Natural history of pathologically confirmed pulmonary subsolid nodules with deep learning-assisted nodule segmentation.

OBJECTIVE: To explore the natural history of pulmonary subsolid nodules (SSNs) with different pathological types by deep learning-assisted nodule segmentation. METHODS: Between June 2012 and June 2019, 95 resected SSNs with preoperative long-term follow-up were enrolled in this retrospective study. SSN detection and segmentation were performed on preoperative follow-up CTs using the deep learning-based Dr. Wise system. SSNs were categorized into invasive adenocarcinoma (IAC, n = 47) and non-IAC (n = 48) groups; according to the interval change during the preoperative follow-up, SSNs were divided into growth (n = 68), nongrowth (n = 22), and new emergence (n = 5) groups. We analyzed the cumulative percentages and pattern of SSN growth and identified significant factors for IAC diagnosis and SSN growth. RESULTS: The mean preoperative follow-up was 42.1 ± 17.0 months. More SSNs showed growth or new emergence in the IAC than in the non-IAC group (89.4% vs. 64.6%, p = 0.009). Volume doubling time was non-significantly shorter for IACs than for non-IACs (1436.0 ± 1188.2 vs. 2087.5 ± 1799.7 days, p = 0.077). Median mass doubling time was significantly shorter for IACs than for non-IACs (821.7 vs. 1944.1 days, p = 0.001). Lobulated sign (p = 0.002) and SSN mass (p = 0.004) were significant factors for differentiating IACs. IACs showed significantly higher cumulative growth percentages than non-IACs in the first 70 months of follow-up. The growth pattern of SSNs may conform to the exponential model. The initial volume (p = 0.042) was a predictor for SSN growth. CONCLUSIONS: IACs appearing as SSNs showed an indolent course. The mean growth rate was larger for IACs than for non-IACs. SSNs with larger initial volume are more likely to grow. KEY POINTS: • Invasive adenocarcinomas (IACs) appearing as subsolid nodules (SSNs), with a mean volume doubling time (VDT) of 1436.0 ± 1188.2 days and median mass doubling time (MDT) of 821.7 days, showed an indolent course. • The VDT was shorter for IACs than for non-IACs (1436.0 ± 1188.2 vs. 2087.5 ± 1799.7 days), but the difference was not significant (p = 0.077). The median MDT was significantly shorter for IACs than for non-IACs (821.7 vs. 1944.1 days, p = 0.001). • SSNs with lobulated sign and larger mass (> 390.5 mg) may very likely be IACs. SSNs with larger initial volume are more likely to grow.

Comparison of Radiation Dose and Image Quality Between Split-Filter Twin Beam Dual-Energy Images and Single-Energy Images in Single-Source Contrast-Enhanced Chest Computed Tomography.

OBJECTIVE: To compare image quality and radiation dose of split-filter TwinBeam dual-energy (SF-TBDE) with those of single-energy images (SECT) in the contrast-enhanced chest computed tomography (CT). METHODS: Two hundred patients who underwent SF-TBDE (n = 100) and SECT (n = 100) contrast-enhanced chest scanning were retrospectively analyzed. The contrast-to-noise ratio (CNR) and figure of merit (FOM)-CNR of 5 structures (lung, aorta, pulmonary artery, thyroid, and erector spinae) were calculated and subjectively evaluated by 2 independent radiologists. Radiation dose was compared using volume CT dose index and size-specific dose estimate. RESULTS: The CNR and FOM-CNR of lung and erector spinae in SF-TBDE were higher than those of SECT (P < 0.001). The differences in the subjective image quality between the 2 groups were not significant (P = 0.244). Volume CT dose index and size-specific dose estimate of SF-TBDE were lower than those of SECT (6.60 ± 1.56 vs 7.81 ± 3.02 mGy, P = 0.001; 9.25 ± 1.60 vs. 10.55 ± 3.54; P = 0.001). CONCLUSIONS: The SF-TBDE CT can provide similar image quality at a lower radiation dose compared with SECT.

Long-term follow-up of persistent pulmonary pure ground-glass nodules with deep learning-assisted nodule segmentation.

