Minor (≤ 10%) Ground-Glass Opacity Component in Clinical Stage I Non-Small Cell Lung Cancer: Associations With Pathologic Characteristics and Clinical Outcomes.

BACKGROUND. The presence of a ground-glass opacity (GGO) component is a favorable prognostic factor in non-small cell lung cancer (NSCLC), although the prognostic impact of a very small GGO component remains poorly investigated. OBJECTIVE. The purpose of this article is to investigate the impact of a minor (≤ 10%) GGO component on the prognosis of clinical stage I NSCLC in comparison with pure-solid nodules. METHODS. This retrospective study included 382 patients (mean age, 60.8 years; 210 men, 172 women) who underwent surgical resection between January 1, 2015, and December 31, 2015, for clinical stage I NSCLC appearing on preoperative chest CT as a nodule with a consolidation-to-tumor ratio (CTR) of 0.9 to 1.0. Two radiologists independently assigned nodules to groups as either minor GGO (CTR, ≥ 0.9 and < 1.0) or pure solid (CTR = 1.0). Recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed by Kaplan-Meier curves and compared between groups using log-rank tests. Cox proportional hazards models were used to assess associations with outcomes. RESULTS. The two radiologists agreed for all nodules' classification into the minor-GGO (n = 106) or pure-solid (n = 276) groups. The mean CTR of the minor-GGO group was 0.93 ± 0.02 (SD) (range, 0.90-0.97). Minor-GGO nodules, in comparison with pure-solid nodules, showed greater solid-component diameter (2.68 vs 2.16 cm; p < .001) and total nodule diameter (2.89 vs 2.16 cm; p < .001). The minor-GGO group, in comparison with the pure-solid group, showed lower frequencies of visceral pleural invasion (6.6% vs 17.0%, p = .009) and pathologic lymph node involvement (4.7% vs 20.3%, p < .001), and EGFR mutation (71.6% vs 39.9%; p < .001). The minor-GGO group, in comparison with the pure-solid group, showed better 5-year RFS (83.4% vs 55.0%; p < .001) and higher frequency of better 5-year CSS (92.4% vs 76.4%, p = .004). In multivariable analysis adjusting for patient, imaging, pathologic, and genetic factors, a minor-GGO component was independently associated with a decreased likelihood of recurrence (HR = 0.37, p = .001) but not with the likelihood of CSS. CONCLUSION. Among patients with clinical stage I NSCLC, cancers with a minor-GGO component were associated with a better prognosis versus those with a pure-solid appearance. CLINICAL IMPACT. Radiologists encountering predominantly solid nodules on CT should carefully assess images for even a minor-GGO component given the favorable prognosis.

Clinicopathologic Features and Survival Outcomes of Primary Lung Mucinous Adenocarcinoma Based on Different Radiologic Subtypes.

BACKGROUND: Primary lung mucinous adenocarcinomas (LMAs) could be subclassified as the pure-solid, part-solid, and pneumonic types according to the findings of high-resolution computed tomography. This study aimed to expound on the clinicopathologic, radiologic, and prognostic characteristics of LMAs based on radiologic classification within a large set of patients. METHODS: From November 2009 to December 2016, this study enrolled 294 resected LMAs, which were divided into the pure-solid (n = 169), part-solid (n = 87), and pneumonic (n = 38) types. The clinicopathologic and radiologic characteristics of the tumors were evaluated, and patient prognosis was determined through follow-up evaluation. Survival outcomes were calculated by Kaplan-Meier curves and compared using log-rank tests. The prognostic impact of clinicopathologic variables, including radiologic presentations, were evaluated by establishing a Cox proportional hazards model. RESULTS: The LMAs were infrequently associated with lymph node metastasis (5.4 %), lymphatic/vascular invasion (4.4 %), or visceral pleural invasion (5.1 %). During the median 71-month follow-up period, recurrence was observed in 62 patients and death in 44 patients. The patients with pneumonic-type LMAs had a poorer prognosis (5-year recurrence-free survival [RFS], 23.7 %; 5-year overall survival [OS], 44.7 %) than those with the pure-solid type (RFS, 83.2 %; OS, 100 %) or part-solid type (RFS, 93.7 %; OS, 100 %). Besides, lymph node metastasis, emphysema, and clinical T stage were independent predictors of RFS and OS. CONCLUSION: Solitary-type LMA patients had excellent prognoses, whereas the survival outcomes for pneumonic-type LMA patients were dismal. Furthermore, pneumonic-type LMA patients were prone to intrapulmonary metastasis by means of aerogenous dissemination rather than distant metastasis.

