In lung adenocarcinoma (LUAD), the appearance of morphologically diverse tumor regions, termed histological patterns, is closely associated with disease progression and lymph node metastasis. ...However, the molecular characteristics of the histological patterns in LUAD and the underlying molecular evolutionary mechanisms between the histological patterns in primary tumors and lymph node metastases are poorly understood. Here, we re‐analyzed the large TCGA‐LUAD dataset and depicted a comprehensive profiling of the genome and transcriptome across the histological patterns in LUAD. Tumor phylogenetic trajectory analysis suggested that the complex glands is more apt to metastasize to the lymph node. Further deconvolution of the tumor microenvironment demonstrated that the complex glands had a higher infiltration of cancer‐associated fibroblasts (CAFs). Single‐cell transcriptome profiling of complex glands pattern identified a novel CAF subtype co‐expressing fibroblast activation protein‐alpha (FAP) and stimulator of interferon genes (STING). Moreover, our data demonstrated that FAP is an important downstream effector of STING in CAFs. In summary, our results provide the basis for the development of innovative therapeutic guidelines and intervention strategies for LUAD patients.
Combining TCGA‐LUAD and our own validation data, we systematically revealed the heterogeneity of genomic alterations profiles and tumor microenvironment across the histological patterns in lung adenocarcinoma. We found the most aggressive complex glands were enriched cancer‐associated fibroblasts exhibiting a higher possibility of lymph node metastasis.
To construct a preoperative nomogram to differentiate invasive pulmonary adenocarcinomas (IPAs) from preinvasive lesions in patients with solitary pure ground-glass nodules (GGN).
A primary cohort of ...patients with pathologically confirmed pulmonary solitary pure GGN after surgery were retrospectively studied at five institutions from January 2009 to September 2015. Half of the patients were randomly selected and assigned to a model-development cohort, and the remaining patients were assigned to a validation cohort. A nomogram predicting the invasive extent of the solitary GGNs was constructed based on the independent risk factors. Predictive performance was evaluated by concordance index (C-index) and calibration curve.
Out of 898 cases included in the study, 501 (55.8%) were preinvasive lesions and 397 (44.2%) were IPAs. In the univariate analysis, lesion size (p < 0.001), lesion margin (p = 0.041), lesion shape (p < 0.001), mean computed tomography (CT) value (p = 0.018), presence of pleural indentation (p = 0.017), and smoking status (p = 0.014) were significantly associated with invasive extent. In multivariate analysis, lesion size (p < 0.001), lesion margin (p = 0.042), lesion shape (p < 0.001), mean CT value (p = 0.014), presence of pleural indentation (p = 0.026), and smoking status (p = 0.004) remained the predictive factors of invasive extent. A nomogram was developed and validation results showed a C-index of 0.94, demonstrating excellent concordance between predicted and observed results.
We established and validated a novel nomogram that can identify IPAs from preinvasive lesions in patients with solitary pure GGN.
Recently, various tissue engineering based strategies have been pursued for the regeneration of tracheal tissues. However, previously developed tracheal scaffolds do not accurately mimic the ...microstructure and mechanical behavior of the native trachea, which restrict their clinical translation. Here, tracheal scaffolds are fabricated by using 3D printing and short nanofibers (SF) dispersion of poly(l‐lactide)/gelatin (0.5–1.5 wt%) to afford tracheal constructs. The results display that the scaffolds containing 1.0 wt % of SF exhibit low density, good water absorption capacity, reasonable degradation rate, and stable mechanical properties, which were comparable to the native trachea. Moreover, the designed scaffolds possess good biocompatibility and promote the growth and infiltration of chondrocytes in vitro. The biocompatibility of tracheal scaffolds is further assessed after subcutaneous implantation in mice for up to 4 and 8 weeks. Histological assessment of tracheal constructs explanted at week 4 shows that scaffolds can maintain their structural integrity and support the formation of neo‐vessels. Furthermore, cell‐scaffold constructs gradually form cartilage‐like tissues, which mature with time. Collectively, these engineered tracheal scaffolds not only possess appropriate mechanical properties to afford a stabilized structure but also a biomimetic extracellular matrix‐like structure to accomplish tissue regeneration, which may have broad implications for tracheal regeneration.
