•Around one fifth of participants presented with multiple new nodules.•An increased number of new nodules correlated with greater largest new nodule size.•When assessed with nodule size, new nodule ...count had a negative relationship with lung cancer.•The nodule count at baseline had no association with new nodule lung cancer.
New nodules are regularly found after the baseline round of low-dose computed tomography (LDCT) lung cancer screening. The relationship between a participant’s number of new nodules and lung cancer probability is unknown.
Participants of the ongoing Dutch-Belgian Randomized Lung Cancer Screening (NELSON) Trial with (sub)solid nodules detected after baseline and registered as new by the NELSON radiologists were included. The correlation between a participant’s new nodule count and the largest new nodule size was assessed using Spearman's rank correlation. To evaluate the new nodule count as predictor for new nodule lung cancer together with largest new nodule size, a multivariable logistic regression analysis was performed.
In total, 705 participants with 964 new nodules were included. In 48% (336/705) of participants no nodule had been found previously during baseline screening and in 22% (154/705) of participants >1 new nodule was detected (range 1–12 new nodules). Eventually, 9% (65/705) of the participants had lung cancer in a new nodule. In 100% (65/65) of participants with new nodule lung cancer, the lung cancer was the largest or only new nodule at initial detection. The new nodule lung cancer probability did not differ significantly between participants with 1 (10% 56/551, 95%CI 8–13%) or >1 new nodule (6% 9/154, 95%CI 3–11%, P = .116). An increased number of new nodules positively correlated with a participant’s largest nodule size (P < 0.001, Spearman’s rho 0.177). When adjusted for largest new nodule size, the new nodule count had a significant negative association with lung cancer (odds ratio 0.59, 0.37–0.95, P = .03).
A participant’s new nodule count alone only has limited association with lung cancer. However, a higher new nodule count correlates with an increased largest new nodule size, while the lung cancer probability remains equivalent, and may improve lung cancer risk prediction by size only.
Lung cancer screening with low-dose computed tomography (LDCT) reduces lung cancer mortality. The aim of this study was to evaluate the cost-effectiveness of lung cancer screening with LDCT in a ...high-risk population.
The study used an adapted microsimulation model in a cohort of Dutch heavy smokers for a lifetime horizon from a health insurance perspective. The main outcomes included average cost-effectiveness ratio (ACER), incremental cost-effectiveness ratio (ICER) and lung cancer mortality reduction. The comparator was no screening. Scenarios with different screening intervals and starting and stopping ages were evaluated for 100,000 male heavy smokers and 100,000 female heavy smokers. A cost-effectiveness threshold of 60 k€ per life year gained (LYG) was assumed acceptable.
The evaluated screening scenarios yielded ACERs ranging from 17.7 to 32.4 k€/LYG for men and from 17.8 to 32.1 k€/LYG for women. The lung cancer mortality reduction ranged from 9.3% to 16.8% for men and from 7.8% to 13.7% for women. The optimal screening scenario was annual screening from 55 to 80 years for men and biennial screening from 50 to 80 years for women, with an ICER of 51.6 and 45.8 k€ per LYG compared with its previous efficient alternative, respectively. Compared with no screening, the optimal screening scenario yielded an ICER of 27.6 k€/LYG for men and 21.1 k€/LYG for women. The mortality reduction of lung cancer was 15.9% for men and 10.6% for women.
Lung cancer LDCT screening is cost-effective in a high-risk population. The optimal screening scenario is dependent on sex.
•Lung cancer screening with low-dose computed tomography in a high-risk population is cost-effective.•The optimal strategy for men is annual screening from the age of 55 to 80 years, with a cost of 27.6 k€/LYG.•The optimal strategy for women is biennial screening from the age of 50 to 80 years, with a cost of 21.1 k€/LYG.
Purpose
The Ki67 proliferation index is a prognostic and predictive marker in breast cancer. Manual scoring is prone to inter- and intra-observer variability. The aims of this study were to ...clinically validate digital image analysis (DIA) of Ki67 using virtual dual staining (VDS) on whole tissue sections and to assess inter-platform agreement between two independent DIA platforms.
