Effect of emphysema on AI software and human reader performance in lung nodule detection from low-dose chest CT.

BACKGROUND: Emphysema influences the appearance of lung tissue in computed tomography (CT). We evaluated whether this affects lung nodule detection by artificial intelligence (AI) and human readers (HR). METHODS: Individuals were selected from the "Lifelines" cohort who had undergone low-dose chest CT. Nodules in individuals without emphysema were matched to similar-sized nodules in individuals with at least moderate emphysema. AI results for nodular findings of 30-100 mm3 and 101-300 mm3 were compared to those of HR; two expert radiologists blindly reviewed discrepancies. Sensitivity and false positives (FPs)/scan were compared for emphysema and non-emphysema groups. RESULTS: Thirty-nine participants with and 82 without emphysema were included (n = 121, aged 61 ± 8 years (mean ± standard deviation), 58/121 males (47.9%)). AI and HR detected 196 and 206 nodular findings, respectively, yielding 109 concordant nodules and 184 discrepancies, including 118 true nodules. For AI, sensitivity was 0.68 (95% confidence interval 0.57-0.77) in emphysema versus 0.71 (0.62-0.78) in non-emphysema, with FPs/scan 0.51 and 0.22, respectively (p = 0.028). For HR, sensitivity was 0.76 (0.65-0.84) and 0.80 (0.72-0.86), with FPs/scan of 0.15 and 0.27 (p = 0.230). Overall sensitivity was slightly higher for HR than for AI, but this difference disappeared after the exclusion of benign lymph nodes. FPs/scan were higher for AI in emphysema than in non-emphysema (p = 0.028), while FPs/scan for HR were higher than AI for 30-100 mm3 nodules in non-emphysema (p = 0.009). CONCLUSIONS: AI resulted in more FPs/scan in emphysema compared to non-emphysema, a difference not observed for HR. RELEVANCE STATEMENT: In the creation of a benchmark dataset to validate AI software for lung nodule detection, the inclusion of emphysema cases is important due to the additional number of FPs. KEY POINTS: • The sensitivity of nodule detection by AI was similar in emphysema and non-emphysema. • AI had more FPs/scan in emphysema compared to non-emphysema. • Sensitivity and FPs/scan by the human reader were comparable for emphysema and non-emphysema. • Emphysema and non-emphysema representation in benchmark dataset is important for validating AI.

Correction: Factors associated with SARS-COV-2 positive test in Lifelines.

[This corrects the article DOI: 10.1371/journal.pone.0294556.].

Statin use as a moderator on the association between metformin and breast cancer risk in women with type 2 diabetes mellitus.

INTRODUCTION: Metformin and statins are considered as potential agents for prevention of breast cancer, however, existing evidence does not uniformly substantiate this claim, and the data is scarce concerning their interaction in relation to breast cancer risk. This study aims to investigate whether the effect of metformin on breast cancer incidence varied by statin use among women with type 2 diabetes mellitus (T2DM). METHODS: This study included women with T2DM, without a history of cancers, and followed up for more than one year from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) for the period 1998-2014. The dataset was structured using a person-time approach, where the cumulative medication usage was annually updated for each person. The extended Cox proportional hazards models were employed, reporting adjusted hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: During a median follow-up of 5 years, 515 of 29,498 women received a breast cancer diagnosis. Each additional year of metformin or statins use corresponded to a decrease in breast cancer incidence, while the magnitude attenuated over time. Noteworthily, statin use modified the effect of metformin on breast cancer incidence. For instance, after 5 years of follow-up, one-year increase of metformin use among women who used statins for 3 years was linked to a substantially reduced breast cancer risk (HR, 95% CI: 0.88, 0.84-0.93), however, there was no significant decrease in risk for those non-statins users (HR, 95% CI: 0.96, 0.89-1.04). CONCLUSIONS: Extending metformin or statin usage by one year conferred breast cancer protection in women with T2DM. Enhanced protective effect of metformin was observed among those who also use statins. These results suggest the potential of combined metformin and statin therapy as promising breast cancer prevention strategies.

Head and neck cancer patients with geriatric deficits are more often non-responders and lost from follow-up in quality of life studies.

