Prediction of programmed death-1 expression status in non-small cell lung cancer based on intratumoural and peritumoral computed tomography (CT) radiomics nomogram.

AIMS: This study aimed to predict the expression of programmed death-1 (PD-1) in non-small cell lung cancer (NSCLC) using intratumoral and peritumoral computed tomography (CT) radiomics nomogram. MATERIALS AND METHODS: Two hundred patients pathologically diagnosed with NSCLC from two hospitals were retrospectively analyzed. Of these, 159 NSCLC patients from our hospital were randomly divided into a training cohort (n=96) and an internal validation cohort (n=63) at a ratio of 6:4, while 41 NSCLC patients from another medical institution served as the external validation cohort. The radiomic features of the gross tumor volume (GTV) and peritumoral volume (PTV) were extracted from the CT images. Optimal radiomics features were selected using least absolute shrinkage and selection operator regression analysis. Finally, a CT radiomics nomogram of clinically independent predictors combined with the best rad-score was constructed. RESULTS: Compared with the 'GTV' and 'PTV' radiomics models, the combined 'GTV + PTV' radiomics model showed better predictive performance, and its area under the curve (AUC) values in the training, internal validation, and external validation cohorts were 0.90 (95% confidence interval [CI]: 0.83-0.97), 0.85 (95% CI: 0.74-0.96) and 0.78 (95% CI: 0.63-0.92). The nomogram constructed by the rad-score of the 'GTV + PTV' radiomics model combined with clinical independent predictors (prealbumin and monocyte) had the best performance, with AUC values in each cohort being 0.92 (95% CI: 0.85-0.98), 0.88 (95% CI: 0.78-0.97), and 0.80 (95% CI: 0.66-0.94), respectively. CONCLUSION: The intratumoral and peritumoral CT radiomics nomogram may facilitate individualized prediction of PD-1 expression status in patients with NSCLC.

Radiomics nomogram integrating intratumoural and peritumoural features to predict lymph node metastasis and prognosis in clinical stage IA non-small cell lung cancer: a two-centre study.

AIM: To investigate the value of a radiomics nomogram integrating intratumoural and peritumoural features in predicting lymph node metastasis and overall survival (OS) in patients with clinical stage IA non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: This study retrospectively enrolled 199 patients (training cohort: 71 patients from Affiliated Tumour Hospital of Nantong University; internal validation cohort: 46 patients from Affiliated Tumour Hospital of Nantong University; external validation cohort: 82 patients from the public database). CT radiomics models were constructed based on four volumes of interest: gross tumour volume (GTV), gross and 3 mm peritumoural volume (GPTV3), gross and 6 mm peritumoural volume (GPTV6), and gross and 9 mm peritumoural volume (GPTV9). The optimal radiomics signature was further combined with independent clinical predictors to develop a nomogram. Univariable and multivariable Cox regression analysis were applied to determine the relationship between factors and OS. RESULTS: GPTV6 radiomics yielded better performance than GTV, GPTV3, and, GPTV9 radiomics in the training (area under the curve [AUC], 0.81), internal validation (AUC, 0.79), and external validation cohorts (AUC, 0.71), respectively. The nomogram integrating GPTV6 radiomics and spiculation improved predictive ability, with AUCs of 0.85, 0.80, and 0.74 in three cohorts, respectively. Pathological lymph node metastasis, nomogram-predicted lymph node metastasis, and pleural indentation were independent risk predictors of OS (p<0.05). CONCLUSIONS: The nomogram integrating GPTV6 radiomics features and independent clinical predictors performed well in predicting lymph node metastasis and prognosis in patients with clinical stage IA NSCLC.

[Clinical value of a differentiation prediction model for invasive lung adenocarcinoma].

