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BACKGROUND: The gut mycobiome of patients with lung adenocarcinoma (LUAD) remains unexplored. This study aimed to characterize the gut mycobiome in patients with LUAD and evaluate the potential of gut fungi as non-invasive biomarkers for early diagnosis. METHODS: In total, 299 fecal samples from Beijing, Suzhou, and Hainan were collected prospectively. Using internal transcribed spacer 2 sequencing, we profiled the gut mycobiome. Five supervised machine learning algorithms were trained on fungal signatures to build an optimized prediction model for LUAD in a discovery cohort comprising 105 patients with LUAD and 61 healthy controls (HCs) from Beijing. Validation cohorts from Beijing, Suzhou, and Hainan comprising 44, 17, and 15 patients with LUAD and 26, 19, and 12 HCs, respectively, were used to evaluate efficacy. RESULTS: Fungal biodiversity and richness increased in patients with LUAD. At the phylum level, the abundance of Ascomycota decreased, while that of Basidiomycota increased in patients with LUAD. Candida and Saccharomyces were the dominant genera, with a reduction in Candida and an increase in Saccharomyces, Aspergillus, and Apiotrichum in patients with LUAD. Nineteen operational taxonomic unit markers were selected, and excellent performance in predicting LUAD was achieved (area under the curve (AUC) = 0.9350) using a random forest model with outcomes superior to those of four other algorithms. The AUCs of the Beijing, Suzhou, and Hainan validation cohorts were 0.9538, 0.9628, and 0.8833, respectively. CONCLUSIONS: For the first time, the gut fungal profiles of patients with LUAD were shown to represent potential non-invasive biomarkers for early-stage diagnosis.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Micobioma , Humanos , Estudos Transversais , Fungos , Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Diagnóstico PrecoceRESUMO
BACKGROUND: Hyper progressive disease (HPD) describes the phenomenon that patients can't benefit from immunotherapy but cause rapid tumor progression. HPD is a particular phenomenon in immunotherapy but lacks prediction methods. Our study aims to screen the factors that may forecast HPD and provide a predictive model for risky stratifying. METHODS: We retrospectively reviewed advanced-stage tumor patients who received immune checkpoint inhibitors (ICI) in the General PLA Hospital. Subsequently, we calculated the tumor growth kinetics ratio (TGKr) and identified typical HPD patients. Differences analysis of clinical characteristics was performed, and a predictive binary classification model was constructed. RESULTS: 867 patients with complete image information were screened from more than 3000 patients who received ICI between January 2015 and January 2020. Among them, 36 patients were identified as HPD for TGKr > 2. After the propensity score matched, confounding factors were limited. Survival analysis revealed that the clinical outcome of HPD patients was significantly worse than non-HPD patients. Besides, we found that Body Mass Index (BMI), anemia, lymph node metastasis in non-draining areas, pancreatic metastasis, and whether combined with anti-angiogenesis or chemotherapy therapy were closely connected with the HPD incidence. Based on these risk factors, we constructed a visualised predicted nomogram model, and the Area Under Curve (AUC) is 0.850 in the train dataset, whereas 0.812 in the test dataset. CONCLUSION: We carried out a retrospective study for HPD based on real-world patients and constructed a clinically feasible and practical model for predicting HPD incidence, which could help oncologists to stratify risky patients and select treatment strategies.
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BACKGROUND: Patients with pulmonary large cell carcinoma (LCC) have a high incidence of synchronous brain metastases (SBM) and a poor prognosis. Our study was to evaluate the predictive and prognostic value of the clinical characteristics of pulmonary LCC patients with SBM at initial diagnosis by utilizing the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: LCC patients, diagnosed from 2010 to 2019, were identified from the latest SEER database which was released in April 2022. Logistic regression and Cox regression were used to identify the predictive and prognostic factors for LCC patients with SBM. Propensity score matching (PSM) and Kaplan-Meier analyses were applied to assess different therapy modalities. RESULTS: A total of 1375 LCC patients were enrolled in this study and 216 (15.7%) of them had SBM at the initial diagnosis. The median overall survival (OS) of LCC patients with SBM was 4 months. Multivariate Cox regression identified age 60-79 (OR 0.57; 95% CI 0.41-0.78; p < 0.001), age ≥ 80 (OR 0.23; 95% CI 0.12-0.45; p < 0.001) and bone metastases (OR 1.75; 95% CI 1.22-2.51; p < 0.001) as significant independent predictors for developing SBM. Multivariable Cox regression revealed that age 60-79, T stage, bone metastases and chemotherapy were independent prognostic factor for OS. The surgery combined with chemotherapy and radiotherapy group, in which all patients were N0 stage and had no other site-specific metastases, exhibited the best median OS of 15 months. CONCLUSIONS: LCC patients with age < 60 or bone metastases were more likely to have SBM at initial diagnosis. Age, T stage, bone metastases and chemotherapy were independent prognostic factors for OS of LCC patients with SBM. Highly selected patients might achieve the best survival benefit from surgery combined with chemotherapy and radiotherapy.
