Effectiveness of Nonmydriatic Ultra-Widefield Retinal Imaging to Screen for Diabetic Eye Disease: A Randomized Controlled Trial (Clearsight).

OBJECTIVE: Suboptimal diabetic eye disease screening is a major cause of preventable vision loss. Screening barriers include mydriasis and the need for dedicated screening appointments. The Clearsight trial assessed whether nonmydriatic ultra-widefield (NM UWF) screening on the day of a diabetes clinic visit improved detection of clinically important eye disease versus usual screening. RESEARCH DESIGN AND METHODS: This single-center, randomized, parallel-group controlled trial was conducted at St. Joseph's Health Care, London, Ontario, Canada. Adults with diabetes due for screening were randomized to same-day, on-site screening (NM UWF imaging) on the day of a scheduled diabetes clinic visit or usual screening (encouraged to arrange optometrist screening). The primary outcome was detection of actionable eye disease (AED), defined as the need for an ophthalmology referral or increased ocular surveillance. The primary analysis (modified intention-to-screen) compared the proportions of AED between groups within 1 year of enrollment. RESULTS: Of 740 participants randomized between 7 March 2016 and 17 April 2019, 335 on-site screening and 323 usual screening participants met criteria for the primary analysis. More AED was detected in the on-site screening group than in the usual screening group (50 of 335 [14.9%] vs. 22 of 323 [6.8%]; adjusted odds ratio 2.51; 95% CI 1.49-4.36). The number needed to screen by on-site screening in order to detect 1 additional patient with AED was 13 (95% CI 8-29). CONCLUSIONS: Same-day, on-site screening by NM UWF imaging increased the detection of clinically important diabetic eye disease versus usual screening. Integration of NM UWF imaging into routine diabetes clinic visits improved screening adherence and has the potential to prevent vision loss.

A randomised trial of non-mydriatic ultra-wide field retinal imaging versus usual care to screen for diabetic eye disease: rationale and protocol for the Clearsight trial.

INTRODUCTION: Suboptimal screening for diabetic eye disease is a major cause of preventable vision loss. Screening barriers include mydriasis and the extra time patients need to attend dedicated eye screening appointments. In the Clearsight trial, we are testing whether screening by non-mydriatic ultra-wide field (NM UWF) imaging on the day patients attend their diabetes outpatient clinic visit improves detection of clinically important eye disease compared with usual screening. METHODS AND ANALYSIS: Patients with diabetes due for a screening eye exam by the 2013 Canadian Diabetes Association (CDA) practice guidelines are being randomised to on-site screening by NM UWF imaging on the day of their clinic visit or to usual screening where, per CDA guidelines, they are encouraged to arrange an exam by an optometrist. The primary outcome is actionable eye disease (AED) based on a need for referral to ophthalmology and/or increased ocular surveillance. The primary analysis will use an intention-to-screen approach that compares the proportions of detected AED between on-site and usual screening groups under a superiority hypothesis in favour of on-site screening. With 740 randomised participants, the study will have 80% power to detect ≥5% absolute increase in the AED rate among on-site screening versus usual screening participants. This difference translates into a number-needed-to-screen by on-site screening of 20 to detect 1 additional person with AED. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board of Western University. The findings of the trial will be disseminated directly to participants and through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials.Gov NCT02579837 (registered 16 October 2015). PROTOCOL ISSUE DATE: 18 November 2015.

Influence of patterns of hormone replacement therapy use and mammographic density on breast cancer detection.

