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Background and Objective: Traditional cell line models are the commonly used preclinical models for lung cancer research. However, cell lines cannot recapitulate the complex tumor heterogeneity and cannot mimic the microenvironment of human cancer. Recently, 3D multicellular in vitro self-assembled models called "organoids" have been developed at a fast pace in the field of research, which can mimic the actual primary tumor. At present, several studies have reported on protocols of lung cancer organoids (LCOs) generation, and using LCOs can provide novel insight into the basic and translational research of lung cancer. However, the establishment of the LCO models remains challenging due to the complexity of lung cancer and the immaturity of organoid technology, so it is necessary to understand the influences of different methodologies on LCO generation and review the applications and limitations of LCO models. Methods: In this review, we searched the literature in the recent ten years in the field of LCOs. Key Content and Findings: We summarized the methodology, the problems, and the solutions in the LCOs generation, its application and limitations, as well as proposing future challenges and perspectives. Conclusions: Currently, LCOs are successfully generated via exploring the methodology by the researchers. Though there are still challenges in clinical application, LCOs are applied in some cancer studies including investigation of anti-cancer treatment response in vitro, modeling tumor immune microenvironment, and construction of organ chips, which are forging a promising path towards precision medicine.
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BACKGROUND: Hypothyroidism is a major manifestation of autoimmune thyroid diseases (AITD). We previously reported that a low selenium (Se) status was linked to an elevated prevalence of thyroid diseases. We hypothesized that Se status may also influence the restoration of thyroid function. Thus, this study aimed to investigate the factors affecting the recovery of thyroid function in patients with (sub-)clinical hypothyroidism, with a specific focus on Se status. METHODS: We conducted a 6-year prospective cohort study comparing two counties with different Se concentrations. Demographic and disease data were collected from 1,190 individuals (549 Se-adequate and 641 Se-deficient) who completed a follow-up study in 2019. In addition, urinary iodine (I) levels, thyroid function, and serum and nail Se levels were measured. Logistic regression was used to investigate the relationship between Se deficiency and recovery of thyroid function. RESULTS: Sex and smoking status was similar between the two counties studied. Thyroid function recovery rate was significantly higher in Se-deficient counties (46.0% vs. 30.6%, P = 0.008). In the multivariate analysis, our results show that female sex (odds ratio [OR] (95% confidence interval [CI]) = 1.875 (1.080-3.257), P = 0.026] and increasing age [OR (95%CI) = 1.028(1.007-1.049), P = 0.009] were associated with the recovery rate. Additionally, our study revealed that while Se status was significant in the univariate analysis, this association appeared to disappear in the multivariate analysis. CONCLUSIONS: Female sex and increasing age have unfavorable effects on the recovery of thyroid function in patients over 30 years of age with (sub-) clinical hypothyroidism.
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Hipotireoidismo , Selênio , Doenças da Glândula Tireoide , Humanos , Feminino , Adulto , Seguimentos , Estudos Prospectivos , Hipotireoidismo/epidemiologiaRESUMO
OBJECTIVE: Antithyroid drug (ATD)-induced agranulocytosis (TIA) is the most serious adverse effect during ATD treatment of Graves' disease (GD). Previously, the MICA gene was reported to be associated with TIA. MICA protein is an important ligand for the NKG2D protein, which is encoded by the KLRK1 gene and KLRC4-KLRK1 read-through transcription. This study further investigated the association between KLRC4-KLRK1 gene polymorphisms and susceptibility to TIA. METHODS: Twenty-eight candidate single nucleotide polymorphisms (SNPs) on KLRC4-KLRK1 read-through transcription were evaluated by the iPLEX MassARRAY system in 209 GD control patients and 38 TIA cases. RESULTS: A significant association of rs2734565 polymorphism with TIA was found (p=0.02, OR=1.80, 95% CI=1.09-2.96). The haplotype C-A-A-C-G, including rs2734565-C, was associated with a significantly higher risk of TIA (p=4.79E-09, OR=8.361, 95% CI=3.737-18.707). In addition, the interval time from hyperthyroidism to agranulocytosis onset was shorter in patients carrying the rs2734565-C allele than in non-carrying groups (45.00 (14.00-6570.00) d vs. 1080.00 (30.00-3600.00) d, p=0.046), and the interval from ATD treatment to agranulocytosis onset was also shorter in patients carrying rs2734565-C allele (29.00 (13.00-75.00) d vs. 57.50 (21.00-240.00) d, p=0.023). CONCLUSIONS: The findings suggest that the KLRC4-KLRK1 gene polymorphism is associated with susceptibility and progression of ATD-induced agranulocytosis. Patients carrying the rs2734565-C allele had a higher susceptibility and faster onset time of TIA.