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Neoplasias Encefálicas , Carcinoma de Células Grandes , Humanos , Pessoa de Meia-Idade , Idoso , Incidência , Prognóstico , Estimativa de Kaplan-Meier , Neoplasias Encefálicas/terapiaRESUMO
Microbial catalase is a key enzyme that affects the activities of microorganisms, and the catalase activity is affected by pollutants in wastewater. However, the effects of mixed pollutants on catalase activity are rather complex. To reveal the effect of the mixed pollutants on catalase activity of microorganisms, the present study investigated tetracycline and copper ion as pollutants during the biological phosphorus removal. Three concentration ratios of tetracycline and copper ion and 27 different concentration gradients were designed through the direct equipartition ray and the dilution factor method. The effects of mixed pollutants on the catalase activity of microorganisms were analyzed by the nonlinear regression equation and concentration-addition model. The results showed that, with the increase of actuation duration and the pollutant concentration, the inhibitory effects on the catalase activity of microorganisms obviously increased, which indicated that the inhibitory effects are concentration-dependent and time-dependent. The concentration-addition model suggested that when the ratio was 0.297, the combined effect of mixed pollutants on the activity of microbial catalase was mainly antagonism. When the ratio is 0.894, the combined effect was mainly additivity. When the ratio was 2.676, the combined effect transformed from synergism to additivity and antagonism. The study of the combined effects of tetracycline and copper ion on the catalase activity is helpful to further study their ecotoxicological mechanisms in wastewater treatment.
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Fósforo , Poluentes Químicos da Água , Catalase , Cobre , Tetraciclina , Águas ResiduáriasRESUMO
BACKGROUND: Rationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited. METHOD: Efficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). RESULTS: This retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0-42.0%), with a DCR of 85.0% (95% CI, 73.4-96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events. CONCLUSION: PARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker.
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Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Pessoa de Meia-Idade , Neoplasias/mortalidade , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Cisplatin resistance of non-small-cell lung cancer (NSCLC) needs to be well elucidated. RING finger protein (RNF38) has been proposed as a biomarker of NSCLC poor prognosis. However, its role in drug resistance in NSCLC is poorly understood. RNF38 expression was detected in normal lung epithelial cell and four NSCLC cell lines. RNF38 was stably overexpressed in A549 and H460 cells or silenced in H1975 and cisplatin-resistant A549 cells (A549-CDDP resistant) using lentiviral vectors. RNF38 expression levels were determined using quantitative real-time polymerase chain reaction and western blotting analysis. Cell viability in response to different concentrations of cisplatin was evaluated by Cell Counting Kit-8 assay. RNF38 expression levels were markedly elevated in NSCLC cells and cells harboring high RNF38 were less sensitive to cisplatin. Overexpression of RNF38 reduced, while RNF38 silencing increased the drug sensitivity of cisplatin in NSCLC cells. Cisplatin-resistant cells expressed high RNF38 level. RNF38 silencing promoted cell apoptosis and enhanced the drug sensitivity of cisplatin in cisplatin-resistant NSCLC cells. These findings indicate that RNF38 might induce cisplatin resistance of NSCLC cells via promoting cell apoptosis and RNF38 could be a novel target for rectify cisplatin resistance in NSCLC cases.
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Carcinoma Pulmonar de Células não Pequenas , Proteínas de Transporte/fisiologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Células A549 , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Sobrevivência Celular , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismoRESUMO
Background and Objective: Lung cancer, mainly non-small cell lung cancer (NSCLC), is a serious threat to human life. In particular, the prognosis for advanced patients is poor, with the 5-year survival rate being exceedingly low. In recent years, immune checkpoint inhibition has changed the pattern of the treatment of a variety of cancers, including lung cancer; however, not all patients can benefit from immunotherapy, and thus finding the right biomarkers is particularly important for guiding precise treatment. Programmed death-ligand 1 (PD-L1) expression is one of the most valuable biomarkers for predicting the efficacy of lung cancer immunotherapy. Several studies have confirmed that patients with high PD-L1 expression are more likely to benefit from immunotherapy, but there is a high proportion of people with negative PD-L1 expression constituting a patient population that cannot be ignored. This article reviews the distribution of PD-L1 expression, the methods for evaluating PD-L1, and the effectiveness of immunotherapy for advanced NSCLC with negative PD-L1 expression. Methods: We performed a literature review to identify relevant data published until September 2022. In order to organize related information, we searched for literature in PubMed; abstracts and reports published in the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the World Conference on Lung Cancer (WCLC), and other congresses; and clinical trial information registered on ClinicalTrials.gov. Information on the distribution of PD-L1 expression, detection of PD-L1, and immunotherapy efficacy for NSCLC with negative PD-L1 expression was collated and reviewed. Key Content and Findings: The incidence of PD-L1 expression in patients with stage IIIB/IV NSCLC is similar in all regions of the world, but PD-L1 expression level is associated with certain clinicopathological features. The expression of PD-L1 can be evaluated by various detecting methods. Some immunotherapy regimens have better efficacy than traditional chemotherapy in patients with negative PD-L1 expression. Conclusions: Patients with NSCLC and negative PD-L1 expression can receive better survival benefits under some immunotherapy types, and these may represent a better treatment option for this relatively small patient population.
