Disparities in 5-year outcomes and imaging surveillance following elective endovascular repair of abdominal aortic aneurysm by sex, race, and ethnicity.

OBJECTIVES: Sex, racial, and ethnic disparities in postoperative outcomes following abdominal aortic aneurysm repair have been described, but differences in long-term outcomes are poorly understood. Our aim was to identify differences in 5-year outcomes and imaging surveillance after elective endovascular aortic aneurysm repair (EVAR) by sex, race, and ethnicity and to explore potential mechanisms underlying these differences. METHODS: We identified patients undergoing elective EVAR in the Vascular Quality Initiative from 2003 to 2017 with linkage to Medicare claims through 2018 for long-term outcomes. Our primary outcome was 5-year aneurysm rupture. Secondary outcomes were 5-year reintervention and mortality and 2-year loss-to-imaging follow-up (defined as no aortic imaging from 6 to 24 months after EVAR). We used Kaplan-Meier and Cox regression analyses to evaluate these outcomes by sex/race/ethnicity and constructed multivariable models to explore potential contributing factors. RESULTS: Among 16,040 patients, 11,764 (73%) were White males, 2891 (18%) were White females, 417 (2.6%) were Black males, 175 (1.1%) were Black females, 141 (0.9%) were Asian males, 34 (0.2%) were Asian females, 277 (1.7%) were Hispanic males, and 60 (0.4%) were Hispanic females. At 5 years, rupture rates were highest in Black females at 6.4% and lowest in white males at 2.3%. Compared with White males, rupture rates were higher in White females (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.1-2.0), Black females (HR, 2.5; 95% CI, 1.0-6.0), and Asian females (HR, 5.2; 95% CI, 1.3-21). White females also had higher mortality (HR, 1.2; 95% CI, 1.2-1.3) and loss-to-imaging-follow-up (HR, 1.2; 95% CI, 1.1-1.3), whereas Black females had higher mortality (HR, 1.4; 95% CI, 1.1-1.8) and reintervention (HR, 2.0; 95% CI, 1.4-2.8). Among other groups, Black males had higher reintervention (HR, 1.4; 95% CI, 1.0-1.8), and both Black and Hispanic males had higher loss-to-imaging-follow-up (Black: HR, 1.4; 95% CI, 1.1-1.7; Hispanic: HR, 1.3; 95% CI, 1.0-1.8). In adjusted analyses, White, Black, and Asian females remained at significantly higher risk for 5-year rupture after accounting for procedure year, clinical and anatomic characteristics, surgeon and hospital volume, and loss-to-imaging follow-up. CONCLUSIONS: Compared with White male patients, Black females had higher 5-year aneurysm rupture, reintervention, and mortality after elective EVAR, whereas White females had higher rupture, mortality and loss-to-imaging-follow-up. Asian females also had higher rupture, and Black males had higher reintervention and loss-to-imaging-follow-up. These populations may benefit from improved preoperative counseling and clinical outreach after EVAR. A larger-scale investigation of current practice patterns and their impact on sex, racial, and ethnic disparities in late outcomes after EVAR is needed to identify tangible targets for improvement.

Endovascular aneurysm repair in patients over 75 is associated with excellent 5-year survival, which suggests benefit from expanded screening into this cohort.

BACKGROUND: Endovascular aneurysm repair (EVAR) has decreased the perioperative mortality for patients undergoing abdominal aortic aneurysm repair and has increased the rates of elective aneurysm repair in the elderly. However, Medicare will not cover abdominal aortic aneurysm screening for beneficiaries over 75 years of age. Consequently, abdominal aortic aneurysm treatment in this population depends on incidental detection. Targeted coverage for screening in this population, however, might be beneficial for a subgroup of patients. METHODS: To identify a subset of elderly patients who would potentially benefit from an expanded screening policy, we reviewed all patients greater than 75 years old undergoing elective EVAR in the Vascular Quality Initiative between 2003 and 2016. We used Cox regression with multivariable fractional polynomials to construct a risk model for 5-year survival in elderly patients to identify a subpopulation who might benefit the most from screening and performed internal validation using the bootstrapping technique. RESULTS: We identified 10,676 patients greater than 75 years old undergoing elective EVAR. Although perioperative mortality varied with age, it was only 2.1% in the oldest group of patients (>85 years). Significant predictors included in our final risk model for 5-year survival in the elderly included age, aortic diameter, hemoglobin, current smoking, white race, body mass index, renal function, congestive heart failure, statin use, chronic obstructive pulmonary disease, and ejection fraction. The risk model produced risk scores ranging from a possible -2 to 33. The mean and median risk score were 6.9 and 6.0, respectively, with a right skew. We categorized the risk scores into four groups: -2 to 4 points, 5-8 points, 9-13 points, and more than 13 points, with associated 5-year survivals of 88%, 79%, 68%, and 49%, respectively. The model showed adequate discrimination and calibration, with a C-statistic of 0.69 and a calibration score of 0.99 (predicted 5-year survival of 0.78 compared with an observed 5-year survival of 0.77) and a Brier score of 0.15. Internal validation demonstrated an optimism-corrected C-statistic of 0.69 and a calibration slope of 1.0. CONCLUSIONS: Elective EVAR in elderly patients chosen to undergo repair is associated with acceptable perioperative mortality. Our risk score can be used to define optimal patients for expanded screening into all but the highest risk group based on expected postoperative 5-year survival to justify removing this Medicare coverage restriction.

