Does dual-layer spectral detector CT provide added value in predicting spread through air spaces in lung adenocarcinoma? A preliminary study.

OBJECTIVES: To examine the predictive value of dual-layer spectral detector CT (DLCT) for spread through air spaces (STAS) in clinical lung adenocarcinoma. METHODS: A total of 225 lung adenocarcinoma cases were retrospectively reviewed for demographic, clinical, pathological, traditional CT, and spectral parameters. Multivariable logistic regression analysis was carried out based on three logistic models, including a model using traditional CT features (traditional model), a model using spectral parameters (spectral model), and an integrated model combining traditional CT and spectral parameters (integrated model). Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) were performed to assess these models. RESULTS: Univariable analysis showed significant differences between the STAS and non-STAS groups in traditional CT features, including nodule density (p < 0.001), pleural indentation types (p = 0.006), air-bronchogram sign (p = 0.031), the presence of spiculation (p < 0.001), long-axis diameter of the entire nodule (LD) (p < 0.001), and consolidation/tumor ratio (CTR) (p < 0.001). Multivariable analysis revealed that LD > 20 mm (odds ratio [OR] = 2.271, p = 0.025) and CTR (OR = 24.208, p < 0.001) were independent predictors in the traditional model, while electronic density (ED) in the venous phase was an independent predictor in the spectral (OR = 1.062, p < 0.001) and integrated (OR = 1.055, p < 0.001) models. The area under the curve (AUC) for the integrated model (0.84) was the highest (spectral model, 0.83; traditional model, 0.80), and the difference between the integrated and traditional models was statistically significant (p = 0.015). DCA showed that the integrated model had superior clinical value versus the traditional model. CONCLUSIONS: DLCT has added value for STAS prediction in lung adenocarcinoma. CLINICAL RELEVANCE STATEMENT: Spectral CT has added value for spread through air spaces prediction in lung adenocarcinoma so may impact treatment planning in the future. KEY POINTS: • Electronic density may be a potential spectral index for predicting spread through air spaces in lung adenocarcinoma. • A combination of spectral and traditional CT features enhances the performance of traditional CT for predicting spread through air spaces.

Prognostic impact of deep learning-based quantification in clinical stage 0-I lung adenocarcinoma.

OBJECTIVES: To evaluate the performance of automatic deep learning (DL) algorithm for size, mass, and volume measurements in predicting prognosis of lung adenocarcinoma (LUAD) and compared with manual measurements. METHODS: A total of 542 patients with clinical stage 0-I peripheral LUAD and with preoperative CT data of 1-mm slice thickness were included. Maximal solid size on axial image (MSSA) was evaluated by two chest radiologists. MSSA, volume of solid component (SV), and mass of solid component (SM) were evaluated by DL. Consolidation-to-tumor ratios (CTRs) were calculated. For ground glass nodules (GGNs), solid parts were extracted with different density level thresholds. The prognosis prediction efficacy of DL was compared with that of manual measurements. Multivariate Cox proportional hazards model was used to find independent risk factors. RESULTS: The prognosis prediction efficacy of T-staging (TS) measured by radiologists was inferior to that of DL. For GGNs, MSSA-based CTR measured by radiologists (RMSSA%) could not stratify RFS and OS risk, whereas measured by DL using 0HU (2D-AIMSSA0HU%) could by using different cutoffs. SM and SV measured by DL using 0 HU (AISM0HU% and AISV0HU%) could effectively stratify the survival risk regardless of different cutoffs and were superior to 2D-AIMSSA0HU%. AISM0HU% and AISV0HU% were independent risk factors. CONCLUSION: DL algorithm can replace human for more accurate T-staging of LUAD. For GGNs, 2D-AIMSSA0HU% could predict prognosis rather than RMSSA%. The prediction efficacy of AISM0HU% and AISV0HU% was more accurate than of 2D-AIMSSA0HU% and both were independent risk factors. CLINICAL RELEVANCE STATEMENT: Deep learning algorithm could replace human for size measurements and could better stratify prognosis than manual measurements in patients with lung adenocarcinoma. KEY POINTS: • Deep learning (DL) algorithm could replace human for size measurements and could better stratify prognosis than manual measurements in patients with lung adenocarcinoma (LUAD). • For GGNs, maximal solid size on axial image (MSSA)-based consolidation-to-tumor ratio (CTR) measured by DL using 0 HU could stratify survival risk than that measured by radiologists. • The prediction efficacy of mass- and volume-based CTRs measured by DL using 0 HU was more accurate than of MSSA-based CTR and both were independent risk factors.