Objective: To investigate the value of predicting the degree of differentiation of pulmonary invasive adenocarcinoma (IAC) based on CT image radiomics model and the expression difference of immunohistochemical factors between different degrees of differentiation of lesions. Methods: The clinicopathological data of patients with pulmonary IAC confirmed by surgical pathology in the Affiliated Huai'an First People's Hospital to Nanjing Medical University from December 2017 to September 2018 were collected. High-throughput feature acquisition was performed for all outlined regions of interest, and prediction models were constructed after dimensionality reduction by the minimum absolute shrinkage operator. Receiver operating characteristic curve was used to assess the predictive efficacy of clinical characteristic model, radiomics model and individualized prediction model combined with both to identify the degree of pulmonary IAC differentiation, and immunohistochemical expressions of Ki-67, NapsinA and TTF-1 were compared between groups with different degrees of IAC differentiation using rank sum test. Results: A total of 396 high-throughput features were extracted from all IAC lesions, and 10 features with high generalization ability and correlation with the degree of IAC differentiation were screened. The mean radiomics score of poorly differentiated IAC in the training group (1.206) was higher than that of patients with high and medium differentiation (0.969, P=0.001), and the mean radiomics score of poorly differentiated IAC in the test group (1.545) was higher than that of patients with high and medium differentiation (-0.815, P<0.001). The differences in gender (P<0.001), pleural stretch sign (P=0.005), and burr sign (P=0.033) were statistically significant between patients in the well and poorly differentiated IAC groups. Multifactorial logistic regression analysis showed that gender and pleural stretch sign were related to the degree of IAC differentiation (P<0.05). The clinical feature model consisted of age, gender, pleural stretch sign, burr sign, tumor vessel sign, and vacuolar sign, and the individualized prediction model consisted of gender, pleural stretch sign, and radiomic score, and was represented by a nomogram. The Akaike information standard values of the radiomics model, clinical feature model and individualized prediction model were 54.756, 82.214 and 53.282, respectively. The individualized prediction model was most effective in identifying the degree of differentiation of pulmonary IAC, and the area under the curves (AUC) of the individualized prediction model in the training group and the test group were 0.92 (95% CI: 0.86-0.99) and 0.88 (95% CI: 0.74-1.00, respectively). The AUCs of the radiomics group model for predicting the degree of differentiation of pulmonary IAC in the training group and the test group were 0.91 (95% CI: 0.83-0.98) and 0.87 (95% CI: 0.72-1.00), respectively. The AUCs of the clinical characteristics model for predicting the degree of differentiation of pulmonary IACs in the training and test groups were 0.75 (95% CI: 0.63-0.86) and 0.76 (95% CI: 0.59-0.94), respectively. The expression level of Ki-67 in poorly differentiated IAC was higher than that in well-differentiated IAC (P<0.001). The expression levels of NapsinA, TTF-1 in poorly differentiated IAC were higher than those in well-differentiated IAC (P<0.05). Conclusions: Individualized prediction model consisted of gender, pleural stretch sign and radiomics score can discriminate the differentiation degree of IAC with the best performance in comparison with clinical feature model and radiomics model. Ki-67, NapsinA and TTF-1 express differently in different degrees of differentiation of IAC.

A radiomics-based model to differentiate glioblastoma from solitary brain metastases.

AIM: To differentiate glioblastoma (GBM) from solitary brain metastases (MET) using radiomic analysis. MATERIALS AND METHODS: Two hundred and fifty-three patients with solitary brain tumours (157 GBM and 98 solitary brain MET) were split into a training cohort (n=178) and a validation cohort (n=77) by stratified sampling using computer-generated random numbers at a ratio of 7:3. After feature extraction, minimum redundancy maximum relevance (mRMR) and the least absolute shrinkage and selection operator (LASSO) were used to build the radiomics signature on the training cohort and validation cohort. Performance was assessed by radiomics score (Rad-score), receiver operating characteristic (ROC) curve, calibration, and clinical usefulness. RESULTS: Eleven radiomic features were selected as significant features in the training cohort. The Rad-score was significantly associated with the differentiation between GBM and solitary brain MET (p<0.001) both in the training and validation cohorts. The radiomics signature yielded area under the curve (AUC) values of 0.82 and 0.81 in the training and validation cohorts to distinguish between GBM and solitary brain MET. CONCLUSIONS: The radiomics model might be a useful supporting tool for the preoperative differentiation of GBM from solitary brain MET, which could aid pretreatment decision-making.

