Nomograms Predict PFS and OS for SCLC Patients After Standardized Treatment: A Real-World Study.

Purpose: This study aims to investigate the process of small cell lung cancer (SCLC) patients from achieving optimal efficacy to experiencing disease progression until death. It examines the predictive value of the treatment response on progression free survival (PFS) and overall survival (OS) of SCLC patients. Patients and Methods: We conducted a retrospective analysis on 136 SCLC patients diagnosed from 1992 to 2018. Important prognostic factors were identified to construct nomogram models. The predictive performance of the models was evaluated using the receiver operating characteristic curves and calibration curves. Survival differences between groups were compared using Kaplan-Meier survival curves. Subsequently, an independent cohort consisting of 106 SCLC patients diagnosed from 2014 to 2021 was used for validation. Results: We constructed two nomograms to predict first-line PFS (PFS1) and OS of SCLC. The area under the receiver operating characteristic curves for the PFS1 nomogram predicting PFS at 3-, 6-, and 12-months were 0.919 (95% CI: 0.867-0.970), 0.908 (95% CI: 0.860-0.956) and 0.878 (95% CI: 0.798-0.958), and for the OS nomogram predicting OS at 6-, 12-, and 24-months were 0.814 (95% CI: 0.736-0.892), 0.819 (95% CI: 0.749-0.889) and 0.809 (95% CI: 0.678-0.941), indicating those two models with a high discriminative ability. The calibration curves demonstrated the models had a high degree of consistency between predicted and observed values. According to the risk scores, patients were divided into high-risk and low-risk groups, showing a significant difference in survival rate. And these findings were validated in another independent validation cohort. Conclusion: Based on the patients' treatment response after standardized treatment, we developed and validated two nomogram models to predict PFS1 and OS of SCLC. The models demonstrated good accuracy, reliability and clinical applicability by validating in an independent cohort.

Efficacy and safety of anti-PD-1 inhibitor versus anti-PD-L1 inhibitor in first-line treatment of extensive-stage small cell lung cancer: a multicenter retrospective study.

BACKGROUND: Immunotherapy targeting PD-1/PD-L1 has revolutionized the treatment of extensive-stage small cell lung cancer (ES-SCLC). However, clinical trials suggest differential efficacy of anti-PD-1 agents and anti-PD-L1 agents in first-line treatment of ES-SCLC. This retrospective multicenter study aimed to compare the efficacy and safety of anti-PD-1 agents versus anti-PD-L1 agents in first-line treatment of ES-SCLC in real-world practice. METHODS: Patients with pathologically or cytologically confirmed ES-SCLC treated with platinum plus etoposide combined with anti-PD-1 or PD-L1 agents as first-line treatment in different centers of PLA General Hospital between January 2017 and October 2021 were included for this study. Survival outcomes and safety were compared between patients receiving anti-PD-1 and PD-L1 agents. RESULTS: Of the total 154 included patients, 68 received anti-PD-1 agents plus chemotherapy (PD-1 group), and 86 received anti-PD-L1 agents plus chemotherapy (PD-L1 group). Progression-free survival (PFS) and overall survival (OS) in the entire cohort were 7.6 months (95% confidence interval [CI]: 6.5-8.2 months) and 17.4 months (95% CI: 15.3-19.3 months), respectively. Median PFS and OS were comparable between the PD-1 group and PD-L1 group (PFS: 7.6 months vs. 8.3 months, HR = 1.13, 95% CI: 0.79-1.62, p = 0.415; OS: 26.9 months vs. 25.6 months, HR = 0.96, 95% CI: 0.63-1.47, p = 0.859. The objective response rate and disease control rate were comparable between the two groups: 79.4% vs. 79.1% and 92.6% vs. 94.2%, respectively. The 6-month, 12-month, and 18-month PFS and OS rates were slightly higher in the PD-L1 group than in the PD-1 group, while the 24-month PFS rate was slightly higher in the PD-1 group than in the PD-L1 group. Stratified analysis showed that locoregional thoracic radiotherapy and normal lactate dehydrogenase level were independent predictors of better OS in ES-SCLC patients treated with first-line chemotherapy plus ICI. Adverse events were not significantly different between the two groups. CONCLUSIONS: Anti-PD-1 agents and anti-PD-L1 agents combined with chemotherapy as first-line treatment for ES-SCLC are comparably effective and well tolerated.

