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Purpose The composition of thrombi retrieved during endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) due to large vessel occlusion (LVO) may differ depending on their origin. In this study, we investigated the association between thrombus composition and stroke etiology in a large population of patients from the Dutch MR CLEAN Registry treated with EVT in daily clinical practice. Methods The thrombi of 332 patients with AIS were histologically analyzed for red blood cells (RBC), fibrin/platelets (F/P), and white blood cells (leukocytes) using a machine learning algorithm. Stroke etiology was assessed using the Trial of Org 10,172 in acute stroke treatment (TOAST) classification. Results The thrombi of cardioembolic origin contained less RBC and more F/P than those of non-cardioembolic origin (25.8% vs 41.2% RBC [p = 0.003] and 67.1% vs 54.5% F/P [p = 0.004]). The likelihood of a non-cardioembolic source of stroke increased with increasing thrombus RBC content (OR 1.02; [95% CI 1.00–1.06] for each percent increase) and decreased with a higher F/P content (OR 1.02; [95% CI 1.00–1.06]). Thrombus composition in patients with a cardioembolic origin and undetermined origin was similar. Conclusion Thrombus composition is significantly associated with stroke etiology, with an increase in RBC and a decrease in F/P raising the odds for a non-cardioembolic cause. No difference between composition of cardioembolic thrombi and of undetermined origin was seen. This emphasizes the need for more extensive monitoring for arrhythmias and/or extended cardiac analysis in case of an undetermined origin.

Cribriform adenocarcinoma of salivary gland (CASG) is a rare, salivary gland tumor. In this report, we describe a case of CASG harboring a novel PPP2R2A::PRKD1 fusion. A 58-year-old female presented with an intraoral mass adjacent to the lower left third molar region. Morphological features at histological examination, immunohistochemical staining (p63+, p40-), and tumor location were indicative of CASG. However, due to the potential focal presence of a biphasic component within the tumor, RNA sequencing was performed to confirm the diagnosis. The subsequently found novel PPP2R2A::PRKD1 fusion adds to the rapidly evolving molecular landscape of salivary gland tumors. Additionally, we report that CASG may show some entrapment of pre-existent salivary gland ducts, which may be misinterpreted as tumor cells with myoepithelial differentiation.

BACKGROUND: Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA).METHODS: MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220.FINDINGS: Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2-5] vs 4 [2-6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1·67 [95% CI 1·20-2·32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0·72 [95% CI 0·44-1·18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4·59 [95% CI 1·49-14·10]).INTERPRETATION: In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6-24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow.FUNDING: Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

INTRODUCTION: This phase I study primarily addresses the safety and tolerability of Stereotactic radiotherapy on the primary tumor combined with double Immune Checkpoint Inhibition (SICI) in patients with non-small cell lung cancer (NSCLC). Increasing the release of neoantigens by radiotherapy might enhance response to immunotherapy. Especially, by targeting trunk mutations in the primary tumor.MATERIALS AND METHODS: In three sequential cohorts, immunotherapy regimes combined with stereotactic body radiotherapy (SBRT) on the primary tumor (1x20 Gy on 9 cc) were studied in stage IIIB/IV NSCLC patients progressing on chemotherapy. The first cohort (n = 3) received durvalumab. The second (n = 6) received a combination of tremelimumab and durvalumab followed by durvalumab monotherapy. The third cohort (n = 6) was similar except that the combination was reversed. Descriptive statistics were used to assess safety parameters and the exploratory outcomes of efficacy. Adverse events were reported using NCI CTCAE version 4.03. Exhaled breath was analyzed at baseline.RESULTS: Fifteen patients were included. Median irradiated volume was 9.13 cc, on a median primary tumor volume of 79 cc. There were seven patients with grade 1-2, and two patients with grade 3 treatment related adverse events. There was 1 dose limiting toxicity (colitis) with double immunotherapy.CONCLUSION: The combination of SBRT to the primary tumor and double immunotherapy in advanced NSCLC patients is safe and feasible.

Chronic obstructive pulmonary disease (COPD) is characterized by a persistent inflammatory state in the lungs and defective tissue repair. Although the inflammatory response in patients with COPD is well characterized and known to be exaggerated during exacerbations, its contribution to lung injury and abnormal repair is still unclear. In this study, we aimed to investigate how the inflammatory microenvironment affects the epithelial progenitors and their supporting mesenchymal niche cells involved in tissue repair of the distal lung. We focused on IL-1 beta, a key inflammatory mediator that is increased during exacerbations of COPD, and used an organoid model of lung epithelial cells and fibroblasts to assess the effect of IL-1 beta treatment on these cells' transcriptome and secreted factors. Whereas direct treatment of the lung organoids with IL-1 beta promoted organoid growth, this switched toward inhibition when it was added as fibroblast pretreatment followed by organoid treatment. We then investigated the IL-1 beta-driven mechanisms in the fibroblasts and found an inflammatory response related to (C-X-Cmotif) ligand (CXCL) chemokines; we confirmed that these chemokines were responsible for the impaired organoid growth and found that targeting their C-X-C chemokine receptors 1/2 (CXCR1/2) receptors or the IL-1 beta intracellular signaling reduced the proinflammatory response and restored organoid growth. These data demonstrate that IL-1 beta alters the fibroblasts' state by promoting a distinct inflammatory response, switching their supportive function on epithelial progenitors toward an inhibitory one in an organoid assay. These results imply that chronic inflammation functions as a shift toward inhibition of repair, thereby contributing to chronic inflammatory diseases like COPD.

Background: The aim of this study was to evaluate the long-term patient satisfaction and quality of life 9 to 13 years after autologous versus alloplastic breast reconstruction and compare the data to those of an earlier study.Methods: This is a 9-year follow-up study of 92 women who underwent breast reconstruction (47 autologous and 45 alloplastic) between 2006 and 2010 and filled out the BREAST-Q questionnaire in 2010. Changes in BREAST-Q scores were analyzed by using a change score from baseline (2010) to follow-up (2019), which was presented by a mean change score with 95% confidence intervals. Linear regression analyses were performed to test which patient characteristics were related to the BREAST-Q change scores.Results: The response rate at follow-up was 60% (25 autologous and 30 alloplastic). Responders at follow-up had a lower body mass index and had less frequently undergone unilateral breast reconstruction compared to the nonresponders. Women undergoing both autologous and alloplastic breast reconstruction had significantly decreased satisfaction with breasts (-4 points), satisfaction with outcome (-8 points), and satisfaction with nipples (-20 points) over time. None of the patient characteristics, including reconstruction technique, were related to the BREAST-Q change scores.Conclusions: Satisfaction with breasts, satisfaction with outcome, and satisfaction with nipples decreased slightly over time for women undergoing alloplastic and autologous breast reconstruction. Women undergoing autologous breast reconstruction seemed to remain more satisfied with their breasts 9 to 13 years after breast reconstruction compared to women undergoing alloplastic breast reconstruction. Because of the small sample size, conclusions should be carefully drawn. However, the results were in line with the expectations based on previous literature.

Objective Voice prosthesis leakage significantly affects the quality of life of patients undergoing laryngectomy, causing insecurity and frequent unplanned hospital visits and costs. In this study, the concept of prophylactic voice prosthesis replacement was explored to prevent leakages. Study Design Retrospective cohort study. Setting Tertiary hospital. Methods This study included all patients who underwent laryngectomy between 2000 and 2012 in the Netherlands Cancer Institute. Device lifetimes and voice prosthesis replacements of a retrospective cohort were used to calculate the number of needed voice prostheses per patient per year to prevent 70% of the leakages by prophylactic replacement. Various strategies for the timing of prophylactic replacement were considered: adaptive strategies based on the individual patient's history of replacement and fixed strategies based on the results of patients with similar voice prosthesis or treatment characteristics. Results Patients used a median 3.4 voice prostheses per year (range, 0.1-48.1). We found high inter- and intrapatient variability in device lifetime. When prophylactic replacement is applied, this would become a median 9.4 voice prostheses per year, which means replacement every 38 days, implying >6 additional voice prostheses per patient per year. The individual adaptive model showed that preventing 70% of the leakages was impossible for most patients and only a median 25% can be prevented. Monte-Carlo simulations showed that prophylactic replacement is not feasible due to the high coefficient of variation (SD/mean) in device lifetime. Conclusion Based on our simulations, prophylactic replacement of voice prostheses is not feasible due to high inter- and intrapatient variation in device lifetime.

