Radiomics and Delta-Radiomics Signatures to Predict Response and Survival in Patients with Non-Small-Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

The aim of our study was to determine the potential role of CT-based radiomics in predicting treatment response and survival in patients with advanced NSCLC treated with immune checkpoint inhibitors. We retrospectively included 188 patients with NSCLC treated with PD-1/PD-L1 inhibitors from two independent centers. Radiomics analysis was performed on pre-treatment contrast-enhanced CT. A delta-radiomics analysis was also conducted on a subset of 160 patients who underwent a follow-up contrast-enhanced CT after 2 to 4 treatment cycles. Linear and random forest (RF) models were tested to predict response at 6 months and overall survival. Models based on clinical parameters only and combined clinical and radiomics models were also tested and compared to the radiomics and delta-radiomics models. The RF delta-radiomics model showed the best performance for response prediction with an AUC of 0.8 (95% CI: 0.65-0.95) on the external test dataset. The Cox regression delta-radiomics model was the most accurate at predicting survival with a concordance index of 0.68 (95% CI: 0.56-0.80) (p = 0.02). The baseline CT radiomics signatures did not show any significant results for treatment response prediction or survival. In conclusion, our results demonstrated the ability of a CT-based delta-radiomics signature to identify early on patients with NSCLC who were more likely to benefit from immunotherapy.

Clinical Utility and Outcomes Impact of Crystal Digital PCR of Sensitizing and Resistance EGFR Mutations in Patients With Advanced Non-Small Cell Lung Cancer.

BACKGROUND: EGFRm represent 15% of advanced NSCLC in European patients. LB for molecular profiling offers a non-invasive alternative to tissue. cdPCR is a high-sensitive and low-cost LB to detect molecular alterations. We aimed to describe cdPCR clinical utility for EGFRm detection in advanced NSCLC. METHODS: Prospective blood sample collection in patients with advanced NSCLC harbouring EGFRm either at diagnosis, under response or at PD between January 16 and September 20 at Gustave Roussy. LB was performed by cdPCR (Stilla): sensitizing (exon19; exon21 [p.L858R]) and exon 20 p.T790M resistance EGFRm. We defined high tumour burden (high-TB) as >2 metastatic sites. We analysed EGFRm detection by cdPCR and its correlation with progression-free and overall survival (PFS, OS). RESULTS: A total of 252 blood samples were collected in 140 patients. At baseline (n=25), sensitizing EGFRm were detected in 64% of samples, 88% in patients with high-TB (n=8) and 40% among those with intracranial/intrathoracic isolated lesions (n=5). At PD to tyrosine-kinase inhibitors (TKI) (n=117), detection rate (sensitizing EGFRm) was 56%; 30% in patients with intracranial/thoracic isolated lesions (n=37) vs. 67% in those with high-TB (n=63). At PD to first/second generation TKI (n=81), the p.T790M mutation was found in 22% (18/81); detection rate was 9% for intracranial/thoracic (n=23) vs. 32% for high-TB (n=41) cases. The clearance of EGFRm allelic frequency was correlated with radiological response. The absence of EGFRm detection at TKI-failure was associated with longer OS (39.1 vs. 18.4 months; P=.02). CONCLUSIONS: cdPCR is a sensitive LB for sensitizing and resistance EGFRm detection. cdPCR positivity was more likely observed in systemic PD cases with high-TB. It is a low-cost EGFRm detecting approach to guide treatment in NSCLC, however metastatic profile should be taken into account.

Telerehabilitation physical exercise for patients with lung cancer through the course of their disease: A systematic review.

