Jingyun Shi

High Discrepancy of Driver Mutations in Patients with NSCLC and Synchronous Multiple Lung Ground-Glass Nodules

Background: The aim of this study was to investigate the discordance rates of eight known driver mutations among multiple matched intrapulmonary ground-glass nodules (GGNs) in non–small-cell lung cancer (NSCLC) patients. Methods: Tumors from 35 patients with multiple lesions resected, including confirmed NSCLC and at least one GGN, were analyzed for mutations in EGFR, KRAS, HER2, BRAF, and PIK3CA together with fusions in ALK, ROS1, and RET. Results: From 35 patients, a total of 72 lesions (60 were GGNs) were analyzed. These included nine adenocarcinoma in situ, nine minimal invasive adenocarcinoma, and 54 invasive adenocarcinoma. Among them, 33 tumor lesions (45.8 %) were found harboring EGFR mutations: 13 tumors with exon 19 deletion, 18 with L858R on exon 21, and two with both exon 19 del and L858R mutation. There were 5 tumors (6.9 %) harboring EML4-ALK fusion, four HER2 mutations (5.6%), three KRAS mutations (4.2%), one ROS1 fusion and one BRAF mutation. When we used the matched tumors to determine the intertumor discrepancy, only six out of 30 patients harbored identical mutations. The discordance rate of driver mutations was 80% (24 of 30) in those patients harboring at least one of the detected driver mutations. The median disease-free survival was 41.2 months (95% confidence interval: 35.8–52.6 months) and the median overall survival was “still not reached” in this cohort. Conclusions: We found a high discrepancy of driver mutations among NSCLC patients with GGNs and a favorable prognosis after multiple lesions resection, which support surgical resection in this situation as a reasonable approach.

T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients

BACKGROUND AND PURPOSE Continuous EGFR-TKI treatment beyond progression has shown promising benefit for some patients with acquired resistance to EGFR-TKIs. The aim of this study was to investigate the association of secondary T790M mutation at the time of progression with the efficacy of EGFR-TKI treatment beyond progression. METHODS From March 2011 to March 2013, patients with advanced NSCLC who developed acquired resistance to EGFR-TKI and where a re-biopsy was performed at Tongji University Cancer Institute were included into this study. Scorpion ARMS was used to detect EGFR mutation status. RESULTS A total of 54 patients were enrolled in this study with a median progression-free survival time (PFS1) of 10.9 months according to RECIST criteria. In all, 53.7% (29/54) had T790M mutation after the failure of EGFR-TKIs; PFS1 was not statistically significantly different between patients with T790M mutation and without (13.0 vs. 10.5 months, p = 0.894). In all, 41 patients received TKI treatment beyond progression, including 22 with local progression to receive additional local therapy and 19 with gradual progression to receive additional chemotherapy. The median progression-free survival time (PFS2) of patients who received EGFR-TKI beyond progression treatment was 3.5 months (95% CI, 2.689-4.311). Patients with T790M mutation had significantly longer PFS2 (6.3 vs. 2.6 months, p = 0.002) and overall survival (39.8 vs. 23.2 months, p = 0.044) than those without. CONCLUSION Patients with secondary T790M mutation at the time of progression having gradual or local progression after acquired resistance to EGFR-TKI benefit more from EGFR-TKI treatment beyond progression compared to those without T790M mutation.

Dynamic Volume Perfusion Computed Tomography Parameters versus RECIST for the Prediction of Outcome in Lung Cancer Patients Treated with Conventional Chemotherapy