Background: Poor glycemic control prior to cancer diagnosis for patients with preexisting type 2 diabetes (T2DM) may predict a worse cancer diagnosis. We investigated the association between pre-diagnosis glycemic control and all-cause mortality in patients with T2DM who develop cancer. Methods: This prospective cohort study linked data from three sources covering 1989 to 2019: a T2DM benchmarking database, the Netherlands Cancer Registry, and the Personal Records Database. We included patients with T2DM and incident primary breast, colorectal, or prostate cancer (stage 0–III), with target glycemic control defined according to Dutch guidelines. Analysis involved estimating the association between glycemic control and all-cause mortality with Cox proportional hazard models, accounting for individual expected survival relative to the general population and relevant disease (e.g., diabetes duration and medications) and individual (e.g., age and gender) characteristics. Results: Of the 71,648 linked cases, 620 had breast cancer, 774 had colorectal cancer, and 438 had prostate cancer, with follow-up data available for 6.4 (4.2–8.4), 5.6 (2.7–7.6), and 6.3 (4.5–8.2) years, respectively. Compared with patients with pre-diagnosis glycemic control at target, the HRs and 95% confidence intervals for mortality among those with pre-diagnosis glycemic control not at target were 1.40 (1.00–1.96) for breast cancer, 1.45 (1.12–1.88) for colorectal cancer, and 1.39 (0.98–1.98) for prostate cancer. Conclusions: Among patients with T2DM in Dutch primary care, poor glycemic control before diagnosis with breast and colorectal cancer can increase mortality compared with good control. Impact: Glycemic control prior to cancer diagnosis is of prognostic value.

Background: Proton arc technology has recently shown dosimetric gains for various treatment indications. The increased number of beams and energy layers (ELs) in proton arc plans, increases the degrees of freedom in plan optimization and thereby flexibility to spare dose in organs at risk (OARs). A relationship exists between dosimetric plan quality, delivery efficiency, the number of ELs -and beams in a proton arc plan.Purpose: This work aims to investigate the effect of the number of beams and ELs in a proton arc plan, on toxicity and delivery time for oropharyngeal cancer patients (OPC) selected for intensity modulated proton therapy (IMPT) based on the Dutch model-based approach.Methods: The EL reduction algorithm iteratively selects ELs from beams equidistantly spaced over a 360° arc. The beams in the final plan may contain multiple ELs, making them suited for static delivery on the studied treatment machine. The produced plans can therefore be called "step and shoot" proton arc plans. The number of beams and ELs were varied to determine the relationship with the planning cost function value, normal tissue complication probability (NTCP) and delivery time. Proton arc plans with robust target coverage and optimal energy layer reduction (ELR) settings to reduce NTCP, were generated for 10 OPC patients. Proton arc plans were compared to clinical volumetric modulated arc therapy (VMAT) and IMPT plans in terms of integral dose, OAR dose, NTCP for xerostomia and dysphagia and delivery time. Furthermore, dose-weighted average linear energy transfer (LETd ) distributions were compared between the IMPT and proton arc plans. A dry run delivery of a plan containing 20 beams and 360 ELs was performed to evaluate delivery time and accuracy.Results: We found 360 ELs distributed over 30 beams generated proton arc plans with near minimal expected plan toxicity. Relative to corresponding IMPT and VMAT plans, an average reduction of 21 ± 3% and 58 ± 10% in integral dose was observed. Dmean was reduced most in the pharyngeal constrictor muscle (PCM) medius structure, with on average 9.0 ± 4.2 Gy(RBE) (p=0.0002) compared to the clinical IMPT plans. The average NTCP for grade⩾2 and grade⩾3 xerostomia at six months after treatment significantly decreased with 4.7 ± 1.8% (p = 0.002) and 1.7 ± 0.8% (p=0.002), respectively, while the average NTCP for grade⩾2 and grade⩾3 dysphagia decreased with 4.4 ± 2.9% (p=0.002) and 0.9 ± 0.4% (p=0.002), respectively, increasing the benefit of protons relative to VMAT. For a "step and shoot" proton arc delivery with auto beam sequencing the estimated delivery time is 11 min, similar to the delivery time of a 6-field IMPT treatment. Gamma analysis between the planned and delivered dose distribution resulted in a 99.99% pass rate using 1mm/1% dose difference/distance to agreement criteria.Conclusions: "Step and shoot" proton arc demonstrates potential to further reduce toxicity compared to IMPT and VMAT in OPC treatment. By employing 360 ELs and 30 beams in the proposed ELR method, delivery time can reach clinically acceptable levels without compromising plan toxicity when automatic beam sequencing is available.

Purpose The number of M1-like and M2-like tumour-associated macrophages (TAMs) and their ratio can play a role in breast cancer development and progression. Early clinical trials using macrophage targeting compounds are currently ongoing. However, the most optimal detection method of M1-like and M2-like macrophage subsets and their clinical relevance in breast cancer is still unclear. We aimed to optimize the assessment of TAM subsets in different breast cancer subtypes, and therefore related TAM subset numbers and ratio to clinicopathological characteristics and clinical outcome. Methods Tissue microarrays of 347 consecutive primary Luminal-A, Luminal-B, HER2-positive and triple-negative tumours of patients with early-stage breast cancer were serially sectioned and immunohistochemically stained for the pan-macrophage marker CD68 and the M2-like macrophage markers CD163, CSF-1R and CD206. TAM numbers were quantified using a digital image analysis algorithm. M1-like macrophage numbers were calculated by subtracting M2-like TAM numbers from the total TAM number. Results M2-like markers CD163 and CSF-1R showed a moderate positive association with each other and with CD68 (r ≥ 0.47), but only weakly with CD206 (r ≤ 0.06). CD68 + , CD163 + and CSF-1R + macrophages correlated with tumour grade in Luminal-B tumours (P Conclusion In conclusion, macrophages and their subsets can be detected by means of a panel of TAM markers and are related to unfavourable clinicopathological characteristics in Luminal-B breast cancer. However, their impact on outcome remains unclear. Preferably, this should be determined in prospective series.

Purpose: To assess sinoatrial node (SAN) and atrioventricular node (AVN) doses for breast cancer (BC) patients treated with 3D-CRT and evaluate whether “large” cardiac structures (whole heart and four cardiac chambers) would be relevant surrogates. Material and methods: This single center study was based on 116 BCE patients (56 left-sided, 60 right-sided) treated with 3D-CRT without respiratory gating strategies and few IMN irradiations from 2009 to 2013. The heart, the left and right ventricles (LV, RV), the left and right atria (LA, RA) were contoured using multi-atlases for auto-segmentation. The SAN and the AVN were manually delineated using a specific atlas. Based on regression analysis, the coefficients of determination (R2) were estimated to evaluate whether “large” cardiac structures were relevant surrogates (R2 > 0.70) of SAN and AVN doses. Results: For left-sided BC, mean doses were: 3.60 ± 2.28 Gy for heart, 0.47 ± 0.24 Gy for SAN and 0.74 ± 0.29 Gy for AVN. For right-sided BC, mean heart dose was 0.60 ± 0.25 Gy, mean SAN dose was 1.57 ± 0.63 Gy (>85 % of patients with SAN doses > 1 Gy) and mean AVN dose was 0.51 ± 0.14 Gy. Among all “large” cardiac structures, RA appeared as the best surrogate for SAN doses (R2 > 0.80). Regarding AVN doses, the RA may also be an interesting surrogate for left-sided BC (R2 = 0.78), but none of “large” cardiac structures appeared as relevant surrogates among right-sided BC (all R2 < 0.70), except the LA for patients with IMN (R2 = 0.83). Conclusions: In BC patients treated 10 years ago with 3D-CRT, SAN and AVN exposure was moderate but could exceed 1 Gy to the SAN in many right-sided patients with no IMN-inclusion. The RA appeared as an interesting surrogate for SAN exposure. Specific conduction nodes delineation remains necessary by using modern radiotherapy techniques.

•There is a lack of prospective level I evidence for the use of PBT for most adult cancers including oropharyngeal squamous cell carcinoma (OPSCC).•TORPEdO is the UK's first PBT clinical trial and aims to determine the benefits of PBT for OPSCC.•Training and support has been provided before and during the trial to reduce variations of contouring and radiotherapy planning.•There is a strong translational component within TORPEdO. Imaging and physics data along with blood, tissue collection will inform future studies in refining patient selection for IMPT.

