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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]

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]

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]

Objective: Intraoperative frozen section examination of sentinel lymph nodes was conducted to determine the final indication for segmentectomy for clinical T1 N0 M0 non–small cell lung cancer. Methods: Between April 2005 and July 2006, 52 patients with clinical T1 N0 M0 non–small cell lung cancer were prospectively treated by segmentectomy with sentinel node identification. The day before surgery, technetium-99m tin colloid was injected into the peritumoral region. After segmentectomy and lymph node dissection, sentinel nodes identified by measuring radioactive tracer uptake were examined for intraoperative frozen sections, which were serially cut 2 to 3 mm in thickness. When sentinel node metastasis was observed, segmentectomy was converted to lobectomy. Results: Sentinel nodes were identified in 43 (83%) patients. The average number of sentinel nodes was 1.6 ± 0.9 (range: 1–5) per patient. Of 3 patients with metastatic sentinel lymph nodes, 2 underwent lobectomy and 1 larger segmentectomy. None of the other 40 patients had metastatic sentinel lymph nodes and therefore they were treated with segmentectomy. Pathologic staging with permanent sections was N0 in all of the 40 patients. On the other hand, in 9 patients whose sentinel nodes could not be identified, intraoperative frozen sections were required for 5.4 ± 2.3 lymph nodes, which was significantly more than 1.6 ± 0.9 in the 43 patients with sentinel node identification (P < .001). Conclusion: Sentinel node identification is useful to determine the final indication of segmentectomy for clinical T1 N0 M0 non–small cell lung cancer by targeting the lymph nodes needed for intraoperative frozen section diagnosis. [Copyright &y& Elsevier]

Background Methods Results Conclusion 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.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.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).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]

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]

• TSK was found to be highly expressed in lung cancer tissues and cell lines. • TSK regulates epithelial-mesenchymal transition and proliferation in lung cancer cells. • TSK may be a key coordinator of multiple pathways and important structural elements in the lung cancer microenvironment. Tsukushi (TSK), a member of the small leucine-rich repeat proteoglycan (SLRP) family, plays multifunctional roles by interacting with signaling molecules during development. However, the role of TSK in cancer remains unknown. The aim of the present study was to investigate the biological significance of TSK in lung cancer. Immunohistochemistry of lung cancer tissues and reverse transcription polymerase chain reaction (PCR) of lung cancer cell lines were carried out to detect TSK. Then, RNA sequence analysis, Gene Ontology analysis, quantitative real-time PCR, western blotting, cell counting assay, invasion assays, and xenograft studies were done in a human lung adenocarcinoma cell line, H1975 with modification of TSK expression levels, in order to investigate its biological roles, in particular epithelial–mesenchymal transition (EMT) and proliferation. TSK was found to be highly expressed in lung cancer tissues and cell lines. Modification of TSK expression levels in H1975 resulted in changes in molecules related to EMT, including cadherin-1, snail family transcriptional repressor 1, snail family transcriptional repressor 2, and vimentin. The results of cell counting and xenograft assays showed that TSK promotes cell proliferation. In lung cancer cells, TSK is expressed more highly than the other SLRPs family members, and regulates the EMT and proliferation. Thus, TSK may be a key coordinator of multiple pathways and an important structural element in the lung cancer microenvironment. [ABSTRACT FROM AUTHOR]