An Optimized Integrin α6-Targeted Magnetic Resonance Probe for Molecular Imaging of Hepatocellular Carcinoma in Mice.

INTRODUCTION: Integrin α6 is an attractive diagnostic biomarker for molecular imaging of hepatocellular carcinoma (HCC) as it has an extremely high positive rate (approximately 94%) in clinical early-stage HCC. In this study, based on our previously identified integrin α6-targeted peptide, we developed an optimized integrin α6-targeted magnetic resonance (MR) probe dubbed DOTA(Gd)-ANADYWR for MR imaging of HCC in mice. MATERIALS AND METHODS: The longitudinal (R1) relaxivity of DOTA(Gd)-ANADYWR was measured on a 3.0 T MR system . The specific tumor enhancement of the agent was investigated in four distinct mouse models, including subcutaneous, orthotopic, genetically engineered and chemically induced HCC mice. RESULTS: The R1 relaxivity value of DOTA(Gd)-ANADYWR is 5.11 mM-1s-1 at 3.0 T, which is similar to that of the nonspecific clinical agent Gadoteridol. DOTA(Gd)-ANADYWR generated superior enhanced MR signal in HCC lesions and provided complementary enhancement MR signals to the clinically available hepatobiliary MR contrast agent gadoxetate disodium (Gd-EOB-DTPA). Importantly, DOTA(Gd)-ANADYWR could efficiently visualize small HCC lesion (approximately 1 mm) which was hardly detected by the clinical Gd-EOB-DTPA. CONCLUSION: These findings suggest the potential application of this integrin α6-targeted MR probe for the detection of HCC, particularly for small HCC.

Fat-free mass index is superior to body mass index as a novel risk factor for prolonged air leak complicating video-assisted thoracoscopic surgery lobectomy for non-small-cell lung cancer.

BACKGROUND: To evaluate whether fat-free mass index (FFMI) could be predictive of prolonged air leak (PAL) complicating video-assisted thoracoscopic (VATS) lobectomy for non-small-cell lung cancer (NSCLC). METHODS: A retrospective study was conducted on the prospectively-maintained database in our institution between January 2015 and July 2017. The gender-specific median values of FFMI for males and females were applied as their respective cutoffs to stratify patients into low-FFMI group and high-FFMI group in initial univariable analyses. An effective multivariable logistic-regression analysis was then performed to demonstrate the predictive value of dichotomized FFMI. RESULTS: There were 1,091 surgical patients with NSCLC included (616 males and 475 females), with a PAL incidence of 14.6%. The median FFMI values among males and females were 17.3 and 14.6 kg/m2, respectively. PAL cases in both male (16.9±1.5 vs. 17.4±1.5 kg/m2; P=0.002) and female (14.0±0.9 vs. 14.6±1.1 kg/m2; P<0.001) groups had a significantly lower mean FFMI than that of non-PAL cases. The incidence of PAL was significantly increased in male patients with FFMI <17.3 kg/m2 (23.7% vs. 14.3%; P=0.003) and female patients with FFMI <14.6 kg/m2 (12.7% vs. 5.0%; P=0.003). Lower dichotomized FFMI was also significantly associated with prolonged time to air leak cessation and length of stay (LOS). Finally, multivariable logistic-regression analysis indicated that lower dichotomized FFMI [odds ratio (OR) =1.98; 95% confidence interval (CI): 1.33-2.96; P=0.001] could independently predict the occurrence of PAL. CONCLUSIONS: FFMI acts as an excellent categorical risk factor for PAL complicating VATS lobectomy and shows a much superior significance than body mass index (BMI) in terms of the prediction of PAL.

