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Objective: It is unclear whether epidermal growth factor receptor (EGFR) mutation status is a risk factor for postoperative recurrence of surgically resected lung adenocarcinoma (ADC). Therefore, we conducted a multi-institutional study employing matched-pair analysis to compare recurrence-free survival (RFS) and overall survival (OS) of patients with lung ADC according to EGFR mutation status., Methods: We collected the records of 909 patients who underwent surgical resection for lung ADC between 2005 and 2012 at five participating institutions and were also examined their EGFR mutation status. For each patient with an EGFR mutation, we selected one with the wild-type EGFR sequence and matched them according to institution, age, gender, smoking history, pathological stage (pStage), and adjuvant treatment. We compared RFS and OS of the matched cohort., Results: The patients were allocated into groups (n=181 each) with mutated or wild-type EGFR sequences. Both cohorts had identical characteristics as follows: institution, median age (68 years), men (85, 47%), ever smokers (77, 43%), and pStage (IA, 108, 60%; IB, 48, 27%; II, 14, 8%; III, 11, 6%). The 3- and 5-year RFS rates of patients with mutated or wild-type EGFR sequence were 79%, 68% and 77%, 68%, respectively (p=0.557). The respective OS rates were 92%, 81%, and 89%, 79% (p=0.574)., Conclusion: Matched-pair and multi-institutional analysis reveals that an EGFR mutation was not a significant risk factor for recurrence of patients with surgically resected lung adenocarcinoma., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Latent lymph node metastasis is a clinical concern in the surgical treatment of non-small cell lung cancer (NSCLC). The present study identified a simple tool, including the volume-doubling time (VDT), for evaluating the risk of nodal metastasis., Methods: We reviewed, retrospectively, 560 patients who underwent radical resection for cN0M0 NSCLC. The whole tumor VDT and solid component VDT (SVDT) for differentiating the histological type and adenocarcinoma subtype were analyzed and a nomogram was constructed using variables selected through a stepwise selection method. The model was assessed through a calibration curve and decision curve analysis (DCA)., Results: Lymph node metastases were detected in 89 patients (15.9%). The SVDT tended to be longer in patients with adenocarcinoma (294.5 days, p < 0.0001) than in those with other histological types of NSCLC, but was shorter when the solid/micropapillary component was predominant (127.0 days, p < 0.0001). The selected variables (tumor location, solid component diameter, consolidation tumor ratio, SVDT, and carcinoembryonic antigen) demonstrated significant differences and were used for the nomogram. The calibration curve indicated consistency, and the DCA showed validity across most threshold ranges from 0 to 68%., Conclusions: The established nomogram is a useful tool for the preoperative prediction of lymph node metastasis, and the SVDT was the most influential factor in the nomogram., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Aim: In Japan, primary human papilloma virus (HPV) testing has not been introduced for cervical cancer screening due to concerns that HPV-negative lesions may be missed and a lack of Japanese data. The purpose of this study was to evaluate the validity of primary HPV testing in Japan by analyzing cervical intraepithelial neoplasia 2 (CIN2) or more/high-risk HPV- (CIN2+/hrHPV-) cases in cervical cancer screening., Methods: Data from 35 525 cervical cancer screenings with HPV testing and cervical cytology from 2011 to 2019 in Saga City, Japan, were reviewed. The cases with low-grade squamous intraepithelial lesion (LSIL+)/hrHPV- were analyzed in detail., Results: The results of the 35 525 examinees were as follows: 31 123 were negative for intraepithelial lesion or malignancy (NILM)/hrHPV-, 2612 were NILM/hrHPV+, 262 were atypical squamous cells of undetermined significance (ASC-US)/hrHPV-, 213 were ASC-US/hrHPV+, 291 were LSIL+/hrHPV-, and 1024 were LSIL+/hrHPV+. Of the 256 LSIL+/hrHPV- examinees for whom histology was available, CIN2+ were CIN2 9.4% (24/256), CIN3 3.9% (10/256), cervical adenocarcinoma 0.4% (1/256), uterine corpus cancer 1.2% (3/256), and uterine sarcoma 0.4% (1/256). Overall, the rate of LSIL+/hrHPV- was 0.82% (291/35.525), 0.1% (36/35525) of which were cervical lesions with CIN2+. Only one cervical adenocarcinoma was detected, but gastric-type adenocarcinoma was not included., Conclusion: HPV-negative CIN2+ or cervical adenocarcinoma is not a concern for the introduction of primary HPV screening in Japan. Primary HPV testing in cervical cancer screening is considered a feasible method that can be used in Japan, although an algorithm suitable for Japan and a national-level management system need to be established., (© 2023 Japan Society of Obstetrics and Gynecology.)

Objectives: Hypoxia is a key element involved in the development and progression of tumors. HIF-1α may transiently induce and mediate the response to acute and severe hypoxia, while HIF-2α may induce a longer response and may control the response to chronic and moderate hypoxia. Hypoxia increases the cellular uptake of FDG. Therefore, HIF may play an important role in the process of the cellular uptake of FDG. The aim of this study was to compare HIF-1α/HIF-2α expression with FDG uptake, Glut-1 expression, and prognosis in the patients with lung adenocarcinoma and to investigate the role of HIF-1α/HIF-2α in the uptake of FDG in lung adenocarcinoma., Methods: In the current work, we compared the immunohistochemical expression of HIF-1α and HIF-2α in surgical specimens of 44 patients with lung adenocarcinoma. The relationships between HIF-α expression and Glut-1 expression, FDG uptake, and clinicopathological factors, including prognosis, were analyzed., Results: There was a marginal association between HIF-1α and HIF-2α expressions (P = 0.076). We found a significant correlation between HIF-2α expression and FDG uptake (P = 0.0001). HIF-1α expression showed a marginal association with FDG uptake (P = 0.066). FDG uptake correlated more significantly with HIF-2α expression than with HIF-1α expression. A significant correlation was noticed between Glut-1 expression and both HIF-1α and HIF-2α expressions (P = 0.005 and P = 0.003, respectively). Univariate analysis of disease-free survival demonstrated that FDG uptake and HIF-2α expression, but not HIF-1α expression, were related to recurrence (P < 0.0001)., Conclusion: FDG uptake correlated more significantly with HIF-2α expression than with HIF-1α expression, and both FDG uptake and HIF-2α expression, but not HIF-1α expression was correlated with post-operative recurrence in the patients with lung adenocarcinoma. These results suggest that both FDG uptake and HIF-2α expression may represent a more aggressive phenotype and that HIF-2α may play a more important role than HIF-1α in the uptake of FDG in lung adenocarcinoma.

Background: The purpose of this study was to determine the prognostic significance of the maximum standardized uptake value (SUVmax) on F-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) in patients undergoing surgical treatment for non-small cell lung cancer., Materials and Methods: Seventy-eight consecutive patients (58 with adenocarcinomas, 20 with squamous cell carcinomas) treated with potentially curative surgery were retrospectively reviewed., Results: The SUVmax was significantly higher in the patients with recurrent than with non-recurrent adenocarcinoma (p<0.01). However, among the patients with squamous cell carcinoma, there were no differences with or without recurrence (p=0.69). Multivariate analysis indicated that the SUVmax of adenocarcinoma lesions was a significant predictor of disease-free survival (p=0.04). In addition, an SUVmax of 6.19, the cut-off point based on ROC curve analysis of the patients with pathological IB or more advanced stage adenocarcinomas, was found to be a significant predictor of disease-free survival (p<0.01)., Conclusions: SUVmax is a useful predictor of disease-free survival in patients with resected adenocarcinoma, but not squamous cell carcinoma. Patients with adenocarcinoma exhibiting an SUVmax above 6.19 are candidates for more intensive adjuvant therapy.

Background: The epidermal growth factor receptor (EGFR) mutation status of lung cancer is important because it means that EGFR-tyrosine kinase inhibitor treatment is indicated. The purpose of this prospective study is to determine whether EGFR mutation status could be identified with reference to preoperative factors., Materials and Methods: One hundred-forty eight patients with lung cancer (111 adenocarcinomas, 25 squamous cell carcinomas and 12 other cell types) were enrolled in this study. The EGFR mutation status of each lung cancer was analyzed postoperatively., Results: There were 58 patients with mutant EGFR lung cancers (mutant LC) and 90 patients with wild-type EGFR lung cancers (wild-type LC). There were significant differences in gender, smoking status, maximum tumor diameter in chest CT, type of tumor shadow, clinical stage between mutant LC and wild-type LC. EGFR mutations were detected only in adenocarcinomas. Maximum standardized uptake value (SUVmax:3.66±4.53) in positron emission tomography-computed tomography of mutant LC was significantly lower than that (8.26±6.11) of wild-type LC (p<0.0001). Concerning type of tumor shadow, the percentage of mutant LC was 85.7% (6/7) in lung cancers with pure ground glass opacity (GGO), 65.3%(32/49) in lung cancers with mixed GGO and 21.7%(20/92) in lung cancers with solid shadow (p<0.0001). For the results of discriminant analysis, type of tumor shadow (p=0.00036) was most significantly associated with mutant EGFR. Tumor histology (p=0.0028), smoking status (p=0.0051) and maximum diameter of tumor shadow in chest CT (p=0.047) were also significantly associated with mutant EGFR. The accuracy for evaluating EGFR mutation status by discriminant analysis was 77.0% (114/148)., Conclusions: Mutant EGFR is significantly associated with lung cancer with pure or mixed GGO, adenocarcinoma, never-smoker, smaller tumor diameter in chest CT. Preoperatively, EGFR mutation status can be identified correctly in about 77 % of lung cancers.