Air bronchogram on chest CT in radiological pure-solid appearance lung cancer: Correlation analysis with genetic pathological features and survival outcomes.

PURPOSE: To investigate the correlation of air bronchogram sign with clinicopathological characteristics and prognosis in patients with clinical stage (c-stage) I non-small cell lung cancer (NSCLC) with radiological pure-solid appearance. METHOD: We retrospectively evaluated 276 patients with pure-solid c-stage I NSCLC and assessed the correlation between the air bronchogram and clinicopathological characteristics. A Cox proportional hazards model was performed to identify the effect of air bronchogram and clinicopathological variables on oncological outcomes. Recurrence-free survival (RFS) and overall survival (OS) were calculated by Kaplan-Meier curves and were compared using log-rank tests. RESULTS: Presence of air bronchogram was associated with a well differentiated degree (P =.026), higher incidence of EGFR mutation (P <.001) and lower recurrence(P =.021). Kaplan-Meier survival curves showed that air bronchogram group was associated with favorable RFS(67.0% vs. 50.2%; P =.015). A multivariable analysis revealed that air bronchogram and EGFR mutation were independent significant prognostic factors associated with RFS (hazard ratio [HR] = 0.495, 95% confidence interval [CI]: 0.322-0.761, P =.001; HR = 1.625, 95% CI: 1.074-2.457, P =.021; respectively), but not with OS. Additionally, we found that pathological lymph node metastasis was identified as an independent prognostic factor associated with poor RFS and OS(HR = 2.808, 95% CI: 1.913-4.123, P <.001 for RFS; HR = 1.983, 95% CI: 1.185-3.318, P =.009 for OS). CONCLUSIONS: Presence of air bronchogram was associated with well differentiated degree, higher incidence of EGFR mutation and had additional positive prognostic value for RFS in c-stage I NSCLC with a radiological pure-solid appearance.

The development and validation of a circulating tumor cells-based integrated model for improving the indeterminate lung solid nodules diagnosis.

Background: There is a risk of over investigation and delayed treatment in the work up of solid nodules. Thus, the aim of our study was to develop and validate an integrated model that estimates the malignant risk for indeterminate pulmonary solid nodules (IPSNs). Methods: Patients included in this study with IPSNs who was diagnosed malignant or benign by histopathology. Univariate and multivariate logistic regression were used to build integrated model based on clinical, circulating tumor cells (CTCs) and radiomics features. The performance of the integrated model was estimated by applying receiver operating characteristic (ROC) analysis, and tested in different nodules size and intermediate risk IPSNs. Net reclassification index (NRI) was applied to quantify the additional benefit derived from the integrated model. Results: The integrated model yielded areas under the ROC curves (AUCs) of 0.83 and 0.76 in internal and external set, respectively, outperforming CTCs (0.70, P=0.001; 0.68, P=0.128), the Mayo clinical model (0.68, P<0.001; 0.55, P=0.007), the and radiomics model (0.72, P=0.002; 0.67, P=0.050) in both validation sets. Robust performance with high sensitivity up to 98% was also maintained in IPSNs with different solid size and intermediate risk probability. The performance of the integrated model was comparable with positron emission tomography/computed tomography (PET-CT) examination (P=0.308) among the participants with established PET-CT records. NRI demonstrated that the integrated model provided net reclassification of at least 10% on the external validation set compared with single CTCs test. Conclusions: The integrated model could complement conventional risk models to improve the diagnosis of IPSNs, which is not inferior to PET-CT and could help to guide clinician's decision-making on clinically specific population.

The value of completion residual lung resection in ipsilateral recurrent non-small cell lung cancer.

