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Background: Patients with early‐stage lung cancer and interstitial lung disease have a poorer prognosis than those without interstitial lung disease. This study aimed to compare the long‐term outcomes of lobar and sublobar resections in these patients. Methods: We retrospectively analyzed 138 consecutive patients with clinical stage I non‐small cell lung cancer and interstitial lung disease who underwent surgical treatment at two institutions between January 2010 and December 2020. Propensity score matching analysis was performed to adjust for baseline characteristics. Results: Thirty‐six patients underwent sublobar resection and 102 underwent lobar resection. The median follow‐up was 45.7 months. In all patients, 5‐year overall survival (OS) rates were 33.2% and 73.2%, and 5‐year recurrence‐free survival (RFS) rates were 24.2% and 60.1% in the sublobar and lobar resection groups, respectively (p < 0.01, <0.01). Death due to lung cancer and locoregional recurrence were significantly more frequent in the sublobar resection group than in the lobar resection group (p = 0.034, <0.01, respectively). On propensity score matching analysis, the 5‐year OS rates of the 19 matched pairs were 46.3% and 73.2%, and the RFS rates were 31.6% and 67.6% in the sublobar and lobar resection groups, respectively (p = 0.036, <0.01). The Cox proportional hazards model demonstrated a significant association between lobar resection and improved survival (p = 0.047). Conclusion: The patients in the lobar resection group had better survival rates than those in the sublobar resection group. In terms of long‐term prognosis, deliberately limited surgery may not be necessary for patients who tolerate lobectomy. [ABSTRACT FROM AUTHOR]

In non-small cell lung cancer (NSCLC) cases, detecting potential lymph node metastases is essential to determine the indications for sublobar resection or adjuvant therapy. NUF2 is a tumor-specific antigen that is highly expressed in lung cancer tissues. However, the significance of analyzing NUF2 expression in dissected lymph nodes has not yet been studied. Thus, we investigated the association between NUF2 expression in lung cancer tissues and dissected lymph nodes and early recurrence of NSCLC to determine its usefulness as a marker of lymph node micrometastasis. This retrospective study quantified NUF2 expression in the cancer tissues of 88 patients with NSCLC who underwent complete resection using real-time polymerase chain reaction and investigated its relationship with clinicopathological features and prognosis. We also quantified NUF2 RNA expression in mediastinal lymph nodes from 255 patients with pN0 NSCLC who underwent complete resection with lymph node dissection and analyzed its association with prognosis. NUF2 expression in primary tumors was correlated with lymph node metastasis and unfavorable outcomes in terms of poor recurrence-free and cancer-specific survival. In N0 NSCLC cases, high NUF2 expression in mediastinal lymph nodes indicated poor prognosis, especially in lymph node recurrence. NUF2 emerges as a promising marker for predicting lymph node metastatic recurrence, offering potential utility in guiding post-surgical adjuvant therapy for lung cancer or assisting in intraoperative decisions for sublobar resection. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests an association between iron metabolism and lung cancer progression. In biological systems, iron is present in either reduced (Fe2+; ferrous) or oxidized (Fe3+; ferric) states. However, ferrous and ferric iron exhibit distinct chemical and biological properties, the role of ferrous and ferric iron in lung cancer cell growth has not been clearly distinguished. In this study, we manipulated the balance between cellular ferrous and ferric iron status by inducing gene mutations involving the FBXL5–IRP2 axis, a ubiquitin‐dependent regulatory system for cellular iron homeostasis, and determined its effects on lung cancer cell growth. FBXL5 depletion (ferrous iron accumulation) was found to suppress lung cancer cell growth, whereas IRP2 depletion (ferric iron accumulation) did not suppress such growth, suggesting that ferrous iron but not ferric iron plays a suppressive role in cell growth. Mechanistically, the depletion of FBXL5 impaired the degradation of the cyclin‐dependent kinase inhibitor, p27, resulting in a delay in the cell cycle at the G1/S phase. FBXL5 depletion in lung cancer cells also improved the survival of tumor‐bearing mice. Overall, this study highlights the important function of ferrous iron in cell cycle progression and lung cancer cell growth. [ABSTRACT FROM AUTHOR]

T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I–IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin+ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin+ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin+ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8+ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin+ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer. [ABSTRACT FROM AUTHOR]

