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INTRODUCTION: Neoadjuvant immunotherapy plus chemotherapy has ushered in a new era for surgical treatment for patients with NSCLC. This study aimed to examine the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy in NSCLC. METHODS: Eligible studies were identified from PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and conference meeting abstracts. The endpoints included major pathological response (MPR), complete pathological response (pCR), surgical resection rate, R0 resection, treatment-related adverse events (TRAEs), severe adverse events (SAEs), surgical complications, treatment discontinuation, surgical delay, and treatment-related death. Stata 18 software was used for statistical analysis, and p < 0.05 was considered statistically significant. Twenty-two studies including a total of 1108 patients were eligible for this study. RESULTS: Among the patients who received neoadjuvant immunotherapy plus chemotherapy, the pooled MPR rate was 51% (95% CI [0.44-0.58]), and pCR rate was 34% (95% CI [0.28-0.40]). The pooled surgical resection rate was 85% (95% CI [0.81-0.89]), and the pooled R0 rate was 94% (95% CI [0.91-0.96]). The pooled rate of pathological tumor downstaging was 84% (95% CI [0.79-0.88]), and the pooled rate of pathological nodal downstaging was 38% (95% CI [0.23-0.57]). During the treatment of neoadjuvant immunotherapy plus chemotherapy with or without surgery, the pooled rate of TRAEs (any grade) was 84% (95% CI [0.73-0.91]), and the pooled rate of SAEs was 29% (95% CI [0.21-0.38]). Surgical complications pooled rate was 25% (95% CI [0.14-0.41]). The pooled rate of treatment discontinuation (11%, 95% CI [0.09-0.13]), surgical delay (3%, 95% CI [0.02-0.05]), and treatment-related death (2%, 95% CI [0.02-0.03]) were conducted. CONCLUSION: Neoadjuvant immunotherapy plus chemotherapy provides a high pathological response, surgical resection rate, R0 resection rate, and pathological downstage rate and has a low risk of increasing the incidence of SAEs, surgical complications, treatment discontinuation, surgical delay, and treatment-related death. The validation of prospective and large sample studies is needed to confirm this conclusion.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Terapia Neoadjuvante , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/efeitos adversos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Imunoterapia/métodos , Imunoterapia/efeitos adversos , Resultado do Tratamento , Pneumonectomia/métodos , Pneumonectomia/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Masculino , Feminino , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Immunotherapy represents a groundbreaking and monumental achievement in the field of cancer therapy, marking a significant advancement in fighting against this devastating disease. Lung cancer has showed consistent clinical improvements in response to immunotherapy treatments, yet, it is undeniable that challenges such as limited response rates acquire resistance, and the unclear fundamental mechanisms were inevitable problems. METHODS: The cellular composition was defined and distinguished through single-cell RNA sequencing (scRNA-seq) analysis of MPR (major pathologic response) and NMPR (non-major pathologic response) samples in GSE207422, including four primary MPR samples and eight primary NMPR samples. RESULTS: We found obvious difference in CD8+ T cell population between MPR and NMPR samples, with high expression of TYMS, RRM2, and BIRC5 in NPMR samples. Meanwhile, the proportion of macrophages and tumor epithelial cells infiltration increased in the NMPR samples. We discovered biomarkers (ACTN4, ATF3, BRD2, CDKN1A, and CHMP4B) in epithelial cells which were potentially represented worse outcomes. CONCLUSIONS: By exploring the difference of tumor microenvironment (TME) in samples with different corresponding degrees of neoadjuvant immunotherapy, this research introduces a number of novel biomarkers for predicting the response of treatment and a theoretical basis for overcoming immunotherapy resistance.