Here, tracheal scaffolds are successfully manufactured based on 3D printing and electrospinning. These engineered tracheal scaffolds not only possess appropriate mechanical properties to afford a stabilized structure but also a biomimetic extracellular matrix‐like structure to accomplish tissue regeneration, which may have broad implications for tracheal regeneration applications.
Objectives: We prospectively investigate the accuracy of frozen sections for diagnosing visceral pleural invasion (VPI) by autofluorescence and evaluated its usefulness in sublobar resection. ...Methods: We included patients with lung adenocarcinoma 2 cm or less to evaluate the diagnostic performance of autofluorescence for VPI in frozen sections via a fluorescence microscope. Furthermore, the impact of VPI on patients treated with sublobar resection was assessed in another cohort. Results: A total of 112 patients were enrolled. The accuracy, sensitivity, and specificity of autofluorescence for VPI diagnosis was 95.5%, 86.8%, and 100%, respectively. Sublobar resection was an independent risk factor for recurrence in patients with lung adenocarcinomas 2 cm or less with VPI positivity (hazardratio, 3.30; P = .023), whereas it was not in those with VPI negativity. Conclusions: Using autofluorescence in frozen sections appears to be an accurate method for diagnosing VPI, which is helpful for surgical decision making. Key Words: Autofluorescence; Visceral pleural invasion; Frozen section
Our study aimed to evaluate the prognostic significance and adjuvant chemotherapy (ACT) benefits of a micropapillary/solid (MS) pattern in patients with stage IB lung adenocarcinoma.
Patients with ...pathologically-confirmed stage IB adenocarcinoma who underwent surgical resection between January 2009 and December 2011 were included. The tumors were reclassified into three categories: MS patterns absent (MS-); non-predominant MS patterns (MS+); predominant MS (MS++). The correlations of prognosis and ACT with recurrence-free survival (RFS) were evaluated.
Overall, 497 (MS-, n=269; MS+, n=177; MS++, n=51) patients were enrolled in the study. In univariate analysis, the MS+ hazard ratio (HR), 1.437; 95% confidence interval (CI), 1.030-2.006; P=0.033 and MS++ (HR, 2.818; 95% CI, 1.792-4.432; P<0.001) groups had significantly poor prognosis compared with MS- group. Multivariate analysis revealed that age ≥65 (HR, 1.504; 95% CI, 1.077-2.099; P=0.017), serum level of carcinoembryonic antigen (CEA) ≥10 ng/mL (HR, 1.658; 95% CI, 1.048-2.623; P=0.031) and MS++ (HR, 2.529; 95% CI, 1.550-4.126; P<0.001) were significant prognostic factors. Furthermore, subgroup analysis showed that MS++ patients but not MS- and MS+ derived RFS (recurrence-free survival) benefit from ACT (HR, 0.357; 95% CI, 0.152-0.836; P=0.018).
MS pattern successfully differentiated the prognosis difference among stage IB lung adenocarcinomas and identified patients who benefitted from ACT.
Patients in the ground-glass opacity (GGO)-dominant subgroup had a better prognosis than those in solid-dominant subgroup. Multivariate analysis confirmed that consolidation diameter to tumor ...diameter ratio was an independent risk factor of recurrence. In the analysis of solid-dominant subgroups, limited resection was an independent risk factor of recurrence. As to the GGO-dominant subgroup, surgical type was not a risk factor of recurrence in these patients.
In this study we aimed to identify the risk factors of recurrence in patients with clinical stage IA adenocarcinoma presented as ground glass nodule (GGN) on computed tomography scans.
The study included 245 patients with clinical stage IA adenocarcinoma presented as GGN who underwent surgery during 2010 to 2013. All patients were divided into 2 subgroups on the basis of consolidation diameter to tumor diameter (C/T) ratio on lung window: (1) ground-glass opacity (GGO)-dominant subgroup (C/T ≤ 0.5; n = 179); (2) solid-dominant subgroup (C/T > 0.5; n = 66). Recurrence-free survival (RFS) was analyzed to identify independent risk factors of recurrence using the Kaplan–Meier approach and multivariable Cox models.
