Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients - a randomized controlled trial. (OxaNeuro).

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors' quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN. METHODS: The OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months. The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy. DISCUSSION: If readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT05404230 Protocol version: 1.2, April 25th. 2023.

Missingness mechanisms and generalizability of patient reported outcome measures in colorectal cancer survivors - assessing the reasonableness of the "missing completely at random" assumption.

BACKGROUND: Patient-Reported Outcome Measures (PROM) provide important information, however, missing PROM data threaten the interpretability and generalizability of findings by introducing potential bias. This study aims to provide insight into missingness mechanisms and inform future researchers on generalizability and possible methodological solutions to overcome missing PROM data problems during data collection and statistical analyses. METHODS: We identified 10,236 colorectal cancer survivors (CRCs) above 18y, diagnosed between 2014 and 2018 through the Danish Clinical Registries. We invited a random 20% (2,097) to participate in a national survey in May 2023. We distributed reminder e-mails at day 10 and day 20, and compared Initial Responders (response day 0-9), Subsequent Responders (response day 10-28) and Non-responders (no response after 28 days) in demographic and cancer-related characteristics and PROM-scores using linear regression. RESULTS: Of the 2,097 CRCs, 1,188 responded (57%). Of these, 142 (7%) were excluded leaving 1,955 eligible CRCs. 628 (32%) were categorized as initial responders, 418 (21%) as subsequent responders, and 909 (47%) as non-responders. Differences in demographic and cancer-related characteristics between the three groups were minor and PROM-scores only marginally differed between initial and subsequent responders. CONCLUSION: In this study of long-term colorectal cancer survivors, we showed that initial responders, subsequent responders, and non-responders exhibit comparable demographic and cancer-related characteristics. Among respondents, Patient-Reported Outcome Measures were also similar, indicating generalizability. Assuming Patient-Reported Outcome Measures of subsequent responders represent answers by the non-responders (would they be available), it may be reasonable to judge the missingness mechanism as Missing Completely At Random.

Ceramic-on-Ceramic Total Hip Arthroplasty and Noises: A Prospective Blinded Randomized Controlled Trial of Influence of Component Design.

BACKGROUND: Noises have been associated with ceramic-on-ceramic bearings in total hip arthroplasties. The etiology is multifactorial, but a high prevalence of noises was reported in studies using a specific acetabular component system. We examined if specific ceramic component designs are associated with the prevalence of noises in 2 commonly used component systems. We hypothesized that there would be no difference in noises between the 2 systems. METHODS: In this randomized controlled trial, 2 different component designs with ceramic bearings were compared. Inclusion criteria were primary total hip arthroplasties, age between 18 and 65 years, and body mass index less than 35. The primary outcome was prevalence of noises, whereas secondary outcomes consisted of European Quality of Life index, visual analog scale, and University of California and Los Angeles activity scale. Follow-up data were collected at 3 and 12 months postoperatively. Data were available for 91 patients in Group 1 and for 92 patients in Group 2. Preoperative patient characteristics were comparable between groups. RESULTS: At 12-month follow-up, the prevalence of noises was 19% in Group 1 and 14% in Group 2 (P = .41). European Quality of Life index were 0.89 in Group 1 versus 0.90 in Group 2 (P = .42). The visual analog scale was 81 in both groups (P = .88). When evaluating level of activity, University of California and Los Angeles activity scale scores were 8.2 in both groups (P = .92). CONCLUSION: At 12-month follow-up, there was no difference in the prevalence of noises between the 2 component designs.

Metabolic Syndrome and Morbid Obesity are Not Risk Factors for Revision Surgery in Patients Undergoing Hip and Knee Arthroplasty.