Background: Recurrence is one of the most important challenges to manage lung cancer. Selected patients might be candidates for resection. This study assessed the outcomes and hazard factors of patients after completion of lung resection for recurrence, focusing specifically on postrecurrence survival (PRS) and overall survival (OS) after surgery. Methods: This retrospective study enrolled 63 patients who underwent complete pulmonary resection for recurrence between January 2015 and December 2018. Inclusion criteria include potentially curative first resection for primary lung cancer, histologically proven recurrent or new malignancy, and complete pathological report after both operations. PRS and OS were assessed and the influence of patient and treatment features on these endpoints was evaluated. Results: Most of the patients recurred at stage IIIA, and nearly three-fourth received complete pneumonectomy. The overall 2- and 5-year survival rates were 95% and 75%, whereas the overall 2- and 5-year postrecurrence survival rates were 55% and 36%, respectively. No patient died within 30 or 90 days after completion of residual lung resection, and no serious complications occurred during follow-up. Upon selection of clinically important variables by the Cox proportional hazards regression model, the r-stage [hazard ratio (HR), 3.35; 95% CI, 1.11-10.10; P = 0.03] and stage of primary tumor (HR, 6.26; 95% CI, 2.00-19.55; P < 0.01) were hazard factors for PRS and OS respectively. Conclusions: Complete pulmonary resection is an acceptable option in selected patients with recurrent lung cancer after surgery. The patients with r-stage earlier than IIIA may benefit from completion pulmonary resection but not IIIB. Completion pneumonectomy failed to significantly prolong the OS. The OS in the enrolled cases was mainly affected by the p-TNM stage assessed by the first resection for primary lung cancer.

Feasibility of double sleeve lobectomy after neoadjuvant chemotherapy in patients with non-small-cell lung cancer.

OBJECTIVES: This study intends to appraise the feasibility of double sleeve lobectomy after neoadjuvant chemotherapy in central non-small-cell lung cancer with bronchovascular aggression. METHODS: This retrospective study included non-small-cell lung cancer patients who received double sleeve lobectomy from January 2014 to June 2020. Patients were divided into 2 groups: the neoadjuvant chemotherapy group and the non-neoadjuvant chemotherapy group. Demographic data and perioperative outcomes were compared between these 2 groups. RESULTS: Of the 110 patients who received double sleeve lobectomy during this period, 35 patients (31.8%) received neoadjuvant chemotherapy. Compared with the non-neoadjuvant chemotherapy group, patients who received neoadjuvant chemotherapy were associated with younger age (P = 0.026), smaller pathologic tumour size (P = 0.005), higher forced expiratory volume in 1 s (P = 0.007), higher forced expiratory volume in 1 s of predicted value (P = 0.005) and higher clinical stage (P < 0.001). In the neoadjuvant chemotherapy group, 18 patients (51.4%) attained a partial response and 17 patients (48.6%) achieved stable disease. The postoperative hospital stays (P = 0.042) and chest tube drainage duration (P = 0.030) were longer in the neoadjuvant chemotherapy group and other perioperative performances were similar between these 2 groups. No statistically significant difference was reported in postoperative complications and mortality between these 2 groups. CONCLUSIONS: The intraoperative performance and postoperative outcomes of double sleeve lobectomy following neoadjuvant chemotherapy were similar to direct surgery, indicating that double sleeve lobectomy after neoadjuvant chemotherapy is feasible and safe in central lung cancer involving both the pulmonary artery and bronchus.

The learning curve for uniportal video-assisted thoracoscopic anatomical segmentectomy.

OBJECTIVES: The aim of this study is to evaluate the time course and caseload required to achieve proficiency by plotting the learning curve of uniportal thoracoscopic segmentectomy. METHODS: We retrospectively analyzed the first 238 and 159 cases of uniportal thoracoscopic segmentectomy performed by two surgeons (A and B). The learning curves were assessed using cumulative sum analysis. Perioperative outcomes were evaluated as the learning curve developed. Two subtypes of this surgical approach, simple and complex segmentectomy, were separately analyzed. RESULTS: Based on the learning curve, the inflection points occurred at 64 and 90 cases for surgeon A, 71 and 100 cases for surgeon B. Significantly longer operative time (p = .013), length of stay (p = .002), and drainage duration (p = .039) were observed between phase I and phase II compared to phase III for surgeon A. Operative times (p = .001) were significantly reduced for surgeon B. Furthermore, 26-28 and 52-56 cases were necessary to master the simple and complex segmentectomy, respectively. CONCLUSIONS: A total 64-71 cases were required to master uniportal thoracoscopic segmentectomy and 90-100 cases were necessary to achieve proficiency.