Patients in the GGO-dominant subgroup had a better prognosis than those in the solid-dominant subgroup (5-year RFS: 98% vs. 87%; P < .001). Multivariate analysis confirmed that C/T ratio was an independent risk factor for RFS in patients with clinical stage IA adenocarcinoma presented as GGN (hazard ratio HR, 9.47; 95% confidence interval CI, 1.75-51.1; P = .009). In the analysis of the solid-dominant group, multivariate analysis showed that limited resection was an independent risk factor of recurrence in this subgroup (HR, 6.86; 95% CI, 1.50-31.42; P = .013). Regarding the GGO-dominant subgroup, surgical type was not a risk factor of recurrence.
Patients with clinical stage IA solid-dominant adenocarcinoma (C/T ratio > 0.5) had a higher rate of recurrence after limited resection than lobectomy. Thus, limited resection should be performed cautiously in these patients (C/T ratio > 0.5).
Background
This study aimed to investigate the significance of lymph node micrometastasis (LNMM) in the lung cancer nodal categories.
Methods
Between 1 January 2009 and 31 December 2013, 589 patients ...with suspected c-stage 1 and p-T1-2aN0-1M0 lung adenocarcinoma were enrolled in this study. The study evaluated LNMM with cytokeratin (AE1/AE3) and transcription factor-1 (TTF1) (8G7G3/1) expression by immunohistochemistry. Recurrence-free survival (RFS) and overall survival (OS) were compared among the T1-2aN0-1M0 patients stratified by the new N categories.
Results
From 589 patients, 7892 removed lymph nodes were examined, and LNMM was observed in 55 (9.3%) of the patients. The patients without LNMM or N1 had the best RFS (5-year rate: 80% vs 25%;
P
< 0.001) and OS (5-year rate: 87% vs 43%;
P
< 0.001), followed by the patients with LNMM, compared with those in the N1 category (RFS: 5-year rate, 25% vs 8%;
P
= 0.010; OS: 5-year rate, 43% vs 20%;
P
= 0.009). Similarly, this trend was observed when patients were subdivided into the T1 and T2a categories. Multivariate analysis showed that the new N categories with the addition of LNMM were an independent prognostic factor. This result also was noticed in all subgroups.
Conclusions
The findings showed LNMM to be clinically significant as a risk factor for lung cancer. Clinicians should consider LNMM when estimating N categories to determine prognosis and the best treatment strategy.
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.
Non‐small cell lung cancer (NSCLC) remains a leading cause of cancer‐related mortality. This study presents a highly effective and non‐invasive blood test for detection of early‐stage NSCLC. Notably, the 5hmC‐based model excelled at identifying individuals with high‐risk pulmonary nodules and lung cancer of different subtypes, underscoring novel epigenetic biomarkers as a promising diagnostic tool for lung cancer.
Abstract
Objectives
We prospectively investigate the accuracy of frozen sections for diagnosing visceral pleural invasion (VPI) by autofluorescence and evaluated its usefulness in sublobar resection.
...Methods
We included patients with lung adenocarcinoma 2 cm or less to evaluate the diagnostic performance of autofluorescence for VPI in frozen sections via a fluorescence microscope. Furthermore, the impact of VPI on patients treated with sublobar resection was assessed in another cohort.
Results
A total of 112 patients were enrolled. The accuracy, sensitivity, and specificity of autofluorescence for VPI diagnosis was 95.5%, 86.8%, and 100%, respectively. Sublobar resection was an independent risk factor for recurrence in patients with lung adenocarcinomas 2 cm or less with VPI positivity (hazard ratio, 3.30; P = .023), whereas it was not in those with VPI negativity.
Conclusions
Using autofluorescence in frozen sections appears to be an accurate method for diagnosing VPI, which is helpful for surgical decision making.
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