Albumin-to-alkaline phosphatase ratio as a novel prognostic indicator for patients undergoing minimally invasive lung cancer surgery: Propensity score matching analysis using a prospective database.

OBJECTIVES: To evaluate prognostic significance of albumin-to-alkaline phosphatase ratio (AAPR) for patients undergoing video-assisted thoracoscopic surgery (VATS) lobectomy for non-small-cell lung cancer (NSCLC) by a propensity score-matching (PSM) analysis. METHODS: This PSM study was conducted on the prospectively-maintained database in our institution between December 2013 and March 2015. Overall survival analyses and further subgroup analyses were both performed to distinguish the differences in postoperative survival between patients stratified by an optimal cutoff of AAPR. Multivariable Cox proportional hazards regression models were established to determine the independent prognostic factors. RESULTS: There were 390 patients with operable NSCLCs included. An AAPR of 0.57 was identified as the optimal cutoff regarding to postoperative survival. Both overall survival (OS) and disease-free survival (DFS) in patients with AAPR≤0.57 were significantly shortened compared to those in patient with AAPR>0.57 (Log-rank P < 0.001). Patients with AAPR≤0.57 had significantly lower rates of OS and DFS than those of patients with AAPR>0.57 (P < 0.001). These differences still remained significant after subgroup analyses and PSM analyses. Multivariate analyses on the entire cohort and the PSM cohort commonly indicated that low preoperative AAPR could be an independent prognostic factor for unfavorable OS and DFS of resected NSCLCs. CONCLUSIONS: AAPR can serve as a novel risk stratification tool to refine prognostic prediction for surgical NSCLC. It may help surgeons to screen high-surgical-risk patients and further formulate individualized treatment schemes.

Prognostic value of the C-reactive protein to albumin ratio: a novel inflammation-based prognostic indicator in osteosarcoma.

The prognostic role of the C-reactive protein to albumin ratio (CRP/Alb ratio) in patients with osteosarcoma has not been investigated. A total of 216 osteosarcoma patients were enrolled in the study. Univariate and multivariate survival analyses between the groups were performed and Kaplan-Meier analysis was conducted to plot the survival curves. Receiver operating characteristic curves were generated and areas under the curve (AUCs) were compared to assess the discriminatory ability of the inflammation-based indicators, including CRP/Alb ratio, Glasgow prognostic score (GPS), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR). The optimal cutoff value was 0.210 for CRP/Alb ratio with a Youden index of 0.319. Higher values of CRP/Alb ratio were significantly associated with poorer overall survival in univariate (HR =2.62, 95% CI =1.70-4.03; P<0.001) and multivariate (HR =2.21, 95% CI =1.40-3.49; P=0.001) analyses. In addition, the CRP/Alb ratio had significantly higher AUC values compared with GPS (P=0.003), NLR (P<0.001), and PLR (P<0.001). The study demonstrated that the CRP/Alb ratio is an effective inflammation-based prognostic indicator in osteosarcoma, which potentially has a discriminatory ability superior to that of other inflammatory indicators including GPS, NLR, and PLR.

Clinical implications of six inflammatory biomarkers as prognostic indicators in Ewing sarcoma.

