Outcomes of Hypogastric Coverage and Occlusion during Endovascular Treatment of Aortoiliac Occlusive Disease.

BACKGROUND: The risk of hypogastric occlusion (HO) following bare-metal stent (BMS) coverage of the hypogastric origin during endovascular treatment of aortoiliac occlusive disease (AIOD) is unclear. This study sought to determine the rate and clinical significance of HO following BMS coverage during iliac stenting for complex AIOD. METHODS: Consecutive patients undergoing elective iliac stenting for AIOD from 2010-2018 at Cleveland Clinic were reviewed. Patients with BMS coverage of a patent hypogastric origin were included. Rate of HO were determined by review of intraoperative angiography and follow up imaging. Predictors of HO were identified by univariable and multivariable logistic regression. Outcomes were compared between those who did and did not develop HO. RESULTS: There were 251 patients (338 limbs) with BMS coverage of the hypogastric origin during treatment of AIOD. Lesion severity was classified as TASC C/D in 249/338 (73.7%) of cases. Bilateral hypogastric coverage occurred in 93/251 (37.1%) patients. Hypogastric patency was 78.1% at 24-months following coverage. Recanalization of an ipsilateral external iliac artery (EIA) occlusion was predictive of HO (HR 3.12, 95% CI: 1.33, 7.34; P= 0.009). Increased luminal diameter of the hypogastric origin protected against HO (HR 0.64; 95% CI: 0.47, 0.88; P= 0.006). Perioperative outcomes were no different between patients with and without HO. There were no cases of gluteal necrosis, spinal cord ischemia, or pelvic organ ischemia. Four-year mortality and limb salvage were not affected by HO. HO was associated with decreased primary patency of ipsilateral iliac stents and increased risk of ipsilateral reintervention (HR 5.49; 95% CI: 1.82, 16.58; P= 0.002). CONCLUSIONS: HO is relatively infrequent following BMS coverage during treatment of AIOD. Luminal diameter of the hypogastric origin and ipsilateral EIA occlusion are associated with occlusion. HO is well tolerated in AIOD, though it is potentially associated with increased risk iliac stent occlusion and reintervention.

First isolation of disubstituted cis-5,6-dihydro-1,10-phenanthrolines. Lipase-mediated resolution of cis- and trans-phenoxy alcohol isomers and assignment of absolute stereochemistry via CD and NMR spectroscopy.

5,6-Dihydro-1,10-phenanthrolines can display axial and central chirality. In conjunction with the ligating properties of the diimino moiety, this class of compounds is of great interest to applications in supramolecular chemistry. We report the first preparation of cis-5,6-dihydro-1,10-phenanthroline derivatives by reacting triphenyl borate with the corresponding epoxide precursor. We found that solvent and temperature choice determined the stereoselectivity of the epoxide opening giving rise to the cis (14:1 dr) or trans (99:1 dr) product. Racemates of each stereoisomeric mixture, cis- and trans-phenoxy alcohol, were separated via highly enantioselective transesterifications with lipase PSCI from Burkholderia cepacia (97% ee, E > 200). Stereochemical assignments were carried out using CD and X-ray analyses in conjunction with NMR studies of α-methoxy-α-(trifluoromethyl)phenylacetic acid and α-methoxyphenylacetic acid esters.

Low Rates of Chest Wall Toxicity When Individualizing the Planning Target Volume Margin in Patients With Early Stage Lung Cancer Treated With Stereotactic Body Radiation Therapy.

PURPOSE: Chest wall (CW) toxicity is a potentially debilitating complication of stereotactic body radiation therapy for non-small cell lung cancer, occurring in 10% to 40% of patients. Smaller tumor-to-CW distance has been identified as a risk factor for CW toxicity. We report our experience with individualizing the planning target volume (PTV) along the CW in an effort to reduce the volume of this organ at risk receiving 30 Gy to 50 Gy. METHODS AND MATERIALS: We performed an institutional review board-approved retrospective analysis of patients with stage I (T1-2aN0M0) non-small cell lung cancer who received stereotactic body radiation therapy between June 2009 and July 2016. Four-dimensional computed tomography was used for treatment planning. A uniform 5-mm expansion of the internal target volume was generated for the PTV. Areas of overlap with the CW were removed from the PTV. Treatment was delivered with cone beam computed tomography guidance. CW toxicity was assessed per the Common Terminology Criteria for Adverse Events, version 5. Descriptive statistics were used to analyze outcomes. RESULTS: The median follow-up time was 36.8 months. A total of 260 tumors were treated in 225 patients. 225 tumors in 203 patients were peripheral. The internal target volumes for 143 tumors (63.6%) were located within 5 mm of the CW. The median total dose was 48 Gy (range, 42-60 Gy) in 4 fractions (range, 3-5 fractions). The overall rate of grade 1 to 2 CW toxicity was 2.2%, and 2.8% for tumors located within 5 mm of the CW. There were no grade 3/4 cases and no increase in local recurrences with the use of a truncated PTV with a 3-year local control of 92.1% (95% confidence interval, 87.4%-96.8%). CONCLUSIONS: Truncation of the PTV margin along the CW resulted in a marked reduction of CW toxicity for tumors in close proximity to the CW, with only a 2.8% rate of grade 1 to 2 CW toxicity. Despite PTV reduction, there was no appreciable increase in local failures. A multi-institutional validation of this technique is needed before general incorporation into clinical practice.