BACKGROUND: There is evidence that factors such as current hormone replacement therapy (HRT) use and mammographic density may each lower the sensitivity of mammography and are associated with a greater risk of developing an interval cancer. This study explores this relationship further by examining the influence of patterns of HRT use and the percentage of mammographic density on the detection of breast cancer by classification of interval cancer. METHODS: This study uses a case-case design nested within a cohort of women screened by the Ontario Breast Screening Program between 1994 and 2002. Interval cancers, both those missed at screening but seen on retrospective review (n = 87) or true intervals without visible tumor signs at screening (n = 288) were matched to 450 screen-detected cancers. The association between the percentage of mammographic density, measured by radiologists and a computer-assisted method, and HRT use, ascertained from a mailed questionnaire, and the risk of being diagnosed with an interval cancer was estimated using conditional logistic regression. RESULTS: A monotonic gradient of increasing risk for interval cancers was found for each 25% increase in mammographic density [odds ratio (OR), 1.77; 95% confidence intervals (95% CI), 1.07-2.95 for missed intervals and OR, 2.16; 95% CI, 1.59-2.94 for true intervals]. After adjusting for mammographic density, a significantly increased risk for true-interval cancers remained for women taking estrogen alone (OR, 1.75; 95% CI, 1.11-2.83) as well as for missed- (OR, 2.84; 95% CI, 1.32-6.13) and true-interval cancers (OR, 1.79; 95% CI, 1.10-2.90) for women taking combined HRT. CONCLUSIONS: Information on mammographic density and HRT use should routinely be collected at the time of screening. Women at risk should be made aware of the lower sensitivity of mammography and offered alternative procedures for screening.

Etiologic and other factors predicting nevus-associated cutaneous malignant melanoma.

Cutaneous malignant melanomas with histologic evidence of an associated nevus (N+) may have a different risk factor profile from that of melanomas without it (N-). To address this question, a case-only analysis of 932 people with cutaneous malignant melanoma was done to identify etiologic and other factors associated with N+ melanoma. Evidence of an associated nevus was found in 36% of melanomas. N+ melanomas were thinner (Ptrend=0.0009) and more likely to be of the superficial spreading type than other types of melanoma. Subjects with N+ melanomas were younger (Ptrend<0.0001) and reported a higher nevus density on their skin than subjects with N- melanomas [odds ratio (OR), 3.1; 95% confidence interval (CI), 1.6-6.0, for high nevus density versus no nevi]. Indicators of high accumulated sun exposure were less prevalent among subjects with N+ melanomas (OR, 0.3; 95% CI, 0.2-0.4, for melanoma location on the head and neck versus location on trunk; OR, 0.2; 95% CI, 0.1-0.4, for severe solar elastosis adjacent to the melanoma versus no elastosis; OR, 0.2; 95% CI, 0.1-0.4, for lentigo maligna melanoma subtype versus superficial spreading subtype). With the exception of solar elastosis and age, all of the aforementioned variables remained significantly associated with N+ melanomas in multivariate analyses. No associations with self-reported measures of sun exposure, sunburn, or pigmentation phenotype were apparent. Our findings provide some support for the hypothesis of etiologically separate pathways for melanoma, with N+ melanomas appearing less likely to develop in the presence of characteristics suggesting high accumulated sun exposure than N- melanomas. However, it is possible that high UV exposure causes involution of nevi, thus reducing the density of nevi in exposed skin and thereby the probability of N+ melanoma.

Effect of screening result on waiting times to assessment and breast cancer diagnosis: results from the Ontario Breast Screening Program.

BACKGROUND: The effect of severity of screening result on delays to diagnosis has primarily been examined for mammographic abnormalities. This study will examine delays to assessment and diagnosis for women with an abnormal mammogram compared to women with an abnormal clinical breast examination (CBE) or abnormal CBE and mammogram. METHODS: Using data routinely collected by Ontario Breast Screening Program (OBSP), 12,675 women aged 50 to 69 with an abnormal screening result between January 1, 2000 and December 31, 2000 were followed prospectively to the completion of their assessment process. Median waiting times from abnormal screen to first assessment procedure and diagnosis were compared by modality of referral and among women with a breast cancer diagnosis by prognostic features. RESULTS: The median waiting time to first assessment and to diagnosis was significantly longer for women with only a clinical abnormality compared to women with a mammographic abnormality. In addition, women diagnosed with cancers of larger size had longer delays when the abnormality was detected only clinically. However, women referred by both modalities had significantly shorter waiting times to first assessment procedure and to diagnosis of poor prognosis cancers compared to women referred by mammography alone. INTERPRETATION: Women with an abnormal CBE and mammogram are assessed more promptly and have shorter diagnostic times. However, women with only a CBE abnormality had delays to diagnosis as a result of longer waiting times to first assessment procedure. Integration of the OBSP with assessment centres should improve times to diagnosis irrespective of modality of referral.