OBJECTIVES: To identify associations between frailty and non-response to follow-up questionnaires, in a longitudinal head and neck cancer (HNC) study with patient-reported outcome measures (PROMs). MATERIALS AND METHODS: Patients referred with HNC were included in OncoLifeS, a prospective data-biobank, underwent Geriatric Assessment (GA) and frailty screening ahead of treatment, and were followed up at 3, 6, 12 and 24 months after treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Head and Neck 35. Statistical analysis for factors associated with non-response was done using Generalized Linear Mixed Models. RESULTS: 289 patients were eligible for analysis. Mean age was 68.4 years and 68.5% were male. Restrictions in Activities of Daily Living [OR 4.46 (2.04-9.78)] and Instrumental Activities of Daily Living [OR 4.33 (2.27-8.24)], impaired mobility on Timed Up and Go test [OR 3.95 (1.85-8.45)], cognitive decline [OR 4.85 (2.28-10.35)] and assisted living (OR 5.54 (2.63-11.67)] were significantly associated with non-response. Frailty screening, with Geriatric 8 and Groningen Frailty Indicator, was also associated with non-response [OR, respectively, 2.64 (1.51-4.59) and 2.52 (1.44-4.44)]. All findings remained significant when adjusted for other factors that were significantly associated with non-response, such as higher age, longer study duration and subsequent death. CONCLUSION: Frail HNC patients respond significantly worse to follow-up PROMs. The drop-out and underrepresentation of frail patients in studies may lead to attrition bias, and as a result underestimating the effect sizes of associations. This is of importance when handling and interpreting such data.

The relationship of fat and muscle measurements with emphysema and bronchial wall thickening in smokers.

Introduction: Differences in body composition in patients with COPD may have important prognostic value and may provide opportunities for patient-specific management. We investigated the relation of thoracic fat and muscle with computed tomography (CT)-measured emphysema and bronchial wall thickening. Methods: Low-dose baseline chest CT scans from 1031 male lung cancer screening participants from one site were quantified for emphysema, bronchial wall thickening, subcutaneous fat, visceral fat and skeletal muscle. Body composition measurements were performed by segmenting the first slice above the aortic arch using Hounsfield unit thresholds with region growing and manual corrections. COPD presence and severity were evaluated with pre-bronchodilator spirometry testing. Results: Participants had a median age of 61.5 years (58.6-65.6, 25th-75th percentile) and median number of 38.0 pack-years (28.0-49.5); 549 (53.2%) were current smokers. Overall, 396 (38.4%) had COPD (256 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1, 140 GOLD 2-3). Participants with COPD had less subcutaneous fat, visceral fat and skeletal muscle (p<0.001 for all). With increasing GOLD stages, subcutaneous (p=0.005) and visceral fat values (p=0.004) were higher, and skeletal muscle was lower (p=0.004). With increasing severity of CT-derived emphysema, subcutaneous fat, visceral fat and skeletal muscle values were lower (p<0.001 for all). With increasing CT-derived bronchial wall thickness, subcutaneous and visceral fat values were higher (p<0.001 for both), without difference in skeletal muscle. All statistical relationships remained when adjusted for age, pack-years and smoking status. Conclusion: COPD presence and emphysema severity are associated with smaller amounts of thoracic fat and muscle, whereas bronchial wall thickening is associated with fat accumulation.

Heart Rate Variability in Surgical Patients Experiencing Live Bedside Music; An Explorative Study.

It's known that surgery elicits a stress response involving the autonomic nervous system (ANS) which is important in general recovery but can also have detrimental effects in older patients. Music seems to positively effect postoperative recovery, although the mechanism requires further unravelling. Our objective was to explore the response of the ANS to live bedside music in older surgical patients, by using heart rate variability (HRV) as a proxy. This explorative prospective non-randomized controlled cohort study included 101 older non-cardiac surgical patients, with a median age of 70 (range 60-88 years). HRV was measured in a cohort receiving live bedside music provided by professional musicians and in a control group that did not receive music. HRV was measured pre-intervention, during the intervention, 30 min after the intervention, and again after three hours. Mixed linear modelling was used to assess the effect of the intervention compared to the control group over time. A significant change in both the low and high frequency bands (p = 0.041) and (p = 0.041) respectively, was found over time in the music group compared to the control group indicating relaxation and increased parasympathetic activity in the music group. Other measures revealed a trend but no significant effect was shown. These results provide a first glance and contribute to a better understanding of the effect of music on the recovery of older surgical patients.