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Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Análise de Célula Única , Microambiente Tumoral , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Imunoterapia/métodos , Análise de Célula Única/métodos , Biomarcadores Tumorais/genética , Análise de Sequência de RNA/métodos , Regulação Neoplásica da Expressão Gênica , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Perfilação da Expressão GênicaRESUMO
PURPOSE: Limited studies have used natural language processing (NLP) in the context of non-small cell lung cancer (NSCLC). This study aimed to validate the application of an NLP model to an NSCLC cohort by extracting NSCLC concepts from free-text medical notes and converting them to structured, interpretable data. METHODS: Patients with a lung neoplasm, NSCLC histology, and treatment information in their notes were selected from a repository of over 27 million patients. From these, 200 were randomly selected for this study with the longest and the most recent note included for each patient. An NLP model developed and validated on a large solid and blood cancer oncology cohort was applied to this NSCLC cohort. Two certified tumor registrars and a curator abstracted concepts from the notes: neoplasm, histology, stage, TNM values, and metastasis sites. This manually abstracted gold standard was compared with the NLP model output. Precision and recall scores were calculated. RESULTS: The NLP model extracted the NSCLC concepts with excellent precision and recall with the following scores, respectively: Lung neoplasm 100% and 100%, NSCLC histology 99% and 88%, histology correctly linked to neoplasm 98% and 79%, stage value 98.8% and 92%, stage TNM value 93% and 98%, and metastasis site 97% and 89%. High precision is related to a low number of false positives, and therefore, extracted concepts are likely accurate. High recall indicates that the model captured most of the desired concepts. CONCLUSION: This study validates that Optum's oncology NLP model has high precision and recall with clinical real-world data and is a reliable model to support research studies and clinical trials. This validation study shows that our nonspecific solid tumor and blood cancer oncology model is generalizable to successfully extract clinical information from specific cancer cohorts.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Processamento de Linguagem Natural , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico , Registros Eletrônicos de Saúde , Oncologia/métodos , Oncologia/normasRESUMO
Background: Cerebral radiation necrosis (RN), a severe complication of stereotactic radiotherapy (SRT), has been shown to significantly decrease patient survival time and quality of life. The purpose of this study was to analyze whether bevacizumab can prevent or reduce the occurrence of SRT-induced cerebral RN in non-small cell lung cancer (NSCLC) patients with brain metastases. Materials and methods: We retrospectively reviewed the clinical records of NSCLC patients with brain metastases from March 2013 to June 2023 who were treated with SRT. Patients were divided into two groups: those in the bevacizumab group received SRT with four cycles of bevacizumab, and patients in the control group received SRT only. Inverse probability of treatment weighting (IPTW) was performed based on a multinomial propensity score model to balance the baseline characteristics. The chi-square test was used. A Cox model was used to evaluate overall survival (OS). Results: A total of 80 patients were enrolled, namely, 28 patients in the bevacizumab group and 52 patients in the control group. The possibility of developing cerebral RN and/or symptomatic edema (RN/SE) was significantly decreased in patients treated with bevacizumab compared to those who did not receive bevacizumab before IPTW (p=0.036) and after IPTW (p=0.015) according to chi-square analysis. The IPTW-adjusted median OS was 47.7 months (95% CI 27.4-80.8) for patients in the bevacizumab group and 44.1 months (95% CI 36.7-68.0) (p=0.364) for patients in the control group. Conclusion: The application of bevacizumab concurrent with SRT may prevent or reduce the occurrence of cerebral RN in NSCLC patients with brain metastases.
Assuntos
Bevacizumab , Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Necrose , Lesões por Radiação , Radiocirurgia , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Masculino , Feminino , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Pessoa de Meia-Idade , Radiocirurgia/efeitos adversos , Idoso , Estudos Retrospectivos , Lesões por Radiação/etiologia , Lesões por Radiação/prevenção & controle , Antineoplásicos Imunológicos/uso terapêuticoRESUMO
In recent years, there has been significant research interest in the field of immunotherapy for non-small cell lung cancer (NSCLC) within the academic community. Given the observed variations in individual responses, despite similarities in histopathologic type, immunohistochemical index, TNM stage, or mutation status, the identification of a reliable biomarker for early prediction of therapeutic responses is of utmost importance. Conventional medical imaging techniques primarily focus on macroscopic tumor monitoring, which may no longer adequately fulfill the requirements of clinical diagnosis and treatment. CT (computerized tomography) or PEF/CT-based radiomics has the potential to investigate the molecular-level biological attributes of tumors, such as PD-1/PD-L1 expression and tumor mutation burden, which offers a novel approach to assess the effectiveness of immunotherapy and forecast patient prognosis. The utilization of cutting-edge radiological imaging techniques, including radiomics, PET/CT, machine learning, and artificial intelligence, demonstrates significant potential in predicting diagnosis, treatment response, immunosuppressive characteristics, and immune-related adverse events. The current review highlights that CT scan-based radiomics is a reliable and feasible way to predict the benefits of immunotherapy in patients with advanced NSCLC.
