RESUMO
Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasia Residual , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Prognóstico , Masculino , Feminino , Resultado do Tratamento , Biomarcadores Tumorais , Pessoa de Meia-Idade , DNA Tumoral CirculanteRESUMO
Neoadjuvant immunotherapy has significantly changed the therapeutic approach for treating patients with surgically resectable non-small cell lung cancer (NSCLC). Here, peripheral blood inflammation-based biomarkers as well as previously less focused eosinophil fraction, modified Glasgow prognostic score (mGPS), and prognostic nutritional index (PNI) were systematically included to comprehensively analyze their potential in predicting neoadjuvant immunotherapy efficacy and prognosis. We enrolled 189 patients (94 in training and 95 in validation cohorts) with stage I-III B surgically resectable NSCLC treated with neoadjuvant immunotherapy from the National Cancer Center of China. Baseline and post-treatment eosinophils fraction, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), monocyte-to-lymphocyte ratio (MLR), PNI, mGPS, and their changes were calculated and analyzed for correlation with neoadjuvant immunotherapy efficacy and prognosis. In patients in the major pathological response (MPR) group, the post-treatment eosinophil fraction was significantly high, and NLR, PLR, SII, and MLR were significantly lower compared to the non-MPR group in both the training and validation cohorts. The receiver operating characteristic curve showed that post-treatment, eosinophil fraction and SII and their changing were two of the most important factors. Univariate and multivariate logistic regression analyses showed that post-treatment eosinophil fraction, SII, mGPS, and ΔSII could independently predict MPR in patients treated with neoadjuvant immunotherapy. Survival analysis showed a significant correlation between high post-treatment NLR, PLR, SII, mGPS, and their changes in ΔNLR and ΔSII elevation with poor overall survival and event-free survival of patients. Our results suggest that inflammatory biomarkers could predict the patient's response to neoadjuvant immunotherapy and prognosis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia Neoadjuvante , Estudos Retrospectivos , Prognóstico , Biomarcadores , Linfócitos , Neutrófilos/patologia , Inflamação/patologia , ImunoterapiaRESUMO
Mammalian oocytes are arrested at G2/prophase of the first meiosis. After a hormone surge, oocytes resume meiosis, undergoing germinal vesicle breakdown (GVBD). This process is regulated by Cdk1/cyclin B1. Here, we report that Mis12 is required for G2/M transition by regulating cyclin B1 accumulation via Cdc14B-mediated APC/CCdh1 regulation, but is not essential for spindle and chromosome dynamics during meiotic maturation. Depletion of Mis12 severely compromised GVBD by impairing cyclin B1 accumulation. Importantly, impaired GVBD after Mis12 depletion was rescued not only by overexpressing cyclin B1 but also by depleting Cdc14B or Cdh1. Notably, oocytes rescued by cyclin B1 overexpression exhibited normal spindle and chromosome organization with intact kinetochore-microtubule attachments. In addition, after being rescued by cyclin B1 overexpression, Mis12-depleted oocytes normally extruded polar bodies. Moreover, Mis12-depleted oocytes formed pronuclear structures after fertilization but failed to develop beyond zygotes. Interestingly, Mis12 was localized in the cytoplasm and spindle poles in oocytes, in contrast to kinetochore localization in somatic cells. Therefore, our results demonstrate that Mis12 is required for meiotic G2/M transition but is dispensable for meiotic progression through meiosis I and II.