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Agranulocitose , Doença de Graves , Hipertireoidismo , Humanos , Agranulocitose/induzido quimicamente , Agranulocitose/genética , Agranulocitose/tratamento farmacológico , Antitireóideos/efeitos adversos , Doença de Graves/tratamento farmacológico , Doença de Graves/genética , Hipertireoidismo/tratamento farmacológico , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/uso terapêutico , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Low-dose computed tomography screening can increase the detection for non-small-cell lung cancer (NSCLC). To improve the diagnostic accuracy of early-stage NSCLC detection, ultrasensitive methods are used to detect cell-free DNA (cfDNA) 5-hydroxymethylcytosine (5hmC) in plasma. Genome-wide 5hmC is profiled in 1990 cfDNA samples collected from patients with non-small cell lung cancer (NSCLC, n = 727), healthy controls (HEA, n = 1,092), as well as patients with small cell lung cancer (SCLC, n = 41), followed by sample randomization, differential analysis, feature selection, and modeling using a machine learning approach. Differentially modified features reflecting tissue origin. A weighted diagnostic model comprised of 105 features is developed to compute a detection score for each individual, which showed an area under the curve (AUC) range of 86.4%-93.1% in the internal and external validation sets for distinguishing lung cancer from HEA controls, significantly outperforming serum biomarkers (p < 0.001). The 5hmC-based model detected high-risk pulmonary nodules (AUC: 82%)and lung cancer of different subtypes with high accuracy as well. A highly sensitive and specific blood-based test is developed for detecting lung cancer. The 5hmC biomarkers in cfDNA offer a promising blood-based test for lung cancer.
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Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Ácidos Nucleicos Livres/genética , Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Estudos de Casos e ControlesRESUMO
BACKGROUND: The precise characterization of individual tumors and immune microenvironments using transcriptome sequencing has provided a great opportunity for successful personalized cancer treatment. However, the cancer treatment response is often characterized by in vitro assays or bulk transcriptomes that neglect the heterogeneity of malignant tumors in vivo and the immune microenvironment, motivating the need to use single-cell transcriptomes for personalized cancer treatment. METHODS: Here, we present comboSC, a computational proof-of-concept study to explore the feasibility of personalized cancer combination therapy optimization using single-cell transcriptomes. ComboSC provides a workable solution to stratify individual patient samples based on quantitative evaluation of their personalized immune microenvironment with single-cell RNA sequencing and maximize the translational potential of in vitro cellular response to unify the identification of synergistic drug/small molecule combinations or small molecules that can be paired with immune checkpoint inhibitors to boost immunotherapy from a large collection of small molecules and drugs, and finally prioritize them for personalized clinical use based on bipartition graph optimization. RESULTS: We apply comboSC to publicly available 119 single-cell transcriptome data from a comprehensive set of 119 tumor samples from 15 cancer types and validate the predicted drug combination with literature evidence, mining clinical trial data, perturbation of patient-derived cell line data, and finally in-vivo samples. CONCLUSIONS: Overall, comboSC provides a feasible and one-stop computational prototype and a proof-of-concept study to predict potential drug combinations for further experimental validation and clinical usage using the single-cell transcriptome, which will facilitate and accelerate personalized tumor treatment by reducing screening time from a large drug combination space and saving valuable treatment time for individual patients. A user-friendly web server of comboSC for both clinical and research users is available at www.combosc.top . The source code is also available on GitHub at https://github.com/bm2-lab/comboSC .