BACKGROUND AND OBJECTIVE: Evidence is shown for the benefits of physical activity, for patients with lung cancer, at different times through the course of the disease. Telerehabilitation can overcome some of barriers often met by patients to practice physical activity. The objective of this systematic review is to assess feasibility and safety of telerehabilitation for patients with lung cancer, its effects on physical capacity, quality of life, symptoms severity, depression and anxiety, survival, lung function, post-operative outcomes, dyspnoea and body composition. Secondary aim was to distinguish the telerehabilitation efficacy between the different phases of the disease. DATA SOURCE AND SELECTION CRITERIA: Pubmed, PEDro, Scopus, ScienceDirect, randomized controlled trials and non-randomized controlled trials, written in French or English, of telerehabilitation among patients with lung cancer. RESULTS: Eight studies were included. Telerehabilitation is safe but was characterized by a low recruitment and attendance rate (<70%). It enhances quality of life, muscle mass, depression and anxiety but it does not improve physical capacity (except in preoperative period), symptoms severity, survival, lung function or dyspnoea. After surgery, it ameliorates quality of life, depression and anxiety. During systemic treatments of lung cancer, it improves quality of life, symptoms severity and muscle mass. CONCLUSION: Telerehabilitation could be proposed in patients with lung cancer as a complementary intervention of hospital-based programme to increase physical activity volume, compliance and self-efficacy. In case the classic programmes are not possible, it could also be an alternative approach for patients unable to participate to a hospital or community-based training programme.

Follow-up of functional exercise capacity in patients with COVID-19: It is improved by telerehabilitation.

BACKGROUND: The impact of the COVID-19 pandemic on functional exercise capacity seemed quickly clinically evident. The objective of this study was to assess the functional exercise capacity of patients with severe COVID-19 and to evaluate the effect of a telerehabilitation program in the specific context of the COVID-19 pandemic. METHOD: Patients hospitalized for severe or critical COVID-19 were recruited. The functional exercise capacity (1-min sit-to-stand test (STST)) was prospectively quantified at discharge. A telerehabilitation program was then proposed. A control group was composed with the patients refusing the program. RESULTS: At discharge, none of the 48 recruited patients had a STST higher than the 50th percentile and 77% of them were below the 2.5th percentile. SpO2 was 92.6 ± 3.0% after STST and 15 patients had oxygen desaturation. After 3-months of follow-up, the number of repetitions during STST significantly increased either in telerehabilitation (n = 14) (p < 0.001) or in control groups (n = 13) (p = 0.002) but only one patient had a result higher than the 50th percentile (in Telerehabilitation group) and 37% of them were still under the 2.5th percentile for this result. The improvement was significantly and clinically greater after the telerehabilitation program (p = 0.005). No adverse events were reported by the patients during the program. CONCLUSIONS: Patients hospitalized for COVID-19 have a low functional exercise capacity at discharge and the recovery after three months is poor. The feasibility and the effect of a simple telerehabilitation program were verified, this program being able to substantially improve the functional recovery after three months.

Determinants of IgG antibodies kinetics after severe and critical COVID-19.

The kinetics of IgG antibodies after coronavirus disease 2019 (COVID-19) remain poorly understood. We investigated factors influencing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibody levels and time to seronegativation during the follow-up of severe and critically ill patients. We retrospectively reviewed serological evaluations drawn during the follow-up of severe or critical laboratory-proven COVID-19 patients hospitalized at a large academic hospital. Specific IgG titers were measured using a chemiluminescent assay targeting anti-spike and anti-nucleocapsid protein IgG. The influence of time, demographic factors, clinical and paraclinical characteristics, and COVID-19 therapeutics on IgG levels were assessed through linear regression using a mixed-effect model, and delay until IgG negativation through a Weibull regression model. The cohort included 116 patients with a total of 154 IgG measurements drawn at a median of 79 days after diagnosis. IgG antibodies were increased with age (p = 0.005) and decreased significantly over time (p = 0.0002). Using elapsed time and age as covariates, we demonstrated higher IgG levels in patients with a higher body mass index (BMI) (p = 0.0026) and lower IgG levels in immunocompromised patients (p = 0.032). A high BMI was further found to delay and immunodeficiency to hasten significantly seronegativation, whereas no significant effect was observed with corticosteroids. These data highlight the waning over time of IgG antibodies after severe or critical COVID-19. Age, BMI, and immunosuppression also appear to influence the IgG kinetics, while short-term corticotherapy does not. Those data improve the understanding of SARS-CoV-2 serology while further research should determine the determinants of long-term seroprotection.