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Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Ciclina B1/metabolismo , Fosfatases de Especificidade Dupla/metabolismo , Fase G2 , Meiose , Proteínas Associadas aos Microtúbulos/metabolismo , Oócitos/metabolismo , Animais , Feminino , Cinetocoros/metabolismo , Camundongos , Modelos Biológicos , Membrana Nuclear/metabolismo , Estabilidade Proteica , Fuso Acromático/metabolismo , Polos do Fuso/metabolismoRESUMO
BACKGROUND: A Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Sixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m2 IV, day 1/8) and cisplatin (75 mg/m2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety. RESULTS: A total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1-84.0% vs. 42.4-78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1-60.9% vs. 13.5-47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature. CONCLUSIONS: The neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates. TRIAL REGISTRATION: Registration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma. REGISTRATION NUMBER: NCT04460066.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Cisplatino , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Inibidores de Checkpoint Imunológico , Terapia NeoadjuvanteRESUMO
BACKGROUND: The most common form of treatment for non-metastatic lung cancer is surgery-based combination therapy, which may also include adjuvant radiotherapy or chemotherapy. Second primary malignancies (SPMs) are uncommon but significant radiation side effects in patients with resectable lung cancer, and SPMs have not been adequately investigated. Our study aims to assess the correlations of radiotherapy with the development of SPMs in patients with resectable lung cancer. METHODS: We screened for any primary malignancy that occurred more than five years after the diagnosis of resectable lung cancer. Based on the large cohort of the Surveillance, Epidemiology and End Results database, radiotherapy-correlated risks were estimated using the Poisson regression analysis and the cumulative incidence of SPMs was calculated using Fine-Gray competing risk regression analysis. RESULTS: Among the 62,435 patients with non-metastatic lung cancer undergoing surgery, a total of 11,341 (18.16%) patients have received radiotherapy. Our findings indicated that radiotherapy was substantially related to a high risk of main second solid malignancies (RR = 1.21; 95%CI, 1.08 to 1.35) and a negligible risk of main second hematologic malignancies (RR = 1.08; 95%CI, 0.84 to 1.37). With the greatest number of patients, the risk of acquiring a second primary gastrointestinal cancer was the highest overall (RR = 1.77; 95 percent CI, 1.44 to 2.15). The cumulative incidence and standardized incidence ratios of SPMs revealed similar findings. Furthermore, the young and the elderly may be more vulnerable, and the highest risk of acquiring most SPMs was seen more than ten years after lung cancer diagnosis. Additionally, more attention should be paid to the second primary gastrointestinal cancer in young individuals with resectable lung cancer. CONCLUSION: After receiving radiotherapy, an increased risk of developing second primary solid and gastrointestinal cancers was observed for patients with resectable lung cancer. The prevention of SPMs associated with radiotherapy requires further attention.
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Neoplasias Pulmonares , Segunda Neoplasia Primária , Humanos , Idoso , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Medição de Risco , Incidência , Terapia Combinada , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/radioterapia , Fatores de Risco , Programa de SEERRESUMO
Pulmonary sarcomatoid carcinoma (PSC) is a unique form of poorly differentiated nonsmall cell lung cancer (NSCLC) and is notorious for its highly malignant nature and dismal prognosis. To introduce effective treatment for PSC patients, precise subtyping of PSC is demanding. In our study, TTF-1 and P40 immunohistochemistry (IHC) staining were applied to 56 PSC patients with multiomics data. According to IHC results, we categorized these patients into three subgroups and profiled their molecular contexture using bioinformatic skills. IHC results classified these patients into three subgroups: TTF-1 positive subgroup (n = 27), P40 positive subgroup (n = 15) and double-negative subgroup (n = 14). Spindle cell samples accounted for 35.71% (5/14) of double-negative patients, higher than others (P = .034). The three subgroups were heterogeneous in the genomic alteration spectrum, showing significant differences in the RTK/RAS pathway (P = .004) and the cell cycle pathway (P = .030). The methylation profile of the double-negative subgroup was between the other two subgroups. In similarity analysis, the TTF-1 and p40 subgroups were closely related to LUAD and LUSC, respectively. The TTF-1 positive subgroup had the highest leukocyte fraction (LF) among several cancer types, and the tumor mutation burden (TMB) of the p40 positive subgroup ranked third in the TMB list, suggesting the applicability of immunotherapy for PSC. The study established a new subtyping method of PSC based on IHC results and reveals three subgroups with distinct molecular features, providing evidence for refined stratification in the treatment of PSC.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma , Neoplasias Pulmonares , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologiaRESUMO
Mammalian oocytes remain arrested at the first prophase of meiosis in ovarian follicles for an extended period. During this protracted arrest, oocytes are remarkably susceptible to the accumulation of DNA damage. Melatonin (N-acetyl-5-methoxytryptamine), a hormone secreted by the pineal gland, has diverse effects on various physiological processes. However, the effect of melatonin on DNA damage response in mammalian oocytes has not been explored. Here, we showed that melatonin protected mouse oocytes from DNA damage induced by double-strand breaks (DSBs) during prophase arrest and subsequently improved oocyte quality. We found that DNA damage during prophase arrest impaired subsequent meiotic maturation and deteriorated oocyte quality, increasing chromosome fragmentation, spindle abnormality, mitochondrial aggregation, and oxidative stress. However, melatonin treatment during DNA damage accumulation at prophase improved meiotic maturation and relieved the quality decline of oocytes. In addition, melatonin inhibited the accumulation of DNA damage during prophase arrest by reducing the γ-H2AX levels. Although activated ATM levels were decreased by melatonin treatment, the effect of melatonin on DNA damage response was not a direct consequence of ATM inhibition. Instead, melatonin enhanced DNA repair via nonhomologous end-joining (NHEJ) pathway. Interestingly, these actions of melatonin on DNA damage response are receptor-independent in mouse oocytes. Therefore, our results demonstrated that melatonin protects oocytes from DNA damage during prophase arrest by enhancing DNA repair via NHEJ and subsequently prevents the deterioration of oocyte quality during meiotic maturation.