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Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Tomografia Computadorizada por Raios X , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Imunoterapia/métodos , Resultado do Tratamento , Prognóstico , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Checkpoint Imunológico/metabolismo , Proteínas de Checkpoint Imunológico/genética , RadiômicaRESUMO
This study aimed to explore potential radiomics biomarkers in predicting the efficiency of chemo-immunotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients were prospectively assigned to receive chemo-immunotherapy, and were divided into a primary cohort (n = 138) and an internal validation cohort (n = 58). Additionally, a separative dataset was used as an external validation cohort (n = 60). Radiomics signatures were extracted and selected from the primary tumor sites from chest CT images. A multivariate logistic regression analysis was conducted to identify the independent clinical predictors. Subsequently, a radiomics nomogram model for predicting the efficiency of chemo-immunotherapy was conducted by integrating the selected radiomics signatures and the independent clinical predictors. The receiver operating characteristic (ROC) curves demonstrated that the radiomics model, the clinical model, and the radiomics nomogram model achieved areas under the curve (AUCs) of 0.85 (95% confidence interval [CI] 0.78-0.92), 0.76 (95% CI 0.68-0.84), and 0.89 (95% CI 0.84-0.94), respectively, in the primary cohort. In the internal validation cohort, the corresponding AUCs were 0.93 (95% CI 0.86-1.00), 0.79 (95% CI 0.68-0.91), and 0.96 (95% CI 0.90-1.00) respectively. Moreover, in the external validation cohort, the AUCs were 0.84 (95% CI 0.72-0.96), 0.75 (95% CI 0.62-0.87), and 0.86 (95% CI 0.75-0.96), respectively. In conclusion, the radiomics nomogram provides a convenient model for predicting the effect of chemo-immunotherapy in advanced NSCLC patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Nomogramas , Tomografia Computadorizada por Raios X , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Idoso , Tomografia Computadorizada por Raios X/métodos , Imunoterapia/métodos , Curva ROC , Resultado do Tratamento , Estudos Prospectivos , RadiômicaRESUMO
In addressing the challenges of lung cancer, attention has increasingly turned to molecular diagnostics and targeted therapies, with nucleolin (NCL) assuming a pivotal role, especially in non-small cell lung cancer. The aberrant activity and cellular distribution of NCL act as crucial biomarkers for early detection and treatment monitoring, showing a strong correlation with disease progression and patient prognosis. Elevated NCL levels signal advanced disease and poorer outcomes, underscoring its significance in evaluating disease severity and therapeutic response. Strategies targeting the molecular interactions of NCL have spurred innovative approaches to inhibit tumour growth, overcome drug resistance and improve treatment efficacy. These advancements are paving the way for personalized therapies tailored to the unique molecular profiles of patients' tumours. Consequently, NCL stands at the forefront of lung cancer management, symbolizing the move towards more precise and individualized oncology care, and marking substantial progress in therapeutic development.