Background: The significance of diffusion-weighted imaging (DWI) is uncertain for the diagnosis of nodal involvement. The purpose of this study was to examine diagnostic capability of DWI compared with PET-CT for nodal involvement of lung cancer., Methods: A total of 160 lung cancers (114 adenocarcinomas, 36 squamous cell carcinomas, and 10 other cell types) were analyzed in this study. DWI and PET-CT were performed preoperatively., Results: The optimal cutoff values to diagnose metastatic lymph nodes were 1.70 × 10(-3) mm(2)/s for ADC value and 4.45 for SUVmax. DWI correctly diagnosed N staging in 144 carcinomas (90 %) but incorrectly diagnosed N staging in 16 (10 %) [3 (1.9 %) had overstaging, 13 (8.1 %) had understaging]. PET-CT correctly diagnosed N staging in 133 carcinomas (83.1 %) but incorrectly diagnosed N staging in 27 (16.8 %) [4 (2.5 %) had overstaging, 23 (14.4 %) had understaging]. Sensitivity, accuracy, and negative predictive value for N staging by DWI were significantly higher than those by PET-CT. Of the 705 lymph node stations examined, 61 had metastases, and 644 did not. The maximum diameter of metastatic lesions in lymph nodes were 3.0 ± 0.9 mm in 21 lymph node stations not detected by either DWI or PET-CT: 7.2 ± 4.1 mm in 39 detected by DWI, and 11.9 ± 4.1 mm in 24 detected by PET-CT. There were significant differences among them. The sensitivity (63.9 %) for metastatic lymph node stations by DWI was significantly higher than that (39.3 %) by PET-CT. The accuracy (96.2 %) for all lymph node stations by DWI was significantly higher than that (94.3 %) by PET-CT., Conclusions: DWI has advantages over PET-CT in diagnosing malignant from benign lymph nodes of lung cancers.

The aim of this study was to interpret diffusion-weighted imaging (DWI) signals in lung cancers. They were converted into several three-dimensional DWI signals patterns, which represent the degree of DWI signal intensity by height and the degree of distribution by area: flat, low elevation, irregular elevation, single-peak elevation, multiple-peak elevation, and nodular elevation. There were 39 adenocarcinomas and 21 squamous cell carcinomas. Three-dimensional DWI signals decreased significantly in order of cell differentiation. Tumor cellular densities were increased according to the increase in three-dimensional DWI signals. DWI signal intensity and distribution can represent the amount of cancer cells and their distribution in the carcinoma., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We report a case of a female in her 80s who was diagnosed with recurrent lung adenocarcinoma after primary surgery. She was treated with a systemic chemotherapy regimen consisting of carboplatin plus paclitaxel until the disease showed progression. On detection of epidermal growth factor receptor(EGFR)mutations, we administered gefitinib, an EGFR tyrosine kinase inhibitor, at a dosage of 250 mg daily. After 6 months of gefitinib therapy, laboratory findings revealed elevated serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels(grade 2), indicative of hepatotoxicity. Gefitinib was discontinued and erlotinib was initiated at a dosage of 50 mg daily. She continued the therapy for 3 years, during which her disease stabilized without any further complications or hepatotoxicity. Thus, low-dose erlotinib may be effective and well tolerated by patients with non-small cell lung cancer harboring EGFR mutations who are intolerant to gefitinib.

An oncogenic capacity of aquaporins, transmembrane channels for water, was recently proposed. This study seeks to elucidate the involvement of aquaporin 1, 3, and 5 in the development and progression of lung cancer. Expression of aquaporin 1, 3, and 5 was examined by immunohistochemistry, Western blot, and laser-captured microdissection/real-time reverse transcription polymerase chain reaction in 160 lung cancers of various histologic subtypes; and its correlation with clinicopathological factors and survival was analyzed. Aquaporin 1, 3, and 5 were expressed in tumor cells in 71%, 40%, and 56% of lung cancers, respectively. Aquaporin expressions were frequent in adenocarcinomas, whereas aquaporin 1 and 5 were negative in squamous cell carcinomas. Bronchioloalveolar carcinoma cells exhibited an apicolateral aquaporin 1 and apicolateral or basolateral aquaporin 3 localization in nonmucinous type, and apical aquaporin 1 and 5 and basolateral aquaporin 3 expression in mucinous type, which corresponded to aquaporins expression of nonneoplastic lung tissue. Basolateral aquaporin 5 expression was acquired during tumorigenesis of nonmucinous bronchioloalveolar carcinoma. In contrast, invasive adenocarcinoma tumor cells overexpressed aquaporin 1 and 5 with loss of subcellular polarization and with an intracytoplasmic distribution. Overexpression of aquaporin 1 correlated with high postoperative adenocarcinoma metastasis ratios and unfavorable disease-free survival rates (P = .031). We conclude that expression patterns of aquaporin 1, 3, and 5 in lung cancer cells are mostly associated with cellular differentiation. However, the expression of aquaporin 1 and 5 is up-regulated in invading lung cancer cells, particularly in adenocarcinomas; and the overexpression of aquaporin 1 with loss of subcellular polarization is suggested to be involved in their invasive and metastatic potential., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to determine if glucose transporter-1 (Glut1) expression correlates with (18)F-FDG ((18)F-fluoro-2-deoxyglucose) uptake on positron emission tomography (PET) in lung cancer and to examine the similarities and differences between them., Methods: A total of 34 patients with resected primary lung cancers were investigated in this study. There were 17 adenocarcinomas, 12 squamous cell carcinomas, and 5 cancers of other cell types. Immunohistochemical Glut1 intensity was categorized into three groups: negative, positive, and strongly positive. Glut1 frequency was defined by the proportion of positive cells among all cancer cells, and it was graded on a semiquantitative scale as 0-100% in 10% increments. The data are expressed as the mean +/- SD., Results: Maximum standardized uptake values (SUVmax) were 4.8 +/- 6.3 in "negative" Glut1 intensity cases, 4.7 +/- 3.1 in "positive" Glut1 intensity cases, and 11.2 +/- 5.2 in "strongly positive" Glut1 intensity cases. Although SUVmax correlated significantly with tumor size (correlation coefficient 0.58, P = 0.00033), Glut1 frequency did not correlate significantly with tumor size (correlation coefficient 0.18, P = 0.301). Cell type and cell differentiation correlated significantly with Glut1 expression and (18)F-FDG uptake., Conclusion: Glut1 expression correlates significantly with (18)F-FDG uptake. There are similarities in cell differentiation and cell type between Glut1 expression and (18)F-FDG uptake. (18)F-FDG uptake correlates significantly with tumor size, but Glut1 expression does not.

Purpose: Noguchi and colleagues reported that the growth pattern of small-sized adenocarcinoma was related to the vascular involvement and the prognosis of the patient. Noguchi's type A/B tumors had no lymph node metastasis, rare vascular involvement, and an excellent prognosis, which meant that Noguchi's type A/B tumors were preinvasive tumors of the peripheral type. Although Noguchi's classification was usually determined based on resected specimens, it would be useful to make a decision about the therapeutic strategy if the classification could be determined preoperatively based on the fluorodeoxyglucose (FDG) uptake., Methods: The FDG uptake in 61 pulmonary adenocarcinomas measuring 3 cm or smaller in diameter was compared with the mediastinal uptake and was classified into five grades. The relationship between the FDG uptake and Noguchi's classification (A to F) was analyzed., Results: The FDG uptake was significantly lower in Noguchi's type A/B tumors than in type C or in type D/E/F. Eleven of 12 tumors (92%) with no increased or a weak FDG uptake were classified as type A/B, whereas 32 of 33 tumors (97%) with a strong or very strong FDG uptake were classified as type C-F., Conclusions: The FDG uptake is helpful for making an accurate diagnosis of Noguchi's classification preoperatively in patients with pulmonary adenocarcinoma.