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Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Melatonina/farmacologia , Oócitos/metabolismo , Animais , Feminino , Camundongos , Camundongos Endogâmicos ICR , Oócitos/patologiaRESUMO
Somatic cell nuclear transfer (SCNT) is an important technique for life science research. However, most SCNT embryos fail to develop to term due to undefined reprogramming defects. Here, we show that abnormal Xi occurs in somatic cell NT blastocysts, whereas in female blastocysts derived from cumulus cell nuclear transfer, both X chromosomes were inactive. H3K27me3 removal by Kdm6a mRNA overexpression could significantly improve preimplantation development of NT embryos, and even reached a 70.2% blastocyst rate of cleaved embryos compared with the 38.5% rate of the control. H3K27me3 levels were significantly reduced in blastomeres from cloned blastocysts after overexpression of Kdm6a. qPCR indicated that rDNA transcription increased in both NT embryos and 293T cells after overexpression of Kdm6a. Our findings demonstrate that overexpression of Kdm6a improved the development of cloned mouse embryos by reducing H3K27me3 and increasing rDNA transcription.
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Blastocisto/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Histona Desmetilases/genética , Lisina/metabolismo , Técnicas de Transferência Nuclear , Animais , Clonagem de Organismos/métodos , Células do Cúmulo/citologia , DNA Ribossômico/genética , Feminino , Células HEK293 , Histona Desmetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Camundongos Endogâmicos , Inativação do Cromossomo XRESUMO
Mouse parthenogenetic embryonic stem cells (PgESCs) could be applied to study imprinting genes and are used in cell therapy. Our previous study found that stem cells established by aggregation of two parthenogenetic embryos at 8-cell stage (named as a2 PgESCs) had a higher efficiency than that of PgESCs, and the paternal expressed imprinting genes were observably upregulated. Therefore, we propose that increasing the number of parthenogenetic embryos in aggregation may improve the development of parthenogenetic mouse and imprinting gene expression of PgESCs. To verify this hypothesis, we aggregated four embryos together at the 4-cell stage and cultured to the blastocyst stage (named as 4aPgB). qPCR detection showed that the expression of imprinting genes Igf2, Mest, Snrpn, Igf2r, H19, Gtl2 in 4aPgB were more similar to that of fertilized blastocyst (named as fB) compared to 2aPgB (derived from two 4-cell stage parthenogenetic embryos aggregation) or PgB (single parthenogenetic blastocyst). Post-implantation development of 4aPgB extended to 11 days of gestation. The establishment efficiency of GFP-a4 PgESCs which derived from GFP-4aPgB is 62.5%. Moreover, expression of imprinting genes Igf2, Mest, Snrpn, notably downregulated and approached the level of that in fertilized embryonic stem cells (fESCs). In addition, we acquired a 13.5-day fetus totally derived from GFP-a4 PgESCs with germline contribution by 8-cell under zona pellucida (ZP) injection. In conclusion, four embryos aggregation improves parthenogenetic development, and compensates imprinting genes expression in PgESCs. It implied that a4 PgESCs could serve as a better scientific model applied in translational medicine and imprinting gene study.
