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Irritable bowel syndrome (IBS) is a prevalent health challenge in a Danish welfare context. Drawing on ethnographic fieldwork at two Danish gastroenterology clinics, and inspired by Charles E. Rosenberg's idea of styles of explaining widespread diseases, we outline three styles of understanding and treating gut trouble in daily clinical work: "The microbial gut," "the mindful gut," and "the lifestyled gut." Moreover, we suggest the concept of fluidity to characterize IBS as a diagnostic category that allows clinicians and patients to operate through complex understandings of permeable boundaries between body, mind, and environment to negotiate personalized solutions for embodied gut sensations. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is one of the deadliest cancers worldwide, and the prognosis is poor. The disease is potentially curable if detected at an early stage, but currently, the only widely implemented screening tool is low-dose computed tomography. Biomarkers such as methylated tumor DNA may be used for the early detection of lung cancer, and sputum is an appealing, non-invasive sample type. With this systematic review and meta-analysis, we aimed to identify all studies evaluating the quantitative methylation of tumor DNA in sputum samples for lung cancer detection. A systematic overview of all the available evidence may highlight areas of improvement as well as certain high-performing genes to prioritize in future studies. 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. [ABSTRACT FROM AUTHOR]

Patients with detectable ctDNA after radical-intent treatment of metastatic spread from colorectal cancer (mCRC) have a very high risk of recurrence, which may be prevented with intensified adjuvant chemotherapy (aCTh). In the OPTIMISE study, we investigate ctDNA-guided aCTh after radical-intent treatment of mCRC. Here we present results from the preplanned interim analysis. The study is an open-label 1:1 randomized clinical trial comparing ctDNA-guided aCTh against standard of care (SOC), with a run-in phase investigating feasibility measures. Key inclusion criteria; radical-intent treatment for mCRC and clinically eligible for triple-agent chemotherapy. Patients underwent a PET-CT scan before randomization. ctDNA analyses of plasma samples were done by ddPCR, detecting CRC-specific mutations and methylation of the NPY gene. In the ctDNA-guided arm, ctDNA positivity led to an escalation strategy with triple-agent chemotherapy, and conversely ctDNA negativity led to a de-escalation strategy by shared-decision making. Patients randomized to the standard arm were treated according to SOC. Feasibility measures for the run-in phase were; the inclusion of 30 patients over 12 months in two Danish hospitals, compliance with randomization >80%, rate of PET-CT-positive findings <20%, and eligibility for triple-agent chemotherapy >80%. Thirty-two patients were included. The rate of PET-CT-positive cases was 22% (n = 7/32). Ninety-seven percent of the patients were randomized. Fourteen patients were randomly assigned to SOC and sixteen to ctDNA-guided adjuvant treatment and follow-up. All analyses of baseline plasma samples in the ctDNA-guided arm passed the quality control, and 19% were ctDNA positive. The median time to result was three working days. All ctDNA-positive patients were eligible for triple-agent chemotherapy. The study was proven to be feasible and continues in the planned large-scale phase II trial. Results from the OPTIMISE study will potentially optimize the adjuvant treatment of patients undergoing radical-intent treatment of mCRC, thereby improving survival and reducing chemotherapy-related toxicity. [ABSTRACT FROM AUTHOR]

Aim: Clinical utility of the dynamics of ctDNA is sparse. This study aimed at evaluating the prognostic impact of early ctDNA dynamics in patients with metastatic cancer treated with chemotherapy. Materials & methods: The ctDNA dynamics were evaluated in 595 patients with metastatic cancer using droplet digital PCR. Results: Patients with an increase in ctDNA after one treatment cycle (n = 73; 12.2%) had an overall survival of 5.6 months compared with 8.6 months in patients with stable or decreasing ctDNA (n = 328; 55.1%) and 21.0 months in patients with undetectable ctDNA (p < 0.001; hazard ratio: 0.47; 95% CI: 0.41–0.53). Conclusion: Early ctDNA dynamics hold important prognostic information and have great implications for evaluation with the perspective of a more individualized treatment strategy. [ABSTRACT FROM AUTHOR]

This explorative prospective observational pilot study investigated if suggested risk factors, rectal cancer and lung metastases, could add to a relevant detection rate of asymptomatic brain metastases (BM) from colorectal cancer (CRC). Secondary, prognostic biological aspects were investigated by translational analysis of plasma samples. The study enrolled patients with rectal cancer and lung metastases. At inclusion, patients underwent a standard MRI scan of the brain. Cell-free DNA (cfDNA) level was measured by a direct fluorescence assay (DFA), and circulating tumor DNA (ctDNA) by ddPCR. BM was detected in one of twenty-nine included patients. Patients had higher cfDNA levels than healthy subjects (p < 0.01). Patients with the primary tumor in situ had higher cfDNA levels than those with resected primary tumor (p < 0.01). Patients with liver involvement had higher cfDNA levels (p = 0.12) and circulating tumor DNA levels (p = 0.01) than those without liver involvement. In conclusion, the modest incidence of BM does not justify routine MRI of the brain in this selected population. cfDNA by DFA could be a valuable tool when planning treatment and follow-up for CRC patients. Future studies should focus on identifying further characteristics and biomarkers associated with a high risk of BM, enhancing the possibility for early intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is the leading cause of cancer-related deaths and has a poor prognosis. Early detection could improve survival for this large patient group. Certain genes are more frequently changed by methylation in cancer cells compared to healthy cells. This methylated tumor DNA is present in the blood in small quantities and has been suggested as a diagnostic biomarker in many diseases, including lung cancer. The aim of the present literature review was to identify and collate the current evidence on methylated circulating tumor DNA in blood samples as a diagnostic tool for lung cancer. A systematic collection and presentation of the existing evidence will aid future research in this field. 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. [ABSTRACT FROM AUTHOR]