Programmed death (PD)‐1/PD‐ligand 1 (PD‐L1) antibodies have shown an intense clinical effect in some patients with PD‐L1+ tumors, and their applications have rapidly expanded to various cancer types with or without the application of new companion diagnostics (CDx) with a lower cutoff value and inclusion of macrophage evaluation. However, the pathological background explaining the difference in the cutoff value remains unknown. To address this, we evaluated tissue array samples from 231 patients with lung adenocarcinoma, 186 with lung squamous cell carcinoma, and 38 with renal cell carcinoma (RCC) who were not receiving PD‐1/PD‐L1 antibodies to investigate the relationship between PD‐L1 expression on tumor cells and CD8+ T‐cell infiltration in tumor tissues. PD‐L1 expression in RCC was clearly lower than that in non–small‐cell lung cancer (NSCLC) tissue, whereas CD8+ T‐cell infiltration was low in all cancers. We next analyzed PD‐L1 expression by interferon (α, β, and γ) and LPS stimulation in both macrophages and 41 cancer cell lines derived from various organs and histological types. The PD‐L1 expression patterns were classified into three types, which differed depending on each organ or tissue type. Interestingly, NSCLC cell lines showed highly diverse PD‐L1 expression patterns compared with RCC cell lines. Conversely, PD‐L1 expression was stronger and more prolonged in macrophages than in typical cell lines. Here, we revealed the diversity of the PD‐L1 expression patterns in tumor cells and macrophages, demonstrating the pathological and cytological significance of the transition of cutoff values in PD‐L1 CDx for PD‐1/PD‐L1 antibody administration. [ABSTRACT FROM AUTHOR]

CD163 is one of the scavenger receptors expressed on macrophages. However, several immunohistochemical studies have demonstrated that CD163 is also detected on cancer cells, and is associated with a poor prognosis. In the present study, we detected CD163 staining on cancer cells in lung adenocarcinoma and squamous cell carcinoma (SCC), and investigated the relationship between CD163 on cancer cells and the clinical prognosis. CD163 staining was seen in 128 of 342 adenocarcinoma cases and 35 of 103 SCC cases. Among the lung adenocarcinoma cases, the progression‐free survival and overall survival were significantly shorter in the CD163 high group than the CD163 low group. A similar trend was observed among the SCC cases, but the difference was not statistically significant. Additionally, a higher number of macrophages was detected in areas with CD163‐positive cancer cells when compared to areas with CD163‐negative cancer cells. In summary, we found that CD163‐positive cancer cells are a predictor of a worse clinical course in lung adenocarcinoma and SCC. [ABSTRACT FROM AUTHOR]

Abstract Background To prevent postoperative air leakage after lung segmentectomy, we used two methods for the intersegmental plane: closing it by suturing the pleural edge (pleural closure), or opening it with coverage using polyglycolic acid mesh and fibrin glue (mesh-cover). The preserved forced expiratory volume in one second (FEV1) of each lobe and the postoperative air leakage were compared between the two groups. Methods For 61 patients who underwent pleural closure and 36 patients who underwent mesh-cover, FEV1 of the lobe before and after segmentectomy was measured using lung-perfusion single-photon-emission computed tomography and CT (SPECT/CT). The groups' results were compared, revealing differences of the preserved FEV1 of the lobe for several segmentectomy procedures and postoperative duration of chest tube drainage. Results Although left upper division segmentectomy showed higher preserved FEV1 of the lobe in the mesh-cover group than in the pleural closure one (p = 0.06), the other segmentectomy procedures showed no differences between the groups. The durations of postoperative chest drainage in the two groups (2.0 ± 2.5 vs. 2.3 ± 2.2 days) were not different. Conclusions Mesh-cover preserved the pulmonary function of remaining segments better than the pleural closure method in left upper division segmentectomy, although no superiority was found in the other segmentectomy procedures. However, the data include no results obtained using a stapler, which cuts the segment without recognizing even the intersegmental plane and the intersegmental vein. Mesh-cover prevented postoperative air leakage as well as the pleural closure method did.

