No study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non-small-cell lung cancer (NSCLC).
We analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC ...patients from The Cancer Genome Atlas (n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types.
In prognostic cohorts, high CD8A expression was associated with longer OS (p = 0.02), while high CD274 mRNA was associated with poor prognosis (p = 0.05). In predictive cohort, high CD8 expression and CD8A mRNA were associated with longer progression-free survival (PFS) (p = 0.0002). There was no significant association between PD-L1 expression and PFS while high CD274 mRNA was associated with longer PFS (p = 0.009). A combination of CD8A and CD274 was highly predictive of outcome. These results were confirmed in the validation cohorts. This two-genes signature demonstrated similar results compared to gold standard signatures.
CD8 represents both a prognostic and predictive factor of outcomes, while PD-L1 share different prognostic and predictive roles.
Venous thromboembolism (VTE) is highly prevalent in cancer patients and can cause severe morbidity. VTE treatment is essential, but anticoagulation increases the risk of major bleeding. The purpose ...was to evaluate the impact of VTE and major bleeding on survival and to identify significant risk factors for these events in lung cancer patients.
Data were extracted from a permanent sample of the French national health information system (including hospital and out-of-hospital care) from 2009 to 2016. All episodes of VTE and major bleeding events within one year after cancer diagnosis were identified. A Cox model was used to analyse the effect of VTE and major bleeding on the patients' one-year survival. VTE and major bleeding risk factors were analysed with a Fine and Gray survival model.
Among the 2553 included patients with lung cancer, 208 (8%) had a VTE episode in the year following diagnosis and 341 (13%) had major bleeding. Almost half of the patients died during follow-up. Fifty-six (60%) of the patients presenting with pulmonary embolism (PE) died, 48 (42%) of the patients presenting with deep vein thrombosis (DVT) alone died and 186 (55%) of those presenting with a major bleeding event died. The risk of death was significantly increased following PE and major bleeding events. VTE concomitant with cancer diagnosis was associated with an increased risk of VTE recurrence beyond 6 months after the first VTE event (sHR = 4.07 95% CI: 1.57-10.52). Most major bleeding events did not appear to be related to treatment.
VTE is frequent after a diagnosis of lung cancer, but so are major bleeding events. Both PE and major bleeding are associated with an increased risk of death and could be indicators of lung cancer mortality.
Tumor somatic mutation analysis is part of the standard management of metastatic lung cancer. However, physicians often have to deal with small biopsies and consequently with challenging mutation ...testing. Circulating free DNA (cfDNA) is a promising tool for accessing the tumor genome as a liquid biopsy. Here, we evaluated next-generation sequencing (NGS) on cfDNA samples obtained from a consecutive series of patients for the screening of a range of clinically relevant mutations.
A total of 107 plasma samples were collected from the BioCAST/IFCT-1002 lung cancer study (never-smokers cohort). Matched tumor DNA (tDNA) was obtained for 68 cases. Multiplex PCR-based assays were designed to target specific coding regions in EGFR, KRAS, BRAF, ERBB2, and PI3KCA genes, and amplicon sequencing was performed at deep coverage on the cfDNA/tDNA pairs using the NGS IonTorrent Personal Genome Machine Platform.
CfDNA concentration in plasma was significantly associated with both stage and number of metastatic sites. In tDNA, 50 mutations (36 EGFR, 5 ERBB2, 4 KRAS, 3 BRAF, and 2 PIK3CA) were identified, of which 26 were detected in cfDNA. Sensitivity of the test was 58% (95% confidence interval, 43%-71%) and the estimated specificity was 87% (62%-96%).
These data demonstrate the feasibility and potential utility of mutation screening in cfDNA using IonTorrent NGS for the detection of a range of tumor biomarkers in patients with metastatic lung cancer.
