PD-L1 expression is the most useful predictive biomarker for immunotherapy efficacy on non-small cell lung cancer (NSCLC), and CD8+ tumor-infiltrating lymphocytes (CD8+ TILs) play an essential role ...in the clinical activity of immunotherapy. PD-L1 is found on the exosome's surface, and PD-L1 expressing exosomes can inhibit antitumor immune responses. This study aimed to analyze tumor PD-L1 expression, serum exosomal PD-L1, and CD8+ TILs to investigate anti-PD-1 response and clinicopathological outcomes in NSCLC. One hundred twenty patients with stage I-III NSCLC were enrolled, and serum samples collected during the initial surgery were pooled. The Human CD274/PD-L1 ELISA kit was used to quantify the exosomal PD-L1. Exosomal PD-L1 levels were significantly correlated with tumor PD-L1 levels (p < 0.001) and the number of CD8+ TILs (p = 0.001). Patients with exosomal PD-L1 ≥ 166 pg/mL tended to have a worse RFS than those with < 166 pg/mL in all stage (p = 0.163) and stage I patients (p = 0.116). Seventeen patients exhibited postoperative recurrences and received anti-PD-1 treatment. The disease control rate of patients with exosomal PD-L1 ≥ 166 pg/mL was 100%. The measurement of serum exosomal PD-L1 as a quantitative factor with tumor PD-L1 status may help predict anti-PD-1 response and clinical outcomes in patients with NSCLC.
Background
Reports on the prognosis for 5-year survivors with lung adenocarcinoma after resection are sparse. This study aimed to identify factors associated with overall survival (OS) and ...cancer-specific survival (CSS) for 5-year survivors with completely resected lung adenocarcinoma, and to determine whether preoperative imaging factors, including the presence of ground-glass opacity (GGO) components, affect late recurrence in long-term survivors.
Methods
Complete resection of lung adenocarcinoma was performed for 1681 patients between January 2000 and December 2013. Of these patients, 936 who survived 5 years or longer after surgery were identified, and factors associated with OS and CSS were determined using the Cox proportional hazard model.
Results
Multivariable analysis demonstrated that lymph node metastasis (
p
< 0.01) and absence of GGO components (
p
< 0.01) were independently associated with OS and CSS for the 5-year survivors. The absence of GGO components was significantly associated with OS (
p
< 0.01) and CSS (
p
< 0.01) also for the 5-year survivors with stage 1 disease (
n
= 782) and for the 5-year survivors without recurrence (
n
= 809). The incidence of recurrence anytime during the 10-year postoperative follow-up period differed significantly between the 5-year survivors with and without GGO components.
Conclusions
The absence of GGO components was significantly associated with an unfavorable prognosis for the 5-year survivors with completely resected lung adenocarcinoma regardless whether they had recurrences not.
High‐grade neuroendocrine lung cancer (HGNEC), which includes small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung is a rapidly proliferating, aggressive form of ...lung cancer. The initial standard chemotherapeutic regimens of platinum doublets are recommended for SCLC and have been frequently used for LCNEC. However, there are currently no molecularly targeted agents with proven clinical benefit for this disease. The deubiquitinating enzyme ubiquitin C‐terminal hydrolase‐L1 (UCHL1) is a neuroendocrine cell‐specific product that is known as a potential oncogene in several types of cancer, but little is known about the biological function of UCHL1 and its therapeutic potential in HGNEC. In this study, we found that preclinical efficacy evoked by targeting UCHL1 was relevant to prognosis in HGNEC. UCHL1 was found to be expressed in HGNEC, particularly in cell lines and patient samples of SCLC, and the combined use of platinum doublets with selective UCHL1 inhibitors improved its therapeutic response in vitro. Immunohistochemical expression of UCHL1 was significantly associated with postoperative survival in patients with HGNEC and contributed towards distinguishing SCLC from LCNEC. Circulating extracellular vesicles (EV), including exosomes isolated from lung cancer cell lines and serum from early‐stage HGNEC, were verified by electron microscopy and nanoparticle tracking analysis. Higher levels of UCHL1 mRNA in EV were found in the samples of patients with early‐stage HGNEC than those with early‐stage NSCLC and healthy donors’ EV. Taken together, UCHL1 may be a potential prognostic marker and a promising druggable target for HGNEC.
