Characterization of Patients with EGFR Mutation-Positive NSCLC Following Emergence of the Osimertinib Resistance Mutations, L718Q or G724S: A Multicenter Retrospective Observational Study in France.

Purpose: The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is an effective first-line therapy for patients with common EGFR mutation-positive non-small cell lung cancer (NSCLC). However, almost all patients become resistant to treatment. In some patients, emergence of tertiary EGFR mutations is implicated as a resistance mechanism. This study describes patients with NSCLC who acquired the rare EGFR mutations, L718Q or G724S, following EGFR TKI treatment. Patients and Methods: This was a retrospective, observational study undertaken in France from Feb-Nov 2021, in patients with EGFR mutation-positive NSCLC with an acquired L718Q or G724S mutation. Primary objectives were description of tumor characteristics, progression, and progression under treatment. Results: Nine eligible patients were identified. Acquired resistance to initial EGFR TKI treatment was associated with T790M emergence in six patients, who then received osimertinib monotherapy. Overall, eight patients received osimertinib monotherapy treatment at some point (average treatment duration: 18.3 months). Following the emergence of L718Q or G724S, patients received chemotherapy (n = 4; two of whom subsequently received afatinib), nivolumab (n = 2), afatinib (n = 2), or immunochemotherapy (n = 1). In the four patients who received afatinib after identification of L718Q or G724S, 2 achieved a partial response, one had stable disease and one had progressive disease. Treatment duration was 1.6-31.7 months. In patients with controlled disease (n = 3), progression-free survival was 6.1-31.7 months. Two of these patients had previously received osimertinib. Conclusion: Currently, there is no consensus regarding the treatment of EGFR mutation-positive NSCLC following emergence of the osimertinib resistance mutations, L718Q or G724S. Afatinib appears to be a promising treatment option in this setting.

Metabolomic profiling of cardiac allografts after controlled circulatory death.

BACKGROUND: Assessment of myocardial viability during ex situ heart perfusion (ESHP) is based on the measurement of lactate concentrations. As this provides with limited information, we sought to investigate the metabolic signature associated with donation after circulatory death (DCD) and the impact of ESHP on the myocardial metabolome. METHODS: Porcine hearts were retrieved either after warm ischemia (DCD group, N = 6); after brain-stem death (BSD group, N = 6); or without DCD nor BSD (Control group, N = 6). Hearts were perfused using normothermic oxygenated blood for 240 minutes. Plasma and myocardial samples were collected respectively every 30 and 60 minutes, and analyzed by an untargeted metabolomic approach using liquid chromatography coupled to high-resolution mass spectrometry. RESULTS: Median duration of warm ischemia was 23 minutes [19-29] in DCD animals. Lactate level within myocardial biopsies was not significantly different between groups at T0 (p = 0.281), and remained stable over the 4-hour period of ESHP. More than 300 metabolites were detected in plasma and heart biopsy samples. Compared to BSD animals, metabolomics changes involving energy and nucleotide metabolisms were observed in plasma samples of DCD animals before initiation of ESHP, whereas 2 metabolites (inosine monophosphate and methylbutyrate) exhibited concentration changes in biopsy samples. Normalization of DCD metabolic profile was remarkable after 4 hours of ESHP. CONCLUSION: A specific metabolic profile was observed in DCD hearts, mainly characterized by an increased nucleotide catabolism. DCD and BSD metabolomes proved normalized during ESHP. Complementary investigations are needed to correlate these findings to cardiac performances.

Characterization of lung cancers in patients with BRCA germline variants: A multicenter series.

INTRODUCTION: BRCA1 and BRCA2 (BReast CAncer susceptibility genes) are two tumor-suppressor genes associated with the hereditary breast and ovarian cancer susceptibility syndrome. Recent studies also suggest an increased lung adenocarcinoma risk in carriers. METHODS: We conducted a multi-center retrospective study in 18 different French pulmonology and/or oncology departments on medico-administrative and clinical data prospectively collected in the Clinical Data Warehouse (CDW) of Greater Paris University Hospitals (Assistance Publique-Hôpitaux de Paris, AP-HP). Clinical characteristics and outcomes of patients with LC and a previously known BRCA1/2gl variant were retrospectively evaluated. RESULTS: 17 patients with LC and known BRCA1/2gl variant were included. Patients were most women, former smokers with localized disease and BRCA2 variants. All LC were adenocarcinoma. For patients with medical history of cancer, median time from the first cancer in the BRCA spectrum and the LC occurrence was 20 years. Median disease-free survival (DFS) and overall survival (OS) in localized tumor (Stage I and II) was not reached and 78.6 months, respectively. In advanced cancer (Stade III and IV) median progression free survival was 9.7 months and median OS was 17.8 months. Univariate OS and DFS/PFS analyses by BRCA status did not find significant differences. CONCLUSION: Results seem to show particular LC features in carriers of BRCA2 variants: adenocarcinoma subtype, woman, former or non-smoker.