OBJECTIVE: To investigate the natural history of persistent pulmonary pure ground-glass nodules (pGGNs) with deep learning-assisted nodule segmentation. METHODS: Between January 2007 and October 2018, 110 pGGNs from 110 patients with 573 follow-up CT scans were included in this retrospective study. pGGN automatic segmentation was performed on initial and all follow-up CT scans using the Dr. Wise system based on convolution neural networks. Subsequently, pGGN diameter, density, volume, mass, volume doubling time (VDT), and mass doubling time (MDT) were calculated automatically. Enrolled pGGNs were categorized into growth, 52 (47.3%), and non-growth, 58 (52.7%), groups according to volume growth. Kaplan-Meier analyses with the log-rank test and Cox proportional hazards regression analysis were conducted to analyze the cumulative percentages of pGGN growth and identify risk factors for growth. RESULTS: The mean follow-up period of the enrolled pGGNs was 48.7 ± 23.8 months. The median VDT of the 52 pGGNs having grown was 1448 (range, 339-8640) days, and their median MDT was 1332 (range, 290-38,912) days. The 12-month, 24.7-month, and 60.8-month cumulative percentages of pGGN growth were 10%, 25.5%, and 51.1%, respectively, and they significantly differed among the initial diameter, volume, and mass subgroups (all p < 0.001). The growth pattern of pGGNs may conform to the exponential model. Lobulated sign (p = 0.044), initial mean diameter (p < 0.001), volume (p = 0.003), and mass (p = 0.023) predicted pGGN growth. CONCLUSIONS: Persistent pGGNs showed an indolent course. Deep learning can assist in accurately elucidating the natural history of pGGNs. pGGNs with lobulated sign and larger initial diameter, volume, and mass are more likely to grow. KEY POINTS: • The pure ground-glass nodule (pGGN) segmentation accuracy of the Dr. Wise system based on convolution neural networks (CNNs) was 96.5% (573/594). • The median volume doubling time (VDT) of 52 pure ground-glass nodules (pGGNs) having grown was 1448 days (range, 339-8640 days), and their median mass doubling time (MDT) was 1332 days (range, 290-38,912 days). The mean time to growth in volume was 854 ± 675 days (range, 116-2856 days). • The 12-month, 24.7-month, and 60.8-month cumulative percentages of pGGN growth were 10%, 25.5%, and 51.1%, respectively, and they significantly differed among the initial diameter, volume, and mass subgroups (all p values < 0.001). The growth pattern of pure ground-glass nodules may conform to exponential model.

Induction of G1 Cell Cycle Arrest in Human Glioma Cells by Salinomycin Through Triggering ROS-Mediated DNA Damage In Vitro and In Vivo.

Chemotherapy has always been one of the most effective ways in combating human glioma. However, the high metastatic potential and resistance toward standard chemotherapy severely hindered the chemotherapy outcomes. Hence, searching effective chemotherapy drugs and clarifying its mechanism are of great significance. Salinomycin an antibiotic shows novel anticancer potential against several human tumors, including human glioma, but its mechanism against human glioma cells has not been fully elucidated. In the present study, we demonstrated that salinomycin treatment time- and dose-dependently inhibited U251 and U87 cells growth. Mechanically, salinomycin-induced cell growth inhibition against human glioma was mainly achieved by induction of G1-phase arrest via triggering reactive oxide species (ROS)-mediated DNA damage, as convinced by the activation of histone, p53, p21 and p27. Furthermore, inhibition of ROS accumulation effectively attenuated salinomycin-induced DNA damage and G1 cell cycle arrest, and eventually reversed salinomycin-induced cytotoxicity. Importantly, salinomycin treatment also significantly inhibited the U251 tumor xenograft growth in vivo through triggering DNA damage-mediated cell cycle arrest with involvement of inhibiting cell proliferation and angiogenesis. The results above validated the potential of salinomycin-based chemotherapy against human glioma.

[Primary tumor SUVmax measured on (18)F-FDG PET-CT correlates with histologic grade and pathologic stage in non-small cell lung cancer].

