Limited Additional Value of a Chest CT in Whole-Body Staging with PET-MRI: A Retrospective Cohort Study.

Hybrid PET-MRI systems are being used more frequently. One of the drawbacks of PET-MRI imaging is its inferiority in detecting lung nodules, so it is often combined with a computed tomography (CT) of the chest. However, chest CT often detects additional, indeterminate lung nodules. The objective of this study was to assess the sensitivity of detecting metastatic versus indeterminate nodules with PET-MRI compared to chest CT. A total of 328 patients were included. All patients had a PET/MRI whole-body scan for (re)staging of cancer combined with an unenhanced chest CT performed at our center between 2014 and 2020. Patients had at least a two-year follow-up. Six percent of the patients had lung metastases at initial staging. The sensitivity and specificity of PET-MRI for detecting lung metastases were 85% and 100%, respectively. The incidence of indeterminate lung nodules on chest CT was 30%. The sensitivity of PET-MRI to detect indeterminate lung nodules was poor (23.0%). The average size of the indeterminate lung nodules detected on PET-MRI was 7 ± 4 mm, and the missed indeterminate nodules on PET-MRI were 4 ± 1 mm (p < 0.001). The detection of metastatic lung nodules is fairly good with PET-MRI, whereas the sensitivity of PET-MRI for detecting indeterminate lung nodules is size-dependent. This may be an advantage, limiting unnecessary follow-up of small, indeterminate lung nodules while adequately detecting metastases.

Biologic and clinical analysis of childhood gamma delta T-ALL identifies LMO2/STAG2 rearrangements as extremely high-risk.

Acute lymphoblastic leukemia expressing the gamma delta T cell receptor (yo T-ALL) is a poorly understood disease. We studied 200 children with yo T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. yo T-ALL diagnosed in children under three years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by Poly(ADP-ribose) polymerase (PARP) inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric yo T-ALL.

Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia.

ABSTRACT: A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.

Tyrosine kinase inhibitor response of ABL-class acute lymphoblastic leukemia: the role of kinase type and SH3 domain.

ABSTRACT: Acute lymphoblastic leukemia (ALL) with fusions of ABL-class tyrosine kinase genes other than BCR::ABL1 occurs in ∼3% of children with ALL. The tyrosine kinase genes involved in this BCR::ABL1-like (Ph-like) subtype include ABL1, PDGFRB, ABL2, and CSF1R, each of which has up to 10 described partner genes. ABL-class ALL resembles BCR::ABL1-positive ALL with a similar gene expression profile, poor response to chemotherapy, and sensitivity to tyrosine kinase inhibitors (TKIs). There is a lack of comprehensive data regarding TKI sensitivity in the heterogeneous group of ABL-class ALL. We observed variability in TKI sensitivity within and among each ABL-class tyrosine kinase gene subgroup. We showed that ALL samples with fusions for any of the 4 tyrosine kinase genes were relatively sensitive to imatinib. In contrast, the PDGFRB-fused ALL samples were less sensitive to dasatinib and bosutinib. Variation in ex vivo TKI response within the subset of samples with the same ABL-class tyrosine kinase gene was not associated with the ALL immunophenotype, 5' fusion partner, presence or absence of Src-homology-2/3 domains, or deletions of IKZF1, PAX5, or CDKN2A/B. In conclusion, the tyrosine kinase gene involved in ABL-class ALL is the main determinant of TKI sensitivity and relevant for specific TKI selection.

Tyrosine kinase inhibitor resistance in de novo BCR::ABL1-positive BCP-ALL beyond kinase domain mutations.

ABSTRACT: A better understanding of ABL1 kinase domain mutation-independent causes of tyrosine kinase inhibitor (TKI) resistance is needed for BCR::ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Although TKIs have dramatically improved outcomes, a subset of patients still experiences relapsed or refractory disease. We aimed to identify potential biomarkers of intrinsic TKI resistance at diagnosis in samples from 32 pediatric and 19 adult patients with BCR::ABL1-positive BCP-ALL. Reduced ex vivo imatinib sensitivity was observed in cells derived from newly diagnosed patients who relapsed after combined TKI and chemotherapy treatment compared with cells derived from patients who remained in continuous complete remission. We observed that ex vivo imatinib resistance was inversely correlated with the amount of (phosphorylated) BCR::ABL1/ABL1 protein present in samples that were taken at diagnosis without prior TKI exposure. This suggests an intrinsic cause of TKI resistance that is independent of functional BCR::ABL1 signaling. Simultaneous deletions of IKZF1 and CDKN2A/B and/or PAX5 (IKZF1plus), as well as deletions of PAX5 alone, were related to ex vivo imatinib resistance. In addition, somatic lesions involving ZEB2, SETD2, SH2B3, and CRLF2 were associated with reduced ex vivo imatinib sensitivity. Our data suggest that the poor prognostic value of IKZF1(plus) deletions is linked to intrinsic mechanisms of TKI resistance other than ABL1 kinase domain mutations in newly diagnosed pediatric and adult BCR::ABL1-positive BCP-ALL.