Methods
Serial whole tissue sections of 154 consecutive invasive breast carcinomas were stained for Ki67 and cytokeratin 8/18 with immunohistochemistry in a clinical setting. Ki67 proliferation index was determined using two independent DIA platforms, implementing VDS to identify tumor tissue. Manual Ki67 score was determined using a standardized manual counting protocol. Inter-observer agreement between manual and DIA scores and inter-platform agreement between both DIA platforms were determined and calculated using Spearman’s correlation coefficients. Correlations and agreement were assessed with scatterplots and Bland–Altman plots.
Results
Spearman’s correlation coefficients were 0.94 (
p
< 0.001) for inter-observer agreement between manual counting and platform A, 0.93 (
p
< 0.001) between manual counting and platform B, and 0.96 (
p
< 0.001) for inter-platform agreement. Scatterplots and Bland–Altman plots revealed no skewness within specific data ranges. In the few cases with ≥ 10% difference between manual counting and DIA, results by both platforms were similar.
Conclusions
DIA using VDS is an accurate method to determine the Ki67 proliferation index in breast cancer, as an alternative to manual scoring of whole sections in clinical practice. Inter-platform agreement between two different DIA platforms was excellent, suggesting vendor-independent clinical implementability.
Aims
We aimed to compare digital image analysis (DIA) of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) in breast cancer by two platforms: (i) to validate DIA against ...standard diagnostics; and (ii) to evaluate the added value of DIA in clinical practice.
Methods and results
HER2 IHC and in‐situ hybridisation (ISH) were performed on 152 consecutive invasive breast carcinomas. IHC scores were determined with DIA using two independent platforms. Manual scoring was performed by two independent observers. HER2 status was considered positive in 3+ and ISH‐positive 2+ cases. HER2 status using DIA was compared to HER2 status with standard diagnostics (manual scoring with ISH in 2+ cases). Interplatform agreement of IHC scores was ‘moderate’ (linear weighted κ = 0.58), agreement between manual scoring and platform A was ‘moderate’ (κ = 0.60) and between manual scoring and platform B ‘almost perfect’ (κ = 0.85). Compared to manual scoring, DIA resulted in a reduction of 2+ cases from 17.1 to 1.3% with platform A and from 17.1 to 15.8% with platform B. However, compared to standard diagnostics, there were three false‐negative cases with DIA using platform A 81.3% sensitivity, 100% specificity, 100% positive predictive value (PPV), 97.8% negative predictive value (NPV). Sensitivity, specificity, PPV and NPV were 100% with DIA using platform B.
Conclusions
DIA of HER2 IHC is a valid tool in determining HER2 status in breast carcinoma. Algorithms in different platforms can behave differently, and optimal calibration is essential. In clinical practice, DIA offers an objective alternative to manual scoring, but a reduction in 2+ cases could result in loss of sensitivity.
Objectives
This study aimed to evaluate the association between visual emphysema and the presence of lung nodules, and Lung-RADS category with low-dose CT (LDCT).
Methods
Baseline LDCT scans of 1162 ...participants from a lung cancer screening study (Nelcin-B3) performed in a Chinese general population were included. The presence, subtypes, and severity of emphysema (at least trace) were visually assessed by one radiologist. The presence, size, and classification of non-calcified lung nodules (≥ 30 mm
3
) and Lung-RADS category were independently assessed by another two radiologists. Multivariable logistic regression and stratified analyses were performed to estimate the association between emphysema and lung nodules, Lung-RADS category, after adjusting for age, sex, BMI, smoking status, pack-years, and passive smoking.
Results
Emphysema and lung nodules were observed in 674 (58.0%) and 424 (36.5%) participants, respectively. Participants with emphysema had a 71% increased risk of having lung nodules (adjusted odds ratios, aOR: 1.71, 95% CI: 1.26–2.31) and 70% increased risk of positive Lung-RADS category (aOR: 1.70, 95% CI: 1.09–2.66) than those without emphysema. Participants with paraseptal emphysema (
n
= 47, 4.0%) were at a higher risk for lung nodules than those with centrilobular emphysema (CLE) (aOR: 2.43, 95% CI: 1.32–4.50 and aOR: 1.60, 95% CI: 1.23–2.09, respectively). Only CLE was associated with positive Lung-RADS category (
p
= 0.02). CLE severity was related to a higher risk of lung nodules (ranges aOR: 1.44–2.61, overall
p
< 0.01).
