Corrigendum: Convolutional neural network-based diagnostic model for a solid, indeterminate solitary pulmonary nodule or mass on computed tomography.

[This corrects the article DOI: 10.3389/fonc.2021.792062.].

Impact of genetic status on the survival outcomes of patients with clinical stage I non-small cell lung cancer with a radiological pure-solid appearance.

PURPOSE: To investigate whether genetic status is associated with the prognosis of patients with clinical stage (c-stage) I non-small cell lung cancer (NSCLC) with radiological pure-solid manifestations. MATERIALS AND METHODS: We included 340 patients with pure-solid c-stage I NSCLC and evaluated their clinicopathological and genetic information. Disease recurrence and death were also observed at the end of the 5-year follow-up period. A Cox proportional hazards model was performed to identify the effect of clinicopathological variables, including genetic status, on oncological outcomes. Recurrence-free survival (RFS) and overall survival (OS) were calculated by Kaplan-Meier curves and were compared using log-rank tests. RESULTS: The gene-mutation rate of c-stage I NSCLC with a radiological pure-solid appearance was 55.9% (190/340), and the frequencies of EGFR, KRAS, ALK, ROS1 and fused genes were 69.5% (132/190), 16.8% (32/190), 8.9% (17/190), 1.6% (3/190) and 3.2% (6/190), respectively. The 5-year RFS and OS rates of eligible patients were 57.1% and 76.5%, respectively. A multivariable analysis revealed that genetic status was an independent significant prognostic factor associated with RFS (hazard ratio [HR] = 1.416, 95% confidence interval [CI]: 1.020-1.964, p = 0.038) but not with OS. RFS was lower in the genetic mutation group compared with the wild-type group (p = 0.027), with 5-year RFS rate (65.7 vs. 51.6%), but the difference in OS (mutated group vs. wild-type group: 78.0% vs. 75.3%) was not statistically significant (p = 0.602). Additionally, we found that pathological nodal involvement (HR = 2.455, 95% CI: 1.745-3.454, p < 0.001 for RFS; HR = 2.204, 95% CI: 1.409-3.447, p = 0.001 for OS) was also a valuable prognostic factor in patients with pure-solid c-stage I NSCLC. CONCLUSION: Our study provides a comprehensive description of the mutational landscape of c-stage I NSCLC, and indicates that genetic status has an impact on disease recurrence in patients with c-stage I NSCLC with pure-solid appearance.

A clinicopathological study of lung adenocarcinomas with pure ground-glass opacity > 3 cm on high-resolution computed tomography.

OBJECTIVES: This study aimed to discuss whether a diameter of 3 cm is a threshold for diagnosing lung adenocarcinomas presenting with radiological pure ground-glass mass (PGGM, pure ground-glass opacity > 3 cm) as adenocarcinomas in situ or minimally invasive adenocarcinomas (AIS-MIAs). Another aim was to identify CT features and patient prognosis that differentiate AIS-MIAs from invasive adenocarcinomas (IACs) in patients with PGGMs. METHODS: From June 2007 to October 2015, 69 resected PGGMs with HRCT and followed up for ≥ 5 years were included in this study and divided into AIS-MIA (n = 13) and IAC (n = 56) groups. Firth's logistic regression model was performed to determine CT characteristics that helped distinguish IACs from AIS-MIAs. The discriminatory power of the significant predictors was tested with the area under the receiver operating characteristics curve (AUC). Disease recurrence was also evaluated. RESULTS: Univariable and multivariable analyses identified that the mean CT attenuation (odds ratio: 1.054, p = 0.0087) was the sole significant predictor for preoperatively discriminating IACs from AIS-MIAs in patients with PGGMs. The CT attenuation had an excellent differentiating accuracy (AUC: 0.981), with the optimal cut-off value at -600 HU (sensitivity: 87.5%; specificity: 100%). Additionally, no recurrence was observed in patients manifesting with PGGMs > 3 cm, and the 5-year recurrence-free survival and overall survival rates were both 100%, even in cases of IAC. CONCLUSIONS: This study demonstrated that PGGMs > 3 cm could still be AIS-MIAs. When PGGMs are encountered in clinical practice, the CT value may be the only valuable parameter to preoperatively distinguish IACs from AIS-MIAs. KEY POINTS: • Patients with pure ground-glass opacity > 3 cm in diameter are rare but can be diagnosed as adenocarcinomas in situ or minimally invasive adenocarcinomas. • The mean CT attenuation is the sole significant CT parameter that differentiates invasive adenocarcinoma from adenocarcinoma in situ or minimally invasive adenocarcinoma in patients with pure ground-glass opacity > 3 cm. • Lung adenocarcinoma with pure ground-glass opacity > 3 cm has an excellent prognosis, even in cases of invasive adenocarcinoma.

Development and Validation of a Radiomics Nomogram for Differentiating Pulmonary Cryptococcosis and Lung Adenocarcinoma in Solitary Pulmonary Solid Nodule.