Impact of health-related behavioral factors on participation in a cervical cancer screening program: the lifelines population-based cohort.

BACKGROUND: Regular participation in cervical cancer screening is critical to reducing mortality. Although certain sociodemographic factors are known to be associated with one-time participation in screening, little is known about other factors that could be related to regular participation. Therefore, this study evaluated the association between health-related behavioral factors and regular participation in cervical cancer screening. METHODS: The Lifelines population-based cohort was linked to data for cervical cancer screening from the Dutch Nationwide Pathology Databank. We included women eligible for all four screening rounds between 2000 and 2019, classifying them as regular (4 attendances), irregular (1-3 attendances), and never participants. Multinomial logistic regression was performed to evaluate the association between behavioral factors and participation regularity, with adjustment made for sociodemographic factors. RESULTS: Of the 48,325 included women, 55.9%, 35.1%, and 9% were regular, irregular, and never screening participants. After adjustment for sociodemographic factors, the likelihood of irregular or never screening participation was increased by smoking, obesity, marginal or inadequate sleep duration, alcohol consumption and low physical activity, while it was decreased by hormonal contraception use. CONCLUSION: An association exists between unhealthy behavioral factors and never or irregular participation in cervical cancer screening.

Relationships of pericoronary and epicardial fat measurements in male and female patients with and without coronary artery disease.

INTRODUCTION: Although pericoronary adipose tissue (PCAT) is a component of the epicardial adipose tissue (EAT) depot, they may have different associations to coronary artery disease (CAD). We explored relationships between pericoronary adipose tissue mean attenuation (PCATMA) and EAT measurements in coronary CT angiography (CCTA) in patients with and without CAD. MATERIAL AND METHODS: CCTA scans of 185 non-CAD and 81 CAD patients (86.4% >50% stenosis) were included and retrospectively analyzed. PCATMA and EAT density/volume were measured and analyzed by sex, including associations with age, risk factors and tube voltage using linear regression models. RESULTS: In non-CAD and CAD, mean PCATMA and EAT volume were higher in men than in women (non-CAD: -92.5 ± 10.6HU vs -96.2 ± 8.4HU, and 174.4 ± 69.1 cm3 vs 124.1 ± 57.3 cm3; CAD: -92.2 ± 9.0HU vs -97.4 ± 9.7HU, and 193.6 ± 62.5 cm3 vs 148.5 ± 50.5 cm3 (p < 0.05)). EAT density was slightly lower in men than women in non-CAD (-96.4 ± 6.3HU vs -94.4 ± 5.5HU (p < 0.05)), and similar in CAD (-98.2 ± 5.2HU vs 98.2 ± 6.4HU). There was strong correlation between PCATMA and EAT density (non-CAD: r = 0.725, p < 0.001, CAD: r = 0.686, p < 0.001) but no correlation between PCATMA and EAT volume (non-CAD: r = 0.018, p = 0.81, CAD: r = -0.055, p = 0.63). A weak inverse association was found between EAT density and EAT volume (non-CAD: r = -0.244, p < 0.001, CAD: r = -0.263, p = 0.02). In linear regression models, EAT density was significantly associated with PCATMA in both non-CAD and CAD patients independent of risk factors and tube voltage. CONCLUSION: In CAD and non-CAD patients, EAT density, but not EAT volume, showed significant associations with PCATMA. Compared to women, men had higher PCATMA and EAT volume independently of disease status, but similar or slightly lower EAT density. Differences in trends and relations of PCATMA and EAT by sex could indicate that personalized interpretation and thresholding is needed.