In this study, we found that preclinical efficacy evoked by targeting UCHL1 was relevant to prognosis in HGNEC. UCHL1 may be a potential prognostic marker and a promising druggable target for HGNEC.
Distinguishing lung squamous cell carcinoma (LSQCC) from a solitary metastatic lung tumor (MSQCC) from head and neck squamous cell carcinoma (HNSQCC) presents a difficult diagnostic challenge even ...after detailed pathological assessment. Treatment options and estimated survival outcomes after pulmonary resection differ between patients with LSQCC and MSQCC. This study aimed to investigate whether microRNA (miRNA) profiling by RNA sequencing of HNSQCC, MSQCC, and LSQCC was useful for differential diagnosis of MSQCC and LSQCC. RNA sequencing was performed to identify bioinformatically significant miRNAs from a formalin-fixed paraffin-embedded (FFPE) block from a derivation set. MiRNA levels were confirmed by validation sets using FFPE samples and serum extracellular vesicles from patients. Step-wise discriminant analysis and canonical discriminant analysis identified 13 miRNAs by which the different expression patterns of LSQCC, MSQCC, and HNSQCC groups were demonstrated. Six miRNAs (miR-10a/28/141/320b/3120) were assessed in validation sets, and 4 miRNAs (miR-10a/28/141/3120) were significantly upregulated in LSQCCs compared with MSQCCs and HNSQCCs. Serum extracellular vesicles from LSQCC patients demonstrated significantly elevated miR-10a (p = .042), miR-28 (p = .041), and miR-3120 (p = .047) levels compared with those from MSQCC patients. RNA sequencing is useful for differential diagnosis of LSQCC and MSQCC, and the expression level of miR-10a, miR-28, and miR-3120 in serum extracellular vesicles are promising noninvasive tools for this purpose.
Gene fusions play an important role in the carcinogenesis of lung adenocarcinoma. The recent association of four oncogenic driver genes, ALK, ROS1, RET, and NTRK1, as lung tumor predictive biomarkers ...has increased the need for precision medicine. We used formalin‐fixed, paraffin‐embedded tissue samples of non‐small cell lung cancer from 150 EGFR mutation‐negative cases and 10 fusion status‐known cases and compared the performance of the Oncomine Dx Fusion Transcript Test (ODxFT) with FISH break‐apart for the detection of ALK, RET, and ROS1 fusion genes. RNA was extracted from the paraffin‐embedded tissue samples with or without macrodissection under hematoxylin and eosin staining, and the ALK fusion gene was independently determined using these assays. Fusion detection analyses were successfully carried out using ODxFT in 150 cases, with only one invalid case. ALK fusion genes were detected at a frequency of 7.3% (11/150) in the lung cancer specimens. Concordance rate between the ODxFT and ALK‐FISH analyses was 99.3% (148/149). Sensitivity and specificity were 91.7% and 99.3%, respectively. All the samples with a known fusion status were accurately matched between the two assays. Our results show a high concordance rate between the ODxFT and ALK‐FISH analyses. ODxFT was thus validated as an effective method for detecting clinically significant ALK fusion genes in paraffin‐embedded tissue samples.
NGS‐based kit (ODxFT) detects four oncogenic fusion transcripts, ALK, ROS1, RET, and NTRK1. ODxFT analyzed RNA from FFPE tumor samples of 150 lung cancers successfully. The concordance rate between the ODxFT and ALK‐FISH analyses was 99.3% (148/149).
