ING2 (Inhibitor of Growth 2) is a tumor suppressor gene that has been implicated in critical biological functions (cell-cycle regulation, replicative senescence, DNA repair and DNA replication), most ...of which are recognized hallmarks of tumorigenesis occurring in the cell nucleus. As its close homolog ING1 has been recently observed in the mitochondrial compartment, we hypothesized that ING2 could also translocate into the mitochondria and be involved in new biological functions. In the present study, we demonstrate that ING2 is imported in the inner mitochondrial fraction in a redox-sensitive manner in human cells and that this mechanism is modulated by 14-3-3η protein expression. Remarkably, ING2 is necessary to maintain mitochondrial ultrastructure integrity without interfering with mitochondrial networks or polarization. We observed an interaction between ING2 and mtDNA under basal conditions. This interaction appears to be mediated by TFAM, a critical regulator of mtDNA integrity. The loss of mitochondrial ING2 does not impair mtDNA repair, replication or transcription but leads to a decrease in mitochondrial ROS production, suggesting a detrimental impact on OXPHOS activity. We finally show using multiple models that ING2 is involved in mitochondrial respiration and that its loss confers a protection against mitochondrial respiratory chain inhibition in vitro. Consequently, we propose a new tumor suppressor role for ING2 protein in the mitochondria as a metabolic shift gatekeeper during tumorigenesis.
The optimal management of large cell neuroendocrine cancer of the lung (LCNEC) is unclear, and data regarding anti–programmed cell death protein 1 (PD-1) antibodies are scarce. This study reports the ...clinical efficacy of a PD-1 inhibitor in patients with advanced LCNEC.
All patients with stage III to IV LCNEC treated with at least one previous cycle of chemotherapy between January 1, 2015 and December 31, 2018 were reviewed retrospectively. Patients were divided into two groups depending on their exposure to nivolumab as second-line treatment or beyond. The primary objective was to assess nivolumab’s efficacy.
A total of 51 patients with advanced LCNEC from eight centers were analyzed, including 17 who received nivolumab. The PD-1 inhibitor was used as second-line treatment in 77% of cases, with a median number of eight doses (range: 1–62). After nivolumab treatment, the median overall survival was 12.1 months (95% confidence interval CI: 7.10–14.20). The objective response rate was 29.4% (95% CI: 10.3–56.0), and median progression-free survival was 3.9 months (95% CI: 1.68–7.17). The programmed death-ligand 1 status was unknown. There was no difference in the efficacy of first-line chemotherapy; the objective response rate was 23.5% (n = four of 17) in the nivolumab group versus 32.4% (n = 11 of 34) in the conventional treatment group, and progression-free survival was 3.5 months (95% CI: 1.7–4.4) versus 2.1 months (95% CI: 1.4–4.2), respectively.
In a real-world setting, nivolumab seems to be an effective second-line treatment in patients with advanced LCNEC. Large prospective studies in this setting are still required.
•Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer.•Atezolizumab plus chemotherapy improves overall survival in 1st-line treatment of extensive SCLC.•IFCT-1905 CLINATEZO ...studied consecutive patients receiving this regimen in France.•Our studyreproduced in a real life setting thekey survival outcomesof the landmark trial.
Small cell lung cancer (SCLC) has a tendency towards recurrence and limited survival. Standard-of-care in 1st-line is platinum-etoposide chemotherapy plus atezolizumab or durvalumab,based on landmarkclinical trials.
IFCT-1905 CLINATEZO is a nationwide, non-interventional, retrospectivestudy of patients with extensive-SCLC receivingatezolizumab plus chemotherapy as part of French Early Access Program. Objectives were to analyse effectiveness,safetyand subsequent treatments.
The population analyzed included 518 patients who received atezolizumabin 65 participating centers. There were 66.2% male,mean age was 65.7 years; 89.1% had a performance status (PS) 0/1 and 26.6% brain metastases. Almost all(95.9%) were smokers. Fifty-five (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7.0 (range 1.0–48.0) for a median duration of 4.9 months (95% CI 4.5–5.1). Atezolizumab was continued beyond progression in 122 patients (23.6%) for a median duration of 1.9 months (95% CI: 1.4–2.3). Best objective response was complete and partialin 19 (3.9%) and 378 (77.1%)patients. Stable diseasewas observed in 50 patients (10.2%). Median follow-up was30.8 months (95% CI: 29.9–31.5). Median overall survival (OS), 12-, 24-month OS rates were 11.3 months (95% CI: 10.1–12.4), 46.7% (95% CI 42.3–50.9) and 21.2% (95% CI 17.7–24.8). Median real-world progression-free survival, 6-, 12-month rates were 5.2 months (95% CI 5.0–5.4), 37.5% (95% CI 33.3–41.7) and 15.2% (95% CI 12.2–18.6). For patients with PS 0/1, median OS was 12.2 months (95% CI 11.0–13.5). For patients with previous treatment, median OS was 14.9 months (95% CI 10.1–21.5). Three-hundred-and-twenty-six patients(66.4%) received subsequent treatment and27 (5.2%) were still underatezolizumabat date of last news.
IFCT-1905 CLINATEZO shows reproductibility, in real-life,ofIMpower-133survival outcomes, possibly attributed to selection of patients fit for this regimen, adoption of pragmatic approaches,including concurrent radiotherapy and treatment beyond progression.
•In 681 non-squamous aNSCLC PD-L1 ≥ 50 % patients, 12.5 % had a KRAS G12C mutation.•No clinical or biological difference between KRAS G12C and KRAS non-G12C patients.•KRAS G12C had no impact on ...first-line pembrolizumab efficacy in non-squamous aNSCLC.