Introduction: To compare dynamic volume perfusion computed tomography (dVPCT) parameters with Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for prediction of therapy response and overall survival (OS) in non–small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) patients treated with conventional chemotherapy. Methods: A total of 173 lung cancer patients (131 men; 61 ± 10 years) undergoing dVPCT before (T1) and after chemotherapy (T2) and follow-up were prospectively included. dVPCT-derived blood flow, blood volume, mean transit time, and permeability (PERM) were assessed, compared between NSCLC and SCLC and patients’ response to therapy was determined according to RECIST 1.1. Results: One hundred of one hundred and seventy-three patients underwent dVPCT at T1 and T2 within a median of 44 (range, 31–108) days. dVPCT values were differing in NSCLC and SCLC, but were not significantly differing between patients with partial response, stable, or progressive disease. Eighty-five patients (NSCLC = 72 and SCLC = 13) with a follow-up for greater than or equal to 6 months were analyzed for OS. Fifty-six of eighty-five patients died during follow-up. Receiver operating characteristic analysis determined T1/T2 with highest predictive values regarding OS for blood flow, blood volume, mean transit time, and permeability (area under the curve: 0.53, 0.61, 0.54, and 0.53, respectively, all p > 0.05). Kaplan–Meier statistics revealed OS of patient groups assigned according to dVPCT T1/T2 cutoff values was not differing for neither dVPCT parameter, whereas RECIST groups significantly differed in OS (p = 0.02). Cox proportional hazards regression determined progressive disease status to independently predict OS (p = 0.004), while none of the dVPCT parameters did so. Conclusions: dVPCT values, differ between NSCLC and SCLC, are not related to RECIST 1.1 classification and do not improve OS prediction in lung cancer patients treated with conventional chemotherapy.

Preoperative nomogram for identifying invasive pulmonary adenocarcinoma in patients with pure ground-glass nodule: A multi-institutional study.

Purpose To construct a preoperative nomogram to differentiate invasive pulmonary adenocarcinomas (IPAs) from preinvasive lesions in patients with solitary pure ground-glass nodules (GGN). Methods A primary cohort of patients with pathologically confirmed pulmonary solitary pure GGN after surgery were retrospectively studied at five institutions from January 2009 to September 2015. Half of the patients were randomly selected and assigned to a model-development cohort, and the remaining patients were assigned to a validation cohort. A nomogram predicting the invasive extent of the solitary GGNs was constructed based on the independent risk factors. Predictive performance was evaluated by concordance index (C-index) and calibration curve. Results Out of 898 cases included in the study, 501 (55.8%) were preinvasive lesions and 397 (44.2%) were IPAs. In the univariate analysis, lesion size (p < 0.001), lesion margin (p = 0.041), lesion shape (p < 0.001), mean computed tomography (CT) value (p = 0.018), presence of pleural indentation (p = 0.017), and smoking status (p = 0.014) were significantly associated with invasive extent. In multivariate analysis, lesion size (p < 0.001), lesion margin (p = 0.042), lesion shape (p < 0.001), mean CT value (p = 0.014), presence of pleural indentation (p = 0.026), and smoking status (p = 0.004) remained the predictive factors of invasive extent. A nomogram was developed and validation results showed a C-index of 0.94, demonstrating excellent concordance between predicted and observed results. Conclusions We established and validated a novel nomogram that can identify IPAs from preinvasive lesions in patients with solitary pure GGN.

Air bronchogram: A potential indicator of epidermal growth factor receptor mutation in pulmonary subsolid nodules

OBJECTIVES Evaluation of pulmonary subsolid nodule is a longstanding clinical problem. We aimed to validate the computed tomography (CT) features correlating with pathological invasiveness and to explore any imaging findings associated with epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma. METHODS A total of 204 patients with pathologically proven stage IA adenocarcinoma who had preoperative CT and data on EGFR status were enrolled in this retrospective study. Quantitative CT features including tumor size and solid volume proportion (SVP) were measured on multiplanar reconstructed images. Pathological analysis was stratified into adenocarcinoma in situ and minimally invasive adenocarcinoma (AIS/MIA), and invasive adenocarcinomas (IAs). RESULTS There were 93 AIS/MIA and 111 IAs. EGFR mutation was detected in 109 (53.4%) cases. In radiopathological analysis, IAs were significantly in larger tumor size (15.8mm vs. 10.9mm), higher SVP (18.3% vs. 1.1%) and more likely to present air bronchogram, vascular invasion, lobulated/irregular shape, non-smooth margin and pleural tag than AIS/MIA. The multivariate logistic regression indicated that tumor size (OR=1.337) and SVP (OR=1.198) were significant differentiating factors of IAs from AIS/MIA. In radiogenomic analysis, EGFR status differed in tumor size, air bronchogram and margin. The multivariate logistic regression disclosed that the presence of an air bronchogram (OR=3.451) was significantly associated with EGFR mutation after adjustment for age, gender and smoking status. CONCLUSIONS In subsolid nodules, tumor size and SVP were significant predictors of pathological invasiveness. In addition, the presence of air bronchogram was suggestive of activated EGFR mutation.