Background: PD-1/PD-L1 inhibitors have improved survival for patients with non-small cell lung cancer (NSCLC). We evaluated natural killer cell activity (NKA) and methylated HOXA9 circulating tumor DNA (ctDNA) as prognostic biomarkers in NSCLC patients treated with PD-1/PD-L1 inhibitors. Methods: Plasma was prospectively collected from 71 NSCLC patients before treatment with PD-1/PD-L1 inhibitors and before cycles 2–4. We used the NK Vue® assay to measure the level of interferon gamma (IFNγ) as a surrogate for NKA. Methylated HOXA9 was measured by droplet digital PCR. Results: A score combining NKA and ctDNA status measured after one treatment cycle had a strong prognostic impact. Group 1 had IFNγ < 250 pg/ml and detectable ctDNA (n = 27), group 2 consisted of patients with either low levels of IFNγ and undetectable ctDNA or high levels of IFNγ and detectable ctDNA (n = 29), group 3 had IFNγ ≥250 pg/ml and undetectable ctDNA (n = 15). Median OS was 221 days (95% CI 121–539 days), 419 days (95% CI 235–650 days), and 1158 days (95% CI 250 days—not reached), respectively (P = 0.002). Group 1 had a poor prognosis with a hazard ratio of 5.560 (95% CI 2.359–13.101, n = 71, P < 0.001) adjusting for PD-L1 status, histology, and performance status. Conclusions: Combining NKA and ctDNA status after one cycle of treatment was prognostic in patients with NSCLC treated with PD-1/PD-L1 inhibitors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The dietary vitamin D intake of the Danish population is low, and food fortification is a strategy to increase intake. This paper explores the possibility of vitamin D fortification on the current population food intake in Denmark, such that the population receives adequate amounts of vitamin D without having to change current dietary patterns. A mixed-integer programming approach is used to arrive at a solution for the optimal fortification required at each food group level so that the majority of the population receive the minimum intake of average requirement (AR) and do not exceed the tolerable upper intake level (UL). The method shows a significant increase in vitamin D intake compared to the current scenario, keeping a neutral approach towards preferences of one food group over others. The method can also be fine-tuned in different scenarios where certain food group preferences are known, which can be encoded into the model in the form of constraints. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is an urgent need for early detection of lung cancer. Screening with low-dose computed tomography (LDCT) is now implemented in the US. Supplementary use of a lung cancer biomarker with high specificity is desirable. OBJECTIVE: To assess the diagnostic properties of a biomarker panel consisting of cytokeratin 19 fragment (CYFRA 21-1), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125). METHODS: A cohort of 250 high-risk patients was investigated on suspicion of lung cancer. Ahead of diagnostic work-up, blood samples taken. Cross-validated prediction models were computed to assess lung cancer detection properties. RESULTS: In total 32% (79/250) of patients were diagnosed with lung cancer. Area under the curve (AUC) for the three biomarkers was of 0.795, with sensitivity/specificity of 57%/93% and negative predictive value of 83%. When combining the biomarkers with US screening criteria, the AUC was 0.809, while applying only US screening criteria on the cohort, yielded an AUC of 0.62. The ability of the biomarkers to detect stage I-II lung cancer was substantially lower; AUC 0.54. CONCLUSIONS: In a high-risk cohort, the detection properties of the three biomarkers were acceptable compared to current LDCT screening criteria. However, the ability to detect early stage lung cancer was low. [ABSTRACT FROM AUTHOR]

Food fortification is a strategy to increase low vitamin D intake. In order to avoid the intake of a population exceeding the upper tolerable intake level, the right choice of food groups to fortify is of crucial importance. An automated fortification tool was developed based on dietary intake data from the Danish National Survey of Dietary Habits and Physical Activity 2011–2013 (DANSDA), taking into account the energy contribution of the fortified food. The fortification of food group is a variant in the linear modelling, where the optimization ensures the lowest possible variation in deviation of the calculated intake and the target intake. The resulting tool demonstrated that the lowest limit of fortification, where the model works, is 12 µg/10 MJ, when fortification of any food group is allowed. The tool also demonstrated that, by increasing the allowed upper level of fortification from 12 µg/10 MJ up to 30 µg/10 MJ, the food groups selected for fortification and the level of fortification in those food groups may change. Specifically, fewer food groups seem to be needed as the upper level of fortification is increased. The optimized scenarios, using the food groups, including milk, cheese, cereals, fats, and juice, were tested on dietary-survey data and demonstrated that all the projected scenarios manage to lift the median vitamin D intake to the targeted intake safely. A data-driven approach was used to develop a simple, fast, and automated fortification tool to test different vitamin D food fortification strategies. [ABSTRACT FROM AUTHOR]

Purpose: Chronic, abdominal pain remains a problem in a subset of patients after cholecystectomy. The cause is often obscure but central sensitization may be an important component and could theoretically be mediated by spinal PGE2, which is regulated by several cytokines. The aim of the study was to examine cerebrospinal fluid (CSF) of participants with post cholecystectomy syndrome and healthy volunteers for signs of PGE2 and cytokine mediated central sensitization. Patients and Methods: In phase 1 of the study, 83 subjects were included for DNA analysis, eight of these subjects with post cholecystectomy syndrome. We examined the SNPs rs5275, rs16944 and rs1800795 from the Cox-2, IL-1β and IL-6 genes respectively. In phase 2 of the study, we examined concentrations of PGE2-metabolite (PGEM), IL-1β and IL-6 in CSF and plasma from 6 patients with post cholecystectomy syndrome and visceral hyperalgesia and 11 pain free volunteers. Results: We found a significant difference in distribution of the rs5275 SNP of the Cox-2 enzyme (CT-genotype=88% in pain group, 45% in pain free group, TT-genotype=0 in pain group, 41% in pain free group, p=0.05) but not in the other SNPs. PGEM, but not IL-6, was significantly elevated in CSF of the pain group (3.6 pg/mL, sd=1.9 vs 2.1 pg/mL, p=0.03), IL-1β was undetectable. Conclusion: We found elevated PGEM levels in CSF of patients with post cholecystectomy syndrome and visceral hyperalgesia, suggesting a central, possibly inflammatory component to the pain, and overrepresentation of the CT-genotype in the rs5275 SNP in the Cox2 gene, suggesting overexpression of Cox2 as a possible cause for elevated PGEM levels. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-resectable biliary tract cancer is incurable. The balance between last-line treatment, with limited improvement in survival, and potential adverse events calls for prognostic biomarkers aiding the decision making process. The aim of this retrospective study was to investigate the clinical impact of the circulating tumor DNA (ctDNA), methylated homeobox A9, in plasma from 39 patients receiving erlotinib and bevacizumab for non-resectable biliary tract cancer. Treatment effect and adverse events were also investigated. The study found an increase in ctDNA after one treatment cycle implying that the biomarker is negatively associated with survival in patients with late stage BTC. Methylated homeobox A9 (meth-HOXA9) is tumor specific and has been suggested as a prognostic biomarker in several types of cancer. ctDNA measured as meth-HOXA9 may be a valuable biomarker in the decision-making process about last-line treatment of biliary tract cancer (BTC). The aim of the study was to investigate the clinical impact of meth-HOXA9 in plasma from patients receiving erlotinib and bevacizumab for late-stage BTC and to investigate the treatment effect and adverse events. Droplet digital PCR was applied to detect meth-HOXA9 in 39 patients. Response rates were registered according to RECIST (1.1) and adverse events according to Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE (4.0)). Endpoints were progression-free survival (PFS), overall survival (OS), response rate, and toxicity. A significant difference in PFS and OS between patients with increasing and non-increasing meth-HOXA9 was detected after one treatment cycle, hazard ratio (HR) 12.4 (p < 0.0001) and HR 2.75 (p = 0.04), respectively. The most common adverse events of erlotinib were fatigue, pain, and rash, and those of bevacizumab were bleeding and wounds. This study found meth-HOXA9 to be negatively associated with survival in patients with late-stage BTC. Hence, meth-HOXA9 may guide early discontinuation of ineffective treatment. [ABSTRACT FROM AUTHOR]

The article reports that in oligometastatic colorectal cancer, there can be a curative potential from treating metastases. Topics include examines some patients obtain long-term survival whereas others show aggressive biology with early recurrence and systemic dissemination and no current parameters have shown a clinically relevant potential to predict the course of the disease nor the optimal selection of post-treatment chemotherapy.