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Neoplasias , Transcriptoma , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Terapia Combinada , Software , Combinação de Medicamentos , Microambiente Tumoral , Análise de Célula ÚnicaRESUMO
Immunotherapy is considered a major breakthrough in the treatment of small cell lung cancer (SCLC), although its anti-tumor efficacy is limited. With a high degree of malignancy and high heterogeneity, SCLC is difficult to treat in the clinic. A new combination strategy is urgently needed to further improve the efficacy of immunotherapy in patients with SCLC. By immunofluorescence, 100 SCLC patients in a local cohort were classified into the SCLC-A (high ASCL1 expression; n = 36), SCLC-N (high NEUROD1 expression; n = 32), SCLC-P (high POU2F3 expression; n = 14), and SCLC-Y (high YAP1 expression; n = 18) subtypes. Each SCLC molecular subtype represented different prognoses, tumor microenvironment traits, and immunotherapy sensitivities. Analysis of both the local and public cohorts suggested that the SCLC-Y subtype exhibited the worst clinical outcome (p < 0.05) when compared with other subtypes. SCLC with high YAP1 expression was characterized by high PD-L1 expression, high stromal score, T-cell functional impairment, and a close relationship with immune-related pathways. YAP1 upregulated PD-L1 expression and suppressed T cell activation, thus leading to immune evasion. In in vitro experiments, blockade of YAP1 promoted cancer cell apoptosis, immune cell proliferation, T-cell activation, and cytotoxic T-cell infiltration, thus further potentiating the efficacy of immunotherapy in patients with the SCLC-Y subtype.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/genética , Antígeno B7-H1 , Terapia de Imunossupressão , Imunoterapia , Neoplasias Pulmonares/genética , Microambiente TumoralRESUMO
BACKGROUND: Small cell lung cancer (SCLC) is a highly malignant cancer characterized by metastasis and an extremely poor prognosis. Although combined chemoimmunotherapy improves the prognosis of extensive-stage (ES)-SCLC, the survival benefits remain limited. Furthermore, no reliable biomarker is available so far to predict the treatment outcomes for chemoimmunotherapy. METHODS: This retrospective study included patients with ES-SCLC treated with first-line combined atezolizumab or durvalumab with standard chemotherapy between Janauray 1, 2019 and October 1, 2022 at five medical centers in China as the chemoimmunotherapy group. The patients were divided into one training cohort and two independent external validation cohorts. Additionally, we created a control group of ES-SCLC who was treated with first-line standard chemotherapy alone. The Radiomics Score was derived using machine learning algorithms based on the radiomics features extracted in the regions of interest delineated on the chest CT obtained before treatment. Cox proportional hazards regression analysis was performed to identify clinical features associated with therapeutic efficacy. The log-rank test, time-dependent receiver operating characteristic curve, and Concordance Index (C-index) were used to assess the effectiveness of the models. RESULTS: A total of 341 patients (mean age, 62±8.7 years) were included in our study. After a median follow-up time of 12.1 months, the median progression-free survival (mPFS) was 7.1 (95% CI 6.6 to 7.7) months, whereas the median overall survival (mOS) was not reached. The TNM stage, Eastern Cooperative Oncology Group performance status, and Lung Immune Prognostic Index showed significant correlations with PFS. We proposed a predictive model based on eight radiomics features to determine the risk of chemoimmunotherapy resistance among patients with SCLC (validation set 1: mPFS, 12.0 m vs 5.0 m, C-index=0.634; validation set 2: mPFS, 10.8 m vs 6.1 m, C-index=0.617). By incorporating the clinical features associated with PFS into the radiomics model, the predictive efficacy was substantially improved. Consequently, the low-progression-risk group exhibited a significantly longer mPFS than the high-progression-risk group in both validation set 1 (mPFS, 12.8 m vs 4.5 m, HR=0.40, p=0.028) and validation set 2 (mPFS, 9.2 m vs 4.6 m, HR=0.30, p=0.012). External validation set 1 and set 2 yielded the highest 6-month area under the curve and C-index of 0.852 and 0.820, respectively. Importantly, the integrated prediction model also exhibited considerable differentiation power for survival outcomes. The HR for OS derived from the low-progression-risk and high-progression-risk groups was 0.28 (95% CI 0.17 to 0.48) in all patients and 0.20 (95% CI 0.08 to 0.54) in validation set. By contrast, no significant differences were observed in PFS and OS, between high-progression-risk patients receiving chemoimmunotherapy and the chemotherapy cohort (mPFS, 5.5 m vs 5.9 m, HR=0.90, p=0.547; mOS, 14.5 m vs 13.7 m, HR=0.97, p=0.910). CONCLUSIONS: The integrated clinical and radiomics model can predict the treatment outcomes in patients with ES-SCLC receiving chemoimmunotherapy, rendering a convenient and low-cost prognostic model for decision-making regarding patient management.