A real-world study of immune checkpoint inhibitors in advanced triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Immune checkpoint inhibitors (ICIs) have been widely used to treat various tumors and have changed the landscape of tumor management, but the data from real-world studies of ICIs for TNBC treatment remain limited. The aim of this study was to evaluate the efficacy of ICIs in the treatment of patients with advanced TNBC in a real-world setting and to explore possible correlates. Methods: The clinical data of advanced TNBC patients who received ICI treatment in the Chinese People's Liberation Army (PLA) General Hospital were collected. Treatment responses, outcomes and adverse events (AEs) were assessed. Results: Eighty-one patients were included in the study. The confirmed objective response rate (ORR) was 32.1%, and the disease control rate (DCR) was 64.2%. The median progression-free survival (PFS) was 4.2 months, and the median overall survival (OS) was 11.0 months. PFS and OS were longer in patients who achieved clinical benefit from ICIs and shorter in patients who received later-line ICIs and higher levels of inflammation; specifically, patients with higher TILs had longer PFS. Overall AEs were tolerable. Conclusions: ICIs are effective in the treatment of advanced TNBC, and the adverse reactions are tolerable. A panel of biomarkers including LDH, ALP, and bNLR were identified to predict the efficacies of ICIs in TNBC treatment.

Recent advancements in Mg-based micromotors for biomedical and environmental applications.

Synthetic micro/nanomotors have attracted considerable attention due to their promising potential in the field of biomedicine. Despite their great potential, major micromotors require chemical fuels or complex devices to generate external physical fields for propulsion. Therefore, for future practical medical and environmental applications, Mg-based micromotors that exhibit water-powered movement and thus eliminate the need for toxic fuels, and that display optimal biocompatibility and biodegradability, are attracting attention. In this review, we summarized the recent microarchitectural design of Mg-based micromotors for biomedical applications. We also highlight the mechanism for realizing their water-powered motility. Furthermore, recent biomedical and environmental applications of Mg-based micromotors are introduced. We envision that advanced Mg-based micromotors will have a profound impact in biomedicine.

Nomogram for predicting survival in patients with advanced hepatocellular carcinoma treated with PD-1 inhibitors: incorporating pre-treatment and post-treatment clinical parameters.

BACKGROUND: Immunotherapy has transformed cancer treatment patterns for advanced hepatocellular carcinoma (aHCC) in recent years. Therefore, the identification of predictive biomarkers has important clinical implications. METHODS: We collected medical records from 117 aHCC patients treated with anti-PD-1 antibody. Kaplan-Meier analysis and Cox proportional hazard regression were used to evaluate the association between peripheral blood biomarkers and overall survival (OS) and progression-free survival (PFS). Finally, the prognostic nomogram was constructed. RESULTS: The mPFS and mOS were 7.0 months and 18.7 months, respectively. According to Kaplan-Meier analysis and Cox regression analysis, we regarded the treatment regimen (p = 0.020), hemoglobin (Hb) at 6-week (p = 0.042), neutrophil-to-lymphocyte ratio (NLR) at 6-week (p < 0.001), system immune inflammation index (SII) at 6-week (p = 0.125) as predictors of PFS, and alpha fetoprotein (AFP) (p = 0.035), platelet-to-lymphocyte ratio (PLR) (p = 0.012), Hb at 6-week (p = 0.010) and NLR at 6-week (p = 0.020) as predictors of OS. Furthermore, the results suggest that the OS and PFS nomogram model were in agreement with actual observations. CONCLUSION: Biomarkers in peripheral blood can predict the prognosis of patients with aHCC treated with anti-PD-1 antibody. The development of nomogram models can help us to screen potential patients who can benefit from immunotherapy.

Integrative transcriptional characterization of cell cycle checkpoint genes promotes clinical management and precision medicine in bladder carcinoma.