Across rehabilitation fields, rehabilitees and professionals meet to set rehabilitation goals. Portrayed as an ordinary, yet foundational practice in rehabilitation, participants often find goal-setting meetings challenging; ideal and real seem to clash. Based on a long-term fieldwork in Danish Parkinson's disease rehabilitation, we explore goal-setting and its rationale to gain insight into why goal-setting qualifies as challenging. We find that challenges relate to disease, organizational matters and an imbalance in institutional knowledge, but also that different logics, of choice, interdependence, and accountability, entangle and affect goal-setting. A competitive aspect between goal-setting logics appears pivotal to understand the challenges in goal-setting. [ABSTRACT FROM AUTHOR]

Introduction: Understanding whether human papillomavirus (HPV) may establish latency in the uterine cervix is important. A better understanding of HPV natural history is useful for clinical counseling of women attending screening and to accurately inform health prevention strategies such as screening and HPV vaccination. We evaluated the extent of latent HPV infections in older women with a history of abnormal cytology. Material and Methods: We conducted a cross‐sectional study in Aarhus, Denmark, from March 2013 through April 2015. Women were enrolled if they underwent cervical amputation or total hysterectomy because of benign disease. Prior to surgery, women completed a questionnaire and a cervical smear was collected for HPV testing and morphological assessment. For evaluation of latency (i.e., no evidence of active HPV infection, but HPV detected in the tissue), we selected women with a history of abnormal cervical cytology or histology, as these women were considered at increased risk of harboring a latent infection. Cervical tissue underwent extensive HPV testing using the SPF10‐DEIA‐LipA25 assay. Results: Of 103 women enrolled, 26 were included in this analysis. Median age was 55 years (interquartile range [IQR] 52–65), and most women were postmenopausal and parous. The median number of sexual partners over the lifetime was six (IQR 3–10), and 85% reported no recent new sexual partner. Five women (19.2%) had evidence of active infection at the time of surgery, and 19 underwent latency evaluation. Of these, a latent infection was detected in 11 (57.9%), with HPV16 being the most prevalent type (50%). Nearly 80% (n = 14) of the 18 women with a history of previous low‐grade or high‐grade cytology with no treatment had an active or latent HPV infection, with latent infections predominating. HPV was detected in two of the six women with a history of high‐grade cytology and subsequent excisional treatment, both as latent infections. Conclusions: HPV can be detected in cervical tissue specimens without any evidence of an active HPV infection, indicative of a latent, immunologically controlled infection. Modeling studies should consider including a latent state in their model when estimating the appropriate age to stop screening and when evaluating the impact of HPV vaccination. [ABSTRACT FROM AUTHOR]

This commentary attempts to discuss the required standardization of circulating tumor DNA (ctDNA) analyses and thereby improve the clinical validity of ctDNA monitoring in the metastatic setting of solid tumors. [ABSTRACT FROM AUTHOR]

Featured Application: Interactive smart farming educational system for schools. We present the GrowBot as an educational robotic system to facilitate hands-on experimentation with the control of environmental conditions for food plant growth. The GrowBot is a tabletop-sized greenhouse automated with sensors and actuators to become a robotic system for the control of plant's growth. The GrowBot includes sensors for humidity, CO2, temperature, water level, RGB camera images, and actuators to control the grow conditions, including full spectrum lights, IR lights, and UV lights, nutrients pump, water pump, air pump, air change pump, and fan. Inspired by educational robotics, we developed user-friendly graphical programming of the GrowBots on several means: a touch display, a micro:bit, and a remote webserver interface. This allows school pupils to easily program the GrowBots to different growth conditions for the natural plants in terms of temperature, humidity, day light cycle, wavelength of LED light, nutrient rate, etc. The GrowBot system also allows the user to monitor the environmental conditions, such as CO2 monitoring for photosynthesis understanding, on both the touch display and the remote web–interface. An experiment with nine GrowBots shows that the different parameters can be controlled, that this can control the growth of the food plants, and that control to make an environmental condition with blue light results in higher and larger plants than red light. Further, the pilot experimentation in school settings indicates that the comprehensive system design method results in a deployable system, which can become well adopted in the educational domain. [ABSTRACT FROM AUTHOR]

Routine [18F]2‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) may help predict clinical outcomes after response to immunotherapy. With a European Medicines Agency‐recommended treatment length until disease progression or unacceptable toxicity, the optimal duration of immunotherapy remains to be defined. In a retrospective study, we retrieved from the Danish Metastatic Melanoma Database (DAMMED), all patients that were annotated as a partial or complete response based on the computed tomography (CT) of serial FDG‐PET‐CT scans. Patients treated with an anti‐Programmed Death (PD)‐1‐containing regimen for <18 months, and ≥4 months without disease progression after halting anti‐PD‐1 were included. Cases were divided into an "elective" and a "toxicity" group based on the reason for treatment discontinuation. A total of 140 patients were included. At 29.3 months of median follow‐up, a higher proportion of patients remained alive in the "elective" group (93% vs 75%, P =.0031) with an improved melanoma‐specific (HR 0.07, 95% CI 0.02‐0.32, P =.0041) survival (MSS). Patients without FDG‐avid lesions at the time of treatment discontinuation had an improved MSS (HR 0.03, 95% CI 0.01‐0.17, P =.0002), and the absence of FDG‐avid lesions was the only independent predictive feature of improved MSS in multivariate analysis. In conclusion, patients with metastatic melanoma who obtain an early response and early discontinue immunotherapy have an excellent prognosis, especially in the absence of FDG‐PET avid lesions when discontinuing treatment. These data support the option of early discontinuation, limiting possible overtreatment and thereby toxicity, health and economic expenses and improving logistics. [ABSTRACT FROM AUTHOR]