Computer-based video training is effective in teaching basic surgical skills to novices without faculty involvement using a self-directed, sequential and incremental program.

INTRODUCTION: Computer-based video training (CBVT) of surgical skills overcomes limitations of 1:1 instruction. We hypothesized that a self-directed CBVT program could teach novices by dividing basic surgical skills into sequential, easily-mastered steps. METHODS: We developed a 12 video program teaching basic knot tying and suturing skills introduced in discrete, incremental steps. Students were evaluated pre- and post-course with a self-assessment, a written exam and a skill assessment. RESULTS: Students (n = 221) who completed the course demonstrated significant improvement. Their average pre-course product quality score and assessment of technique using standard Global Rating Scale (GRS) were <0.4 for 6 measured skills (scale 0-5) and increased post-course to ≥3.25 except for the skill tying on tension whose GRS = 2.51. Average speed increased for all skills. Students' self-ratings (scale 1-5) increased from an average of 1.4 ± 0.7 pre-elective to 3.9 ± 0.9 post-elective across all skills (P < 0.01). CONCLUSION: Self-directed, incremental and sequential video training is effective teaching basic surgical skills and may be a model to teach other skills or to play a larger role in remote learning.

Canonical transient receptor potential 6 channel deficiency promotes smooth muscle cells dedifferentiation and increased proliferation after arterial injury.

OBJECTIVE: Previous studies showed the benefit of canonical transient receptor potential 6 (TRPC6) channel deficiency in promoting endothelial healing of arterial injuries in hypercholesterolemic animals. Long-term studies utilizing a carotid wire-injury model were undertaken in wild-type (WT) and TRPC6-/- mice to determine the effects of TRPC6 on phenotypic modulation of vascular smooth muscle cells (SMC) and neointimal hyperplasia. We hypothesized that TRPC6 was essential in the maintenance or reexpression of a differentiated SMC phenotype and minimized luminal stenosis following arterial injury. METHODS: The common carotid arteries (CCA) of WT and TRPC6-/- mice were evaluated at baseline and 4 weeks after wire injury. At baseline, CCA of TRPC6-/- mice had reduced staining of MYH11 and SM22, fewer elastin lamina, luminal dilation, and wall thinning. After carotid wire injury, TRPC6-/- mice developed significantly more pronounced luminal stenosis compared with WT mice. Injured TRPC6-/- CCA demonstrated increased medial/intimal cell number and active cell proliferation when compared with WT CCA. Immunohistochemistry suggested that expression of contractile biomarkers in medial SMC were essentially at baseline levels in WT CCA at 28 days after wire injury. By contrast, at 28 days after injury medial SMC from TRPC6-/- CCA showed a significant decrease in the expression of contractile biomarkers relative to baseline levels. To assess the role of TRPC6 in systemic arterial SMC phenotype modulation, SMC were harvested from thoracic aortae of WT and TRPC6-/- mice and were characterized. TRPC6-/- SMC showed enhanced proliferation and migration in response to serum stimulation. Expression of contractile phenotype biomarkers, MYH11 and SM22, was attenuated in TRPC6-/- SMC. siRNA-mediated TRPC6 deficiency inhibited contractile biomarker expression in a mouse SMC line. CONCLUSIONS: These results suggest that TRPC6 contributes to the restoration or maintenance of arterial SMC contractile phenotype following injury. Understanding the role of TRPC6 in phenotypic modulation may lead to mechanism-based therapies for attenuation of IH.