Few data are available on the impact of KRAS mutation in patients with advanced non-squamous non-small cell lung cancer (aNSCLC) treated with immunotherapy. This analysis assessed the impact of KRAS mutation on the efficiency of first-line pembrolizumab immunotherapy in aNSCLC patients with PD-L1 ≥ 50 %.
This was a secondary analysis of the ESCKEYP study, a retrospective, national, multicenter study which included consecutively all metastatic NSCLC patients who initiated first-line treatment with pembrolizumab monotherapy from May 2017 (date of pembrolizumab availability in this indication in France) to November 22, 2019 (pembrolizumab-chemotherapy combination approval). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of pembrolizumab treatment by the Kaplan-Meier method. Tumor response and PFS were assessed locally.
Among the 681 non-squamous aNSCLC PD-L1 ≥ 50 % patients treated with pembrolizumab in the first line, 227 (33.0 %) had a KRAS mutation (KRAS G12C, 12.5 %; KRAS non-G12C, 20.5 %). Except among non-smokers (KRAS G12C, 0 %; KRAS non-G12C, 2.9 %; no KRAS mutation, 9.2 %), patients presented no differences in terms of sex, age, number and sites of metastatic disease at diagnosis, use of corticosteroids, use of antibiotics, and for biological factors between wild-type KRAS, KRAS G12C and non-KRAS G12C groups. Median (95 % CI) PFS in months were 7.0 (3.7–14) for KRAS G12C, 4.8 (3.4–6.7) for KRAS non-G12C and 8.5 (7.3–10.6) for wild-type KRAS genotypes (p = 0.23). Median OS were 18.4 (12.6-NR), 20.6 (11.4-NR) and 27.1 (18.7–34.2) months, respectively (p = 0.57).
No difference in efficacy was observed in non-squamous aNSCLC patients treated with first-line pembrolizumab immunotherapy whether they presented a KRAS G12C, non KRAS G12C or wild-type KRAS genotype.
Highlights • EGFR-mutated lung adenocarcinoma belongs to the spectrum of predisposed neoplasms in LFS. • We provide the first description of resistance mutation to EGFR-TKI in a patient with LFS and ...lung adenocarcinoma. • Response to targeted therapy may benefit to the same extent to LFS patient as in the general population.
Background and Aims: A risk of tracheal mucosa injury induced by subglottic suctioning has been raised. Therefore, this prospective randomized study aims to compare the effect of continuous ...suctioning of subglottic secretions versus intermittent suctioning of subglottic secretions (CSSS vs. ISSS) secretions on tracheal mucosa in front of the suctioning port of the endotracheal tube. Patients and Methods: Patients requiring intubation or reintubation in Intensive Care Unit with an expected ventilation duration > 24 h were eligible. Participants received CSSS at −20 mmHg or ISSS at −100 mmHg during 15 s and no suction during 8 s. The effect on tracheal mucosa in front of the suction port was assessed after intubation (T0) and before extubation (T1) using bronchoscopy. Tracheal mucosa damages were graded into five categories (no injury, erythema, edema, ulceration, or necrosis). The occurrence (no injury observed at T0 but present at T1) or the worsening (injury observed at T0 exacerbating at T1) was studied. Results: Seventy-three patients were included and 53 patients (CSSS, n = 26 and ISSS, n = 27) were evaluable on the primary endpoint. The occurrence or worsening of tracheal mucosal damages did not differ between the two groups (CSSS, n = 7 27% vs. ISSS, n = 5 17%, P = 0.465). Daily average volume of suctioned secretion was higher with ISSS (74 ± 100 ml vs. 20 ± 25 ml, P < 0.001). Impossibility to aspirate was higher with CSSS (0.14 ± 0.16 per day vs. 0.03 ± 0.07 per day, P < 0.001). Conclusions: Our results suggest that tracheal mucosal damages did not differ between CSSS and ISSS. The aspirated volume was higher and impossibility to aspirate was lower with ISSS. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01555229.
The impact of the most recent advances, including targeted therapies and immune checkpoint inhibitors, on early (3-month) mortality in lung cancer is unknown. The aims of this study were to evaluate ...the real-world rate of and risk factors for early mortality, as well as trends in early mortality over the last 20 years.
The KBP prospective observational multicenter studies have been conducted every 10 years since 2000. These studies collect data on all newly diagnosed patients with lung cancer (all stages and histologies) over 1 year in non-academic public hospital pulmonology or oncology units in France. In this study, we analyzed data on patient and tumor characteristics from participants in the KBP-2020 cohort and compared the characteristics of patients who died within 3 months of diagnosis with those of all other patients within the cohort. We also carried out a comparative analysis with the KBP-2000 and KBP-2010 cohorts.
Overall, 8999 patients from 82 centers were included in the KBP-2020 cohort. Three-month survival data were available for 8827 patients, of whom 1792 (20.3%) had died. Risk factors for early mortality were: male sex, age >70 years, symptomatic disease at diagnosis, ever smoker, weight loss >10 kg, poor Eastern Cooperative Oncology Group performance status (≥1), large-cell carcinoma or not otherwise specified, and stage ≥IIIC disease. The overall 3-month mortality rate was found to have decreased significantly over the last 20 years, from 24.7% in KBP-2000 to 23.4% in KBP-2010 and 20.3% in KBP-2020 (P < 0.0001).
Early mortality among patients with lung cancer has significantly decreased over the last 20 years which may reflect recent improvements in treatments. However, early mortality remained extremely high in 2020, particularly when viewed in light of improvements in longer-term survival. Delays in lung cancer diagnosis and management could contribute to this finding.
•Of 8827 patients with lung cancer included in the KBP-2020 study, 1792 (20.3%) were dead at 3 months after diagnosis.•Early mortality in LC patients has decreased significantly over the last 20 years but remained extremely high in 2020.•Risk factors for 3-month mortality were similar to those reported in other studies.
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