BACKGROUND: The effect of metabolic syndrome (MetS) on the risk of revision after hip and knee arthroplasty is debated. The aim of our study was to investigate the risk of short-term (minimum 2.7 years) revision due to periprosthetic joint infection (PJI) after hip and knee arthroplasty. Secondly, we aimed to investigate the risk of revision due to any cause and mortality. METHODS: During May 2017 to November 2019, a cohort of 2,901 patients undergoing a total of 3,024 hip and knee arthroplasties was established. In the cohort, 62.1% met the criteria for MetS. Data from national registries and a local database were used to determine the presence of MetS and revision surgeries, with a follow-up of at least two years and eight months. Cox regression was applied to the present hazard ratio (HR), associated 95% confidence intervals, and P values. Survival analyses were presented in a Kaplan-Meier plot. RESULTS: The risk of PJI (HR 1.6 (0.5 to 4.9), P = .380), any revision (HR 0.8 (0.4 to 1.3), P = .295), and death (HR 1.3 (0.8 to 2.1), P = .282) was not increased in patients suffering from MetS compared with patients who did not have MetS. There was no PJI in patients not having MetS and receiving a knee arthroplasty. The risk of death was increased in the MetS group receiving a knee arthroplasty (HR 2.7 (1.3 to 5.9), P = .010), but not different from the MetS group receiving a hip arthroplasty. There was no elevated risk of PJI when analyzing morbid obesity (body mass index over 40), men, or diabetes as the exposures. CONCLUSIONS: Patients suffering from MetS do not have an increased risk of revision caused by PJI. In general, performing hip and knee arthroplasty in patients suffering from MetS is without increased risk of revision surgery.

Validity and screening capacity of the FCR-1r for fear of cancer recurrence in long-term colorectal cancer survivors.

PURPOSE: Existing fear of cancer recurrence (FCR) screening measures is being shortened to facilitate clinical use. This study aimed to evaluate the validity and screening capacity of a single-item FCR screening measure (FCR-1r) in long-term colorectal cancer (CRC) survivors with no recurrence and assess whether it performs as well in older as in younger survivors. METHODS: All Danish CRC survivors above 18, diagnosed and treated with curative intent between 2014 and 2018, were located through a national patient registry. A questionnaire including the FCR-1r, which measures FCR on a 0-10 visual analog scale, alongside the validated Fear of Cancer Recurrence Inventory Short Form (FCRI-SF) as a reference standard was distributed between November 2021 and May 2023. Screening capacity and cut-offs were evaluated with a receiver-operating characteristic analysis (ROC) in older (≥ 65 years) compared to younger (< 65 years) CRC survivors. Hypotheses regarding associations with other psychological variables were tested as indicators of convergent and divergent validity. RESULTS: Of the CRC survivors, 2,128/4,483 (47.5%) responded; 1,654 (36.9%) questionnaires were eligible for analyses (median age 76 (range 38-98), 47% female). Of the responders, 85.2% were aged ≥ 65. Ninety-two participants (5.6%) reported FCRI-SF scores ≥ 22 indicating clinically significant FCR. A FCR-1r cut-off ≥ 5/10 had 93.5% sensitivity and 80.4% specificity for detecting clinically significant FCR (AUC = 0.93, 95% CI 0.91-0.94) in the overall sample. The discrimination ability was significantly better in older (AUC = 0.93, 95% CI 0.91-0.95) compared to younger (0.87, 95% (0.82-0.92), p = 0.04) CRC survivors. The FCR-1r demonstrated concurrent validity against the FCRI-SF (r = 0.71, p < 0.0001) and convergent validity against the short-versions of the Symptom Checklist-90-R subscales for anxiety (r = 0.38, p < 0.0001), depression (r = 0.27, p < 0.0001), and emotional distress (r = 0.37, p < 0.0001). The FCR-1r correlated weakly with employment status (r = - 0.09, p < 0.0001) and not with marital status (r = 0.01, p = 0.66) indicating divergent validity. CONCLUSIONS: The FCR-1r is a valid tool for FCR screening in CRC survivors with excellent ability to discriminate between clinical and non-clinical FCR, particularly in older CRC survivors.

The effect of farming environment on asthma; time dependent or universal?

The increasing prevalence of asthma is linked to westernization and urbanization. Farm environments have been associated with a lower risk of asthma development. However, this may not be universal, as the association differs across birth cohorts and farming methods. The aim of this study was to investigate the associations of farm upbringing with asthma in different generations and at different times in history. The study population consisted of three generations: 13,868 subjects participating in the ECRHS in 2010, their 9,638 parents, and their 8,885 offspring participating in RHINESSA in 2013. Information on place of upbringing and self-reported ever asthma was provided via questionnaires. Logistic regression was performed including subgroup analysis stratified by generation and birthyear into ten-year-intervals. The prevalence of asthma increased from 8% among grandparents to 13% among parents and to 18% among offspring. An overall analysis showed an inverse association of farm upbringing on the risk of asthma (OR = 0.64; 95%CI 0.55-0.74). Subgroup analysis stratified into ten-year-intervals showed a tendency towards a more pronounced inverse association between growing up on a farm and asthma among subjects born in the 1940s (0.74; 0.48-1.12), 1950s (0.70; 0.54-0.90) and 1960s (0.70; 0.52-0.93). For subjects born in 1970 and thereafter this association appeared less consistent. While growing up on a farm was associated with a reduced risk of developing asthma in participants born between 1945-1999, this was mainly driven by generations born from 1945 to 1973.

