BackgroundAfter an acute infection, older persons may benefit from geriatric rehabilitation (GR).ObjectivesThis study describes the recovery trajectories of post-COVID-19 patients undergoing GR and... Show moreBackgroundAfter an acute infection, older persons may benefit from geriatric rehabilitation (GR).ObjectivesThis study describes the recovery trajectories of post-COVID-19 patients undergoing GR and explores whether frailty is associated with recovery.DesignMulticentre prospective cohort study.Setting59 GR facilities in 10 European countries.ParticipantsPost-COVID-19 patients admitted to GR between October 2020 and October 2021.MethodsPatients’ characteristics, daily functioning (Barthel index; BI), quality of life (QoL; EQ-5D-5L) and frailty (Clinical Frailty Scale; CFS) were collected at admission, discharge, 6 weeks and 6 months after discharge. We used linear mixed models to examine the trajectories of daily functioning and QoL.Results723 participants were included with a mean age of 75 (SD: 9.91) years. Most participants were pre-frail to frail (median [interquartile range] CFS 6.0 [5.0–7.0]) at admission. After admission, the BI first steeply increased from 11.31 with 2.51 (SE 0.15, P < 0.001) points per month and stabilised around 17.0 (quadratic slope: −0.26, SE 0.02, P < 0.001). Similarly, EQ-5D-5L first steeply increased from 0.569 with 0.126 points per month (SE 0.008, P < 0.001) and stabilised around 0.8 (quadratic slope: −0.014, SE 0.001, P < 0.001). Functional recovery rates were independent of frailty level at admission. QoL was lower at admission for frailer participants, but increased faster, stabilising at almost equal QoL values for frail, pre-frail and fit patients.ConclusionsPost-COVID-19 patients admitted to GR showed substantial recovery in daily functioning and QoL. Frailty at GR admission was not associated with recovery and should not be a reason to exclude patients from GR. Show less
Introduction: Zr-89-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([Zr-89]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune... Show moreIntroduction: Zr-89-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([Zr-89]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune system. The measured uptake consists of target-specific and non-specific components, and it can be influenced by plasma availability of the tracer. To find evidence for target-specific uptake, i.e., target engagement, we studied five immune-checkpoint-targeting [Zr-89]Zr-mAbs to (1) compare the uptake with previously reported baseline values for non-specific organ uptake (ns-baseline) and (2) look for saturation effects of increasing mass doses. Method: Zr-89-immuno-PET data from five [Zr-89]Zr-mAbs, i.e., nivolumab and pembrolizumab (anti-PD-1), durvalumab (anti-PD-L1), BI 754,111 (anti-LAG-3), and ipilimumab (anti-CTLA-4), were analysed. For each mAb, 2-3 different mass doses were evaluated. PET scans and blood samples from at least two time points 24 h post injection were available. In 35 patients, brain, kidneys, liver, spleen, lungs, and bone marrow were delineated. Patlak analysis was used to account for differences in plasma activity concentration and to quantify irreversible uptake (K-i). To identify target engagement, K-i values were compared to ns-baseline K-i values previously reported, and the effect of increasing mass doses on K-i was investigated. Results: All mAbs, except ipilimumab, showed K-i values in spleen above the ns-baseline for the lowest administered mass dose, in addition to decreasing K-i values with higher mass doses, both indicative of target engagement. For bone marrow, no ns-baseline was established previously, but a similar pattern was observed. For kidneys, most mAbs showed K-i values within the ns-baseline for both low and high mass doses. However, with high mass doses, some saturation effects were seen, suggestive of a lower ns-baseline value. K-i values were near zero in brain tissue for all mass doses of all mAbs. Conclusion: Using Patlak analysis and the established ns-baseline values, evidence for target engagement in (lymphoid) organs for several immune checkpoint inhibitors could be demonstrated. A decrease in the K-i values with increasing mass doses supports the applicability of Patlak analysis for the assessment of target engagement for PET ligands with irreversible uptake behavior. Show less
Tohidinezhad, F.; Bontempi, D.; Zhang, Z.; Dingemans, A.M.; Aerts, J.; Bootsma, G.; ... ; Ruysscher, D. de 2023