Assuntos
Biomarcadores Tumorais , Neoplasias Pulmonares , Nucleolina , Fosfoproteínas , Proteínas de Ligação a RNA , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Prognóstico , Animais , Terapia de Alvo MolecularRESUMO
Introductions: Identifying patients with non-small cell lung cancer (NSCLC) who are optimal candidates for immunotherapy is a cornerstone in clinical decision-making. The tumor immune microenvironment (TIME) is intricately linked with both the prognosis of the malignancy and the efficacy of immunotherapeutic interventions. CD8+ T cells, and more specifically, tissue-resident memory CD8+ T cells [CD8+ tissue-resident memory T (TRM) cells] are postulated to be pivotal in orchestrating the immune system's assault on tumor cells. Nevertheless, the accurate quantification of immune cell infiltration-and by extension, the prediction of immunotherapeutic efficacy-remains a significant scientific frontier. Methods: In this study, we introduce a cutting-edge non-invasive radiomic model, grounded in TIME markers (CD3+ T, CD8+ T, and CD8+ TRM cells), to infer the levels of immune cell infiltration in NSCLC patients receiving immune checkpoint inhibitors and ultimately predict their response to immunotherapy. Data from patients who had surgical resections (cohort 1) were employed to construct a radiomic model capable of predicting the TIME. This model was then applied to forecast the TIME for patients under immunotherapy (cohort 2). Conclusively, the study delved into the association between the predicted TIME from the radiomic model and the immunotherapeutic outcomes of the patients. Result: For the immune cell infiltration radiomic prediction models in cohort 1, the AUC values achieved 0.765, 0.763, and 0.675 in the test set of CD3+ T, CD8+ T, and CD8+ TRM, respectively. While the AUC values for the TIME-immunotherapy predictive value were 0.651, 0.763, and 0.829 in the CD3-immunotherapy response model, CD8-immunotherapy response model, and CD8+ TRM-immunotherapy response model in cohort 2, respectively. The CD8+ TRM-immunotherapy model exhibited the highest predictive value and was significantly better than the CD3-immunotherapy model in predicting the immunotherapy response. The progression-free survival (PFS) analysis based on the predicted levels of CD3+ T, CD8+ T, and CD8+ TRM immune cell infiltration showed that the CD8+ T cell infiltration level was an independent factor (P=0.014, HR=0.218) with an AUC value of 0.938. Discussion: Our empirical evidence reveals that patients with substantial CD8+ T cell infiltration experience a markedly improved PFS compared with those with minimal infiltration, asserting the status of the CD8+ T cell as an independent prognosticator of PFS in the context of immunotherapy. Although CD8+ TRM cells demonstrated the greatest predictive accuracy for immunotherapy response, their predictive strength for PFS was marginally surpassed by that of CD8+ T cells. These insights advocate for the application of the proposed non-invasive radiomic model, which utilizes TIME analysis, as a reliable predictor for immunotherapy outcomes and PFS in NSCLC patients.
Assuntos
Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Linfócitos do Interstício Tumoral , Microambiente Tumoral , Humanos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Feminino , Imunoterapia/métodos , Linfócitos T CD8-Positivos/imunologia , Masculino , Microambiente Tumoral/imunologia , Pessoa de Meia-Idade , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Resultado do Tratamento , Prognóstico , RadiômicaRESUMO
BACKGROUND: In the pursuit of improved clinical outcomes and patient experience in health care, shared decision-making (SDM) stands as a pivotal concept garnering increasing attention, but SDM utilization varies widely, often leading to confusion regarding team members' roles. This study explores knowledge, skills, and attitudes of oncology clinicians engaged in a pioneering educational initiative at a comprehensive cancer care center, aimed at enhancing frontline SDM capabilities. METHODS: Utilizing a prospective cohort qualitative approach, the team conducted interviews with 6 clinicians in a multidisciplinary oncology program who were engaged in an SDM continuing education program. In the program, participants were immersed in experiential learning activities including standardized didactic sessions and