Abstract Background For small peripheral c-T1N0M0 non-small cell lung cancers involving multiple segments, we have conducted a resection of subsegments belonging to different segments, i.e. combined subsegmentectomy (CSS), to avoid resection of multiple segments or lobectomy. Tumor size, location of tumor, and forced expiratory volume in 1 second (FEV1) of each preserved lobe were compared among the CSS, resection of single segment, and that of multiple segments. Methods FEV1 of each preserved lobe were examined in 17 patients who underwent CSS, 56 who underwent resection of single segment, and 41 who underwent resection of multiple segments, by measuring pulmonary function and lung-perfusion single-photon-emission computed tomography and computed tomography before and after surgery. Results Tumor size in the CSS was significantly smaller than that in the resection of multiple segments (1.4 ± 0.5 vs. 2.0 ± 0.8 cm, p = 0.002). Tumors in the CSS were located in the right upper lobe more frequently than those in the resection of multiple segments (53% vs. 5%, p < 0.001). Postoperative of FEV1 of each lobe after the CSS was higher than that after the resection of multiple segments (0.3 ± 0.2 vs. 0.2 ± 0.2 l, p = 0.07). Mean FEV1 of each preserved lobe per subsegment after CSS was significantly higher than that after resection of multiple segments (0.05 ± 0.03 vs. 0.03 ± 0.02 l, p = 0.02). There was no significant difference of these factors between the CSS and resection of single segment. Conclusions The CSS is effective for preserving pulmonary function of each lobe, especially for small sized lung cancer involving multiple segments in the right upper lobe, which has fewer segments than other lobes.

Tumor‐associated calcium signal transducer 2 (TROP2) is a cell‐surface glycoprotein involved in the high malignant potential of several cancers. Antibody‐drug conjugates that target TROP2 represent a promising approach for the treatment of TROP2‐expressing cancers including lung cancer and breast cancer. TROP2 expression was tested by immunohistochemistry in lung adenocarcinoma (ADC) and squamous cell carcinoma samples, and its correlation with clinicopathological factors, including survival rate and p53 mutation, was statistically analyzed. We found that increased TROP2 expression was significantly associated with a poor clinical course in patients with ADC, but not in patients with squamous cell carcinoma. A more significant association with poor outcome was seen in ADC cases with a high histological grade as well as those without the epidermal growth factor receptor (EGFR) mutation. A significant correlation between TROP2 expression and abnormal p53 nuclear accumulation/expression was also found in ADC. In the present study, we discovered a significant correlation between TROP2 expression and p53 mutation in ADC, and that TROP2 expression was a prognostic factor in ADC cases with a high histological grade as well as those without the EGFR mutation. Signals mediated by mutated p53 might influence TROP2 expression in ADC. [ABSTRACT FROM AUTHOR]

We previously revealed that tumor cell‐derived angiopoietin‐like protein 2 (ANGPTL2) accelerates the metastatic capacity of tumors in an autocrine/paracrine manner by activating tumor cell motility and invasiveness and the epithelial‐mesenchymal transition. However, the effects of ANGPTL2 on cancer cell glycolytic metabolism, which is a hallmark of tumor cells, are unknown. Here we report evidence supporting a role for tumor cell‐derived ANGPTL2 in establishing a preference for glycolytic metabolism. We report that a highly metastatic lung cancer cell subline expressing abundant ANGPTL2 showed upregulated expression of the glucose transporter GLUT3 as well as enhanced glycolytic metabolism relative to a less metastatic parental line. Most notably, ANGPTL2 overexpression in the less metastatic line activated glycolytic metabolism by increasing GLUT3 expression. Moreover, ANGPTL2 signaling through integrin α5β1 increased GLUT3 expression by increasing transforming growth factor‐β (TGF‐β) signaling and expression of the downstream transcription factor zinc finger E‐box binding homeobox 1 (ZEB1). Conversely, ANGPTL2 knockdown in the highly metastatic subline decreased TGF‐β1, ZEB1, and GLUT3 expression and antagonized glycolytic metabolism. In primary tumor cells from patients with lung cancer, ANGPTL2 expression levels correlated with GLUT3 expression. Overall, this work suggests that tumor cell‐derived ANGPTL2 accelerates activities associated with glycolytic metabolism in lung cancer cells by activating TGF‐β‐ZEB1‐GLUT3 signaling. [ABSTRACT FROM AUTHOR]