OBJECTIVE: To establish a CT-based radiomics nomogram model for classifying pulmonary cryptococcosis (PC) and lung adenocarcinoma (LAC) in patients with a solitary pulmonary solid nodule (SPSN) and assess its differentiation ability. MATERIALS AND METHODS: A total of 213 patients with PC and 213 cases of LAC (matched based on age and gender) were recruited into this retrospective research with their clinical characteristics and radiological features. High-dimensional radiomics features were acquired from each mask delineated by radiologists manually. We adopted the max-relevance and min-redundancy (mRMR) approach to filter the redundant features and retained the relevant features at first. Then, we used the least absolute shrinkage and operator (LASSO) algorithms as an analysis tool to calculate the coefficients of features and remove the low-weight features. After multivariable logistic regression analysis, a radiomics nomogram model was constructed with clinical characteristics, radiological signs, and radiomics score. We calculated the performance assessment parameters, such as sensitivity, specificity, accuracy, negative predictive value (NPV), and positive predictive value (PPV), in various models. The receiver operating characteristic (ROC) curve analysis and the decision curve analysis (DCA) were drawn to visualize the diagnostic ability and the clinical benefit. RESULTS: We extracted 1,130 radiomics features from each CT image. The 24 most significant radiomics features in distinguishing PC and LAC were retained, and the radiomics signature was constructed through a three-step feature selection process. Three factors-maximum diameter, lobulation, and pleural retraction-were still statistically significant in multivariate analysis and incorporated into a combined model with radiomics signature to develop the predictive nomogram, which showed excellent classification ability. The area under curve (AUC) yielded 0.91 (sensitivity, 80%; specificity, 83%; accuracy, 82%; NPV, 80%; PPV, 83%) and 0.89 (sensitivity, 81%; specificity, 83%; accuracy, 82%; NPV, 81%; PPV, 82%) in training and test cohorts, respectively. The net reclassification indexes (NRIs) were greater than zero (p < 0.05). The Delong test showed a significant difference (p < 0.0001) between the AUCs from the clinical model and the nomogram. CONCLUSIONS: The radiomics technology can preoperatively differentiate PC and lung adenocarcinoma. The nomogram-integrated CT findings and radiomics feature can provide more clinical benefits in solitary pulmonary solid nodule diagnosis.

MicroRNA-21-containing microvesicles from tubular epithelial cells promote cardiomyocyte hypertrophy.

BACKGROUND: Cardiomyocyte hypertrophy has been reported as one of the important mechanisms for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). MiroRNA-21(miR-21) was determined to play an important role in myocardial hypertrophy. However, the role of microvesicles (MVs) containing miR-21 in CKD-related cardiomyocyte hypertrophy remains largely unexplored. METHODS: Renal tubular epithelial cells were stimulated by transforming growth factor (TGF-ß1), and the conditioned medium was extracted by differential centrifugation. Renal tubular epithelial cells were labeled with Dil-C18 dye and the recipient cardiomyocytes were observed by fluorescence microscope. MiR-21 level in MVs was detected by qRT-PCR, and the length and diameter of cardiomyocytes were measured by microscope. BCA protein kit and ANP kit were used to detect the content of cell protein and the level of ANP. MiR-21 inhibitor was transfected into cardiomyocytes to observe the effect of miR-21 on myocardial hypertrophy. RESULTS: TGF-ß1 could induce donor renal tubular epithelial cells to produce MVs and delivered into cardiomyocytes, followed by the diameter, protein concentration and ANP content of cardiomyocytes significantly increased. Meanwhile, MiR-21 levels were markedly increased in MVs isolated from donor renal tubular epithelial cells and recipient cardiomyocytes. Pre-transfection of miR-21 inhibitors could inhibit MV-induced cardiomyocyte hypertrophy. CONCLUSION: Tubular cells could secrete miR-21 by MVs and deliver it into recipient cardiomyocytes to induce cardiomyocyte hypertrophy. It might shed a new light on the mechanism and treatment of CKD-related cardiac dysfunction.

Convolutional Neural Network-Based Diagnostic Model for a Solid, Indeterminate Solitary Pulmonary Nodule or Mass on Computed Tomography.