Conclusion
In a Chinese general population, visual emphysema based on LDCT is independently related to the presence of lung nodules (≥ 30 mm
3
) and specifically CLE subtype is related to positive Lung-RADS category. The risk of lung nodules increases with CLE severity.
Key Points
• Participants with emphysema had an increased risk of having lung nodules, especially smokers.
• Participants with PSE were at a higher risk for lung nodules than those with CLE, but nodules in participants with CLE had a higher risk of positive Lung-RADS category.
• The risk of lung nodules increases with CLE severity.
Abstract Objective To determine the prevalence, localisation and type of occult (non)invasive cancer in risk-reducing salpingo-oophorectomy (RRSO) specimens in BRCA -mutation carriers and high-risk ...women from BRCA -negative families. Methods A consecutive series of RRSO specimens of asymptomatic, screen-negative high-risk women were prospectively collected in our tertiary multidisciplinary cancer clinic from January 2000 until March 2012. All high-risk women in this study underwent genetic testing on BRCA -mutations. The surgico-pathological protocol comprised complete resection of ovaries and fallopian tubes, transverse sectioning at 2–3 mm (sectioning and extensively examining the fimbrial end SEE-FIM protocol from 2006) and double independent pathology review of morphologically deviant sections. Results Three hundred and sixty RRSOs were performed in 188 BRCA1- carriers, 115 BRCA2 -carriers and 57 BRCA -negative women at a median age of 44.0 years. Four occult invasive cancers were detected in BRCA -carriers (1.3%, 95%-confidence interval (CI) 0.03–2.61), all in BRCA1 -carriers >40 years of age. All cancers, of which two tubal and two ovarian cancers, were FIGO-stage I/II. Three non-invasive serous intraepithelial carcinomas (STICs) were detected in BRCA -carriers (1.0%, 95%-CI 0.00–2.10). In BRCA -negative women one STIC was found (1.8%, 95%-CI 0.00–5.16), however she carried an unclassified variant in BRCA2 . Total follow-up after RRSO was 1691 woman-years, in which one BRCA1 -carrier developed peritoneal cancer (0.3%, 95%-CI 0.00–0.82). Conclusions A low prevalence of occult invasive cancer (1.1%) was found in young asymptomatic, screen-negative women at increased ovarian cancer risk undergoing RRSO. This study adds to the advice to perform RRSO in BRCA1 -carriers before the age of 40. Our findings support the hypothesis of the fallopian tube as the primary site of origin of pelvic high-grade serous cancer.
•There is limited knowledge about CT characteristics of solid lung nodules in never and former smokers.•Minor differences in nodule CT characteristics were found for never and former smokers compared ...to current smokers in a population-based setting.•Among individuals with solid nodules, the odds of ‘high-risk’ nodules were similar for never smokers and current smokers, which might impact follow-up recommendations.
Aim was to assess CT characteristics of lung nodules in never and former smokers compared to current smokers in a population-based setting.
We included individuals aged 45–60 years taking part in the ImaLife (Imaging in Lifelines) study, with at least one solid lung nodule (≥30 mm3) on low-dose chest CT. Qualitative (location, shape, margin, nodule type, attached structures) and quantitative (count, diameter, volume) nodule characteristics were evaluated. Based on Fleischner criteria, ‘high risk’ nodules were defined. To examine the association between smoking status and nodule CT characteristics of participants, multi-level multinomial logistic regression corrected for clustering of nodules within participants was performed, where all odds ratios (aORs) were adjusted for age and sex.
Overall, 1,639 individuals (median age: 55.0, IQR:50.5–58.5, 50.5% men) were included, with 42.1% never smokers, 35.3% former smokers and 22.6% current smokers. A total of 3,222 solid nodules were identified; 39.7% of individuals had multiple nodules. Nodule size, location, type and attachment were similar for never compared to current smokers. The odds of nodules with an irregular shape and irregular margin was lower in never smokers (aOR:0.64, 95 %CI:0.44–0.93; aOR:0.60, 95 %CI:0.41–0.88, respectively) and former smokers (aOR:0.61, 95 %CI:0.41–0.90; aOR:0.57, 95 %CI:0.38–0.85, respectively) compared to current smokers. The odds of a detected nodule being ‘high risk’ was similar for never versus current smokers (never smokers: aOR = 0.90; 95% CI:0.73–1.11).