Cancer-related systemic inflammation responses have been correlated with cancer development and progression. The prognostic significance of several inflammatory indicators, including neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), Glasgow Prognostic Score (GPS), C-reactive protein to albumin ratio (CRP/Alb ratio), lymphocyte-monocyte ratio (LMR), and neutrophil-platelet score (NPS), were found to be correlated with prognosis in several cancers. However, the prognostic role of these inflammatory biomarkers in Ewing sarcoma has not been evaluated. This study enrolled 122 Ewing patients. Receiver operating characteristic (ROC) analysis was generated to determine optimal cutoff values; areas under the curves (AUCs) were assessed to show the discriminatory ability of the biomarkers; Kaplan-Meier analysis was conducted to plot the survival curves; and Cox multivariate survival analysis was performed to identify independent prognostic factors. The optimal cutoff values of CRP/Alb ratio, NLR, PLR, and LMR were 0.225, 2.38, 131, and 4.41, respectively. CRP/Alb ratio had a significantly larger AUC than NLR, PLR, LMR, and NPS. Higher levels of CRP/Alb ratio (hazard ratio [HR] 2.41, P=0.005), GPS (HR 2.27, P=0.006), NLR (HR 2.07, P=0.013), and PLR (HR 1.85, P=0.032) were significantly correlated with poor prognosis. As the biomarkers had internal correlations, only the CRP/Alb ratio was involved in the multivariate Cox analysis and remained an independent prognostic indicator. The study demonstrated that CRP/Alb ratio, GPS, and NLR were effective prognostic indicators for patients with Ewing sarcoma, and the CRP/Alb ratio was the most robust prognostic indicator with a discriminatory ability superior to that of the other indicators; however, PLR, LMR, and NPS may not be suitable as prognostic indicators in Ewing sarcoma.

Clinicopathological and prognostic significance of chemokine receptor CXCR4 in patients with bone and soft tissue sarcoma: a meta-analysis.

The prognostic significance of CXC chemokine receptor 4 (CXCR4) in patients with bone and soft tissue sarcomas remains controversial. To investigate the impact of its expression on survival and clinicopathological features, we performed a meta-analysis. Comprehensive literature searches were conducted in PubMed, Web of Science, Embase and Cochrane Library for relevant studies. In total, 12 studies with 997 sarcoma patients were included. CXCR4 expression was found to be significantly associated with poor overall survival (HR 2.37, 95 % CI 1.86-3.01; P < 0.001). Further, when the analysis was stratified by histological subtypes (bony sarcoma including osteosarcoma and Ewing sarcoma and soft tissue sarcoma including synovial sarcoma and rhabdomyosarcoma), statistical analysis method (multivariate analysis and univariate analysis) and CXCR4 measuring method (IHC or RT-PCR), the significant correlation to poor overall survival was also observed except for that in Ewing sarcoma and RT-PCR groups. As for clinicopathological features, CXCR4 expression was significantly associated with higher rate of metastasis (OR 6.97, 95 % CI 2.28-21.31; P = 0.001) and higher tumor stage (OR 7.55, 95 % CI 1.25-45.47; P = 0.027), but not associated with gender, age and tumor site. In conclusion, CXCR4 expression may be an effective predictive factor of poor prognosis and clinicopathological features for bone and soft tissue sarcomas. Further studies are needed to validate our findings.

Clinicopathological and prognostic significance of Oct-4 expression in patients with non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Octamer-binding transcription factor 4 (Oct-4) has been identified to participate in the tumorigenicity and malignancy of non-small cell lung cancer (NSCLC). However, its definite prognostic roles in NSCLC still remain a debate. Therefore, we conducted this meta-analysis to evaluate the prognostic value of Oct-4 expression in NSCLC and its relationship to some major clinicopathological characteristics. METHODS: A comprehensive literature retrieval was performed in PubMed, EMBASE and the Web of Science to identify the full-text articles that met our eligibility criteria. Odds ratio (OR) with 95% confidence interval (CI) severed as the summarized statistics for clinicopathological assessments, and hazard ratio (HR) with 95% CI served as the summarized statistics for prognostic assessments. Q-test and I(2)-statistic were used to evaluate the level of heterogeneity. Potential publication bias was detected by both Begg's test and Egger's test. RESULTS: There were 16 retried articles with 1,363 NSCLC cases included into this meta-analysis. Oct-4 expression was found to be significantly associated with the unfavorable outcomes for differentiation degree (OR: 3.065; 95% CI: 1.568-5.957; P=0.001), TNM stage (OR: 3.695; 95% CI: 2.252-6.063; P<0.001) and lymphatic metastasis (OR: 2.372; 95% CI: 1.504-3.742; P<0.001), but not associated with the histological subtypes, gender, age and smoking status. Oct-4 expression was also significantly associated with the poor prognosis of NSCLC (HR: 3.030; 95% CI: 2.283-4.021; P<0.001). The prognostic roles of Oct-4 expression in NSCLC still remained statistically reliable in the subgroups stratified by statistical analysis, patients' origins, positively-stained sites and histological subtypes. CONCLUSIONS: Our meta-analysis indicates that Oct-4 can serve as a strong biomarker predicting the poor clinicopathological and prognostic characteristics of NSCLC. More high-quality studies based on a large sample size will be very helpful to further validate and modify our findings in the future.