Introduction: Immunotherapy-induced pneumonitis (IIP) is a serious side-effect which requires accurate diagnosis and management with high-dose corticosteroids. The differ-ential diagnosis between... Show moreIntroduction: Immunotherapy-induced pneumonitis (IIP) is a serious side-effect which requires accurate diagnosis and management with high-dose corticosteroids. The differ-ential diagnosis between IIP and other types of pneumonitis (OTP) remains challenging due to similar radiological patterns. This study was aimed to develop a prediction model to differentiate IIP from OTP in patients with stage IV non-small cell lung cancer (NSCLC) who developed pneumonitis during immunotherapy. Methods: Consecutive patients with metastatic NSCLC treated with immunotherapy in six centres in the Netherlands and Belgium from 2017 to 2020 were reviewed and cause-specific pneumonitis events were identified. Seven regions of interest (segmented lungs and sphe-roidal/cubical regions surrounding the inflammation) were examined to extract the most pre-dictive radiomic features from the chest computed tomography images obtained at pneumonitis manifestation. Models were internally tested regarding discrimination, calibra-tion and decisional benefit. To evaluate the clinical application of the models, predicted labels were compared with the separate clinical and radiological judgements. Results: A total of 556 patients were reviewed; 31 patients (5.6%) developed IIP and 41 pa-tients developed OTP (7.4%). The line of immunotherapy was the only predictive factor in the clinical model (2nd versus 1st odds ratio Z 0.08, 95% confidence interval:0.01-0.77). The best radiomic model was achieved using a 75-mm spheroidal region of interest which showed an optimism-corrected area under the receiver operating characteristic curve of 0.83 (95% confidence interval:0.77-0.95) with negative and positive predictive values of 80% and 79%, respectively. Good calibration and net benefits were achieved for the radiomic model across the entire range of probabilities. A correct diagnosis was provided by the radiomic model in 10 out of 12 cases with non-conclusive radiological judgements. Conclusion: Radiomic biomarkers applied to computed tomography imaging may support cli-nicians making the differential diagnosis of pneumonitis in patients with NSCLC receiving immunotherapy, especially when the radiologic assessment is non-conclusive. 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
This open-label Phase II study conducted prior to routine EGFR mutation testing, assessed whether acquired resistance to erlotinib in NSCLC patients with a given MET protein expression level... Show moreThis open-label Phase II study conducted prior to routine EGFR mutation testing, assessed whether acquired resistance to erlotinib in NSCLC patients with a given MET protein expression level enriched for EGFRmt could be overcome by emibetuzumab, an antibody against MET. Although some responses were seen, the trial did not meet its primary endpoint.Introduction: The hepatocyte growth factor receptor MET represents a resistance mechanism to epidermal growth factor receptor (EGFR) inhibition in EGFR mutant (mt) non-small cell lung cancer (NSCLC). This Phase 2 study tested whether acquired resistance to erlotinib in MET protein positive NSCLC patients enriched for EGFRmt can be overcome by emibetuzumab plus erlotinib. Patient and Methods: Patients with Stage IV NSCLC with acquired resistance to erlotinib and MET diagnostic (+) (>= 10% of cells expressing MET at >= 2+ IHC staining intensity at any time) were randomized (3:1) to receive emibetuzumab 750 mg every 2 weeks with or without erlotinib 150 mg once daily. The primary objective was to evaluate the overall response rate (ORR) relative to historic control, with a co-primary objective of ORR in patients with MET expression in >= 60% of cells >= 2+ (MET > 60%). Results: One hundred and eleven MET+ patients received emibetuzumab plus erlotinib (N = 83) or emibetuzumab monotherapy (N = 28). 89 of 111 MET+ samples were post-erlotinib. ORR was 3.0% for emibetuzumab plus erlotinib (95% CI: 0.4, 10.5) and 4.3% for emibetuzumab (95% CI: 0.1, 21.9), in patients with post-erlotinib progression biopsies available (n = 89). Similar results were observed in patients with MET >= 60% expression (n = 74). Disease control rate and progression-free survival were higher for emibetuzumab plus erlotinib (50%/3.3 months) than for emibetuzumab (26%/1.6 months). No unexpected safety signals emerged. Partial responses were observed in patients with and without EGFRmt or MET amplification. EGFR sensitizing mutations were identified retrospectively in 84.2% of those with available tissue (85/101). Conclusion: Acquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit. (C) 2022 Elsevier Inc. All rights reserved. Show less
MET exon 14 ( MET ex14) skipping mutations occur in 3% to 4% of non-small cell lung cancer (NSCLC) cases. Currently, four oral MET tyrosine kinase inhibitors (TKIs) are in use for the treatment of... Show moreMET exon 14 ( MET ex14) skipping mutations occur in 3% to 4% of non-small cell lung cancer (NSCLC) cases. Currently, four oral MET tyrosine kinase inhibitors (TKIs) are in use for the treatment of patients with MET ex14 skipping NSCLC (tepotinib, capmatinib, savolitinib, and crizotinib). To support optimal management of MET ex14 skipping NSCLC in this typically older patient population, the safety profiles of these treatment options are reviewed here. Published safety data from prospective clinical trials with MET TKIs in patients with MET ex14 skipping NSCLC were reviewed. Treatmentrelated adverse events (TRAEs) occurring in > 10% of patients were reported where feasible. Guidance on clinical monitoring and management of key MET TKI TRAEs and dr ug-dr ug interactions is provided. Across the clinical trials, safety data for MET TKIs were reported for 442 patients with MET ex14 skipping. Peripheral edema was the most reported TRAE (50%-63% of patients; grade > 3: 1%-11%), followed by nausea (26%-46% of patients; grade > 3: 0%1%). TRAEs led to dose reductions in 33% to 38% of patients and to discontinuation in 7% to 14% of patients, across the MET TKIs. Considerations on interpreting available safety data are provided, along with insights into monitoring and managing specific MET TKI TRAEs of interest and dr ug-dr ug interactions. Overall, MET TKIs are tolerable treatment options for patients with MET ex14 skipping NSCLC, an older population for whom chemo- or immuno-therapy may not be an effective nor tolerable option. More data regarding the effectiveness of safety interventions and management strategies are needed. Show less
Ven, M. van de; Koffijberg, H.; Retel, V.; Monkhorst, K.; Smit, E.; Harten, W. van; IJzerman, M. 2021
The continued introduction of biomarkers and innovative testing methods makes already complex diagnosis in patients with stage IV nonesmall-cell lung cancer (NSCLC) even more complex. This study... Show moreThe continued introduction of biomarkers and innovative testing methods makes already complex diagnosis in patients with stage IV nonesmall-cell lung cancer (NSCLC) even more complex. This study primarily analyzed variations in biomarker testing in clinical practice in patients referred to a comprehensive cancer center in the Netherlands. The secondary aim was to compare the cost of biomarker testing with the cost of whole-genome sequencing. The cohort included 102 stage IV NSCLC patients who received biomarker testing in 2017 or 2018 at the comprehensive cancer center. The complete biomarker testing history of the cohort was identified using linked data from the comprehensive cancer center and the nationwide network and registry of histopathology and cytopathology in the Netherlands. Unique biomarker-test combinations, costs, turnaround times, and test utilization were examined. The results indicate substantial variation in test utilization and sequences. The mean cost per patient of biomarker testing was 2259.92 +/- 1217.10 USD, or 1881.23 +/- 1013.15 EUR. Targeted gene panels were most frequently conducted, followed by IHC analysis for programmed cell death protein ligand 1. Typically, the most common biomarkers were assessed within the first tests, and emerging biomarkers were tested further down the test sequence. At the cost of current biomarker testing, replacing current testing with whole-genome sequencing would have led to costsavings in only two patients (2%). Show less
PD-L1, as assessed by immunohistochemistry, is a predictive biomarker for immuno-oncology treatment in lung cancer. Different scoring methods have been used to assess its status, resulting in a... Show morePD-L1, as assessed by immunohistochemistry, is a predictive biomarker for immuno-oncology treatment in lung cancer. Different scoring methods have been used to assess its status, resulting in a wide range of positivity rates. We use the European Thoracic Oncology Platform Lungscape non-small cell lung carcinoma cohort to explore this issue. PD-L1 expression was assessed via immunohistochemistry on tissue microarrays (up to four cores per case), using the DAKO 28-8 immunohistochemistry assay, following a two-round external quality assessment procedure. All samples were analyzed under the same protocol. Cross-validation of scoring between tissue microarray and whole sections was performed in 10% randomly selected samples. Cutoff points considered: >= 1, 50 (primarily), and 25%. At the two external quality assessment rounds, tissue microarray scoring agreement rates between pathologists were: 73% and 81%. There were 2008 cases with valid immunohistochemistry tissue microarray results (50% all cores evaluable). Concordant cases at 1, 25, and 50% were: 85, 91, and 93%. Tissue microarray core results were identical for 70% of cases. Sensitivity of the tissue microarray method for 1, 25, and 50% was: 80, 78, and 79% (specificity: 90, 95, 98%). Complete agreement between tissue microarrays and whole sections was achieved for 60% of the cases. Highest sensitivity rates for 1% and 50% cutoffs were detected for higher number of cores. Underestimation of PD-L1 expression on small samples is more common than overestimation. We demonstrated that classification of PD-L1 on small biopsy samples does not represent the overall expression of PD-L1 in all non-small cell cancer carcinoma cases, although the majority of cases are 'correctly' classified. In future studies, sampling more and larger biopsies, recording the biopsy size and tumor load may permit further refinement, increasing predictive accuracy. Show less
Zoest, R.A. van; Law, M.; Sabin, C.A.; Vaartjes, I.; Valk, M. van der; Arends, J.E.; ... ; Elst-Laurijssen, D.H. 2019