For the past decade, within family medicine there has been a focus on cultivating doctors gut feelings as 'a way of knowing' in cancer diagnostics. In this paper, building on interviews with family doctors in Oxford shire, UK we explore the embodied and temporal dimensions of clinical reasoning and how the cultivation of doctors' gut feelings is related to hierarchies of medical knowledge, professional training, and doctors' fears of litigation. Also, we suggest that the introduction of gut feeling in clinical practice is an attempt to develop a theory of clinical reasoning that fits the biopolitics of our contemporary. The turn towards predictive medicine and the values introduced by accelerated diagnostic regimes, we conclude, introduce a need for situated and embodied modes of reading bodies. We contribute theoretically by framing our analysis within a sensorial anthropology approach. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer remains a clinical challenge with considerable mortality. Circulating tumor DNA (ctDNA) has been suggested as a prognostic biomarker and enables the longitudinal evaluation of a patient's disease and response to treatment. However, the role of ctDNA in treatment monitoring and for guiding treatment decisions in ovarian cancer remains unclear. We aimed to examine a gene methylation biomarker in the plasma of patients suffering a relapse of ovarian cancer in order to investigate prognostic potential and identify patients most likely to benefit from treatment, measured by overall survival. In the study, the methylated gene HOXA9 was found to be significantly related to poor survival, with the potential to observe the progression of the disease at an early stage and spare patients from ineffective treatment. Monitoring ctDNA during treatment is clinically feasible, further efforts are, however, required for standardization and for demonstrating improvement in treatment management. Methylated Homeobox A9 circulating tumor DNA (meth-HOXA9) has been suggested as a blood-based biomarker in epithelial ovarian cancer (EOC), although its prognostic significance remains unproven. The aim of the present study was to investigate the prognostic impact of meth-HOXA9 in patients with recurrent EOC. DNA was purified from 4 mL plasma and, following bilsulfite conversion, meth-HOXA9 was analyzed using a methylation-specific droplet digital PCR. Detection of meth-HOXA9 was reported as a percentage of total DNA and as a binary variable (detectable and undetectable). Meth-HOXA9 status and its dynamics during palliative treatment were correlated with overall survival (OS) as the primary endpoint. At baseline, meth-HOXA9 was detected in 65.9% (83/126) of the patients. The median OS was 8.9 and 17.9 months in patients with detectable and undetectable meth-HOXA9 at baseline (hazard ratio: 2.04, p = 0.002), which remained significant in the multivariate analysis. Median OS in patients with an increase in meth-HOXA9 after one treatment cycle was 5.3 months compared to 33 months in patients with undetectable meth-HOXA9 (p < 0.001). Meth-HOXA9 was significantly related to poor survival and may serve as a prognostic marker in patients with recurrent EOC. The longitudinal monitoring of meth-HOXA9 is clinically feasible with the perspective of aiding clinical decision making. [ABSTRACT FROM AUTHOR]

Context and purpose: There is an urgent need to develop vitamin D dietary recommendations for dark-skinned populations resident at high latitude. Using data from randomised controlled trials (RCTs) with vitamin D3-supplements/fortified foods, we undertook an individual participant data-level meta-regression (IPD) analysis of the response of wintertime serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among dark-skinned children and adults residing at ≥ 40° N and derived dietary requirement values for vitamin D. Methods: IPD analysis using data from 677 dark-skinned participants (of Black or South Asian descent; ages 5–86 years) in 10 RCTs with vitamin D supplements/fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D intake estimates across a range of 25(OH)D thresholds. Results: To maintain serum 25(OH)D concentrations ≥ 25 and 30 nmol/L in 97.5% of individuals, 23.9 and 27.3 µg/day of vitamin D, respectively, were required among South Asian and 24.1 and 33.2 µg/day, respectively, among Black participants. Overall, our age-stratified intake estimates did not exceed age-specific Tolerable Upper Intake Levels for vitamin D. The vitamin D intake required by dark-skinned individuals to maintain 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L was 66.8 µg/day. This intake predicted that the upper 2.5% of individuals could potentially achieve serum 25(OH)D concentrations ≥ 158 nmol/L, which has been linked to potential adverse effects in older adults in supplementation studies. Conclusions: Our IPD-derived vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25, 30 and 50 nmol/L are substantially higher than the equivalent estimates for White individuals. These requirement estimates are also higher than those currently recommended internationally by several agencies, which are based predominantly on data from Whites and derived from standard meta-regression based on aggregate data. Much more work is needed in dark-skinned populations both in the dose–response relationship and risk characterisation for health outcomes. Trail registration: PROSPERO International Prospective Register of Systematic Reviews (Registration Number: CRD42018097260) [ABSTRACT FROM AUTHOR]

Drawing upon ethnographic fieldwork in a Danish pediatric oncology ward we explore how children – as cancer patients – respond to the time constraints of cancer treatment that may save their lives but simultaneously hold them under a spell of time. Children respond through practices of what we have called "tinkering with time," which enable them to seize control not of life, but of time. We suggest that tinkering be understood as time work through which children mold their experience of the constraints of time. We regard this as an expression of existential agency that simultaneously sustains children's sense of autonomy. [ABSTRACT FROM AUTHOR]

Background: Gut feelings may be useful when dealing with uncertainty, which is ubiquitous in primary care. Both patients and GPs experience this uncertainty but patients' views on gut feelings in the consultation have not been explored.Aim: To explore patients' perceptions of gut feelings in decision making, and to compare these perceptions with those of GPs.Design and Setting: Qualitative interviews with 21 patients in Oxfordshire, UK.Method: Patients whose referral to a cancer pathway was based on their GP's gut feeling were invited to participate. Semi-structured interviews were conducted from November 2019 to January 2020, face to face or over the telephone. Data were analysed with a thematic analysis and mind-mapping approach.Results: Some patients described experiencing gut feelings about their own health but often their willingness to share this with their GP was dependent on an established doctor-patient relationship. Patients expressed similar perspectives on the use of gut feelings in consultations to those reported by GPs. Patients saw GPs' gut feelings as grounded in their experience and generalist expertise, and part of a process of evidence gathering. Patients suggested that GPs were justified in using gut feelings because of their role in arranging access to investigations, the difficult 'grey area' of presentations, and the time- and resource-limited nature of primary care. When GPs communicated that they had a gut feeling, some saw this as an indication that they were being taken seriously.Conclusion: Patients accepted that GPs use gut feelings to guide decision making. Future research on this topic should include more diverse samples and address the areas of concern shared by patients and GPs. [ABSTRACT FROM AUTHOR]

We hypothesized that the amount of antigen produced in the body during a COVID-19 infection might differ between patients, and that maximum concentrations would predict the degree of both inflammation and outcome for patients. Eighty-four hospitalized and SARS-CoV-2 PCR swab-positive patients, were followed with blood sampling every day until discharge or death. A total of 444 serial EDTA plasma samples were analyzed for a range of biomarkers: SARS-CoV-2 nuclear antigen and RNA concentration, complement activation as well as several inflammatory markers, and KL-6 as a lung marker. The patients were divided into outcome groups depending on need of respiratory support and death/survival. Circulating SARS-CoV-2 nuclear antigen levels were above the detection limit in blood in 65 out of 84 COVID-19 PCR swab-positive patients on day one of hospitalization, as was viral RNA in plasma in 30 out of 84. In all patients, complete antigen clearance was observed within 24 days. There were definite statistically significant differences between the groups depending on their biomarkers, showing that the concentrations of virus RNA and antigen were correlated to the inflammatory biomarker levels, respiratory treatment and death. Viral antigen is cleared in parallel with the virus RNA levels. The levels of antigens and SARS-CoV-2 RNA in the blood correlates with the level of IL-6, inflammation, respiratory failure and death. We propose that the antigens levels together with RNA in blood can be used to predict the severity of disease, outcome, and the clearance of the virus from the body. [ABSTRACT FROM AUTHOR]