Integrative respiratory follow-up of severe COVID-19 reveals common functional and lung imaging sequelae.

BACKGROUND: COVID-19 pandemic resulted in an unprecedented number of hospitalizations in general wards and intensive care units (ICU). Severe and critical COVID-19 patients suffer from extensive pneumonia; therefore, long-term respiratory sequelae may be expected. RESEARCH QUESTION: We conducted a cohort study to determine respiratory sequelae in patients with severe and critical COVID-19. We aimed at evaluating the proportion of patients with persisting respiratory symptoms and/or abnormalities in pulmonary function tests (PFT) or in lung imaging. STUDY DESIGN: and methods: This is a single center cohort study including COVID-19 survivors who underwent a three-month follow-up with clinical evaluation, PFT and lung high-resolution computed tomography (HRCT). All clinical, functional, and radiological data were centrally reviewed. Multiple linear regression analysis was performed to identify factors associated with residual lesions on HRCT. RESULTS: Full clinical evaluation, PFT and lung HRCT were available for central review in 126, 122 and 107 patients, respectively. At follow-up, 25% of patients complained from dyspnea and 35% from fatigue, lung diffusion capacity (DLCO) was decreased in 45%, 17% had HRCT abnormalities affecting more than 5% of their lung parenchyma while signs of fibrosis were found in 21%. In multiple linear regression model, number of days in ICU were related to the extent of persisting lesions on HRCT, while intubation was associated with signs of fibrosis at follow-up (P = 0.0005, Fisher's exact test). In contrast, the severity of lung imaging or PFT changes were not predictive of fatigue and dyspnea. INTERPRETATION: Although most hospitalized COVID-19 patients recover, a substantial proportion complains from persisting dyspnea and fatigue. Impairment of DLCO and signs suggestive of fibrosis are common but are not strictly related to long-lasting symptoms.

Tumour-infiltrating lymphocyte density is associated with favourable outcome in patients with advanced non-small cell lung cancer treated with immunotherapy.

BACKGROUND: The established role of morphological evaluation of tumour-infiltrating lymphocytes (TILs) with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. We aimed to determine TIL association with the outcome for ICIs and for chemotherapy in advanced NSCLC. METHODS: This is a multicenter retrospective study of a nivolumab cohort of 221 patients treated between November 2012 and February 2017 and a chemotherapy cohort of 189 patients treated between June 2009 and October 2016. Patients with available tissue for stromal TIL evaluation were analysed. The presence of a high TIL count (high-TIL) was defined as ≥10% density. The primary end-point was overall survival (OS). RESULTS: Among the nivolumab cohort, 64% were male, with median age of 63 years, 82.3% were smokers, 77% had performance status ≤1 and 63% had adenocarcinoma histology. High-TIL was observed in 22% patients and associated with OS (hazard ratio [HR] 0.48; 95% confidence interval [95% CI]: 0.28-0.81) and progression-free survival [PFS] (HR = 0.40; 95% CI: 0.25-0.64). Median PFS was 13.0 months (95% CI: 5.0-not reached) with high-TIL versus 2.2 months (95% CI: 1.7-3.0) with the presence of a low TIL count (low-TIL). Median OS for high-TIL was not reached (95% CI: 12.2-not reached) versus 8.4 months (95% CI: 5.0-11.6) in the low-TIL group. High-TIL was associated with the overall response rate (ORR) and disease control rate (DCR) (both, P < .0001). Among the chemotherapy cohort, 69% were male, 89% were smokers, 86% had performance status ≤1 and 90% had adenocarcinoma histology. High-TIL was seen in 37%. Median PFS and OS were 5.7 months (95% CI: 4.9-6.7) and 11.7 months (95% CI: 9.3-13.0), respectively, with no association with TILs. CONCLUSIONS: High-TIL was associated with favourable outcomes in a real-world immunotherapy cohort of patients with NSCLC, but not with chemotherapy, suggesting that TILs may be useful in selecting patients for immunotherapy.

