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Circulating tumor DNA (ctDNA) detection has multiple promising applications in oncology, but the road toward implementation in clinical practice is unclear. We aimed to support the implementation process by exploring potential future pathways of ctDNA testing. To do so, we studied four ctDNA‐testing applications in two cancer types and elicited opinions from 30 ctDNA experts in the Netherlands. Our results showed that the current available evidence differed per application and cancer type. Tumor profiling and monitoring treatment response were found most likely to be implemented in non‐small cell lung cancer (NSCLC) within 5 years. For colorectal cancer, applications of ctDNA testing were found to be at an early stage in the implementation process. Demonstrating clinical utility was found a key aspect for successful implementation, but there was no consensus regarding the evidence requirements. The next step toward implementation is to define how clinical utility of biomarkers should be evaluated. Finally, these data indicate that specific challenges for each clinical application and tumor type should be appropriately addressed in a deliberative process involving all stakeholders to ensure implementation of ctDNA testing and timely access for patients. [ABSTRACT FROM AUTHOR]

In the Baltic Sea, sea level variations are often very pronounced. During the winter season, storm surges caused by strong extratropical cyclones (ETCs) can have major societal impacts on coastal cities. In this study, using reanalysis‐based cyclone tracks and in‐situ tide gauge records, we show that serial cyclone clustering (SCC) leads to higher sea levels in the Baltic Sea than situations where only one ETC passes the tide gauge. Consequently, almost half of extreme sea level events in the Baltic Sea are associated with cyclone clustering periods. For example, in Helsinki, 45% of the extreme sea level events coincided with SCC periods of three or more ETCs, while only 6% of the events coincided with a single ETC. Our study represents a significant advance in the understanding of the factors influencing sea level variations in the Baltic Sea. Plain Language Summary: Sea levels in the Baltic Sea can vary a lot. In winter, powerful storms can lead to storm surges that seriously affect coastal towns. Our research studied storm paths and sea level observations. We found that multiple consecutive storms within a week raise sea levels in the Baltic Sea more than when only one storm passes the same location. As a result, most of the high sea level events in the Baltic Sea are linked to periods when several storms pass the region. In Helsinki, for instance, almost half of all analyzed high sea level events co‐occurred with periods when at least three storms occurred, while only 6% of high sea level events occurred due to a single storm. Our analysis is a significant progression in understanding the reasons that impact the Baltic Sea water levels. Hence, these results could aid in preparing for possible coastal floods. Key Points: Serial cyclone clustering (SCC) commonly causes elevated sea levels in the Baltic SeaPeak storm surges during SCC are on average 2–2.7 times (25–48 cm) higher than during single cyclonesThe intensity of the cyclones within the SCC modulates the storm surge levels, with deeper cyclones more likely to induce higher surges [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most common EGFR mutations in patients with non–small cell lung cancer (NSCLC) and are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). There is evidence of activity of combining EGFR TKIs with monoclonal antibodies. This study reports on the efficacy and safety of afatinib in combination with cetuximab. Methods: In this single‐arm phase 2 trial, patients with advanced NSCLC harboring an EGFR ex20ins mutation were treated with afatinib 40 mg once daily in combination with cetuximab 500 mg/m2 every 2 weeks. The primary end point was disease control rate (DCR) at 18 weeks of treatment. Results: Thirty‐seven patients started treatment, with a median age of 65 years (range, 40–80 years), 78% female, and 95% White. The study achieved its primary end point with a DCR of 54% at 18 weeks, an overall response rate (ORR) of 43%, and a 32% confirmed ORR. Best responses were partial (n = 16), stable (n = 16), progressive disease (n = 2), or not evaluable (n = 3). Median progression‐free survival was 5.5 months (95% CI, 3.7–8.3 months) and median overall survival was 16.8 months (95% CI, 10.7–25.8 months). The most common treatment‐related adverse events (TRAEs) were diarrhea (70%), rash (65%), dry skin (59%), paronychia (54%), and erythema (43%). Grade 3 TRAEs were reported in 54% of all patients. Conclusions: Combination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 54% at 18 weeks and a 32% confirmed ORR. Toxicity was significant, although manageable, after dose reduction. Combination treatment with afatinib and cetuximab in patients with non–small cell lung cancer harboring an EGFR exon 20 insertion mutation demonstrated antitumor activity with a disease control rate of 54% at 18 weeks of treatment and a 32% confirmed overall response rate. [ABSTRACT FROM AUTHOR]