simulation-based SDM case role-play activities. RESULTS: Thematic analysis of interview data revealed 5 major categories: 1) perceptions of SDM; 2) training; 3) patient-centered care; 4) challenges and constraints; and 5) leadership buy-in. Participants perceived benefits, including adopting a better approach to integrate SDM into their practice, heightened engagement, emphasizing team collaboration, and embracing a patient-centric care model. CONCLUSIONS: This study underscores the transformative impact of education and training on enhancing SDM capabilities among oncology clinicians and is not intended for generalizability. By promoting a basic understanding and application of SDM principles, practicing clinicians can be better empowered to improve health care outcomes and experience. Our findings contribute to the broader endeavor of embedding practical SDM principles within clinical practice, thereby fostering a more patient-centered and effective health care environment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Tomada de Decisão Compartilhada , Estudos de Viabilidade , Neoplasias Pulmonares , Pesquisa Qualitativa , Humanos , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Estudos Prospectivos , Assistência Centrada no Paciente , Masculino , Feminino , Atitude do Pessoal de Saúde , Equipe de Assistência ao Paciente , Treinamento por Simulação/métodosRESUMO
OBJECTIVE: To explore the survival effect of thoracic gross tumor volume (GTV) in three-dimensional (3D) radiotherapy for stage IV non-small cell lung cancer (NSCLC). METHODS: The data cases were obtained from a single-center retrospective analysis. From May. From 2008 to August 2018, 377 treatment criteria were enrolled. GTV was defined as the volume of the primary lesion and the hilus as well as the mediastinal metastatic lymph node. Chemotherapy was a platinum-based combined regimen of two drugs. The number of median chemotherapy cycles was 4 (2-6), and the cut-off value of the planning target volume (PTV) dose of the primary tumor was 63 Gy (30-76.5 Gy). The cut-off value of GTV volume was 150 cm3 (5.83-3535.20 cm3). RESULTS: The survival rate of patients with GTV <150 cm3 is better than patients with GTV ≥150 cm3. Multivariate Cox regression analyses suggested that peripheral lung cancer, radiation dose ≥63 Gy, GTV <150 cm3, 4-6 cycles of chemotherapy, and CR + PR are good prognostic factors for patients with stage IV non-small cell lung cancer. The survival rate of patients with GTV <150 cm3 was longer than patients with ≥150 cm3 when they underwent 2 to 3 cycles of chemotherapy concurrent 3D radiotherapy (p < 0.05). When performing 4 to 6 cycles of chemotherapy concurrent 3D radiotherapy, there was no significant difference between <150 cm3 and ≥150 cm3. CONCLUSIONS: The volume of stage IV NSCLC primary tumor can affect the survival of patients. Appropriate treatment methods can be opted by considering the volume of tumors to extend patients' lifetime to the utmost.
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Carcinoma Pulmonar de Células não Pequenas , Quimiorradioterapia , Neoplasias Pulmonares , Estadiamento de Neoplasias , Carga Tumoral , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Feminino , Quimiorradioterapia/métodos , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou mais , Prognóstico , Taxa de SobrevidaRESUMO
Extracellular vesicles (EVs) have emerged as a potential delivery vehicle for nucleic-acid-based therapeutics, but challenges related to their large-scale production and cargo-loading efficiency have limited their therapeutic potential. To address these issues, we developed a novel "shock wave extracellular vesicles engineering technology" (SWEET) as a non-genetic, scalable manufacturing strategy that uses shock waves (SWs) to encapsulate siRNAs in EVs. Here, we describe the use of the SWEET platform to load large quantities of KRASG12C-targeting siRNA into small bovine-milk-derived EVs (sBMEVs), with high efficiency. The siRNA-loaded sBMEVs effectively silenced oncogenic KRASG12C expression in cancer cells; they inhibited tumour growth when administered intravenously in a non-small cell lung cancer xenograft mouse model. Our study demonstrates the potential for the SWEET platform to serve as a novel method that allows large-scale production of cargo-loaded EVs for use in a wide range of therapeutic applications.