Next‐generation sequencing (NGS) and digital PCR technologies allow analysis of the mutational profile of circulating cell‐free DNA (cfDNA) in individuals with advanced lung cancer. We have now ...evaluated the feasibility of cfDNA sequencing for mutation detection in patients with non‐small cell lung cancer at earlier stages. A total of 150 matched tumor and serum samples were collected from non‐small cell lung cancer patients at stages IA–IIIA. Amplicon sequencing with DNA extracted from tumor tissue detected frequent mutations in EGFR (37% of patients), TP53 (39%), and KRAS (10%), consistent with previous findings. In contrast, NGS of cfDNA identified only EGFR, TP53, and PIK3CA mutations in three, five, and one patient, respectively, even though adequate amounts of cfDNA were extracted (median of 4936 copies/mL serum). Next‐generation sequencing showed a high accuracy (98.8%) compared with droplet digital PCR for cfDNA mutation detection, suggesting that the low frequency of mutations in cfDNA was not due to a low assay sensitivity. Whereas the yield of cfDNA did not differ among tumor stages, the cfDNA mutations were detected in seven patients at stages IIA–IIIA and at T2b or T3. Tumor volume was significantly higher in the cfDNA mutation‐positive patients than in the negative patients at stages T2b–T4 (159.1 ± 58.0 vs. 52.5 ± 9.9 cm3, P = 0.014). Our results thus suggest that tumor volume is a determinant of the feasibility of mutation detection with cfDNA as the analyte.
The detectability of somatic mutations in cfDNA obtained from lung cancer patients at earlier stages. Detection of the mutations relies on the tumor burden in the patients. Deep sequencing as well as digital PCR is reliable technology for detection of somatic mutations in serum.
Abstract Background We previously reported the prognostic impact of the number of involved lymph nodes (LNs) on survival in non-small cell lung cancer (NSCLC). However, it remains unknown whether the ...total number or anatomic location of involved LNs is a superior prognostic factor. Methods A total of 689 patients with NSCLC who underwent complete resection involving dissection of the hilar and mediastinal LNs with curative intent of ≥ 10 LNs were enrolled. The association between the total number of LNs (nN) involved and survival was assessed by comparison with the anatomic location of LN involvement (pathologic lymph node pN), the present nodal category. Results We classified the patients into five categories according to the combined pN and nN status as follows: pN0-nN0, pN1-nN1-3, pN1-nN4−, pN2-nN1-3, and pN2-nN4. Although there was no statistically significant difference between the pN1-nN4− and pN2-nN1-3 categories, pN2-nN1-3 had better prognoses than pN1-nN4−. On multivariate analysis, the nN category was an independent prognostic factor for overall survival and disease-free survival (vs nN4−; the hazard ratios of nN0 and nN1-3 for overall survival were 0.223 and 0.369, respectively, P < .0001 for all), similar to the pN category. We propose a new classification based on a combination of the pN and nN categories: namely, N0 becomes pN0-nN0, the N1 category becomes pN1-nN1-3, the N2a category becomes pN2-nN1-3 + pN1-nN4−, and the N2b category becomes pN2-nN4. Each survival curve was proportional and was well distributed among the curves. Conclusions A combined anatomically based pN stage classification and numerically based nN stage classification is a more accurate prognostic determinant in patients with NSCLC, especially in the prognostically heterogeneous pN1 and pN2 cases. Further large-scale international cohort validation analyses are warranted.
Abstract Objective The objective of this study was to identify the clinicopathologic factors influencing postrecurrence survival (PRS) in and the effect of postrecurrence therapy (PRT) on patients ...with completely resected stage I non-small cell lung cancer (NSCLC). Methods We reviewed the data of 919 patients in whom complete resection of stage I NSCLC had been performed. Results Of the 919 patients, 170 (18.5%) had recurrent disease. Initial PRT was performed in 118 patients (69.1%) (surgery in eight, chemotherapy in 79, radiotherapy in 10, and chemoradiotherapy in 21). On multivariate analyses, PRT (hazard ratio HR, 0.542; 95% CI, 0.344-0.853; P = .008), female sex (HR, 0.487; 95% CI, 0.297-0.801; P = .005), and differentiation (HR, 1.810; 95% CI, 1.194-2.743; P = .005) demonstrated a statistically significant association with favorable PRS. Bone metastasis (HR, 3.288; 95% CI, 1.783-6.062; P < .001), liver metastasis (HR, 4.518; 95% CI, 1.793-11.379; P = .001), chemotherapy (HR, 0.478; 95% CI, 0.236-0.975; P = .040), epidermal growth factor receptor-tyrosine kinase inhibitors treatment (EGFR-TKIs) (HR, 0.460; 95% CI, 0.245-0.862; P = .015), and nonadenocarcinoma (HR, 2.136; 95% CI, 1.273-3.585; P = .004) were independently and significantly associated with PRS in the 118 patients who underwent any PRT. Subgroup analysis with a combination of these five PRS factors in the patients who underwent any PRT revealed median PRS times of 42.4 months for 20 patients lacking all five risk factors and 18.8 months for 98 patients with at least one of these risk factors ( P = .001). Conclusions PRT, sex, and differentiation were independently associated with PRS. In the patients who underwent any PRT, PRS was related to EGFR-TKIs, chemotherapy, histology, and initial recurrence sites. One challenge for the future will be to create systematic treatment strategies for recurrent NSCLC according to the risk factor status of individual patients.