Clinical T1aN0M0 lung cancer: differences in clinicopathological patterns and oncological outcomes based on the findings on high-resolution computed tomography.

OBJECTIVES: To elucidate the clinicopathological characteristics and oncological outcomes of clinical T1aN0M0 (c-T1N0M0) lung cancer based on the newest 8th TNM classification. METHODS: A total of 257 patients with c-T1aN0M0 lung cancer were retrospectively included in this study. According to the solid component size manifesting on the high-resolution computed tomography (HRCT), all lesions were classified as the pure ground-glass nodule (pure-GGN) with a diameter > 3 cm (n = 19), part-solid (n = 174), and pure-solid (n = 64) groups. We evaluated the prognostic impact of clinicopathologic variables including radiological presentations by establishing Cox proportional hazards model. RESULTS: When we evaluated the prognostic impact based on the radiological subtypes, the 5-year recurrence-free survival (RFS) and overall survival (OS) were significantly different among pure-GGN, part-solid, and pure-solid groups (RFS: 100% versus 95.4% versus 76.6%, p < 0.0001; OS: 100% versus 98.9% versus 87.5%, p < 0.0001). Cox regression analysis revealed the preoperative carcinoembryonic antigen (CEA) level and consolidation tumor ratio (CTR) were independently significant prognosticators related to RFS and OS. Furthermore, a receiver operating characteristic (ROC) verified the CTR (area under ROC [AUC] 0.784, 95%CI 0.697-0.869) was equipped with good performance to predict the postoperative recurrence with a cutoff point at 0.5. Lung cancer with higher CTR tended to be associated with lower survival in the c-T1aN0M0 stage. CONCLUSIONS: For the c-T1aN0M0 lung cancer, pulmonary nodules manifested as the pure-GGN and part-solid subtypes had an excellent prognosis and may be considered as the "early-stage" cancer, whereas those with pure-solid appearance were associated with the high risk of recurrence despite the sub-centimeter size. KEY POINTS: • Radiological subtypes could further stratify the risk of lung cancer in cT1a. • Sub-solid nodule has a favorable survival in c-T1a lung cancer, whereas pure-solid nodule is not always "early-stage" lung cancer and is relatively prone to postoperative recurrence despite the sub-centimeter size. • The preoperative CEA level and CTR are valuable prognosticators to predict the recurrence in c-T1a lung cancer.

Clinicopathologic features and lymph node metastatic characteristics in patients with adenocarcinoma manifesting as part-solid nodule exceeding 3 cm in diameter.

PURPOSE: The purpose of this study was to elucidate the clinicopathologic and lymph node metastatic characteristics in patients with adenocarcinoma manifested as persistent ground glass mass (GGM, ground glass opacity [GGO] exceeding 3 cm in diameter). MATERIALS AND METHODS: 304 patients with adenocarcinoma manifested as persistent GGM > 3 cm, who underwent complete surgical resection between November 2013 and December 2017 were included in this study. We elucidated the lymph node metastatic incidence and characteristics according to the primary tumor lobe location and extracted the associated clinicopathological factors, especially thin-section computed tomographic findings, with lymph node involvement. RESULTS: All of the GGMs were invasive adenocarcinoma in histopathology. The total incidence of lymph node metastasis was 2.0% (6/304). All of the 6 cases with hilar or mediastinal lymph node metastasis were manifested as solid-predominant GGM > 3 cm and no cases with lymph node metastasis were identified in GGO-predominant GGM > 3 cm. Lymph node metastases were more likely to present in younger patients (p = 0.032), tumors with solid size >2.0 cm (p = 0.000), more advanced clinical T stage (p = 0.000), radiological solid-predominant tumors (p = 0.002) and acinar-predominant or papillary-predominant adenocarcinoma (p = 0.002). As for solid-predominant GGMs >3 cm, lymph node metastases were more likely to be found in tumors with solid size >2.0 cm (p = 0.026), more advanced clinical T stage(p = 0.026), acinar-predominant or papillary-predominant adenocarcinoma (p = 0.029). Whole tumor size was not associated with the presence of lymph node metastases. There were 2 right upper-lobe cases with upper mediastinal lymph nodes skip metastasis without intrapulmonary, interlobar, and hilar lymph node metastasis. CONCLUSION: All of the GGMs >3 cm were invasive adenocarcinoma. The incidence of lymph node metastasis in GGO-predominant GGMs >3 cm was extremely low. Solid size would be a better predictor of lymph node metastasis than whole tumor size in sold-predominant GGMs >3 cm.