Background: The aberrant regulation of cell cycle is significantly correlated with cancer carcinogenesis and progression, in which cell cycle checkpoints control phase transitions, cell cycle entry, progression, and exit. However, the integrative role of cell cycle checkpoint-related genes (CRGs) in bladder carcinoma (BC) remains unknown. Methods: The transcriptomic data and clinical features of BC patients were downloaded from The Cancer Genome Atlas (TCGA), used to identify CRGs correlated with overall survival (OS) by univariate Cox regression analysis. Then, the multivariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses further developed a prognostic CRG signature, which was validated in three external datasets retrieved from Gene Expression Omnibus (GEO). The receiver operating characteristic curve (ROC) analysis was conducted for evaluating the performance of the CRG signature in prognosis prediction. RNA sequencing (RNA-Seq) was performed to explore the expression difference in the identified CRGs between tumor and normal tissue samples from 11 BC patients in the local cohort. Ultimately, genomic profiles and tumor microenvironment (TME), and the Genomics of Drug Sensitivity in Cancer (GDSC) were investigated to guide precision treatment for BC patients with different CRG features. Results: The novel constructed 23-CRG prognostic signature could stratify BC patients into high-risk and low-risk groups with significantly different outcomes (median OS: 13.64 vs. 104.65 months). Notably, 19 CRGs were the first to be identified as being associated with BC progression. In three additional validation datasets (GSE13507, GSE31684, and GSE32548), higher CRG scores all indicated inferior survival, demonstrating the robust ability of the CRG signature in prognosis prediction. Moreover, the CRG signature as an independent prognostic factor had a robust and stable risk stratification for BC patients with different histological or clinical features. Then, a CRG signature-based nomogram with a better performance in prognostic prediction [concordance index (C-index): 0.76] was established. Functional enrichment analysis revealed that collagen-containing extracellular matrix (ECM), and ECM-related and MAPK signaling pathways were significantly associated with the signature. Further analysis showed that low-risk patients were characterized by particularly distinctive prevalence of FGFR3 (17.03% vs. 6.67%, p < 0.01) and POLE alterations (7.97% vs. 2.50%, p < 0.05), and enrichment of immune infiltrated cells (including CD8+ T cells, CD4+ naïve T cells, follicular helper T cells, Tregs, and myeloid dendritic cells). RNA-seq data in our local cohort supported the findings in the differentially expressed genes (DEGs) between tumor and normal tissue samples, and the difference in TME between high-risk and low-risk groups. Additionally, CRG signature score plus FGFR3 status divided BC patients into four molecular subtypes, with distinct prognosis, TME, and transcriptomic profiling of immune checkpoint genes. Of note, CRG signature score plus FGFR3 status could successfully distinguish BC patients who have a higher possibility of response to immunotherapy or chemotherapy drugs. Conclusions: The CRG signature is a potent prognostic model for BC patients, and in combination with FGFR3 alterations, it had more practical capacity in the prediction of chemotherapy and immunotherapy response, helping guide clinical decision-making.

Anti-SARS-CoV-2 IgM/IgG antibodies detection using a patch sensor containing porous microneedles and a paper-based immunoassay.

Infectious diseases are among the leading causes of mortality worldwide. A new coronavirus named severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) was identified in Wuhan, China in 2019, and the World Health Organization (WHO) declared its outbreak, coronavirus disease 2019 (COVID-19), as a global pandemic in 2020. COVID-19 can spread quickly from person to person. One of the most challenging issues is to identify the infected individuals and prevent potential spread of SARS-CoV-2. Recently, anti-SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody tests using immunochromatographic methods have been used as a complement to current detection methods and have provided information of the approximate course of COVID-19 infection. However, blood sampling causes pain and poses risks of infection at the needle puncture site. In this study, a novel patch sensor integrating porous microneedles and an immunochromatographic assay (PMNIA) was developed for the rapid detection of anti-SARS-CoV-2 IgM/IgG in dermal interstitial fluid (ISF), which is a rich source of protein biomarkers, such as antibodies. Biodegradable porous microneedles (MNs) made of polylactic acid were fabricated to extract ISF from human skin by capillary effect. The extracted ISF was vertically transported and flowed into the affixed immunoassay biosensor, where specific antibodies could be detected colorimetrically on-site. Anti-SARS-CoV-2 IgM/IgG antibodies were simultaneously detected within 3 min in vitro. Moreover, the limit of detection of anti-SARS-CoV-2 IgM and IgG concentrations was as low as 3 and 7 ng/mL, respectively. The developed device integrating porous MNs and immunochromatographic biosensors is expected to enable minimally invasive, simple, and rapid anti-SARS-CoV-2 IgM/IgG antibody testing. Furthermore, the compact size of the MN and biosensor-integrated device is advantageous for its widespread use. The proposed device has great potential for rapid screening of various infectious diseases in addition to COVID-19 as an effective complementary method with other diagnostic tests.

Gas-particle partitioning of polycyclic aromatic hydrocarbons from oil combustion involving condensate, diesel and heavy oil.