Contains fulltext : 291298.pdf (Publisher’s version ) (Open Access) Circulating tumor DNA (ctDNA) is a promising new biomarker with multiple potential applications in cancer care. Estimating total cost of ctDNA testing is necessary for reimbursement and implementation, but challenging because of variations in workflow. We aimed to develop a micro-costing framework for consistent cost calculation of ctDNA testing. First, the foundation of the framework was built, based on the complete step-wise diagnostic workflow of ctDNA testing. Second, the costing method was set up, including costs for personnel, materials, equipment, overhead, and failures. Third, the framework was evaluated by experts and applied to six case studies, including PCR-, mass spectrometry-, and next-generation sequencing-based platforms, from three Dutch hospitals. The developed ctDNA micro-costing framework includes the diagnostic workflow from blood sample collection to diagnostic test result. The framework was developed from a Dutch perspective and takes testing volume into account. An open access tool is provided to allow for laboratory-specific calculations to explore the total costs of ctDNA testing specific workflow parameters matching the setting of interest. It also allows to straightforwardly assess the impact of alternative prices or assumptions on the cost per sample by simply varying the input parameters. The case studies showed a wide range of costs, from €168 to €7638 ($199 to $9124) per sample, and generated information. These costs are sensitive to the (coverage of) platform, setting, and testing volume. 01 januari 2023

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

Objective: Hemangioblastomas in the central nervous system are the most common manifestation of von Hippel-Lindau (VHL) disease. Because the growth rate of hemangioblastomas is unpredictable, regular follow-up is mandatory, focusing on clinical symptoms and imaging of the central nervous system. However, clinical symptoms may be subtle and nonspecific, and data about the relationship between the radiologic findings and clinical symptoms are sparse. This study aims to evaluate if and how findings of magnetic resonance imaging (MRI) regarding spinal hemangioblastomas are associated with symptoms of VHL disease, with special attention to peritumoral edema and spinal cysts. Methods: Serial spinal MRI scans of 43 genetically or clinically established VHL patients with at least 2 years of follow-up were reevaluated to examine the volume, growth rate, and location of spinal hemangioblastomas and the presence, size, and growth rate of peritumoral edema and cysts. Findings were compared with clinical symptoms using the Fisher exact test. Results: We observed a total of 77 spinal hemangioblastomas in 28 patients. Eight of the 28 patients showed peritumoral edema and spinal cysts, and 1 patient showed peritumoral edema without cyst formation; 6 of these 9 patients showed clinical symptoms. Both peritumoral edema and spinal cysts were associated with clinical symptoms (P = 0.023 and P = 0.011, respectively). Conclusions: The presence of peritumoral edema and/or spinal cysts shown on MRI in VHL patients with spinal hemangioblastomas is associated with symptoms in more than half of the patients and may alert the clinician to intensify clinical and radiologic surveillance.

Programmed death ligand-1 (PD-L1) immunostaining, which aids clinicians in decision-making on immunotherapy for non-small cell lung cancer (NSCLC) patients, is sometimes performed on cytological specimens. In this study, differences in cytology fixation and cell block (CB) processing between pathology laboratories were assessed, and the influence of these differences on interlaboratory variation in PD-L1 positivity was investigated. Questionnaires on cytology processing were sent to all Dutch laboratories. Information gathered from the responses was added to data on all Dutch NSCLC patients with a mention of PD-L1 testing in their cytopathology report from July 2017 to December 2018, retrieved from PALGA (the nationwide network and registry of histo- and cytopathology in the Netherlands). Case mix-adjusted PD-L1 positivity rates were determined for laboratories with known fixation and CB method. The influence of differences in cytology processing on interlaboratory variation in PD-L1 positivity was assessed by comparing positivity rates adjusted for differences in the variables fixative and CB method with positivity rates not adjusted for differences in these variables. Twenty-eight laboratories responded to the survey and reported 19 different combinations of fixation and CB method. Interlaboratory variation in PD-L1 positivity was assessed in 19 laboratories. Correcting for differences in the fixative and CB method resulted in a reduction (from eight (42.1%) to five (26.3%)) in the number of laboratories that differed significantly from the mean in PD-L1 positivity. Substantial variation in cytology fixation and CB processing methods was observed between Dutch pathology laboratories, which partially explains the existing considerable interlaboratory variation in PD-L1 positivity.

Parathyroid diseases are characterized by dysregulation of calcium homeostasis and alterations in parathyroid hormone (PTH) excretion. The development of parathyroid-targeted treatment and imaging tracers could benefit from in vitro models. Therefore, we aim to establish a patient-derived parathyroid organoid model representing human parathyroid tissue. Hyperplastic parathyroid tissue was dispersed, and parathyroid organoids (PTOs) were cultured and characterized. PTO-derived cells exhibited self-renewal over several passages, indicative of the presence of putative stem cells. Immunofluorescence and RNA sequencing confirmed that PTOs phenocopy hyperplastic parathyroid tissue. Exposure of PTOs to increasing calcium concentrations and PTH-lowering drugs resulted in significantly reduced PTH excretion. PTOs showed specific binding of the imaging tracers 11C-methionine and 99mTc-sestamibi. These data show the functionality of PTOs resembling the parathyroid. This PTO model recapitulates the originating tissue on gene and protein expression and functionality, paving the way for future physiology studies and therapeutic target and tracer discovery.

Contains fulltext : 287508.pdf (Publisher’s version ) (Closed access) BACKGROUND: Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset. METHODS: MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308. FINDINGS: On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1-4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65-1·47]). In the target population (n=291), the 90-day mRS score was 2 (2-4) in the glyceryl trinitrate group and 3 (1-4) in the control group (0·92 [0·59-1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53-2·14]) or serious adverse events (unadjusted OR 1·23 [0·76-1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78-44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18-4·17]). INTERPRETATION: We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting. FUNDING: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

PURPOSE Determining the estrogen receptor (ER) status is essential in metastatic breast cancer (MBC) management. Whole-body ER imaging with 16α-[18F]fluoro-17β-estradiol positron emission tomography ([18F]FES-PET) is increasingly used for this purpose. To establish the clinical validity of the [18F]FES-PET, we studied the diagnostic accuracy of qualitative and quantitative [18F]FES-PET assessment to predict ER expression by immunohistochemistry in a metastasis. METHODS In a prospective multicenter trial, 200 patients with newly diagnosed MBC underwent extensive workup including molecular imaging. For this subanalysis, ER expression in the biopsied metastasis was related to qualitative whole-body [18F]FES-PET evaluation and quantitative [18F]FES uptake in the corresponding metastasis. A review and meta-analysis regarding [18F]FES-PET diagnostic performance were performed. RESULTS Whole-body [18F]FES-PET assessment predicted ER expression in the biopsied metastasis with good accuracy: a sensitivity of 95% (95% CI, 89 to 97), a specificity of 80% (66 to 89), a positive predictive value (PPV) of 93% (87 to 96), and a negative predictive value (NPV) of 85% (72 to 92) in 181 of 200 evaluable patients. Quantitative [18F]FES uptake predicted ER immunohistochemistry in the corresponding metastasis with a sensitivity/specificity of 91%/69% and a PPV/NPV of 90%/71% in 156 of 200 evaluable patients. For bone metastases, PPV/NPV was 92%/81%. Meta-analysis with addition of our data has increased diagnostic performance and narrowed the 95% CIs compared with previous studies with a sensitivity/specificity of both 86% (81 to 90 and 73 to 93, respectively). CONCLUSION In this largest prospective series so far, we established the clinical validity of [18F]FES-PET to determine tumor ER status in MBC. In view of the high diagnostic accuracy of qualitatively assessed whole-body [18F]FES-PET, this noninvasive imaging modality can be considered a valid alternative to a biopsy of a metastasis to determine ER status in newly MBC (ClinicalTrials.gov identifier: NCT01957332 ).