[Role of Bruton's tyrosine kinase in endotoxin/lipopolysaccharide-induced pyroptosis of intestinal cells in scalded mice].

Objective: To investigate the role of Bruton's tyrosine kinase (BTK) in pyroptosis of intestinal cells caused by endotoxin/lipopolysaccharide (LPS) in scalded mice. Methods: The experimental research method was applied. One hundred and twenty-eight male C57BL/6 mice aged 6-8 weeks were divided into sham injury group, scald alone group, scald+LPS group, scald+LPS+3 mg/kg LFM-A13 group, scald+LPS+10 mg/kg LFM-A13 group, and scald+LPS+30 mg/kg LFM-A13 group. There were 8 mice in sham injury group, and there were 24 mice in the other 5 groups, respectively. Mice in 5 scald groups were inflicted with 10% total body surface area full-thickness scald on the back, and mice in sham injury group were sham injured on the back. At post injury hour (PIH) 0 (immediately), mice in sham injury group and scald alone group were intraperitoneally injected with normal saline, mice in scald+LPS group were intraperitoneally injected with LPS, and mice in scald+LPS+3 mg/kg LFM-A13 group, scald+LPS+10 mg/kg LFM-A13 group, and scald+LPS+30 mg/kg LFM-A13 group were intraperitoneally injected with LPS and LFM-A13 in corresponding doses. Mice in sham injury group were sacrificed at PIH 0 to collect serum and intestinal tissue, and 8 mice in each group of 5 scald groups were sacrificed at PIH 0, 12, and 24 to collect intestinal tissue and serum at PIH 12. Immunohistochemistry was used to detect phosphorylation of BTK in intestinal tissue of mice. Western blotting was used to detect the protein expressions of phosphorylated BTK (p-BTK), cleaved cysteine aspartic acid specific protease 1 (caspase-1), and cleaved caspase-11 in intestinal tissue of mice. Enzyme-linked immunosorbent assay method was used to detect interleukin-1ß (IL-1ß) in serum and intestinal tissue of mice. Data were statistically analyzed with one-way analysis of variance and least significant difference test. Results: There was no obvious phosphorylation of BTK in intestinal tissue of mice in 6 groups at PIH 0 and scald alone group at PIH 12 and 24. Phosphorylation of BTK in intestinal tissue of mice in scald+LPS group at PIH 12 and 24 were obviously increased compared with those in scald alone group. Phosphorylation of BTK in intestinal tissue of mice in scald+LPS+3 mg/kg LFM-A13 group, scald+LPS+10 mg/kg LFM-A13 group, and scald+LPS+30 mg/kg LFM-A13 group were obviously decreased compared with those in scald+LPS group, and the degrees of decline gradually increased with increase of dose in LFM-A13. Compared with (0.130±0.010) of sham injury group and (0.120±0.040 and 0.110±0.040) of scald alone group, protein expressions of p-BTK in intestinal tissue of mice in scald+LPS group at PIH 12 and 24 were obviously increased (0.470±0.090 and 0.430±0.080, P<0.01). Compared with those in scald+LPS group, protein expressions of p-BTK in intestinal tissue of mice in scald+LPS+3 mg/kg LFM-A13 group at PIH 24, and scald+LPS+10 mg/kg LFM-A13 group and scald+LPS+30 mg/kg LFM-A13 group at PIH 12 and 24 were obviously decreased (0.280±0.060, 0.300±0.120, 0.150±0.050, 0.280±0.090, 0.140±0.040, P<0.05 or P<0.01). Compared with those in scald+LPS+3 mg/kg LFM-A13 group, protein expressions of p-BTK in intestinal tissue of mice in scald+LPS+10 mg/kg LFM-A13 group and scald+LPS+30 mg/kg LFM-A13 group at PIH 24 were obviously decreased (P<0.01). Compared with those in sham injury group and scald alone group, protein expressions of cleaved caspase-1 and caspase-11 in intestinal tissue of mice in scald+LPS group were obviously increased at PIH 12 and 24 (P<0.01). Compared with those in scald+LPS group, protein expressions of cleaved caspase-1 at PIH 12 and cleaved caspase-11 at PIH 12 and 24 in intestinal tissue of mice in scald+LPS+3 mg/kg LFM-A13 group and protein expressions of cleaved caspase-1 and caspase-11 in intestinal tissue of mice in scald+LPS+10 mg/kg LFM-A13 group and scald+LPS+30 mg/kg LFM-A13 group at PIH 12 and 24 were obviously decreased (P<0.01). Compared with those in scald+LPS+3 mg/kg LFM-A13 group, protein expressions of cleaved caspase-1 and caspase-11 in intestinal tissue of mice in scald+LPS+10 mg/kg LFM-A13 group and scald+LPS+30 mg/kg LFM-A13 group at PIH 12 and 24 were obviously decreased (P<0.05 or P<0.01). At PIH 12, content of IL-1ß in intestinal tissue and serum of mice in scald+LPS group were obviously higher than those in sham injury group and scald alone group (P<0.01), and content of IL-1ß in intestinal tissue and serum of mice in scald+LPS+30 mg/kg LFM-A13 group were obviously lower than those in scald+LPS group (P<0.01). Conclusions: Phosphorylation of BTK is related to increases of cleaved caspase-1 and caspase-11 in intestinal tissue, and IL-1ß content in intestinal tissue and serum of scalded septic mice caused by LPS. Phosphorylation of BTK mediates intestinal cell pyroptosis of scalded mice caused by LPS. Inhibiting phosphorylation of BTK can alleviate intestinal cell pyroptosis of scalded mice, with protective effect on intestinal injury intestine.