This study focuses on the gas-particle (G-P) partitioning of 16 polycyclic aromatic hydrocarbons (PAHs) from oil combustion, which is one of the important contributors of anthropogenic PAHs but has been rarely studied. The combustions of different types of oils involving ultra-light to heavy oils were investigated, and the PAH partitioning mechanism was determined by the widely used Junge-Pankow adsorption model, Koa absorption model, and dual sorption model, respectively. The results show that the source-specific diagnostic ratios of Ant/(Ant+Phe) are between 0.09 and 0.24, the estimated regression slopes of G-P partition coefficients (KP) of the total PAHs on their sub-cooled liquid vapor pressures (PLO) are in the range of - 0.34 to - 0.25, and the predicted fractions of PAHs in the particle phase (φ) by Koa absorption model are close to the measured values, while the log KPvalues of the LMW PAHs from the combustions of diesel and heavy oil are better represented by the dual sorption model. Our findings indicate that PAHs are derived from mixed sources that include the unburned original oil and combustion products, and the PAH partitioning mechanism is governed by the process of absorption into organic matter because of the unburned oil, but both adsorption and absorption exist simultaneously in the lighter PAHs from the combustions of heavier oils (i.e., diesel and heavy oil). Based on these findings, the understanding of the fate and transport of PAH emissions and the optimization of the emergency responses to accidents such as marine oil spills would be potentially improved.

Lactate Dehydrogenase B Is Required for Pancreatic Cancer Cell Immortalization Through Activation of Telomerase Activity.

Telomerase activity is elevated in most cancer cells and is required for telomere length maintenance and immortalization of cancer cells. Glucose metabolic reprogramming is a hallmark of cancer and accompanied with increased expression of key metabolic enzymes. Whether these enzymes influence telomerase activity and cell immortalization remains unclear. In the current study, we screened metabolic enzymes using telomerase activity assay and identified lactate dehydrogenase B (LDHB) as a regulator of telomerase activity. Sodium lactate and sodium pyruvate did not influence telomerase activity, indicating LDHB regulates telomerase activity independent of its metabolism regulating function. Further studies revealed that LDHB directly interacted with TERT and regulated the interaction between TERT and TERC. Additionally, long-term knockdown of LDHB inhibited cancer cell growth and induced cell senescence in vitro and in vivo. Higher LDHB expression was detected in pancreatic cancer tissues compared with that in adjacent normal tissues and expression of LDHB correlated negatively with prognosis. Thus, we identified LDHB as the first glucose metabolic enzyme contributing to telomerase activity and pancreatic cancer cell immortalization.

Safety and efficacy of mutant neoantigen-specific T-cell treatment combined anti-PD-1 therapy in stage IV solid tumors.

Aims: This trial explored the safety and efficacy of neoantigen-specific T cells (Nas-Ts) combined with anti-PD-1 (Nas-T + anti-PD-1). Patients & methods: This non-randomized trial recruited participants with solid tumors treated with at least two prior systemic treatment lines. For comparison, 1:1-matched controls who received anti-PD-1 alone were recruited. The primary end point was safety. Results: 15 participants were enrolled in the Nas-T + anti-PD-1 group, the objective response rate was 33.3%, and the disease control rate was 93.3%. The median progression-free survival was significantly different between the Nas-T + anti-PD-1 and control groups (13.8 vs 4.2 months; p = 0.024), but no difference in overall survival was found (p = 0.126). The most common adverse events were maculopapular skin reaction (53.3%), rash (53.3%), hepatotoxicity (53.3%) and fever (53.3%) in the Nas-T + anti-PD-1 group. No serious safety issues were experienced. Conclusion: Nas-Ts combined with anti-PD-1 could be more effective than anti-PD-1 alone in prolonging progression-free survival, with good safety.

Cancer immune escape is a major mechanism allowing cancer cells to avoid treatments, and PD-1 is one of those mechanisms. Nevertheless, therapies targeting PD-1 are still somewhat unsatisfactory. In this trial, we explored the safety and efficacy of mutant neoantigen-specific T cells (Nas-Ts) as adoptive cell immunotherapy individualized for each tumor, combined with an anti-PD-1 regimen (Nas-T + anti-PD-1). We recruited participants with solid tumors treated with at least two prior systemic treatment lines: 15 participants were enrolled in the Nas-T + anti-PD-1 group and 15 more in the control group. After the last follow-up, the percentage of patients on whom a therapy had some defined effect as well as the percentage of patients with advanced and metastatic cancer who achieved complete response was significantly higher for those who received Nas-T + anti-PD-1. No serious safety issues were experienced. This study confirmed that Nas-Ts combined with anti-PD-1 could be more effective than anti-PD-1 alone in delaying progression, with good safety.

Chemical fingerprinting and characterization of spilled oils and burnt soot particles - A case study on the Sanchi oil tanker collision in the East China Sea.