The percentage of programmed death ligand 1 (PD‐L1) positivity in cancer cells, named as the tumor proportion score, is considered to be a predictive biomarker for anti‐PD‐1/PD‐L1 therapy in lung cancer. PD‐L1 is expressed on not only cancer cells but also on immune cells, including macrophages. Although previous studies related to PD‐L1/2 expression in cancer tissues have been generally based on single immunohistochemistry (IHC), in the present study, we attempted to evaluate accurate PD‐L1/2 expression in cancer cells in lung adenocarcinoma cells using double IHC to also evaluate macrophages. Of the 231 patients, PD‐L1 expression was negative in 169 patients (73.2%), 1%‐49% positive in 47 patients (20.3%), and ≥50% positive in 15 patients (6.5%). Interestingly, PD‐L1 positivity was decreased when using double IHC compared with the estimation by single IHC. High PD‐L1 expression was associated with high‐grade cancer cells and in higher stage cancer. PD‐L2 was negative in 109 patients (47.2%), 1%‐49% positive in 50 patients (21.6%), and ≥50% positive in 72 patients (31.2%). The number of PD‐L2‐positive patients was increased in cases that had an epidermal growth factor receptor (EGFR) mutation and in lower stage cancer. Thirty‐five patients (15.2%) were positive for both PD‐L1 and PD‐L2, whereas 81 patients (35.1%) were negative for both PD‐L1 and PD‐L2. Log‐rank analysis showed that progression‐free survival and overall survival were significantly the longest in the PD‐L1‐negative and PD‐L2‐positive groups (P < .0001 and P = .0120). We observed lower PD‐L1 or PD‐L2 expression in lung adenocarcinoma than previously reported. Double IHC for macrophages may help clinicians to evaluate PD‐L1 or PD‐L2 expression specifically in cancer cells. [ABSTRACT FROM AUTHOR]

Background: The detection rate of synchronous multiple lung adenocarcinomas (SMLA), which display multiple ground glass opacity nodules in the peripheral lung, is increasing due to advances in high resolution computed tomography. The backgrounds of multicentric development of adenocarcinoma are unknown. In this study, we quantitated estrogen concentration in the peripheral lungs of postmenopausal female patients with SMLA. Methods: The tissue concentration of estrogens (estrone [E1] and estdadiol [E2]) in the noncancerous peripheral lung were measured with liquid chromatography/electrospray tandem mass spectrometry in postmenopausal female patients with lung adenocarcinoma. The expression levels of CYP19A1 in the normal lung were also quantitated with real-time PCR. Thirty patients with SMLA and 79 cases of control patients with single lung adenocarcinoma were analyzed. Results: The concentrations of E1 and E2 in the noncancerous tissue were significantly higher in SMLA cases than control cases (P = 0.004 and P = 0.02, respectively). The minor allele (A) of single nucleotide polymorphism rs3764221 were significantly associated with higher concentration of E1 and E2 (P = 0.002 and P = 0.01, respectively) and higher CYP19A1 mRNA expression (P = 0.03). Conclusion: The tissue estrogen concentration of peripheral lung was significantly higher in SMLA than control cases. The high concentration of estrogen may be one of the causes of multicentric development of peripheral lung adenocarcinomas. [ABSTRACT FROM AUTHOR]

Background Solute carrier family 5 member A8 ( SLC5A8 ) is a sodium-coupled transporter for several chemicals. The SLC5A8 gene has been reported to function as a tumor suppressor gene that contributes to carcinogenesis and tumor progression. The expression of SLC5A8 is silenced in colon neoplasia by hypermethylation of CpG-rich islands located in exon 1. In this study, we assessed the significance of aberrant methylation of the SLC5A8 gene as a prognostic factor for lung adenocarcinoma (AD). Methods We analyzed the methylation levels of a consecutive series of 143 node-negative stage I and II lung AD samples using pyrosequencing. Results The methylation level of exon 1 in the SLC5A8 gene was significantly associated with poor prognosis in cases of node-negative stage I and II lung AD. Conclusions Gene silencing of SLC5A8 by hypermethylation was associated with poor prognosis in cases of node-negative stage I and II lung AD. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma has never before been reported to be associated with von Hippel-Lindau (VHL) disease. Here, we report a case of VHL disease in a patient who had metachronous multiple lung adenocarcinomas. The patient is a 64-year-old-woman with VHL disease. She underwent surgical resection of one adenocarcinoma and one atypical adenomatous hyperplasia. A second lung adenocarcinoma developed metachronously. A point mutation in the VHL gene was confirmed in DNA from a blood sample, and loss of heterozygosity at the VHL locus was detected in the lung adenocarcinoma. The VHL dysfunction may have a role in the development of multiple lung adenocarcinomas. [ABSTRACT FROM AUTHOR]