The objective was to investigate the effects of substitution (SUB) dietary guidelines (DG) targeted at the prevention of IHD on dietary intake and IHD risk factors in Danish adults with minimum one self-assessed IHD risk factor. A 6-month single-blinded parallel randomised controlled trial with a follow-up at month 12 included 219 subjects (median age 51 years, 59 % female, 73 % overweight or obese) randomised into an SUB DG, an official (OFF) DG or a control group following their habitual diet (HAB). Participants in the DG intervention groups received bi-weekly reminders of their DG and recipes for dishes and the HAB group received a greeting. Dietary intake and fasting blood, anthropometric and blood pressure measurements were obtained at baseline, month 6 and month 12. Linear regression analyses were applied. At month 6, when compared with the HAB, the SUB had a greater impact on the extent of dietary changes with increased intake of whole grains, dietary fibre and low fibre vegetables compared with the OFF DG, and both DG groups had similar decreased percentage of energy (E%) intake from SFA. The extent of dietary changes was similar at month 12. No overall significant changes from baseline were found in blood pressure, anthropometrics and IHD risk markers. In conclusion, both SUB and OFF DG resulted in cardioprotective dietary changes. However, neither the SUB nor the OFF DG resulted in any overall effects on the selected intermediate risk factors for IHD. [ABSTRACT FROM AUTHOR]

Aims: Nordic countries share fairly similar food culture and geographical location as well as common nutrition recommendations. The aim of this paper was to review the latest data on vitamin D status and intake and to describe the national supplementation and food fortification policies to achieve adequate vitamin D intake in the Nordic countries. Methods: The data are based on results derived from a literature search presented in a workshop held in Helsinki in November 2018 and completed by recent studies. Results: Vitamin D policies and the implementation of the recommendations differ among the Nordic countries. Vitamin D fortification policies can be mandatory or voluntary and widespread, moderate or non-existent. Vitamin D supplementation recommendations differ, ranging from all age groups being advised to take supplements to only infants. In the general adult population of the Nordic countries, vitamin D status and intake are better than in the risk groups that are not consuming vitamin D supplements or foods containing vitamin D. Non-Western immigrant populations in all Nordic countries share the problem of vitamin D insufficiency and deficiency. Conclusions: Despite the common nutrition recommendations, there are differences between the Nordic countries in the implementation of the recommendations and policies to achieve adequate vitamin D intake and status. There is a need for wider Nordic collaboration studies as well as strategies to improve vitamin D status, especially in risk groups. [ABSTRACT FROM AUTHOR]

Background: The use of gut feelings to guide clinical decision making in primary care has been frequently described but is not considered a legitimate reason for cancer referral.Aim: To explore the role that gut feeling plays in clinical decision making in primary care.Design and Setting: Qualitative interview study with 19 GPs in Oxfordshire, UK.Method: GPs who had referred patients to a cancer pathway based on a gut feeling as a referral criterion were invited to participate. Interviews were conducted between November 2019 and January 2020, and transcripts were analysed using the one sheet of paper method.Results: Gut feeling was seen as an essential part of decision making that facilitated appropriate and timely care. GPs distanced their gut feelings from descriptions that could be seen as unscientific, describing successful use as reliant on experience and clinical knowledge. This was especially true for patients who fell within a 'grey area' where clinical guidelines did not match the GP's assessment of cancer risk, either because the guidance inadequately represented or did not include the patient's presentation. GPs sought to legitimise their gut feelings by gathering objective clinical evidence, careful examination of referral procedures, and consultation with colleagues.Conclusion: GPs described their gut feelings as important to decision making in primary care and a necessary addition to clinical guidance. The steps taken to legitimise their gut feelings matched that expected in good clinical practice. [ABSTRACT FROM AUTHOR]

Context and purpose: Individual participant data-level meta-regression (IPD) analysis is superior to meta-regression based on aggregate data in determining Dietary Reference Values (DRV) for vitamin D. Using data from randomized controlled trials (RCTs) with vitamin D3-fortified foods, we undertook an IPD analysis of the response of winter serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among children and adults and derived DRV for vitamin D. Methods: IPD analysis using data from 1429 participants (ages 2–89 years) in 11 RCTs with vitamin D-fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D DRV estimates across a range of serum 25(OH)D thresholds using unadjusted and adjusted models. Results: Our IPD-derived estimates of vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25 and ≥ 30 nmol/L are 6 and 12 µg/day, respectively (unadjusted model). The intake estimates to maintain 90%, 95% and 97.5% of concentrations ≥ 50 nmol/L are 33.4, 57.5 and 92.3 µg/day, respectively (unadjusted) and 17.0, 28.1 and 43.6 µg/day, respectively (adjusted for mean values for baseline serum 25(OH)D, age and BMI). Conclusions: IPD-derived vitamin D intakes required to maintain 90%, 95% and 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L are much higher than those derived from standard meta-regression based on aggregate data, due to the inability of the latter to capture between person-variability. Our IPD provides further evidence that using food-based approaches to achieve an intake of 12 µg/day could prevent vitamin D deficiency (i.e., serum 25(OH)D < 30 nmol/L) in the general population. [ABSTRACT FROM AUTHOR]

The Koldal and Løyning intrusions are small (1.8 km² and 0.25 km²,respectively), dominantly noritic to gabbronoritic bodies emplaced in the foliated southern margin of the Egersund-Ogna anorthosite massif. Modal layering has a different orientation in each of three lobes constituting the Koldal body. The Høgåsen and Forefjellet lobes consist dominantly of leuconorites/norites and have similar An% and Mg#opx compositions to each other. The Koldal lobe is gabbronoritic with similar An% but more Fe-rich orthopyroxenes than the other two lobes. A minor mangeritic unit may represent a fractionation product of the Koldal gabbronorites. The Høgåsen and Forefjellet lobes crystallised in two related (and maybe connected) small chambers with sloping floors. Parental magma to the Koldal gabbronorites was emplaced from an underlying evolving chamber and also crystallised on a sloping floor. The underlying chamber eventually produced mangeritic magma which was emplaced into the preexisting lobes. The narrow, elongate Løyning intrusion consists of leuconorites to the north and norites ± olivine to the south. Modal layering dips 55-80° to the south. The leuconorites and norites have different An% and Mg#opx compositions and may not be related to each other by simple in situ fractionation. Modal layering in the noritic rocks is laterally discontinuous and contains autoliths, consistent with its formation on a steeply sloping crystallisation front. Modal grading suggests that the rocks young to the south. The fact that the relatively primitive norites overlie the more evolved leuconorites suggests that the norites are the crystallisation product of an influx of relatively primitive magma. [ABSTRACT FROM AUTHOR]