Continuous PEGasparaginase Dosing Reduces Hypersensitivity Reactions in Pediatric ALL: A Dutch Childhood Oncology Group ALL11 Randomized Trial.

PURPOSE: The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule. METHODS: Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25). Hypersensitivity reactions were defined as allergies, allergic-like reactions, and silent inactivation. Secondary end points were other asparaginase-related toxicities, asparaginase activity and antibody levels, and outcome. RESULTS: During induction, 27 of 818 patients (3.3%) experienced hypersensitivity reactions. After random assignment, 4 of 155 (2.6%) in the continuous treatment arm versus 17 of 157 (10.8%) patients in the noncontinuous treatment arm had hypersensitivity reactions (P < .01), of which two (1.3%) versus 13 (8.3%) were inactivating reactions (P < .01). The occurrence of inactivating hypersensitivity reactions was seven times lower in the continuous arm (odds ratio, 0.15 [0.032-0.653]). In addition, antibody levels were significantly lower in the continuous arm (P < .01). With exception of a lower incidence of increased amylase in the continuous arm, there were no significant differences in total number of asparaginase-associated toxicities between arms. However, the timing of the toxicities was associated with the timing of the asparaginase administrations. No difference in 5-year cumulative incidence of relapse, death, or disease-free survival was found between both treatment arms. CONCLUSION: A continuous dosing schedule of PEGasp is an effective approach to prevent antibody formation and inactivating hypersensitivity reactions. The continuous PEGasp schedule did not increase toxicity and did not affect the efficacy of the therapy.

How subjective CT image quality assessment becomes surprisingly reliable: pairwise comparisons instead of Likert scale.

OBJECTIVES: The aim of this study is to improve the reliability of subjective IQ assessment using a pairwise comparison (PC) method instead of a Likert scale method in abdominal CT scans. METHODS: Abdominal CT scans (single-center) were retrospectively selected between September 2019 and February 2020 in a prior study. Sample variance in IQ was obtained by adding artificial noise using dedicated reconstruction software, including reconstructions with filtered backprojection and varying iterative reconstruction strengths. Two datasets (each n = 50) were composed with either higher or lower IQ variation with the 25 original scans being part of both datasets. Using in-house developed software, six observers (five radiologists, one resident) rated both datasets via both the PC method (forcing observers to choose preferred scans out of pairs of scans resulting in a ranking) and a 5-point Likert scale. The PC method was optimized using a sorting algorithm to minimize necessary comparisons. The inter- and intraobserver agreements were assessed for both methods with the intraclass correlation coefficient (ICC). RESULTS: Twenty-five patients (mean age 61 years ± 15.5; 56% men) were evaluated. The ICC for interobserver agreement for the high-variation dataset increased from 0.665 (95%CI 0.396-0.814) to 0.785 (95%CI 0.676-0.867) when the PC method was used instead of a Likert scale. For the low-variation dataset, the ICC increased from 0.276 (95%CI 0.034-0.500) to 0.562 (95%CI 0.337-0.729). Intraobserver agreement increased for four out of six observers. CONCLUSION: The PC method is more reliable for subjective IQ assessment indicated by improved inter- and intraobserver agreement. CLINICAL RELEVANCE STATEMENT: This study shows that the pairwise comparison method is a more reliable method for subjective image quality assessment. Improved reliability is of key importance for optimization studies, validation of automatic image quality assessment algorithms, and training of AI algorithms. KEY POINTS: • Subjective assessment of diagnostic image quality via Likert scale has limited reliability. • A pairwise comparison method improves the inter- and intraobserver agreement. • The pairwise comparison method is more reliable for CT optimization studies.

Repurposing catheter ablation work-up to detect expiratory airflow limitation in patients with atrial fibrillation.