Objective: to determine if the tumor marker squamous cell carcinoma antigen (SCC‐Ag) observed over time may contribute to the early detection of recurrence, metastasis, and second primary tumors in the follow‐up of patients with head and neck squamous cell carcinoma (HNSCC). Study Design: A retrospective analysis of patients with HNSCC and at least one SCC‐Ag measurement was conducted. Hazard ratios (HRs) were used to determine the correlation between SCC‐Ag and an event. Setting: patients with HNSCC, treated in the Antoni van Leeuwenhoek Hospital in The Netherlands between 2010 and 2020 were used for the analysis. Methods: Data from 789 patients were used on event‐free survival (EFS) with time‐dependent Cox models. In addition to current (most recent) SCC‐Ag (also dichotomized into high and low as done for clinical practice), average SCC‐Ag and change between SCC‐Ag measurements (delta SCC‐Ag) were considered, using restricted cubic splines to explore nonlinear relationships. Results: Dichotomized SCC‐Ag values (HR = 3.01, 95% confidence interval [CI]: 2.17‐4.18) and the delta SCC‐Ag (HR = 1.15, 95% CI: 1.07‐1.22) predicted EFS better than models using the cumulative average or current value of SCC‐Ag, also after adjusting for tumor site, stage, age, and gender. A strong association was observed when using delta SCC‐Ag as a linear predictor in the subgroup of oropharynx patients (HR = 4.88, 95% CI: 2.71‐8.79). Conclusion: Dichotomized and delta SCC‐Ag values can be important markers for EFS, during the follow‐up of patients treated for HNSCC. These results were more evident in patients with oropharyngeal cancer. [ABSTRACT FROM AUTHOR]

Correlations between increasing concentrations of circulating tumor DNA (ctDNA) in plasma and disease progression have been shown. A nonlinear mixed effects model to describe the dynamics of epidermal growth factor receptor (EGFR) ctDNA data from patients with non‐small cell lung cancer (NSCLC) combined with a parametric survival model were developed to evaluate the ability of these modeling techniques to describe ctDNA data. Repeated ctDNA measurements on L858R, exon19del, and T790M mutants were available from 54 patients with EGFR mutated NSCLC treated with erlotinib or gefitinib. Different dynamic models were tested to describe the longitudinal ctDNA concentrations of the driver and resistance mutations. Subsequently, a parametric time‐to‐event model for progression‐free survival (PFS) was developed. Predicted L858R, exon19del, and T790M concentrations were used to evaluate their value as predictor for disease progression. The ctDNA dynamics were best described by a model consisting of a zero‐order increase and first‐order elimination (19.7/day, 95% confidence interval [CI] 14.9–23.6/day) of ctDNA concentrations. In addition, time‐dependent development of resistance (5.0 × 10−4, 95% CI 2.0 × 10−4–7.0 × 10−4/day) was included in the final model. Relative change in L858R and exon19del concentrations from baseline was identified as most significant predictor of disease progression (p = 0.001). The dynamic model for L858R, exon19del, and T790M concentrations in ctDNA and time‐to‐event model adequately described the observed concentrations and PFS data in our clinical cohort. In addition, it was shown that nonlinear mixed effects modeling is a valuable method for the analysis of longitudinal and heterogeneous biomarker datasets obtained from clinical practice. [ABSTRACT FROM AUTHOR]