Background: Genome-wide DNA hypomethylation is known to play important roles in genomic instability and carcinogenesis. Methylation in long interspersed nucleotide element 1 (LINE-1) is a good indicator of the global DNA methylation level within a cell. The aim of this study was to evaluate prognostic significance of LINE-1 hypomethylation in lung adenocarcinoma. Methods: A consecutive series of 211 lung adenocarcinoma patients who underwent curative resections without any preoperative chemotherapy or radiotherapy at Kumamoto University Hospital between April 2010 and December 2012 were included. The LINE-1 methylation levels were quantified in tumor and noncancerous tissue by Pyrosequencing assay. Results: Higher histologic grade and positive findings for vascular invasion were significantly associated with lower methylation levels. The disease-free survival in the hypomethylation group was significantly shorter than that of the non-hypomethylation group. The prognostic difference was more obvious in advanced cases (stage II, III) than in stage I cases. Conclusions: The LINE-1 methylation level is associated with histologic grade and vascular invasion of lung adenocarcinoma. Additionally, LINE-1 hypomethylation is a useful biomarker to predict early recurrence of lung adenocarcinoma. [Copyright &y& Elsevier]

Background: To prevent postoperative air leakage after lung segmentectomy, we used two methods for the intersegmental plane: closing it by suturing the pleural edge (pleural closure), or opening it with coverage using polyglycolic acid mesh and fibrin glue (mesh-cover). The preserved forced expiratory volume in one second (FEV1 ) of each lobe and the postoperative air leakage were compared between the two groups. Methods: For 61 patients who underwent pleural closure and 36 patients who underwent mesh-cover, FEV1 of the lobe before and after segmentectomy was measured using lung-perfusion single-photon-emission computed tomography and CT (SPECT/CT). The groups' results were compared, revealing differences of the preserved FEV1 of the lobe for several segmentectomy procedures and postoperative duration of chest tube drainage. Results: Although left upper division segmentectomy showed higher preserved FEV1 of the lobe in the meshcover group than in the pleural closure one (p = 0.06), the other segmentectomy procedures showed no differences between the groups. The durations of postoperative chest drainage in the two groups (2.0 ± 2.5 vs. 2.3 ± 2.2 days) were not different. Conclusions: Mesh-cover preserved the pulmonary function of remaining segments better than the pleural closure method in left upper division segmentectomy, although no superiority was found in the other segmentectomy procedures. However, the data include no results obtained using a stapler, which cuts the segment without recognizing even the intersegmental plane and the intersegmental vein. Mesh-cover prevented postoperative air leakage as well as the pleural closure method did. [ABSTRACT FROM AUTHOR]

Background: For small peripheral c-T1N0M0 non-small cell lung cancers involving multiple segments, we have conducted a resection of subsegments belonging to different segments, i.e. combined subsegmentectomy (CSS), to avoid resection of multiple segments or lobectomy. Tumor size, location of tumor, and forced expiratory volume in 1 second (FEV1) of each preserved lobe were compared among the CSS, resection of single segment, and that of multiple segments. Methods: FEV1 of each preserved lobe were examined in 17 patients who underwent CSS, 56 who underwent resection of single segment, and 41 who underwent resection of multiple segments, by measuring pulmonary function and lung-perfusion single-photon-emission computed tomography and computed tomography before and after surgery. Results: Tumor size in the CSS was significantly smaller than that in the resection of multiple segments (1.4 ± 0.5 vs. 2.0 ± 0.8 cm, p = 0.002). Tumors in the CSS were located in the right upper lobe more frequently than those in the resection of multiple segments (53% vs. 5%, p < 0.001). Postoperative of FEV1 of each lobe after the CSS was higher than that after the resection of multiple segments (0.3 ± 0.2 vs. 0.2 ± 0.2 l, p = 0.07). Mean FEV1 of each preserved lobe per subsegment after CSS was significantly higher than that after resection of multiple segments (0.05 ± 0.03 vs. 0.03 ± 0.02 l, p = 0.02). There was no significant difference of these factors between the CSS and resection of single segment. Conclusions: The CSS is effective for preserving pulmonary function of each lobe, especially for small sized lung cancer involving multiple segments in the right upper lobe, which has fewer segments than other lobes. [ABSTRACT FROM AUTHOR]

A novel germline transmission of the epidermal growth factor receptor (EGFR) mutation V843I in a family with multiple members with lung cancer is reported. The proband was a 70-year-old woman with multiple adenocarcinomas who exhibited secondary EGFR mutations, either L858R or L861Q, in the specimens of resected tumors, in addition to a germline EGFR V843I mutation. These observations suggest that the germline EGFR V843I mutation might have altered EGFR signaling in the multicentric development of adenocarcinoma, bronchoalveolar carcinoma, and atypical adenomatous hyperplasia and also might have had a role in the development of lung cancer in multiple members of her family. [Copyright &y& Elsevier]