Background: In atrial fibrillation (AF) patients, presence of expiratory airflow limitation may negatively impact treatment outcomes. AF patients are not routinely screened for expiratory airflow limitation, but existing examinations can help identify at-risk individuals. We aimed to assess the diagnostic value of repurposing existing assessments from the pre-ablation work-up to identify and understand the characteristics of affected patients. Methods: We screened 110 consecutive AF patients scheduled for catheter ablation with handheld spirometry. Routine pre-ablation work-up included cardiac computed tomographic angiography (CCTA), transthoracic echocardiography and polygraphy. CCTA was analyzed qualitatively for emphysema and airway abnormalities. Multivariate logistic regression analysis was performed to determine predictors of expiratory airflow limitation. Results: We found that 25 % of patients had expiratory airflow limitation, which was undiagnosed in 86 % of these patients. These patients were more likely to have pulmonary abnormalities on CCTA, including emphysema (odds ratio [OR] 4.2, 95 % confidence interval [CI] 1.12-15.1, p < 0.05) and bronchial wall thickening (OR 2.6, 95 % CI 1.0-6.5, p < 0.05). The absence of pulmonary abnormalities on CCTA accurately distinguished patients with normal lung function from those with airflow limitation (negative predictive value: 85 %). Echocardiography and polygraphy did not contribute significantly to identifying airflow limitation. Conclusions: In conclusion, routine pre-ablation CCTA can detect pulmonary abnormalities in AF patients with airflow limitation, guiding further pulmonary assessment. Future studies should investigate its impact on ablation procedure success.

Characterization and prognostic impact of ACTBL2-positive tumor-infiltrating leukocytes in epithelial ovarian cancer.

Actin beta-like 2 (ACTBL2) was recently identified as a new mediator of migration in ovarian cancer cells. Yet, its impact on tumor-infiltrating and thus migrating leukocytes (TILs) remains to date unknown. This study characterizes the subset of ACTBL2-expressing TILs in epithelial ovarian cancer (EOC) and elucidates their prognostic influence on the overall survival of EOC patients with special regard to different histological subtypes. Comprehensive immunohistochemical analyses of Tissue-Microarrays of 156 ovarian cancer patients revealed, that a tumor infiltration by ACTBL2-positive leukocytes was significantly associated with an improved overall survival (OS) (61.2 vs. 34.4 months; p = 0.006) and was identified as an independent prognostic factor (HR = 0.556; p = 0.038). This significant survival benefit was particularly evident in patients with low-grade serous carcinoma (OS: median not reached vs. 15.6 months, p < 0.001; HR = 0.058, p = 0.018). In the present cohort, ACTBL2-positive TILs were mainly composed of CD44-positive cytotoxic T-cells (CD8+) and macrophages (CD68+), as depicted by double-immunofluorescence and various immunohistochemical serial staining. Our results provide significant evidence of the prognostic impact and cellular composition of ACTBL2-expressing TILs in EOC. Complementary studies are required to analyze the underlying molecular mechanisms of ACTBL2 as a marker for activated migrating leukocytes and to further characterize its immunological impact on ovarian carcinogenesis.

A multidimensional analysis reveals distinct immune phenotypes and tertiary lymphoid structure-like aggregates in the bone marrow of pediatric acute myeloid leukemia.

Because of the low mutational burden, children with acute myeloid leukemia (AML) are thought to have a 'cold' tumor microenvironment and consequently, a low likelihood of response to T cell-directed immunotherapies. Here, we provide a multidimensional overview of the tumor immune microenvironment in newly diagnosed pediatric AML. On a cohort level, we demonstrate wide variation in T cell infiltration with nearly one-third of cases harboring an immune-infiltrated bone marrow. These immune-infiltrated cases are characterized by a decreased abundance of M2-like macrophages, which we find to be associated with response to T cell-directed immunotherapy in adult AML. On an organizational level, we reveal the composition of spatially organized immune aggregates in pediatric AML, and show that in the adult setting such aggregates in post-treatment bone marrow and extramedullary sites associate with response to ipilimumab-based therapy. Altogether, our study provides immune correlates of response to T cell-directed immunotherapies and indicates starting points for further investigations into immunomodulatory mechanisms in AML.

Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

PURPOSE: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease. METHODS: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts. RESULTS: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], P =9.5 x 10 -5 ) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10], P =0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activating LMO2 activation and inactivating STAG2 inactivation ( STAG2/LMO2 ). Mechanistically, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping resulting in deregulation of gene expression associated with T-cell differentiation. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine. CONCLUSION: γδ T-ALL in children under the age of three is extremely high-risk and enriched for STAG2/LMO2 ALL. STAG2 loss perturbs chromatin conformation and differentiation, and STAG2/LMO2 ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL. SUPPORT: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.