Stage II-IIIA nonsmall cell lung cancer (NSCLC) patients receive adjuvant chemotherapy after surgery as standard-of-care treatment, even though only approximately 5.8% of patients will benefit. Identifying patients with minimal residual disease (MRD) after surgery using tissue-informed testing of postoperative plasma circulating cell-free tumour DNA (ctDNA) may allow adjuvant therapy to be withheld from patients without MRD. However, the detection of MRD in the postoperative setting is challenging, and more sensitive methods are urgently needed. We developed a method that combines variant calling and a novel ctDNA fragment length analysis using hybrid capture sequencing data. Among 36 stage II-IIIA NSCLC patients, this method distinguished patients with and without recurrence of disease in a 20 times repeated 10-fold cross validation with 75% accuracy (P = 0.0029). In contrast, using only variant calling or only fragment length analysis, no signification distinction between patients was shown (P = 0.24 and P = 0.074 respectively). In addition, a variant-level fragmentation score was developed that was able to classify variants detected in plasma cfDNA into tumourderived or white-blood-cell-derived variants with 84% accuracy. The findings in this study may help drive the integration of various types of information from the same data, eventually leading to cheaper and more sensitive techniques to be used in this challenging clinical setting. [ABSTRACT FROM AUTHOR]

Introduction: Many women with benign pelvic masses, suspected of ovarian cancer, are unnecessarily referred for treatment at specialized centers. There is an unmet clinical need to improve diagnostic assessment in these patients. Our objective was to obtain summary estimates of the accuracy of human epididymis protein (HE4) for diagnosing ovarian cancer and to compare the performance of HE4 with that of cancer antigen 125 (CA125). Material and methods: We searched PubMed, Ovid and Scopus using search terms for "pelvic masses" and "HE4", to identify studies that evaluated HE4 for diagnosing malignant ovarian masses, in adult women presenting with a pelvic mass, suspected of ovarian cancer, and with diagnosis confirmed by histopathology. Screening, data extraction and Risk of Bias assessment with the QUADAS‐2 tool were done independently by two authors. We performed a meta‐analysis of the accuracy of HE4 and CA125 using a random‐effects bivariate logit‐normal model. A study protocol was registered at PROSPERO (CRD42020158073). Results: In the 17 eligible studies, which included 3404 patients, ovarian cancer prevalence ranged from 15% to 71%. Overall, the studies were heterogeneous. All studies seemed to have recruited patients in specialized settings. A meta‐analysis of seven HE4 studies resulted in a mean sensitivity of 79.4% (95% confidence interval [CI] 74.1%–83.8%) and a mean specificity of 84.1% (95% CI 79.6%–87.8%), for cut‐off values of 67–72 pmol/L. Based on eight studies, the mean sensitivity of CA125 was 81.4% (95% CI 74.6%–86.2%) and the mean specificity was 56.8% (95% CI 47.9%–65.4%), at a cut‐off of 35 U/ml. Given a 40% ovarian cancer prevalence, the positive predictive value (PPV) for HE4 would be 76.9% (71.9%–81.2%) vs 55.6% (50.2%–60.9%) for CA125. The negative predictive value (NPV) would be 85.9 (82.8%–88.6%) and 81.9% (76.2%–86.4%), respectively. At a 15% prevalence, the NPV would be 95.8% (95% CI 94.4%–96.7%) for HE4 and 94.4% (95% CI 92.3%–96.0%) for CA125. The PPV would be 46.9% (40.4%–53.4%) and 24.9% (21.1%–29.2%), respectively. Conclusions: HE4 had higher specificity and similar sensitivity compared with CA125. At high prevalence, PPV was also higher for HE4, but at low prevalence, it had a similar NPV to CA125. The field would benefit from studies conducted in general settings. [ABSTRACT FROM AUTHOR]