Investigation of thermo-sensitive amphiphilic micelles as drug carriers for chemotherapy in cholangiocarcinoma in vitro and in vivo.

Cholangiocarcinoma is an epithelial cancer of the bile ducts with poor prognosis and, in recent years, a rapidly increasing incidence. In this study, nano-sized thermo-sensitive micelles were investigated as drug carriers to improve chemotherapy in cholangiocarcinoma. Thermo-sensitive amphiphilic block copolymer, P-(N,N-isopropylacrylamide-co-N-hydroxymethylacrylamide)-b-caprolactone [P-(NIPAAm-co-NHMAAm)-b-PCL] with lower critical solution temperature (LCST) at about 38°C was synthesized. Doxorubicin (DOX)-loaded micelles were prepared by dialysis method. The micelles exhibited a sustained and temperature-dependent DOX release. Toxicity of the blank micelles for human cholangiocarcinoma (QBC939) cells was minimal both in vitro and in vivo. In contrast, the DOX-loaded micelles effectively inhibited proliferation and induced apoptosis of QBC939 cells in vitro (p<0.05) and inhibited tumor growth in nude mice by 21.49%. These results indicated that thermo-sensitive amphiphilic micelles are a promising and effective drug carrier, and show potential for improving chemotherapy for cholangiocarcinoma.

[Somatostatin enhanced anti-tumor effect of doxorubicin on gallbladder cancer cells through the regulation of intracellular drug concentration].

OBJECTIVE: To investigate the possible mechanisms by which Somatostatin (SST) enhances the anti-tumor effect of doxorubicin (DOX) on gallbladder cancer cells. METHODS: GBC-SD cells were grouped into 4 groups: SST-treated group, DOX-treated group, SST+DOX co-treated group and control group. The concentrations of SST and DOX were 75 µg/ml and 5 µg/ml based on our previous studies. In control group, cells were cultivated with phosphate buffered saline (PBS). In experimental groups, cells were cultivated with medium and the corresponding drugs. After drug treatment, cell viability was examined by MTT assay at 6, 12, 24 and 36 h respectively. Meanwhile, intracellular concentrations of doxorubicin in each group was determined by microspectrofluorimetry; Real-time polymerase chain reaction (RT-PCR) was used to determine the expressions of MDR1 mRNA in the cells at different time points and the expressions of P-gp protein, a product of MDR1 mRNA, were determined by Western blot analysis. RESULTS: SST did not exhibit significant inhibitory effect on the proliferation of GBC-SD cells as compared to that of control group (P>0.05). SST+DOX co-treatment group and DOX showed significantly inhibitory effect on the growth of GBC-SD cells at Hour 12 post-treatment. However no statistical difference was found between SST+DOX and DOX groups. Interestingly, at Hour 24 post-treatment, SST+DOX group showed more robust inhibitory effect on GBC-SD cells as compared to DOX alone group. Moreover, SST could significantly down-regulate the expressions of MDR1 mRNA and P-gp protein. SST could increase intracellular DOX concentration. And the difference of intracellular DOX concentration between SST+DOX group and DOX group at Hour 24 was statistically significant. CONCLUSIONS: In our experiment, SST decreases the expression of MDR1 mRNA and P-gp protein so as to reduce the efflux of DOX and elevate DOX concentrations in GBC-SD cells. This eventually leads to enhanced cytotoxic effects of DOX on GBC-SD cells.