Prognostic value of stromal decorin expression in patients with breast cancer: a meta-analysis.

BACKGROUND: Numbers of studies have investigated the biological functions of decorin (DCN) in oncogenesis, tumor progression, angiogenesis and metastasis. Although many of them aim to highlight the prognostic value of stromal DCN expression in breast cancer, some controversial results still exist and a consensus has not been reached until now. Therefore, our meta-analysis aims to determine the prognostic significance of stromal DCN expression in breast cancer patients. METHODS: PubMed, EMBASE, the Web of Science and China National Knowledge Infrastructure (CNKI) databases were searched for full-text literatures met out inclusion criteria. We applied the hazard ratio (HR) with 95% confidence interval (CI) as the appropriate summarized statistics. Q-test and I(2) statistic were employed to estimate the level of heterogeneity across the included studies. Sensitivity analysis was conducted to further identify the possible origins of heterogeneity. The publication bias was detected by Begg's test and Egger's test. RESULTS: There were three English literatures (involving 6 studies) included into our meta-analysis. On the one hand, both the summarized outcomes based on univariate analysis (HR: 0.513; 95% CI: 0.406-0.648; P<0.001) and multivariate analysis (HR: 0.544; 95% CI: 0.388-0.763; P<0.001) indicated that stromal DCN expression could promise the high cancer-specific survival (CSS) of breast cancer patients. On the other hand, both the summarized outcomes based on univariate analysis (HR: 0.504; 95% CI: 0.389-0.651; P<0.001) and multivariate analysis (HR: 0.568; 95% CI: 0.400-0.806; P=0.002) also indicated that stromal DCN expression was positively associated with high disease-free survival (DFS) of breast cancer patients. No significant heterogeneity or publication bias was observed within this meta-analysis. CONCLUSIONS: The present evidences indicate that high stromal DCN expression can significantly predict the good prognosis in patients with breast cancer. The discoveries from our meta-analysis have better be confirmed in the updated review pooling more relevant investigations in the future.

Expression of MMP-1 and TIMP-1 in irradiated mandibles during distraction osteogenesis.

OBJECTIVES: The study aimed to evaluate the expression of MMP-1 and TIMP-1 in irradiated mandibles during distraction osteogenesis. STUDY DESIGN: Rabbits in the experimental group received preoperative radiation of 9 Gy for 5 fractions. After 1 month, all rabbits underwent osteotomy and distraction osteogenesis with 7 days of latency. Three rabbits in the control and experimental groups were killed at days 7, 12, 18, and 25. Specimens were subjected to immunohistochemical examination and real-time polymerase chain reaction analysis. RESULTS: At day 7, expression of MMP-1 and TIMP-1 was significantly suppressed in the radiotherapy group in contrast to the control group. At day 12, expression of MMP-1 was significantly higher in the control group. At day 18, expression of MMP-1 and TIMP-1 was significantly higher in the control than in the radiotherapy group. CONCLUSIONS: Radiotherapy changes the expression pattern of MMP-1 and TIMP-1.

Treatment of irradiated mandibles with mesenchymal stem cells transfected with bone morphogenetic protein 2/7.