Assuntos
Blastômeros/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Impressão Genômica/genética , Células-Tronco Embrionárias Murinas/metabolismo , Partenogênese/genética , Animais , Blastocisto/citologia , Blastocisto/metabolismo , Blastômeros/citologia , Agregação Celular/genética , Diferenciação Celular/genética , Desenvolvimento Embrionário/genética , Feminino , Imunofluorescência , Camundongos , Camundongos Transgênicos , Células-Tronco Embrionárias Murinas/citologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de TempoRESUMO
BACKGROUND: Neoadjuvant immunotherapy has evolved as an effective option to treat non-small cell lung cancer (NSCLC). B cells play essential roles in the immune system as well as cancer progression. However, the repertoire of B cells and its association with clinical outcomes remains unclear in NSCLC patients receiving neoadjuvant immunotherapy. METHODS: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data for LUAD samples were accessed from the TCGA and GEO databases. LUAD-related B cell marker genes were confirmed based on comprehensive analysis of scRNA-seq data. We then constructed the B cell marker gene signature (BCMGS) and validated it. In addition, we evaluated the association of BCGMS with tumor immune microenvironment (TIME) characteristics. Furthermore, we validated the efficacy of BCGMS in a cohort of NSCLC patients receiving neoadjuvant immunotherapy. RESULTS: A BCMGS was constructed based on the TCGA cohort and further validated in three independent GSE cohorts. In addition, the BCMGS was proven to be significantly associated with TIME characteristics. Moreover, a relatively higher risk score indicated poor clinical outcomes and a worse immune response among NSCLC patients receiving neoadjuvant immunotherapy. CONCLUSIONS: We constructed an 18-gene prognostic signature derived from B cell marker genes based on scRNA-seq data, which had the potential to predict the prognosis and immune response of NSCLC patients receiving neoadjuvant immunotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Terapia Neoadjuvante , Análise de Sequência de RNA , Análise de Célula Única , Microambiente Tumoral , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Prognóstico , Imunoterapia/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Feminino , Masculino , Biomarcadores Tumorais/genética , Linfócitos B/imunologia , Pessoa de Meia-Idade , IdosoRESUMO
BACKGROUND: In China, real-world data on surgical challenges and postoperative complications after neoadjuvant immunotherapy of lung cancer are limited. METHODS: Patients were retrospectively enrolled from January 2018 to January 2023, and their clinical and pathological characters were subsequently analyzed. Surgical difficulty was categorized into a binary classification according to surgical duration: challenging or routine. Postoperative complications were graded using Clavien-Dindo grades. Logistic regression was used to identify risk factors affecting the duration of surgery and postoperative complications greater than Clavien-Dindo grade 2. RESULTS: In total, 261 patients were included. Of these, stage III patients accounted for 62.5% (163/261) at initial diagnosis, with 25.3% (66/261) at stage IIIB. Central-type non-small-cell lung cancer accounted for 61.7% (161/261). One hundred and forty patients underwent video-assisted thoracoscopic surgery and lobectomy accounted for 53.3% (139/261) of patients. Surgical time over average duration was defined as challenging surgeries, accounting for 43.7%. The postoperative complications rate of 261 patients was only 22.2%. Smoking history (odds ratio [OR] = 9.96, 95% [CI] 1.15-86.01, p = 0.03), chemoimmunotherapy (OR = 2.89, 95% CI 1.22-6.86, p = 0.02), and conversion to open surgery (OR = 11.3, 95% CI 1.38-92.9, p = 0.02) were identified as independent risk factors for challenging surgeries, while pneumonectomy (OR = 0.36, 95% CI 0.15-0.86, p= 0.02) was a protective factor. Meanwhile, pneumonectomy (OR = 7.51, 95% CI 2.40-23.51, p < 0.01) and challenging surgeries (OR = 5.53, 95% CI 1.50-20.62, p = 0.01) were found to be risk factors for postoperative complications greater than Clavien-Dindo grade 2. CONCLUSIONS: Compared to immunotherapy alone or in combination with apatinib, neoadjuvant chemoimmunotherapy could increase the difficulty of surgery while the incidence of postoperative complications remained acceptable. The conversion to open surgery and pneumonectomy after neoadjuvant immunotherapy should be reduced.
