Comprehensive genomic and spatial immune infiltration analysis of survival outliers in extensive-stage small cell lung cancer receiving first-line chemoimmunotherapy.

BACKGROUND: A minority of patients with extensive-stage small cell lung cancer (ES-SCLC) exhibit prolonged survival following first-line chemoimmunotherapy, which warrants the use of reliable biomarkers. Here, we investigated the disparities in genomics and immune cell spatial distribution between long- and short-term survival of patients with ES-SCLC. METHODS: We retrospectively recruited 11 long-term (>2 years) and 13 short-term (<9 months) ES-SCLC survivors receiving first-line chemoimmunotherapy. The samples were processed using targeted next-generation sequencing (tNGS), programmed death ligand-1 staining, multiplex immunohistochemical staining for immune cells (mIHC), tumor mutation burden (TMB), and chromosomal instability score measurements. The expression of putative genes in SCLC at the bulk and single-cell RNA-sequencing levels, as well as the role of putative genes in pan-cancer immunotherapy cohorts, were analyzed. RESULTS: At the genomic level, a greater proportion of the smoking signature and higher TMB (>3.1) were associated with favorable survival. At the single-gene and pathway levels, tNGS revealed that MCL1 and STMN1 amplification and alterations in the apoptosis pathway were more common in short-term survivors, whereas alterations in the DLL3, KMT2B, HGF, EPHA3, ADGRB3, lysine deprivation, and HGF-cMET pathways were observed more frequently in long-term survivors. mIHC analysis of immune cells with different spatial distributions revealed that long-term survivors presented increased numbers of M1-like macrophages in all locations and decreased numbers of CD8+ T cells in the tumor stroma. Bulk transcriptomic analysis demonstrated that high levels of STMN1 and DLL3 represented an immune-suppressive tumor immune microenvironment (TIME), whereas HGF indicated an immune-responsive TIME. The expression levels of our putative genes were comparative in both TP53/RB1 mutant-type and TP53/RB1 wild-type. At the single-cell level, STMN1, MCL1, and DLL3 were highly expressed among all molecular subtypes (SCLC-A, SCLC-N, and SCLC-P), with STMN1 being enriched in cell division and G2M checkpoint pathways. CONCLUSIONS: For ES-SCLC patients receiving first-line chemoimmunotherapy, alterations in DLL3, KMT2B, HGF, EPHA3, and ADGRB3 and a greater proportion of M1-like macrophages infiltration in all locations were predictors of favorable survival, while MCL1 and STMN1 amplification, as well as a greater proportion of CD8+ T cells infiltrating the tumor stroma, predicted worse survival.

Efficacy and safety of first-line PD-L1/PD-1 inhibitors in limited-stage small cell lung cancer: a multicenter propensity score matched retrospective study.

Background: The prognosis of small cell lung cancer (SCLC) patients is poor, and the standard first-line treatment for limited-stage small cell lung cancer (LS-SCLC) is still chemotherapy and thoracic radiotherapy. The primary objectives of our study were to confirm the superior efficacy of first-line immune checkpoint inhibitors (ICIs) plus etoposide and platinum (EP) for LS-SCLC and find crucial biomarkers. Methods: We analyzed LS-SCLC patients from three medical centers, employing propensity score matching for group comparability. Survival outcomes were estimated by Kaplan-Meier and Cox regression analyses. Additionally, we conducted univariate and multivariate analyses to investigate potential predictive factors. Results: Among 150 patients in our study, we successfully matched 41 pairs. The median overall survival (OS) was 29.5 months in the EP + ICIs group and 20.0 months in the EP group {hazard ratio (HR) =0.64 [95% confidence interval (CI): 0.41-1.02], P=0.059}. The median progression-free survival (PFS) was significantly extended in the EP + ICIs group (14.6 months), compared to the EP group (8.6 months) [HR =0.42 (95% CI: 0.28-0.63), P<0.001]. After matching, patients receiving chemo-immunotherapy had a median OS of 36.1 months, significantly surpassing those receiving chemotherapy alone (19.0 months) [HR =0.51 (95% CI: 0.28-0.93), P=0.02]. And the patients in the EP + ICIs group also had longer PFS after matching [HR =0.42 (95% CI: 0.25-0.71), P=0.001]. No significant difference in the objective response rate (ORR) and treatment-related adverse events (trAEs) between the two groups was found (ORR: EP: 81.0%, EP + ICIs: 90.0%, P=0.14; trAEs: EP: grade 1-2, 49.3%; grade 3-4, 42.5%; EP + ICIs: grade 1-2, 40.0%; grade 3-4, 49.1%, P=0.62). The multivariate analysis presented that the history of immunotherapy [EP + PD-1 inhibitors: HR =0.33 (95% CI: 0.17-0.62), P=0.001; EP + PD-L1 inhibitors: HR =0.18 (95% CI: 0.06-0.60), P=0.005] and baseline lung immune prognostic index (LIPI) [intermediate: HR =2.22 (95% CI: 1.20-4.13), P=0.01; poor: HR =2.03 (95% CI: 0.71-5.77), P=0.18] were independent prognostic factors for PFS among all LS-SCLC cases. However, no independent prognostic factor was identified for OS. Conclusions: Our real-world data showed promising clinical efficacy and tolerable safety of first-line programmed cell death protein 1 (PD-1) inhibitors or programmed cell death ligand 1 (PD-L1) inhibitors in cases with LS-SCLC. Additionally, LIPI may serve as a valuable prognostic factor.