Background: We previously reported that the computed tomographic M/L ratio (area of the tumor in the mediastinal computed tomographic image/area of the tumor in the lung computed tomographic image) of small peripheral lung adenocarcinoma is correlated with patient prognosis., Methods: Immunostaining for p53, bcl-2, Ki-67, vascular endothelial growth factor, CD34, matrix metalloproteinase 2, matrix metalloproteinase 9, tissue inhibitor of matrix metalloproteinase 2, and mutation of K-ras was assessed in 131 surgically resected, primary peripheral lung adenocarcinomas of 30 mm or less in maximum diameter to clarify the relationship between computed tomographic findings and biologic activities., Results: The numbers of patients with high labeling indexes of Ki-67 and high expression of vascular endothelial growth factor, CD34, matrix metalloproteinase 2, and matrix metalloproteinase 9 in the solid-type group (computed tomographic M/L ratio > or = 50%) were significantly higher than those in the faint density-type group (computed tomographic M/L ratio < 50%; P = .04 for Ki-67, P = .03 for vascular endothelial growth factor, P = .0009 for CD34, P = .001 for matrix metalloproteinase 2, and P = .00001 for matrix metalloproteinase 9). The number of patients with high levels of CD44v6 or tissue inhibitor of matrix metalloproteinase 2 staining in the faint density-type group was significantly higher than that in the solid-type group (P = .02 for CD44v6 and P = .01 for tissue inhibitor of matrix metalloproteinase 2). Independent variables capable of predicting computed tomographic M/L ratio included CD34, matrix metalloproteinase 2, matrix metalloproteinase 9, and tissue inhibitor of matrix metalloproteinase 2 (P = .0093, P = .0003, P = .0027, and P = .01, respectively; binary logistic regression analysis)., Conclusions: Our results suggest that the computed tomographic image of small lung adenocarcinoma is correlated with biologic activities and thus provides possible prognostic information.

We experienced a rare case of lung cancer without hilar/mediastinal nodal involvement or direct invasion to the thoracic wall, but with metastasis to a lymph node in the thoracic wall. A 72-year-old woman with lung cancer was admitted to our hospital for the surgical therapy. She had suffered from right pleuritis in her childhood. During the dissection of the pleural adhesion around the whole lung, one small black lymph node was found in the thoracic wall and resected. Then, right middle and lower lobectomy and systematic nodal dissection were performed. The postoperative pathological examination revealed that nodal involvement was not observed in all samples except in the lymph node in the thoracic wall. In lung cancer patients with broad pleural adhesion, we should pay attention to lymph nodes in the thoracic wall. If we find them, the nodes should be resected for accurate staging.

Objectives: The purpose of this study was to determine whether the ratio of the area of the mediastinal computed tomographic image to that of the lung computed tomographic image can be a prognostic factor of small peripheral lung adenocarcinoma., Methods: We studied the computed tomographic images of 143 patients with primary peripheral lung adenocarcinoma of 30 mm or less in maximum diameter. Two groups were categorized according to the tumor's ratio of the area of the mediastinal computed tomographic image to that of the lung computed tomographic image (tumor's area in the mediastinal computed tomographic image/tumor's area in lung computed tomographic image x 100%), both faint density-type (<50%) and solid-type images (>/=50%). Clinical factors and prognoses of the 2 groups were analyzed., Results: There were 58 patients with the solid-type tumor image and 85 patients with the faint density-type tumor image. The number of patients with tumor size of less than 20 mm in the faint density-type tumor group (n = 30) was significantly higher than that in the solid-type tumor group (n = 8, P =.008). The 5-year survival of patients with faint density-type tumors was 74.1%, whereas that in patients with solid-type tumors was 54.2% (P =.013). Furthermore, the survival curve of patients with the solid-type computed tomographic image combined with ground-glass opacity was similar to that of patients with the faint density-type image. Multivariate analysis revealed the prognostic influence of the ratio of the area of the mediastinal computed tomographic image to that of the lung computed tomographic image on survival (P =.029, relative risk = 0.48) and showed to be of second highest influence after the N factor., Conclusions: It is suggested that the ratio of the area of the mediastinal computed tomographic image to that of the lung computed tomographic image can be a prognostic factor in patients with small peripheral lung adenocarcinoma.

In order to evaluate the efficacy of annual chest X-ray screening for lung cancer, a case-control study was conducted in Gunma Prefecture, Japan. Population-based annual lung cancer screening programmes have been conducted by the local government in Gunma Prefecture since the mid-1970s. A total of 121 case subjects, including 91 high-risk males and 30 non-high-risk females between the ages of 40 and 79 years who died of lung cancer from 1992 to 1997 were evaluated. A total of 536 controls (3-5 controls for each case) were matched to case subjects by gender, year of birth, address and smoking habits. Controls were selected from screening programme lists provided by the local governments. All case subjects were also included on these lists. The smoking-adjusted odds ratio (OR) of lung cancer death for those subjects screened within 12 months prior to diagnosis versus those not screened was 0.68 (95% confidence interval (CI): 0.44-1.05; P=0.084). When the analysis was conducted without matching case and control subjects by smoking habits, the OR was 0.79 (95% CI: 0.53-1.18). When stratified by histological type, the OR was 0.62 (95% CI: 0.31-1.24) for adenocarcinoma, and 1.01 (95% CI: 0.44-2.31) for squamous cell carcinoma. The results of this study suggest 20-30% of deaths attributable to lung cancer, especially adenocarcinoma, might be prevented by annual chest X-rays.

Background: P120 is a proliferation-associated nucleolar protein found in most human malignant tumors, but not in resting normal cells. In our previous studies, the expression of p120 was statistically correlated with the proliferation capacity in human lung cancer cells and could be a prognostic marker for resected lung adenocarcinoma., Patients and Methods: The expression levels of p120 in tumors were assessed by immunohistochemistry in 59 patients with stage I lung adenocarcinoma who underwent radical resection. Using clinical follow-up data, the prognostic significance of p120 calculated by labeling indices was evaluated using Cox's proportional hazard model., Results: A mean +/- SD of the labeling index of p120 was 35.3+/-14.4%. No significant correlation was found between the expression levels of p120 and clinicopathological factors. Using a cutoff value of 35% in the labeling index of p120, patients with high expression of p120 experienced early recurrence and shorter survival compared with those having low expression of p120 (P = 0.04). Multivariate analysis revealed that p120 served as an independent and strongest prognostic factor for resected lung adenocarcinoma (P = 0.033)., Conclusion: This article provides the first evidence that the expression levels of p120 in tumor tissues can be used as an independent and powerful prognostic marker for resected stage I lung adenocarcinoma.

Purpose: In this study we investigated the prognostic significance of proliferation-associated nucleolar protein p120 in primary resected lung adenocarcinoma because it reflects tumor growth fractions in vitro., Patients and Methods: Expression levels of p120 in tumors were assessed by immunohistochemistry in 74 patients who underwent radical resection. With clinical follow-up data, the prognostic significance of p120 calculated by labeling indices was evaluated using the Cox proportional hazards model., Results: p120 protein was clearly detected in nucleoli of adenocarcinoma cells. Its expression levels widely varied in each sample from 8.5% to 67. 2%, with a mean +/- SD of 35.2% +/- 15.1%. No significant correlation was found between expression levels of p120 and clinicopathologic factors. However, the expression levels of p120 were negatively correlated with the tumor doubling time calculated with retrospective chest roentgenograms. Using a cutoff value of 35% in the labeling index of p120, patients with high expression of p120 experienced early recurrence and shorter survival compared with those who had low expression of p120. Multivariate analysis showed that p120 served as an independent, as well as the strongest, prognostic factor for resected lung adenocarcinoma., Conclusion: This report provides the first evidence that expression levels of p120 in tumor tissues can be used as an independent and powerful prognostic marker for resected lung adenocarcinoma.

In order to determine the topographical distribution of the K-ras codon 12 mutations in carcinoma and preneoplastic lesions of the lung, selective ultraviolet radiation fractionation, as well as microdissection followed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP), was performed. Fourteen of 61 samples amplified (23.0%) had a mutation in the K-ras codon 12. Of 41 adenocarcinoma, 12 samples (29.3%) had a mutation, whereas none of the squamous cell carcinomas had a mutation. One of six large-cell carcinomas, one of three carcinoid tumours and none of three other carcinomas had a mutation. Direct sequencing revealed that K-ras codon 12 of six samples were TGT (Cys), five samples were GTT (Val), two samples were GCT (Ala) and one sample was TTT (Phe). A total of 113 lesions of 13 cases covered by dot were amplified after UV radiation. All of 74 carcinoma lesions had the mutation, and intratumour heterogeneity was not observed. Of 39 non-malignant lesions, one type II cell hyperplasia had the mutation, which suggests that the K-ras mutation occurs in the early stage of carcinogenesis. The lack of intratumour heterogeneity supports the hypothesis.