Functional CT imaging techniques for the assessment of angiogenesis in lung cancer

Lung cancer remains the leading cause of cancer mortality worldwide. Only 7% of patients will survive five years (1). At the time of diagnosis most patients already will have advanced disease and may only be treated by palliation. However, ongoing developments of chemotherapy and the availability of targeted therapies have improved the survival of patients with NSCLC.

Hemostasis and Lipoprotein Indices Signify Exacerbated Lung Injury in TB With Diabetes Comorbidity

Background Exacerbated immunopathology is a frequent consequence of TB that is complicated by diabetes mellitus (DM); however, the underlying mechanisms are still poorly defined. Methods In the two groups of age‐ and sex‐matched patients with TB and DM (DM‐TB) and with TB and without DM, we microscopically evaluated the areas of caseous necrosis and graded the extent of perinecrotic fibrosis in lung biopsies from the sputum smear‐negative (SN) patients. We scored acid‐fast bacilli in sputum smear‐positive (SP) patients and compiled CT scan data from both the SN and SP patients. We compared inflammatory biomarkers and routine hematologic and biochemical parameters. Binary logistic regression analyses were applied to define the indices associated with the extent of lung injury. Results Enlarged caseous necrotic areas with exacerbated fibrotic encapsulations were found in SN patients with DM‐TB, consistent with the higher ratio of thick‐walled cavities and more bacilli in the sputum from SP patients with DM‐TB. Larger necrotic foci were detected in men compared with women within the SN TB groups. Significantly higher fibrinogen and lower high‐density lipoprotein cholesterol (HDL‐C) were observed in SN patients with DM‐TB. Regression analyses revealed that diabetes, activation of the coagulation pathway (shown by increased platelet distribution width, decreased mean platelet volume, and shortened prothrombin time), and dyslipidemia (shown by decreased low‐density lipoprotein cholesterol, HDL‐C, and apolipoprotein A) are risk factors for severe lung lesions in both SN and SP patients with TB. Conclusions Hemostasis and dyslipidemia are associated with granuloma necrosis and fibroplasia leading to exacerbated lung damage in TB, especially in patients with DM‐TB.

From diagnosis to therapy in lung cancer: management of CT detected pulmonary nodules, a summary of the 2015 Chinese-German Lung Cancer Expert Panel

The first Chinese-German Lung Cancer Expert Panel was held in November 2015 one day after the 7th Chinese-German Lung Cancer Forum, Shanghai. The intention of the meeting was to discuss strategies for the diagnosis and treatment of lung cancer within the context of lung cancer screening. Improved risk classification criteria and novel imaging approaches for screening populations are highly required as more than half of lung cancer cases are false positive during the initial screening round if the National Lung Screening Trial (NLST) demographic criteria [≥30 pack years (PY) of cigarettes, age ≥55 years] are applied. Moreover, if the NLST criteria are applied to the Chinese population a high number of lung cancer patients are not diagnosed due to non-smoking related risk factors in China. The primary goal in the evaluation of pulmonary nodules (PN) is to determine whether they are malignant or benign. Volumetric based screening concepts such as investigated in the Dutch-Belgian randomized lung cancer screening trial (NELSON) seem to achieve higher specificity. Chest CT is the best imaging technique to identify the origin and location of the nodule since 20% of suspected PN found on chest X-ray turn out to be non-pulmonary lesions. Moreover, novel state-of-the-art CT systems can reduce the radiation dose for lung cancer screening acquisitions down to a level of 0.1 mSv with improved image quality to novel reconstruction techniques and thus reduce concerns related to chest CT as the primary screening technology. The aim of the first part of this manuscript was to summarize the current status of novel diagnostic techniques used for lung cancer screening and minimally invasive treatment techniques for progressive PNs that were discussed during the first Chinese-German Lung Cancer. This part should serve as an educational part for the readership of the techniques that were discussed during the Expert Panel. The second part summarizes the consensus recommendations that were interdisciplinary discussed by the Expert Panel.