Efficacy of immunotherapy in patients with oncogene-driven non-small-cell lung cancer: a systematic review and meta-analysis.

Background: Immunotherapy is an emerging antitumor therapy that can improve the survival of patients with advanced non-small-cell lung cancer (NSCLC). However, only about 20% of NSCLC patients can benefit from this treatment. At present, whether patients with driving gene-positive NSCLC can benefit from immunotherapy is one of the hot issues. Therefore, we conducted a meta-analysis to evaluate the efficacy of immunotherapy in patients with oncogene-driven NSCLC and concluded the efficacy of altered subtypes. Methods: A literature search was performed using PubMed, Web of Science, and Cochrane databases. The primary endpoints included the objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients with oncogene-driven NSCLC. Results: In all, 86 studies involving 4524 patients with oncogene-driven NSCLC were included in this meta-analysis. The pooled ORRs in clinical trials treated with monoimmunotherapy of EGFR, ALK, and KRAS alteration were 6%, 0%, and 23%, respectively. In retrospective studies, the pooled ORRs of EGFR, ALK, KRAS, BRAF, MET, HER2, RET, and ROS1 alteration were 8%, 3%, 28%, 24%, 23%, 14%, 7%, and 8%, respectively. Among them, the pooled ORRs of KRAS non-G12C mutation, KRAS G12C mutation, BRAF V600E mutation, BRAF non-V600E mutation, MET-exon 14 skipping, and MET-amplification were 33% 40%, 20%, 34%, 17%, and 60%, respectively. In addition, the pooled mPFS rates of EGFR, KRAS, MET, HER2, and RET alteration were 2.77, 3.24, 2.48, 2.31, and 2.68 months, while the pooled mOS rates of EGFR and KRAS alteration were 9.98 and 12.29 months, respectively. In prospective data concerning EGFR mutation, the pooled ORR and mPFS treated with chemo-immunotherapy (IC) reached 38% and 6.20 months, while 58% and 8.48 months with chemo-immunotherapy plus anti-angiogenesis therapy (ICA). Moreover, the pooled mPFS and mOS of monoimmunotherapy was 2.33 months and 12.43 months. Conclusions: EGFR-, ALK-, HER2-, RET-, and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation, and MET amplification have better responses to immunotherapy, and more prospective studies are needed for further research.