Background: We aimed to assess whether the effect of intravenous alteplase treatment (IVT) before endovascular treatment (EVT) on outcome is modified by first-line technique during EVT in IVT eligible patients. Methods: This was a post hoc analysis from MR CLEAN-NO IV (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands - Intravenous Treatment Followed by Intra-Arterial Treatment Versus Direct Intra-Arterial Treatment for Acute Ischemic Stroke Caused by a Proximal Intracranial Occlusion), a randomized trial of IVT followed by EVT versus EVT alone in patients presenting directly to EVT-capable centers. We included data from all patients who underwent EVT with a thrombectomy attempt. We compared patients treated with stent retriever (with or without aspiration) to aspiration alone as first-line EVT technique and assessed the interaction of first-line EVT technique with IVT treatment. Primary outcome was the 90-day modified Rankin Scale score, analyzed with mixed model ordinal regression for a shift towards better outcome. Secondary outcomes included successful reperfusion (extended Thrombolysis in Cerebral Infarction score 2b–3). Results: Of 473 included patients, 102 (21.6%) were treated with aspiration alone as first-line technique. In the full population, functional outcome was similar for patients treated with stent retriever versus aspiration only (adjusted common odds ratio [acOR]‚ 1.07 [95% CI, 0.69–1.66]). We observed a significant interaction between IVT and first-line EVT technique ( P =0.03). In the aspiration-only group, patients treated with EVT alone had worse functional outcome compared to those treated with IVT and EVT (acOR, 0.44 [95% CI, 0.21–0.90]). In the stent retriever group, functional outcome did not differ between patients treated with or without IVT (acOR, 1.08 [95% CI, 0.74–1.57]). There was no statistically significant interaction for successful reperfusion. Conclusions: In MR CLEAN-NO IV, the treatment effect of IVT was modified by first-line EVT technique. Patients treated with aspiration only as first-line technique had worse clinical outcomes if they did not receive IVT. No such difference was observed in patients treated with stent retrievers. Confirmation by pooling with results from other trials is needed to confirm these findings.

Biogenesis of nuclear pore complexes (NPCs) includes the formation of the permeability barrier composed of phenylalanine-glycine-rich nucleoporins (FG-Nups) that regulate the selective passage of biomolecules across the nuclear envelope. The FG-Nups are intrinsically disordered and prone to liquid–liquid phase separation and aggregation when isolated. How FG-Nups are protected from making inappropriate interactions during NPC biogenesis is not fully understood. Here we find that DNAJB6, a molecular chaperone of the heat shock protein network, forms foci in close proximity to NPCs. The number of these foci decreases upon removal of proteins involved in the early steps of interphase NPC biogenesis. Conversely, when this process is stalled in the last steps, the number of DNAJB6-containing foci increases and these foci are identified as herniations at the nuclear envelope. Immunoelectron tomography shows that DNAJB6 localizes inside the lumen of the herniations arising at NPC biogenesis intermediates. Loss of DNAJB6 results in the accumulation of cytosolic annulate lamellae, which are structures containing partly assembled NPCs, a feature associated with disturbances in NPC biogenesis. We find that DNAJB6 binds to FG-Nups and can prevent the aggregation of the FG region of several FG-Nups in cells and in vitro. Together, our data show that the molecular chaperone DNAJB6 provides quality control during NPC biogenesis and is involved in the surveillance of native intrinsically disordered FG-Nups.

Yu Pu,1,&ast; Xiuxiu Zhou,1,&ast; Di Zhang,1,&ast; Yu Guan,1,&ast; Yi Xia,1 Wenting Tu,1 Yang Lu,2 Weidong Zhang,2 Chi-Cheng Fu,2 Qu Fang,2 Geertruida H de Bock,3 Shiyuan Liu,1 Li Fan1 1Department of Radiology, Changzheng Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Scientific Research, Shanghai Aitrox Technology Corporation Limited, Shanghai, People’s Republic of China; 3Department of Epidemiology, University Medical Center Groningen, Groningen, the Netherlands&ast;These authors contributed equally to this workCorrespondence: Shiyuan Liu; Li Fan, Department of Radiology, ChangZheng Hospital, Naval Medical University, No. 415 Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel +86 21 81886012 ; Tel +86 21 81886012, Fax +86 21 63587668, Email cjr.liushiyuan@vip.163.com; fanli0930@163.comPurpose: To explore optimal threshold of FEV1% predicted value (FEV1%pre) for high-risk chronic obstructive pulmonary disease (COPD) using the parameter response mapping (PRM) based on machine learning classification model.Patients and Methods: A total of 561 consecutive non-COPD subjects who were screened for chest diseases in our hospital between August and October 2018 and who had complete questionnaire surveys, pulmonary function tests (PFT), and paired respiratory chest CT scans were enrolled retrospectively. The CT quantitative parameter for small airway remodeling was PRM, and 72 parameters were obtained at the levels of whole lung, left and right lung, and five lobes. To identify a more reasonable thresholds of FEV1% predicted value for distinguishing high-risk COPD patients from the normal, 80 thresholds from 50% to 129% were taken with a partition of 1% to establish a random forest classification model under each threshold, such that novel PFT-parameter-based high-risk criteria would be more consistent with the PRM-based machine learning classification model.Results: Machine learning-based PRM showed that consistency between PRM parameters and PFT was better able to distinguish high-risk COPD from the normal, with an AUC of 0.84 when the threshold was 72%. When the threshold was 80%, the AUC was 0.72 and when the threshold was 95%, the AUC was 0.64.Conclusion: Machine learning-based PRM is feasible for redefining high-risk COPD, and setting the optimal FEV1% predicted value lays the foundation for redefining high-risk COPD diagnosis.Keywords: chronic obstructive pulmonary disease, computed tomography, pulmonary function test, quantitative imaging, artificial intelligence

Psychoneurological symptoms are commonly reported by newly diagnosed head and neck cancer (HNC) patients, yet there is limited research on the associations of these symptoms with biomarkers of stress and inflammation. In this article, pre-treatment data of a multi-center cohort of HNC patients were analyzed using a network analysis to examine connections between symptoms (poor sleep quality, anxiety, depression, fatigue, and oral pain), biomarkers of stress (diurnal cortisol slope), inflammation markers (c-reactive protein [CRP], interleukin [IL]-6, IL-10, and tumor necrosis factor alpha [TNF-α]), and covariates (age and body mass index [BMI]). Three centrality indices were calculated: degree (number of connections), closeness (proximity of a variable to other variables), and betweenness (based on the number of times a variable is located on the shortest path between any pair of other variables). In a sample of 264 patients, poor sleep quality and fatigue had the highest degree index; fatigue and CRP had the highest closeness index; and IL-6 had the highest betweenness index. The model yielded two clusters: a symptoms—cortisol slope—CRP cluster and a IL-6—IL-10—TNF-α—age—BMI cluster. Both clusters were connected most prominently via IL-6. Our findings provide evidence that poor sleep quality, fatigue, CRP, and IL-6 play an important role in the interconnections between psychoneurological symptoms and biomarkers of stress and inflammation in newly diagnosed HNC patients.

Targeted therapy in lung cancer requires the assessment of multiple oncogenic driver alterations, including fusion genes. This retrospective study evaluated the Idylla GeneFusion prototype, an automated and ease-of-use (

This study aimed to assess the prognostic value of intratumoral CD57+ cells in head and neck squamous cell carcinoma (HNSCC) and to examine the reproducibility of these analyses using QuPath. Pretreatment biopsies of 159 patients with HPV-negative, stage III/IV HNSCC treated with chemoradiotherapy were immunohistochemically stained for CD57. The number of CD57+ cells per mm2 tumor epithelium was quantified by two independent observers and by QuPath, software for digital pathology image analysis. Concordance between the observers and QuPath was assessed by intraclass correlation coefficients (ICC). The correlation between CD57 and clinicopathological characteristics was assessed; associations with clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves. The patient cohort had a 3-year OS of 65.8% with a median follow-up of 54 months. The number of CD57+ cells/mm2 tumor tissue did not correlate to OS, DFS, or LRC. N stage predicted prognosis (OS: HR 0.43, p = 0.008; DFS: HR 0.41, p = 0.003; LRC: HR 0.24, p = 0.007), as did WHO performance state (OS: HR 0.48, p = 0.028; LRC: 0.33, p = 0.039). Quantification by QuPath showed moderate to good concordance with two human observers (ICCs 0.836, CI 0.805–0.863, and 0.741, CI 0.692–0.783, respectively). In conclusion, the presence of CD57+ TILs did not correlate to prognosis in advanced stage, HPV-negative HNSCC patients treated with chemoradiotherapy. Substantial concordance between human observers and QuPath was found, confirming a promising future role for digital, algorithm driven image analysis.