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Pessoa de Meia-Idade , Idoso , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Imunoterapia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Though immunotherapy has to some extent improved the prognosis of patients with advanced non-small cell lung cancer (NSCLC), only a few patients benefit. Furthermore, immunotherapy efficacy is affected by inflammatory and nutritional status of patients. To investigate whether dynamics of inflammatory and nutritional indexes were associated with prognosis, 223 patients were analysed retrospectively. The inflammatory indexes of interest were neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) while prognostic nutritional index (PNI) and the haemoglobin, albumin, lymphocyte and platelet (HALP) score were considered as nutritional indexes. Patients were divided into high and low groups or into 'increase' and 'decrease' groups based on pre-treatment cut-off values and index dynamics after 6-week follow-up respectively. High pre-treatment PLR (OR = 2.612) and increase in NLR during follow-up (OR = 2.516) were significantly associated with lower objective response rates. Using multivariable analysis, high pre-treatment PLR (HR, 2.319) and increase in SII (HR, 1.731) predicted shorter progression-free survival, while high pre-treatment NLR (HR, 1.635), increase in NLR (HR, 1.663) and PLR (HR, 1.691) and decrease in PNI (HR, 0.611) predicted worse overall survival. The nomogram's C-index in inside validation was 0.718 (95% CI: 0.670-0.766). Our results indicated both nutritional and inflammatory indexes are associated with survival outcomes. Inflammatory indexes were additionally linked to treatment response. Index dynamics are better predictors than baseline values in predicting survival in advanced NSCLC patients receiving PD-1 inhibitor combined with chemotherapy as first-line.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Prognóstico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Avaliação Nutricional , Estudos Retrospectivos , Contagem de Linfócitos , Inflamação/tratamento farmacológico , NeutrófilosRESUMO
Background: Although examinations and therapies for bronchial lung cancer, also called lung cancer (LC), have become more effective and precise, the morbidity and mortality of LC remain high worldwide. Describing the changing profile of LC characteristics over time is indispensable. This study aimed to understand the changes in real-world settings of LC and its characteristics in China. Methods: In this study, 119,785 patients were enrolled from 2012 to 2020 in the Shanghai Pulmonary Hospital. The patients' medical records were extracted from the hospital's database. Demographic characteristics, general clinicopathological information, and blood coagulation indices at the initial diagnoses were analyzed using the Kruskal-Wallis, Nemenyi, chi-squared, and Bonferroni tests. Changes in demographic characteristics during the 8-year study period, namely dynamic changes among different stages and different pathological types, were evaluated. Results: The percentages of female (from 38.50% [323/839] in 2012 to 48.29% [5112/10,585] in 2020) and non-smoking LC (from 69.34% [475/685] to 80.48% [8055/10,009]) patients increased significantly during the study period, with a trend toward a younger age at diagnosis (from 3.58% [30/839] to 8.99% [952/10,585]). Over the study period, the proportion and absolute number of lung adenocarcinoma cases increased (from 67.97% [433/637] to 76.31% [6606/8657]) while the proportion of lung squamous cell carcinoma decreased (from 21.19% [135/637] to 12.08% [1046/8657]). Comprehensive driver gene mutation examination became more common, and epidermal growth factor receptor (EGFR) mutation occurred more frequently in female vs. male (62.03% [12793/20625] vs. 29.90% [8207/27,447]) and non-smoking vs. smoking (53.54% [17,203/32,134] vs. 23.73% [3322/13,997]) patients (both P < 0.001). The distribution of the common driver genes differed among different stages of LC. EGFR mutation was detected most frequently at each stage, and other driver gene alterations were more common in advanced stages (P <0.001). The combination of chemotherapy, targeted therapy, and immunotherapy, as a comprehensive management regimen, gradually became predominant over the study period (P < 0.001). A hypercoagulable state was shown in advanced-stage LC patients and patients with the anaplastic lymphoma kinase fusion, indicated by significantly elevated levels of d-dimer, fibrinogen, and fibrinogen degradation products. Conclusions: This study comprehensively depicted the changing characteristics of Chinese LC patients over an 8-year period to provide preliminary insights into LC treatment.Trial registration: ClinicalTrials.gov, NCT05423236.