OBJECTIVE: To assess the relationship between preoperative maximum standardized uptake value (SUVmax) measured on (18)F-FDG PET-CT and clinicopathologic parameters in patients with surgically resected non-small cell lung cancer (NSCLC). METHODS: A total of 540 patients (348 men and 192 women, mean age 60 ± 10 years) with histologically proven non-small cell lung cancer, who had undergone both preoperative (18)F-FDG PET-CT imaging and curative surgery in our institution from October 2006 to January 2013, were analyzed retrospectively in this study. Primary tumor (18)F-FDG uptake, measured as SUVmax corrected for lean body mass, was compared among different variables and correlated with tumor size, histologic grade and postoperative pathologic TNM stage. Histologic grade was categorized into three degrees, where grade I represents highly, grade II moderately and grade III poorly differentiated. Large cell carcinomas were all assessed as poorly differentiated (grade III). Pathologic stage was assigned according to the seventh AJCC TNM staging system. RESULTS: There were 344 adenocarcinomas (AC, non- BAC type), 146 squamous cell carcinomas (SCC), 28 bronchioloalveolar carcinomas (BAC), 10 adenosquamous carcinomas (ASC) and 12 other type carcinomas (OTC, including 6 large cell carcinomas, 5 sarcomatoid carcinomas and 1 lymphoepitheloid carcinoma); the SUVmax in ascending order was BAC (1.3 ± 1.1), AC (5.1 ± 3.4), ASC (8.5 ± 2.8), SCC (9.9 ± 4.6) and OTC (10.9 ± 5.1), respectively. There were 76 grade I, 251 grade II and 213 grade III; the SUVmax in ascending order was grade I (2.4 ± 2.2), grade II(5.9 ± 3.9), grade III (8.4 ± 4.4), respectively, and significant difference was identified among grade I, grade II and grade III (all P < 0.01). The SUV max was positively correlated with tumor size (r = 0.564, P < 0.01), histologic grade (r = 0.492, P < 0.01), T stage (r = 0.306, P < 0.01), N stage (r = 0.368, P < 0.01), and TNM stage (r = 0.437, P < 0.01). CONCLUSIONS: The preoperative SUV max of the primary tumor differed significantly among histologic types in NSCLC. There were positive correlations between SUV max and tumor size, histologic grade and pathologic stage. Our findings may suggest that a high SUVmax could be used to identify a high-risk population who would benefit most from adjuvant therapies.

Developing a Screening Procedure During the COVID-19 Pandemic: Process and Challenges Faced by a Low-Incidence Area.

Purpose: To summarize the imaging results of COVID-19 pneumonia and develop a computerized tomography (CT) screening procedure for patients at our institution with malignant tumors. Methods: Following epidemiological investigation, 1,429 patients preparing to undergo anti-tumor-treatment underwent CT scans between February 17 and April 16, 2020. When CT findings showed suspected COVID-19 pneumonia after the supervisor radiologist and the thoracic experience radiologist had double-read the initial CT images, radiologists would report the result to our hospital infection control staff. Further necessary examinations, including the RT-PCR test, in the assigned hospital was strongly recommended for patients with positive CT results. The CT examination room would perform sterilization for 30 min to 1 h. If the negative results of any suspected COVID-19 pneumonia CT findings were identified, the radiologists would upload the results to our Hospital Information Systems and inform clinicians within 2 h. Results: Fifty (0.35%, 50/1,429) suspected pneumonia cases, including 29 males and 21 females (median age: 59.5 years old; age range 27-79 years), were identified. A total of 34.0% (17/50) of the patients had a history of lung cancer and 54.0 (27/50) underwent chemotherapy or targeted therapy. Forty-six patients (92.0%) had prior CT scans, and 35 patients (76.1%) with suspected pneumonia were newly seen (median interval time: 62 days). Sub-pleura small patchy or strip-like lesions most likely due to fibrosis or hypostatic pneumonia and cluster of nodular lesions were the two main signs of suspected cases on CT images (34, 68.0%). Twenty-seven patients (54.0%) had, at least once, follow-up CT scan (median interval time: 18.0 days). Only one patient had an increase in size (interval time: 8 days), the immediately RT-PCR test result was negative. Conclusion: CT may be useful as a screening tool for COVID-19 based on imaging features. But the differential diagnosis between COVID-19 and other pulmonary infection and/or non-infectious disease is very difficult due to its overlapping imaging features.The confirmed diagnosis of the COVID-19 infection should be based on the etiologic eventually. The cancer patients at a low-incidence area would continue treatment by screening carefully before admission.

