ABSTRACT
OBJECTIVE: The purpose of this study was to create a risk score for the event of mortality within 3 years of complex fenestrated visceral segment endovascular aortic repair utilizing variables existing at the time of preoperative presentation. METHODS: After exclusions, 1916 patients were identified in the Vascular Quality Initiative who were included in the analysis. The first step in development of the risk score was univariable analysis for the primary outcome of mortality within 3 years of surgery. χ2 analysis was performed for categorical variables, and comparison of means with independent Student t-test was performed for ordinal variables. Variables that achieved a univariable P value less than 0.1 were then placed into Cox regression multivariable time dependent analysis for the development of mortality within 3 years. Variables that achieved a multivariable significance of less than 0.1 were utilized for the risk score, with point weighting based on the beta-coefficient. Variables with a beta coefficient of 0.25 to 0.49 were assigned 1 point, 0.5 to 0.74 2 points, 0.75 to 0.99 3 points, and 1.0 to 1.25 4 points. A cumulative score for each patient was then summed, the percentage of patients at each score experiencing mortality within 3 weeks was then calculated, and a comparison of score outcomes was conducted with binary logistic regression. Area under the curve analysis was performed. RESULTS: The primary outcome of mortality within 3 years of surgery occurred in 12.8% of patients (245/1916). The mean age for the study population was 73.35 years (standard deviation [SD], 8.26 years). The mean maximal abdominal aortic aneurysm (AAA) diameter was 60.43 mm (SD, 10.52 mm). The mean number of visceral vessels stented was 3.3 (SD, 0.76). Variables present at the time of surgery that were included in the risk score were: hemodialysis (3 points); age >87, chronic obstructive pulmonary disease, hypertension, AAA diameter >77 mm (all 2 points); and body mass index <20 kg/m2, female sex, congestive heart failure, active smoking, chronic renal insufficiency, age 80 to 87 years, and AAA diameter 67 to 77 mm (all 1 point). BMI >30 kg/m2 (mean, 34.46 kg/m2) and age <67 years were protective (-1 point). Testing the model resulted in an area under the curve of 0.706. Hosmer and Lemeshow goodness of fit test for logistic regression utilizing the 15 different risk score total groups revealed a model predictive accuracy of 87.3%. Significant escalations in 3-year mortality were noted to occur at scores of 6 and greater. Mean AAA diameter was significantly larger for patients who had higher risk scores (P < .001). CONCLUSIONS: A novel risk score for mortality within 3 years of fenestrated visceral segment aortic endograft has been developed that has excellent accuracy in predicting which patients will survive and derive the strongest benefit from intervention. This facilitates risk-benefit analysis and counseling of patients and families with realistic long-term expectations. This potentially enhances patient-centered decision-making.
ABSTRACT
Rationale: Although surgery and radiation therapy in patients with low risk prostate cancer appear appropriate and effective, those with high-risk localized disease almost always become hormone refractory and then rapidly progress. A new treatment strategy is urgently needed for patients with high-risk localized prostate cancer, particularly an approach that combines two drugs with different mechanisms. Combinations of photodynamic therapy (PDT) and chemotherapy have shown synergistic effects in clinical trials, but are limited by off-target toxicity. Prostate specific membrane antigen (PSMA) is a well-established biomarker for prostate cancer. Here we describe the use of a PSMA ligand to selectively and simultaneously deliver a potent microtubule inhibiting agent, monomethyl auristatin E (MMAE), and a PDT agent, IR700, to prostate cancers. Methods: Using a bifunctional PSMA ligand PSMA-1-Cys-C6-Lys, we created a novel theranostic molecule PSMA-1-MMAE-IR700. The molecule was tested in vitro and in vivo for selectivity and antitumor activity studies. Results: PSMA-1-MMAE-IR700 showed selective and specific uptake in PSMA-positive PC3pip cells, but not in PSMA-negative PC3flu cells both in vitro and in vivo. In in vitro cytotoxicity studies, when exposed to 690 nm light, PSMA-1-MMAE-IR700 demonstrated a synergistic effect leading to greater cytotoxicity for PC3pip cells when compared to PSMA-1-IR700 with light irradiation or PSMA-1-MMAE-IR700 without light irradiation. In vivo antitumor activity studies further showed that PSMA-1-MMAE-IR700 with light irradiation significantly inhibited PC3pip tumor growth and prolonged survival time as compared to mice receiving an equimolar amount of PSMA-1-IR700 with light irradiation or PSMA-1-IR700-MMAE without light irradiation. Conclusion: We have synthesized a new multifunctional theranostic molecule that combines imaging, chemotherapy, and PDT for therapy against PSMA-expressing cancer tissues. This work may provide a new treatment option for advanced prostate cancer.