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Pyroptosis is a type of programed cell death that differs from apoptosis, ferroptosis, or necrosis. Numerous studies have reported that it plays a critical role in tumorigenesis and modification of the tumor microenvironment in multiple tumors. In this review, we briefly describe the canonical, non-canonical, and alternative mechanisms of pyroptotic cell death. We also summarize the potential roles of pyroptosis in oncogenesis, tumor development, and lung cancer treatment, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Pyroptosis has double-edged effects on the modulation of the tumor environment and lung cancer treatment. Further exploration of pyroptosis-based drugs could provide novel therapeutic strategies for lung cancer.
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Background: Low baseline prognostic nutritional index (PNI) scores are associated with poor survival for various malignancies; however, they vary based on the cohort and time resulting in inaccurate results. We determined the predictive value of the PNI score variations in addition to the baseline PNI scores for patients with advanced non-small cell lung cancer (NSCLC) who received programmed cell death protein 1 (PD-1) inhibitor. Methods: We retrospectively analysed 115 patients with advanced NSCLC who received PD-1 inhibitor. The median follow-up period was 28 months. Patients were clustered into four groups based on the combined PNI scores (combination of baseline and variation of PNI scores): ΔPNI-L-L, ΔPNI-L-H, ΔPNI-H-L, and ΔPNI-H-H subgroups. For instance, if PNI scores of patients with high baseline PNI score increased from baseline to 6 weeks after treatment, they were included in the ΔPNI-H-H subgroup. Cox regression models were used to identify the factors associated with survival. Results: The baseline PNI score was only related to the overall survival (OS) (P = .026), and not to the overall response rate (ORR) (P = .299) and progression-free survival (PFS) (P = .207). The ORR was associated with the combined PNI scores (P = .017). A multivariable Cox regression analysis confirmed that the combined PNI scores were independent factors for PFS (ΔPNI-L-H, 12 months, hazard ratio [HR] = 0.449, P = .009; ΔPNI-H-L, 14 months, HR = 0.500, P = .019; and ΔPNI-H-H, 17 months, HR = 0.390, P = .012; vs ΔPNI-L-L, 8 months) and OS (ΔPNI-L-H, 27 months, HR = 0.403, P = .019; ΔPNI-H-L, 28 months, HR = 0.369, P = .010; and ΔPNI-H-H, not reached, HR = 0.087, P = .002; vs ΔPNI-L-L, 15 months). Conclusions: Patients with high baseline PNI and increased PNI score had the better survival outcome. On dynamic monitoring and comprehensive assessment, the combined PNI scores significantly enhanced the survival predictive ability of patients with NSCLC treated with PD-1 inhibitor.
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In vivo simultaneous visualization of multiple biomarkers is critical to accurately diagnose disease and decipher fundamental processes at a certain pathological evolution, which however is rarely exploited. Herein, a multimodal activatable imaging probe (P-125 I) is reported with activatable fluoro-photoacoustic and radioactive signal for in vivo imaging of biomarkers (i.e., hepsin and prostate-specific membrane antigen (PSMA)) associated with prostate cancer diagnosis and prognosis. P-125 I contains a near-infrared (NIR) dye that is caged with a hepsin-cleavable peptide sequence and linked with a radiolabeled PSMA-targeted ligand (PSMAL). After systemic administration, P-125 I actively targets the tumor site via specific recognition between PSMA and PSMAL moiety and in-situ generates of activated fluoro-photoacoustic signal after reacting with hepsin to release the free dye (uncaged state). P-125 I achieves precisely early detection of prostate cancer and renal clearance to alleviate toxicity issues. In addition, the accumulated radioactive and activated photoacoustic signal of probe correlates well with the respective expression level of PSMA and hepsin, which provides valuable foreseeability for cancer progression and prognosis. Thus, this study presents a multimodal activatable probe for early detection and in-depth deciphering of prostate cancer.