Ifenprodil Improves Long-Term Neurologic Deficits Through Antagonizing Glutamate-Induced Excitotoxicity After Experimental Subarachnoid Hemorrhage.

Excessive glutamate leading to excitotoxicity worsens brain damage after SAH and contributes to long-term neurological deficits. The drug ifenprodil is a non-competitive antagonist of GluN1-GluN2B N-methyl-d-aspartate (NMDA) receptor, which mediates excitotoxic damage in vitro and in vivo. Here, we show that cerebrospinal fluid (CSF) glutamate level within 48 h was significantly elevated in aSAH patients who later developed poor outcome. In rat SAH model, ifenprodil can improve long-term sensorimotor and spatial learning deficits. Ifenprodil attenuates experimental SAH-induced neuronal death of basal cortex and hippocampal CA1 area, cellular and mitochondrial Ca2+ overload of basal cortex, blood-brain barrier (BBB) damage, and cerebral edema of early brain injury. Using in vitro models, ifenprodil declines the high-concentration glutamate-mediated intracellular Ca2+ increase and cell apoptosis in primary cortical neurons, reduces the high-concentration glutamate-elevated endothelial permeability in human brain microvascular endothelial cell (HBMEC). Altogether, our results suggest ifenprodil improves long-term neurologic deficits through antagonizing glutamate-induced excitotoxicity.

Early High Cerebrospinal Fluid Glutamate: A Potential Predictor for Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) is an important complication after aneurysmal subarachnoid hemorrhage (aSAH). Early identification of cerebrospinal fluid (CSF) markers is helpful for warning of impending DCI. This study assessed whether early high CSF glutamate levels can be observed in aSAH patients who later developed DCI. In this prospective clinical study, patients with normal pressure hydrocephalus or aSAH were enrolled. We found that the early CSF levels of glutamate were significantly elevated in aSAH patients compared to patients with normal pressure hydrocephalus. There was a significant difference in early CSF levels of glutamate between aSAH patients without DCI and with DCI. The early CSF levels of glutamate are significantly related to the Hunt and Hess grade, the World Federation of Neurological Surgeons (WFNS) grade, and the modified Fisher score on admission and occurrence of DCI in aSAH patients. Preliminary evidence of this study suggests that early high CSF glutamate levels are correlated with DCI in aSAH patients.

Selective mGluR1 Negative Allosteric Modulator Reduces Blood-Brain Barrier Permeability and Cerebral Edema After Experimental Subarachnoid Hemorrhage.

The blood-brain barrier (BBB) disruption leads to the vasogenic brain edema and contributes to the early brain injury (EBI) after subarachnoid hemorrhage (SAH). However, the mechanisms underlying the BBB damage following SAH are poorly understood. Here we reported that the neurotransmitter glutamate of cerebrospinal fluid (CSF) was dramatically increased in SAH patients with symptoms of cerebral edema. Using the rat SAH model, we found that SAH caused the increase of CSF glutamate level and BBB permeability in EBI, intracerebroventricular injection of exogenous glutamate deteriorated BBB damage and cerebral edema, while intraperitoneally injection of metabotropic glutamate receptor 1(mGluR1) negative allosteric modulator JNJ16259685 significantly attenuated SAH-induced BBB damage and cerebral edema. In an in vitro BBB model, we showed that glutamate increased monolayer permeability of human brain microvascular endothelial cells (HBMEC), whereas JNJ16259685 preserved glutamate-damaged BBB integrity in HBMEC. Mechanically, glutamate downregulated the level and phosphorylation of vasodilator-stimulated phosphoprotein (VASP), decreased the tight junction protein occludin, and increased AQP4 expression at 72 h after SAH. However, JNJ16259685 significantly increased VASP, p-VASP, and occludin, and reduced AQP level at 72 h after SAH. Altogether, our results suggest an important role of glutamate in disruption of BBB function and inhibition of mGluR1 with JNJ16259685 reduced BBB damage and cerebral edema after SAH.