Pre-treatment neutrophil-lymphocyte ratio is associated with overall mortality in localized non-small cell lung cancer treated with stereotactic body radiotherapy.

BACKGROUND: Neutrophil-lymphocyte ratio (NLR) has been associated with mortality in several disease sites. We hypothesized that NLR is associated with inferior outcomes in localized non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). METHODS: We evaluated the association of pre-treatment NLR, obtained within 6 months of starting SBRT, with overall survival, as well as primary tumor, regional, and distant recurrence. Multivariate Cox regression was then used to assess pre-treatment NLR as a predictor of mortality. We validated our findings in an independent cohort of patients treated at two other institutions. In a secondary analysis, we also evaluated the association of post-treatment NLR with mortality in the training cohort. RESULTS: A total of 156 patients and 166 tumors were included in the training cohort with a median follow-up of 13.4 months. After dichotomization by median, NLR > 3.6 was associated with mortality on univariate (p = 0.010) and multivariate analysis (p = 0.023). In the validation cohort, NLR > 3.6 was similarly associated with mortality on univariate (p = 0.031) and multivariate (p = 0.007) analysis. In a secondary analysis in the training cohort, we found post-treatment NLR was significantly increased compared to pre-treatment NLR (p < 0.001) and associated with mortality on univariate analysis (p = 0.005) and multivariate analysis (p = 0.010). CONCLUSIONS: Pre-treatment NLR > 3.6 is associated with mortality in patients treated with SBRT. This finding was validated in an independent cohort of patients treated at two other institutions. Additionally, post-treatment NLR was significantly increased from pre-treatment and associated with overall survival.

Pre-treatment serum bicarbonate predicts for primary tumor control after stereotactic body radiation therapy in patients with localized non-small cell lung cancer.

BACKGROUND: Tumor aggressiveness and hypoxia are linked to acidosis in the tumor microenvironment (TME). We hypothesized that low pre-treatment serum bicarbonate, potentially correlating with an acidic and hypoxic TME, predicts for poor outcomes after stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC). METHODS: We included patients with localized NSCLC treated to a biologically effective dose (BED) ≥ 100 Gy, with available pre-treatment bicarbonate values within 3 months of treatment. We used receiver operating characteristic analysis to determine the bicarbonate concentration optimally predicting for primary tumor recurrence, and evaluated its association with recurrence and survival. We validated our findings in an independent cohort of patients from three collaborating institutions. RESULTS: A total of 110 patients and 114 tumors were included in the training cohort, with median follow-up of 15.0 months. Bicarbonate < 26 mEq/L was associated with primary tumor recurrence on univariate (HR = 5.92; 95% CI 1.69-24.88; p = 0.005) and multivariate analysis (HR = 5.48; 95% CI 1.37-25.19; p = 0.020). The validation cohort consisted of 195 patients and 208 tumors with median follow-up of 27.5 months. In the validation cohort, bicarbonate < 26 mEq/L was again associated with primary tumor recurrence on univariate (HR = 3.38; 95% CI 1.27-9.37; p = 0.015) and multivariate analysis (HR = 3.33; 1.18-10.07; p = 0.023). CONCLUSIONS: Pre-treatment bicarbonate predicts for primary tumor control in NSCLC treated with SBRT and may be useful for risk stratification. These findings should be confirmed prospectively.

Genetic predisposition to pass the standard SICCT test for bovine tuberculosis in British cattle.

Bovine tuberculosis (bTB) imposes an important financial burden on the British cattle industry, yet despite intense efforts to control its spread, incidence is currently rising. Surveillance for bTB is based on a skin test that measures an immunological response to tuberculin. Cattle that fail the test are classified as "reactors" and slaughtered. Recent studies have identified genetic markers associated with the reaction of cattle to the tuberculin test. At marker INRA111 a relatively common '22' genotype occurs significantly more frequently in non-reactor cattle. Here we test the possibility that the putative protective '22' genotype does not confer resistance but instead causes cattle that carry it to react less strongly to the prescribed test, and hence avoid slaughter, potentially even though they are infected. We show that, after controlling for age and breed, '22' cattle react less strongly to the immunological challenge and may therefore be less likely to be classified as a reactor. These results highlight the potential discrepancy between infection and test status and imply that the effectiveness of the test-and-slaughter policy may be being compromised by selection for cattle that are genetically predisposed to react less strongly to tuberculin.

A preliminary study of genetic factors that influence susceptibility to bovine tuberculosis in the British cattle herd.