The impact of mammographic screening on the surgical management of breast cancer.

BACKGROUND AND OBJECTIVES: Mammographic screening has been shown to result in downward stage migration, reflected by smaller tumor sizes and less extensive nodal involvement. National guidelines restrict screening recommendations in women age 40-49. The purpose of this study is to evaluate the specific impact of mammographic screening patterns on the surgical management of breast cancer in women aged 40-49. METHODS: The study is a population-based retrospective review of the Vermont Breast Cancer Surveillance System of women aged 40-49 with a diagnosis of breast cancer. Tumor stage and related characteristics at the time of diagnosis, as well as the type of surgical intervention performed were recorded for women presenting with screen-detected versus non-screen-detected breast cancer. RESULTS: Screen-detected breast cancers in women aged 40-49 were associated with a greater incidence of DCIS, smaller invasive tumor size, fewer cases of positive nodes, and higher rates of breast conservation compared to non-screened women presenting with symptomatic disease. CONCLUSIONS: Mammographic screening is associated with less aggressive surgical treatment of breast cancer including higher rates of breast conservation. The observed changes in surgical management should factor into individual decision-making regarding screening mammography. J. Surg. Oncol. 2016;113:496-500. © 2016 Wiley Periodicals, Inc.

Paclitaxel-loaded expansile nanoparticles in a multimodal treatment model of malignant mesothelioma.

BACKGROUND: Malignant mesothelioma has a poor prognosis even when treated aggressively with multimodal therapy. Traditional murine tumor models can be used to evaluate drug efficacy and toxicity in malignant mesothelioma, but not to assess the effect of a multimodal approach that includes the surgical resection of tumor. We therefore developed a murine model of multimodal therapy in which we evaluated paclitaxel-loaded expansile nanoparticles (Pax-eNP) for delivering intracavitary chemotherapy in malignant mesothelioma. METHODS: Paclitaxel-loaded expansile nanoparticles (Pax-eNP) of 100 nm, designed to release drug at an endosomal pH below 5, were synthesized. Xenografts of human malignant mesothelioma were established intraperitoneally in nude mice, followed by cytoreductive surgery (CRS) via laparotomy, and with omentectomy and resection of abdominal fat pads done 14 days later. At fascial closure, 10 mg/kg paclitaxel was delivered as traditional paclitaxel/paclitaxel Cremophor-EL (Pax-CE) or Pax-eNP. Morbidity and survival were assessed over a period of 90 days. RESULTS: Cytoreductive surgery in mice was feasible and reproducible, and incurred less than 5% operative mortality. By itself, CRS did not significantly prolong survival; however, the addition of intraoperative Pax-CE or Pax-eNP significantly increased survival as compared with that of mice with untreated disease. In the case of Pax-eNP, the increase in survival was also statistically significant as compared with that following resection alone. CONCLUSIONS: A murine model of CRS for malignant mesothelioma allows the in vivo assessment of multimodal therapy, including nanoparticle delivery. Combination therapy was superior to no treatment or CRS alone in prolonging survival. Treatment with Pax-eNP improved overall survival in the setting of CRS, suggesting that Pax-eNP merits further evaluation for intracavitary drug delivery following the surgical resection of malignant mesothelioma.

Hidden in plain sight: subtle effects of the 8-oxoguanine lesion on the structure, dynamics, and thermodynamics of a 15-base pair oligodeoxynucleotide duplex.