A 71-year-old male was admitted to our hospital because of a chest abnormal shadow. His chest X-ray film showed a mass in the right lower lobe (S6), which was diagnosed as adenocarcinoma by transbronchial lung biopsy. A lab data on the admission showed thrombocytopenia (44,000 per cu. mm), and the results of the bone marrow aspiration was compatible with idiopathic thrombocytopenic purpura. Immediately after the right lower lobectomy with lymphnode dissection, intrathoracic bleeding from the wound due to hemorrhagic tendency appeared necessitating a re-thoracotomy. High-dose intravenous gamma-globulin infusion for 4 days and the frequent concentrated platelet transfusion were employed to prevent the hemorrhagic tendency after the 2nd operation, and the postoperative hemorrhage was successfully controlled. Perioperative high-dose intravenous gamma-globulin infusion was concluded to be useful in the patient of idiopathic thrombocytopenic purpura for preventing hemorrhagic tendency after the operation.

We analyzed stage III and IV lung cancer with tumor size smaller than 3.0 cm. The percentage of adenocarcinoma among the patients with stage III A lung cancer was high. In survival rate, there was no observable difference between the patients with tumor size smaller than 3.0 cm and the patients with tumor size larger than 3.1 cm. But the ratio of the people who had a long survival was high in the latter group. Among the stage IV patients, the pm 1 group with N0 or N1 had a good prognosis (52%, 50% at 5 years).

Molecular biomarkers have the potential to predict the recurrence risk of early-stage lung adenocarcinoma (LUAD) after complete resection, but the study results are controversial. We aimed to clarify the association of molecular alterations with disease-free survival (DFS) and recurrence-free survival (RFS) in early-stage LUAD with R0 resection. Comprehensive searches were conducted in PubMed/MEDLINE, Web of Science, and Cochrane Library for this systematic review and meta-analysis with date restrictions from 2012 to 2022. In the 18 included studies, data from a total of 7417 participants in 11 studies and 4167 participants in 9 studies were collected for the EGFR and KRAS meta-analyses, respectively. Two studies were assessed as having a moderate risk of bias, and the others were all assessed as having a high individual risk of bias. The molecular alterations in KRAS rather than EGFR, were associated with a high risk of recurrence for early-stage LUAD patients suffering from R0 resection, especially for those in pStage I, the pooled hazard ratios (HRs) of KRAS were 2.71 (95% CI, 1.81–4.06; I2 = 22%; P < 0.00001) and 1.95 (95% CI, 1.25–3.20; I2 = 57%; P = 0.003) with small interstudy heterogeneity in univariate and multivariate analyses, respectively. This finding suggests that molecular alterations in KRAS that could be detected by polymerase chain reaction techniques would provide new insight into stratifying risk and personalizing patient postoperative follow-up. [ABSTRACT FROM AUTHOR]

Aquaporins (AQPs) are selective, transmembrane proteins, which are primarily responsible for the transport of water and small molecules. They have been demonstrated to play a key role in the development and progression of cancer. Lung adenocarcinoma is the most common primary lung cancer diagnosed in patients in Europe and the USA. The research done so far has provided firm evidence that some AQPs can be biomarkers for various diseases. The objective of this review article is to present a potential role of AQP5 in the development of lung adenocarcinoma. Original papers discussing the involvement of AQP5 in carcinogenesis and containing relevant clinical data were identified. In order to analyze the research material in accordance with PRISMA guidelines, a systematic search of the ScienceDirect, Web of Science, and Pubmed databases was conducted. Out of the total number of 199 papers identified, 14 original articles were subject to analysis. This article presents the pathophysiological role of AQP5 in the biology of lung adenocarcinoma as well as its prognostic value. The analysis substantiates the conclusion that the prognostic value of AQP5 in lung cancer requires further research. Another aim of this paper is to disseminate knowledge about AQPs among clinicians. [ABSTRACT FROM AUTHOR]

Background: Sublobectomy for early‐stage non‐small cell lung cancer (NSCLC) remains a matter of debate. This study aimed to discuss the feasibility of sublobectomy in patients with pathological‐stage IA1‐2 confirmed as pathologically invasive but radiologically noninvasive adenocarcinoma. Methods: From 2011 to 2019, we screened clinical stage IA1–IA2 lung cancer patients who underwent surgery at the Guangdong Provincial People's Hospital (GDPH). Inclusion criteria were maximum tumor diameter of 2.0 cm or less, consolidation tumor ratio (CTR) ≤ 0.25, and pathologically confirmed invasive adenocarcinoma. Sublobectomy (segmentectomy and wedge resection) and lobectomy groups were created, and propensity scores were computed. The primary endpoints were lung cancer‐specific overall survival (LCSS) and LCS‐ relapse‐free survival (LCS‐RFS) after adjusting propensity scores. Results: A total of 1731 patients were screened, and 100 patients were enrolled. The lobectomy group had 51 patients and the limited resection group had 49. No cases relapsed, and two patients died from nontumor causes. For the entire cohort, the 5‐year LCSS and 5‐year LCS‐RFS were 100% in the lobectomy and limited resection groups. When propensity scores matched, there were no differences in LCSS and LCS‐RFS between the two groups (LCSS:100%, LCS‐RFS 100% in lobectomy and limited resection, respectively). Discussion: Sublobectomy may be curative for pathologically invasive but radiologically noninvasive adenocarcinoma at pathological stage IA1‐2. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted therapy against epidermal growth factor (EGFR) mutations has become the standard of care for non-small cell lung cancer, and there has not been an efficient genetic test for non-small cell lung cancer patients. The present study aims to find a novel data-driven genetic testing method that can effectively predict the mutation status of EGFR based on a prediction model combining clinical features. The results of this study provide a powerful theoretical basis for the establishment of an effective mutation prediction model. The prediction model can provide a high reference value aiding in EGFR mutation diagnosis and subsequent treatment course. Data from 758 patients with lung adenocarcinoma were retrospectively collected. All patients had undergone computed tomography imaging and EGFR gene testing. Radiomic features were extracted using the medical imaging tool 3D-Slicer and were combined with the clinical features to build a machine learning prediction model. The high-dimensional feature set was screened for optimal feature subsets using principal component analysis (PCA) and the least absolute shrinkage and selection operator (LASSO). Model prediction of EGFR mutation status in the validation group was evaluated using multiple classifiers. We showed that six clinical features and 622 radiomic features were initially collected. Thirty-one radiomic features with non-zero correlation coefficients were obtained by LASSO regression, and 24 features correlated with label values were obtained by PCA. The shared radiomic features determined by these two methods were selected and combined with the clinical features of the respective patient to form a subset of features related to EGFR mutations. The full dataset was partitioned into training and test sets at a ratio of 7:3 using 10-fold cross-validation. The area under the curve (AUC) of the four classifiers with cross-validations was: (1) K-nearest neighbor (AUCmean = 0.83, Acc = 81%); (2) random forest (AUCmean = 0.91, Acc = 83%); (3) LGBM (AUCmean = 0.94, Acc = 88%); and (4) support vector machine (AUCmean = 0.79, Acc = 83%). In summary, the subset of radiographic and clinical features selected by feature engineering effectively predicted the EGFR mutation status of this NSCLC patient cohort. [ABSTRACT FROM AUTHOR]

Background: NOP2 nucleolar protein plays a crucial role in early embryo development and cell proliferation. The role of NOP2 in human gastric adenocarcinoma has not been elucidated. In the present study, we aimed to examine the expression levels of NOP2 and dissected whether NOP2 expression was associated with aggressive clinicopathological outcomes of patients with gastric adenocarcinoma. Methods: Clinicopathological analysis was performed in patients with gastric adenocarcinoma. Expression of NOP2 was tested by immunohistochemistry staining and quantitative RT-PCR. The prognostic role of NOP2 in gastric adenocarcinoma patients was assessed by univariate and multivariate analysis. The effect of NOP2 on cell proliferation was examined through cellular experiments and mice models. Results: NOP2 expression was elevated in gastric adenocarcinoma tissues compared to normal gastric tissues. High expression of NOP2 was significantly correlated with tumor size, invasion depth, and lymph node metastasis. Moreover, patients with high NOP2 expression had poorer overall survival, and NOP2 was identified as an independent prognosis factor. Using the gastric adenocarcinoma cells, we found that NOP2 can promote tumor cell proliferation both in vitro and in vivo. Conclusions: Overexpression of NOP2 significantly correlates with a poorer prognosis of gastric adenocarcinoma patients and suggested the potential of NOP2, which may serve as a novel prognostic biomarker in gastric adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Solitary fibrous tumor (SFT) is a rare tumor of mesenchymal origin and accounts for < 2% of all soft tissue masses. Although SFT has been identified in multiple anatomic locations and can grow anywhere in the body, intrapulmonary SFT are rare. Case presentation: In this report, we presented a rare case of intrapulmonary solitary fibrous tumor (SFT) coexisting with lung adenocarcinoma in a 74-year-old man. Chest computed tomography showed a well-defined nodule with punctate calcification and measuring 2.3 × 2.1 cm and two ground-grass nodules with solid component. To obtain a definitive diagnosis and achieve complete resection, surgery was performed. The postoperative diagnosis was intrapulmonary SFT coexisting with lung adenocarcinoma. After surgery, he survived for 6 months without any signs of recurrence. Conclusion: Complete resection may be the best treatment for intrapulmonary SFT. Careful follow-up of the postoperative course is important, because differentiating between benignity and malignancy is difficult by histologic findings alone. [ABSTRACT FROM AUTHOR]