The impact of COVID-19 lockdown on glycaemic control and use of health services among children followed at a Danish diabetes clinic.

AIM: During COVID-19 restrictions, the paediatric clinic only accepted essential outpatient visits, schools closed, sports activities and social life were limited. Most employees worked at home. This quasi-experiment evaluates how this affected glycaemic control and use of health services among children with diabetes. METHODS: Paired t-tests were used to compare HbA1c-values before, during and after lockdown. Sub-analyses were stratified by pre-lockdown HbA1c-values. RESULTS: Overall mean HbA1c decreased from 58.3 to 56.9 mmol/mol (p = 0.025) from pre- to post-lockdown, a decrease also seen during the same season the previous year. HbA1c decreased by -4.2 mmol/mol (p = 0.002) for patients with pre-lockdown HbA1c > 59 mmol/mol, but increased slightly by 0.8 mmol/mol (p = 0.176) for patients with HbA1c < 52 mmol/mol. HbA1c measured 8 months post-lockdown increased again, most pronounced for patients with lowest HbA1c. During lockdown, virtual contacts increased from 0.1 to 0.5 contacts/patient/month and stayed post-lockdown at 0.3 contacts/patient/month. CONCLUSION: Compared to 2019, overall the COVID-19 restrictions did not influence the glycaemic control negatively. However, patients with pre-lockdown HbA1c < 52 mmol/mol experienced a deterioration, whereas those with HbA1c > 59 mmol/mol experienced an improvement. Less stress and more contact with parents may contribute to the last-mentioned finding. The lockdown enforced more virtual contacts between patients and the clinic.

Asthma and selective migration from farming environments in a three-generation cohort study.

Individuals raised on a farm appear to have less asthma than individual raised elsewhere. However, selective migration might contribute to this as may also the suggested protection from farm environment. This study investigated if parents with asthma are less likely to raise their children on a farm. This study involved three generations: 6045 participants in ECRHS/RHINE cohorts (born 1945-1973, denoted G1), their 10,121 parents (denoted G0) and their 8260 offspring participating in RHINESSA (born 1963-1998, denoted G2). G2-offspring provided information on parents not participating in ECRHS/RHINE. Asthma status and place of upbringing for all three generations were reported in questionnaires by G1 in 2010-2012 and by G2 in 2013-2016. Binary regressions with farm upbringing as outcome were performed to explore associations between parental asthma and offspring farm upbringing in G0-G1 and G1-G2. Having at least one parent with asthma was not associated with offspring farm upbringing, either in G1-G2 (RR 1.11, 95% CI 0.81-1.52) or in G0-G1 (RR 0.99, 0.85-1.15). G1 parents with asthma born in a city tended to move and raise their G2 offspring on a farm (RR 2.00, 1.12-3.55), while G1 parents with asthma born on a farm were less likely to raise their G2 offspring on a farm (RR 0.34, 0.11-1.06). This pattern was not observed in analyses of G0-G1. This study suggests that the protective effect from farm upbringing on subsequent asthma development could not be explained by selective migration. Intriguingly, asthmatic parents appeared to change environment when having children.

Agreement in reporting of asthma by parents or offspring - the RHINESSA generation study.