Factors associated with SARS-COV-2 positive test in Lifelines.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) can affect anyone, however, it is often mixed with other respiratory diseases. This study aimed to identify the factors associated with SARS-COV-2 positive test. METHODS: Participants from the Northern Netherlands representative of the general population were included if filled in the questionnaire about well-being between June 2020-April 2021 and were tested for SARS-COV-2. The outcome was a self-reported test as measured by polymerase chain reaction. The data were collected on age, sex, household, smoking, alcohol use, physical activity, quality of life, fatigue, symptoms and medications use. Participants were matched on sex, age and the timing of their SARS-COV-2 tests maintaining a 1:4 ratio and classified into those with a positive and negative SARS-COV-2 using logistic regression. The performance of the model was compared with other machine-learning algorithms by the area under the receiving operating curve. RESULTS: 2564 (20%) of 12786 participants had a positive SARS-COV-2 test. The factors associated with a higher risk of SARS-COV-2 positive test in multivariate logistic regression were: contact with someone tested positive for SARS-COV-2, ≥1 household members, typical SARS-COV-2 symptoms, male gender and fatigue. The factors associated with a lower risk of SARS-COV-2 positive test were higher quality of life, inhaler use, runny nose, lower back pain, diarrhea, pain when breathing, sore throat, pain in neck, shoulder or arm, numbness or tingling, and stomach pain. The performance of the logistic models was comparable with that of random forest, support vector machine and gradient boosting machine. CONCLUSIONS: Having a contact with someone tested positive for SARS-COV-2 and living in a household with someone else are the most important factors related to a positive SARS-COV-2 test. The loss of smell or taste is the most prominent symptom associated with a positive test. Symptoms like runny nose, pain when breathing, sore throat are more likely to be indicative of other conditions.

The effect of extended participation windows on attendance at cervical cancer screening.

Research has long since confirmed the benefits of regular cervical cancer screening (CCS) worldwide. However, some developed countries have low participation rates despite well-organized screening programs. Given that studies in Europe typically define participation in 12-month windows from an invitation, we evaluated both whether extending this defined time window could reveal the true participation rate and how sociodemographic determinants affect participation delays. This involved linking data from the Lifelines population-based cohort with CCS-related data from the Dutch Nationwide Pathology Databank and including data for 69 185 women eligible for screening in the Dutch CCS program between 2014 and 2018. We then estimated and compared the participation rates for 15- and 36-month time windows and categorized women by the primary screening window into timely participation (within 15 months) and delayed participation (within 15-36 months) groups, before performing multivariable logistic regression to evaluate the association between delayed participation and the sociodemographic determinants. Participation rates for the 15- and 36-month windows were 71.1% and 77.0%, respectively, with participation considered timely in 49 224 cases and delayed in 4047 cases. Delayed participation was associated with age 30-35 years (odds ratio [OR]: 2.88, 95 %CI: 2.67-3.11), higher education (OR: 1.50, 95 %CI: 1.35-1.67), the high-risk human papillomavirus test-based program (OR: 1.67, 95 %CI: 1.56-1.79), and pregnancy (OR: 4.61, 95 %CI: 3.88-5.48). These findings show that a 36-month window for monitoring attendance at CCS better reflects the actual participation rate by accommodating possible delayed uptake among younger, pregnant, and highly educated women.

Multi-source data approach for personalized outcome prediction in lung cancer screening: update from the NELSON trial.

Trials show that low-dose computed tomography (CT) lung cancer screening in long-term (ex-)smokers reduces lung cancer mortality. However, many individuals were exposed to unnecessary diagnostic procedures. This project aims to improve the efficiency of lung cancer screening by identifying high-risk participants, and improving risk discrimination for nodules. This study is an extension of the Dutch-Belgian Randomized Lung Cancer Screening Trial, with a focus on personalized outcome prediction (NELSON-POP). New data will be added on genetics, air pollution, malignancy risk for lung nodules, and CT biomarkers beyond lung nodules (emphysema, coronary calcification, bone density, vertebral height and body composition). The roles of polygenic risk scores and air pollution in screen-detected lung cancer diagnosis and survival will be established. The association between the AI-based nodule malignancy score and lung cancer will be evaluated at baseline and incident screening rounds. The association of chest CT imaging biomarkers with outcomes will be established. Based on these results, multisource prediction models for pre-screening and post-baseline-screening participant selection and nodule management will be developed. The new models will be externally validated. We hypothesize that we can identify 15-20% participants with low-risk of lung cancer or short life expectancy and thus prevent ~140,000 Dutch individuals from being screened unnecessarily. We hypothesize that our models will improve the specificity of nodule management by 10% without loss of sensitivity as compared to assessment of nodule size/growth alone, and reduce unnecessary work-up by 40-50%.

