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Background: Current patient selection for adjuvant chemotherapy (ACT) after curative surgery for stage II colon cancer (CC) is suboptimal, causing overtreatment of high-risk patients and undertreatment of low-risk patients. Postoperative circulating tumor DNA (ctDNA) could improve patient selection for ACT. Objectives: We conducted an early model-based evaluation of the (cost-)effectiveness of ctDNA-guided selection for ACT in stage II CC in the Netherlands to assess the conditions for cost-effective implementation. Methods: A validated Markov model, simulating 1000 stage II CC patients from diagnosis to death, was supplemented with ctDNA data. Five ACT selection strategies were evaluated: the current guideline (pT4, pMMR), ctDNA-only, and three strategies that combined ctDNA status with pT4 and pMMR status in different ways. For each strategy, the costs, life years, quality-adjusted life years (QALYs), recurrences, and CC deaths were estimated. Sensitivity analyses were performed to assess the impact of the costs of ctDNA testing, strategy adherence, ctDNA as a predictive biomarker, and ctDNA test performance. Results: Model predictions showed that compared to current guidelines, the ctDNA-only strategy was less effective (+2.2% recurrences, −0.016 QALYs), while the combination strategies were more effective (−3.6% recurrences, +0.038 QALYs). The combination strategies were not cost-effective, since the incremental cost-effectiveness ratio was €67,413 per QALY, exceeding the willingness-to-pay threshold of €50,000 per QALY. Sensitivity analyses showed that the combination strategies would be cost-effective if the ctDNA test costs were lower than €1500, or if ctDNA status was predictive of treatment response, or if the ctDNA test performance improved substantially. Conclusion: Adding ctDNA to current high-risk clinicopathological features (pT4 and pMMR) can improve patient selection for ACT and can also potentially be cost-effective. Future studies should investigate the predictive value of post-surgery ctDNA status to accurately evaluate the cost-effectiveness of ctDNA testing for ACT decisions in stage II CC. Plain language summary: Effectiveness and cost-effectiveness of circulating tumour DNA-guided selection for adjuvant chemotherapy in patients with stage II colon cancer Most patients with stage II colon cancer (CC) are cured by surgery. Therefore, guidelines recommend to only offer adjuvant chemotherapy to patients who have a tumor with high-risk features. However, current selection is suboptimal, leading to recurrence of cancer in 13% of low-risk patients and unnecessary administration of chemotherapy in some high-risk patients. Previous studies indicate that a biomarker, so-called circulating tumour DNA (ctDNA), could improve the selection of high-risk patients for adjuvant chemotherapy, as patients who have detectable ctDNA in their blood after surgery are likely to develop a recurrence. Despite its potential, implementation is still pending. Our study assessed the long-term effectiveness and costs associated with various ctDNA-guided strategies for selecting high-risk patients for adjuvant chemotherapy in stage II CC. We used an health-economic model to simulate a cohort of 1000 Dutch patients with stage II CC from diagnosis to death. Next, we compared the health outcomes and costs of the ctDNA-guided strategies to those when selection is based on the Dutch guideline. We found that a combination of the Dutch guideline and ctDNA was the most effective strategy, but not cost-effective. Additional analyses showed that ctDNA-guided selection were cost-effective if the costs of the ctDNA test were below 1500 euros, if the ctDNA test performed significantly better, or if patients with detectable ctDNA responded better to chemotherapy. Thus, while post-surgery ctDNA status is a good indicator for recurrence risk, specific criteria related to ctDNA test performance and costs, in addition to combining ctDNA with current high-risk features, should be met to achieve cost-effective implementation. Looking ahead, future studies should explore how patients with detectable ctDNA respond to chemotherapy for next assessments of the cost-effectiveness of ctDNA-guided strategies in selecting patients with stage II CC for adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Background: In vitro haemolysis is a major operational challenge for medical laboratories. A new experimental design was used to investigate under what conditions algorithms could be designed to report either quantitative or qualitative aspartate aminotransferase and lactate dehydrogenase results outside the manufacturer's haemolysis specifications. Quantitative corrections were required to meet prespecified quality specifications. Methods: Twenty-five patient samples were used to design reporting algorithms and another 41 patient samples were used to validate the algorithms. Aspartate aminotransferase, lactate dehydrogenase and haemolysis index were determined using a Cobas 6000 analyser (Roche diagnostics, Mannheim, Germany). Correction factors were determined, and the accuracy of the correction was investigated. Reporting algorithms were designed based on (i) the manufacturer's cut-off for the haemolysis index, (ii) corrections within the total allowable error specification and (iii) qualitative reporting based on obtained results. The impact of the reporting algorithms was retrospectively determined by recalculating six months of aspartate aminotransferase and lactate dehydrogenase results. Results: No correction for aspartate aminotransferase/lactate dehydrogenase was possible for results below the upper reference interval limit, while results equal to or greater than the upper reference interval limit could, up to mild haemolysis, be corrected within the total error criterion. All samples generated from the validated patient cohort fulfilled the set criteria. The algorithms allowed reporting 88.5% and 85.9% of otherwise unreported aspartate aminotransferase and lactate dehydrogenase results, respectively. Conclusions: An approach is presented that allows to generate and validate reporting algorithms for aspartate aminotransferase and lactate dehydrogenase compatible with prespecified quality specifications. The designed algorithms resulted in a significant reduction of otherwise unreported aspartate aminotransferase and lactate dehydrogenase results. [ABSTRACT FROM AUTHOR]