BACKGROUND: Self-report questionnaires are commonly used in epidemiology, but may be susceptible to misclassification, especially if answers are given on behalf of others, e.g. children or parents. The aim was to determine agreement and analyse predictors of disagreement in parents' reports of offspring asthma, and in offspring reports of parents' asthma. METHODS: In the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study, 6752 offspring (age range 18-51 years) and their parents (age range 39-66 years) reported their own and each other's asthma status. Agreement between asthma reports from offspring and parents was determined by calculating sensitivity, specificity, positive and negative predictive value and Cohen's kappa. The participants' own answers regarding themselves were defined as the gold standard. To investigate predictors for disagreement logistic regression analyses were performed to obtain odds ratios (OR) with 95% confidence intervals (CI) for sex, smoking status, education, comorbidity and severity of asthma. RESULTS: Agreement was good for parental report of offspring early onset asthma (< 10 years, Cohen's kappa 0.72) and moderate for offspring later onset asthma (Cohen's kappa 0.46). Specificity was 0.99 for both, and sensitivity was 0.68 and 0.36, respectively. For offspring report of maternal and paternal asthma the agreement was good (Cohen's kappa 0.69 and 0.68), specificity was 0.96 and 0.97, and sensitivity was 0.72 and 0.68, respectively. The positive predictive value (PPV) was lowest for offspring report of maternal asthma (0.75), and highest for parents' report of early onset asthma in the offspring (0.83). The negative predictive value (NPV) was high for all four groups (0.94-0.97). In multivariate analyses current smokers (OR = 1.46 [95% CI 1.05, 2.02]) and fathers (OR = 1.31 [95% CI 1.08, 1.59]) were more likely to report offspring asthma incorrectly. Offspring wheeze was associated with reporting parental asthma incorrectly (OR = 1.60 [95% CI 1.21, 2.11]), both under- and over reporting. CONCLUSIONS: Asthma reports across generations show moderate to good agreement, making information from other generations a useful tool in the absence of direct reports.

Place of upbringing in early childhood as related to inflammatory bowel diseases in adulthood: a population-based cohort study in Northern Europe.

BACKGROUND: The two inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease, has increased rapidly during the twentieth century, but the aetiology is still poorly understood. Impaired immunological competence due to decreasing biodiversity and altered microbial stimulation is a suggested explanation. OBJECTIVE: Place of upbringing was used as a proxy for the level and diversity of microbial stimulation to investigate the effects on the prevalence of IBD in adulthood. METHODS: Respiratory Health in Northern Europe (RHINE) III is a postal follow-up questionnaire of the European Community Respiratory Health Survey (ECRHS) cohorts established in 1989-1992. The study population was 10,864 subjects born 1945-1971 in Denmark, Norway, Sweden, Iceland and Estonia, who responded to questionnaires in 2000-2002 and 2010-2012. Data were analysed in logistic and Cox regression models taking age, sex, smoking and body mass index into consideration. RESULTS: Being born and raised on a livestock farm the first 5 years of life was associated with a lower risk of IBD compared to city living in logistic (OR 0.54, 95 % CI 0.31; 0.94) and Cox regression models (HR 0.55, 95 % CI 0.31; 0.98). Random-effect meta-analysis did not identify geographical difference in this association. Furthermore, there was a significant trend comparing livestock farm living, village and city living (p < 0.01). Sub-analyses showed that the protective effect was only present among subjects born after 1952 (OR 0.25, 95 % CI 0.11; 0.61). CONCLUSION: This study suggests a protective effect from livestock farm living in early childhood on the occurrence of IBD in adulthood, however only among subjects born after 1952. We speculate that lower microbial diversity is an explanation for the findings.

Immunohistochemical analysis of tumor budding in stage II colon cancer: exploring zero budding as a prognostic marker.

Tumor budding, a biomarker traditionally evaluated using hematoxylin and eosin (H&E) staining, has gained recognition as a prognostic biomarker for stage II colon cancer. Nevertheless, while H&E staining offers valuable insights, its limitations prompt the utilization of pan-cytokeratin immunohistochemistry (IHC). Consequently, this study seeks to evaluate the prognostic significance of tumor budding using IHC in a contemporary cohort of stage II colon cancer patients, aiming to deepen our understanding of this critical facet in cancer prognosis. We conducted a retrospective, population-based cohort study including 493 patients with stage II colon cancer and evaluated tumor budding using IHC, following the H&E-based guidelines proposed by the International Tumor Budding Consensus Conference Group. Correlation between H&E-based and IHC-based tumor budding was assessed using a four-tiered scoring system that included a zero budding (Bd0) category. Survival analyses explored the prognostic significance of tumor budding assessed by IHC and H&E. As expected, IHC-based tumor budding evaluation yielded significantly higher bud counts compared to H&E (p < 0.01). Interestingly, 21 patients were identified with no tumor budding using IHC. This was associated with significantly improved recurrence-free survival (HR = 5.19, p = 0.02) and overall survival (HR = 4.47, p = 0.04) in a multivariate analysis when compared to tumors with budding. The Bd0 category demonstrated a 100% predictive value for the absence of recurrence. In conclusion, IHC-based tumor budding evaluation in stage II colon cancer provides additional prognostic information. The absence of tumor budding is associated with a favorable prognosis and may serve as a potential marker for identifying patients with no risk of recurrence.