Associations between specific host genes and susceptibility to Mycobacterial infections such as tuberculosis have been reported in several species. Bovine tuberculosis (bTB) impacts greatly the UK cattle industry, yet genetic predispositions have yet to be identified. We therefore used a candidate gene approach to study 384 cattle of which 160 had reacted positively to an antigenic skin test ('reactors'). Our approach was unusual in that it used microsatellite markers, embraced high breed diversity and focused particularly on detecting genes showing heterozygote advantage, a mode of action often overlooked in SNP-based studies. A panel of neutral markers was used to control for population substructure and using a general linear model-based approach we were also able to control for age. We found that substructure was surprisingly weak and identified two genomic regions that were strongly associated with reactor status, identified by markers INRA111 and BMS2753. In general the strength of association detected tended to vary depending on whether age was included in the model. At INRA111 a single genotype appears strongly protective with an overall odds ratio of 2.2, the effect being consistent across nine diverse breeds. Our results suggest that breeding strategies could be devised that would appreciably increase genetic resistance of cattle to bTB (strictly, reduce the frequency of incidence of reactors) with implications for the current debate concerning badger-culling.

Effects of environmentally-relevant levels of perfluorooctane sulfonate on clinical parameters and immunological functions in B6C3F1 mice.

In the first part of a series of studies to account for perfluorooctane sulfonate (PFOS)-induced sheep red blood cell (SRBC)-specific immunoglobulin M (IgM) antibody suppression in mice, a survey of clinical and immunotoxicological endpoints was examined. Adult female B6C3F1 mice were exposed orally for 28 days to a total administered dose (TAD) of 0, 0.1, 0.5, 1, or 5 mg PFOS/kg. Uterus wet weight was significantly decreased compared with control at the 5 mg/kg dose. No indications of wasting syndrome, malnutrition, alteration of thyroid homeostasis, or signs of overt toxicity were observed. Numbers of splenic CD19+/CD21⁻, CD19+/CD21+, B220+/CD40+, CD4+/CD154⁻, CD4+/CD154+, and MHC-II+ cells were not altered. Additionally, ex vivo interleukin-4 (IL-4), IL-5, and IL-6 production by in vitro anti-CD3- or phorbol myristate acetate-stimulated CD4+ T-cells was not affected. Ex vivo IL-6 production by B-cells was significantly increased by in vitro stimulation with either anti-CD40 or lipopolysaccharide. Increased IL-6 production by B-cells was the most sensitive endpoint assessed resulting in alterations at the lowest dose tested (0.1 mg/kg TAD) following anti-CD40 stimulation. Further studies are required to characterize effects on inflammatory markers such as IL-6 at environmentally relevant concentrations of PFOS and to determine the key events associated with PFOS-induced IgM suppression to address potential human health risks.

Mechanisms governing the level of susceptibility of erythrocyte membranes to secretory phospholipase A2.

Although cell membranes normally resist the hydrolytic action of secretory phospholipase A(2) (sPLA(2)), they become susceptible during apoptosis or after cellular trauma. Experimentally, susceptibility to the enzyme can be induced by loading cells with calcium. In human erythrocytes, the ability of the calcium ionophore to cause susceptibility depends on temperature, occurring best above approximately 35 degrees C. Considerable evidence from experiments with artificial bilayers suggests that hydrolysis of membrane lipids requires two steps. First, the enzyme adsorbs to the membrane surface, and second, a phospholipid diffuses from the membrane into the active site of the adsorbed enzyme. Analysis of kinetic experiments suggested that this mechanism can explain the action of sPLA(2) on erythrocyte membranes and that temperature and calcium loading promote the second step. This conclusion was further supported by binding experiments and assessment of membrane lipid packing. The adsorption of fluorescent-labeled sPLA(2) was insensitive to either temperature or ionophore treatment. In contrast, the fluorescence of merocyanine 540, a probe sensitive to lipid packing, was affected by both. Lipid packing decreased modestly as temperature was raised from 20 to 60 degrees C. Calcium loading enhanced packing at temperatures in the low end of this range, but greatly reduced packing at higher temperatures. This result was corroborated by measurements of the rate of extraction of a fluorescent phosphatidylcholine analog from erythrocyte membranes. Furthermore, drugs known to inhibit susceptibility in erythrocytes also prevented the increase in phospholipid extraction rate. These results argue that the two-step model applies to biological as well as artificial membranes and that a limiting step in the hydrolysis of erythrocyte membranes is the ability of phospholipids to migrate into the active site of adsorbed enzyme.