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Imunoterapia , Neoplasias Pulmonares , Terapia Neoadjuvante , Complicações Pós-Operatórias , Humanos , Masculino , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Feminino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Imunoterapia/métodos , Imunoterapia/efeitos adversos , Estudos Retrospectivos , Idoso , Pneumonectomia/efeitos adversos , Pneumonectomia/métodos , AdultoRESUMO
BACKGROUND: Radiomics is increasingly utilized to distinguish pulmonary nodules between lung adenocarcinoma (LUAD) and tuberculosis (TB). However, it remains unclear whether different segmentation criteria, such as the inclusion or exclusion of the cavity region within nodules, affect the results. METHODS: A total of 525 patients from two medical centers were retrospectively enrolled. The radiomics features were extracted according to two regions of interest (ROI) segmentation criteria. Multiple logistic regression models were trained to predict the pathology: (1) The clinical model relied on clinical-radiological semantic features; (2) The radiomics models (radiomics+ and radiomics-) utilized radiomics features from different ROIs (including or excluding cavities); (3) the composite models (composite+ and composite-) incorporated both above. RESULTS: In the testing set, the radiomics+/- models and the composite+/- models still possessed efficient prediction performance (AUC ≥ 0.94), while the AUC of the clinical model was 0.881. In the validation set, the AUC of the clinical model was only 0.717, while that of the radiomics+/- models and the composite+/- models ranged from 0.801 to 0.825. The prediction performance of all the radiomics+/- and composite+/- models were significantly superior to that of the clinical model (p < 0.05). Whether the ROI segmentation included or excluded the cavity had no significant effect on these models (radiomics+ vs. radiomics-, composite+ model vs. composite-) (p > 0.05). CONCLUSIONS: The present study established a machine learning-based radiomics strategy for differentiating LUAD from TB lesions. The ROI segmentation including or excluding the cavity region may exert no significant effect on the predictive ability.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Tuberculose , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Radiômica , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/patologia , Aprendizado de MáquinaRESUMO
INTRODUCTION: The number of patients with synchronous multiple primary lung cancer (sMPLC) has increased recently. However, diagnosing and selecting the appropriate therapeutic strategy for this type of disease is not simple. CASE PRESENTATION: This report presented a case of sMPLC with lymph node metastasis. With no smoking and cancer history, this patient had seven nodules in the right lung and underwent single-portal video-assisted thoracoscopic surgery (VATS). In addition, she received four cycles of chemotherapy after the operation. Whole exon sequencing (WES) was performed in five resected tissue samples (four tumors and one lymph node). We conducted genomic profiling and clone evolution analysis of the five samples. Gene detection helped to confirm that the metastasis lymph node was transferred from one nodule. There was apparent heterogeneity of gene mutations among the five samples of the patient, with only one shared "neurofilament heavy polypeptide" (NEFH) mutation. A dominant substitution of C > T/G > A was found in all the samples. Pyclone model was used to calculate all tissues' cellular prevalence (CP) values, and NEFH mutations were thought to be the ancestral clones. During the follow-up period, residual lesions showed no apparent changes and limited response to chemotherapy. CONCLUSIONS: This report showed an essential role in genomic detection and selecting the appropriate treatment of sMPLC. Surgery remains the primary treatment strategy for this type of disease, and the occurrence and development of sMPLC need more in-depth research.
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Neoplasias Pulmonares , Neoplasias Primárias Múltiplas , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Excisão de Linfonodo , Éxons/genética , Neoplasias Primárias Múltiplas/cirurgiaRESUMO
INTRODUCTION: Oesophageal cancer is a prevalent and deadly cancer around the world. OBJECTIVES: We aimed to present a comprehensive analysis of the global geographic patterns and temporal trends in the mortality and incidence of oesophageal cancer. METHODS: The mortality and incidence data of oesophageal cancer in 2020 were obtained from the GLOBOCAN database. Based on World Health Organization (WHO) mortality database and the Cancer Incidence in Five Continents (CI5), we also retrieved the mortality and incidence age-standardized rates (ASRs) of oesophageal cancer. The average annual percentage changes (AAPCs) of mortality and incidence were calculated using the joinpoint regression analysis. RESULTS: Globally, 0.54 million deaths and 0.6 million new cases were identified in 2020. In the majority of countries of South America and Asia, the mortality and incidence trends have substantially decreased, but trends in European countries have varied. The prevalence in European nations varied, but the incidence in most other continents decreased dramatically. In terms of mortality, the global average rate was 5.6 per 100000, ranging from 16.7 (Malawi) to 0.28 (Belize). European countries varied in mortality, such as Norway (AAPC, male: 0.68; female: 0.89) and Ireland (AAPC, male: -0.96; female: -1.52). Most non-European countries saw large decreases in mortality, such as Singapore (AAPC, male: -4.78; female: -6.89). The elderly had more noticeable trends in mortality and incidence in most countries. CONCLUSIONS: We have identified different trends in mortality and incidence among European countries, whereas declining trends were identified in most non-European countries. However, increasing trends were identified in specific subgroups of some countries, such as men in Thailand. For populations with rising mortality and incidence trends, more preventative efforts are required.