Aims Erythropoietin (EPO) resistance, an important cause of anaemia in patients with heart and renal failure, is associated with increased mortality. The hypothesis of the present study was that exogenous EPO decreases hepcidin levels and that the decrease in hepcidin levels upon EPO treatment is related to the bone marrow response. Methods and results In the EPOCARES trial, patients with renal failure (glomerular filtration rate 20-70 mL/min), heart failure, and anaemia were randomized to receive 50 IU/kg/week EPO (n = 20) or not (n = 13). Haemoglobin (Hb), hepcidin- 25, ferritin, reticulocytes, serum transferrin receptor (sTfR), IL-6, and high-sensitivity C-reactive protein were measured at baseline and during treatment. Hepcidin-25 was measured by weak cation exchange chromatography/ matrix assisted laser desorption ionization time-of-flight mass spectrometry. Baseline hepcidin levels were increased compared with a healthy reference population and were inversely correlated with Hb (r² = 0.18, P = 0.02), and positively with ferritin (r² = 0.51, P < 0.001), but not with renal function, high-sensitivity C-reactive protein or IL-6. Erythropoietin treatment increased reticulocytes (P < 0.001) and sTfR (P < 0.001), and decreased hepcidin (P , 0.001). Baseline hepcidin levels and the magnitude of the decrease in hepcidin correlated with the increase in reticulocytes (r² = 0.23, P = 0.03) and sTfR (r² = 0.23, P = 0.03) and also with the Hb response after 6 months (r² = 0.49, P = 0.001). Conclusion In this group of patients with combined heart and renal failure and anaemia, increased hepcidin levels were associated with markers of iron load and not with markers of inflammation. The (change in) hepcidin levels predicted early and long-term bone marrow response to exogenous EPO. In our group hepcidin seems to reflect iron load and response to EPO rather than inflammation and EPO resistance. [ABSTRACT FROM AUTHOR]

Colony phase variation is a regulatory mechanism at the DNA level which usually results in high frequency, reversible switches between colonies with a different phenotype. A number of molecular mechanisms underlying phase variation are known: slipped-strand mispairing, genomic rearrangements, spontaneous mutations and epigenetic mechanisms such as differential methylation. Most examples of phenotypic variation or phase variation have been described in the context of host–pathogen interactions as mechanisms allowing pathogens to evade host immune responses. Recent reports indicate that phase variation is also relevant in competitive root colonization and biological control of phytopathogens. Many rhizospere Pseudomonas species show phenotypic variation, based on spontaneous mutation of the gacA and gacS genes. These morphological variants do not express secondary metabolites and have improved growth characteristics. The latter could contribute to efficient root colonization and success in competition, especially since (as shown for one strain) these variants were observed to revert to their wild-type form. The observation that these variants are present in rhizosphere-competent Pseudomonas bacteria suggests the existence of a conserved strategy to increase their success in the rhizosphere. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to determine the effect of food intake on uracil and dihydrouracil plasma levels. These levels are a promising marker for dihydropyrimidine dehydrogenase activity and for individualizing fluoropyrimidine anticancer therapy., Methods: A randomized, cross-over study in 16 healthy volunteers was performed, in which subjects were examined in fasted and fed state on two separate days. In fed condition, a high-fat, high-caloric breakfast was consumed between 8:00 h and 8:30 h. Whole blood for determination of uracil, dihydrouracil and uridine plasma levels was drawn on both test days at predefined time points between 8:00 h and 13:00 h., Results: Uracil levels were statistically significantly different between fasting and fed state. At 13:00 h, the mean uracil level in fasting state was 12.6 ± 3.7 ng ml -1 and after a test meal 9.4 ± 2.6 ng ml -1 (P < 0.001). Dihydrouracil levels were influenced by food intake as well (mean dihydrouracil level at 13:00 h in fasting state 147.0 ± 36.4 ng ml -1 and in fed state 85.7 ± 22.1 ng ml -1 , P < 0.001). Uridine plasma levels showed curves with similar patterns as for uracil., Conclusions: It was shown that both uracil and dihydrouracil levels were higher in fasting state than in fed state. This is hypothesized to be an direct effect of uridine plasma levels, which were previously shown to be elevated in fasting state and reduced after intake of food. These findings show that, when assessing plasma uracil and dihydrouracil levels for adaptive fluoropyrimidine dosing in clinical practice, sampling should be done between 8:00 h and 9:00 h after overnight fasting to avoid bias caused by circadian rhythm and food effects., (© 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)