Background: As part of the process of updating national dietary reference values (DRVs) and food-based dietary guidelines (FBDGs), the Nordic Nutrition Recommendations 2022 project (NNR2022) will select a limited number of topics for systematic reviews (SRs). Objective: To develop and transparently describe the results of a procedure for prioritisation of topics that may be submitted for SRs in the NNR2022 project. Design: In an open call, scientists, health professionals, national food and health authorities, food manufacturers, other stakeholders and the general population in the Nordic and Baltic countries were invited to suggest SR topics. The NNR2022 Committee developed scoping reviews (ScRs) for 51 nutrients and food groups aimed at identifying potential SR topics. These ScRs included the relevant nominations from the open call. SR topics were categorised, ranked and prioritised by the NNR2022 Committee in a modified Delphi process. Existing qualified SRs were identified to omit duplication. Results: A total of 45 nominations with suggestion for more than 200 exposure--outcome pairs were received in the public call. A number of additional topics were identified in ScRs. In order to omit duplication with recently qualified SRs, we defined criteria and identified 76 qualified SRs. The NNR2022 Committee subsequently shortlisted 52 PI/ECOTSS statements, none of which overlapped with the qualified SRs. The PI/ ECOTSS statements were then graded 'High' (n = 21), 'Medium' (n = 9) or 'Low' (n = 22) importance, and the PI/ECOTSS statements with 'High' were ranked in a Delphi process. The nine top prioritised PI/ECOTSS included the following exposure--outcome pairs: 1) plant protein intake in children and body growth, 2) pulses/legumes intake, and cardiovascular disease and type 2 diabetes, 3) plant protein intake in adults, and atherosclerotic/cardiovascular disease and type 2 diabetes, 4) fat quality and mental health, 5) vitamin B12 and vitamin B12 status, 6) intake of white meat (no consumption vs. high consumption and white meat replaced with red meat), and all-cause mortality, type 2 diabetes and risk factors, 7) intake of n-3 LPUFAs from supplements during pregnancy, and asthma and allergies in the offspring, 8) nuts intake and cardiovascular disease (CVD) and type 2 diabetes in adults, 9) dietary fibre intake (high vs. low) in children and bowel function. Discussion: The selection of topics for de novo SRs is central in the NNR2022 project, as the results of these SRs may cause adjustment of existing DRVs and FBDGs. That is why we have developed this extensive process for the prioritisation of SR topics. For transparency, the results of the process are reported in this publication. Conclusion: The principles and methodologies developed in the NNR2022 project may serve as a framework for national health authorities or organisations when developing national DRVs and FBDGs. This collaboration between the food and health authorities in Denmark, Estonia, Finland, Iceland, Latvia, Lithuania, Norway and Sweden represents an international effort for harmonisation and sharing of resources and competence when developing national DRVs and FBDGs. [ABSTRACT FROM AUTHOR]

In recent years, the organisation of healthcare in many welfare states is gradually moving towards an individualised and responsibility-driven self-care and use of healthcare services. Departing in this restructuring of care, this article explores how bodies are experienced and how care is sough, by socially disadvantaged cancer patients. Based on repeated ethnographic interviews with 10 socially deprived cancer patients in Denmark, the article illustrates that socially disadvantaged cancer patients often experience their bodies and move between feeling fine and feeling sick in a disjunctive manner engulfed by the practicality of getting through the day. From a critical phenomenological perspective, we argue that this way of being in the world appears counterfactual to welfare expectations of proactive attention to the body, and contemporary moves towards increased individual responsibility for preventing serious disease and monitoring the body. [ABSTRACT FROM AUTHOR]

Purpose: Treatment of multi-resistant epithelial ovarian cancer represents a clinical challenge with limited choices. Anti-angiogenic therapy has shown great potential in combination with frontline-therapy. Studies investigating heavily pre-treated patients are few. This study investigated the effect of re-treating patients with carboplatin combined with bevacizumab and cell-free DNA (cfDNA) as a potential predictor of outcome. Methods: This single-center study enrolled 73 multi-resistant ovarian cancer patients from 2008 to 2015. Patients were treated with a combination of bevacizumab (10 mg/kg) and carboplatin (AUC5) every 3 weeks. Baseline plasma samples were analyzed for cfDNA levels. Treatment response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria and CA125 blood values. Results: The response rate according to RECIST and/or CA125 was 57%. Median number of cycles was 6. The median progression-free survival and overall survival was 5.0 and 11.2 months, respectively. Eighteen patients developed allergic reactions to carboplatin. Patients were grouped into two cfDNA-groups according to median value. The cfDNA value was correlated to progression-free survival (PFS, p = 0.015), but not to overall survival (OS, p = 0.067) in the univariate analysis. In the multivariate analysis both PFS and OS were highly correlated to the levels of cfDNA (PFS, hazard ratio = 1.87, p = 0.012; OS, hazard ratio = 1.67, p = 0.037) with patients with high levels of cfDNA having poorest outcome. Conclusion: Our results might provide guidance in cases with heavily pre-treated patients, where alternatives are limited. Carboplatin and bevacizumab treatment should be weighed against best supportive care, current non-platinum therapies and experimental treatment. cfDNA seems to offer prognostic insight. [ABSTRACT FROM AUTHOR]

Informal caregiving is increasingly considered a health care delivery-resource within the North European welfare states. While 'informal' often refers to non-professional, 'caregiving' connotes both affective concern (caring about) and practical action (caring for). This duality of meanings, however, often refers to the one direction in which care is given. Care, we suggest, is relational and also requires that people receiving care are able to or wanting to share their needs. Informal caregiving thus requires sharing. Based on 155 semi-structured, narrative interviews with people with lung or bowel cancer, living in Denmark, Sweden or England, this paper explores how and with whom people 'share' when they fall ill. We approach sharing as a heuristic for reflecting on informal-caregiving, and illustrate how being cared for or asking for care are entangled with the management of social risks and notions of selfhood. We conclude that informal caregiving should explicitly be recognised as morally and sympathetically committed practices, which attend to the diversity of local moral worlds of patients, their needs and experiences. [ABSTRACT FROM AUTHOR]

Background: Immunocytochemical staining with p16/Ki67 has been suggested as a promising triage biomarker in cervical cancer screening. As dual staining is a subjective method, proper training may be required to ensure safe implementation in routine laboratories and reduce risk of misclassification. We determined concordance between novice evaluators and an expert, stratified by number of slides reviewed at three reading points. Methods: The study was conducted at the Department of Pathology, Randers, Denmark. Women were eligible if they were aged ≥45, had been enrolled in one of two ongoing clinical studies, and had a dual stain slide available. Dual staining was performed using the CINtec plus assay. Slides were randomly selected from three reading points at which novice evaluators had reviewed <30, ~300, and ≥500 dual stain slides respectively. Level of concordance was estimated using Cohen's Kappa, κ. Results: Of 600 eligible slides, 50 slides were selected for review as recommended by the manufacturer. Median age was 68 years (range: 58‐74). Overall concordance was good (κ = 0.68, 95% confidence interval [CI]: 0.60‐0.76), with an overall agreement of 84% (95% CI: 70.9%‐92.8%). Concordance improved with increasing number of slides reviewed at a given reading point, from a moderate concordance (κ = 0.47, 95% CI: 0.05‐0.90) after reviewing <30 slides to a good concordance (κ = 0.66, 95% CI: 0.20‐0.88) and a very good concordance (κ = 0.88, 95% CI: 0.66‐1.00) after reviewing ~300 and ≥500 slides, respectively. Conclusions: When interpreting dual stain slides from older women, concordance increased slightly as novice evaluators received more training and experience. Although further evaluation is warranted, these findings indicate that a significant amount of training and experience of novice evaluators may be needed to ensure accurate dual stain interpretation in this age group. Future studies should accurately describe training and experience of evaluators to enable a better comparison of concordance and diagnostic accuracy across studies. Trial registration: NCT04114968 and NCT04298957. [ABSTRACT FROM AUTHOR]