Risk stratification and treatment of pulmonary embolism with intermediate-risk of mortality.

PURPOSE OF REVIEW: Intermediate-risk pulmonary embolisms (PE) represent a heterogeneous group at the high end of hemodynamically stable patients, characterized by a higher mortality rate. This challenging population gathers many unsolved question regarding its therapeutic management. The purpose of this review is to provide an updated overview of the literature regarding further risk stratification and treatment options in this population. RECENT FINDINGS: If anticoagulation represents the undisputed first line of treatment, some patients especially in the intermediate-high risk subgroup may necessitate or could benefit from therapeutic escalation with reperfusion therapies. This includes systemic thrombolysis (ST) or catheter-directed therapies (CDT). ST, despite its high efficacy, is not recommended in this population because of prohibitive bleeding complications. Therefore, reduced-dose ST appears to be a promising option and is actually under evaluation. CDT are percutaneous reperfusion techniques developed to acutely decrease pulmonary vascular obstruction with lower-dose or no thrombolytic agents and, thus, potentially improved safety compared to ST. SUMMARY: Great progress has been made in the recent years providing a wide range of therapeutic options. Optimal selection of patients who could benefit from these treatments is the key and is based on clinical, biological and radiological parameters evaluating right ventricle function and allowing accurate risk stratification. Pulmonary Embolism Response Team represents an efficient modality for therapeutic management especially in the intermediate-high risk subgroup.

Lung cancer is also a hereditary disease.

Pathogenic genetic variants (formerly called mutations) present in the germline of some individuals are associated with a clinically relevant increased risk of developing lung cancer. These germline pathogenic variants are hereditary and are transmitted in an autosomal dominant fashion. There are two major lung cancer susceptibility syndromes, and both seem to be specifically associated with the adenocarcinoma subtype. Li-Fraumeni syndrome is caused by variants in the TP53 tumour-suppressor gene. Carriers are mainly at risk of early-onset breast cancer, sarcoma, glioma, leukaemia, adrenal cortical carcinoma and lung cancer. EGFR variants, T790M in particular, cause the EGFR susceptibility syndrome. Risk seems limited to lung cancer. Emerging data suggest that variants in ATM, the breast and pancreatic cancer susceptibility gene, also increase lung adenocarcinoma risk. As for inherited lung disease, cancer risk is increased in SFTPA1 and SFTPA2 variant carriers independently of the underlying fibrosis. In this review, we provide criteria warranting the referral of a lung cancer patient to the cancer genetics clinic. Pathogenic variants are first identified in patients with cancer, and then in a subset of their relatives. Lung cancer screening should be offered to asymptomatic carriers, with thoracic magnetic resonance imaging at its core.

Encephalitis related to immunotherapy for lung cancer: Analysis of a multicenter cohort.

INTRODUCTION: Using immune-checkpoint inhibitors (ICIs) to manage cancer is associated with various immune-related adverse events. Central and/or peripheral neurological disorders are rare and potentially serious. We analyzed the characteristics of non-small-cell lung cancer (NSCLC) patients who developed immune-related encephalitis under anti-programmed-death protein-1 or its ligand (PD-1/PD-L1). METHODS: Clinical, biological and radiological characteristics of ICI-treated NSCLC patients with immune-related encephalitis, from 6 centers, were evaluated retrospectively. RESULTS: The 6 centers included 9 patients: all men, all smokers, median (range) age 67 (48-77) years, 78% adenocarcinomas, first- or second-line ICI for 5 and 4 patients, respectively. Two patients had non-active cerebral metastases at ICI onset. A median of 5 (1-22) ICI infusions preceded neurological symptoms, the most frequent being confusion (78%), fever (45%) and cerebellar ataxia (33%). CSF analyses revealed a median white blood cell count of 22/mm3 (1-210/mm3), with hyperlymphocytosis in 8 patients and high protein levels in all. All bacteriological and virological analyses were negative. Cerebral MRI was considered normal for 5 patients; 4 patients had FLAIR hypersignals consistent with brain parenchyma inflammation. Three patients required intensive care. All patients received corticosteroids (different doses), a median of 8.5 (6-18) days post-onset. Corticosteroids achieved rapid symptom regression without sequelae in 8 patients. The last patient, with the longest time until corticosteroid introduction, died. ICIs were never restarted in any patient. CONCLUSION: Immune encephalitis, a rare but serious complication of anti-PD-1/PD-L1 therapy, carries a good prognosis when managed with early corticosteroids.

Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome.

BACKGROUND: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, ß 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. RESULTS: We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. CONCLUSIONS: These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.