Sex influences the association between haemostasis and the extent of lung lesions in tuberculosis

BackgroundWorldwide tuberculosis (TB) reports show a male bias in morbidity; however, the differences in pathogenesis between men and women with TB, as well as the mechanisms associated with such differences, are poorly investigated. We hypothesized that comparison of the degree of lung injury and clinical indices of well-matched men and women with newly diagnosed TB, and statistical analysis of the correlation between these indices and the extent of lung lesions, can provide insights into the mechanism of gender bias in TB.MethodsWe evaluated the acid-fast bacilli grading of sputum samples and compiled computed tomography (CT) data of the age-matched, newly diagnosed male and female TB patients without history of smoking or comorbidities. Inflammatory biomarker levels and routine haematological and coagulation-associated parameters were compared. Binary logistic regression analysis was used to define the association between the indices and lung lesions, and the influence of sex adjustment.ResultsWomen with TB have a longer delay in seeking healthcare than men after onset of the TB-associated symptoms. Men with TB have significantly more severe lung lesions (cavities and healing-associated features) and higher bacterial counts compared to women with TB. Scoring of the CT images before and after anti-TB treatment showed a faster response to therapy in women than in men. Coagulation- and platelet-associated indices were in models from multivariate regression analysis with groups of males or females with TB or in combination. In univariate regression analysis, lower lymphocyte counts were associated with both cavity and more bacterial counts, independent of sex, age and BMI. The association of international normalized ratios (INR), prothrombin times (PTs), mean platelet volumes (MPVs) and fibrinogen (FIB) level with lung lesions was mostly influenced by sex adjustment.ConclusionsSex influences the association between haemostasis and extent of TB lung lesions, which may be one mechanism involved in sex bias in TB pathogenesis.

Imaging features of TSCT predict the classification of pulmonary preinvasive lesion, minimally and invasive adenocarcinoma presented as ground glass nodules

OBJECTIVES To comprehensively investigate the role of thin section computed tomography(TSCT) features to distinguish invasive adenocarcinoma(IA) from preinvasive or minimally invasive adenocarcinoma(MIA) appearing as pure or mixed ground glass nodules (pGGNs, mGGNs), and to distinguish adenocarcinoma in situ (AIS) from atypical adenomatous hyperplasia (AAH) in pGGNs. MATERIALS AND METHODS Three hundred thirteen patients with 334 pathologically diagnosed GGNs according to the 2011 IASLC/ATS/ERS classification were included into this study. The TSCT features of the AAH-MIAs and IAs were compared and analyzed respectively in pGGNs (158 cases) and mGGNs (176 cases). Additionally, AIS (30 cases) and AAH (33 cases) were further analyzed in pGGNs. Receiver operating characteristic(ROC) analysis were performed to determine the cutoff values for the qualitative variables and their diagnostic performances. RESULTS In pGGNs, significant differences were found in the tumor volume(p=0.017, OR=4.98, 95%CI 1.33-18.62) and tumor mass(p=0.03, OR=5.04, 95%CI 1.17-21.59) between AAH-MIAs (AAH, AIS, MIA) group and IAs group, and tumor mass(p=0.037, OR=4.32, 95%CI 1.09-17.10) and standard deviation(SD) (p=0.019, OR=13.92, 95%CI 1.53-126.57) could distinguish AIS from AAH. In mGGNs, significant differences were found in consolidation size (p=0.006, OR=21.98, 95%CI 2.46-196.67) and consolidation mean CT value (p=0.011, OR=18.20, 95%CI1.96-168.88) between AAH-MIAs group and IAs group. Multivariate and ROC analyses revealed that in pGGNs, tumor size (≥1125mm) and mass (>386) were significantly associated with IAs. SD (≥68) and mass (≥70) were significant in distinguishing AIS from AAH. Larger consolidation of nodules (≥8.1mm) and higher CT values of the solid components (≥-222 HU) in mGGNs were significantly associated with IAs. CONCLUSION TSCT features can help distinguish IAs from AAH-MIAs both in pGGNs and mGGNs, and identify AIS from AAH in pGGNs, which indicated that imaging features may be helpful to guide the therapeutic choice for patients with GGNs which were considered as high risk of malignant diseases.