The prognostic value of tumor budding in a thoroughly characterized stage II colon cancer population in the context of a national screening program.

Tumor budding as a prognostic marker in colorectal cancer has not previously been investigated in a cohort of screened stage II colon cancer patients. We assessed the prognostic significance of tumor budding in a thoroughly characterized stage II colon cancer population comprising surgically resected patients in the Region of Southern Denmark from 2014 to 2016. Tumors were re-staged according to the 8th edition of UICC TNM Classification, undergoing detailed histopathological evaluation and tumor budding assessment following guidelines from the International Tumor Budding Consensus Conference. Prognostic evaluation utilized Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models for time to recurrence (TTR), recurrence-free survival (RFS), and overall survival (OS). Out of 497 patients, 20% were diagnosed through the national colorectal cancer screening program. High-grade tumor budding (Bd3) was found in 19% of tumors and was associated with glandular subtype, perineural invasion, mismatch repair proficient tumors, and tumor recurrence (p < 0.001, p < 0.001, p = 0.045, and p = 0.007 respectively). In multivariable Cox regression, high-grade budding was a significant prognostic factor for TTR compared to low-grade (Bd3 HR 2.617; p = 0.007). An association between tumor budding groups and RFS was observed, and the difference was significant in univariable analysis for high-grade compared to low-grade tumor budding (Bd3 HR 1.461; p = 0.041). No significant differences were observed between tumor budding groups and OS. High-grade tumor budding is a predictor of recurrence in a screened population of patients with stage II colon cancer and should be considered a high-risk factor in a shared decision-making process when stratifying patients to adjuvant chemotherapy.

Methylated Cell-Free Tumor DNA in Sputum as a Tool for Diagnosing Lung Cancer-A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related mortality worldwide. Early diagnosis is pivotal for the prognosis. There is a notable overlap between lung cancer and chronic bronchitis, and the potential use of methylated tumor DNA in sputum as a biomarker for lung cancer detection is appealing. This systematic review and meta-analysis followed the PRISMA 2020 statement. A comprehensive search was conducted in Embase, Medline, Web of Science, and the Cochrane Library, using these search strings: Lung cancer, sputum, and methylated tumor DNA. A total of 15 studies met the eligibility criteria. Studies predominantly utilized a case-control design, with sensitivity ranging from 10 to 93% and specificity from 8 to 100%. A meta-analysis of all genes across studies resulted in a summary sensitivity of 54.3% (95% CI 49.4-59.2%) and specificity of 79.7% (95% CI 75.0-83.7%). Notably, two less explored genes (TAC1, SOX17) demonstrated sensitivity levels surpassing 85%. The study's findings highlight substantial variations in the sensitivity and specificity of methylated tumor DNA in sputum for lung cancer detection. Challenges in reproducibility could stem from differences in tumor site, sample acquisition, extraction methods, and methylation measurement techniques. This meta-analysis provides a foundation for prioritizing high-performing genes, calling for a standardization and refinement of methodologies before potential application in clinical trials.

Shared decision making with breast cancer patients - does it work? Results of the cluster-randomized, multicenter DBCG RT SDM trial.