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A 63‐year‐old Japanese man with amyopathic dermatomyositis treated with immunosuppressants became aware of distortion of his left visual field, and a metastatic choroidal tumor was suspected. His chest computed tomography (CT) showed a pulmonary nodule in the right upper lobe and mediastinal lymphadenopathy, and he was diagnosed with advanced lung adenocarcinoma with choroidal metastasis. Malignancies associated with dermatomyositis (DM) are often rapidly progressive and, in choroidal metastasis associated with lung cancer, a choroidal lesion is often diagnosed prior to lung cancer; therefore, CT performed at the time of diagnosis of choroidal metastasis may show lung cancer lesions. When ocular symptoms are observed in DM patients, metastatic malignancies should be suspected, and systemic examinations, such as positron emission tomography (PET)‐CT, should also be performed. [ABSTRACT FROM AUTHOR]

Background There are currently no studies synthesizing the screening rate and influential factors of low-dose computed tomography (LDCT)-screened lung cancer in Asian population. Methods A systematic review was conducted, using both English and Chinese language databases on March, 2019. The pooled screening rate and estimated odds ratios (ORs) of influential factors were analyzed using random effects models. Subgroup and meta-regression analyses were also employed to explore the heterogeneity. Results The pooled LDCT lung cancer screening rate was 1.12% (95% confidence interval (CI): 0.94%, 1.32%), and increased with age. Adenocarcinoma and stage I lung cancer had higher screening rates. Analysis of influential factors in the general population showed that female and elder age (≥50 years) were significantly influencing LDCT lung cancer screening rate (for female, OR = 1.32, 95% CI: 1.15–1.52; for adults ≥ 50 years, OR = 1.94, 95% CI: 1.52–2.49). Meta-regression analysis indicated that the heterogeneity maybe significantly correlated with the sample size, risk population and source of population. Conclusions Unlike European and American populations, female and adults > 50 years rather than smoking adults were positively associated with screening rate in Asian populations. It is important to further study the benefits of lung cancer screening with LDCT in Asian populations. [ABSTRACT FROM AUTHOR]

Introduction: To develop and validate a simple-to-use nomogram based on preoperative CT to predict spread through air space (STAS) status of stage IA lung adenocarcinoma (ADC). Methods: In this retrospective study, 434 patients with pathological proven periphery stage IA lung adenocarcinoma were included, which consisted of 349 patients from center I for training group and 85 patients from Center II for test group. STAS was identified in 53 patients (40 patient in the training group and 13 patients in the test group). On the basis of preoperative CT images, 19 morphological characteristics were analyzed. Univariable analysis was used to explore the association between clinical and CT characteristics and STAS status in the training group (P < 0.002). Independent risk factors for STAS were identified using multivariable logistic regression analysis and then used to build a nomogram for preoperative predicting STAS status. Results: Type of nodules, diameter of solid component, lobulation and percentage of the solid component (PSC) were associated with STAS status of peripheral stage IA lung ADCs statistical significantly. Multivariate logistics regression analysis revealed that PSC and lobulation were independent risk factors for STAS. The nomogram based on these factors achieved good predictive performance for STAS with a C-index of 0.803 in the training group and a well-fitted calibration curve. Using a cut-off value which was obtained from Youden index of the receiver operating characteristic (ROC) curve, a diagnosis accuracy of 70.6% was obtained in the test group with sensitivity, specificity, positive prediction value (PPV) and negative prediction value (NPV) of 92.3%, 66.7%, 33.3% and 98.0%, respectively. Conclusion: The nomogram based on preoperative CT images could achieve good predictive performance for STAS status of lung adenocarcinomas. This simple-to-used model can facilitate surgeons for a rational operation pattern choice at bedside. [ABSTRACT FROM AUTHOR]

Background: Glypican 3 (GPC3) is a heparin sulphate proteoglycan whose expression is associated with several malignancies. However, its expression in non-small-cell lung carcinoma (NSCLC) is limited and ambiguous. This study aimed to comprehensively evaluate the expression of GPC3 in NSCLC and develop a risk-score model for predicting the prognosis of NSCLC. Methods: The gene expression profiles of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were downloaded from the UCSC Xena database. Using the limma package, the differentially expressed genes (DEGs) between different comparison groups were analysed and the differential expression of GPC3 was calculated. A functional enrichment analysis was conducted for GPC3-associated genes using the DAVID tool. For the GPC3-associated genes shared by the four comparison groups, a protein–protein interaction network was built using the Cytoscape software. After conducting a survival analysis and a Cox regression analysis, the genes found to be significantly correlated with prognosis were selected to construct a risk-score model. Besides, the gene and protein levels of GPC3 were examined by quantitative reverse transcriptase-PCR (qRT-PCR) and immunohistochemistry (IHC) in LUSC tissues and paracancer tissues. Results: The differential expression of GPC3 was significant (adjusted P < 0.05) in the NSCLC vs. normal, LUAD vs. normal, LUSC versus normal, and LUAD versus. LUSC comparison groups. GPC3 directly interacted with SERPINA1, MFI2, and FOXM1. Moreover, GPC3 expression was significantly correlated with pathologic N, pathologic T, gender, and tumour stage in LUAD samples. Finally, the risk-score model (involving MFI2, FOXM1, and GPC3) for LUAD and that (involving SERPINA1 and FOXM1) for LUSC were established separately. The qRT-PCR result showed that GPC3 expression was much higher in the LUSC tissues than that in the normal group. The IHC results further showed that GPC3 is highly expressed in LUSC tissues, but low in paracancer tissues. Conclusion: The three-gene risk-score model for LUAD and the two-gene risk-score model for LUSC might be valuable in improving the prognosis of these carcinomas. [ABSTRACT FROM AUTHOR]

Background and Aims: Nodular ground-glass lesions have become increasingly common with the increased use of computed tomography (CT), while the genomic features of ground-glass opacities (GGOs) remain unclear. This study aims to comprehensively investigate the molecular alterations of GGOs and their correlation with radiological progression. Methods: Studies from PubMed, Embase, Cochrane Library, and Web of Science, using PCR, targeted panel sequencing, whole exosome sequencing, and immunohistochemistry, and reporting genomic alterations or PD-L1 expressions in lung nodules presenting as GGOs until January 21, 2021 were included in this study. Chi-square test, random-effects model, and Z-test analysis were adopted to analyze the data. Results: A total of 22 studies describing mutations in lung adenocarcinoma (LUAD) with GGOs were analyzed. EGFR was the most frequently mutative gene (51%, 95%CI 47%–56%), followed by TP53 (18%, 95%CI 6%–31%), HER2 (10%, 95%CI 0%–21%), ROS1 (6%, 95%CI 0%–18%), and KRAS (6%, 95%CI 3%–9%). The correlation between the frequency of EGFR mutation and radiological was observed and the differences were found to be not statistically significant in the subgroups, which are listed as below: radiological: gGGO 47.40%, 95%CI [38.48%; 56.40%]; sGGO 51.94%, 95%CI [45.15%; 58.69%]. The differences of the frequency of KRAS mutation in the different subgroups were also consistent with this conclusion, which are listed as: radiological gGGO 3.42, 95%CI [1.35%; 6.13%]; sGGO 12.27%, 95%CI [3.89%; 23.96%]. The pooled estimated rate of PD-L1 was 8.82%, 95%CI [5.20%–13.23%]. A total of 11.54% (3/26) of the SMGGNs were confirmed to be intrapulmonary spread by WES. Conclusions: Somatic genetic alterations are considered in early-stage GGO patients without distinct changes of the frequency following the progress of the tumor. This review sheds insight on molecular alterations in LUAD with GGOs. [ABSTRACT FROM AUTHOR]