Efficacy of immunotherapy in patients with oncogene-driven non-small cell lung cancer: a systematic review and meta analysis Immunotherapy is an emerging antitumor therapy that can improve the survival of patients with advanced NSCLC. However, only about 20% of NSCLC patients can benefit from this treatment. At present, whether patients with driving gene positive NSCLC can benefit from immunotherapy is one of the hot issues. Therefore, we conducted a meta-analysis to evaluate the efficacy of immunotherapy in patients with oncogene-driven NSCLC, and concluded the efficacy of altered subtypes. 86 studies involving 4524 patients with oncogene-driven NSCLC were included in this meta-analysis. The pooled ORR in clinical trials treated with monoimmunotherapy was of EGFR, ALK and KRAS alteration was 6%, 0%, and 23%, respectively. While in retrospective studies, the pooled ORR of EGFR, ALK, KRAS, BRAF, MET, HER2, RET and ROS1 alteration was 8%, 3%, 28%, 24%, 23%, 14%, 7% and 8%, respectively. Among them, the pooled ORR of KRAS non-G12C mutation, KRAS G12C mutation, BRAF V600E mutation, BRAF non-V600E mutation, MET-exon 14 skipping and MET-amplification was 33% 40%, 20%, 34%, 17% and 60%, respectively. Additionally, the pooled mPFS of EGFR, KRAS, MET, HER2 and RET alteration was 2.77, 3.24, 2.48, 2.31 and 2.68 months, while the pooled mOS of EGFR and KRAS alteration was 9.98 and 12.29 months. In prospective data concerning EGFR mutation, the pooled ORR and mPFS treated with chemo-immunotherapy (IC) was reached 38% and 6.20 months, while 58% and 8.48 months with chemo-immunotherapy plus anti-angiogenesis therapy (ICA). Moreover, the pooled mPFS and mOS of monoimmunotherapy was 2.33 months and 12.43 months. EGFR, ALK, HER2, RET and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy, but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation and MET amplification have better response to immunotherapy, and more prospective studies are needed for further research.

Safety and efficacy of thoracic radiotherapy combined with chemo-immunotherapy in patients with extensive-stage small cell lung cancer: a multicenter retrospective analysis.

Background: Immunotherapy has greatly increased the survival time of patients with extensive-stage small cell lung cancer (ES-SCLC), and is now a standard first-line treatment for these patients. Increasing evidence suggests a possible synergistic effect between immunotherapy and radiotherapy, yet there is a paucity of evidence regarding the efficacy and safety of thoracic radiotherapy (TRT) combined with chemo-immunotherapy for ES-SCLC. Methods: The medical records of 78 consecutive patients with ES-SCLC who received TRT in combination with chemo-immunotherapy at Jinling Hospital and Jiangsu Cancer Hospital from January 2019 to January 2023 were retrospectively reviewed. The median overall survival (mOS) time and median progression-free survival (mPFS) time were used to evaluate efficacy, and the incidence of adverse events (AEs) was used to evaluate safety. Results: The median follow-up time was 31.9 months, the objective response rate (ORR) was 59%, and the disease control rate (DCR) was 89.8%. The mOS time was 20.0 months, and the 6-month OS rate was 95%. The mPFS time was 9.2 months, and the 6-month PFS rate was 78%. There were no treatment-related deaths. The incidence of pneumonitis was 23.1%, the incidence of radiation esophagitis was 5.1%, and 2 patients experienced high-grade pneumonitis. Primary liver metastasis was a predictor of poor OS and PFS. Patients who received consolidative TRT after chemo-immunotherapy experienced more benefit than those who received TRT as palliative or salvage treatment for superior vena cava syndrome or disease progression. Conclusions: TRT is a feasible treatment for patients who receive chemo-immunotherapy for the management of ES-SCLC in consideration of its considerable efficacy and tolerable safety risk. This treatment is especially useful for patients without primary liver metastasis and who receive consolidative TRT after chemo-immunotherapy. Large-scale prospective studies are needed to confirm the efficacy and safety of this treatment modality.

Safety and efficacy of retreatment with immune checkpoint inhibitors in non-small cell lung cancer: a systematic review and meta-analysis.