The base lesion 8-oxoguanine is formed readily by oxidation of DNA, potentially leading to G → T transversion mutations. Despite the apparent similarity of 8-oxoguanine-cytosine base pairs to normal guanine-cytosine base pairs, cellular base excision repair systems effectively recognize the lesion base. Here we apply several techniques to examine a single 8-oxoguanine lesion at the center of a nonpalindromic 15-mer duplex oligonucleotide in an effort to determine what, if anything, distinguishes an 8-oxoguanine-cytosine (8oxoG-C) base pair from a normal base pair. The lesion duplex is globally almost indistinguishable from the unmodified parent duplex using circular dichroism spectroscopy and ultraviolet melting thermodynamics. The DNA mismatch-detecting photocleavage agent Rh(bpy)(2)chrysi(3+) cleaves only weakly and nonspecifically, revealing that the 8oxoG-C pair is locally stable at the level of the individual base pairs. Nuclear magnetic resonance spectra are also consistent with a well-conserved B-form duplex structure. In the two-dimensional nuclear Overhauser effect spectra, base-sugar and imino-imino cross-peaks are strikingly similar between parent and lesion duplexes. Changes in chemical shift due to the 8oxoG lesion are localized to its complementary cytosine and to the 2-3 bp immediately flanking the lesion on the lesion strand. Residues further removed from the lesion are shown to be unperturbed by its presence. Notably, imino exchange experiments indicate that the 8-oxoguanine-cytosine pair is strong and stable, with an apparent equilibrium constant for opening equal to that of other internal guanine-cytosine base pairs, on the order of 10(-6). This collection of experiments shows that the 8-oxoguanine-cytosine base pair is incredibly stable and similar to the native pair.

Paclitaxel-loaded expansile nanoparticles delay local recurrence in a heterotopic murine non-small cell lung cancer model.

BACKGROUND: Surgical resection remains the most effective treatment option for patients with early stage non-small cell lung cancer; however, comorbidities and poor pulmonary reserve often limit the extent of resection. Limited resections are associated with a twofold to threefold increase in locoregional recurrence, suggesting that microscopic disease remains near the resection margin. We hypothesized that local delivery of paclitaxel through 100-nm expansile polymer nanoparticles (pax-eNP) immediately after tumor resection could prevent local recurrence. METHODS: Primary tumors, initiated on the dorsum of C57BL/6J mice through subcutaneous injection of 750,000 Lewis lung carcinoma cells, were excised when tumor volume reached 300 mm(3). After resection, animals were randomized to receive 300 µg paclitaxel intravenously or as pax-eNP locally at the tumor resection site versus unloaded eNP or saline controls. RESULTS: In all mice receiving saline, unloaded eNP, or paclitaxel intravenously, visible local tumor recurrence developed at a median of 6 days. In contrast, tumor recurrence after pax-eNP was delayed to 10 days (pax-eNP versus all other groups, Kaplan-Meier, p < 0.05). Delay in local recurrence was associated with increased survival in the pax-eNP group (16 days) versus all other groups (11 and 12 days, p < 0.05). CONCLUSIONS: The pax-eNP placed at the time of surgical resection delayed local tumor recurrence and modestly prolonged survival in a murine Lewis lung carcinoma recurrence model.

The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis.

Carcinomatosis from peritoneal surface malignancies, such as mesothelioma, appendiceal carcinoma or ovarian metastases, significantly decreases survival and quality of life. Given a 60-80% locoregional recurrence rate after surgical debulking for mesothelioma, the current study explores the use of polymeric nanoparticles, specifically engineered to expand and locally deliver chemotherapeutic agents at endosomal pH, for the prevention of progressive carcinomatosis. Anti-tumor efficacy of paclitaxel-loaded pH-responsive expansile nanoparticles (Pax-eNP) was evaluated in vitro and in in vivo murine models of malignant peritoneal mesothelioma. Pax-eNP inhibited mesothelioma growth in vitro, markedly decreased tumor growth and disease severity in vivo, prevented initial intraperitoneal tumor implants, and significantly prolonged survival compared to other intraperitoneal drug delivery methods. These outcomes suggest that the mechanism of pH-triggered drug delivery and tumor affinity associated with eNP may effectively improve the local control of residual microscopic disease following surgical debulking of locoregionally aggressive malignancies.