The condensate spill accident from the Sanchi oil tanker collision in the East China Sea is unique in world history. To date, the spilled and burnt amounts of condensate remain unknown. The present study demonstrates the chemical fingerprints of a surrogate condensate (SC) from the same source, and of the carried heavy fuel oil (HFO) of the Sanchi accident. The evaporative features of the condensate are demonstrated by allowing the SC to naturally volatilize in a dark fume hood. In addition, the combustion emission of the SC is characterized by conducting a laboratory-scale combustion experiment. The evaporation experiment suggests that the volatilization process plays a significant role in the weathering of the condensate. The results show that the SC and HFO can be clearly distinguished based on their chemical fingerprints of C27-C35 hopanes and C9-C36 n-alkanes, along with priority polycyclic aromatic hydrocarbons (PAHs) and their alkylated derivatives. The compositional data reveal that the lighter component is predominant in the SC, thereby supporting its high volatility and flammability. The greater amounts of heavier components in the HFO indicate its long-term degradation and potential ecological risks to the environment. Further, the trisnorhopane thermal indicator (Ts/Tm) and C29/C30 ratio of hopanes are validated for identification of the SC and the HFO. More importantly, the changes in the hopane ratios of the soot particles are analyzed for the first time in this study, and the results demonstrate the validity of using hopane ratios to fingerprint the condensate soot particles. The diagnostic ratios of 2-MP/1-MP, 9/4-MP/1-MP, and InP/(InP+BghiP) also show decent performance on source identification after the condensate evaporation and combustion processes.

Immunotherapy plus chemotherapy showed superior clinical benefit to chemotherapy alone in advanced NSCLC patients after progression on osimertinib.

BACKGROUND: Osimertinib is the standard first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation. Resistance to osimertinib remains a clinical challenge. However, the optimal therapy for these patients is still controversial. In this study, we aimed to assess the efficacy and safety of immunotherapy plus chemotherapy (IO+C) compared with chemotherapy (C) in NSCLC patients after progression on osimertinib. METHODS: Advanced NSCLC patients after progression on osimertinib were retrospectively reviewed. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated between the patients treated with IO+C and C. RESULTS: A total of 40 patients were included in the study. There were 20 patients each in the IO+C group or C group. The ORR was significantly higher in patients in the IO+C group (45% vs. 25%, p < 0.01). The median PFS was 6.4 months for patients in the IO+C group compared to 2.8 months for patients in C group (HR: 0.41, 95% confidence interval [CI]: 0.20-0.82, p < 0.01). The median OS was significantly longer in the IO+C group than the C group (OS: 12.8 vs. 10.5 months, HR: 0.39, 95% CI: 0.19-0.80, p < 0.01). In subgroup analysis, patients of both sexes, age ≤ 65, bone or adrenal metastasis, exon19 del mutation, and third-line treatment obtained more OS benefits from immunotherapy. The safety profile of both groups was comparable. CONCLUSIONS: Our study provides the clinical evidence of favoring immunotherapy plus chemotherapy in NSCLC patients after progression on osimertinib.

Study of epirubicin sustained-release chemoablation in tumor suppression and tumor microenvironment remodeling.

Introduction: Although intratumoral chemoablation can obtain an impressive therapeutic effect, there is still incomplete ablation and tumor recurrence in some patients. This could be due to the short retention time of the drug in the tumor, the limited distribution of intratumoral drugs, and, beyond that, the immunotolerance caused by the tumor microenvironment (TME). There is still an urgent need to find an optimal drug sustained-release carrier and figure out the impact of regional injection to TME. Methods: In this study, we supposed to use polyethylene glycol (PEG) hydrogel as a drug carrier to improve the retention time of the drug to extend the exposure of tumor cells and investigate the feasibility of combination local Epirubicin injection with anti-PD-L1. Results: The results revealed obvious tumor suppression based on the tumor volume and the inhibition time of tumor growth in the A549 lung cancer mouse model after local injection. Furthermore, the enhanced antitumor effects of the combination of systematic anti- programmed death ligand 1 (PD-L1) therapy with local chemoablation (EPI-GEL/PD-L1) for abscopal tumor reduction in the 4T1 breast model were also observed. Flow cytometry analysis of the tumor and blood samples showed significant variations in the proportions of PD-L1+ and CD3+CD8+PD-1+ cells before and after anti-PD-L1 therapy. On day 4 after local injection of the EPI gel, the expression of PD-L1 in abscopal tumors was upregulated, while the expression of PD-L1 in bilateral tumors in mice was significantly reduced after anti-PD-L1 treatment. The proportion of CD3+CD8+PD-1+ cells in the tumor and circulating blood in the EPI-GEL/PD-L1 group was decreased compared with that in the EPI-GEL (single injection of epirubicin) group. Discussion: The combination of local injection of the chemoablation agent with anti-PD-L1 monoclonal antibody (mAb) therapy may strengthen the antitumor activity, and the use of PEG hydrogel as the drug carrier can extend the retention time of the chemoablation agent around the tumor, maintaining a long-term tumor-killing activity.