•75th percentile CT attenuation value is predictive of lepidic-predominant adenocarcinoma.•Maximum CT attenuation value is associated with lepidic-predominant adenocarcinoma.•SUVmax is also useful in ...distinguishing lepidic adenocarcinoma from non-lepidic ones.•CT histogram analysis is highly beneficial for understanding lung cancer biology.
The aim of this study was to analyze the accuracy of computed tomography (CT) and F-18 fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) to distinguish lepidic growth adenocarcinoma (LGA), including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic-predominant adenocarcinoma, all of which have favorable survival outcomes, from the more aggressive and invasive non-LGA subtypes.
We identified 225 patients with c-0/I adenocarcinoma of the lung who underwent PET/CT and 3DCT followed by complete resection. Maximum standardized uptake values (SUVmax) of FDG and several histogram parameters were analyzed. Histological grades were classified according to the predominant subtype (G1: lepidic; G3: micropapillary or solid; and G2: subtypes other than G1/G3).
The proportion of pathological invasive factors (lymphatic vessel involvement/blood vessel invasion/pleural invasion/lymph node metastasis) of patients with preinvasive adenocarcinoma, G1, G2, and G3 tumors were 0%, 3.6%, 48.0%, and 100%, respectively; p < 0.001). Multivariate analysis with CT-related parameters demonstrated that 75th percentile CT attenuation value (75th%, p < 0.001) and maximum CT attenuation value (maxCT, p = 0.009) were associated with incidence of non-LGA, whereas the value of SUVmax demonstrated a significant correlation (p < 0.001). When all patients were dichotomized according to ground-glass opacities (GGO)/solid-dominancy for CT maximum diameter, a significant correlation with non-LGA was shown in patients with solid-dominant tumor on SUVmax (p < 0.001) and with GGO-dominant tumor on 75th% (p = 0.006) and maxCT (p = 0.007). The combination of one of the two significant histogram parameters and SUVmax revealed higher predictive performance for pathological high malignant features (positive pathological invasive factors, non-LGA, and the highly malignant subtype covering G2 with moderately or poorly-differentiated carcinoma and G3) than the individual use of either factor.
The 75th%, maxCT, and SUVmax were highly useful in distinguishing LGA from non-LGA in c-0/I adenocarcinoma.
Purpose
We aimed to assess the clinical usefulness of the fissureless technique, which avoided dissection of the lung parenchyma over the pulmonary artery, in preventing prolonged air leak after ...video-assisted thoracic surgery right upper lobectomy (VATS RUL).
Methods
Perioperative outcomes, including the frequency of prolonged air leak after fissureless technique or traditional fissure dissection technique, which dissected the lung parenchyma through the fissure, were compared in patients who underwent VATS RUL (
n
= 213) between January 2016 and March 2020. We adopted our fissural grade to evaluate the degree of fused fissure ranging from II (light incomplete fissure) to IV (severe incomplete fissure), which covered all fissural grades in 213 patients.
Results
Fifty-four and 159 patients underwent fissureless and traditional techniques, respectively. Significant differences in the incidence of prolonged air leak (
p
= 0.037), time to air leak cessation (
p
= 0.047), and duration of chest tube placement (
p
= 0.017) were observed between fissureless and traditional technique groups. On multivariable analysis, traditional technique (
p
= 0.005), and greater fissural grade (III vs II,
p
= 0.020; IV vs II, p = 0.001) were significantly associated with prolonged air leak.
Conclusions
Fissureless technique during VATS RUL can be a superior alternative to the traditional technique to prevent prolonged air leak in treating incomplete fissures.
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