Ultrastructural investigation of changes of pulmonary surfactant system in experimental emphysema produced by intratracheal elastase instillation.

In this study the dynamic changes of the pulmonary surfactant system in guinea pigs were observed by scanning electron microscopy, transmission electron microscopy and special electron stain for surfactant. The results showed that in the early stage of instillation of elastase, the pulmonary surfactant decreased. After one week, it increased gradually. Type II epithelial cells proliferated and their secretion increased. By the 25th day, the pulmonary surfactant system tended to return to normal, indicating that the changes of the pulmonary surfactant system may have some effect during the developing process of emphysema.

Effects of exercise on pulmonary gas exchange and oxygen transport in chronic obstructive pulmonary diseases.

The effect of exercise on pulmonary gas exchange, arterial oxygenation, oxygen transport and delivery, and hemodynamics are studied in 100 patients with chronic obstructive pulmonary diseases. According to the change of PaO2 or PaCO2 induced by exercise, patients were divided into two groups. Group A (n = 52) had significantly increased of PaO2 with little change in PaCO2. Mixed venous PO2, oxygen transport and coefficient of oxygen delivery decreased while the alveolar-arterial PO2 gradients and venous admixture increased significantly in Group B as compared with these parameters in Group A during exercise. Our data imply that exercise may lead to marked deterioration of pulmonary gas exchange, arterial oxygenation, oxygen transport and hemodynamic abnormalities in patients in whom PaO2 is decreased during exercise.

[Effect of ligustrazine controlled release capsule on hemorrheology in patients with cor pulmonale].

Before and after oral administration of Ligustrazine controlled release capsule, changes of hemorrheology and TXA2/PGI2 were evaluated in 16 patients with advanced cor pulmonale. It was shown that the effects of decreasing whole blood and plasma viscosity and lowering hematocrit and fibrinogen level were noted after one course of treatment with this medication. It is suggests that anticoagulant, effect of Ligustrazine is probably related to its role of improving inbalance between TXA2 and PGI2 in patients with cor pulmonale.

[Evaluation of the immediate effect of ligustrazine in chronic cor pulmonale].

Twenty patients with chronic cor pulmonale were studied to assess the immediate effect of Ligustrazini on hemodynamic and right cardiac function. After intravenous administration of Ligustrazini at rest, there was statistically significant decrease in pulmonary arterial pressure, pulmonary vascular resistance and heart rate, increase in cardiac output and improvement in right cardiac function. Maximal effect was observed half an hour after treatment. But the effect disappeared after discontinuing the treatment of Ligustrazini for one hour. It is suggested that the effect of Ligustrazini appears early but does not last long.