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Esophageal squamous cell carcinoma (ESCC) presents significant clinical and therapeutic challenges due to its aggressive nature and generally poor prognosis. We initiated a Phase II clinical trial (ChiCTR1900027160) to assess the efficacy of a pioneering neoadjuvant chemo-immunotherapy regimen comprising programmed death-1 (PD-1) blockade (Toripalimab), nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the oral fluoropyrimidine derivative S-1, in patients with locally advanced ESCC. This study uniquely integrates clinical outcomes with advanced spatial proteomic profiling using Imaging Mass Cytometry (IMC) to elucidate the dynamics within the tumor microenvironment (TME), focusing on the mechanistic interplay of resistance and response. Sixty patients participated, receiving the combination therapy prior to surgical resection. Our findings demonstrated a major pathological response (MPR) in 62% of patients and a pathological complete response (pCR) in 29%. The IMC analysis provided a detailed regional assessment, revealing that the spatial arrangement of immune cells, particularly CD8+ T cells and B cells within tertiary lymphoid structures (TLS), and S100A9+ inflammatory macrophages in fibrotic regions are predictive of therapeutic outcomes. Employing machine learning approaches, such as support vector machine (SVM) and random forest (RF) analysis, we identified critical spatial features linked to drug resistance and developed predictive models for drug response, achieving an area under the curve (AUC) of 97%. These insights underscore the vital role of integrating spatial proteomics into clinical trials to dissect TME dynamics thoroughly, paving the way for personalized and precise cancer treatment strategies in ESCC. This holistic approach not only enhances our understanding of the mechanistic basis behind drug resistance but also sets a robust foundation for optimizing therapeutic interventions in ESCC.
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BACKGROUND: MicroRNAs miR-9-3 and miR-193a have recently been found to be hypermethylated in a variety of non-small cell lung cancer (NSCLC) cells and primary human tumors. The objectives of this study were to investigate the role of demethylation of miR-9-3 and miR-193a genes in regulating proliferation and apoptosis in NSCLCs, and to decipher the potential mechanisms underlying the properties. METHODS: MTT and population doubling time by flow cytometry were used to assess cell proliferation. Enzyme-Linked Immunosorbent Assay and caspase-3 activity assay were employed to evaluate apoptosis. Real-time RT-PCR and Western blot were used to quantify gene expression at mRNA and protein levels, respectively. Methylation-specific PCR was utilized to assess methylation status. RESULTS: We found that demethylation agent 5-Aza-2'-deoxycytidine (5-AzaC) reduced cell numbers and prolonged population doubling time (PDT), and promoted doxorubicin-induced apoptosis in seven NSCLC cell lines with different methylation statuses on miR-9-3 and miR-193a promoter regions: NCI-H1993/NCI-H1915 (miR-9-3(+)/miR-193a(+)), NCI-H1975/NCI-H200 (miR-9-3(+)/miR-193a(-)), A427/NCI-H2073 (miR-9-3(-)/miR-193a(+)), and NCI-H1703 (miR-9-3(-)/miR-193a(-)). Treatment with 5-AzaC concomitantly upregulated expression of miR-9-3 and miR-193a, and downregulated their respective target genes NF-κB and Mcl-1. The effects of 5-AzaC were abolished by concomitant knockdown of miR-9-3 and miR-193a using the complex antisense technique, whereas forced ectopic expression of miR-9-3 and miR-193a mimicked the effects of 5-AzaC. We further observed that the strength of proliferation inhibition and apoptosis promotion elicited by 5-AzaC was in the order of NCI-H1993/NCI-H1915 > A427/NCI-H2073 > NCI-H1975/NCI-H200 > NCI-H1703. CONCLUSIONS: Methylation-silencing of miR-9-3 and miR-193a may be an important epigenetic mechanisms favoring NSCLC cell growth and survival for carcinogenesis and cancer progression, and demethylation to reactivate expression of miR-9-3 and miR-193a genes contributes, at least partially, to the anti-cancer properties of 5-AzaC and thereby may be worthy of future studies for the possibility of being a new therapeutic strategy for the treatment of human NSCLCs.