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Sondas Moleculares , Neoplasias da Próstata , Biomarcadores Tumorais , Diagnóstico por Imagem/métodos , Corantes Fluorescentes , Humanos , Rim , Masculino , Imagem Molecular/métodos , Neoplasias da Próstata/diagnóstico por imagemRESUMO
Small cell lung cancer (SCLC) lacks effective treatments to overcome chemoresistance. Here we established multiple human chemoresistant xenograft models through long-term intermittent chemotherapy, mimicking clinically relevant therapeutic settings. We show that chemoresistant SCLC undergoes metabolic reprogramming relying on the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) pathway, which can be targeted using clinically approved statins. Mechanistically, statins induce oxidative stress accumulation and apoptosis through the GGPP synthase 1 (GGPS1)-RAB7A-autophagy axis. Statin treatment overcomes both intrinsic and acquired SCLC chemoresistance in vivo across different SCLC PDX models bearing high GGPS1 levels. Moreover, we show that GGPS1 expression is negatively associated with survival in patients with SCLC. Finally, we demonstrate that combined statin and chemotherapy treatment resulted in durable responses in three patients with SCLC who relapsed from first-line chemotherapy. Collectively, these data uncover the MVA-GGPP pathway as a metabolic vulnerability in SCLC and identify statins as a potentially effective treatment to overcome chemoresistance.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Linhagem Celular Tumoral , Farnesiltranstransferase/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Ácido Mevalônico/farmacologia , Fosfatos de Poli-Isoprenil , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
OBJECTIVES: To explore the characteristics of Notch pathway in small cell lung cancer (SCLC), clarify the expression of delta-like protein 3 (DLL3) in SCLC patients undergoing surgical treatment, and explore the correlation between DLL3 expression and clinicopathological features, prognosis, and immune microenvironment. METHODS: A total of 134 patients who received surgical treatment and were diagnosed as SCLC by postoperative histopathology were enrolled. All exon gene sequencing was performed in tumor tissues and adjacent normal tissues of 28 patients to clarify the genomic characteristics of SCLC. The expressions of DLL3 and programmed cell death 1 ligand 1 (PDL1) were detected by immunohistochemistry (IHC) in 101 postoperative pathological specimens. RESULTS: Notch receptor mutations are common, but the overall mutation rate of Notch ligand family is not high and mutually exclusive. The mutation status of Notch and Notch1 gene were not related to the prognosis. Notch1 gene mutation was significantly negatively correlated with the expression of PD-L1. DLL3 was highly expressed in SCLC and had no significant correlation with prognosis. There was a positive correlation between DLL3 expression and PD-L1 expression. Patients with positive DLL3 expression and no NOTCH 1 gene mutation had higher PD-L1 expression. SCLC patients with such characteristics may be more likely to benefit from immunotherapy. CONCLUSION: This study preliminarily explored the genomic characteristics and immune microenvironment of surgical resection of SCLC in China, and found the correlation between Notch gene mutation, DLL3 expression and PD-L1 expression, which provided a new idea for selecting appropriate treatment strategies for SCLC in the future.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Antígeno B7-H1/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/patologia , Microambiente Tumoral/genéticaRESUMO
Background: Percutaneous transthoracic lung biopsy is customarily conducted under computed tomography (CT) guidance, which primarily depends on the conductors' experience and inevitably contributes to long procedural duration and radiation exposure. Novel technique facilitating lung biopsy is currently demanded. Methods: Based on the reconstructed anatomical information of CT scans, a three-dimensionally printed navigational template was customized to guide fine-needle aspiration (FNA). The needle insertion site and angle could be indicated by the template after proper placement according to the reference landmarks. From June 2020 to August 2020, patients with peripheral indeterminate lung lesions ≥30 mm in diameter were enrolled in a pilot trial. Cases were considered successful when the virtual line indicated by the template in the first CT scan was pointing at the target, and the rate of success was recorded. The insertion deviation, procedural duration, radiation exposure, biopsy-related complications, and diagnostic yield were documented as well. Results: A total of 20 patients consented to participate, and 2 withdrew. The remaining 18 participants consisting of 11 men and 7 women with a median age of 63 [inter-quartile range (IQR), 50-68] years and a median body mass index (BMI) of 23.5 (IQR, 20.8-25.8) kg/m2 received template-guided FNA. The median nodule size of the patients was 41.2 (IQR, 36.2-51.9) mm and 17 lesions were successfully targeted (success rate, 94.4%). One lesion was not reached through the designed trajectory due to an unpredictable alteration of the lesion's location resulting from pleural effusion. The median deviation between the actual position of the needle tip and the designed route was 9.4 (IQR, 6.8-11.7) mm. The median procedural duration was 10.7 (IQR, 9.7-11.8) min, and the median radiation exposure was 220.9 (IQR, 198.6-249.5) mGy×cm. No major biopsy-related complication was encountered. Definitive diagnosis of malignancy was reached in 13 of the 17 (76.5%) participants. Conclusions: The feasibility and safety of navigational template-guided FNA were preliminarily validated in lung biopsy cohort. Nonetheless, patients with pleural effusion were not recommended to undergo FNA guided by such technique. Trial Registration: This study was registered with ClinicalTrials.gov (identifier: NCT03325907).