Role of Serum Lipids, Blood Glucose and Blood Pressure in Breast Cancer Risk for Women with Type 2 Diabetes Mellitus.

Purpose: Women with type 2 diabetes mellitus (T2DM) have an increased risk of breast cancer. We aimed to determine the contribution of lipids, glucose and blood pressure to this risk based on the multifactorial nature of T2DM. Patients and Methods: This population-based cohort study used data from a Dutch database (the Groningen Initiative to Analyse Type 2 Diabetes Treatment) for the period 2004-2013. The cohort included women diagnosed with T2DM, aged 30-80 years, with no history of breast cancer and with follow-up data for at least 1 year. We used Cox proportional hazards models to estimate the associations of exposures with breast cancer occurrence, reporting adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Exposures of interest included total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, glycated hemoglobin A (HbA1c) and systolic blood pressure (SBP). Results: During a median of 4.45 years' follow-up, 183 of 10,183 included women received a breast cancer diagnosis. We observed U-shaped associations with breast cancer incidence for total cholesterol and HDL-C at baseline. Compared with moderate elevations, women had significantly higher breast cancer risks associated with high total cholesterol (aHR, 95% CI: 1.72, 1.15-2.55) and HDL-C (aHR, 95% CI: 1.74, 1.18-2.58) levels, while low total cholesterol (aHR, 95% CI: 1.43, 0.94-2.19) and HDL-C (aHR, 95% CI: 1.44, 0.95-2.17) levels produced marginal effects without significance. Women with high LDL-C levels more often received a breast cancer diagnosis than those with medium levels (aHR, 95% CI: 1.56, 1.03-2.35). Conclusion: This real-world dataset highlights the importance of balancing lipid profiles, particularly total cholesterol and HDL-C. Dysregulation of the lipid profile, not the glucose or blood pressure profiles, may increase the risk of breast cancer in women with T2DM.

Influence of Frailty and Life Expectancy on Guideline Adherence and Outcomes in Cutaneous Squamous Cell Carcinoma of the Head and Neck: A Prospective Pilot Study.

BACKGROUND: Cutaneous squamous cell carcinoma is the second most common malignancy of the skin, often occurring in older patients and in the head and neck area (cSCCHN). Age, life expectancy, and frailty are not taken into consideration by current guidelines. OBJECTIVES: The objective of this study was to evaluate the influence of frailty and life expectancy on guideline deviation, treatment outcomes, and quality of life (QoL) after treatment in patients with cSCCHN. METHODS: Patients with cSCCHN were prospectively included. A geriatric assessment was performed, including the Geriatric 8 (G8), Groningen Frailty Indicator, and Timed Up and Go test (TUG). The Lee index was used to predict a limited life expectancy, and the Adult Comorbidity Evaluation-27 was used as a comorbidity index. QoL was assessed by the Basal and Squamous cell carcinoma Quality of Life (BaSQoL) questionnaire at three time points. RESULTS: Seventy-seven patients with cSCCHN were included. Frail patients had significantly more high-risk tumours. Guideline deviation occurred in 7.8% and was more common in patients who were frail (G8), with high-risk tumours (≥T2), with a limited life expectancy or an increased TUG. Guideline deviation did not lead more often to progression of disease in our study. No predictors for post-operative complications were found. BaSQoL subscores were very low at each time point and did not change significantly with time in the total group. Frail patients reported more fear of recurrence or new tumours 3 months after treatment, and less concern about other people's skin 6 months after treatment, compared to non-frail patients. Complication rate, gender, or guideline deviation did not affect any subscale scores. CONCLUSIONS: Assessment of frailty and life expectancy can guide physicians and patients in treatment decisions. Deviation from guidelines towards less aggressive treatment schedules can be considered in frail patients with a limited life expectancy, since it did not negatively affect short-term outcomes or QoL in patients with cSCCHN in our study. However, these results should be confirmed by other, larger prospective studies with a longer follow-up period.