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Neoplasias Esofágicas , Saúde Global , Humanos , Masculino , Feminino , Idoso , Incidência , Organização Mundial da Saúde , Neoplasias Esofágicas/epidemiologia , TailândiaRESUMO
In recent decades, multiple primary lung cancer (MPLC) has been increasingly prevalent in clinical practice. However, many details about MPLC have not been completely settled, such as understanding the driving force, clinical management, pathological mechanisms, and genomic architectures of this disease. From the perspective of diagnosis and treatment, distinguishing MPLC from lung cancer intrapulmonary metastasis (IPM) has been a clinical hotpot for years. Besides, compared to patients with single lung lesion, the treatment for MPLC patients is more individualized, and non-operative therapies, such as ablation and stereotactic ablative radiotherapy (SABR), are prevailing. The emergence of next-generation sequencing has fueled a wave of research about the molecular features of MPLC and advanced the NCCN guidelines. In this review, we generalized the latest updates on MPLC from definition, etiology and epidemiology, clinical management, and genomic updates. We summarized the different perspectives and aimed to offer novel insights into the management of MPLC.
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PURPOSE: The aim of present study was to investigate the efficiency of 18F-FDG uptake in predicting major pathological response (MPR) in resectable non-small cell lung cancer (NSCLC) patients with neoadjuvant immunotherapy. METHODS: A total of 104 patients with stage I-IIIB NSCLC were retrospectively derived from National Cancer Center of China, of which 36 cases received immune checkpoint inhibitors (ICIs) monotherapy (I-M) and 68 cases with ICI combination therapy (I-C). 18F-FDG PET-CT scans were performed at baseline and after neoadjuvant therapy (NAT). Receiver-operating characteristic (ROC) curve analyses were conducted and area under ROC curve (AUC) was calculated for biomarkers including maximum standardized uptake value (SUVmax), inflammatory biomarkers, tumor mutation burden (TMB), PD-L1 tumor proportion score (TPS) and iRECIST. RESULTS: Fifty-four resected NSCLC tumors achieved MPR (51.9%, 54/104). In both neoadjuvant I-M and I-C cohorts, post-NAT SUVmax and the percentage changes of SUVmax (ΔSUVmax%) were significantly lower in the patients with MPR versus non-MPR (p < 0.01), and were also negatively correlated with the degree of pathological regression (p < 0.01). The AUC of ΔSUVmax% for predicting MPR was respectively 1.00 (95% CI: 1.00-1.00) in neoadjuvant I-M cohort and 0.94 (95% CI: 0.86-1.00) in I-C cohort. Baseline SUVmax had a statistical prediction value for MPR only in I-M cohort, with an AUC up to 0.76 at the threshold of 17.0. ΔSUVmax% showed an obvious advantage in MPR prediction over inflammatory biomarkers, TMB, PD-L1 TPS and iRECIST. CONCLUSION: 18F-FDG uptake can predict MPR in NSCLC patients with neoadjuvant immunotherapy.
RESUMO
Multiple primary lung cancer (MPLC) with lymph node metastasis (LNM) is a rare phenomenon of multifocal lung cancer. The genomic landscapes of MPLC and the clonal evolution pattern between primary lung lesions and lymph node metastasis haven't been fully illustrated. We performed whole-exome sequencing (WES) on 52 FFPE (Formalin-fixed Paraffin-Embedded) samples from 11 patients diagnosed with MPLC with LNM. Genomic profiling and phylogenetic analysis were conducted to infer the evolutional trajectory within each patient. The top 5 most frequently mutated genes in our study were TTN (76.74%), MUC16 (62.79%), MUC19 (55.81%), FRG1 (46.51%), and NBPF20 (46.51%). For most patients in our study, a substantial of genetic alterations were mutually exclusive among the multiple pulmonary tumors of the same patient, suggesting their heterogenous origins. Individually, the genetic profile of lymph node metastatic lesions overlapped with that of multiple lung cancers in different degrees but are more genetically related to specific pulmonary lesions. SETD2 was a potential metastasis biomarker of MPLC. The mean putative neo-antigen number of the primary tumor (646.5) is higher than that of lymph node metastases (300, p = 0.2416). Primary lung tumors and lymph node metastases are highly heterogenous in immune repertoires. Our findings portrayed the comprehensive genomic landscape of MPLC with LNM. We characterized the genomic heterogeneity among different tumors. We offered novel clues to the clonal evolution between MPLC and their lymphatic metastases, thus advancing the treatment strategies and preventions of MPLC with LNM.
