Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for patients with non-small cell lung cancer (NSCLC). In spite of durable responses in some patients, many patients develop early disease progression during the ICI treatment. Thus, early identification of patients with no durable benefit would facilitate the clinical decision for these patients. In this prospective, multicenter study, 101 non-EGFR/ALK patients who received ICI treatment were enrolled after screening 328 stage III-IV NSCLC patients. At the date of cutoff, 83 patients were eligible for ICI efficacy evaluation, with 56 patients having progress-free survival (PFS) over 6 months, which was defined as durable clinical benefit (DCB). A multimodal model was established by integrating normalized bTMB, early dynamic of ctDNA and the first RECIST response. This model could robustly predict DCB with area under the curve (AUC) of 0.878, sensitivity of 79.2% at 86.4% specificity (accuracy = 80.0%). This model was further validated in the independent cohort of the DIREct-On study with AUC of 0.887, sensitivity of 94.7% at 85.3% specificity (accuracy = 90.3%). Patients with higher predict scores had substantially longer PFS than those with lower scores (training cohort: median PFS 13.6 vs 4.2 months, P < 0.001, HR = 0.24; validation cohort: median PFS 11.0 vs 2.2 months, P < 0.001, HR = 0.17). Taken together, these results demonstrate that integrating early changes of ctDNA, normalized bTMB, and the first RECIST response can provide accurate, noninvasive, and early prediction of durable benefits for NSCLC patients treated with ICIs. Further prospective studies are warranted to validate these findings and guide clinical decision-making for optimal immunotherapy in NSCLC patients.

Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing’s syndrome (CS). BMAH is predominantly believed to be caused by two mutations, a germline and somatic one, respectively, as described in the two-hit hypothesis. In many familial cases of BMAH, mutations in armadillo repeat containing 5 (ARMC5), a putative tumor suppressor gene, are thought to induce the disorder. The objective of this study was to report a case in which the patient presented with BMAH induced by a novel heterozygous germline ARMC5 mutation (c. 517C > T, p. Arg173*) alone rather than a two-hit mutation. A 51-year-old woman was identified with masses in the bilateral adrenals. Serum cortisol levels were increased significantly both in the morning (08:00 AM) and late at night (24:00 AM), while plasma adrenocorticotropic hormone was normal. The patient underwent a left adrenalectomy and histopathology substantiated the BMAH diagnosis. WES of the germline DNA discovered a novel heterozygous germline ARMC5 mutation (c. 517C > T, p. Arg173*) and in silico analysis predicted that the mutation significantly impaired protein function, resulting in inactivated ARMC5. Subsequently, WES of the tumor specimen identified 79 somatic single nucleotide polymorphisms (SNPs)/insertion-deletion (indel) mutations, including 32 missense/nonsense/splice/stop-loss mutations. None of these mutations were CS-related. A novel germline ARMC5 mutation (c. 517C > T, p. Arg173*) was identified that induced BMAH alone without a second mutation. ARMC5 sequencing may improve the identification of clinical forms of BMAH and allow earlier diagnosis of this disease.

Background: Pulmonary hypertension (PH) is a lethal vascular disease with limited therapeutic options. The mechanistic connections between alveolar hypoxia and PH are not well understood. The aim of this study was to investigate the role of mitotic regulator Polo-like kinase 1 (PLK1) in PH development.Methods: Mouse lungs along with human pulmonary arterial smooth muscle cells and endothelial cells were used to investigate the effects of hypoxia on PLK1. Hypoxia- or Sugen5416/hypoxia was applied to induce PH in mice.Plk1heterozygous knockout mice and PLK1 inhibitors (BI 2536 and BI 6727)-treated mice were checked for the significance of PLK1 in the development of PH.Results: Hypoxia stimulated PLK1 expression through induction of HIF1α and RELA. Mice with heterozygous deletion ofPlk1were partially resistant to hypoxia-induced PH. PLK1 inhibitors ameliorated PH in mice.Conclusions: Augmented PLK1 is essential for the development of PH and is a druggable target for PH.

Background: Aberrant mesenchymal–epithelial transition/hepatocyte growth factor (MET/HGF) regulation presented in a wide variety of human cancers. MET exon 14 skipping, copy number gain (CNG), and kinase domain mutations/arrangements were associated with increased MET activity, and considered to be oncogenic drivers of non-small cell lung cancers (NSCLCs). Methods: We retrospectively analyzed 564 patients with MET alterations. MET alterations were classified into structural mutations or small mutations. MET CNG, exon 14 skipping, gain of function (GOF) mutations, and kinase domain rearrangement were defined as actionable mutations. Results: Six hundred thirty-two MET mutations were identified including 199 CNG, 117 exon 14 skipping, 12 GOF mutations, and 2 actionable fusions. Higher percentage of MET structural alterations (CNG + fusion) were detected in advanced NSCLC patients. Moreover, MET CNG was enriched while exon 14 skipping was rare in epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI)-treated advanced NSCLC patients. Ten of the 12 MET GOF mutations were also in EGFR-TKI-treated patients. Fifteen (68.1%) of the 22 patients treated with crizotinib or savolitinib had a partial response. Interestingly, one patient had a great response to savolitinib with a novel MET exon 14 skipping mutation identified after failure of immune-checkpoint inhibitor. Conclusions: Half of the MET alterations were actionable mutations. MET CNG, exon 14 skipping and GOF mutations had different distribution in different clinical scenario but all defined a molecular subgroup of NSCLCs for which MET inhibition was active.