Dietary factors and risk of non-Hodgkin lymphoma by histologic subtype: a case-control analysis.

There is speculation that etiologic heterogeneity exists among tumors classified as non-Hodgkin lymphoma (NHL), although it is not known whether diet-related associations vary between tumor subgroups. We analyzed data on 1,642 NHL cases and 5,039 controls aged 20 to 74 years from a population-based case-control study conducted in eight Canadian provinces to explore associations between dietary factors and NHL by histologic subtype. Dietary information was collected using a 69-item food frequency questionnaire. Tumors were categorized into histologic subtypes using the contents of pathology reports from the original histopathologic review of diagnostic material. Odds ratios (OR) relating consumption of dietary factors (divided into three categories) to each NHL subtype (diffuse, follicular, small lymphocytic, high grade, peripheral T cell, and unspecified lymphomas) were calculated using polytomous logistic regression. We found an increased risk of NHL with high (versus low) intake of processed meat (OR, 1.49), cheese (OR, 1.38), eggs (OR, 1.49), and dessert foods (OR, 1.24). Positive associations with NHL were also found for high consumption of total fat (OR, 1.28), saturated fat (OR, 1.29), and monounsaturated fat (OR, 1.27). Associations for consumption of some vegetables and fats were found to differ between lymphoma subtypes. Given the large number of diet/subtype comparisons done, however, the possibility that this heterogeneity arose by chance cannot be ruled out. In conclusion, these findings generally do not support the existence of etiologic heterogeneity between histologic subtypes of NHL in their associations with components of dietary intake.

Etiologic factors associated with p53 immunostaining in cutaneousmalignant melanoma.

Findings from a case-control study of cutaneous malignant melanoma (CMM) in Queensland, Australia, suggest that melanomas exhibiting p53 immunostaining possess different risk factors from those of other melanomas. To further explore this hypothesis, a case-only analysis of risk factors for p53 immunostaining with anti-p53 MAb DO-7 was undertaken in 523 people diagnosed with CMM in Canada and Australia. Phenotypic factors and past sun exposure were measured using a self-administered questionnaire and telephone interview. The presence of strong p53 staining (>10% of cell nuclei positively stained vs. <1% staining) was positively associated with some indicators of high cumulative sun exposure: lentigo maligna melanoma subtype (OR = 3.2 vs. superficial spreading subtype), melanoma location on the head and neck (OR = 2.8 vs. back), histopathologic evidence of solar elastosis (OR = 2.1) and previous diagnosis of nonmelanoma skin cancer (OR = 2.4). Strong staining was negatively associated with high nevus density on the back (OR = 0.2 for >25 nevi vs. 0-3 nevi) and histologic evidence of a coexisting nevus (OR = 0.3). Other factors associated with strong p53 immunostaining include greater Breslow thickness (OR = 7.4 for >4.00 vs. <0.76 mm), male sex (OR = 2.2) and dense freckling (OR = 6.6 vs. few freckles). Of these, thickness, male sex, dense freckling, low nevus density on the back, histologic subtype and history of nonmelanoma skin cancer appeared to be independently associated with strong p53 staining. Our findings are consistent with the Queensland study in suggesting that variables indicating high accumulated sun exposure are positively associated with p53 staining and that an increased number of nevi is positively associated with its absence; they may reflect etiologic and pathogenetic heterogeneity in melanoma.