Background: The early identification of treatment effect is wanted in several settings, including the management of metastatic colorectal cancer (mCRC). A potential universal marker is circulating tumor DNA (ctDNA). Our prospective study explored the association between progression-free survival (PFS) and overall survival (OS), and early change of ctDNA after one cycle of chemotherapy in patients with mCRC. Methods: The study included mCRC patients receiving standard first line combination chemotherapy with 5-Fluorouracil (FU), oxaliplatin, and bevacizumab. Hypermethylated neuropeptide Y (NPY) ctDNA (meth-ctDNA) served as a marker analyzed by droplet digital polymerase chain reaction (PCR). The meth-ctDNA level was analyzed in plasma before treatment start and again before cycle two. The patients were divided into two groups according to the dynamics of meth-ctDNA. Low ctDNA (LctDNA) included patients with zero or values of meth-ctDNA decreasing to a level including zero in the 95% confidence interval. High ctDNA (HctDNA) included all other patients (stable, increasing, or slightly decreasing values). The two groups were compared as to PFS and OS. Results: The study included 123 patients. The PFS in the two groups differed significantly with a median of 9.2 and 6.7 months in LctDNA and HctDNA, respectively (p = 0.0005). This translated into a 12-month difference in OS with a median of 25.4 and 13.5 months, respectively (p = 0.0001). Conclusions: Early therapeutic reconsideration is of utmost importance. A low level of meth-ctDNA after one cycle of chemotherapy in the first line setting is a potential marker for excellent clinical outcomes. The clinical utility should be confirmed in randomized clinical trials. [ABSTRACT FROM AUTHOR]

Experiences of cancer diagnosis are changing in light of both the increasingly technological‐clinical diagnostic processes and the socio‐political context in which interpersonal relations take place. This has raised questions about how we might understand patient–doctor relationship marked by asymmetries of knowledge and social capital, but that emphasise patients' empowered choices and individualised care. As part of an interview study of 155 participants with bowel or lung cancer across Denmark, England and Sweden, we explored participants' stories of the decisions made during their cancer diagnostic process. By focusing on the intersections of care, choice and medical authority – a convivial pastoral dynamic – we provide a conceptual analysis of the normative ambivalences in people's stories of their cancer diagnosis. We found that participants drew from care, choice and medical authority to emphasise their relationality and interdependence with their doctors in their stories of their diagnosis. Importantly negotiations of an asymmetrical patient–doctor relationship were part of an on‐going realisation of the healthcare processes as a human endeavour. We were therefore able to draw attention to the limitations of dichotomising emancipatory‐empowerment discourses and argue for a theorisation of the patient–doctor relationship as a contextually bounded and relationally ambivalent humanity. [ABSTRACT FROM AUTHOR]

Mutation-derived neoantigens are important targets for T cell-mediated reactivity toward tumors and, due to their unique tumor expression, an attractive target for immunotherapy. Neoepitope-specific T cells have been detected across a number of solid cancers with high mutational burden tumors, but neoepitopes have been mostly selected from single nucleotide variations (SNVs), and little focus has been given to neoepitopes derived from in-frame and frameshift indels, which might be equally important and potentially highly immunogenic. Clear cell renal cell carcinomas (ccRCCs) are medium-range mutational burden tumors with a high pan-cancer proportion of frameshift mutations. In this study, the mutational landscape of tumors from six RCC patients was analyzed by whole-exome sequencing (WES) of DNA from tumor fragments (TFs), autologous tumor cell lines (TCLs), and tumor-infiltrating lymphocytes (TILs, germline reference). Neopeptides were predicted using MuPeXI, and patient-specific peptide–MHC (pMHC) libraries were created for all neopeptides with a rank score < 2 for binding to the patient's HLAs. T cell recognition toward neoepitopes in TILs was evaluated using the high-throughput technology of DNA barcode-labeled pMHC multimers. The patient-specific libraries consisted of, on average, 258 putative neopeptides (range, 103–397, n = 6). In four patients, WES was performed on two different sources (TF and TCL), whereas in two patients, WES was performed only on TF. Most of the peptides were predicted from both sources. However, a fraction was predicted from one source only. Among the total predicted neopeptides, 16% were derived from frameshift indels. T cell recognition of 52 neoepitopes was detected across all patients (range, 4–18, n = 6) and spanning two to five HLA restrictions per patient. On average, 21% of the recognized neoepitopes were derived from frameshift indels (range, 0–43%, n = 6). Thus, frameshift indels are equally represented in the pool of immunogenic neoepitopes as SNV-derived neoepitopes. This suggests the importance of a broad neopeptide prediction strategy covering multiple sources of tumor material, and including different genetic alterations. This study, for the first time, describes the T cell recognition of frameshift-derived neoepitopes in RCC and determines their immunogenic profile. [ABSTRACT FROM AUTHOR]

Background: Molecular markers may identify subgroups of patients with clinically distinct behavior and response to treatment. In some gastrointestinal tumors, KRAS has prognostic value and negative predictive value. This is the first prospective study to report the outcome of combination chemotherapy in biliary tract cancer patients with KRAS mutation. Methods: From 2009 to 2015, 25 patients were included from two Scandinavian centers. Main inclusion criteria were non-resectable biliary tract cancer, ECOG performance status 0–2 and tumor KRAS mutation. A bi-weekly cycle of chemotherapy was administered as gemcitabine 1000 mg/m2 and oxaliplatin 85 mg/m2 day 1, followed by 7 days of oral capecitabine 1000 mg/m2. Response evaluation was done every six treatment and the primary endpoint was the fraction with progression free survival (PFS) at 6 months. The study also included a non-preplanned analysis of circulating tumor specific DNA. Results: Chemotherapy was given for a median of 5 months (range 0–14) and among 17 patients evaluable for response, best responses were complete response (1), partial response (2), and stable disease (14). Eighteen patients had CT-verified progression, six died between evaluations and one patient is still progression-free. Median PFS was 6.8 months (95% CI 3.1–11.0) and median overall survival (OS) was 11.2 months (95% CI 6.6–14.3). The fraction with PFS at 6 months was 52% (95% CI 31–69%). Exploratory analyses found an improved survival in patients with a low level of plasma DNA. Conclusion: Pretreatment molecular characterization was feasible in BTC, but the rate of KRAS mutations was low. The study met its primary endpoint with a fraction of PFS at six months of 52%. The effect of combination chemotherapy with gemcitabine, oxaliplatin and capecitabine in this selected population was comparable to results from unselected groups with PFS and OS of 6.8 and 11.2 months, respectively. ClinicalTrials.gov NCT00779454 [ABSTRACT FROM AUTHOR]