The validity of self-reported cancer in a population-based cohort compared to that in formally registered sources.

BACKGROUND: Self-reported cancer has been validated with heterogeneous results across populations. The aim was to assess the validity of self-reported cancer in the Lifelines population-based cohort and to search for explanations for not reporting cancer. METHODS: Data from adult participants (n = 152,780) from Lifelines was linked to the Dutch-Nationwide pathology databank (PALGA), which has nearly 100% coverage of cancer diagnoses in the Netherlands and is considered as the gold standard for ascertainment of cancer diagnosis in this study. Sensitivity and positive predictive value (PPV) for self-reported cancers -reported as hand-written free text- were described. Logistic regressions analyses were performed to evaluate whether socio-demographic factors were associated with the presence of self-reported cancer when there was a diagnosis in PALGA. RESULTS: 6611 (4.50%) participants had at least one self-reported diagnosis of cancer, where 9960 (6.97%) participants had at least one cancer diagnosis in PALGA. The sensitivity of self-reported cancer was 64.68% [95%CI:63.71-65.66], and 70.18% [95%CI:68.83-71.56] after excluding skin and cervical cancers. Skin and cervical cancers represented 61.24% of non-self-reported cancers. The overall PPV was 97.45% [95%CI:97.45-97.81], and 97.33% [95%CI:96.72-97.82] after the exclusion of skin and cervical cancers. Participants who did not self-report their cancer were more likely to be male, had longer time since diagnosis and lower educational level. CONCLUSION: Overall, the reports of cancer in Lifelines have a high positive predictive value and moderate sensitivity. One third of the cancers were not reported, mainly skin and cervical cancers. Male participants, those with a lower educational level and those with longer time since diagnosis were less likely to self-report a diagnosed cancer.

Timely administration of tocilizumab improves outcome of hospitalized COVID-19 patients.

INTRODUCTION: The aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease. METHODS: Open-label randomized phase II clinical trial investigating tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation. RESULTS: A total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39-0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9-28) in the standard arm versus 9 days (IQR 5-14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42-0.98; p = 0.042). CONCLUSIONS: This randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone. TRIAL REGISTRATION: https://www.trialregister.nl/trial/8504.

Sex-Specific Cut-Off Values for Low Skeletal Muscle Mass to Identify Patients at Risk for Treatment-Related Adverse Events in Head and Neck Cancer.

A low skeletal muscle index (SMI), defined with cut-off values, is a promising predictor for adverse events (AEs) in head and neck squamous cell cancer (HNSCC) patients. The aim was to generate sex-specific SMI cut-off values based on AE to diagnose low SMI and to analyse the relationship between low SMI and AEs in HNSCC patients. In this present study, HNSCC patients were prospectively included in a large oncological data-biobank and SMI was retrospectively measured using baseline neck scans. In total, 193 patients were included and were stratified according to treatment modality: (chemo-)radiotherapy ((C)RT) (n = 135) and surgery (n = 61). AE endpoints were based on the occurrence of clinically relevant toxicities (Common Terminology Criteria for Adverse Events grade ≥ III) and postoperative complications (Clavien-Dindo Classification grade ≥ II). Sex-specific SMI cut-off values were generated with receiver operating characteristic curves, based on the AE endpoints. The relationship of the baseline characteristics and AEs was analysed with logistic regression analysis, with AEs as the endpoint. Multivariable logistic analysis showed that low SMI (OR 3.33, 95%CI 1.41-7.85) and tumour stage (OR 3.45, 95%CI 1.28-9.29) were significantly and independently associated to (C)RT toxicity. Low SMI was not related to postoperative complications. To conclude, sex-specific SMI cut-off values, were generated based on the occurrence of AEs. Low SMI and tumour stage were independently related to (C)RT toxicity in HNSCC patients.