Purpose Multiple sclerosis (MS) is a disease characterized by inflammatory demyelinated lesions. New treatment strategies are being developed to stimulate myelin repair. Quantitative myelin imaging could facilitate these developments. This first-in-man study aimed to evaluate [11C]MeDAS as a PET tracer for myelin imaging in humans. Methods Six healthy controls and 11 MS patients underwent MRI and dynamic [11C]MeDAS PET scanning with arterial sampling. Lesion detection and classification were performed on MRI. [11C]MeDAS time-activity curves of brain regions and MS lesions were fitted with various compartment models for the identification of the best model to describe [11C]MeDAS kinetics. Several simplified methods were compared to the optimal compartment model. Results Visual analysis of the fits of [11C]MeDAS time-activity curves showed no preference for irreversible (2T3k) or reversible (2T4k) two-tissue compartment model. Both volume of distribution and binding potential estimates showed a high degree of variability. As this was not the case for 2T3k-derived net influx rate (Ki), the 2T3k model was selected as the model of choice. Simplified methods, such as SUV and MLAIR2 correlated well with 2T3k-derived Ki, but SUV showed subject-dependent bias when compared to 2T3k. Both the 2T3k model and the simplified methods were able to differentiate not only between gray and white matter, but also between lesions with different myelin densities. Conclusion [11C]MeDAS PET can be used for quantification of myelin density in MS patients and is able to distinguish differences in myelin density within MS lesions. The 2T3k model is the optimal compartment model and MLAIR2 is the best simplified method for quantification. Trial registration. NL7262. Registered 18 September 2018.

BACKGROUND AND PURPOSE: Supervised deep learning is the state-of-the-art method for stroke lesion segmentation on NCCT. Supervised methods require manual lesion annotations for model development, while unsupervised deep learning methods such as generative adversarial networks do not. The aim of this study was to develop and evaluate a generative adversarial network to segment infarct and hemorrhagic stroke lesions on follow-up NCCT scans.MATERIALS AND METHODS: Training data consisted of 820 patients with baseline and follow-up NCCT from 3 Dutch acute ischemic stroke trials. A generative adversarial network was optimized to transform a follow-up scan with a lesion to a generated baseline scan without a lesion by generating a difference map that was subtracted from the follow-up scan. The generated difference map was used to automatically extract lesion segmentations. Segmentation of primary hemorrhagic lesions, hemorrhagic transformation of ischemic stroke, and 24-hour and 1-week follow-up infarct lesions were evaluated relative to expert annotations with the Dice similarity coefficient, Bland-Altman analysis, and intraclass correlation coefficient.RESULTS: The median Dice similarity coefficient was 0.31 (interquartile range, 0.08-0.59) and 0.59 (interquartile range, 0.29-0.74) for the 24-hour and 1-week infarct lesions, respectively. A much lower Dice similarity coefficient was measured for hemorrhagic transformation (median, 0.02; interquartile range, 0-0.14) and primary hemorrhage lesions (median, 0.08; interquartile range, 0.01-0.35). Predicted lesion volume and the intraclass correlation coefficient were good for the 24-hour (bias, 3 mL; limits of agreement, -64-59 mL; intraclass correlation coefficient, 0.83; 95% CI, 0.78-0.88) and excellent for the 1-week (bias, -4 m; limits of agreement,-66-58 mL; intraclass correlation coefficient, 0.90; 95% CI, 0.83-0.93) follow-up infarct lesions.CONCLUSIONS: An unsupervised generative adversarial network can be used to obtain automated infarct lesion segmentations with a moderate Dice similarity coefficient and good volumetric correspondence.

PURPOSE Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naïve, and thus can be used for chemotherapy de-escalation strategies, is unknown. METHODS We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population–based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and ≥ 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk. RESULTS sTILs were scored for 441 patients. High sTILs (≥ 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (χ2 = 46.7, P < .001). CONCLUSION Chemotherapy-naïve, young patients with N0 TNBC with high sTILs (≥ 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies.

Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis1. CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING2,3. These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance. However, cGAS and STING are rarely inactivated in cancer4, and, although they have been implicated in metastasis5, it is not known why loss-of-function mutations do not arise in primary tumours4. Here we show that inactivation of cGAS-STING signalling selectively impairs the survival of triple-negative breast cancer cells that display CIN. CIN triggers IL-6-STAT3-mediated signalling, which depends on the cGAS-STING pathway and the non-canonical NF-κB pathway. Blockade of IL-6 signalling by tocilizumab, a clinically used drug that targets the IL-6 receptor (IL-6R), selectively impairs the growth of cultured triple-negative breast cancer cells that exhibit CIN. Moreover, outgrowth of chromosomally instable tumours is significantly delayed compared with tumours that do not display CIN. Notably, this targetable vulnerability is conserved across cancer types that express high levels of IL-6 and/or IL-6R in vitro and in vivo. Together, our work demonstrates pro-tumorigenic traits of cGAS-STING signalling and explains why the cGAS-STING pathway is rarely inactivated in primary tumours. Repurposing tocilizumab could be a strategy to treat cancers with CIN that overexpress IL-6R.

Cooling at 4°C is routinely used to lower metabolism and preserve cell and tissue integrity in laboratory and clinical settings, including organ transplantation. However, cooling and rewarming produce cell damage, attributed primarily to a burst of reactive oxygen species (ROS) upon rewarming. While DNA represents a highly vulnerable target of ROS, it is unknown whether cooling and/or rewarming produces DNA damage. Here, we show that cooling alone suffices to produce extensive DNA damage in cultured primary cells and cell lines, including double-strand breaks (DSBs), as shown by comet assay and pulsed-field gel electrophoresis. Cooling-induced DSB formation is time- and temperature-dependent and coincides with an excess production of ROS, rather than a decrease in ATP levels. Immunohistochemistry confirmed that DNA damage activates the DNA damage response marked by the formation of nuclear foci of proteins involved in DSB repair, γ-H2Ax, and 53BP1. Subsequent rewarming for 24 h fails to recover ATP levels and only marginally lowers DSB amounts and nuclear foci. Precluding ROS formation by dopamine and the hydroxychromanol, Sul-121, dose-dependently reduces DSBs. Finally, a standard clinical kidney transplant procedure, using cold static storage in UW preservation solution up to 24 h in porcine kidney, lowered ATP, increased ROS, and produced increasing amounts of DSBs with recruitment of 53BP1. Given that DNA repair is erroneous by nature, cooling-inflicted DNA damage may affect cell survival, proliferation, and genomic stability, significantly impacting cellular and organ function, with relevance in stem cell and transplantation procedures.

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

BACKGROUND AND PURPOSE: Radiotherapy during pregnancy is rarely administered due to lack of data and practical challenges. This is the first detailed report of proton therapy as cancer treatment for a pregnant patient with nasopharyngeal carcinoma. MATERIALS AND METHODS: Pencil beam scanning proton therapy was prescribed to a pregnant patient to a total dose of 70 Gy (RBE) to the therapeutic CTV and 54.25 Gy to the prophylactic CTV, delivered in 35 fractions with a simultaneous integrated boost technique. RESULTS: Phantom measurements showed a thirty-fold decrease in fetal radiation dose when using proton compared to photon therapy, with a total fetal dose of 5.5 mSv for the complete proton treatment, compared to 185 and 298 mSv for the photon treatment with and without lead shielding, respectively. After adminstering proton therapy during pregnancy, at 39 weeks of gestation, a healthy boy with a birthweight on the 83th percentile was delivered. Pediatric follow-up at 2 months of age of the offspring showed normal growth and age-adequate motor development with no signs of neurological problems. MR follow-up of the tumor 3 months after the end of treatment showed complete remission. CONCLUSION: This case demonstrates the potential of proton therapy for treatment during pregnancy.Compared to photon therapy, proton therapy can significantly limit fetal dose, while simultaneously offering a more optimized treatment to the patient. ispartof: CLINICAL AND TRANSLATIONAL RADIATION ONCOLOGY vol:35 pages:33-36 ispartof: location:Ireland status: published

Background Radiotherapy (RT) and chemotherapy are components of standard multi-modality treatment of high grade gliomas (HGG) aimed at achieving local tumor control. Treatment is neurotoxic and RT plays an important role in this, inducing damage even distant to the RT target volume. Purpose This retrospective longitudinal study evaluated the effect of treatment on white matter and gray matter volume in the tumor-free hemisphere of HGG patients using voxel based morphometry (VBM). Method 3D T1-weighted MR images of 12 HGG patients at multiple timepoints during standard treatment were analyzed using VBM. Segmentation of white matter and gray matter of the tumor-free hemisphere was performed. Multiple general linear models were used to asses white matter and gray matter volumetric differences between time points. A mean RT dose map was created and compared to the VBM results. Results Diffuse loss of white matter volume, mainly throughout the frontal and parietal lobe, was found, grossly overlapping regions that received the highest RT dose. Significant loss of white matter was first noticed after three cycles of chemotherapy and persisted after the completion of standard treatment. No significant loss of white matter volume was observed between pre-RT and the first post-RT follow-up timepoint, indicating a delayed effect. Conclusion This study demonstrated diffuse and early-delayed decreases in white matter volume of the tumor-free hemisphere in HGG patients after standard treatment. White matter volume changes occurred mainly throughout the frontal and parietal lobe and grossly overlapped with areas that received the highest RT dose.

