Effect of an Antiracism Intervention on Racial Disparities in Time to Lung Cancer Surgery

PURPOSE Timely lung cancer surgery is a metric of high-quality cancer care and improves survival for early-stage non-small-cell lung cancer. Historically, Black patients experience longer delays to surgery than White patients and have lower survival rates. Antiracism interventions have shown benefits in reducing racial disparities in lung cancer treatment.METHODSWe conducted a secondary analysis of Accountability for Cancer Care through Undoing Racism and Equity, an antiracism prospective pragmatic trial, at five cancer centers to assess the impact on overall timeliness of lung cancer surgery and racial disparities in timely surgery. The intervention consisted of (1) a real-time warning system to identify unmet care milestones, (2) race-specific feedback on lung cancer treatment rates, and (3) patient navigation. The primary outcome was surgery within 8 weeks of diagnosis. Risk ratios (RRs) and 95% CIs were estimated using log-binomial regression and adjusted for clinical and demographic factors.RESULTSA total of 2,363 patients with stage I and II non-small-cell lung cancer were included in the analyses: intervention (n = 263), retrospective control (n = 1,798), and concurrent control (n = 302). 87.1% of Black patients and 85.4% of White patients in the intervention group (P =.13) received surgery within 8 weeks of diagnosis compared with 58.7% of Black patients and 75.0% of White patients in the retrospective group (P <.01) and 64.9% of Black patients and 73.2% of White patients (P =.29) in the concurrent group. Black patients in the intervention group were more likely to receive timely surgery than Black patients in the retrospective group (RR 1.43; 95% CI, 1.26 to 1.64). White patients in the intervention group also had timelier surgery than White patients in the retrospective group (RR 1.10; 95% CI, 1.02 to 1.18). CONCLUSION Accountability for Cancer Care through Undoing Racism and Equity is associated with timelier lung cancer surgery and reduction of the racial gap in timely surgery

Natural history of cone disease in the murine model of Leber congenital amaurosis due to CEP290 mutation: determining the timing and expectation of therapy.

Mutations in the CEP290 (cilia-centrosomal protein 290 kDa) gene in Leber congenital amaurosis (LCA) cause early onset visual loss but retained cone photoreceptors in the fovea, which is the potential therapeutic target. A cone-only mouse model carrying a Cep290 gene mutation, rd16;Nrl-/-, was engineered to mimic the human disease. In the current study, we determined the natural history of retinal structure and function in this murine model to permit design of pre-clinical proof-of-concept studies and allow progress to be made toward human therapy. Analyses of retinal structure and visual function in CEP290-LCA patients were also performed for comparison with the results in the model.Rd16;Nrl-/- mice were studied in the first 90 days of life with optical coherence tomography (OCT), electroretinography (ERG), retinal histopathology and immunocytochemistry. Structure and function data from a cohort of patients with CEP290-LCA (n = 15; ages 7-48) were compared with those of the model.CEP290-LCA patients retain a central island of photoreceptors with normal thickness at the fovea (despite severe visual loss); the extent of this island declined slowly with age. The rd16;Nrl-/- model also showed a relatively slow photoreceptor layer decline in thickness with ∼80% remaining at 3 months. The number of pseudorosettes also became reduced. By comparison to single mutant Nrl-/- mice, UV- and M-cone ERGs of rd16;Nrl-/- were at least 1 log unit reduced at 1 month of age and declined further over the 3 months of monitoring. Expression of GNAT2 and S-opsin also decreased with age.The natural history of early loss of photoreceptor function with retained cone cell nuclei is common to both CEP290-LCA patients and the rd16;Nrl-/- murine model. Pre-clinical proof-of-concept studies for uniocular therapies would seem most appropriate to begin with intervention at P35-40 and re-study after one month by assaying interocular difference in the UV-cone ERG

OCT abnormalities in <i>rd16;Nrl^−/−</i> mice.

<p>(A) Upper panels: Representative OCT scans vertically across ∼2 mm of retina (centered at the ONH, optic nerve head) in a WT mouse and in two <i>rd16;Nrl^−/−</i> mice of different ages. Lower panels: Magnified parts of the superior region of the retinal sections with overlaid longitudinal reflectivity profiles (LRPs) to demonstrate the reflective abnormalities in the outer retinal region in <i>rd16;Nrl^−/−</i> mice (b and c) compared with C57BL6 WT (a). (B) Upper two panels: Vertical OCT sections quantified for ONL+ thickness in two age groups of <i>rd16;Nrl^−/−</i> mice. Regions of outer retina with pseudorosettes were excluded in the measurement. ONL+ profiles in the older (P83–89, n = 12 eyes) age group were thinner than those in younger (P31–41, n = 35 eyes) mice; gray bands in the P83–89 plot represent mean±2 SD for ONL+ thickness of the P31–41 mice. For reference, insets at lower right of the upper two plots show original raw data before suppression of pseudorosette regions. Third panel from top: Means of ONL+ data across the vertical meridian in two age groups (error bar: ± SD; P31–41, open circles; P83–89, filled triangles). Lowest panel: Histograms showing average ONL+ fraction across vertical meridian of two age groups (*represents <i>p</i><0.001). (C) Histological sections of <i>rd16;Nrl^−/−</i> retina at 4 different ages from P21 to P80, compared with a WT retinal section. Histograms show ONL fraction (based on the earlier age group) in <i>rd16;Nrl^−/−</i> mice from peripheral retina (n = 6 eyes in each of the two age groups, *represents <i>p</i> = 0.01).</p

Spatial and temporal distribution of pseudorosettes in <i>rd16;Nrl^−/−</i> retina.