Background: Retreatment with immune checkpoint inhibitors (ICIs) might be a subsequent therapeutic option for patients with non-small cell lung cancer (NSCLC) who discontinued initial ICIs treatment because of disease progression, immune-related adverse events (irAEs) or completion of a fixed course, yet little evidence exists on the safety and efficacy of ICIs retreatment to support this strategy. Methods: We searched PubMed, Web of Science, Embase, Cochrane and major meeting libraries for articles about ICIs retreatment in NSCLC for systematic review and meta-analysis. The outcomes included objective response rate (ORR) and disease control rate (DCR) for efficacy and the incidence of all-grade and high-grade irAEs for safety. ICIs rechallenge implies retreatment that can be applied to patients who progressed, while ICIs resumption refers to retreatment for patients who discontinued prior treatment due to an irAE or completion of a fixed course of immunotherapy. Results: Eighteen studies were enrolled in our analysis. The pooled ORR and DCR of ICIs retreatment were respectively 20% and 54%. ICIs retreatment was associated with a decrease in ORR and DCR compared to prior ICIs treatment (ORR: OR, 0.29, 95% CI: 0.14, 0.63, P=0.002; DCR: OR, 0.53, 95% CI: 0.28-0.99, P=0.05). The pooled ORR and DCR of ICIs rechallenge were 8% and 39%. ICIs rechallenge showed a lower ORR compared with initial ICIs treatment (P<0.05). ICIs resumption presented an ORR of 34% and a DCR of 71%, showing no significant difference in ORR and DCR compared with initial ICIs treatment (P>0.05). Retreated with the same type of ICIs as before showed no difference in ORR and DCR (P>0.05), while with different ICIs was associated with a decrease in ORR and DCR in contrast to initial treatment (P<0.05). The pooled incidence of all-grade and high-grade irAEs after ICIs retreatment in patients with NSCLC were separately 41% and 13% which showed a similar incidence compared with initial ICIs treatment (P>0.05). Discussion: Retreatment with ICIs is feasible for patients with NSCLC in consideration of its encouraging efficacy and tolerable safety, especially in resumption with ICIs. When it comes to ICIs rechallenge, it is necessary to accurately identify the potential targeted beneficiary population. More large-scale prospective studies are warranted to confirm our discoveries. More attention could be paid to further exploring the efficacy and safety of retreatment concurrently with ICIs and chemotherapy.

Investigation on Reaction Sequence and Group Site of Citric Acid with Cellulose Characterized by FTIR in Combination with Two-Dimensional Correlation Spectroscopy.

Cotton fabrics are prone to wrinkles and can be treated with citric acid (CA) to obtain good anti-wrinkle properties. However, the yellowing of the CA-treated fabrics is one big obstacle to the practical application of citric acid. The changing sequence order of CA anhydride and unsaturated acid (the reason for yellowing), such as aconitic acid (AA), has not been investigated. Herein, Fourier transform infrared (FTIR) spectroscopy, two-dimensional correlation spectroscopy (2Dcos), and Gaussian calculation were employed to characterize the reaction mechanism between CA with cellulose. FTIR spectra of the CA-treated fabrics heated under different temperatures were collected and further analyzed with 2Dcos. The results indicated the changing sequence order: 1656 cm-1→1784 cm-1→1701 cm-1, ("→" means earlier than), i.e., unsaturated acid→anhydride→ester. Moreover, a change of Gibbs free energy (ΔG) showed that trans-AA (ΔG = -22.10 kJ/mol) is more thermodynamically favorable to be formed than CA anhydride 1 (ΔG = -0.90 kJ/mol), which was proved by Gaussian computational modeling. By taking cellobiose as a model of cellulose, the ΔG results proved that O(6)-H(6) on the glucose ring is the most likely hydroxyl to react with anhydride originated from CA or AA, especially with the terminal carbonyl group.

Blood metal levels and serum testosterone concentrations in male and female children and adolescents: NHANES 2011-2012.

Environmental exposure to metals is ubiquitous, but its relation to androgen hormone levels is not well understood, especially in children and adolescents. This study aimed to explore the relationship between blood metal concentrations (lead, cadmium, total mercury, selenium, and manganese) and serum total testosterone (TT) levels in 6-19-year-old children and adolescents in the National Health and Nutrition Examination Survey (NHANES) 2011-2012. Weighted multivariable linear regression models using NHANES sampling weights were employed to evaluate the association between log-transformed serum TT and each metal categories in male and female children (age 6-11years) and adolescents (age 12-19 years). We established that blood cadmium and manganese levels were associated with significantly higher serum TT levels in the female adolescents. Additionally, the blood selenium levels in male adolescents were related to significantly higher serum TT. No significant associations between blood lead or total mercury levels and TT were observed in children or adolescents of either sex. These findings suggest that environmental exposure to certain metals could affect serum TT levels in adolescents, which might have important implications for the health of adolescents. Further research is required to confirm and extend our present findings.