BACKGROUND AND PURPOSE: Shared decision making (SDM) is a patient engaging process advocated especially for preference-sensitive decisions, such as adjuvant treatment after breast cancer. An increasing call for patient engagement in decision making highlights the need for a systematic SDM approach. The objective of this trial was to investigate whether the Decision Helper (DH), an in-consultation patient decision aid, increases patient engagement in decisions regarding adjuvant whole breast irradiation. MATERIAL AND METHODS: Oncologists at four radiotherapy units were randomized to practice SDM using the DH versus usual practice. Patient candidates for adjuvant whole breast irradiation after breast conserving surgery for node-negative breast cancer were eligible. The primary endpoint was patient-reported engagement in the decision process assessed with the Shared Decision Making Questionnaire (SDM-Q-9) (range 0-100, 4 points difference considered clinical relevant). Other endpoints included oncologist-reported patient engagement, decisional conflict, fear of cancer recurrence, and decision regret after 6 months. RESULTS: Of the 674 included patients, 635 (94.2%) completed the SDM-Q-9. Patients in the intervention group reported higher level of engagement (median 80; IQR 68.9 to 94.4) than the control group (71.1; IQR 55.6 to 82.2; p < 0.0001). Oncologist-reported patient engagement was higher in the invention group (93.3; IQR 82.2 to 100) compared to control group (73.3; IQR 60.0 to 84.4) (p < 0.0001). CONCLUSION: Patient engagement in medical decision making was significantly improved with the use of an in-consultation patient decision aid compared to standard. The DH on adjuvant whole breast irradiation is now recommended as standard of care in the Danish guideline.

Methylated Circulating Tumor DNA in Blood as a Tool for Diagnosing Lung Cancer: A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related deaths, and early detection is crucial for improving patient outcomes. Current screening methods using computed tomography have limitations, prompting interest in non-invasive diagnostic tools such as methylated circulating tumor DNA (ctDNA). The PRISMA guidelines for systematic reviews were followed. The electronic databases MEDLINE, Embase, Web of Science, and Cochrane Library were systematically searched for articles. The search string contained three main topics: Lung cancer, blood, and methylated ctDNA. The extraction of data and quality assessment were carried out independently by the reviewers. In total, 33 studies were eligible for inclusion in this systematic review and meta-analysis. The most frequently studied genes were SHOX2, RASSF1A, and APC. The sensitivity and specificity of methylated ctDNA varied across studies, with a summary sensitivity estimate of 46.9% and a summary specificity estimate of 92.9%. The area under the hierarchical summary receiver operating characteristics curve was 0.81. The included studies were generally of acceptable quality, although they lacked information in certain areas. The risk of publication bias was not significant. Based on the findings, methylated ctDNA in blood shows potential as a rule-in tool for lung cancer diagnosis but requires further research, possibly in combination with other biomarkers.

Phase II trial of delta-tocotrienol in neoadjuvant breast cancer with evaluation of treatment response using ctDNA.

Neoadjuvant treatment of breast cancer is applied to an increasing extent, but treatment response varies and side effects pose a challenge. The vitamin E isoform delta-tocotrienol might enhance the efficacy of chemotherapy and reduce the risk of side effects. The aim of this study was to investigate the clinical effect of delta-tocotrienol combined with standard neoadjuvant treatment and the possible association between detectable circulating tumor DNA (ctDNA) during and after neoadjuvant treatment with pathological treatment response. This open-label, randomized phase II trial included 80 women with newly diagnosed, histologically verified breast cancer randomized to standard neoadjuvant treatment alone or in combination with delta-tocotrienol. There was no difference in the response rate or frequency of serious adverse events between the two arms. We developed a multiplex digital droplet polymerase chain reaction (ddPCR) assay for the detection of ctDNA in breast cancer patients that targets a combination of two methylations specific for breast tissue (LMX1B and ZNF296) and one cancer specific methylation (HOXA9). The sensitivity of the assay increased when the cancer specific marker was combined with the ones specific to breast tissue (p < 0.001). The results did not show any association between ctDNA status and pathological treatment response, neither at midterm nor before surgery.

Disease-Specific Anxiety in Chronic Obstructive Pulmonary Disease: Translation and Initial Validation of a Questionnaire.

Background: Commonly applied measures of symptoms of anxiety are not sensitive to disease-specific anxiety in patients with chronic obstructive pulmonary disease (COPD). There is a need for validated instruments measuring COPD-specific anxiety. Therefore, we translated the COPD-Anxiety Questionnaire (CAF) into Danish (CAF-R-DK) and performed an initial validation of the psychometric properties in a sample of patients with COPD. Materials and Methods: Translation procedures followed the World Health Organization guidelines. Participants with COPD completed questionnaires measuring COPD-specific anxiety (CAF-R-DK), general psychological distress (Hospital Anxiety and Depression Scale) as well as variables related to COPD (COPD Assessment Test; modified Medical Research Council dyspnea scale), quality of life (the 12-item Short Form survey, SF12), and socio-demography. Results: A total of 260 patients with COPD (mean age: 65.0, 69% female) completed questionnaires. The Danish version of CAF-R-DK demonstrated acceptable Cronbach's α values that were comparable with those of the original CAF. As expected, the CAF-R-DK showed positive correlations with convergent constructs (CAT; HADS) and negative correlations with discriminant constructs (SF-12). However, the results for specific subdomains of the CAF-R-DK indicated inconsistency in the underlying concept of disease-specific anxiety, which was also suggested based on the subsequent confirmatory and exploratory factor analyzes. Conclusion: The CAF could serve as an important supplement to generic psychological distress screening of patients with COPD in somatic health care settings, and the questionnaire is now available in Danish. Translation into other languages is needed with the purpose of obtaining data for further testing the psychometric properties of the questionnaire.