<p>(A) Histological sections from peripheral retina of two <i>rd16;Nrl^−/−</i> mice at different ages demonstrating the presence of pseudorosettes (arrows). Calibration = 50 μm. (B) Schematic drawing of the mouse retina indicating the coverage of the central OCT raster scans (red circle). ONH is centered in the drawing. Integrated <i>en face</i> image of the central region of a P41 <i>rd16;Nrl^−/−</i> mouse showing how pseudorosettes appear as white dots (B, right panel, red circle). (C) Pseudorosette distribution within the central retinal region in a young (P31) and an older (P83) <i>rd16;Nrl^−/−</i> eyes. Insets (up and right) show average pseudorosettes as density in different sectors of the central retinal region sampled (n = 8 eyes for both age groups). (D) Upper: Histograms comparing number of pseudorosettes in the central retina by OCT at two different ages (P31, n = 10 eyes; P83, n = 8 eyes). Lower: Pseudorosette counts from histological sections of peripheral retina of two different age groups (P21–40, n = 6 eyes; P60–80, n = 6 eyes). Both data sets in <i>rd16;Nrl^−/−</i> mice indicate that the number of rosettes decreases with age (*represents <i>p</i><0.001 and <i>p = </i>0.01 for the upper and lower graphs, respectively). Error bars, ± SD from the mean.</p

Expression of photoreceptor proteins is reduced over time in <i>rd16;Nrl^−/−</i> mice.

<p>Representative cross sections (20X) from central and peripheral retina of P21, P40, P60 and P80 <i>rd16;Nrl^−/−</i> mice were immunostained for the presence of cone transducin alpha (GNAT2) (A) or S- cone opsin (B) and PNA (A,B). Despite maintenance of cone outer segment sheaths (PNA), both GNAT2 and S-opsin expression are markedly reduced by P60 in both central and peripheral retina. INL- inner nuclear layer, ONL- outer nuclear layer, IS/OS- inner segments/outer segments. Calibration = 35 μm.</p

Structure and function in the central retina of <i>CEP290</i>-LCA patients.

<p>(A) Cross-sectional OCT scans along the horizontal meridian through the fovea in a normal subject, a <i>CEP290</i>-LCA patient, and an RP patient. ONL is highlighted in blue. Inset shows location of scan. (B) Relationship of foveal ONL thickness and visual acuity in <i>CEP290</i>-LCA patients. Bar graph represents the average ±1SD foveal ONL thickness of eyes in the different visual acuity ranges (n = 3, for 0.1–1 LogMAR; n = 5, for 1–2 LogMAR; and n = 11, for 2–NLP). Dashed line is lower limit of normal and emphasizes that despite low acuities, foveal ONL is within normal limits. Inset, data from a series of RP patients plotted similarly to show the more expected relationship between structure and visual acuity in retinal degenerations (n = 3, for 0–0.2 LogMAR; n = 20, for 0.2–1 LogMAR; and n = 3 for 1–2 LogMAR). Dashed line is also lower limit of normal. (C) Relationship in <i>CEP290</i>-LCA patients of width of the ONL in the central retina and patient age at time of examination. ONL width was unable to be defined in a 32-year-old <i>CEP290</i>-LCA patient with maculopathy. Solid line is linear regression. Inset, traced central ONL peaks in representative patients of different ages.</p

Structure and function in the <i>rd16;Nrl^−/−</i> mouse retina.

<p>(A) ERG b-wave amplitudes of responses to UV- and M-cone stimuli as a function of age in <i>rd16;Nrl^−/−</i> mice from P34 to P83 (n = 95) with comparisons to data from previously recorded signals in <i>Nrl^−/−</i> (squares <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092928#pone.0092928-Cheng1" target="_blank">[11]</a>; square with cross <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092928#pone.0092928-Mears1" target="_blank">[19]</a>), and <i>rd16</i> (crosses <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092928#pone.0092928-Cideciyan3" target="_blank">[7]</a>) mice. Upper: Cone b-wave responses to ultraviolet (UV, 360 nm peak) stimuli in the <i>rd16;Nrl^−/−</i> mice are severely reduced compared with those of <i>Nrl^−/−</i> mice at comparable ages. Amplitudes in <i>rd16</i> mice are low compared to the other mice. It is also notable that ERGs of the <i>Nrl^−/−</i> mice remain relatively stable throughout this age range, while ERGs of the <i>rd16; Nrl^−/−</i> and <i>rd16</i> mice decline in amplitude with age. Lower: Responses to green (510 nm) stimuli are substantially lower in amplitude than those from UV-cone stimuli. Again, <i>Nrl^−/−</i> mice have the largest amplitudes and do not decline with increasing age within this time period. The <i>rd16;Nrl^−/−</i> waveforms are lower in amplitude and there is a reduction with age. Only limited data were available for <i>rd16</i> mice and these fell within the range of <i>rd16;Nrl^−/−</i> amplitudes. Waveforms for representative <i>rd16;Nrl^−/−</i> mice at various ages (grey-filled circles) are illustrated in the panels at right. Grey lines: linear regression fit to log-converted data (dashes) and 95% prediction intervals (solid). Squares with cross at earliest age in graphs: <i>Nrl^−/−</i> data from Mears et al., 2001 (B) Photoreceptor structure (ONL+) as a function of the combined UV- and M-cone ERG b-wave amplitudes. ONL+ remains similar to the value at P31 (youngest age <i>rd16;Nrl^−/−</i> we studied) across various degrees of ERG amplitude reduction. Horizontal dashed line is the reference level for the lower limit of retinal structure thickness at P31 (−2SD from the mean at this age); photoreceptor structure above this lower limit indicates no difference compared to the data of P31 (error bars, +2SD from mean).</p