Driver gene alterations profiling of Chinese non-small cell lung cancer and the effects of co-occurring alterations on immunotherapy.

BACKGROUND: Molecular testing for alterations in oncogenic driver genes and targeted therapies have become standard procedures for non-small cell lung cancer (NSCLC) patients. However, little evidence has shed light on the pattern of co-existence of driver genes in NSCLC, and whether they may have different tumor features affecting immunotherapy is still unclarified. METHODS: Genomic alterations in 14 lung cancer-related genes were conducted in 3440 Chinese NSCLC patients using next-generation sequencing. Meanwhile, tumor mutational burden and immunotherapy dataset from the Memorial sloan kettering cancer center (MSKCC) and lung adenocarcinoma dataset from The Cancer Genome Atlas (TCGA) were utilized for analyzing the impact of the co-occurring alterations on patients' survival following immunotherapy. RESULTS: In this cohort, 90.17% of patients had at least one somatic alteration in the 14 genes, including 51% of co-occurring alterations. TP53 and epidermal growth factor receptor (EGFR) were the most prevalent genes (54.74% and 53.55%, respectively), followed by KRAS, ERBB2, ALK, PIK3CA, ROS1, RET, MET, BRAF, KIT, FGFR1, PDGFRA, and NRAS. The prevalence of TP53, EGFR, and ERBB2 in our cohort were significantly higher than that from the TCGA database, whereas KRAS, BRAF, and PDGFRA were significantly lower than the latter. Furthermore, the patients who harbored multiple alterations (8.86%, 31/350) in eight driver genes survived longer and have a higher tumor mutation burden compared to the patients with a single alteration. Similar result was found between the patients with co-occurring alteration of EGFR and other driver genes and the patients with single EGFR alteration. Meanwhile, we found a distinct immune cell infiltration feature between patients with single and multiple driver gene alterations, as well as between patients with only EGFR alteration and co-occurring groups. CONCLUSION: This study identified a unique driver gene feature and found patients harboring co-occurring alterations of EGFR and other driver genes may benefit from immunotherapy, which may provide more therapeutic selections for EGFR-mutated NSCLC patients and merit additional investigation.

Real-World Efficacy and Safety of Anlotinib With and Without Immunotherapy in Advanced Non-Small Cell Lung Cancer.

AIMS: Combination of anti-angiogenesis therapy and immunotherapy has showed synergistic effects in non-small cell lung cancer (NSCLC). The aim of this retrospective study was to investigate the efficacy and safety of anlotinib with and without immunotherapy in NSCLC. METHODS: Pathologically confirmed NSCLC patients (stage IIIB-IV) receiving anlotinib between November 2018 and February 2020 were enrolled for retrospective analysis. The outcomes and safety of overall patients were evaluated, and the efficacies of anlotinib plus immunotherapy and anlotinib alone was compared. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 80 patients (median age: 62 years, range: 29-86 years) were included. Overall median PFS was 4.3 months (95% confidence interval (CI): 2.7-5.9 months). In univariate analysis, patients without EGFR mutation, previous EGFR target therapy, and brain metastasis had significantly longer PFS. Cox regression analysis showed that only brain metastasis was an independent predictor of PFS. The median PFS of patients receiving anlotinib plus immunotherapy was slightly longer than that of patients receiving anlotinib alone (4.2 vs 3.1 months); however, the difference was not statistically significant. A tendency of longer median PFS was observed in patients with adenocarcinoma, EGFR wild type, stage IV, no liver metastasis, former smoker, ≥2 previous treatment lines, no previous VEGF or EGFR target therapies in anlotinib plus immunotherapy group. Treatments with anlotinib alone or anlotinib plus immunotherapy were well tolerable. The most common adverse events were fatigue, decreased hemoglobin count, hypertension, hand-foot syndrome, oral mucositis and hoarseness. CONCLUSION: Anlotinib is well tolerable and effective in advanced NSCLC patients. Brain metastasis is an independent predictor of PFS in NSCLC patients receiving anlotinib. Future prospective studies with larger sample size and extended follow-up are needed to confirm the clinical benefit in NSCLC patients treated with anlotinib combined with immunotherapy.