Introduction: Due to the introduction of low-dose computed tomography (CT) and screening procedures, the proportion of early-stage lung cancer with ground glass opacity (GGO) manifestation is increasing in clinical practice. However, its epidemiological characteristics is still not fully investigated. Methods: We retrieved all solitary GGO adenocarcinoma lung cancer (ADLC) on the PubMed, Cochrane Library, and Embase databases until January 1, 2019 and extracted the general information to perform the meta-analysis, mainly focusing on age, gender, and smoking status. Results: A total of 8,793 solitary GGO ADLC patients from 53 studies were included in this analysis. The final pooled analysis showed that the female proportion, average diagnosis age, and non-smoking proportion of solitary GGO ADLC was 0.62 (95% CI, 0.60–0.64), 56.97 (95% CI, 54.56–59.37), and 0.72 (95% CI, 0.66–0.77), respectively. The cumulative meta-analysis and meta-trend analysis confirmed that the average age at diagnosis has been decreasing while the non-smoking proportion significantly increased in the past two decades. Conclusions: From our epidemiological analysis, it demonstrates that the clinical characteristics of GGO lung cancer patients may be out of the high-risk factors. Therefore, we propose to reconsider the risk assessment and current lung cancer screening criteria. [ABSTRACT FROM AUTHOR]

Disruption of tissue function activates cellular stress which triggers a number of mechanisms that protect the tissue from further damage. These mechanisms involve a number of homeostatic modules, which are regulated at the level of gene expression by the transactivator NF-κB. This transcription factor shifts between activation and repression of discrete, cell-dependent gene expression clusters. Some of its target genes provide feedback to NF-κB itself, thereby strengthening the inflammatory response of the tissue and later terminating inflammation to facilitate restoration of tissue homeostasis. Disruption of key feedback modules for NF-κB in certain cell types facilitates the survival of clones with genomic aberrations, and protects them from being recognized and eliminated by the immune system, to enable thereby carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: We aimed to assess if quantitative radiomic features can predict programmed death ligand 1 (PD‐L1) expression in advanced stage lung adenocarcinoma. Methods: This retrospective study included 153 patients who had advanced stage (>IIIA by TNM classification) lung adenocarcinoma with pretreatment thin section computed tomography (CT) images and PD‐L1 expression test results in their pathology reports. Clinicopathological data were collected from electronic medical records. Visual analysis and radiomic feature extraction of the tumor from pretreatment CT were performed. We constructed two models for multivariate logistic regression analysis (one based on clinical variables, and the other based on a combination of clinical variables and radiomic features), and compared c‐statistics of the receiver operating characteristic curves of each model to identify the model with the higher predictability. Results: Among 153 patients, 53 patients were classified as PD‐L1 positive and 100 patients as PD‐L1 negative. There was no significant difference in clinical characteristics or imaging findings on visual analysis between the two groups (P > 0.05 for all). Rad‐score by radiomic analysis was higher in the PD‐L1 positive group than in the PD‐L1 negative group with a statistical significance (−0.378 ± 1.537 vs. −1.171 ± 0.822, P = 0.0008). A prediction model that uses clinical variables and CT radiomic features showed higher performance compared to a prediction model that uses clinical variables only (c‐statistic = 0.646 vs. 0.550, P = 0.0299). Conclusions: Quantitative CT radiomic features can predict PD‐L1 expression in advanced stage lung adenocarcinoma. A prediction model composed of clinical variables and CT radiomic features may facilitate noninvasive assessment of PD‐L1 expression. Key points: Significant findings of the study Quantitative CT radiomic features can help predict PD‐L1 expression, whereas none of the qualitative imaging findings is associated with PD‐L1 positivity. What this study adds A prediction model composed of clinical variables and CT radiomic features may facilitate noninvasive assessment of PD‐L1 expression. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficiency of radiomics model on CT images of intratumoral and peritumoral lung parenchyma for preoperative prediction of lymph node (LN) metastasis in clinical stage T1 peripheral lung adenocarcinoma patients.Methods: Three hundred sixty-six peripheral lung adenocarcinoma patients with clinical stage T1 were evaluated using five CT scanners. For each patient, two volumes of interest (VOIs) on CT were defined as the gross tumor volume (GTV) and the peritumoral volume (PTV, 1.5 cm around the tumor). One thousand nine hundred forty-six radiomic features were obtained from each VOI, and then refined for reproducibility and redundancy. The refined features were investigated for usefulness in building radiomic signatures by mRMR feature ranking method and LASSO classifier. Multivariable logistic regression analysis was used to develop a radiomic nomogram incorporating the radiomic signature and clinical parameters. The prediction performance was evaluated on the validation cohort.Results: The radiomic signatures using the features of GTV and PTV showed a good ability in predicting LN metastasis with an AUC of 0.829 (95% CI, 0.745-0.913) and 0.825 (95% CI, 0.733-0.918), respectively. By incorporating the features of GTV and PTV, the AUC of radiomic signature increased to 0.843 (95% CI, 0.770-0.916). The AUC of radiomic nomogram was 0.869 (95% CI, 0.800-0.938).Conclusions: Radiomic signatures of GTV and PTV both had a good prediction ability in the prediction of LN metastasis, and there is no significant difference of AUC between the two groups. The proposed nomogram can be conveniently used to facilitate the preoperative prediction of LN metastasis in T1 peripheral lung adenocarcinomas.Key Points: • Radiomics from peritumoral lung parenchyma increase the efficiency of the prediction for lymph node metastasis in clinical stage T1 lung adenocarcinoma on CT. • A radiomic nomogram was developed and validated to predict LN metastasis. • Different scan parameters on CT showed that radiomics signature had good predictive performance. [ABSTRACT FROM AUTHOR]

Tumor-infiltrating lymphocytes are related to positive clinical prognoses in numerous cancer types. Programmed death ligand 1 (PD-L1), a mediator of the PD-1 receptor, plays an inhibitory role in cancer immune responses. PD-L1 upregulation can impede infiltrating T-cell functions in lung adenocarcinoma (LUAD), a lung cancer subtype. However, associations between the expression of PD-L1 and infiltration of B cells (a major immunoregulatory cell) remain unknown. Therefore, we investigated the role of infiltrating B cells in LUAD progression and its correlation with PD-L1 expression. The Cancer Genome Atlas (TCGA) LUAD data set was used to explore associations among B-cell infiltration, PD-L1 expression, clinical outcome, and gene landscape. Gene set enrichment analysis was used to explore putative signaling pathways and candidate genes. The drug enrichment analysis was used to identify candidate genes and the related drugs. We found that high B-cell infiltration was correlated with better prognoses; however, PD-L1 may interfere with the survival advantage in patients with high B-cell infiltration. The gene landscape was characterized comprehensively, with distinct PD-L1 levels in cell populations with high B-cell infiltration. We obtained five upregulated signaling pathways from the gene landscape: apoptosis, tumor necrosis factor (TNF)-α signaling via nuclear factor (NF)-κB, apical surface, interferon-α response, and KRAS signaling. Moreover, four candidate genes and their related target drugs were also identified, namely interleukin-2β receptor (IL2RB), IL-2γ receptor (IL2RG), Toll-like receptor 8 (TLR8), and TNF. These findings suggest that tumor-infiltrating B cells could act as a clinical factor in anti-PD-L1 immunotherapy for LUAD. [ABSTRACT FROM AUTHOR]

Lung microinvasive adenocarcinoma (MIA) is a newly-defined subtype of early stage non-small cell lung cancer (NSCLC). However, its epidermal growth factor receptor (EGFR) mutation status and clinical significance remain unclear. The present study aimed to determine EGFR mutation characteristics and identify their significance in patients with resected lung MIA. The present study also analyzed clinicopathological differences between EGFR molecular subgroups defined as 19Del and L858R. The present study examined EGFR mutations in 79 consecutive lung MIA resection specimens and compared the differences in clinicopathological features between the EGFR wild-type and mutation groups, as well as between the 19Del and L858R subgroups. EGFR mutations were detected in 60 (75.95%) tumors. The most common mutations were 19Del (28 cases; 35.44%) and L858R (30 cases; 37.97%). Two patients harbored rare mutations and one of them had a concomitant double mutation. EGFR mutations were significantly associated with microinvasion component, thyroid transcription factor 1 (TTF-1) expression, intratumoral fibrosis and inflammatory cell infiltration. Subgroup evaluation indicated that there was a significant association between 19Del and tumor size, maximum diameter of microinvasion, presence of intratumoral fibrosis and inflammatory cell infiltration. Similar associations were observed for the L858R subgroup, and L858R was associated with TTF-1 expression. In particular, 19Del occurred more frequently in MIA with a smaller size, with a smaller microinvasive area, without TTF-1 expression, and lacking intratumoral fibrosis and inflammatory cell infiltration. By contrast, L858R was detected more frequently in MIA with entirely different tumor features. In conclusion, the results of the present study indicated that surgically resected MIA cases harboring different EGFR gene statuses exhibit distinct clinicopathological features. Significant differences in pathological features associated with the tumor microenvironment were identified in MIA with 19Del or L858R mutations. Therefore, the present study proposed that MIA should be classified into molecular subgroups based on EGFR mutation subtypes. The molecular sub-classification should be taken into account for prognostic evaluation and clinical management of MIA. [ABSTRACT FROM AUTHOR]