Lung cancer imaging methods in China from 2005 to 2014: A national, multicenter study.

BACKGROUND: The study was conducted to examine changes in diagnostic and staging imaging methods for lung cancer in China over a 10-year period and to determine the relationships between such changes and socioeconomic development. METHODS: This was a hospital-based, nationwide, multicenter retrospective study of primary lung cancer cases. The data were extracted from the 10-year primary lung cancer databases at eight tertiary hospitals from various geographic areas in China. The chi-squared test was used to assess the differences and the Cochran-Armitage trend test was used to estimate the trends of changes. RESULTS: A total of 7184 lung cancer cases were analyzed. Over the 10-year period, the utilization ratio of diagnostic imaging methods, such as chest computed tomography (CT) and chest magnetic resonance imaging (MRI), increased from 65.79% to 81.42% and from 0.73% to 1.96%, respectively, while the utilization ratio of chest X-ray declined from 50.15% to 30.93%. Staging imaging methods, such as positron emission tomography-CT, neck ultrasound, brain MRI, bone scintigraphy, and bone MRI increased from 0.73% to 9.29%, 22.95% to 47.92%, 8.77% to 40.71%, 42.40% to 62.22%, and 0.88% to 4.65%, respectively; abdominal ultrasound declined from 83.33% to 59.9%. These trends were more notable in less developed areas than in areas with substantial economic development. CONCLUSION: Overall, chest CT was the most common radiological diagnostic method for lung cancer in China. Imaging methods for lung cancer tend to be used in a diverse, rational, and regionally balanced manner.

Clinical characteristics and medical service utilization of lung cancer in China, 2005-2014: Overall design and results from a multicenter retrospective epidemiologic survey.

OBJECTIVES: This study aimed to explore the clinical profile and its trajectory of lung cancer on clinicopathological characteristics and medical service utilization in China. METHODS: Patients diagnosed with primary lung cancer in tertiary hospitals during 2005-14 were selected from seven geographic regions of China. Data on clinical characteristics and medical service utilization was extracted from medical record, and the ten-year trends were explored. RESULTS: A total of 7184 patients were included, the mean age was 58.3 years and the male-to-female-ratio was 2.7. From 2005 to 2014, the proportion of ≥60 year-old patients increased from 41.2% to 56.2% (p < 0.001). The smoking rate decreased from 62.9% to 51.1% (p < 0.001) and the proportion of females increased from 23.5% to 31.9% (p < 0.001). The proportion of advanced stage increased from 41.9% to 47.4% (p < 0.001). Adenocarcinoma's proportion increased from 36.4% to 53.5% (p < 0.001) while that of squamous carcinoma decreased from 45.4% to 34.4% (p < 0.001). The application of chest X-ray dropped from 50.2% to 31.0% (p < 0.001) but that of chest CT increased from 65.8% to 81.4% (p < 0.001). As two main treatment options, chemotherapy (p = 0.290) and surgery (p = 0.497) remained stable. The medical expenditure per patient increased from 40,508 to 66,020 Chinese Yuan (p < 0.001). CONCLUSIONS: The sustaining high smoking exposure, increasing proportion of female patients, advancing clinical stage, shifting of predominant pathology and increasing medical expenditure demonstrate potential challenges and directions on lung cancer prevention and control in China. Despite substantial changes of clinical characteristics, main treatment options remained unchanged, which needs further investigation.

Salinomycin exhibits anti-angiogenic activity against human glioma in vitro and in vivo by suppressing the VEGF-VEGFR2-AKT/FAK signaling axis.