PURPOSE: To establish a non-invasive diagnostic model based on convolutional neural networks (CNNs) to distinguish benign from malignant lesions manifesting as a solid, indeterminate solitary pulmonary nodule (SPN) or mass (SPM) on computed tomography (CT). METHOD: A total of 459 patients with solid indeterminate SPNs/SPMs on CT were ultimately included in this retrospective study and assigned to the train (n=366), validation (n=46), and test (n=47) sets. Histopathologic analysis was available for each patient. An end-to-end CNN model was proposed to predict the natural history of solid indeterminate SPN/SPMs on CT. Receiver operating characteristic curves were plotted to evaluate the predictive performance of the proposed CNN model. The accuracy, sensitivity, and specificity of diagnoses by radiologists alone were compared with those of diagnoses by radiologists by using the CNN model to assess its clinical utility. RESULTS: For the CNN model, the AUC was 91% (95% confidence interval [CI]: 0.83-0.99) in the test set. The diagnostic accuracy of radiologists with the CNN model was significantly higher than that without the model (89 vs. 66%, P<0.01; 87 vs. 61%, P<0.01; 85 vs. 66%, P=0.03, in the train, validation, and test sets, respectively). In addition, while there was a slight increase in sensitivity, the specificity improved significantly by an average of 42% (the corresponding improvements in the three sets ranged from 43, 33, and 42% to 82, 78, and 84%, respectively; P<0.01 for all). CONCLUSION: The CNN model could be a valuable tool in non-invasively differentiating benign from malignant lesions manifesting as solid, indeterminate SPNs/SPMs on CT.

Myosin regulatory light chain phosphorylation is associated with leiomyosarcoma development.

Leiomyosarcoma is a rare malignant smooth muscle tumor which can be very unpredictable. Myosin II is involved in many functions, including cell contraction, migration, and adhesion. The phosphorylation of myosin regulatory light chain (MLC) by myosin light chain kinase (MLCK) determines the activity of Myosin II. However, it is still unclear whether MLC phosphorylation is involved in cell proliferation in leiomyosarcoma. In this study, we aimed to explore the role of MLCK-dependent MLC phosphorylation in leiomyosarcoma development. We found that the expression of MLCK, phosphorylated MLC, and Ki67 in leiomyosarcoma was significantly higher than in leiomyoma and adjacent normal smooth muscle cells. MLCK expression was significantly correlated with phosphorylated MLC level. Kaplan-Meier survival analysis revealed that patients with high expression of MLCK or phosphorylated MLC had shorter overall survival times compared with the patients with low expression of MLCK or phosphorylated MLC. In vitro studies revealed a causative link between MLC phosphorylation and cellular proliferation as expression of phosphomimetic MLC (T19D, S20D) increased cellular proliferation as assessed by Ki67 staining. In contrast, MLCK specific inhibitor reduced cellular proliferation. We concluded that MLCK, phosphorylated MLC and Ki67 were overexpressed in leiomyosarcoma. MLCK dependent MLC phosphorylation might be responsible for the high proliferative state in leiomyosarcoma. MLCK and phosphorylated MLC are potential prognostic indicators of leiomyosarcoma.

Elevated expression of CRYAB predicts unfavorable prognosis in non-small cell lung cancer.

Alpha B-crystallin (CRYAB) is one of the principal members of the small heat-shock protein family, and several studies described the CRYAB expression in human cancers. However, the association between CRYAB expression and the clinical features of non-small cell lung cancer (NSCLC) is rarely elucidated. In this present study, one-step quantitative reverse transcription-polymerase chain reaction with 12 fresh-frozen NSCLC samples and Western blotting as well as immunohistochemistry (IHC) analyses in 101 NSCLC cases were conducted to investigate the relationship between CRYAB expression and the clinicopathological attributes of NSCLC. The results showed that CRYAB mRNA and protein expression levels were significantly higher in NSCLC than in matched non-cancerous tissues (p < 0.05). The IHC data indicated that the CRYAB protein expression in NSCLC was significantly correlated with TNM stage (p = 0.043), and overall survival (p = 0.029). Kaplan-Meier method and Cox multifactor analysis suggested that higher CRYAB protein level (p = 0.032) and TNM stage (p = 0.048) were statistically associated with the poor survival of patients with NSCLC. The data suggested that CRYAB may be identified as a novel prognostic marker and targeting CRYAB may provide a promising strategy for NSCLC treatment.

Rab27b is a potential predictor for metastasis and prognosis in colorectal cancer.

Objective. Rab27b is reported to correlate with cancer development and progression. However, the association between Rab27b expression and the clinical characteristics of colorectal cancer (CRC) is barely investigated. Methods. One-step quantitative reverse transcription-polymerase chain reaction (qPCR) test with 18 fresh-frozen CRC samples and immunohistochemistry (IHC) analysis in 113 CRC cases were performed to explore the relationship between Rab27b expression and the clinicopathological features of CRC. Cox regression and Kaplan-Meier survival analyses were executed to evaluate the prognosis of CRC. Results. The results demonstrated that the expression levels of Rab27b mRNA and protein were significantly higher in CRC tissues than that in matched noncancerous tissues (P < 0.05). Rab27b protein expression in CRC was statistically correlated with serum CEA level (P = 0.004), lymph node metastasis (P = 0.001), distant metastasis (P = 0.009), and TNM stage (P = 0.001). Cox multifactor analysis and Kaplan-Meier method suggested that higher Rab27b protein expression (P = 0.041) and tumor differentiation (P = 0.001) were significantly associated with the overall survival of CRC patients. Conclusions. The data indicated that higher expression of Rab27b was observed in CRC tissues and Rab27b may be identified as a useful predictor of metastasis and prognosis for CRC.