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MicroRNAs/metabolismo , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Sequência de Bases , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Decitabina , Regulação para Baixo , Doxorrubicina/toxicidade , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Oligonucleotídeos Antissenso/metabolismo , Regiões Promotoras Genéticas , Alinhamento de Sequência , Regulação para CimaRESUMO
Importance: Both pembrolizumab and sintilimab have been approved by the Chinese State Drug Administration (NMPA) for the first-line treatment of patients with advanced squamous lung cancer. The differences of the two drugs in efficacy and safety are unclear. Objectives: To compare the real-world efficacy and safety of first-line treatments in patients with advanced squamous lung cancer. Materials and methods: This was a retrospective review of patients with advanced squamous carcinoma who received sintilimab or pembrolizumab in combination with chemotherapy as first-line therapy between June 2018 and April 2022 in the Chinese PLA Hospital. The primary objective was to compare the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) between the two groups. Secondary objectives were to compare the disease control rate (DCR) and to analyze adverse events (AEs) between the two groups. Results: A total of 164 patients were enrolled, including 63 patients (38.4%) in the sintilimab-combined chemotherapy group and 101 patients (61.6%) in the pembrolizumab-combined chemotherapy group. The ORR was 65.10% in the sintilimab group and 61.40% in the pembrolizumab group (P=0.634). The DCR was 92.10% and 92.10% in the sintilimab and pembrolizumab groups, respectively (P=0.991). The median PFS was 22.2 months for patients treated with sintilimab group compared with 16.5 months for patients treated with pembrolizumab group[hazard ratio (HR) = 0.743; 95% confidence interval (CI): 0.479-1.152; P = 0.599]. Patients treated with pembrolizumab did not achieve a median OS, and patients treated with sintilimab had a median OS of 30.7 months. In the sintilimab group, the incidence of all treatment-related adverse events (TRAEs) was 92.1% (58/63), and the incidence of grade 3-4 TRAEs of 42.9% (27/63). In the pembrolizumab group, the incidence of all TRAEs was 90.1% (91/101), and the incidence of grade 3-4 TRAEs was 37.6% (38/101). Conclusion: In the clinical treatment of Chinese patients with advanced squamous lung cancer, first-line treatment with sintilimab in combination with chemotherapy provided similar efficacy to pembrolizumab in combination with chemotherapy, and the treatment-related adverse effect profiles were comparable between the two groups, including similar rates of grade 3-4 and all adverse events.
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Background: The efficacy of anti-programmed cell death (PD)-1 monotherapy in advanced hepatocellular carcinoma (aHCC) is limited, and combination therapy with lenvatinib and pembrolizumab has shown promising results. However, comparative studies between immune monotherapies and combination therapies are lacking. Objectives: To investigate the efficacy and safety of anti-PD-1 monotherapy (PD-1) and anti-PD-1 plus lenvatinib (PD-1 + L) in patients with aHCC to guide clinical treatment decisions. Design: A retrospective study was conducted on a cohort of patients with aHCC who received either PD-1 monotherapy or PD-1 + L combination therapy between January 2018 and January 2020. Methods: The study retrospectively reviewed the medical records of 94 eligible patients with aHCC, with 39 in the PD-1 group and 55 in the PD-1 + L group. The efficacy outcomes, including objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety, were assessed. Results: With a median follow-up of 30.1 months, the PD-1 + L group demonstrated a significantly higher ORR (32.7% versus 10.3%, p = 0.013), better DCR (80.0% versus 53.8%, p = 0.012), longer median PFS (10.6 versus 4.4 months, p < 0.001) and longer median OS (18.4 versus 8.5 months, p = 0.013) than PD-1 group. For the responders, the efficacy of the two groups was durable (DOR was 11.6 versus 3.5 months, p = 0.009). Subgroup analyses based on prior tyrosine kinase inhibitor (TKI) treatment and the presence or absence of macrovascular tumor thrombosis or extrahepatic metastases favored the PD-1 + L group. The combination therapy was a good predictor of PFS and OS in multivariate analysis. Grade 3/4 treatment-related adverse events were more common in PD-1 + L group, with higher incidences of hypertension and hand-foot skin reactions. Conclusions: PD-1 monotherapy and PD-1 plus lenvatinib combination therapy were well-tolerated in patients with aHCC. PD-1 + L showed significantly better survival benefits than PD-1 monotherapy.
