Franz‐Georg Bauernfeind

. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.

Sarcoidosis is a disease characterised by granuloma formation. There is an unmet need for new treatment strategies beyond corticosteroids. The NLRP3 inflammasome pathway is expressed in innate immune cells and senses danger signals to elicit inflammatory interleukin (IL)-1β; it has recently become a druggable target. This prompted us to test the role of the NLRP3 inflammasome and IL-1β pathway in granuloma formation and sarcoidosis. 19 sarcoid patients and 19 healthy volunteers were recruited into this pilot study. NLRP3 inflammasome activity was measured in bronchoalveolar lavage (BAL) cells and lung and skin biopsies using immunohistochemistry, Western blot, reverse-transcriptase PCR and ELISA. For in vivo experiments we used the trehalose 6,6′-dimycolate-granuloma mouse model and evaluated lung granuloma burden in miR-223 knockout and NLRP3 knockout mice, as well as the treatment effects of MCC950 and anti-IL-1β antibody therapy. We found strong upregulation of the NLRP3 inflammasome pathway, evidenced by expression of activated NLRP3 inflammasome components, including cleaved caspase-1 and IL-1β in lung granuloma, and increased IL-1β release of BAL cells from sarcoid patients compared to healthy volunteers (p=0.006). mRNA levels of miR-223, a micro-RNA downregulating NLRP3, were decreased and NLRP3 mRNA correspondingly increased in alveolar macrophages from sarcoid patients (p<0.005). NLRP3 knockout mice showed decreased and miR-223 knockout mice increased granuloma formation compared to wild-type mice. Pharmacological interference using NLRP3 pathway inhibitor MCC950 or an anti-IL-1β antibody resulted in reduced granuloma formation (p<0.02). In conclusion, our data provide evidence of upregulated inflammasome and IL-1β pathway activation in sarcoidosis and suggest both as valid therapeutic targets.

Background Immune checkpoint inhibitors (ICIs) for cancer treatment are associated with a spectrum of immune-related adverse events, including ICI-induced myocarditis; however, the extent of subclinical acute cardiac effects related to ICI treatment is unclear. Purpose To explore the extent of cardiac injury and inflammation related to ICI therapy that can be detected with use of cardiac MRI. Materials and Methods In this prospective study from November 2019 to April 2021, oncologic participants, without known underlying structural heart disease or cardiac symptoms, underwent multiparametric cardiac MRI before planned ICI therapy (baseline) and 3 months after starting ICI therapy (follow-up). The cardiac MRI protocol incorporated assessment of cardiac function, including systolic myocardial strain, myocardial edema, late gadolinium enhancement (LGE), T1 and T2 relaxation times, and extracellular volume fraction. The paired t test, Wilcoxon signed-rank test, and McNemar test were used for intraindividual comparisons. Results Twenty-two participants (mean age ± standard deviation, 65 years ± 14; 13 men) were evaluated, receiving a median of four infusions of ICI therapy (interquartile range, four to six infusions). Compared with baseline MRI, participants displayed increased markers of diffuse myocardial edema at follow-up (T1 relaxation time, 972 msec ± 26 vs 1006 msec ± 36 [P < .001]; T2 relaxation time, 54 msec ± 3 vs 58 msec ± 4 [P < .001]; T2 signal intensity ratio, 1.5 ± 0.3 vs 1.7 ± 0.3 [P = .03]). Left ventricular average systolic longitudinal strain had decreased at follow-up MRI (–23.4% ± 4.8 vs –19.6% ± 5.1, respectively; P = .005). New nonischemic LGE lesions were prevalent in two of 22 participants (9%). Compared with baseline, small pericardial effusions were more evident at follow-up (one of 22 participants [5%] vs 10 of 22 [45%]; P = .004). Conclusion In participants who received immune checkpoint inhibitor therapy for cancer treatment, follow-up cardiac MRI scans showed signs of systolic dysfunction and increased parameters of myocardial edema and inflammation. © RSNA, 2021 Online supplemental material is available for this article.

BACKGROUND: Tumorous SEPT9 (septin 9, SEPTIN9) circulating cell-free DNA (ccfDNA) methylation in blood plasma is a powerful biomarker for diagnosis, molecular staging, prognosis, and recurrence monitoring in head and neck squamous cell carcinoma (HNSCC) patients. The present study aimed to evaluate the clinical performance of SEPT9 ccfDNA methylation to detect post-surgical minimal residual disease (MRD) in patients with localized or locally advanced HNSCC treated with curative intent. METHODS: We applied quasi-digital methylation-specific real-time PCR to quantify SEPT9 ccfDNA methylation levels 2 to 30 days post-surgically in plasma from n = 219 prospectively enrolled HNSCC patients. We tested the associations of SEPT9 ccfDNA methylation with clinicopathological parameters and used Kaplan-Meier and Cox proportional hazards analyses for univariate, pairwise bivariate, and multivariate analyses of disease-free survival. RESULTS: Of 219 patients, 26.5% (58/219) were post-surgically SEPT9 ccfDNA methylation positive. SEPT9 ccfDNA methylation positivity was significantly associated with tumor site, American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC; 8th edition) tumor stage, nodal category and extracapsular extension, lymphatic and vascular invasion, and surgical margin. Bivariate Cox proportional hazards analysis proved post-surgical SEPT9 ccfDNA methylation positivity to be an independent prognostic factor tested together with AJCC/UICC tumor stage (SEPT9: hazard ratio [HR] = 2.43, 95% CI, 1.37-4.30, P = 0.002; AJCC/UICC stage: HR = 1.48, 95% CI, 1.11-1.98, P = 0.008). CONCLUSIONS: Post-surgical SEPT9 ccfDNA methylation may aid to identify high-risk HNSCC patients who could benefit from an intensified adjuvant treatment and surveillance.

Clinical Practice Points Tepotinib, a potent, highly selective, once-daily, oral MET tyrosine kinase inhibitor, is approved in multiple countries for the treatment of advanced/metastatic METex14 skipping NSCLC and can be used in patients with mild-moderate renal impairment without dose adjustment.However, data in severe renal impairment are lacking. We report the feasibility of using the standard dose of tepotinib (500 mg; 450 mg active moiety) in a patient with advanced METex14 skipping NSCLC with end-stage renal disease undergoing hemodialysis, who attained disease control, with only mild adverse events that did not necessitate dose adjustment. Use of the standard dose was supported by tepotinib plasma concentration measurements, which fell within the expected range for a typical patient with NSCLC predicted using a population pharmacokinetic model and indicated no clinically relevant drug loss during dialysis.