CT-based characteristics of solid lung nodules in never and former smokers differed only slightly from current smokers. Among individuals with solid nodules, ‘high-risk’ nodules were equally common in never smokers and current smokers.
•The Chinese population has a higher prevalence of emphysema compared to the Dutch population, which was only seen in never smoker after stratification by smoking status.•Increasing age and male sex ...increased the odds of emphysema to similar magnitudes in both populations.•Factors other than smoking, age, and sex, for example, air pollution or ethnicity may play a key role in emphysema formation. Studies should now focus on elucidating other risk factors that contribute to the high prevalence of CT-defined emphysema in Chinese never smokers.
We determine and compare the prevalence, subtypes, severity, and risk factors for emphysema assessed by low-dose CT(LDCT) in Chinese and Dutch general populations.
This cross-sectional study included LDCT scans of 1143 participants between May and October 2017 from a Chinese Cohort study and 1200 participants with same age range and different smoking status between May and October 2019 from a Dutch population-based study. An experienced radiologist visually assessed the scans for emphysema presence (≥trace), subtype, and severity. Logistic regression analyses, overall and stratified by smoking status, were performed and adjusted for fume exposure, demographic and smoking data.
The Chinese population had a comparable proportion of women to the Dutch population (54.9 % vs 58.9 %), was older (61.7 ± 6.3 vs 59.8 ± 8.1), included more never smokers (66.4 % vs 38.3 %), had a higher emphysema prevalence (58.8 % vs 39.7 %, adjusted odds ratio, aOR = 2.06, 95 %CI = 1.68–2.53), and more often had centrilobular emphysema (54.8 % vs 32.8 %, p < 0.001), but no differences in emphysema severity. After stratification, only in never smokers an increased odds of emphysema was observed in the Chinese compared to the Dutch (aOR = 2.55, 95 %CI = 1.95–3.35). Never smokers in both populations shared older age (aOR = 1.59, 95 %CI = 1.25–2.02 vs 1.26, 95 %CI = 0.97–1.64) and male sex (aOR = 1.50, 95 %CI = 1.02–2.22 vs 1.93, 95 %CI = 1.26–2.96) as risk factors for emphysema.
Only never smokers had a higher prevalence of mainly centrilobular emphysema in the Chinese general population compared to the Dutch after adjusting for confounders, indicating that factors other than smoking, age and sex contribute to presence of CT-defined emphysema.
Aims
Treatment with anti‐HER2 therapy could be beneficial for patients with HER2‐positive endometrial and ovarian clear cell carcinoma (CCC). We studied HER2 overexpression by immunohistochemistry ...(IHC) using three different antibodies, including concordance with amplification by in‐situ hybridisation (ISH).
Methods and results
IHC and ISH were performed on tissue microarrays of 101 tumours: 58 endometrial pure CCC, 19 endometrial mixed carcinomas with a CCC component and 24 ovarian pure CCC. IHC was performed using SP3, 4B5 and HercepTest antibodies, and was scored by two independent observers. ISH was performed using dual‐colour silver ISH. Using IHC, agreement was poor between SP3/4B5 (61.4%), poor between SP3/HercepTest (68.3%) and reasonable between 4B5/HercepTest (75.2%). Interobserver agreement was substantial to almost perfect for all antibodies (SP3: linear weighted κ = 0.89, 4B5: κ = 0.90, HercepTest: κ = 0.76). HER2‐positivity by ISH was 17.8% (endometrial pure CCC: 24.1%, endometrial mixed: 0%, ovarian pure CCC: 16.7%). IHC/ISH concordance was poor, with a high false‐negative rate of all three IHC antibodies: sensitivity (38.9–50.0%) and positive predictive value (PPV) (37.5–58.3%) were poor; specificity (81.9–94.0%) and negative predictive value (NPV) (87.1–88.3%) were reasonable. When excluding 2+ cases, sensitivity declined (26.7–43.8%) but PPV (80.0–87.5%) and specificity (98.6–98.7%) improved.
Conclusions
In ovarian and endometrial CCC, there is considerable difference in HER2 overexpression by different IHC antibodies and marked discordance with ISH. As such, no single antibody can be considered conclusive for determining HER2 status in CCC. Based on these results, the lack of predictive value of different HER2 testing methods, as used in other studies, could be explained.
PDF