Understanding the impact of PD-1 and lenvatinib combination therapy on advanced hepatocellular carcinoma Abstract: This plain language summary provides a description of our research on the combination therapy of PD-1 and lenvatinib for advanced Hepatocellular carcinoma (aHCC). We aimed to investigate the effectiveness and safety of this treatment approach and offer insights for clinical decisions. Why was this study done? HCC is a challenging condition to treat, especially in advanced stages. We explored whether the combination of two drugs, PD-1 and lenvatinib, can offer better outcomes for patients with aHCC than PD-1 monotherapy. What did the researchers do? We conducted a retrospective study on patients diagnosed with aHCC who received PD-1 alone or PD-1 combined with lenvatinib between January 2018 and January 2020. We analysed the medical records to assess the treatment's efficacy and safety. What did the researchers find? After a median follow-up of 30.1 months, we observed significant improvements in the combination therapy group, with higher response rates, better disease control, longer progression free survival, and more extended overall survival than those in the PD-1 monotherapy group. Responders in the combination group also experienced a longer duration of response. What do the findings mean? Our results address the lack of data for real-world clinical experiences regarding anti-PD-1 monotherapy for patients with aHCC compared to immunotherapy plus lenvatinib are lacking. The combination of PD-1 and lenvatinib was more effective and offered better survival benefits for patients with aHCC than PD-1 alone. These results could provide new hope for patients with this challenging condition. Limitations: The study was conducted at a single centre with relatively few patients. Additionally, most patients had hepatitis B-associated liver cancer, which may limit the generalisability of our findings to other populations. Conclusions: PD-1 plus lenvatinib is a promising treatment option for patients with aHCC. It is well-tolerated, and its effectiveness surpasses that of PD-1 therapy alone. Our findings could potentially guide clinicians in making treatment decisions for patients with aHCC.
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Checkpoint inhibitor pneumonitis (CIP) is the most common fatal immune-related adverse event; however, its pathophysiology remains largely unknown. Comprehensively dissecting the key cellular players and molecular pathways associated with CIP pathobiology is critical for precision diagnosis and develop novel therapy strategy of CIP. Herein, we performed a comprehensive single-cell transcriptome analysis to dissect the complexity of the immunological response in the bronchoalveolar lavage fluid (BALF) microenvironment. CIP was characterized by a dramatic accumulation of CXCL13+ T cells and hyperinflammatory CXCL9+ monocytes. T-cell receptor (TCR) analysis revealed that CXCL13+ T cells exhibited hyperexpanded- TCR clonotypes, and pseudotime analysis revealed a potential differentiation trajectory from naïve to cytotoxic effector status. Monocyte trajectories showed that LAMP3+ DCs derived from CXCL9+ monocytes possessed the potential to migrate from tumors to the BALF, whereas the differentiation trajectory to anti-inflammatory macrophages was blocked. Intercellular crosstalk analysis revealed the signaling pathways such as CXCL9/10/11-CXCR3, FASLG-FAS, and IFNGR1/2-IFNG were activated in CIP+ samples. We also proposed a novel immune signature with high diagnostic power to distinguish CIP+ from CIP- samples (AUC = 0.755). Our data highlighted key cellular players, signatures, and interactions involved in CIP pathogenesis.
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Neoplasias Pulmonares , Neoplasias , Pneumonia , Humanos , Pneumonia/induzido quimicamente , Neoplasias/patologia , Transdução de Sinais , Macrófagos/patologia , Receptores de Antígenos de Linfócitos T , Neoplasias Pulmonares/tratamento farmacológico , Microambiente TumoralRESUMO
Objectives: Brain metastases (BMs) are common in extensive-stage small-cell lung cancer (SCLC) and are underrepresented in pivotal clinical trials that demonstrate the efficacy of immune checkpoint inhibitors (ICIs). We conducted a retrospective analysis to assess the role of ICIs in BM lesions in less selected patients. Materials and methods: Patients with histologically confirmed extensive-stage SCLC who were treated with ICIs were included in this study. Objective response rates (ORRs) were compared between the with-BM and without-BM groups. Kaplan-Meier analysis and the log-rank test were used to evaluate and compare progression-free survival (PFS). The intracranial progression rate was estimated using the Fine-Gray competing risks model. Results: A total of 133 patients were included, 45 of whom started ICI treatment with BMs. In the whole cohort, the overall ORR was not significantly different for patients with and without BMs (p = 0.856). The median progression-free survival for patients with and without BMs was 6.43 months (95% CI: 4.70-8.17) and 4.37 months (95% CI: 3.71-5.04), respectively (p =0.054). In multivariate analysis, BM status was not associated with poorer PFS (p = 0.101). Our data showed that different failure patterns occurred between groups, with 7 patients (8.0%) without BM and 7 patients (15.6%) with BM having intracranial-only failure as the first site progression. The cumulative incidences of brain metastases at 6 and 12 months were 15.0% and 32.9% in the without-BM group and 46.2% and 59.0% in the BM group, respectively (Gray's p<0.0001). Conclusions: Although patients with BMs had a higher intracranial progression rate than patients without BMs, the presence of BMs was not significantly associated with a poorer ORR and PFS with ICI treatment in multivariate analysis.