PURPOSE: The study aimed to evaluate whether mesenchymal stem cells transfected with bone morphogenetic protein (BMP) 2/7 could increase bone regeneration after radiotherapy using a rabbit model of mandibular distraction osteogenesis. MATERIALS AND METHODS: Twelve rabbits were randomly assigned to the sham control, radiotherapy control, nontransfected mesenchymal stem cells (MSCs), and MSCs transfected with BMP-2/7 groups. All rabbits, except those in the sham control group, received preoperative radiation of 9 Gy for 5 fractions. One month after radiotherapy, all rabbits underwent unilateral mandibular distraction at a rate of 0.9 mm/d for 11 days. At the end of active distraction, MSCs combined with bovine collagen were injected into the distraction zone. After 4 weeks of consolidation, the mandibular samples were collected and subjected to radiographic, microcomputed tomographic, and histologic examinations. RESULTS: By radiographic examination, animals injected with nontransfected MSCs or MSCs encoding BMP-2/7 exhibited more bone formation than the control groups. Histologic examination showed that the group with MSCs encoding BMP-2/7 had a more mature medullary cavity than the nontransfected MSCs group. CONCLUSIONS: MSCs encoding BMP-2/7 can increase bone healing in irradiated mandibular bone.

Expression of bone morphogenetic protein, vascular endothelial growth factor, and basic fibroblast growth factor in irradiated mandibles during distraction osteogenesis.

PURPOSE: The present study evaluated the expression of bone morphogenetic proteins (BMPs)-2, -4, -7, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in irradiated mandibles during distraction osteogenesis. MATERIALS AND METHODS: A total of 24 rabbits were randomly assigned to the control and experimental groups. Each rabbit in the experimental group underwent preoperative radiation to 9 Gy in 5 fractions. After 1 month, all rabbits underwent osteotomy and distraction osteogenesis with 7 days of latency. Three rabbits in the control and experimental groups were killed at day 7 (end of the latency period), day 12 (middle of active distraction), day 18 (end of active distraction), and day 25 (1 week after consolidation). The specimens were used for immunohistochemical staining and real-time polymerase chain reaction analysis. RESULTS: Histologically, at day 25, cortical bone formation was much better in the control group than in the radiotherapy group. In the radiotherapy group, the bone spicules were aligned in the direction of tension stress. At day 12, the expression of BMP-2, -4, and -7 was elevated in the radiotherapy group compared with the control group. At day 25, the expression of BMP-2 was significantly greater in the radiotherapy group. At day 7, the expression of bFGF was significantly suppressed in the radiotherapy group. At day 12, the expression of bFGF and VEGF was significantly elevated in the radiotherapy group compared with the control group. At day 25, the expression of VEGF was significantly greater in the radiotherapy group. CONCLUSIONS: The results of our study have shown that radiotherapy changes the expression pattern of BMPs, VEGF, and bFGF.

Bone regeneration after radiotherapy in an animal model.

PURPOSE: The study aimed to evaluate dosage-dependent effects of irradiation on bone regeneration and established a radiation-compromised rabbit model of mandibular distraction osteogenesis. MATERIALS AND METHODS: Twenty-three rabbits were divided randomly into 7 groups. Group A served as the control group, whereas experimental groups B, C, D, E, F, and G received preoperative irradiation at doses of 6.5, 7.0, 7.5, 8.0, 8.5, and 9.0 Gy, respectively, for 5 fractions. After 1 month, all rabbits underwent osteotomy and distraction osteogenesis with 7 days of latency, 11 days of active distraction at a rate of 0.9 mm/d, and 4 weeks of consolidation; rabbit mandibles were subsequently subjected to histologic, radiographic, and micro-computed tomography analysis. RESULTS: With increasing doses of irradiation, bone regeneration was markedly hampered. Radiographically, the high-dose groups (8.5 and 9.0 Gy) presented obscure cortical lines. Histologically, in the 8.5- and 9.0-Gy groups, cortical bones were not completely formed, and in the medullary cavity, there existed a large amount of fibrous tissue. CONCLUSION: Radiotherapy compromises bone regeneration during distraction osteogenesis, and the adverse effect is dose dependent.