dependent NADPH oxidation, but only Cbr1 and Cbr3 catalyzed doxorubicinol formation. Doxorubicin-dependent NADPH oxidation by Tr1 was likely due to redox cycling. Subcellular fractionation results showed that doxorubicin-dependent redox cycling activity was primarily microsomal, whereas doxorubicinol-forming activity was exclusively cytosolic, as were all three enzymes. An immunoclearing approach was used to assess the contributions of the three enzymes to doxorubicinol formation in the complex milieu of the cytosol. Immunoclearing Cbr1 eliminated 25% of the total doxorubicinol-forming activity in cytosol, but immunoclearing Cbr3 had no effect, even in Tr1 null livers that overexpressed Cbr3. The immunoclearing results constituted strong evidence that Cbr1 contributed to doxorubicinol formation in mouse liver but that enzymes other than Cbr1 also played a role, a conclusion supported by ammonium sulfate fractionation results, which showed that doxorubicinol-forming activity was found in fractions that contained little Cbr1. In conclusion, the results show that Cbr1 accounts for 25% of the doxorubicinol-forming activity in mouse liver cytosol but that the majority of the doxorubicinol-forming activity remains unidentified. SIGNIFICANCE STATEMENT: Earlier studies suggested carbonyl reductase (Cbr) 1 plays a dominant role in converting chemotherapeutic doxorubicin to cardiotoxic doxorubicinol, but a new immunoclearing approach described herein shows that Cbr1 accounts for only 25% of the doxorubicinol-forming activity in mouse liver cytosol, that two other candidate enzymes-Cbr3 and thioredoxin reductase 1-play no role, and that the majority of the activity remains unidentified. Thus, targeting Cbr1 is necessary but not sufficient to eliminate doxorubicinol-associated cardiotoxicity; identification of the additional doxorubicinol-forming activity is an important next challenge.

Prevalence of Preoperative Lower Urinary Tract Symptoms in Patients Undergoing Elective Lumbar Spine Surgery.

STUDY DESIGN: Cross-sectional cohort study. OBJECTIVE: To determine the prevalence of moderate-to-severe lower urinary tract symptoms (LUTS) in patients undergoing elective lumbar spine surgery, and to describe associations between prevalence, severity of symptoms, demographic variables, and spine pathology. SUMMARY OF BACKGROUND DATA: The prevalence of LUTS is unknown in patients with lumbar spine disease. Furthermore, the extent of LUTS severity and the relationship between spine pathology and LUTS is not well documented. METHODS: We used the validated International Prostate Symptom Score (IPSS) to assess LUTS severity among elective lumbar spine surgery patients from October 2015 to April 2017 at a single academic institution. Moderate-to-severe LUTS was defined as IPSS score of 8 or more. The IPSS also includes a question to assess urinary bother, for which a score of 4 or more indicates clinically significant bother. Prevalence estimates and 95% confidence intervals were computed in the sample overall, and according to sex, age, and lumbar spine diagnosis. RESULTS: IPSS data were obtained from 373 patients (97% of those eligible) undergoing elective lumbar spine surgery. Moderate-to-severe urinary symptoms were reported by 46% of these patients, and by 51% of women and 42% of men. Prevalence of moderate-to-severe urinary symptoms increased with age, rising from 38% in patients younger than 40 years to 57% in patients 70 years or older. LUTS prevalence according to spondylolisthesis, stenosis, scoliosis, and herniated nucleus pulposus diagnostic groups were 51%, 50%, 50%, and 31%, respectively. Clinically significant urinary bother was reported by 14% overall, 10% of men, and 18% of women, and prevalence also increased with age. CONCLUSION: Moderate-to-severe LUTS were highly prevalent in this sample. Urinary symptoms are more prevalent with increasing age, in women, and in patients with stenosis, spondylolisthesis, and scoliosis. Proportionally, fewer patients reported clinically significant urinary bother, which may impact patient reporting and physician identification of urinary symptoms. LEVEL OF EVIDENCE: 3.