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BACKGROUND: Smoking is a serious public health problem that affects human health conditions. Although there is evidence that microorganisms are associated with smoking-related lung diseases, the relationship between the rich lung microbiome of upper respiratory tract groups and smoking has not been studied. OBJECTIVE: In this study, we investigated the effects of smoking on environmental microbes and lung microbiome in the Chinese population and provided clues for the role of smoking in the development of respiratory disease. METHODS: Bronchoalveolar lavage fluid samples were collected from 55 individuals with a history of smoking. Microbial gene sequencing was carried out through NGS technology. We analyzed and compared the diversity, community structure, and species abundance of bronchoalveolar lavage microbiome between smokers and nonsmokers, to speculate the effects of smoking on the lung microbiome. RESULTS: Smoking hardly affected the α diversity of microbial groups of bronchoalveolar lavage, but it had a huge influence on the microbiome composition. The relative abundance of Rothia, Actinomycetes, Haemophilus, Porphyrins, Neisseria, Acinetobacter, and Streptococcus genera had a remarkable increase in the smoking group. On the other hand, the relative abundance of Plusella and Veronella decreased significantly. CONCLUSION: Smoking may change the environmental microbes and then alter the structure of the lung microbiome, which may lead to smoking-related diseases.
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Microbiota , Fumar , Líquido da Lavagem Broncoalveolar , China , Humanos , Pulmão , Microbiota/genética , RNA Ribossômico 16S/genéticaRESUMO
ABSTRACT: Immunotherapy that targets checkpoints, especially programmed cell death protein 1 and programmed cell death ligand 1, has revolutionized cancer therapy regimens. The overall response rate to mono-immunotherapy, however, is limited, emphasizing the need to potentiate the efficacy of these regimens. The functions of immune cells are modulated by multiple stimulatory and inhibitory molecules, including lymphocyte activation gene 3 (LAG-3). LAG-3 is co-expressed together with other inhibitory checkpoints and plays key roles in immune suppression. Increasing evidence, particularly in the last 5âyears, has shown the potential of LAG-3 blockade in anti-tumor immunity. This review provides an update on the biological properties and clinical applications of LAG-3 in cancers.
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Neoplasias , Humanos , Imunoterapia , Linfócitos/metabolismo , Neoplasias/tratamento farmacológicoRESUMO
With a 5-year overall survival of approximately 20%, lung cancer has always been the number one cancer-specific killer all over the world. As a fusion of positron emission computed tomography (PET) and computed tomography (CT), PET/CT has revolutionized cancer imaging over the past 20 years. In this review, we focused on the optimization of the function of 18F-flurodeoxyglucose (FDG)-PET/CT in diagnosis, prognostic prediction and therapy management of lung cancers by computer programs. FDG-PET/CT has demonstrated a surprising role in development of therapeutic biomarkers, prediction of therapeutic responses and long-term survival, which could be conducive to solving existing dilemmas. Meanwhile, novel tracers and optimized procedures are also developed to control the quality and improve the effect of PET/CT. With the continuous development of some new imaging agents and their clinical applications, application value of PET/CT has broad prospects in this area.
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Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
Lung cancer is the top reason for cancer-related deaths worldwide. The 5-year overall survival rate of lung cancer is approximately 20 % due to the delayed diagnosis and low response rate to regular treatments. Microbiota, both host-microbiota and alien pathogenic microbiota, have been investigated to be involved in a complicated and contradictory relationship with lung cancer initiation, treatments, and prognosis. Disorders of certain host-microbiota and pathogen infection are associated with the risk of lung cancers based on epidemiological evidence, and antibiotics (ATBs) could dramatically impair anti-cancer treatment efficacy, including chemotherapy and immunotherapy. Moreover, probiotics and microbe-mediated drugs are potential approaches to enhance regular anti-tumor treatments. Therefore, the knowledge of the complex dual effect of microbes on lung cancer is beneficial to take their essence and remove their dross. This review offers insight into the current trends and advancements in microbiota or microbial components related to lung cancer.