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Vesículas Extracelulares , Proteínas Proto-Oncogênicas p21(ras) , RNA Interferente Pequeno , Vesículas Extracelulares/metabolismo , Animais , RNA Interferente Pequeno/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Humanos , Camundongos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Mutação , BovinosRESUMO
PURPOSE: Lung cancer remains one of the leading causes of cancer-related mortality worldwide. It is the third cause of death among patients with cancer in Puerto Rico (PR) and non-small cell lung cancer (NSCLC) is the most prevalent. This study aims to describe the first-line treatment (1LT) and health care resource utilization (HCRU) among patients with NSCLC in PR. METHODS: A retrospective cohort study was conducted using the PR Central Cancer Registry Health Insurance Linkage Database to describe patients with NSCLC from 2012 to 2016. It describes sociodemographic and clinical characteristics on the basis of stage and histology and includes 1LT patterns and HCRU. RESULTS: A total of 1,011 patients met the inclusion criteria. Most were male (57.1%), married (54.1%), and had no comorbidities (55.8%). A significant proportion of patients (71.1%) were diagnosed at stages III and IV, with nonsquamous cell carcinoma being the most prevalent histology group (75.9%). About 61.7% received systemic therapy, 36.7% received radiotherapy, and 21.9% underwent surgery. Platinum (Pt)-based combinations were the most common 1LT (82.9%). On average, patients had 4.7 emergency room visits, nearly six hospitalizations, and 22.4 outpatient visits annually. The mean frequencies of positron emission tomography, ultrasounds, computerized tomography scans, and magnetic resonance imaging were 0.95, 0.11, 4.88, and 0.91, respectively. CONCLUSION: To our knowledge, this study provides the first description of 1LT patterns, HCRU, and sociodemographic information among patients with NSCLC in PR. A significant number of patients were diagnosed at stage III or higher and received Pt-based systemic therapy as their 1LT. More research is required to investigate treatment patterns beyond the 1LT and to gain a comprehensive understanding of optimal care interventions and factors associated with early NSCLC diagnosis.
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Carcinoma Pulmonar de Células não Pequenas , Atenção à Saúde , Recursos em Saúde , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Porto Rico , Recursos em Saúde/estatística & dados numéricos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Atenção à Saúde/normas , Atenção à Saúde/estatística & dados numéricos , Estudos Retrospectivos , Estudos de Coortes , Fatores Sociodemográficos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou maisRESUMO
INTRODUCTION: Immunotherapy has revolutionized the management of lung cancer and improved lung cancer survival in trials, but its real-world impact at the population level remains unclear. METHODS: Using data obtained from eight Surveillance, Epidemiology, and End Results (SEER) registries from 2004 through 2019, we addressed the long-term trends in the incidence, incidence-based mortality (IBM), and survival of lung cancer patients in the United States. RESULTS: The incidence and IBM of both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) all significantly decreased steadily from 2004 to 2019. The 1-year survival (1-YS) of both NSCLC and SCLC improved over time, with the best improvement observed for Stage 4 NSCLC. Two significant turning points of Stage 4 NSCLC 1-YS were observed over the years: 0.63% (95% confidence interval [CI]: 0.33%-0.93%) from 2004 to 2010, 0.81% (95% CI: 0.41%-1.21%) from 2010 to 2014 and a striking 2.09% (95% CI: 1.70%-2.47%) from 2014 to 2019. The same two turning points in 1-YS were pronounced for Stage 4 NSCLC in women, which were coincident with the introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immunotherapy. However, for Stage 4 NSCLC in men, only one significant turning point in the 1-YS starting in 2014 was found, which might only correspond to immunotherapy. Significant period effects in reduced IBM were also observed for both Stage 4 AD and Stage 4 SQCC during the period. CONCLUSION: This SEER analysis found that immunotherapy improved the survival of Stage 4 NSCLC patients at the population level in the United States. This real-world evidence confirms that immunotherapy has truly revolutionized the management of lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Estadiamento de Neoplasias , Programa de SEER , Humanos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Masculino , Feminino , Estados Unidos/epidemiologia , Imunoterapia/métodos , Idoso , Pessoa de Meia-Idade , Taxa de Sobrevida/tendências , IncidênciaRESUMO