This article presents a description of an analytical, stable, and flexible initial background state for both dry and moist baroclinic wave simulation on an aquaplanet in order to test the dynamical core of numerical weather prediction models and study the dynamics and evolution of extratropical cyclones. The initial background state is derived from an analytical zonal wind speed field, or jet structure, and the hydrostatic primitive equations for moist adiabatic and frictionless flow in spherical coordinates. A baroclinic wave can develop if a perturbation is added to the zonal wind speed field. This new baroclinic wave configuration has been implemented in the Open Integrated Forecasting System (OpenIFS) CY43R3, a global numerical weather prediction model developed by the European Centre for Medium-Range Weather Forecasts. In total, seven parameters can be used to control the generation of the initial background state and hence the development of the baroclinic waves in the OpenIFS configuration file: the jet's width, the jet's height, the maximum zonal mean wind speed of the jet, the horizontal mean of the surface virtual temperature, the surface relative humidity, the lapse rate, and the surface roughness. Nine dry and nine moist initial background states have been generated to test their stability without perturbations. The meteorological stability of the initial states is investigated by examining the spatial distributions of the equivalent potential temperature, the absolute vorticity, and the Brunt–Väisälä frequency. Moreover, the root mean square error (RMSE) of the zonal wind speed has been computed to assess their numerical stability. Finally, six dry and six moist initial background state have been used with an unbalanced perturbation to ensure that the baroclinic life cycles that develop are physically realistic. The resulting baroclinic wave is shown to be sensitive to the jet's width. This configuration for baroclinic wave simulations will be used to create a large ensemble of baroclinic life cycles to study how extratropical cyclones may evolve in the future. [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]

BACKGROUND: Anti-PD-(L)1 immunotherapy has emerged as a promising treatment approach for non-small cell lung cancer (NSCLC), though the response rates remain low. Pre-treatment response prediction may improve patient allocation for immunotherapy. Blood platelets act as active immune-like cells, thereby constraining T-cell activity, propagating cancer metastasis, and adjusting their spliced mRNA content. OBJECTIVE: We investigated whether platelet RNA profiles before start of nivolumab anti-PD1 immunotherapy may predict treatment responses. METHODS: We performed RNA-sequencing of platelet RNA samples isolated from stage III-IV NSCLC patients before treatment with nivolumab. Treatment response was scored by the RECIST-criteria. Data were analyzed using a predefined thromboSeq analysis including a particle-swarm-enhanced support vector machine (PSO/SVM) classification algorithm. RESULTS: We collected and processed a 286-samples cohort, separated into a training/evaluation and validation series and subjected those to training of the PSO/SVM-classification algorithm. We observed only low classification accuracy in the 107-samples validation series (area under the curve (AUC) training series: 0.73 (95% -CI: 0.63–0.84, n = 88 samples), AUC evaluation series: 0.64 (95% -CI: 0.51–0.76, n = 91 samples), AUC validation series: 0.58 (95% -CI: 0.45–0.70, n = 107 samples)), employing a five-RNAs biomarker panel. CONCLUSIONS: We concluded that platelet RNA may have minimally discriminative capacity for anti-PD1 nivolumab response prediction, with which the current methodology is insufficient for diagnostic application. [ABSTRACT FROM AUTHOR]

This article presents a description of an analytical, stable and flexible initial background state for moist baroclinic wave simulation on an aquaplanet in order to test dynamical core of numerical weather prediction models and study the dynamics and evolution of extra-tropical cyclones. The initial background state is derived from an analytical zonal wind speed field, or jet structure, and the hydrostatic primitive equations for moist adiabatic and frictionless flow in spherical coordinates. A baroclinic wave can develop only if a unbalanced perturbation is added to the zonal wind speed field. The implementation of this baroclinic wave simulation have been done on the Open Integrated Forecasting System (OpenIFS) cy43r3, a global numerical weather prediction model developed by the European Centre for Medium-range Weather Forecasts. In total, seven parameters can be used to control the generation of the initial background state and hence the development of the baroclinic waves in the OpenIFS configuration file: the jet's width, the jet's height, the maximum zonal mean wind speed of the jet, the horizontal mean of the surface virtual temperature, the surface relative humidity, the lapse rate and the surface roughness. Nine dry and nine moist initial background states have been generated to test their stability without perturbations. The meteorological stability of the initial state is investigated by examining the spatial distributions of the equivalent potential temperature, the absolute vorticity and the Brunt-Väisälä frequency. Moreover, the Root-Mean-Squared-Error (RMSE) of the zonal wind speed has been computed to assess their numerical stability. Finally, six of these moist initial initial background state have been used with an unbalanced perturbation to ensure that the baroclinic lifecycles developing are physically realistic. The resulting baroclinic wave is shown to be sensitive to the jet's width. This configuration for baroclinic wave simulations will be used to create large baroclinic lifecycles ensemble to study how extra-tropical cyclones may evolve in the future. [ABSTRACT FROM AUTHOR]