Mapping Peptide-Protein Interactions by Amine-Reactive Cleavable Photoaffinity Reagents.

Photoaffinity labeling followed by tandem mass spectrometry is an often used strategy to identify protein targets of small-molecule drugs or drug candidates, which, under ideal conditions, enables the identification of the actual drug binding site. In the case of bioactive peptides, however, identifying the distinct binding site is hampered because of complex fragmentation patterns during tandem mass spectrometry. We here report the development and use of small cleavable photoaffinity reagents that allow functionalization of bioactive peptides for light-induced covalent binding to their protein targets. Upon cleavage of the covalently linked peptide drug, a chemical remnant of a defined mass remains on the bound amino acid, which is then used to unambiguously identify the drug binding site. Applying our approach to known peptide-drug/protein pairs with reported crystal structures, such as the calmodulin-melittin interaction, we were able to validate the identified binding sites based on structural models. Overall, our cleavable photoaffinity labeling strategy represents a powerful tool to enable the identification of protein targets and specific binding sites of a wide variety of bioactive peptides in the future.

Evaluation of the MOVE online exercise programme for young people aged 13-30.

PURPOSE: To evaluate the MOVE exercise programme in supporting the recovery of young people affected by cancer. METHODS: Participants in an 8-week exercise rehabilitation programme delivered online by cancer rehabilitation specialists completed self-reported questionnaires at baseline and after programme completion. Assessments included cancer-related fatigue (FACIT fatigue scale) and health-related quality of life (EORTC-QLC-30). Qualitative data were provided through written accounts of participant experiences and underwent content analysis. RESULTS: Seventy-one participants commenced the exercise rehabilitation programme and 57 completed the programme and provided data for analysis (63% female; median age 22 years). Statistically significant improvements were observed in post-programme scores for all measured outcomes (cancer-related fatigue, quality of life, physical functioning, role functioning, emotional functioning). Content analysis of written experiences generated ten unique codes. The highest frequency codes were enjoyment (n = 34), motivation (n = 14) and fitness (n = 13). CONCLUSIONS: These findings indicate feasibility of delivery, acceptability to patients and physical and psychological benefits of a personalised online exercise rehabilitation programme for young people living with and beyond cancer. Further research involving a control arm and long-term follow-up would be beneficial. IMPLICATIONS FOR CANCER SURVIVORS: These results support the inclusion of a personalised exercise programme as part of cancer rehabilitation for young people living with and beyond cancer.

Multi-source data approach for personalized outcome prediction in lung cancer screening: update from the NELSON trial.

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%.

Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group.

PURPOSE: A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. METHODS: A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS). RESULTS: The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. CONCLUSION: EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.

CT Scan-Derived Muscle, But Not Fat, Area Independently Predicts Mortality in COVID-19.

BACKGROUND: COVID-19 has demonstrated a highly variable disease course, from asymptomatic to severe illness and eventually death. Clinical parameters, as included in the 4C Mortality Score, can predict mortality accurately in COVID-19. Additionally, CT scan-derived low muscle and high adipose tissue cross-sectional areas (CSAs) have been associated with adverse outcomes in COVID-19. RESEARCH QUESTION: Are CT scan-derived muscle and adipose tissue CSAs associated with 30-day in-hospital mortality in COVID-19, independent of 4C Mortality Score? STUDY DESIGN AND METHODS: This was a retrospective cohort analysis of patients with COVID-19 seeking treatment at the ED of two participating hospitals during the first wave of the pandemic. Skeletal muscle and adipose tissue CSAs were collected from routine chest CT-scans at admission. Pectoralis muscle CSA was demarcated manually at the fourth thoracic vertebra, and skeletal muscle and adipose tissue CSA was demarcated at the first lumbar vertebra level. Outcome measures and 4C Mortality Score items were retrieved from medical records. RESULTS: Data from 578 patients were analyzed (64.6% men; mean age, 67.7 ± 13.5 years; 18.2% 30-day in-hospital mortality). Patients who died within 30 days demonstrated lower pectoralis CSA (median, 32.6 [interquartile range (IQR), 24.3-38.8] vs 35.4 [IQR, 27.2-44.2]; P = .002) than survivors, whereas visceral adipose tissue CSA was higher (median, 151.1 [IQR, 93.6-219.7] vs 112.9 [IQR, 63.7-174.1]; P = .013). In multivariate analyses, low pectoralis muscle CSA remained associated with 30-day in-hospital mortality when adjusted for 4C Mortality Score (hazard ratio, 0.98; 95% CI, 0.96-1.00; P = .038). INTERPRETATION: CT scan-derived low pectoralis muscle CSA is associated significantly with higher 30-day in-hospital mortality in patients with COVID-19 independently of the 4C Mortality Score.