The aim of this article is to present a very general view of siliceous raw material sources in the central Pyrenees, with support from recent bibliographic references. To illustrate the use of these ...materials in the Upper Paleolithic, we chose the example of the Gravettian occupation of Gargas Cave (Hautes-Pyrénées, France). Finally, we describe a few economic characteristics of the Pyrenean region, which are distinct from the Perigordian context in several ways.
Non-small cell lung cancer is a very poor prognosis disease. Molecular analyses have highlighted several genetic alterations which may be targeted by specific therapies. In clinical practice, ...progression-free survival on EGFR TKI treatment is between 12 and 14 months. However, some patients progress rapidly in less than 6 months, while others remain free of progression for 16 months or even longer during EGFR TKI treatment.
We sequenced tumor exomes from 135 lung cancer patients (79 with EGFR-wildtype (WT), 56 with EGFR-mutant tumors) enrolled in the ALCAPONE trial (genomic analysis of lung cancers by next generation sequencing for personalized treatment).
Some germline polymorphisms were enriched in the EGFR-mutant subset compared to EGFR-WT tumors or to a reference population. However, the most interesting observation was the negative impact of some germline SNPs in immunity-related genes on survival on EGFR TKI treatment. Indeed, the presence of one of three particular SNPs in the HLA-DRB5 gene was associated with a decreased PFS on EGFR TKI. Moreover, some SNPs in the KIR3DL1 and KIR3DL2 genes were linked to a decrease in both progression-free and overall survival of patients with EGFR-mutant tumors.
Our data suggest that SNPs in genes expressed by immune cells may influence the response to targeted treatments, such as EGFR TKIs. This indicates that the impact of these cells may not be limited to modulating the response to immunotherapies. Further studies are needed to determine the exact mechanisms underlying this influence and to identify the associated predictive and prognostic markers that would allow to refine treatments and so improve lung cancer patient outcomes.
NCT02281214: NGS Genome Analysis in Personalization of Lung Cancer Treatment (ALCAPONE).
An ever-increasing number of drugs can reproduce variegated patterns of naturally occurring interstitial lung disease (ILD), including most forms of interstitial pneumonias, alveolar involvement and, ...rarely, vasculitis. Drugs in one therapeutic class may collectively produce the same pattern of involvement. A few drugs can produce more than one pattern of ILD. The diagnosis of drug-induced ILD (DI-ILD) essentially rests on the temporal association between exposure to the drug and the development of pulmonary infiltrates. The histopathological features of DI-ILD are generally consistent, rather than suggestive or specific to the drug etiology. Thus, the diagnosis of DI-ILD is mainly made by the meticulous exclusion of all other possible causes. Drug dechallenge produces measurable improvement in symptoms and imaging in the majority of patients, whereas corticosteroid therapy is indicated if symptoms are present or drug dechallenge is without an effect. Rechallenge is justified in a minority of patients, and is discouraged for diagnostic purposes only. Pneumotox (www.pneumotox.com) provides updated information on drug-induced respiratory disease.
Small cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma responsible for 200,000 deaths per year worldwide. Platinum-etoposide-based chemotherapy has been the standard of treatment for ...the past 40 years, with an overall survival of 10 months. Since 2019, the addition of immunotherapy (atezolizumab or durvalumab) to chemotherapy has become the standard of care for first-line treatment of extensive-stage SCLC following the demonstration of an improvement in overall survival in phase 3 studies. We aimed to evaluate the efficacy and safety of chemo-immunotherapy compared with chemotherapy alone in a “real-world” setting.
Retrospective observational study including patients undergoing first-line treatment for extensive-stage SCLC between 2014 and 2022. We separated the study population into two arms (chemo-immunotherapy/chemotherapy). For each arm, progression-free survival (PFS), overall survival (OS) and serious side effects were collected. Associations between treatments and survival outcomes were adjusted for potential confounders. Consolidative palliative thoracic radiotherapy was introduced in the models as a time-dependent variable.