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OBJECTIVE: To explore the clinical characteristics and prognostic factors of patients diagnosed with squamous cell carcinoma (SCC) and presented malignancy-associated hypercalcemia (MAH). METHODS: We retrospectively analyzed the clinical data of 36 patients with biopsy-proven SCC and presented MAH who were treated at the our department from January 2001 to December 2010. The survival were analyzed using the Kaplan-Meier method and Cox analysis. RESULTS: Among these 36 patients, the median blood calcium level was 2.94 mmol/L (2.77-4.87 mmol/L), and the median survival time was only 45 days (1-839 d). Log-rank test showed that central nervous system symptoms, bone metastasis, and hypercalcemia occurring over 160 days after cancer diagnosis were predictors for poor survival(p=0.003, P=0.049, P=0.005). In the COX proportional hazard model analysis, central nervous system symptoms and hypercalcemia occurring over 160 days after cancer diagnosis were independent prognostic factors for survival time (RR=5.721, P=0.000; RR=4.624, P=0.001). CONCLUSIONS: Patients with squamous cell carcinoma (SCC) and presented MAH have poor prognosis. Central nervous system symptoms and hypercalcemia occurring over 160 days after cancer diagnosis are independent predictors of the prognosis.
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Carcinoma de Células Escamosas/complicações , Hipercalcemia/etiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
Background: Rechallenge of immunotherapy beyond progression (RIBP) has been demonstrably effective in a variety of cancers. Our study aims to investigate the efficacy of RIBP in small-cell lung cancer (SCLC) patients under real-world conditions. Methods: SCLC patients who experienced progressive disease after receiving programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors combined with chemotherapy from January 2017 to October 2021 were enrolled. The study population was divided into two groups: the RIBP group and the discontinuation of immunotherapy beyond progression (DIBP) group. Inverse propensity score weighting (IPSW) method was used to balance the clinical baseline characteristics. The short-term and long-term efficacy of the two groups was compared. Results: 100 SCLC patients were included in this study. There were 45 patients in the RIBP group and 55 patients in the DIBP group. The disease control rate (DCR) and the proportion of durable clinical benefit (DCB) were significantly higher in the RIBP group (DCR: 79.7% vs. 55.7%, p = 0.027; DCB: 40.7 vs. 20.7%, p = 0.025) after weighting. The median progressive-free survival (PFS) in the RIBP group was significantly longer than the DIBP group in the total population (mPFS: 4.8 vs. 2.4 months, p = 0.002), while there was no significant difference in overall survival (OS) of the two groups (mOS: 17.4 vs. 8.0 months, p = 0.098). In the weighted first-line initial immunotherapy subgroup, PFS and OS were significantly improved in the RIBP group (mPFS: 4.5 vs. 2.8 months, p = 0.017; mOS: 11.6 vs. 5.4 months, p = 0.028). After weighting, the RIBP group had a significantly longer PFS than the DIBP group in the SD/PD response to the initial immunotherapy subgroup (mPFS: 6.8 vs. 1.8 months, p = 0.026). Conclusion: Rechallenge of PD-1/PD-L1 inhibitors could bring benefits to SCLC patients, especially in the first-line initial immunotherapy subgroup or SD/PD response to the initial immunotherapy subgroup.