Diffusion-Weighted MRI in Patients with Testicular Tumors-Intra- and Interobserver Variability.

In general, magnetic resonance (MR) diffusion-weighted imaging (DWI) has shown potential in clinical settings. In testicles parenchyma, the DW imaging helps differentiate and characterize benign from malignant lesions. Placement and size of the region of interest (ROI) may affect the ADC value. Therefore, the aim of this study was to investigate the intra- and interobserver variability in testicular tumors when measuring ADC using various types of regions of interest (ROI). Two observers performed the ADC measurements in testicular lesions based on three ROI methods: (1) whole volume, (2) round, and (3) small sample groups. Intra- and interobserver variability was analyzed for all ROI methods using intraclass correlation coefficients (ICC) and bland-altman plots. The two observers performed the measurements twice, three months apart. A total of 26 malignant testicle tumors were included. Interobserver agreement was excellent in tumor length (ICC = 0.98) and tumor width (ICC = 0.98). In addition, intraobserver agreement was excellent in tumor length (ICC = 0.98) and tumor width (ICC = 0.99). The whole volume interobserver agreement in the first reading was excellent (ICC = 0.93). Round ADC had an excellent (ICC = 0.93) and fair (ICC = 0.58) interobserver agreement, in the first and second reading, respectively. Interobserver agreement in ADC small ROIs was good (ICC = 0.87), and good (ICC = 0.78), in the first and second reading, respectively. Intraobserver agreement varied from fair, good to excellent agreement. The ROI method showed varying inter- and intraobserver agreement in ADC measurement. Using multiple small ROI conceded the highest interobserver variability, and, thus, the whole volume or round seem to be the preferable methods.

Cohort profile: the multigeneration Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) cohort.

PURPOSE: The Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) cohort was established to (1) investigate how exposures before conception and in previous generations influence health and disease, particularly allergies and respiratory health, (2) identify susceptible time windows and (3) explore underlying mechanisms. The ultimate aim is to facilitate efficient intervention strategies targeting multiple generations. PARTICIPANTS: RHINESSA includes study participants of multiple generations from ten study centres in Norway (1), Denmark (1), Sweden (3), Iceland (1), Estonia (1), Spain (2) and Australia (1). The RHINESSA core cohort, adult offspring generation 3 (G3), was first investigated in 2014-17 in a questionnaire study (N=8818, age 18-53 years) and a clinical study (subsample, n=1405). Their G2 parents participated in the population-based cohorts, European Community Respiratory Heath Survey and Respiratory Health In Northern Europe, followed since the early 1990s when they were 20-44 years old, at 8-10 years intervals. Study protocols are harmonised across generations. FINDINGS TO DATE: Collected data include spirometry, skin prick tests, exhaled nitric oxide, anthropometrics, bioimpedance, blood pressure; questionnaire/interview data on respiratory/general/reproductive health, indoor/outdoor environment, smoking, occupation, general characteristics and lifestyle; biobanked blood, urine, gingival fluid, skin swabs; measured specific and total IgE, DNA methylation, sex hormones and oral microbiome. Research results suggest that parental environment years before conception, in particular, father's exposures such as smoking and overweight, may be of key importance for asthma and lung function, and that there is an important susceptibility window in male prepuberty. Statistical analyses developed to approach causal inference suggest that these associations may be causal. DNA methylation studies suggest a mechanism for transfer of father's exposures to offspring health and disease through impact on offspring DNA methylation. FUTURE PLANS: Follow-up is planned at 5-8 years intervals, first in 2021-2023. Linkage with health registries contributes to follow-up of the cohort.