A total of 118 patients with a median age of 63 years were included. 65.2 % of patients were performance status 0 or 1. In univariate analysis, PFS and OS were not significantly different between the chemo-immunotherapy and chemotherapy alone groups (p = 0.70 and 0.24 respectively). In multivariate analysis, the addition of immunotherapy to chemotherapy was not significantly associated with better PFS (HR 0.76, IC (0.49 – 1.19), p = 0.23), but it was significantly associated with better OS (HR 0.61, IC (0.38 – 0.98), p = 0.04). Consolidative palliative thoracic radiotherapy (time-dependent variable), when applied (almost only in the chemotherapy alone group), was significantly associated with better PFS and OS.
In this real-world study, chemo-immunotherapy was associated with slightly better OS compared to chemotherapy alone as a first-line treatment in ES-SCLC patients in multivariate analysis, which is not explained by a benefit in PFS. However, consolidative palliative thoracic radiotherapy seems to be significantly associated with better OS and PFS, suggesting that we should also consider using it in patients receiving chemo-immunotherapy.
While affinities and interactions between archaic and modern human populations (i.e. 200,000-40,000 BP in Eurasia) at macro-evolutionary and continental scales have received considerable attention, ...there has been less emphasis on the population history of Europe between 40,000 and 26,000 BP (i.e. prior to the Last glacial Maximum, LGM) when only modern humans were present. Here we examine the immature mandible from Gargas (France, ca. 29,000 cal BP), which displays a modern morphology overall with some archaic features rarely seen, if at all, in European Pleistocene and Holocene modern humans. In particular, the Gargas child has a very broad mandible, large tooth crowns with extreme deciduous and permanent mesiodistal molar diameters and a deciduous first molar with a quantity of enamel never previously reported. Furthermore, this child exhibits a supernumerary permanent tooth in the incisor region, a rare congenital disorder so far described for only five other pre-LGM modern humans. Finally, our results also highlight previously undocumented spatial differences in the tooth crown dimensions of Upper Palaeolithic fossils.
Background
An international consensus proposed in 2011 a definition and classification system for cachexia (CAX), mainly based on weight loss, sarcopenia skeletal muscle mass (SMM) loss, ...inflammation, and anorexia. The aim of this study was to stage CAX in non‐small‐cell lung cancer (NSCLC) patients by using a classification based on the Fearon criteria and supported by quantifiable parameters.
Methods
This was a cross‐sectional and non‐interventional multicentre study. SMM was assessed by analysing L3 computed tomography‐scan images. Patients completed the anorexia/CAX subscale of the Functional Assessment of Anorexia/Cachexia Therapy, EORTC QLQ‐C30 quality of life (QoL) and International Physical Activity Questionnaire (IPAQ).
Results
Patients were recruited in 56 sites. The analysis population comprised 531 patients, and SMM was assessed in 312 patients. Male patients were 66.5%, with a mean (SD) age of 65.2 (10.0) years, 79.9% were PS 0–1, and the tumour stage was mainly IIIB‐IV (87.3%). Overall, 38.7% of patients had CAX, 33.8% pre‐CAX, and 0.9% refractory CAX. Molecular tumour profiles were significantly associated with the presence of CAX: 23.9% in EGFR, ALK, ROS1, BRAF, or HER2+ patients, 41.4% in K‐RAS+, and 43.2% in patients with no molecular abnormality (P = 0.003). The more advanced the CAX stage, the poorer the scores of functional items of the QoL (P < 0.001) and International Physical Activity Questionnaire (P < 0.001). Sarcopenia was present in 66.7% of CAX and 68.5% of pre‐CAX patients. Overall, 43.8% of pre‐CAX patients had only sarcopenia with limited weight loss (≤2%) and no anorexia.
Conclusions
This is the first study to show the distribution of CAX in a population of NSCLC patients and an association between molecular abnormality in NSCLC and CAX. The original Fearon classification for CAX stages was supported by the associated functional QoL scores and physical activity levels, resulting in a clinically relevant system for detection of early stages of CAX.
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