The aim of this study was to evaluate whether radiologically defined sarcopenia, or a low skeletal muscle index (SMI), could be used as a practical biomarker for frailty and postoperative complications (POC) in patients with head and neck skin cancer (HNSC). This was a retrospective study on prospectively collected data. The L3 SMI (cm2/m2) was calculated with use of baseline CT or MRI neck scans and low SMIs were defined using sex-specific cut-off values. A geriatric assessment with a broad range of validated tools was performed at baseline. POC was graded with the Clavien–Dindo Classification (with a grade of > II as the cut-off). Univariate and multivariable regression analyses were performed with low SMIs and POC as the endpoints. The patients’ (n = 57) mean age was 77.0 ± 9 years, 68.4% were male, and 50.9% had stage III–IV cancer. Frailty was determined according to Geriatric 8 (G8) score (OR 7.68, 95% CI 1.19–49.66, p = 0.032) and the risk of malnutrition was determined according to the Malnutrition Universal Screening Tool (OR 9.55, 95% CI 1.19–76.94, p = 0.034), and these were independently related to low SMIs. Frailty based on G8 score (OR 5.42, 95% CI 1.25–23.49, p = 0.024) was the only variable related to POC. However, POC was more prevalent in patients with low SMIs (∆ 19%, OR 1.8, 95% CI 0.5–6.0, p = 0.356).To conclude, a low SMI is a practical biomarker for frailty and malnutrition in HNSC. Future research should be focused on interventions based on low SMI scores and assess the effect of the intervention on SMI, frailty, malnutrition, and POC.

Purpose: Despite the anticipated clinical benefits of intensity-modulated proton therapy (IMPT), plan robustness may be compromised due to its sensitivity to patient treatment uncertainties, especially for tumours with large motion. In this study, we investigated treatment course-wise plan robustness for intra-thoracic tumours with large motion comparing a 4D pre-clinical evaluation method (4DREM) to our clinical 3D/4D dose reconstruction and accumulation methods.Materials and methods: Twenty patients with large target motion (>10 mm) were treated with five times layered rescanned IMPT. The 3D-robust optimised plans were generated on the averaged planning 4DCT. Using multiple 4DCTs, treatment plan robustness was assessed on a weekly and treatment course-wise basis through the 3D robustness evaluation method (3DREM, based on averaged 4DCTs), the 4D robustness evaluation method (4DREM, including the time structure of treatment delivery and 4DCT phases) and 4D dose reconstruction and accumulation (4DREAL, based on fraction-wise information).Results: Baseline target motion for all patients ranged from 11–17 mm. For the offline adapted course-wise dose assessment, adequate target dose coverage was found for all patients. The target volume receiving 95% of the prescription dose was consistent between methods with 16/20 patients showing differences < 1%. 4DREAL showed the highest target coverage (99.8 ± 0.6%, p < 0.001), while no differences were observed between 3DREM and 4DREM (99.3 ± 1.3% and 99.4 ± 1.1%, respectively).Conclusion: Our results show that intra-thoracic tumours can be adequately treated with IMPT in free breathing for target motion amplitudes up to 17 mm employing any of the accumulation methods. Anatomical changes, setup and range errors demonstrated a more severe impact on target coverage than motion in these patients treated with fractionated proton radiotherapy.

Background: Intensity modulated proton beam therapy (IMPT) for head and neck cancer offers dosimetric benefits for the organs at risk when compared to photon-based volumetric modulated arch therapy (VMAT). However, limited data exists about the potential benefits of IMPT for tooth-bearing regions. The aim of this study was to compare the IMPT and VMAT radiation dosimetrics of the tooth-bearing regions in head and neck cancer patients. Also, we aimed to identify prognostic factors for a cumulative radiation dose of ≥40 Gy on the tooth-bearing areas, which is considered the threshold dose for prophylactic dental extractions. Methods: A total of 121 head and neck cancer patients were included in this retrospective analysis of prospectively collected data. We compared the average Dmean values of IMPT versus VMAT of multiple tooth-bearing regions in the same patients. Multivariate logistic regression analysis was performed for receiving a cumulative radiation dose of ≥40 Gy to the tooth-bearing regions (primary endpoint) in both VMAT and IMPT. Results: A lower Dmean was seen after applying IMPT to the tooth-bearing tumour regions (p < 0.001). Regarding VMAT, oral cavity tumours, T3-T4 tumours, molar regions in the mandible, and regions ipsilateral to the tumour were risk factors for receiving a cumulative radiation dose of ≥40 Gy. Conclusions: IMPT significantly reduces the radiation dose to the tooth-bearing regions.

Background Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia. Methods Hepatocyte-specific G6pc knockout (L-G6pc−/−) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity. Results Hepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged. Conclusions In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease.

Background Insight into outcome variation between hospitals could help to improve quality of care. We aimed to assess the validity of early outcomes as quality indicators for acute ischemic stroke care for patients treated with endovascular therapy (EVT). Methods and Results We used data from the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, a large multicenter prospective cohort study including 3279 patients with acute ischemic stroke undergoing EVT. Random effect linear and proportional odds regression were used to analyze the effect of case mix on between‐hospital differences in 2 early outcomes: the National Institutes of Health Stroke Scale (NIHSS) score at 24 to 48 hours and the expanded thrombolysis in cerebral infarction score. Between‐hospital variation in outcomes was assessed using the variance of random hospital effects (tau 2 ). In addition, we estimated the correlation between hospitals' EVT‐patient volume and (case‐mix–adjusted) outcomes. Both early outcomes and case‐mix characteristics varied significantly across hospitals. Between‐hospital variation in the expanded thrombolysis in cerebral infarction score was not influenced by case‐mix adjustment (tau 2 =0.17 in both models). In contrast, for the NIHSS score at 24 to 48 hours, case‐mix adjustment led to a decrease in variation between hospitals (tau 2 decreases from 0.19 to 0.17). Hospitals' EVT‐patient volume was strongly correlated with higher expanded thrombolysis in cerebral infarction scores ( r =0.48) and weakly with lower NIHSS score at 24 to 48 hours ( r =0.15). Conclusions Between‐hospital variation in NIHSS score at 24 to 48 hours is significantly influenced by case‐mix but not by patient volume. In contrast, between‐hospital variation in expanded thrombolysis in cerebral infarction score is strongly influenced by EVT‐patient volume but not by case‐mix. Both outcomes may be suitable for comparing hospitals on quality of care, provided that adequate adjustment for case‐mix is applied for NIHSS score.

Photosensitizing properties of hydrochlorothiazide may increase skin cancer risk. To date, study findings on the association between hydrochlorothiazide use and skin cancer risk are inconsistent, notably regarding confounding and dose-response. The aim of this study was to investigate the association between hydrochlorothiazide use and incidence of skin cancer in a cohort of unselected Caucasian adults, taking dosing into account. As part of the PharmLines Initiative, which links data from the Lifelines Cohort Study and prescription database IADB.nl, patients aged ≥ 40 years were included from Lifelines, a prospective population-based cohort study in the north of the Netherlands. Skin cancer incidence was compared between subjects starting hydrochlorothiazide treatment (n = 608), subjects starting treatment with other antihypertensives (n = 508), and non-antihypertensive long-term medication users (n = 1,710). Cox regression analyses were performed to obtain hazard ratios, adjusted for potential confounders. The risk of any skin cancer, keratinocyte carcinoma, basal cell carcinoma and squamous cell carcinoma was not significantly increased in general hydrochlorothiazide users. A clear association was observed between high cumulative hydrochlorothiazide use (≥ 5,000 defined daily dose; ≥ 125,000 mg) and the risk of any skin cancer (adjusted hazard ratio 5.32, 95% confidence interval (95% CI) 2.40–11.81), keratinocyte carcinoma (adjusted hazard ratio 7.31, 95% CI 3.12–17.13), basal cell carcinoma (adjusted hazard ratio 7.72, 95% CI 3.11–19.16) and squamous cell carcinoma (adjusted hazard ratio 19.63, 95% CI 3.12–123.56). These findings should lead to awareness with high use of hydrochlorothiazide in Caucasian adults.