Improvement of an interobserver agreement of ARDS diagnosis by adding additional imaging and a confidence scale.

Acute respiratory distress syndrome (ARDS) often is not recognized in clinical practice, largely due to variation in the interpretation of chest x-ray (CXR) leading to poor interobserver reliability. We hypothesized that the agreement in the interpretation of chest imaging for the diagnosis of ARDS in invasively ventilated intensive care unit patients between experts improves when using an 8-grade confidence scale compared to using a dichotomous assessment and that the agreement increases after adding chest computed tomography (CT) or lung ultrasound (LUS) to CXR. Three experts scored ARDS according to the Berlin definition based on case records from an observational cohort study using a dichotomous assessment and an 8-grade confidence scale. The intraclass correlation (ICC), imaging modality, and the scoring method were calculated per day and compared using bootstrapping. A consensus judgement on the presence of ARDS was based on the combined confidence grades of the experts, followed by a consensus meeting for conflicting scores. In total, 401 patients were included in the analysis. The best ICC was found using an 8-grade confidence scale for LUS (ICC: 0.49; 95%-CI: 0.29-0.63) and CT evaluation (ICC: 0.49; 95%-CI: 0.34-0.61). The ICC of CXR increased by 0.022 and of CT by 0.065 when 8-grade scoring was used instead of the dichotomous assessment. Adding information from LUS or chest CT increased the ICC by 0.25 when using the 8-grade confidence assessment. An agreement on the diagnosis of ARDS can increase substantially by adapting the scoring system from a dichotomous assessment to an 8-grade confidence scale and by adding additional imaging modalities such as LUS or chest CT. This suggests that a simple assessment of the diagnosis of ARDS with a chart review by one assessor is insufficient to define ARDS in future studies. Clinical trial registration: Trialregister.nl (identifier NL8226).

Investigation of the added value of CT-based radiomics in predicting the development of brain metastases in patients with radically treated stage III NSCLC.

Introduction: Despite radical intent therapy for patients with stage III non-small-cell lung cancer (NSCLC), cumulative incidence of brain metastases (BM) reaches 30%. Current risk stratification methods fail to accurately identify these patients. As radiomics features have been shown to have predictive value, this study aims to develop a model combining clinical risk factors with radiomics features for BM development in patients with radically treated stage III NSCLC. Methods: Retrospective analysis of two prospective multicentre studies. Inclusion criteria: adequately staged [18F-fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG-PET-CT), contrast-enhanced chest CT, contrast-enhanced brain magnetic resonance imaging/CT] and radically treated stage III NSCLC, exclusion criteria: second primary within 2 years of NSCLC diagnosis and prior prophylactic cranial irradiation. Primary endpoint was BM development any time during follow-up (FU). CT-based radiomics features (N = 530) were extracted from the primary lung tumour on 18-FDG-PET-CT images, and a list of clinical features (N = 8) was collected. Univariate feature selection based on the area under the curve (AUC) of the receiver operating characteristic was performed to identify relevant features. Generalized linear models were trained using the selected features, and multivariate predictive performance was assessed through the AUC. Results: In total, 219 patients were eligible for analysis. Median FU was 59.4 months for the training cohort and 67.3 months for the validation cohort; 21 (15%) and 17 (22%) patients developed BM in the training and validation cohort, respectively. Two relevant clinical features (age and adenocarcinoma histology) and four relevant radiomics features were identified as predictive. The clinical model yielded the highest AUC value of 0.71 (95% CI: 0.58-0.84), better than radiomics or a combination of clinical parameters and radiomics (both an AUC of 0.62, 95% CIs of 0.47-076 and 0.48-0.76, respectively). Conclusion: CT-based radiomics features of primary NSCLC in the current setup could not improve on a model based on clinical predictors (age and adenocarcinoma histology) of BM development in radically treated stage III NSCLC patients.

Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms.

Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPC) before and after cancer treatment of 24 children. Of these children, 19 developed therapy-related myeloid neoplasms (t-MN). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure. SIGNIFICANCE: Our study shows that chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, whereas in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging. This article is highlighted in the In This Issue feature, p. 1825.