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Background: Immune checkpoint inhibitors (ICIs) have become standard treatments for lung cancer patients. Immune checkpoint inhibitor-related pneumonitis (CIP) was the leading cause of death among ICIs-related adverse events (irAEs). Recurrent episodes of CIP without rechallenge of ICIs were reported in several cases and maybe a unique feature of CIP. Knowledge gaps remain regarding the rate and risk factors associated to CIP's recurrence. Methods: Data from 1,102 lung cancer patients receiving ICIs treatment between January 2016 and January 2021 were retrospectively collected and analyzed. CIP was diagnosed according to typical clinical features and/or new typical imaging changes. Recurrence of CIP (CIP-R) was defined as recurrent CIP after initial CIP improved after proper treatment. Logistic regression was used to assess risk factors associated with CIP recurrence. Results: Eighty out of 1,102 (7.26%) patients were diagnosed with CIP. Twenty of those 78 (25.64%) patients suffered CIP-R, 2 patients died and were therefore excluded from the denominator. The median onset of initial pneumonitis for patients without and with recurrence was 3.49 months [interquartile range (IQR), 0.26-31.93 months] and 2.78 months (IQR, 1.22-20.93 months), respectively (P=0.48). The median interval duration between initial CIP and CIP-R was 1.54 months (IQR, 0.98-16.70 months). Recurrence of CIP was more common in males (P=0.03), squamous histology (P=0.016), and in patients who received chest radiotherapy (P=0.049). The duration of prednisolone equivalent dose ≥15 mg/day in CIP-R was significantly shorter, at 3.71 weeks (2.86-6.57 weeks) compared with 6.36 weeks in those without recurrence (IQR, 3.12-9.86 weeks) (P=0.001). Non-squamous histology [odds ratio (OR), 0.182; 95% confidence interval (CI): 0.038-0.860; P=0.031] and prolonged administration of prednisolone equivalent dose ≥15 mg/day for more than 4 weeks (OR, 0.082; 95% CI: 0.02-0.342; P=0.001) were independently associated with a decreased odds of CIP-R development. Conclusions: CIP-R in a real-world lung cancer cohort is not uncommon, both in patients with and without rechallenge of ICIs. A duration of prednisolone equivalent dose ≥15 mg/day of at least 4 weeks during the tapering process of corticosteroids were recommend in patients with CIP.
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BACKGROUND: Crizotinib is a tyrosine kinase inhibitor (TKI) effective in ALK/ROS-1/c-MET positive non-small cell lung cancer (NSCLC) patients. Bevacizumab is an antiangiogenic monoclonal antibody, and improves clinical benefit of NSCLC in combination with EGFR-TKIs or chemotherapy. However, the efficacy and safety of crizotinib plus bevacizumab in treating naive ALK/ROS-1/c-MET positive NSCLC patients have not been studied. METHODS: In this open-label, single-arm, prospective observational study, locally advanced or metastatic ALK rearrangement/ROS-1 fusion/c-MET amplification NSCLC patients were treated with crizotinib (250 mg orally twice daily) and bevacizumab (7.5 mg/kg intravenous every three weeks) until disease progression or intolerant toxicity or death. Primary end point was progressive free survival (PFS), secondary end points were duration of response (DOR), overall response rate (ORR), disease control rate (DCR) and safety. Patients receiving ≥1 cycle of treatment were evaluated. FINDINGS: Fourteen patients were eligible for analyzing between June 2016 and October 2017. There were 12 patients with ALK rearrangement, 1 patient with ROS-1 fusion, and 1 patient with c-MET amplification. The median follow-up time was 42.8 months. The median PFS and DOR of the patients with ALK rearrangement were 13.9 and 14.8 months respectively. Of the 12 patients, 7 gained partial response, 5 gained stable disease. The ORR and DCR were 58.3% and 100%. The PFS were 12.9 months and 1.9 months for patient with ROS-1 fusion or c-MET amplification. The most two common treatment-related adverse events were fatigue (28.6%) and rash (21.4%). 3 patients discontinued therapy because of liver damage or hemoptysis. INTERPRETATION: This study demonstrated that crizotinib plus bevacizumab showed benefit in treating naive ALK rearrangement NSCLC patients, and the toxicity was relatively tolerant. Our results suggested that crizotinib plus bevacizumab might be a promising treatment strategy in ALK/ROS-1/c-MET positive NSCLC patients.
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PURPOSE: Recently, the lung immune prognostic index (LIPI) is considered to be associated with outcomes in multiple solid tumors treated with immune checkpoint inhibitors (ICIs). We sought to determine whether LIPI has the same predictive effect in advanced gastric cancer (AGC). METHODS: The clinical data of a real-world, retrospective cohort of AGC patients treated with ICIs were retrospectively analyzed. Based on pre-treatment dNLR>3 and LDH>250 U/L, patients were assigned to one of three groups: good (0 factors), intermediate (1 factor), and poor (2 factors). The subjects were divided into two groups: LIPI-good and LIPI-intermediate/poor groups. Then, the disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were compared between these two groups. RESULTS: Finally, 120 patients were enrolled in the study, for both the good group and intermediate/poor group, DCR was 69.5% vs. 42.1% (P = 0.004). In a multivariate analysis, the LIPI-intermediate/poor group was associated with progressive disease, with an OR of 2.57 (95% CI, 1.05-6.30; P = 0.039). Patients with a good LIPI score had a longer survival compared with those with intermediate/poor scores, with an estimated median OS of 10.4 vs. 3.9 months (HR = 2.59, 95% CI: 1.69-3.98) and a median PFS of 7.7 vs. 2.1 months (HR=2.95, 95% CI:1.91-4.56). Multivariate analysis indicated that the intermediate/poor LIPI was independently associated with OS (HR: 2.32, 95% CI: 1.44-3.72) and PFS (HR: 2.48, 95% CI: 1.53-4.03). CONCLUSIONS: These data are the first to suggest that the pretreatment LIPI was well correlated with the outcomes of patients with AGC treated with ICIs.