Response to first-line treatment predicts progression-free survival benefit of small-cell lung cancer patients treated with anlotinib.

BACKGROUND: Anlotinib significantly extended progression-free survival (PFS) and overall survival (OS) in small-cell lung cancer (SCLC) as third or later line treatment. METHODS: In this study, we retrospectively analyzed the efficacy and safety of anlotinib in the clinical practice and aimed to identify risk factors for predicting the clinical benefit of anlotinib in SCLC patients. 29 SCLC patients treated with anlotinib monotherapy or combination therapy as second or later line treatment were included. PFS, OS, objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. RESULTS: In whole patients, the median PFS was 2.1 months (95% confidence interval (CI): 1.1-3.2 months); The ORR and DCR were 10.3% and 48.3%, respectively; The median OS was 7.2 months (95%CI: 3.2-11.2 months). Cox regression analysis demonstrated that response to first-line treatment was the independent risk factor for PFS. The ORR (20.0% vs. 0%) and DCR (53.3% vs. 42.9%) were promoted in patients treated with anlotinib combination therapy comparing to anlotinib monotherapy. The most common AEs were hoarseness, fatigue, decreased appetite, oral mucositis, and anemia. No treatment-related AEs graded 3 or more. CONCLUSION: Anlotinib is an effective option for SCLC patients with tolerable toxicity as second or later line treatment. Patients sensitive to first-line treatment had longer PFS when treated with anlotinib. Anloitnib combined with other therapy increased the efficacy without adding toxicity.

The Ratio of IP10 to IL-8 in Plasma Reflects and Predicts the Response of Patients With Lung Cancer to Anti-PD-1 Immunotherapy Combined With Chemotherapy.

Antibodies against checkpoint inhibitors such as anti-programmed cell death protein 1 (PD-1) and its ligand anti-programmed death ligand 1 (PD-L1) have shown clinical efficacy in the treatment of multiple cancers. However, there are only a few studies on biomarkers for these targeted immunotherapies, especially in peripheral blood. We first studied the role of interferon-induced protein-10 (IP10) combined with interleukin-8 (IL-8) in peripheral blood as a biomarker of immune-combined chemotherapy for lung cancer and multiple cancers. We used the high-throughput cytokine detection platform and performed bioinformatics analysis of blood samples from 67 patients with lung cancer and 24 with multiple cancers. We selected the ratio of IP-10 to IL-8 (S2/S0, ratio of changes at 10-12 weeks after treatment to baseline) to predict the response to immunotherapy combined with chemotherapy and evaluate the survival of lung cancer patients and mixed cancer patients. In patients treated with the combination therapy, the specificity and sensitivity of IL-8 and IP10 together as predictors were improved compared with those of IL-8 and IP10 alone. Our conclusion was verified in not only lung cancer but also multiple cancer research cohorts. We then further validated the predictive effect of biomarkers in different histologic types of NSCLC and chemotherapy combined with different PD-1 drug groups. Subsequent validation should be conducted with a larger number of patients. The proposed marker IP10 (S2/S0)/IL-8 (S2/S0), as a predictive immunotherapy biomarker, has broad prospects for future clinical applications in treating patients with multiple intractable neoplasms.

Post-treatment neutrophil-to-lymphocyte ratio (NLR) predicts response to anti-PD-1/PD-L1 antibody in SCLC patients at early phase.

Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) have been identified as predictors of treatment response in a variety of cancers. We conducted a retrospective analysis to investigate the usefulness of NLR, PLR and SII at baseline and at 6 weeks post-treatment as predictors of response to anti-PD-1/PD-L1 antibody treatment in small cell lung cancer (SCLC). Data of 41 SCLC patients receiving immunotherapy as second- or later-line treatment were analyzed. The overall median progression-free survival (PFS) was 5.1 months (95% CI 3.2-6.2). The median PFS was significantly longer in patients with NLR < 5 than in patients with NLR ≥ 5 at 6 weeks post treatment (HR = 0.29, 95%CI 0.09-0.96, P = 0.04). However, median PFS was comparable between patients with NLR < 5 and patients with NLR ≥ 5 at baseline (HR = 0.75, 95% CI 0.24-2.26, P = 0.56). The median PFS was similar between patients with PLR < 169 and those with PLR ≥ 169 at baseline (HR = 0.67, 95% CI 0.25-1.80, P = 0.43) and at 6 weeks post treatment (HR = 0.69, 95% CI 0.25-1.86, P = 0.46). No statistically different PFS was found between patients with SII < 730 and those with SII ≥ 730 at baseline (HR = 0.70, 95% CI 0.26-1.89, P = 0.48) and at 6 weeks post treatment (HR = 0.38, 95% CI 0.013-1.09, P = 0.07). In conclusion, NLR at 6 weeks after start of treatment appears to be a biomarker of response in the early phase in SCLC patients treated with anti-PD-1/PD-L1 antibodies as second- or later-line treatment.