The advent of immunotherapy has greatly improved the prognosis of non-small cell lung (NSCLC) patients. However, given its low response rate and high cost of treatment, the search for valuable predictive markers of treatment efficacy is necessary. Considering the complexity and heterogeneity of the tumour and tumour microenvironment, the construction of a multi-dimensional prediction model is necessary. Therefore, we aimed to integrate clinical parameters, radiomic features, and immune signature data from NSCLC patients receiving immunotherapy to construct a multi-dimensional prediction model to better predict the efficacy of immunotherapy. The current study enrolled 137 NSCLC patients who received immunotherapy. We collected baseline clinical information, CT images, and tumour tissue specimens. Using 3D-Slicer software, radiomic features were extracted from patient CT images, and tumor tissue samples obtained before immunotherapy were subjected to immunohistochemical staining. Then, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to downscale the data, and the radiomic features and immune signatures associated with the prognosis of immunotherapy patients were identified. The modified lung immune predictive index (mLIPI), radiomics score (Radioscore), immune score and multi-dimensional model nomogram were constructed. The C-index and area under the curve (AUC) were applied to evaluate the predictive efficacy of the models. Three radiomic features and three immune signatures that could predict the efficacy of immunotherapy were eventually screened. Multivariate analysis showed that the mLIPI, Radioscore, and immune score were independent predictive factors for PFS and OS (P < 0.05 for all models). The multi-dimensional model combining the three models showed better predictive efficacy than the mLIPI, Radioscore, and immune score (PFS: 0.721 vs. 0.662 vs. 0.610 vs. 0.610; OS: 0.727 vs. 0.661 vs. 0.601 vs. 0.602 respectively). The multi-dimensional model showed the best predictive efficacy, with C-index for PFS and OS higher than mLIPI, radioscore and immune score: 0.721 vs. 0.662 vs. 0.610 vs. 0.610 for PFS and 0.727 vs. 0.661 vs. 0.601 vs. 0.602 for OS, respectively. The AUC for the multi-dimensional model also performed better than those of the individual models: 0.771 vs. 0.684 vs. 0.715 vs. 0.711 for PFS and 0.768 vs. 0.662 vs. 0.661 vs. 0.658 for OS, respectively. The multi-dimensional model combining the three models had better predictive efficacy than any single model and was more likely to help provide patients personalized and precision medicine.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Nomogramas , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Feminino , Masculino , Imunoterapia/métodos , Pessoa de Meia-Idade , Prognóstico , Idoso , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Microambiente Tumoral/imunologiaRESUMO
The study aimed to reveal the function of LXY30 peptide-modified bone marrow mesenchymal stem cell-derived exosomes (LXY30-Exos) in NSCLC. LXY30 peptide is a peptide ligand targeting α3ß1 integrin, and LXY30 specifically binds to Exos derived from different cells. We use transmission electron microscopy to identify LXY30-Exos and tracking analysis for particles, and the LXY30-Exos internalized by NSCLC cells in vitro and targeted NSCLC tumours in vivo were verified by multiple molecular technologies. The functions of LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 were assessed using cell proliferation, migration and cell apoptosis assays. Meanwhile, the safety of the above engineered Exos was evaluated in vivo. After LXY30-Exos were isolated and identified, LXY30-Exos were confirmed to be internalized by NSCLC cells in vitro and specifically targeted NSCLC tumours in vivo. Functionally, LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 weakened the proliferation, migration and cell cycle of NSCLC cells induced cellular apoptosis in vitro and restrained the tumour progression in vivo. Meanwhile, the safety of LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 was confirmed in vivo. Overall, miR-30c, miR-181b and miR-613 encapsulated in LXY30 peptide-modified BMSC-Exos relieved NSCLC.
Assuntos
Apoptose , Carcinoma Pulmonar de Células não Pequenas , Movimento Celular , Proliferação de Células , Exossomos , Neoplasias Pulmonares , Células-Tronco Mesenquimais , MicroRNAs , Exossomos/metabolismo , MicroRNAs/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Animais , Camundongos , Linhagem Celular Tumoral , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologiaRESUMO
BACKGROUND/AIM: Pneumonitis during durvalumab consolidation therapy after chemoradiotherapy (CRT) is a major cause of treatment discontinuation. Although previous studies have revealed an association between antinuclear antibody (ANA) positivity and the safety and efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC), there are no reports on durvalumab consolidation therapy. This study investigated the safety and efficacy of durvalumab after CRT in ANA-positive patients. PATIENTS AND METHODS: We retrospectively reviewed patients with unresectable NSCLC treated with durvalumab after CRT between August 2018 and July 2022 at our institution. We evaluated the association among ANA positivity, treatment-related adverse events (AEs), and survival outcomes. RESULTS: Overall, 80 patients were enrolled, 39 of whom were ANA-positive. Although there were no significant differences in the incidence of each AE of any grade, ANA-positive patients tended to have a higher frequency of pneumonitis of grade 3 to 5 than ANA-negative patients (12.8% vs. 2.4%, p=0.104). ANA-positive patients had a significantly shorter median progression-free survival (PFS) and overall survival (OS) than ANA-negative patients [14.9 months vs. not reached (NR), p=0.005; NR vs. NR, p=0.013]. Multivariate analysis revealed that ANA positivity was an independent predictor of shorter PFS (HR=2.23; 95% CI=1.16-4.29; p=0.016) and OS (HR=2.28; 95% CI=1.01-5.12; p=0.046). CONCLUSION: ANA-positive patients receiving durvalumab after CRT tended to have a higher frequency of severe pneumonitis and significantly worse PFS and OS compared with ANA-negative patients.