[Role of the renin-angiotensin-aldosterone system in the pathogenesis of edema formation in chronic obstructive pulmonary disease].

The pathogenesis of edema in COPD patients is poorly understood. In 50 COPD patients without cor pulmonale, we measured water sodium and potassium excretion in 24 hours, concentration of sodium and potassium in plasma as well as PRA, ATII and aldosterone levels. We found that PRA, ATII, and aldosterone levels in COPD patients with edema are much higher than those in patients without edema and sodium and water excretion decreased significantly in edematous COPD patients. Elevation of PRA, ATII, and aldosterone correlated with inability to excrete sodium and water. These data suggest that, in conjunction with hypercapnia-hypoxia-mediated disturbance in renal function, stimulation of RAAS, especially the resulting increase of aldosterone may contribute to edema formation in COPD patients.

[Changes of thromboxane A2 (TXA2) and prostacyclin (PGI2) in COPD patients with pulmonary hypertension].

We measured the pulmonary arterial pressure and the level of Thromboxane A2 (TXA2), and Prostacyclin (PGI2) in 30 stable COPD patients and the level of TXA2 and PGI2 in 10 normal subjects so as to investigate the changes of TXA2 and PGI2 in COPD patients with pulmonary hypertension. The results showed that the level of TXA2 increased significantly in COPD patients with dominant and latent pulmonary hypertension when compared with that in normal subjects (P less than 0.001, less than 0.01), and the level of TXA2 in COPD patients with dominant pulmonary hypertension was also higher than that in COPD patients with latent pulmonary hypertension (P less than 0.02), but there was no difference in the level of PGI2 among normal subjects and COPD patients with or without pulmonary hypertension. This indicates that TXA2 plays an important role in causing pulmonary hypertension in COPD patients.

[Pulmonary artery compliance and its relation with pulmonary hemodynamics in patients with chronic obstructive pulmonary disease].

In order to investigate pulmonary artery compliance (Cpa) and its relation with the clinical conditions and the other parameters of pulmonary hemodynamics in patients with chronic obstructive pulmonary disease (COPD), we performed right heart Swan-Ganz catheterization in 146 COPD patients and measured their Cpa with Engelberg's method. The results showed that Cpa of BB type patients was lower than that of PP type ones; patients with pulmonary hypertension or cor pulmonale had lower Cpa than those without. These results suggest that Cpa in COPD patients decreases as their clinical condition worsens. Cpa had close relation with other pulmonary hemodynamic parameters. It had significant negative correlation with pulmonary arterial mean pressure, pulmonary vascular resistance and right ventricular stroke work index and significant positive correlation with cardiac index and stroke volume index. Using Engelberg's method as the standard, we also compared Reuben's, Wang's and Zhong's methods which are all simpler than Engelberg's method for measuring Cpa clinically. The results showed that Cpa measured with Wang's method was the closest to that measured with Engelberg's method.

[Investigation of the relation of impedance rheopneumogram with pulmonary hemodynamics and right ventricular function in patients with chronic obstructive pulmonary disease].

In order to investigate the relation of impedance rheopneumogram with pulmonary hemodynamics and right ventricular function in patients with chronic obstructive pulmonary disease (COPD), we measured impedance rheopneumogram and did right heart catheterization in 150 COPD patients simultaneously both at rest and after exercise. The results showed that impedance rheopneumogram was mainly influenced by right ventricular after-load, while the influences of right ventricular pre-load, right ventricular contraction, right ventricular stroke work index and cardiac output were rather small, suggesting that in COPD patients impedance rheopneumogram is valuable in predicting pulmonary arterial pressure noninvasively, but not so use in judging the right ventricular function.

[Renin-angiotensin-aldosterone system and pulmonary hemodynamics in patients with pulmonary artery hypertension].

