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.

Human breast cancer biopsies induce eosinophil recruitment and enhance adjacent cancer cell proliferation.

Chronic inflammation is known to facilitate cancer progression and metastasis. Less is known about the effect of acute inflammation within the tumor microenvironment, resulting from standard invasive procedures. Recent studies in mouse models have shown that the acute inflammatory response triggered by a biopsy in mammary cancer increases the frequency of distal metastases. Although tumor biopsies are part of the standard clinical practice in breast cancer diagnosis, no studies have reported their effect on inflammatory response. The objective of this study is to (1) determine whether core needle biopsies in breast cancer patients trigger an inflammatory response, (2) characterize the type of inflammatory response present, and (3) evaluate the potential effect of any acute inflammatory response on residual tumor cells. The biopsy wound site was identified in the primary tumor resection tissue samples from breast cancer patients. The inflammatory response in areas adjacent (i.e., immediately around previous biopsy site) and distant to the wound biopsy was investigated by histology and immunohistochemistry analysis. Proliferation of tumor cells was also assayed. We demonstrate that diagnostic core needle biopsies trigger a selective recruitment of inflammatory cells at the site of the biopsy, and they persist for extended periods of time. While macrophages were part of the inflammatory response, an unexpected accumulation of eosinophils at the edge of the biopsy wound was also identified. Importantly, we show that biopsy causes an increase in the proliferation rate of tumor cells located in the area adjacent to the biopsy wound. Diagnostic core needle biopsies in breast cancer patients do induce a unique acute inflammatory response within the tumor microenvironment and have an effect on the surrounding tumor cells. Therefore, biopsy-induced inflammation could have an impact on residual tumor cell progression and/or metastasis in human breast cancer. These findings may carry relevance in the clinical management of breast cancer.

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.

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.

Evaluating the effects of a neonatal hypoglycemia bundle on NICU admission and exclusive breastfeeding.

OBJECTIVE: Early feeding, skin-to-skin contact, and dextrose gel have been independently shown to promote breastfeeding and decrease NICU admission for neonatal hypoglycemia. We combined these interventions to decrease NICU admissions for asymptomatic hypoglycemia and increase exclusive breastfeeding rates. PROJECT DESIGN: The IHI Model for Improvement was used to design a bundle including feeding within 1 h of birth, 1 h of uninterrupted skin-to-skin within 2 h of birth, and administration of buccal 40% dextrose gel for hypoglycemic infants. RESULTS: Utilization of dextrose gel was 94% following implementation. There were no trends in exclusive breastfeeding at discharge or NICU admissions for asymptomatic hypoglycemia. Post hoc multivariate analysis identified cesarean delivery as an independent risk factor for compliance failure and failure of exclusive breastfeeding but not for NICU admission. CONCLUSIONS: Despite high compliance with dextrose gel utilization, there was no change in exclusive breastfeeding at discharge or NICU admission rates for asymptomatic hypoglycemia.

Filter Paper-based Nucleic Acid Storage in High-throughput Solid Tumor Genotyping.

Molecular testing of tumors from formalin-fixed paraffin-embedded (FFPE) tissue blocks is central to clinical practice; however, it requires histology support and increases test turnaround time. Prospective fresh frozen tissue collection requires special handling, additional storage space, and may not be feasible for small specimens. Filter paper-based collection of tumor DNA reduces the need for histology support, requires little storage space, and preserves high-quality nucleic acid. We investigated the performance of tumor smears on filter paper in solid tumor genotyping, as compared with paired FFPE samples. Whatman FTA Micro Card (FTA preps) smears were prepared from 21 fresh tumor samples. A corresponding cytology smear was used to assess tumor cellularity and necrosis. DNA was isolated from FTA preps and FFPE core samples using automated methods and quantified using SYBR green dsDNA detection. Samples were genotyped for 471 mutations on a mass spectrophotometry-based platform (Sequenom). DNA concentrations from FTA preps and FFPE correlated for untreated carcinomas but not for mesenchymal tumors (Spearman σ=0.39 and σ=-0.1, respectively). Average DNA concentrations were lower from FTA preps as compared with FFPE, but DNA quality was higher with less fragmentation. Seventy-six percent of FTA preps and 86% of FFPE samples generated adequate DNA for genotyping. FTA preps tended to perform poorly for collection of DNA from pretreated carcinomas and mesenchymal neoplasms. Of the 16 paired DNA samples that were genotyped, 15 (94%) gave entirely concordant results. Filter paper-based sample preservation is a feasible alternative to FFPE for use in automated, high-throughput genotyping of carcinomas.

Identification of infants with significant refractive error and strabismus in a population screening program using noncycloplegic videorefraction and orthoptic examination.

PURPOSE: The second Cambridge Infant Vision Screening Program examined whether screening for accommodative errors by using videorefraction without cycloplegia could effectively serve as a first stage of screening for refractive errors, measured by standard cycloplegic retinoscopy. The screening also included an orthoptic examination for detection of strabismus. METHODS: All infants born in the Cambridge (UK) Health District, over a 2-year period, were invited for screening. Of those 5142 (76%) with mean age 8.1 +/- 0.8 months (SD) attended and received noncycloplegic videorefraction and an orthoptic examination. All those with a focusing error or orthoptic problem, as well as a randomly selected sample of visually normal control subjects, were invited to follow-up a month later for cycloplegic retinoscopy, repeat noncycloplegic videorefraction and orthoptic examination. RESULTS: Of the 5142 screened, 514 had a focusing error or orthoptic problem (positives). Four hundred thirty-nine of these and 284 visually normal control subjects (negatives) attended follow-up. A refractive or orthoptic condition was confirmed in 59.0% of the positive cases, whereas infants in 96.8% of the negative cases were confirmed normal. Adjusting for the proportions of the population represented by those infants seen at follow-up, sensitivity for the screening procedure was calculated at 0.67 and specificity at 0.96. Detailed results are presented in terms of the different conditions detected at screening (far, near, and anisometropic focus and orthoptic error), distribution of greatest axes at screening, and a comparison of initial videorefraction with repeat videorefraction and cycloplegic retinoscopy. CONCLUSIONS: A noncycloplegic screening procedure, simpler to perform than cycloplegic screening, succeeded in detecting a large proportion of infants with significant ametropia, particularly those with significant hyperopia, which is considered to be a strabismogenic and amblyogenic risk factor.

Prospective enterprise-level molecular genotyping of a cohort of cancer patients.

Ongoing cancer genome characterization studies continue to elucidate the spectrum of genomic abnormalities that drive many cancers, and in the clinical arena assessment of the driver genetic alterations in patients is playing an increasingly important diagnostic and/or prognostic role for many cancer types. However, the landscape of genomic abnormalities is still unknown for less common cancers, and the influence of specific genotypes on clinical behavior is often still unclear. To address some of these deficiencies, we developed Profile, a prospective cohort study to obtain genomic information on all patients at a large tertiary care medical center for cancer-related care. We enrolled patients with any cancer diagnosis, and, for each patient (unselected for cancer site or type) we applied mass spectrometric genotyping (OncoMap) of 471 common recurrent mutations in 41 cancer-related genes. We report the results of the first 5000 patients, of which 26% exhibited potentially actionable somatic mutations. These observations indicate the utility of genotyping in advancing the field of precision oncology.

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.

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.