Association of metastatic pattern and molecular status in stage IV non-small cell lung cancer adenocarcinoma.

OBJECTIVES: The aim of our study was to investigate the association between driver oncogene alterations and metastatic patterns on imaging assessment, in a large cohort of metastatic lung adenocarcinoma patients. METHODS: From January 2010 to May 2017, 550 patients with stage IV lung adenocarcinoma with molecular analysis were studied retrospectively including 135 EGFR-mutated, 81 ALK-rearrangement, 47 BRAF-mutated, 141 KRAS-mutated, and 146 negative tumors for these 4 mutations (4N). After review of the complete imaging report by two radiologists (junior and senior) to identify metastatic sites, univariate correlation analyzes were performed. RESULTS: We found differences in metastatic tropism depending on the molecular alteration type when compared with the non-mutated 4N group: in the EGFR group, pleural metastases were more frequent (32% versus 20%; p = 0.021), and adrenal and node metastases less common (6% versus 23%; p < 0.001 and 11% versus 23%; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% versus 29%; p = 0.043 and 37% versus 24%; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (respectively 47% versus 20%; p < 0.001 and 11% versus 3%; p = 0.04) and bone metastases were rarer (21% versus 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK, and BRAF groups (respectively 6%, 7%, and 15% versus 1%); p = 0.016; p = 0.009; and p < 0.001. CONCLUSION: The application of these correlations between molecular status and metastatic tropism in clinical practice may lead to earlier and more accurate identification of patients for targeted therapy. KEY POINTS: • Bone and brain metastasis are the most common organs involved in lung adenocarcinoma but the relative incidence of each metastatic site depends on the molecular alteration. • EGFR-mutated tumors preferentially spread to the pleura and less commonly to adrenals, ALK-rearrangement tumors usually spread to the brain and the lungs, whereas BRAF-mutated tumors are unlikely to spread to bones and have a serous (pericardial ad pleural) tropism. • These correlations could help in the clinical management of patients with metastatic lung adenocarcinoma.

Discovery of new membrane-associated proteins overexpressed in small-cell lung cancer.

INTRODUCTION: Small-cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, with no early detection strategy or targeted therapy currently available. We hypothesized that difference gel electrophoresis (DIGE) may identify membrane-associated proteins (MAPs) specific to SCLC, advance our understanding of SCLC biology, and discover new biomarkers of SCLC. METHODS: MAP lysates were prepared from three SCLCs, three non-small-cell lung cancers, and three immortalized normal bronchial epithelial cell lines and coanalyzed by DIGE. Subsequent protein identification was performed by mass spectrometry. Proteins were submitted to Ingenuity Pathway Analysis. Candidate biomarkers were validated by Western blotting (WB) and immunohistochemistry (IHC). RESULTS: Principal component analysis on the global DIGE data set demonstrated that the four replicates derived from each of the nine cell lines clustered closely, as did samples within the same histological group. One hundred thirty-seven proteins were differentially expressed in SCLC compared with non-small-cell lung cancer and immortalized normal bronchial epithelial cells. These proteins were overrepresented in cellular/tissue morphology networks. Dihydropyrimidinase-related protein 2, guanine nucleotide-binding protein alpha-q, laminin receptor 1, pontin, and stathmin 1 were selected as candidate biomarkers among MAPs overexpressed in SCLC. Overexpression of all candidates but RSSA in SCLC was verified by WB and/or IHC on tissue microarrays. These proteins were significantly associated with SCLC histology and survival in univariables analyses. CONCLUSION: DIGE analysis of a membrane-associated subproteome discovered overexpression of dihydropyrimidinase-related protein 2, guanine nucleotide-binding protein alpha-q, RUVB1, and stathmin 1 in SCLC. Results were verified by WB and/or IHC in primary tumors, suggesting that investigating their functional relevance in SCLC progression is warranted. Association with survival requires further validation in larger clinical data sets.