Assuntos
Anticorpos Antinucleares , Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas , Quimiorradioterapia , Neoplasias Pulmonares , Humanos , Feminino , Masculino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Idoso , Quimiorradioterapia/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Estudos Retrospectivos , Anticorpos Antinucleares/sangue , Idoso de 80 Anos ou mais , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Resultado do TratamentoRESUMO
Lung cancer remains a formidable health challenge due to its high mortality and morbidity rates. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases, with small cell lung cancer (SCLC) accounting for the remainder. Both NSCLC and SCLC cells express receptor tyrosine kinases, which may be overexpressed or mutated in lung cancer, leading to increased activation. The c-Met receptor tyrosine kinase, crucial for cell transformation and tumor growth, invasion, and metastasis, became the focus of our study. We used an E1B55KD-deleted, replication-selective oncolytic adenovirus (Ad.What), driven by the c-Met promoter, targeting lung cancer cells with c-Met overexpression, thus sparing normal cells. Previous studies have shown the enhanced antitumor efficacy of oncolytic adenoviruses when combined with chemotherapeutic agents. We explored combining rapamycin, a selective mTOR inhibitor with promising clinical trial outcomes for various cancers, with Ad.What. This combination increased infectivity by augmenting the expression of coxsackievirus and adenovirus receptors and αV integrin on cancer cells and induced autophagy. Our findings suggest that combining a c-Met promoter-driven oncolytic adenovirus with rapamycin could be an effective lung cancer treatment strategy, offering a targeted approach to exploit lung cancer cells' vulnerabilities, potentially marking a significant advancement in managing this deadly disease.
Assuntos
Adenoviridae , Neoplasias Pulmonares , Terapia Viral Oncolítica , Vírus Oncolíticos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-met , Sirolimo , Humanos , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Regiões Promotoras Genéticas/genética , Adenoviridae/genética , Linhagem Celular Tumoral , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologiaRESUMO
The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of EGFR mutations or ALK gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than EGFR and ALK. To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected EGFR-mutated NSCLC in stage IB-IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable EGFR-mutated NSCLC showed the relevant PFS improvement. In the ALK-positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)-IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in EGFR- and ALK-positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than EGFR or ALK. In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Inibidores de Proteínas Quinases/uso terapêutico , MutaçãoRESUMO
Lung cancer ranks among the most prevalent and deadliest malignancies worldwide. Despite significant strides in targeted therapies and immunotherapy for lung cancer, curing the disease remains a highly prioritized issue. Circular RNAs (circRNAs), recently discovered RNA molecules characterized by covalently closed loop structures, possess features such as structural stability, sequence conservation, and disease-specific expression. Cutting-edge medical research has linked circRNA dysregulation to the progression of various cancers. Among these, circular RNA HIPK3 (circHIPK3), an oncogenic gene primarily derived from the second exon of the HIPK3 gene, has emerged as a focal point of investigation. Increasing evidences suggest that circHIPK3 is involved in the development of non-small cell lung cancer (NSCLC) and other malignancies. Aberrant expression of circHIPK3 is closely associated with the disease mechanisms, diagnosis, treatment, and prognosis of NSCLC. This review discusses the latest research advancements on circHIPK3 in NSCLC, aiming to promote precise diagnosis and treatment of lung cancer.â©.