BACKGROUND: The aim of this study is to explore problems in radiotherapy for breast cancer patients in Yogyakarta, Indonesia, focusing on overall treatment time (OTT) and completion rate.METHODS: A retrospective cohort study was conducted based on data from the Insurance Unit at a tertiary hospital in Yogyakarta, Indonesia. The study included all female outpatients with breast cancer who were treated with radiotherapy from January to December 2017 and met the inclusion criteria. The primary outcomes were OTT and completion rate. The secondary outcomes included the number of radiotherapy fractions, radiotherapy doses, number of radiotherapy interruption days, and reasons for radiotherapy interruption. The chi-squared and Mann-Whitney U tests were used to assess the differences in outcomes between two insurance schemes (JKN-PBI (Beneficiaries of Health Insurance Contribution Assistance) and JKN-NON-PBI (Non-Beneficiaries of Health Insurance Contribution Assistance)).RESULTS: The sample included 285 breast cancer patients (mean age: 53 years). The median OTT was 38 days (IQR: 17-48 days), with 123 (43.2%) patients having prolonged OTT. The completion rate was 57.9%. No significant differences in OTT (44.4% vs. 35.7%, p = 0.445) and completion rate (57.2% vs. 61.9%, p = 0.569) were found between the JKN-NON-PBI and JKN-PBI groups, respectively. In all, the data reported 3,022 interrupted days of radiotherapy across a total of 227 patients. The most common reason for radiotherapy interruption was unknown.CONCLUSION: There are problems in timely delivery and low completion rate of radiotherapy among breast cancer patients in Indonesia. There are no significant differences in OTT and completion rate between the insurance schemes.

PURPOSE: The aim of this study was to evaluate an automated treatment planning method for robustly optimized intensity modulated proton therapy (IMPT) plans for oropharyngeal carcinoma patients and to compare the results with manually optimized robust IMPT plans.METHODS AND MATERIALS: An atlas regression forest-based machine learning (ML) model for dose prediction was trained on CT scans, contours, and dose distributions of robust IMPT plans of 88 oropharyngeal cancer (OPC) patients. The ML model was combined with a robust voxel and dose volume histogram-based dose mimicking optimization algorithm for 21 perturbed scenarios to generate a machine-deliverable plan from the predicted dose distribution. Machine learning optimization (MLO) configuration was performed using a cross-validation approach with 3 × 8 tuning patients and comprised of adjustments to the mimicking optimization, to generate higher-quality MLO plans. Independent testing of the MLO algorithm was performed with another 25 patients. Plan quality of clinical and MLO plans was evaluated by the clinical target volume (D98% voxel-wise minimum dose >94%), organ at risk (OAR) doses, and the normal tissue complication probability (NTCP) (sum (Σ) of grade-2 and grade-3 dysphagia and xerostomia).RESULTS: Adequate robust target coverage was achieved in 24/25 clinical plans and in 23/25 MLO plans in the primary clinical target volume (CTV). In the elective CTV, 22/25 clinical plans and 24/25 MLO plans passed the robust target coverage evaluation threshold. The MLO average Σgrade 2 and Σgrade 3 NTCPs were comparable to the clinical plans (Σgrade 2 NTCPs: clinical 47.5% vs MLO 48.4%, Σgrade 3 NTCPs: clinical 11.9% vs MLO 12.3%). Significant increases in OAR average doses in MLO plans were found in the pharynx constrictor muscles (163 cGy, P = .002) and cervical esophagus (265 cGy, P = .002). The MLO plans were created within 45 minutes.CONCLUSION: This study showed that automated MLO planning can generate robustly optimized MLO plans with quality comparable to clinical plans in OPC patients.

Background: A larger thrombus in patients with acute ischemic stroke might result in more complex endovascular treatment procedures, resulting in poorer patient outcomes. Current evidence on thrombus volume and length related to procedural and functional outcomes remains contradicting. This study aimed to assess the prognostic value of thrombus volume and thrombus length and whether this relationship differs between first-line stent retrievers and aspiration devices for endovascular treatment. Methods: In this multicenter retrospective cohort study, 670 of 3279 patients from the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) for endovascularly treated large vessel occlusions were included. Thrombus volume (0.1 mL) and length (0.1 mm) based on manual segmentations and measurements were related to reperfusion grade (expanded Treatment in Cerebral Infarction score) after endovascular treatment, the number of retrieval attempts, symptomatic intracranial hemorrhage, and a shift for functional outcome at 90 days measured with the reverted ordinal modified Rankin Scale (odds ratio >1 implies a favorable outcome). Univariable and multivariable linear and logistic regression were used to report common odds ratios (cORs)/adjusted cOR and regression coefficients (B/aB) with 95% CIs. Furthermore, a multiplicative interaction term was used to analyze the relationship between first-line device choice, stent retrievers versus aspiration device, thrombus volume, and outcomes. Results: Thrombus volume was associated with functional outcome (adjusted cOR, 0.83 [95% CI, 0.71–0.97]) and number of retrieval attempts (aB, 0.16 [95% CI, 0.16–0.28]) but not with the other outcome measures. Thrombus length was only associated with functional independence (adjusted cOR, 0.45 [95% CI, 0.24–0.85]). Patients with more voluminous thrombi had worse functional outcomes if endovascular treatment was based on first-line stent retrievers (interaction cOR, 0.67 [95% CI, 0.50–0.89]; P =0.005; adjusted cOR, 0.74 [95% CI, 0.55–1.0]; P =0.04). Conclusions: In this study, patients with a more voluminous thrombus required more endovascular thrombus retrieval attempts and had a worse functional outcome. Patients with a lengthier thrombus were less likely to achieve functional independence at 90 days. For more voluminous thrombi, first-line stent retrieval compared with first-line aspiration might be associated with worse functional outcome.

Trials show that low-dose computed tomography (CT) lung cancer screening in long-term (ex-)smokers reduces lung cancer mortality. However, many individuals were exposed to unnecessary diagnostic procedures. This project aims to improve the efficiency of lung cancer screening by identifying high-risk participants, and improving risk discrimination for nodules. This study is an extension of the Dutch-Belgian Randomized Lung Cancer Screening Trial, with a focus on personalized outcome prediction (NELSON-POP). New data will be added on genetics, air pollution, malignancy risk for lung nodules, and CT biomarkers beyond lung nodules (emphysema, coronary calcification, bone density, vertebral height and body composition). The roles of polygenic risk scores and air pollution in screen-detected lung cancer diagnosis and survival will be established. The association between the AI-based nodule malignancy score and lung cancer will be evaluated at baseline and incident screening rounds. The association of chest CT imaging biomarkers with outcomes will be established. Based on these results, multisource prediction models for pre-screening and post-baseline-screening participant selection and nodule management will be developed. The new models will be externally validated. We hypothesize that we can identify 15-20% participants with low-risk of lung cancer or short life expectancy and thus prevent ~140,000 Dutch individuals from being screened unnecessarily. We hypothesize that our models will improve the specificity of nodule management by 10% without loss of sensitivity as compared to assessment of nodule size/growth alone, and reduce unnecessary work-up by 40-50%. ispartof: EUROPEAN JOURNAL OF EPIDEMIOLOGY vol:38 issue:4 pages:445-454 ispartof: location:Netherlands status: published

Objectives This study aimed to evaluate the association between visual emphysema and the presence of lung nodules, and Lung-RADS category with low-dose CT (LDCT). Methods Baseline LDCT scans of 1162 participants from a lung cancer screening study (Nelcin-B3) performed in a Chinese general population were included. The presence, subtypes, and severity of emphysema (at least trace) were visually assessed by one radiologist. The presence, size, and classification of non-calcified lung nodules (≥ 30 mm3) and Lung-RADS category were independently assessed by another two radiologists. Multivariable logistic regression and stratified analyses were performed to estimate the association between emphysema and lung nodules, Lung-RADS category, after adjusting for age, sex, BMI, smoking status, pack-years, and passive smoking. Results Emphysema and lung nodules were observed in 674 (58.0%) and 424 (36.5%) participants, respectively. Participants with emphysema had a 71% increased risk of having lung nodules (adjusted odds ratios, aOR: 1.71, 95% CI: 1.26–2.31) and 70% increased risk of positive Lung-RADS category (aOR: 1.70, 95% CI: 1.09–2.66) than those without emphysema. Participants with paraseptal emphysema (n = 47, 4.0%) were at a higher risk for lung nodules than those with centrilobular emphysema (CLE) (aOR: 2.43, 95% CI: 1.32–4.50 and aOR: 1.60, 95% CI: 1.23–2.09, respectively). Only CLE was associated with positive Lung-RADS category (p = 0.02). CLE severity was related to a higher risk of lung nodules (ranges aOR: 1.44–2.61, overall p < 0.01). Conclusion In a Chinese general population, visual emphysema based on LDCT is independently related to the presence of lung nodules (≥ 30 mm3) and specifically CLE subtype is related to positive Lung-RADS category. The risk of lung nodules increases with CLE severity. Key Points • Participants with emphysema had an increased risk of having lung nodules, especially smokers. • Participants with PSE were at a higher risk for lung nodules than those with CLE, but nodules in participants with CLE had a higher risk of positive Lung-RADS category. • The risk of lung nodules increases with CLE severity.