To investigate the relationship between renin-angiotensin-aldosterone system and pulmonary hemodynamic parameters in patients with chronic pulmonary artery hypertension, we measured plasma levels of renin activity, angiotensin II and aldosterone in 11 patients during right heart catheterization. All patients had chronic obstructive pulmonary disease. At rest, plasma concentration of angiotensin II positively correlated with mean pulmonary artery pressure (r = 0.76, P less than 0.01) and pulmonary vascular resistance (r = 0.64, P less than 0.05). During exercise, plasma level of angiotensin II increased from 70 +/- 21 to 81 +/- 24 pg/ml (P less than 0.01) and plasma renin activity from 0.66 +/- 0.54 to 1.28 +/- 1.2 ng/ml/h (P less than 0.05), whereas mean pulmonary artery pressure increased from 3.73 +/- 0.85 to 6.27 +/- 1.81 kPa (28 +/- 6.4 to 47 +/- 13.6 mmHg). Increase of angiotensin II correlated with changes in mean pulmonary artery pressure (r = 0.69, P less than 0.05) but not with systemic artery pressure. The results of present study suggest that angiotensin II might play a role in the development of pulmonary artery hypertension in patients with chronic obstructive pulmonary disease.

[The effects of persantine on pulmonary arterial pressure of rats exposed to hypoxia].

In the chronic hypoxic model of pulmonary hypertension, the increased wall thickness can be attributed in part to proliferation of endothelial cells, medial smooth muscle cell, and adventitial fibroblasts. The cellular mechanisms responsible for this proliferative response to chronic hypoxia may be due to the action of specific growth factors released in areas of vascular injury. Some growth factors such as platelet-derived growth factor and epidermal growth factor, released from activated platelets at sites of tissue injury and thrombus formation, may play a crucial role in this proliferative process. This paper reported the effects of persantine (dipyridamole), an inhibitor of platelet function, on pulmonary arterial pressure of rats exposed to hypoxia for 2 weeks. The results showed that persantine could prevent elevation of pulmonary arterial pressure and increase of right ventricle weight of hypoxic rats.

[Effect of shen mai injection and its combinations on blood gas and hemodynamics of rats exposed to chronic hypoxia].

Shen Mai Injection (SMI) consisted of Panax ginseng and Ophiopogon japonica might promote the myocardial and diaphragmatic muscle contraction. The effect of SMI and its combinations were examined on the blood gas and hemodynamics of rats exposed to chronic hypoxia. SMI reduced significantly the pulmonary vascular resistance (PVR, P < 0.001), systemic vascular resistance (SVR, P < 0.001) and increased cardiac output (CO, P < 0.001), which effect was superior to the Dobutamine. If SMI was combined with Ligustrazine etc, better effect on blood gas and hemodynamics appeared than that of combined with other drugs. These combined group also presented more selective on pulmonary circulation. The results suggested that SMI and its combined with Ligustrazine could relieve the pulmonary hypertension and diaphragmatic fatigue.

Effects of ligustrazine controlled release capsule in chronic pulmonary heart disease.

Before and after oral administration of ligustrazine controlled release capsule, pulmonary hemodynamics, right cardiac function, arterial blood gas and TXB2/6-keto-PGF1 alpha were studied in 16 patients with advanced cor pulmonale. The decrease of pulmonary arterial pressure and pulmonary vascular resistance, increase of cardiac output, improvement of right cardiac function and arterial blood gas were demonstrated after one course of treatment. The mechanism of these effects may be related to improvement of imbalance of TXB2/6-keto-PGF1 alpha. These results were in agreement with those of intravenous administration of ligustrazine, but no adverse reactions were found.

The acute effects of ligustrazini on hemodynamics and right cardiac function in pulmonary arterial hypertension secondary to chronic obstructive pulmonary disease.

We studied 20 patients with pulmonary arterial hypertension secondary to chronic obstructive pulmonary disease (COPD) to investigate the acute effect of Ligustrazini on hemodynamics and right cardiac function. The results suggested that Ligustrazini had the effects of dilating pulmonary vessel, decreasing mean pulmonary arterial pressure and pulmonary vascular resistance, increasing cardiac output, and improving right cardiac function. The maximum effects of Ligustrazini occurred at 30 min after starting administration of the drug, but its effects disappeared 1 h after its withdrawal. From the above we are led to conclude that Ligustrazini as a vasodilator works rapidly, but its effects do not persist long.