Assuntos
Neoplasias Pulmonares , Neoplasias Primárias Múltiplas , Humanos , Metástase Linfática/genética , Filogenia , Neoplasias Pulmonares/genética , Evolução Clonal/genéticaRESUMO
Multimodal epigenetic characterization of cell-free DNA (cfDNA) could improve the performance of blood-based early cancer detection. However, integrative profiling of cfDNA methylome and fragmentome has been technologically challenging. Here, we adapt an enzyme-mediated methylation sequencing method for comprehensive analysis of genome-wide cfDNA methylation, fragmentation, and copy number alteration (CNA) characteristics for enhanced cancer detection. We apply this method to plasma samples of 497 healthy controls and 780 patients of seven cancer types and develop an ensemble classifier by incorporating methylation, fragmentation, and CNA features. In the test cohort, our approach achieves an area under the curve value of 0.966 for overall cancer detection. Detection sensitivity for early-stage patients achieves 73% at 99% specificity. Finally, we demonstrate the feasibility to accurately localize the origin of cancer signals with combined methylation and fragmentation profiling of tissue-specific accessible chromatin regions. Overall, this proof-of-concept study provides a technical platform to utilize multimodal cfDNA features for improved cancer detection.
Assuntos
Ácidos Nucleicos Livres , Neoplasias , Humanos , Ácidos Nucleicos Livres/genética , Epigenoma , Neoplasias/diagnóstico , Neoplasias/genética , Epigenômica/métodos , Metilação de DNA/genética , Biomarcadores Tumorais/genéticaRESUMO
Maintaining genome integrity in germ cells is essential not only for successful fertilization and embryo development, but also to ensure proper transmission of genetic information across generations. However, unlike oocytes, sperm are incapable of repairing DNA damage. Therefore, sperm DNA damage is repaired after fertilization in zygotes using maternal DNA repair factors. In this study, we found that zygotic repair of paternal DNA damage is enhanced by inhibiting WIP1 activity. Oxidative stress induced DNA damage in sperm and severely impaired motility. Although DNA damage in sperm did not compromise fertilization, it increased DNA damage in the paternal pronucleus of zygotes. However, WIP1 inhibition during fertilization reduced DNA damage in the paternal pronucleus, improving the rate of two-cell development, and subsequent zygotic genome activation. Therefore, our results suggest that WIP1 inhibition could enhance maternal DNA repair capacity and thereby decrease paternal DNA damage in zygotes.
RESUMO
OBJECTIVE: The use of limited anatomic resection for early-stage lung cancer is widely practiced worldwide. However, most studies have focused on standard segmentectomy or subsegmentectomy, and data on the short-term outcomes after anatomic sublobar resection in China are lacking. METHODS: In 2014, the use of anatomic partial lobectomy (APL), which is defined as lesion-centered resection of anatomical sublobular parts, was proposed by the National Cancer Center in China. We retrospectively evaluated all consecutive patients who underwent APL between November 2013 and October 2019 from our database, and the operative techniques and short-term outcomes were analyzed. RESULTS: A total of 3336 patients with a median age of 56 years underwent APL during the study period. Benign lesions were present in 8.5% of all patients and decreased across time. The mean total operation time was 127.3 minutes, the mean overall number of nodal sampling/dissections was 13, and the mean number of stations sampled was 4. Postoperative complications (grade ≥2) developed in 359 patients (10.8%), and no mortality occurred in the 30 days after surgery. Multivariate analysis showed that smoking, surgeon's early experience, thoracotomy or unplanned conversion to thoracotomy, and complex cases were risk factors for the occurrence of postoperative complications. CONCLUSIONS: Despite the increasing proportion of complex cases treated with APL, the incidence of postoperative complications decreased as our center accumulated surgical experience. APL procedures are safe and feasible when conducted in a specialized center.