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Carcinoma Pulmonar de Células não Pequenas , Pulmão/imunologia , Neoplasias Gástricas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológicoRESUMO
The efficacy of current treatment regimens for pancreatic cancer (PC) remains unsatisfactory. In recent years, immune checkpoint blockade (ICB) therapy has shown promising anti-tumor outcomes in many malignancies, including PC. Inexpensive and readily available biomarkers which predict therapeutic responses and prognosis are in critical need. Systemic immune-inflammation index (SII) and neutrophil-lymphocyte ratio (NLR) are emerging predictors for prognosis of various tumors. We aim to investigate the prognostic significance of baseline SII, NLR, and their changes in PC patients treated with ICB. Our retrospective analysis included PC patients treated with ICB therapy in the Chinese PLA General Hospital. All demographic, biological, and clinical data were extracted from medical records. Relative changes of SII after two doses of ICB were defined as ΔSII% and calculated as (SIIafter 2 doses-SIIbaseline)/SIIbaseline, and so was the case for ΔNLR%. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan-Meier curves. The prognostic significance of baseline SII, NLR, and their changes was assessed in univariate and multivariate analyses using the Cox proportional hazard regression model. In total, 122 patients with PC treated with ICB were included in the present analysis. Elevated baseline SII (HR=3.28; 95% CI:1.98-5.27; P=0.03) and ΔNLR% (HR=2.21; 95% CI:1.03-4.74; P=0.04) were significantly correlated with an increased risk of death. For PC patients receiving ICB combined with chemotherapies or radiotherapies as the first-line treatment, increased baseline SII was a negative predictor for both OS (HR=8.06; 95% CI:1.71-37.86; P=0.01) and PFS (HR=2.84; 95%CI:1.37-10.38; P=0.04). Our study reveals the prognostic value of baseline SII and NLR changes in PC patients receiving ICB therapy. The clinical utility of these prognostic biomarkers needs to be further studied in prospective studies.
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PURPOSE: Anti-programmed cell death protein 1 or its ligand (anti-PD-1/L1) monotherapy has become the standard second-line treatment in advanced lung adenocarcinoma. However, the strategy treatment of anti-PD-1/L1 plus anti-angiogenesis therapy has not been evaluated. We conducted this retrospective study to assess the efficacy and safety of anti-PD-1/L1 plus anti-angiogenesis therapy in patients with advanced lung adenocarcinoma in the second-line or later setting. METHODS: Patients with advanced lung adenocarcinoma who received anti-PD-1/L1 plus anti-angiogenesis therapy or anti-PD-1/L1 monotherapy in the second-line or later treatment from March 2015 to May 2019 in PLA General Hospital were retrospectively analyzed. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Multivariate analyses of PFS and OS were performed with Cox proportional hazard regression models. RESULTS: Seventy-four patients were included in our study. Twenty-five patients were treated with anti-PD-1/L1 plus anti-angiogenesis therapy, and forty-nine patients were treated with anti-PD-1/L1 monotherapy. The disease control rate (DCR) was higher in the anti-PD-1/L1 plus anti-angiogenesis group than in the anti-PD-1/L1 monotherapy group (92.0% vs. 46.9%, P = 0.0004). The median progression-free survival (PFS) was 5.1 months vs. 2.0 months (HR 0.551 [95% confidence interval 0.337-0.902], P = 0.002) and median overall survival (OS) was 14.3 months vs. 8.4 months (HR 0.549 [95% CI 0.305-0.990], P = 0.046), respectively. Multivariate Cox proportional hazard regression models showed that anti-PD-1/L1 plus anti-angiogenesis group had prolonged PFS (HR 0.541 [95% CI 0.298-0.981], P = 0.033). The incidences of grade 3/4 adverse events were 12% (3/25) in anti-PD-1/L1 plus anti-angiogenesis group and 6% (3/49) in anti-PD-1/L1 monotherapy group. CONCLUSION: Compared with anti-PD-1/L1 monotherapy, anti-PD-1/L1 plus anti-angiogenesis therapy could significantly improve the clinical response and bring longer PFS and OS in patients with advanced lung adenocarcinoma who had failed first-line or later treatment. Further prospective studies are needed to validate our findings.