Background: Nintedanib in combination with docetaxel is approved in the European Union and other countries for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) of adenocarcinoma histology after first-line chemotherapy, based on the overall survival findings of Phase III LUME-Lung 1 study. Change in target lesion size over time as a treatment effect was assessed in patients from this study. Methods: Tumor size was evaluated using predefined tumor measurements. Mixed-effects models were used to quantify individual relationships between time from randomization and tumor burden, measured as the sum of longest diameter (SLD) of target lesions and assessed by an independent review (Response Evaluation Criteria In Solid Tumors [RECIST] v1.0). Exploratory analyses were conducted on the overall adenocarcinoma population, adenocarcinoma patients with time from start of first-line therapy <9 months (TSFLT <9), adenocarcinoma patients who had progressive disease as best response to first-line therapy (PD-FLT), and in squamous cell carcinoma patients. Results: Estimated mean baseline SLD was 82.5 mm in the adenocarcinoma (n=658), 88.3 mm in the TSFLT <9 (n=405), 98.1 mm in the PD-FLT (n=117), and 94.3 mm in the squamous cell carcinoma (n=555) populations. Treatment with nintedanib/docetaxel showed a significant reduction in tumor size over time (P<0.0001) in patients with adenocarcinoma compared with placebo/docetaxel, and in patients with squamous cell carcinoma (P=0.0049). Treatment difference at 6 months was 9.7 mm in the overall adenocarcinoma population, 16.8 mm in the TSFLT <9 population, 19.7 mm in the PD-FLT population, and 6.8 mm in the squamous cell carcinoma population. SLD at 2 months post-randomization was identified as a surrogate endpoint for overall survival, in addition to progression-free survival, for all except the PD-FLT population. Conclusion: Treatment with nintedanib/docetaxel significantly decreased tumor burden and decelerated tumor size over time compared with placebo/docetaxel in the overall adenocarcinoma population, including in patients with the poorest prognosis due to aggressive tumor dynamics. [ABSTRACT FROM AUTHOR]

Background: To analyse the differences in computed tomography (CT) features between patients with lung adenocarcinoma who have epidermal growth factor receptor (EGFR) mutations and those who have wild-type EGFR.Methods: Patients with lung adenocarcinoma (n = 156) were enrolled from October 2013 to March 2016, including 56 patients with wild-type EGFR and 100 patients with EGFR mutations. Two independent radiologists evaluated patient characteristics and imaging features. Chi-squared test, Fisher’s exact test or ANOVA was applied to discriminate clinical and CT characteristics between the genotypes. A prediction tool for EGFR mutation was devised from principal component analysis.Results: The proportion of females and non-smokers in the exon 19 deletion and exon 21 missense groups was higher than in the wild-type group (P < 0.01). Severe emphysema was higher in the wild-type group than in the exon 19 deletion group (P < 0.01). The maximum diameter in the mediastinal window (MaxDmediastinal) in the wild-type group was longer than in the exon 19 deletion and exon 21 missense groups. The minimum diameter in the mediastinal window (MinDmediastinal) in the wild-type group was also longer than in the exon 21 missense group, with a significant difference (P < 0.05). The tumor shadow disappearance rate (TDR) in the exon 19 deletion group was higher than in the wild-type group. Ground glass opacity (GGO) appeared to be more common in the exon 19 deletion group (P = 0.010). The prediction score for exon 19 deletion mutation was: 0.305 × gender + 0.254 × smoking history + 0.198 × MaxDmediastinal + TDR × 0.254 + 0.280 × GGO + 0.095 × emphysema. The sensitivity and specificity for predicting exon 19 deletion were 59.09 and 76.79%, respectively. The prediction score for the exon 21 missense mutation was: 0.354 × gender + 0.291 × smoking history + 0.410 × MaxDmediastinal + 0.408 × MinDmediastinal. The sensitivity and specificity for predicting exon 21 missense mutation were 72.34 and 78.57%, respectively.Conclusion: As well as gender, smoking history and GGO, adenocarcinomas with EGFR mutation were significantly associated with emphysema, TDR, and the diameter in the mediastinal window. As exon 19 deletion and 21 missense mutations might be predicted by those features, the scoring system might be valuable for clinical diagnosis. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The incidence of small-sized pulmonary adenocarcinomas with ground-glass opacity (GGO) has recently increased, with excellent postoperative prognosis. The limited resection of such cancers has been deemed to be acceptable based on retrospective studies. We conducted a prospective multi-institutional study evaluating the validity of limited resection for small-sized pulmonary adenocarcinoma with GGO. METHODS: The inclusion criteria were 25-80 years of age, no prior treatment, a maximum tumour diameter of 8-20 mm, a GGO ratio of >80%, clinical T1N0M0, lower 18F-fluorodeoxyglucose accumulation than the mediastinum, resectable by sublobar resection, pulmonary lobectomy tolerable and an intraoperative pathological diagnosis of bronchiloalveolar carcinoma. Wedge resection was preferred, but segmentectomy was permitted. Disease-specific survival and overall survival were analysed. RESULTS: From November 2006 to April 2012, 73 patients were enrolled from 13 institutions. One patient was ineligible, and the remaining 72 patients were preregistered. The tumours of 3 and 14 patients were intraoperatively diagnosed as benign lesions and adenocarcinomas with mixed subtype, respectively. Intraoperative cytological/histological examination of surgical margin was not performed in 2 patients, and the remaining 53 patients were ultimately eligible for this study. The mean tumour size was 14.0mm and the mean GGO ratio was 95.9%. Thirty-nine and 14 patients underwent wedge resection and segmentectomy, respectively. Although all tumours were intraoperatively diagnosed as bronchioloalveolar carcinomas, 6 were ultimately diagnosed as adenocarcinoma with a mixed subtype. No completion lobectomy was performed. As of 1 May 2017, no recurrence of the original lung cancer was observed during 60.0-126.3 months after surgery. Two patients died from other diseases. The 5-year disease-specific and overall survival rates were 100% and 98.1%, respectively. The reduction in the pulmonary function after limited resection was minimal. CONCLUSIONS: With these criteria, limited resection was performed safely without any recurrence, and the postoperative pulmonary function was well preserved. The outcomes of limited resection for small-sized lung cancer with GGOs that met the criteria of this study were satisfactory. [ABSTRACT FROM AUTHOR]