CT characteristics of solid pulmonary nodules of never smokers versus smokers: A population-based study.

PURPOSE: Aim was to assess CT characteristics of lung nodules in never and former smokers compared to current smokers in a population-based setting. METHOD: 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. RESULTS: 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). CONCLUSIONS: 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 association of frailty and outcomes of geriatric assessment with acute radiation-induced toxicity in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Geriatric impairments and frailty are highly prevalent in patients with head and neck cancer (HNC). This study investigated the association of frailty and outcomes of geriatric assessment (GA) with radiation-induced toxicity (RIT) in patients undergoing (chemo)radiotherapy ((C)RT) for HNC. MATERIALS AND METHODS: Between October 2014 and April 2016, patients with HNC were prospectively included in OncoLifeS, an institutional data-biobank. Before treatment initiation, patients underwent GA and frailty screening (Groningen Frailty Indicator and Geriatric 8). The main outcome of this study was RIT (weight loss, mucositis, salivary gland inflammation, oral pain, sore throat, hoarseness, dry mouth, dysgeusia, dysphagia and general pain) according to the common terminology criteria of adverse events (CTCAE) version 4.0. Linear mixed models were performed, to analyse factors associated with increasing mean RIT over time during the treatment period. RESULTS: 160 patients were included. 114 (71.3%) were male and the mean age was 66.1 years. Age ≥ 65 (ß = 0.03(95 %CI = 0.01;0.05), p = 0.01), regional RT (ß = 0.05(95 %CI = 0.02;0.09), p = 0.004), and concurrent chemotherapy (ß = 0.04(95 %CI = 0.02;0.07), p = 0.001), were independent factors associated with increasing toxicity during the 7-week treatment period, adjusted for relevant covariates. None of the single items of GA, as well as the frailty screening instruments, were associated with increasing RIT. CONCLUSION: In this study, frailty and GA were not associated with additional RIT during treatment. These results suggest that (C)RT is equally tolerated in frail and non-frail patients, with respect to acute RIT. RT could be a suitable alternative to surgery in selected frail patients.

Association between visual emphysema and lung nodules on low-dose CT scan in a Chinese Lung Cancer Screening Program (Nelcin-B3).

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 mm3) 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 mm3) 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.

Dutch National Round Robin Trial on Plasma-Derived Circulating Cell-Free DNA Extraction Methods Routinely Used in Clinical Pathology for Molecular Tumor Profiling.

BACKGROUND: Efficient recovery of circulating tumor DNA (ctDNA) depends on the quantity and quality of circulating cell-free DNA (ccfDNA). Here, we evaluated whether various ccfDNA extraction methods routinely applied in Dutch laboratories affect ccfDNA yield, ccfDNA integrity, and mutant ctDNA detection, using identical lung cancer patient-derived plasma samples. METHODS: Aliquots of 4 high-volume diagnostic leukapheresis plasma samples and one artificial reference plasma sample with predetermined tumor-derived mutations were distributed among 14 Dutch laboratories. Extractions of ccfDNA were performed according to local routine standard operating procedures and were analyzed at a central reference laboratory for mutant detection and assessment of ccfDNA quantity and integrity. RESULTS: Mutant molecule levels in extracted ccfDNA samples varied considerably between laboratories, but there was no indication of consistent above or below average performance. Compared to silica membrane-based methods, samples extracted with magnetic beads-based kits revealed an overall lower total ccfDNA yield (-29%; P < 0.0001) and recovered fewer mutant molecules (-41%; P < 0.01). The variant allelic frequency and sample integrity were similar. In samples with a higher-than-average total ccfDNA yield, an augmented recovery of mutant molecules was observed. CONCLUSIONS: In the Netherlands, we encountered diversity in preanalytical workflows with potential consequences on mutant ctDNA detection in clinical practice. Silica membrane-based methodologies resulted in the highest total ccfDNA yield and are therefore preferred to detect low copy numbers of relevant mutations. Harmonization of the extraction workflow for accurate quantification and sensitive detection is required to prevent introduction of technical divergence in the preanalytical phase and reduce interlaboratory discrepancies.