Contains fulltext : 273921.pdf (Publisher’s version ) (Open Access) BACKGROUND: T4-classified squamous cell carcinoma (SCC) of external auditory canal (EAC) can potentially involve different anatomical structures, which could translate into different treatment strategies and survival outcomes within one classification. Our aim is to evaluate the clinical added value of T4-subclasses proposed by Lavieille and by Zanoletti. METHODS: Retrospective data, including patients with primary operated cT4-classified EAC SCC, was obtained from 12 international hospitals. We subclassified according to the T4-subclasses. The treatment strategies, disease-free survival (DFS) and overall survival per subclass were calculated. RESULTS: A total of 130 T4-classified EAC SCC were included. We found commonly used treatment strategies per subclass according to Lavieille and the DFS seems also to differ per subclass. Subclass according to Zanoletti showed comparable treatment strategies and survival outcomes per subclass. CONCLUSION: Our study suggests that the subclass according Lavieille might have added value in clinical practice to improve care of T4-classified EAC SCC.

Cellular senescence defines a state of stable and generally irreversible proliferative arrest associated with various morphological, structural and functional changes (Figure 1), including enhanced expression and secretion of pro-inflammatory and tissue-remodelling mediators. This state is crucial in tissue physiology and pathology and arises as a response to potentially damaging stress signals. Whether the activation of a senescence state provides benefits or detriments for tissue function and homeostasis is strictly dependent on the context. Cell senescence acts as a potent tumour-suppressive mechanism limiting the proliferation of cells at risk of malignant transformation and supports the repair of acute tissue damage, but also represents a key driver of ageing and age-related diseases.

OBJECTIVES: The recent accelerated FDA approval of sotorasib, a highly selective KRAS G12C inhibitor, offers new opportunities for the treatment of KRAS p.(G12C)-mutated non-squamous non-small cell lung cancer (NSCLC). The objective of the current study was to the determine the prevalence of KRAS mutations in stage IV non-squamous NSCLC in The Netherlands to reveal the potential impact of upcoming KRAS targeted therapy.MATERIALS AND METHODS: All patients diagnosed with stage IV non-squamous NSCLC in 2013, 2015 and 2017 in the Netherlands were selected by linking the nation-wide Netherlands Cancer Registry (NCR) and the Dutch Pathology Registry (PALGA). Demographic and pathological variables were retrieved from the pathology reports including sex, age, KRAS mutation status, molecular test method used, and the mutation status of other genes.RESULTS: Prevalence for any KRAS mutations in codon 12/13/61/146 was 39.1%. KRAS p.(G12C) was detected in 15.5% of all non-squamous NSCLC cases representing 39.6% of all KRAS-mutant cases. National testing rate for KRAS mutations increased from 70% in 2013 to 82% in 2017. Testing techniques changed significantly over time with next generation sequencing as the main used method in 2017 (71.6%) but did not affect prevalence of KRAS mutations over time. When KRAS was tested as part of a larger panel, the KRAS p.(G12C) mutation was frequently reported with a concurrent mutation in TP53 (47.7%) or STK11 (10.3%).CONCLUSION: The high prevalence for KRAS p.(G12C) offers a promising new specific treatment option for 15% of all stage IV non-squamous NSCLC patients.

Contains fulltext : 252010.pdf (Publisher’s version ) (Open Access) OBJECTIVES: The number of targeted drugs in non-small cell lung cancer (NSCLC) is ever-expanding and requires testing of an increasing number of predictive biomarkers. We present a comprehensive real-world evaluation of molecular testing and treatment selection in stage IV NSCLC patients in the Netherlands from 2017 to 2019. MATERIALS AND METHODS: Molecular pathology reports of NSCLC patients were collected from the Dutch Pathology Registry in time intervals between Oct-2017 and April-2019 (N = 5,038 patients) to study diagnostic yield. Linkage between the Dutch Pathology Registry and the Netherlands Cancer Registry enabled studying molecular testing rates for stage IV NSCLC initially diagnosed in 2017-Q4 (N = 1,193) and application of targeted therapy in stage IV NSCLC patients with potentially druggable alterations reported between Oct-2017 and June-2018 (N = 401). RESULTS: Predictive molecular testing was performed in 85.0% of adenocarcinomas, 60.4% of NSCLC-not otherwise specified (NOS) and 17.4% of squamous cell carcinomas. Testing rates were highest for EGFR and ALK (adenocarcinoma: 82.7% and 80.7%, respectively). Incidence of molecular driver alterations (i.e. EGFR, KRAS, ALK, ROS1, BRAF, MET, ERBB2, FGFR1) was 61.1% for adenocarcinomas, 42.3% for NSCLC-NOS, and 24.7% for squamous cell carcinomas. Therapeutically relevant alterations were detected at a higher frequency by NGS- versus non-NGS-approaches (adenocarcinoma: 62.4% versus 56.5%, respectively (P = 0.004)) due to a lower failure rate, more comprehensive testing and higher sensitivity. Uptake of treatment with a registered targeted therapy in eligible patients varied per actionable target, i.e. EGFR: 85.8%, ALK: 74.7%, ROS1: 33.7%, BRAF: 51.5%. Treatment with agents in clinical studies/compassionate use was lower, i.e. MET: 22.8%, HER2: 18.9%, RET: 6.7%. CONCLUSION: Real-world data show NGS-based approaches to be superior to non-NGS. Uptake of molecular testing and the corresponding targeted treatments was less than expected based on guidelines and even more so for trials, off-label use and compassionate use, indicating less than optimal access to rational treatment options.

INTRODUCTION: In stage III non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduces the brain metastases incidence and prolongs the progression-free survival without improving overall survival. PCI increases the risk of toxicity and is currently not adopted in routine care. Our objective was to assess the cost-effectiveness of PCI compared with no PCI in stage III NSCLC from a Dutch societal perspective.METHODS: A cohort partitioned survival model was developed based on individual patient data from three randomized phase III trials (N=670). Quality-adjusted life years (QALYs) and costs were estimated over a lifetime time horizon.. A willingness-to-pay (WTP) threshold of €80,000 per QALY was adopted. Sensitivity and scenario analyses were performed to address parameter uncertainty and to explore what parameters had the greatest impact on the cost-effectiveness results.RESULTS: PCI was more effective and costly (0.443 QALYs, €10,123) than no PCI, resulting in an incremental cost-effectiveness ratio (ICER) of €22,843 per QALY gained. The probability of PCI being cost-effective at a WTP threshold of €80,000 per QALY was 93%. The probability of PCI gaining three and six additional months of life were 76% and 56%. The scenario analysis adding durvalumab increased the ICER to €35,159 per QALY gained. Using alternative survival distributions had little impact on the ICER. Assuming fewer PCI fractions and excluding indirect costs decreased the ICER to €18,263 and €5,554 per QALY gained.CONCLUSION: PCI is cost-effective compared to no PCI in stage III NSCLC, and could therefore, from a cost-effectiveness perspective, be considered in routine care.

BACKGROUND: To investigate associations between psychological problems and the use of healthcare and informal care and total costs among head and neck cancer (HNC) patients.METHOD: Data were used of the NETherlands QUality of Life and Biomedical Cohort study. Anxiety and depression disorder (diagnostic interview), distress, symptoms of anxiety and depression (HADS), and fear of cancer recurrence (FCR) and cancer worry scale (CWS) were measured at baseline and at 12-month follow-up. Care use and costs (questionnaire) were measured at baseline, 3-, 6-, 12-, and 24-month follow-up. Associations between psychological problems and care use/costs were investigated using logistic and multiple regression analyses.RESULTS: Data of 558 patients were used. Distress, symptoms of anxiety or depression, FCR, and/or anxiety disorder at baseline were significantly associated with higher use of primary care, supportive care, and/or informal care (odds ratios (ORs) between 1.55 and 4.76). Symptoms of anxiety, FCR, and/or depression disorder at 12-month follow-up were significantly associated with use of primary care, supportive care, and/or informal care (ORs between 1.74 and 6.42). Distress, symptoms of anxiety, and FCR at baseline were associated with higher total costs.DISCUSSION: HNC patients with psychological problems make more use of healthcare and informal care and have higher costs. This is not the result of worse clinical outcomes.