Quantification of epidermal growth factor receptor (EGFR) mutations is important for the prediction of tyrosine kinase inhibitor (TKI) efficacy in patients with non‑small cell lung cancer (NSCLC). However, clinicians lack a sensitive and convenient method to quantify EGFR mutant abundance. The present study introduces a novel method, namely amplification refractory mutation system (ARMS)‑Plus, for the quantitative analysis of EGFR exon 19 deletion (19Del), L858R and T790M mutations. Formalin‑fixed paraffin‑embedded tumor samples were collected from 77 patients with lung adenocarcinoma. DNA was extracted and analyzed for EGFR mutations using ARMS‑Plus. The performance of ARMS‑Plus was then compared with that of conventional ARMS‑polymerase chain reaction (ARMS‑PCR) and droplet digital PCR (ddPCR). The results demonstrated that the concordance rate of EGFR mutation testing between ARMS‑Plus and ddPCR was 98.7% (76/77, Kappa=0.9739). 19Del and L858R mutations were detected in 23 and 12 patients, respectively. There was a significant difference between ARMS‑Plus and ddPCR in the evaluation of 19Del mutant abundance (P=0.0002); however, not in that of L858R mutant abundance (P=0.7334). The ARMS‑Plus results in L858R mutant abundance were concordant with that of ddPCR (R2=0.8081). These results indicated that the sensitivity and specificity of ARMS‑Plus in identifying EGFR mutations were similar to that of ddPCR. For quantitative analysis, the results of ARMS‑Plus in evaluating L858R mutant abundance revealed a positive correlation with the ddPCR results. Thus, ARMS‑Plus provides an alternative method, which is reliable and cost‑effective, to quantify EGFR mutations and thereby, aid treatment decisions in patients with lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background/Aims: Triptolide (TP) is a diterpenoid triepoxide extracted from the traditional Chinese medical herb Tripterygium wilfordii that exerts prominent broad-spectrum anticancer activity to repress proliferation and induce cancer cell apoptosis through various molecular pathways. We previously observed that TP inhibits the progression of A549 cells and pancreatic cancer cells (PNCA-1) in vitro. However, the complex molecular mechanism underlying the anticancer activity of TP is not well understood. Methods: To explore the molecular mechanisms by which TP induces lung cancer cell apoptosis, we investigated changes in the protein profile of A549 cells treated with TP using a proteomics approach (iTRAQ [isobaric tags for relative and absolute quantitation] combined with NanoLC-MS/MS [nano liquid chromatographymass spectrometry]). Changes in the profiles of the expressed proteins were analyzed using the bioinformatics tools OmicsBean and the Kyoto Encyclopedia of Genes and Genomes (KEGG) and were verified using western blotting. Apoptosis and cell cycle effects were analyzed using flow cytometry. Results: TP induced apoptosis in A549 cells and blocked A549 cells at the G2/M phase. Using iTRAQ technology, we observed 312 differentially expressed proteins associated in networks and implicated in different KEGG pathways. Gene Ontology (GO) analysis showed the overviews of dysregulated proteins in the biological process (BP), cell component (CC), and molecular function (MF) categories. Moreover, some candidate proteins involved in PARP1/AIF and nuclear Akt signaling pathways or metastasis processes were validated by western blotting. Conclusion: TP exerted anti-tumor activity on non-small cell lung cancer (NSCLC) A549 lung adenocarcinoma cells by dysregulating tumor-related protein expression. Herein, we provide a preliminary study of TP-related cytotoxicity on A549 cells using proteomics tools. These findings may improve the current understanding of the anti-tumor effects of TP on lung cancer cells and may reveal candidate proteins as potential targets for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Background/Aims: Triptolide (TP) is a diterpenoid triepoxide extracted from the traditional Chinese medical herb Tripterygium wilfordii that exerts prominent broad-spectrum anticancer activity to repress proliferation and induce cancer cell apoptosis through various molecular pathways. We previously observed that TP inhibits the progression of A549 cells and pancreatic cancer cells (PNCA-1) in vitro. However, the complex molecular mechanism underlying the anticancer activity of TP is not well understood. Methods: To explore the molecular mechanisms by which TP induces lung cancer cell apoptosis, we investigated changes in the protein profile of A549 cells treated with TP using a proteomics approach (iTRAQ [isobaric tags for relative and absolute quantitation] combined with NanoLC-MS/MS [nano liquid chromatography-mass spectrometry]). Changes in the profiles of the expressed proteins were analyzed using the bioinformatics tools OmicsBean and the Kyoto Encyclopedia of Genes and Genomes (KEGG) and were verified using western blotting. Apoptosis and cell cycle effects were analyzed using flow cytometry. Results: TP induced apoptosis in A549 cells and blocked A549 cells at the G2/M phase. Using iTRAQ technology, we observed 312 differentially expressed proteins associated in networks and implicated in different KEGG pathways. Gene Ontology (GO) analysis showed the overviews of dysregulated proteins in the biological process (BP), cell component (CC), and molecular function (MF) categories. Moreover, some candidate proteins involved in PARP1/AIF and nuclear Akt signaling pathways or metastasis processes were validated by western blotting. Conclusion: TP exerted anti-tumor activity on non-small cell lung cancer (NSCLC) A549 lung adenocarcinoma cells by dysregulating tumor-related protein expression. Herein, we provide a preliminary study of TP-related cytotoxicity on A549 cells using proteomics tools. These findings may improve the current understanding of the anti-tumor effects of TP on lung cancer cells and may reveal candidate proteins as potential targets for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: Summarise survival of patients with resected lung cancers manifesting as part-solid nodules (PSNs).Methods: PubMed/MEDLINE and EMBASE databases were searched for all studies/clinical trials on CT-detected lung cancer in English before 21 December 2015 to identify surgically resected lung cancers manifesting as PSNs. Outcome measures were lung cancer-specific survival (LCS), overall survival (OS), or disease-free survival (DFS). All PSNs were classified by the percentage of solid component to the entire nodule diameter into category PSNs <80% or category PSNs ≥80%.Results: Twenty studies reported on PSNs <80%: 7 reported DFS and 2 OS of 100%, 6 DFS 96.3-98.7%, and 11 OS 94.7-98.9% (median DFS 100% and OS 97.5%). Twenty-seven studies reported on PSNs ≥80%: 1 DFS and 2 OS of 100%, 19 DFS 48.0%-98.0% (median 82.6%), and 16 reported OS 43.0%-98.0% (median DFS 82.6%, OS 85.5%). Both DFS and OS were always higher for PSNs <80%.Conclusion: A clear definition of the upper limit of solid component of a PSN is needed to avoid misclassification because cell-types and outcomes are different for PSN and solid nodules. The workup should be based on the size of the solid component.Key Points: • Lung cancers manifesting as PSNs are slow growing with high cure rates. • Upper limits of the solid component are important for correct interpretation. • Consensus definition is important for the management of PSNs. • Median disease-free-survival (DFS) increased with decreasing size of the nodule. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the value of multislice spiral computed tomography (CT) in differential diagnosis of benign or malignant pulmonary ground-glass opacity (GGO).Materials and Methods: A total of 68 patients with pulmonary GGO who received surgical treatment in our hospital from January 2014 to January 2017 were retrospectively analyzed. Postoperative pathology showed that there were 22 cases of benign GGO and 47 cases of malignant GGO (adenocarcinoma). The diameter, maximum CT value, and mean CT value of benign and malignant GGOs were determined and compared. The clinical value of identifying benign or malignant GGOs with these indices was analyzed through receiver operating characteristic (ROC) curve.Results: The mean GGO diameter, maximum CT value, and mean CT value in the benign group were significantly lower than those of in the malignant group, and the difference was statistically significant (P < 0.05). The diameter, maximum CT value, and mean CT value of GGO were applied to identify benign or malignant GGO: sensitivity was 60.87%, 69.57%, and 63.04%; and the specificity was 63.64%, 63.64%, and 81.82%; the cutoff values were 13.89 (mm), 26.18 (Hu), and 24.61 (Hu); and areas under the ROC curves were 0.66, 0.71, and 0.69, respectively.Conclusion: The possibility of malignancy has been significantly increased for GGOs with a large diameter, high mean CT value and maximum CT value. Surgical treatment should be performed for this type of GGOs. [ABSTRACT FROM AUTHOR]

Introduction Emerging evidence shows that diffusion-weighted magnetic resonance imaging ( DW MRI) and fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography ( 18F- FDG PET/ CT) might be useful in predicting histological type and malignancy of lung cancer, and even in specifically detecting the types of gene mutation. Objective We assessed whether DW MRI is equivalent to PET/ CT in lung cancer diagnosis and evaluation. Methods The institutional review board approved this study, and written informed consent was obtained from all patients. DW MRI and FDG PET/ CT were performed before therapy in 15 lung cancer patients diagnosed by pathological examination. Apparent diffusion coefficient ( ADC), ratio of ADC ( rADC = ADC in tumor/ ADC in spinal cord) and maximal standardized uptake value ( SUVmax) were assessed. Results ADC, rADC and SUVmax did not reveal significant differences among different types of lung cancer. Sensitivity, specificity and accuracy of ADC, rADC and SUVmax proved to be not significantly different in the detection of adenocarcinoma and squamous cell carcinoma. Difference in the abilities of the sensitivity, specificity and accuracy of ADC, rADC and SUVmax to detect adenocarcinoma and squamous cell carcinoma proved to be insignificant. Although Ki-67 score did not show correlation with ADC, rADC and SUVmax, significant positive correlation was found between ADC and rADC, and ADC and SUVmax. Conclusions Both DW MRI and FDG PET/ CT had similar limited diagnostic capability of predicting different histological types and malignancy of lung cancer. This study may help provide a novel insight into diagnostic and therapeutic strategies of lung cancer based on DW MRI. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the association between histopathological subtypes, epidermal growth factor receptor (EGFR) mutations and 18F-fluorodeoxyglucose (FDG) uptake in patients with lung adenocarcinoma (ADC). The cases of 97 patients with lung ADC who underwent 18F-FDG positron emission tomography-computed tomography prior to surgical resection were retrospectively reviewed. The patients were stratified according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification, and graded using a histopathological scoring system. EGFR mutations were identified. Clinicopathological characteristics associated with EGFR mutation status were evaluated using univariate and multivariate analyses. EGFR mutation was identified in 45.4% of the patients and was associated with gender, smoking history, maximum standardized uptake value (SUVmax) and histopathological score. ADC patients with a low SUVmax were more likely to exhibit EGFR mutations compared with patients with a high SUVmax (P=0.018). Patients with a lower histopathological score possessed a significantly lower SUVmax compared with patients with a higher score (P<0.001). Furthermore, the histopathological score and smoking history of the patients were identified to be independent predictors for EGFR mutations, according to multivariate logistic regression analysis. In conclusion, SUVmax and EGFR mutations were associated with lung ADC patients stratified according to the IASLC/ATS/ERS classification. Overall, SUVmax has the potential to be a useful marker in stratifying pre-operative patients with lung ADC and identifying EGFR mutations. [ABSTRACT FROM AUTHOR]