Tumor angiogenesis plays a crucial role in tumor growth, progression and metastasis, and suppression of tumor angiogenesis has been considered as a promising anticancer strategy. Salinomycin (SAL), an antibiotic, displays novel anticancer potential against several human cancer cells in vitro and in vivo. However, little information concerning its anti-angiogenic properties is available. Therefore, the anti­angiogenic effect of SAL and the underlying mechanism in human glioma were evaluated in the present study. The results indicated that SAL treatment significantly inhibited human umbilical vein endothelial cell (HUVEC) proliferation, migration, invasion and capillary-like tube formation. Further investigation on intracellular mechanisms showed that SAL markedly suppressed FAK and AKT phosphorylation, and downregulated vascular endothelial growth factor (VEGF) expression in HUVECs. Pretreatment of cells with a PI3K inhibitor (LY294002) and FAK inhibitor (PF562271) markedly enhanced SAL-induced inhibition of HUVEC proliferation and migration, respectively. Moreover, U251 human glioma xenograft growth was also effectively blocked by SAL treatment in vivo via inhibition of angiogenesis involving FAK and AKT depho-sphorylation. Taken together, our findings validated that SAL inhibits angiogenesis and human glioma growth through suppression of the VEGF-VEGFR2-AKT/FAK signaling axis, indicating the potential application of SAL for the treatment of human glioma.

Selenocysteine induces apoptosis in human glioma cells: evidence for TrxR1-targeted inhibition and signaling crosstalk.

Thioredoxin reductase (TrxR) as a selenium (Se)-containing antioxidase plays key role in regulating intracellular redox status. Selenocystine (SeC) a natural available Se-containing amino acid showed novel anticancer potential through triggering oxidative damage-mediated apoptosis. However, whether TrxR-mediated oxidative damage was involved in SeC-induced apoptosis in human glioma cells has not been elucidated yet. Herein, SeC-induced human glioma cell apoptosis was detected in vitro, accompanied by PARP cleavage, caspases activation and DNA fragmentation. Mechanically, SeC caused mitochondrial dysfunction and imbalance of Bcl-2 family expression. SeC treatment also triggered ROS-mediated DNA damage and disturbed the MAPKs and AKT pathways. However, inhibition of ROS overproduction effectively attenuated SeC-induced oxidative damage and apoptosis, and normalized the expression of MAPKs and AKT pathways, indicating the significance of ROS in SeC-induced apoptosis. Importantly, U251 human glioma xenograft growth in nude mice was significantly inhibited in vivo. Further investigation revealed that SeC-induced oxidative damage was achieved by TrxR1-targeted inhibition in vitro and in vivo. Our findings validated the potential of SeC to inhibit human glioma growth by oxidative damage-mediated apoptosis through triggering TrxR1-targeted inhibition.

Early detection of lung cancer: Low-dose computed tomography screening in China.

Lung cancer is currently the leading cause of cancer-related death in China and western countries for both men and women. Overall, the five-year survival rate of lung cancer is approximately 15%, whereas the five-year survival for patients with surgically resected early-stage disease is 60-80%. Screening is conceptually a good strategy for reducing the mortality rate of lung cancer. Randomized controlled trials in the 1960s and 1970s found that chest radiographic screening did not result in a reduction in mortality for high-risk individuals. Recently published data from the National Lung Screening Trial (NLST) showed a 20% reduction in lung cancer mortality in subjects who underwent low-dose computed tomography (LDCT) screening compared to those randomized to conventional chest X-ray. The encouraging results of the NLST, however, could not be confirmed by the preliminary results of ongoing European trials. More results from European randomized controlled trials are expected in the next few years. Recently, a number of lung cancer screening studies using LDCT have been initiated in China. This article briefly summarizes the results of the current and previous lung cancer screening trials worldwide, and focuses on the current status of LDCT lung cancer screening in China.

Pulmonary-bronchus myelolipoma and review on extra-adrenal myelolipomas in Chinese literature.

Extra-adrenal myelolipomas are extremely rare, especially in bronchus and lung. Up to now, only nine cases of intra pulmonary lesions have been reported all over the world. Here we describe a new discovered pulmonary-bronchus myelolipoma in a 53-year-old man, which is different from the previously reported ones. And we mainly comment on the pathology and diagnosis, comparing with the findings of the extra-adrenal cases reported in Chinese literature.