Immune-Stromal Score Signature: Novel Prognostic Tool of the Tumor Microenvironment in Lung Adenocarcinoma.

Background: Immune and stromal cells in the tumor microenvironment (TME) significantly contribute to the prognosis of lung adenocarcinoma; however, the TME-related immune prognostic signature is unknown. The aim of this study was to develop a novel immune prognostic model of the TME in lung adenocarcinoma. Methods: First, the immune and stromal scores among lung adenocarcinoma patients were determined using the ESTIMATE algorithm in accordance with The Cancer Genome Atlas (TCGA) database. Differentially expressed immune-related genes (IRGs) between high and low immune/stromal score groups were analyzed, and a univariate Cox regression analysis was performed to identify IRGs significantly correlated with overall survival (OS) among patients with lung adenocarcinoma. Furthermore, a least absolute shrinkage and selection operator (LASSO) regression analysis was performed to generate TME-related immune prognostic signatures. Gene set enrichment analysis was performed to analyze the mechanisms underlying these immune prognostic signatures. Finally, the functions of hub IRGs were further analyzed to delineate the potential prognostic mechanisms in comprehensive TCGA datasets. Results: In total, 702 intersecting differentially expressed IRGs (589 upregulated and 113 downregulated) were screened. Univariate Cox regression analysis revealed that 58 significant differentially expressed IRGs were correlated with patient prognosis in the training cohort, of which three IRGs (CLEC17A, INHA, and XIRP1) were identified through LASSO regression analysis. A robust prognostic model was generated on the basis of this three-IRG signature. Furthermore, functional enrichment analysis of the high-risk-score group was performed primarily on the basis of metabolic pathways, whereas analysis of the low-risk-score group was performed primarily on the basis of immunoregulation and immune cell activation. Finally, hub IRGs CLEC17A, INHA, and XIRP1 were considered novel prognostic biomarkers for lung adenocarcinoma. These hub genes had different mutation frequencies and forms in lung adenocarcinoma and participated in different signaling pathways. More importantly, these hub genes were significantly correlated with the infiltration of CD4+ T cells, CD8+ T cells, macrophages, B cells, and neutrophils. Conclusions: The robust novel TME-related immune prognostic signature effectively predicted the prognosis of patients with lung adenocarcinoma. Further studies are required to further elucidate the regulatory mechanisms of these hub IRGs in the TME and to develop new treatment strategies.

Real-world treatment efficacy of anti-programmed death-1 combined with anti-angiogenesis therapy in non-small cell lung cancer patients.

Anti-programmed death-1 (PD-1) therapy has been extensively used to treat cancer. Recently, the combination of immunotherapy and anti-angiogenic therapy has emerged as a novel treatment approach. Therefore, we designed a study to evaluate the real-world benefit of the combination of anti-PD-1 and anti-angiogenesis therapy in patients with non-small cell lung cancer (NSCLC).We obtained the medical records of patients at the Chinese People's Liberation Army General Hospital who received either nivolumab or pembrolizumab combined with anti-angiogenesis therapy from January 2015 to December 2018. The overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated for all patients.Sixty-nine patients with NSCLC were included in our study. The ORR was 31.9% (95% CI: 20.6-43.2%) and the median PFS was 8.37 months (95% CI: 6.5-10.0 months). The subgroup analysis statistically revealed a significant difference in ORR for patients receiving first-line treatment vs other lines, and the values were 58.8% (95% CI: 32.7-84.9%) compared with 23.1% (95% CI: 11.2-34.9%). We also observed a significant improvement in PFS, with a median value of 10.5 months (95% CI: 7.4-13.1 months) for patients without EGFR mutations and 5.4 months (95% CI: 4.0-6.3 months) for patients with EGFR mutations.The real-world ORR, PFS, and OS were comparable to previous clinical trials, despite the patients' different baseline characteristics. Importantly, compared with patients having identified EGFR mutations, patients without EGFR mutations had a better PFS. Furthermore, these data support the use of anti-PD-1 combined with anti-angiogenesis therapy as a novel treatment approach for patients with NSCLC.