Purpose: Low vitamin D status is prevalent worldwide. We aim to investigate the effect of vitamin D fortification on serum 25-hydroxyvitamin D (25(OH)D) concentration in women of Danish and Pakistani origin at risk of vitamin D deficiency. Methods: A 12-week randomized, double-blinded, placebo-controlled intervention trial during winter time, designed to provide 20 µg vitamin D3/day through fortified yoghurt, cheese, eggs and crisp bread, and assess the change in serum 25(OH)D. Participants were 143 women of Danish and Pakistani origin, living in Denmark, randomized into four groups, stratified by ethnicity. Results: Mean (SD) baseline 25(OH)D concentrations among women of Danish and Pakistani origin were 49.6 (18) and 46.9 (22) nmol/L, respectively (P = 0.4). While 9% of Danish women had 25(OH)D < 30 nmol/L, the prevalence among women of Pakistani origin was 24%. Median (IQR) vitamin D intake among Danish and Pakistani women at endpoint was 32.0 (27.0, 34.4) µg/day and 24.2 (19.2, 30.8) µg/day, respectively. Endpoint serum 25(OH)D increased in fortified groups to 77.8 (14) nmol/L among Danish women and 54.7 (18) nmol/L among women of Pakistani origin (P < 0.01). At endpoint, 0% in the Danish-fortified group and 3% in the Pakistani-fortified group had 25(OH)D < 30 nmol/L, compared with 23 % and 34% in their respective control groups. Conclusions: Vitamin D fortification of four different foods for 12 weeks during winter was effective in increasing serum 25(OH)D and reducing the prevalence of very low vitamin D status among women of Danish and Pakistani origin. ClinicalTrials.gov with identifier: NCT02631629. [ABSTRACT FROM AUTHOR]

Background: Systematic reviews (SRs) constitute a major part of the Nordic Nutrition Recommendations (NNRs). The step-by-step procedure used to develop SRs has evolved considerably over time and is often tailored to fit the exposure and outcomes in focus. Objective: To describe a detailed procedure for developing qualified SRs commissioned by the NNR2022 project. Design: Scrutinizing procedures of recent SRs commissioned by leading national food and health authorities or international food and health organizations. Results: The following eight steps must be included when developing qualified SRs for the NNR2022 project: 1) define research question, 2) protocol development, 3) literature search, 4) screening and selection of studies, 5) data extraction, 6) assessing risk of bias, 7) synthesis and grading of total strength of evidence, and 8) reporting according to certain standards. Discussion: This guide is based on the guidelines developed for the fifth edition of NNR but includes some important new domains in order to adhere to more recent, authoritative standards. Conclusion: All qualified SRs in the NNR2022 project will follow the protocol described here. [ABSTRACT FROM AUTHOR]

Background: The Nordic Nutrition Recommendations (NNRs) constitute the scientific basis for national dietary reference values (DRVs) and food-based dietary guidelines (FBDGs) in the Nordic and Baltic countries. Objective: To define principles and methodologies for the sixth edition of NNR to be published in 2022 (NNR2022). Design: The principles and methodologies of the previous edition of NNR were used as a starting point. Recent nutrition recommendations commissioned by other national food and health authorities or international food and health organizations were examined and dissected. Updated principles and methodologies were agreed by the NNR2022 Committee in a consensus-driven process. Results: An organizational model with 'checks and balances' was developed to minimize the influence of subjective biases of the committee members and experts. Individual chapters on all included nutrients and food groups will be updated as scoping reviews. Systematic reviews (SRs), which are the main basis for evaluating causal effects of nutrients or food groups on health outcomes, will be embedded in each chapter. A NNR SR Centre will be established for performing de novo SRs on prioritized topics. To avoid duplication and optimize the use of resources, qualified SRs commissioned by other national and international organizations and health authorities will also inform DRVs and FBDGs in NNR2022. Discussion: The evidence-based methods defined in the NNR2022 project are compatible with most contemporary methods used by leading national food and health authorities. Global harmonization of methodological approaches to nutrition recommendations is strongly encouraged. Conclusion: Evidence-informed principles and methodologies underpinned by SRs will ensure that DRVs and FBDGs defined in the NNR2022 project are based on the best available evidence and as far as possible free from overt bias. [ABSTRACT FROM AUTHOR]

Background: Qualified systematic reviews (SRs) will form the main basis for evaluating causal effects of nutrients or food groups on health outcomes in the sixth edition of Nordic Nutrition Recommendations to be published in 2022 (NNR2022). Objective: To describe rationale and structure of SRs used in NNR2022. Design: The SR methodologies of the previous edition of NNR were used as a starting point. Methodologies of recent SRs commissioned by leading national food and health authorities or international food and health organizations were examined and scrutinized. Methodologies for developing SRs were agreed by the NNR2022 Committee in a consensus-driven process. Results: Qualified SRs will be developed by a cross-disciplinary group of experts and reported according to the requirements of the EQUATOR network. A number of additional requirements must also be fulfilled, including 1) a clearly stated set of objectives and research questions with pre-defined eligibility criteria for the studies, 2) an explicit, reproducible methodology, 3) a systematic search that attempts to identify all studies that would meet the eligibility criteria, 4) an assessment of the validity of the findings of the included studies through an assessment of 'risk of bias' of the studies, 5) a systematic presentation and synthesis of the characteristics and findings of the included studies, and 6) a grading of the overall evidence. The complete definition and requirements of a qualified SR are described. Discussion: Most SRs published in scientific journals do not fulfill all criteria of the qualified SRs in the NNR2022 project. This article discusses the structure and rationale for requirements of qualified SRs in NNR2022. National food and health authorities have only recently begun to use qualified SRs as a basis for nutrition recommendations. Conclusion: Qualified SRs will be used to inform dietary reference values (DRVs) and food-based dietary guidelines (FBDGs) in the NNR2022 project. [ABSTRACT FROM AUTHOR]

Advances within cancer immunotherapy have fueled a paradigm shift in cancer treatment, resulting in increasing numbers of cancer types benefitting from novel treatment options. Despite originally being considered an immunologically silent malignancy, recent studies encourage the research of breast cancer immunogenicity to evaluate immunotherapy as a treatment strategy. However, the epitope landscape in breast cancer is minimally described, limiting the options for antigen-specific, targeted strategies. Aromatase, never in mitosis A-related kinase 3 (NEK3), protein inhibitor of activated STAT3 (PIAS3), and prolactin are known as upregulated proteins in breast cancer. In the present study, these four proteins are identified as novel T cell targets in breast cancer. From the four proteins, 147 peptides were determined to bind HLA-A*0201 and -B*0702 using a combined in silico/in vitro affinity screening. T cell recognition of all 147 peptide-HLA-A*0201/-B*0702 combinations was assessed through the use of a novel high-throughput method utilizing DNA barcode labeled multimers. T cell recognition of sequences within all four proteins was demonstrated in peripheral blood of patients, and significantly more T cell responses were detected in patients compared to healthy donors for both HLA-A*0201 and -B*0702. Notably, several of the identified responses were directed toward peptides, with a predicted low or intermediate binding affinity. This demonstrates the importance of including low-affinity binders in the search for epitopes within shared tumor associated antigens (TAAs), as these might be less subject to immune tolerance mechanisms. The study presents four novel TAAs containing multiple possible targets for immunotherapy of breast cancer. [ABSTRACT FROM AUTHOR]