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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., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

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.

Programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) are target molecules for immunotherapy in non-small cell lung cancer. PD-L1 is expressed not only in cancer cells, but also on macrophages, and has been suggested to contribute to macrophage-mediated immune suppression. We examined the clinical significance of PD-L1 expression on macrophages in human lung adenocarcinoma. The mechanism of PD-L1 overexpression on macrophages was investigated by means of cell culture studies and animal studies. The results showed that high PD-L1 expression on macrophages was correlated with the presence of EGFR mutation, a lower cancer grade, and a shorter cancer-specific overall survival. In an in vitro study using lung cancer cell lines and human monocyte-derived macrophages, the conditioned medium from cancer cells was found to up-regulate PD-L1 expression on macrophages via STAT3 activation, and a cytokine array revealed that granulocyte-macrophage colony-stimulating factor (GM-CSF) was a candidate factor that induced PD-L1 expression. Culture studies using recombinant GM-CSF, neutralizing antibody, and inhibitors indicated that PD-L1 overexpression was induced via STAT3 activation by GM-CSF derived from cancer cells. In a murine Lewis lung carcinoma model, anti-GM-CSF therapy inhibited cancer development via the suppression of macrophage infiltration and the promotion of lymphocyte infiltration into cancer tissue; however, the PD-L1 expression on macrophages remained unchanged. PD-L1 overexpression on macrophages via the GM-CSF/STAT3 pathway was suggested to promote cancer progression in lung adenocarcinoma. Cancer cell-derived GM-CSF might be a promising target for anti-lung cancer therapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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., (© 2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

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., (© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Genome-wide DNA hypomethylation and gene hypermethylation play important roles in instability and carcino-genesis. Methylation in long interspersed nucleotide element 1 (LINE-1) is a good indicator of the global DNA methylation level within a cell. Slit homolog 2 (SLIT2), myelin and lymphocyte protein gene (MAL) and insulin-like growth factor binding protein 7 (IGFBP7) are known to be hypermethylated in various malignancies. The aim of the present study was to assess the precise methylation levels of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer (NSCLC) using a pyrosequencing assay. Methylation of all regions was examined in 56 primary NSCLCs using a pyrosequencing assay. Changes in mRNA expression levels of SLIT2, MAL and IGFBP7 were measured before and after treatment with a demethylating agent. Methylation of these genes was also examined in 9 lung cancer cell lines using RT-PCR and a pyrosequencing assay. Frequencies of hypomethylation of LINE-1 and hypermethylation of SLIT2, MAL and IGFBP7, defined by predetermined cut off values, were 55, 64, 46 and 54% in NSCLCs, respectively and exhibited tumor-specific features. The hypermethylation of all genes was well correlated with changes in expression. The methylation level and frequency of MAL were significantly higher in smokers and in patients without EGFR mutations. Through accurate measurement of methylation levels using pyrosequencing, hypomethylation of LINE-1 and hypermethylation of SLIT2, MAL and IGFBP7 were frequently detected in NSCLCs and associated with various clinical features. Analysis of the methylation profiles of these genes may, therefore, provide novel opportunities for the therapy of NSCLCs.

Background: To examine whether segmentectomy is radical for cT1N0M0 non-small cell lung cancer (NSCLC), a prospective single-arm study was performed at a single institution., Methods: The criteria for segmentectomy were as follows: (1) peripheral-type cT1N0M0 NSCLC; (2) intraoperative frozen sections of sentinel nodes identified with isotope showing no metastasis; (3) surgical margins greater than 2 cm; (4) patient choice for segmentectomy; and (5) exclusion of right middle lobe tumors. From 2005 to 2009, of 245 patients with cT1N0M0 NSCLC, 195 (80%) were enrolled in the present study. Of these 195 patients, 179 ultimately underwent segmentectomy with systematic lymph node dissection. Of these 179 patients, 134 (75%) had tumors 2 cm or smaller, and 45 (25%) had tumors 2.1 cm to 3 cm. The median follow-up period was 43 months., Results: All 181 tumors from 179 patients were stage pN0. Of the 179 patients, 6 developed distant site recurrence and 3 local recurrence (ie, 1 developed pulmonary metastases within the same lobe 21 months after segmentectomy and 2 developed local recurrence at the surgical margin 60 and 62 months after segmentectomy, respectively). The 5-year overall survival was 94% for patients with tumors 2 cm or smaller and 81% for those with 2.1-cm to 3-cm tumors. Postoperative pulmonary function was preserved at 90% ± 12% of preoperative levels., Conclusions: Segmentectomy with systematic lymph node dissection with a sufficient surgical margin could be a radical treatment for selected cT1N0M0/pN0 NSCLC while preserving pulmonary function. The surgical margin should be monitored for the development of local recurrence for a long period after segmentectomy., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

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.

Objective: This retrospective analysis examined whether diffusion-weighted magnetic resonance imaging might be as useful as positron emission tomography with fludeoxyglucose F 18 for (1) discriminating between non-small cell lung cancer and benign pulmonary nodules and (2) predicting aggressiveness of non-small cell lung cancer., Methods: Diffusion-weighted magnetic resonance imaging and positron emission tomography were performed before surgery in 110 patients with 124 pulmonary nodules smaller than 3 cm, including 96 non-small cell lung cancers and 28 benign nodules. Diffusion of water molecules in magnetic resonance imaging was measured by minimum value of apparent diffusion coefficient. The criterion standard was the result of histologic diagnosis or follow-up examination. Sensitivity and specificity for differentiating between cancers and benign nodules were compared between diffusion-weighted imaging and positron emission tomography. Apparent diffusion coefficient in diffusion-weighted imaging and fludeoxyglucose F 18 uptake in positron emission tomography were examined with respect to pathologic tumor stage; lymphatic, vascular and pleural involvements; and histologic differentiation., Results: There were no significant differences between diffusion-weighted magnetic resonance imaging and positron emission tomography in sensitivity or specificity for non-small cell lung cancer. Whereas positron emission tomography showed significant differences in fludeoxyglucose F 18 uptake between pathologic stages IA versus IB or more advanced stages; between tumors with and without lymphatic, vascular, or pleural involvement; and between well-differentiated and moderately or poorly differentiated adenocarcinomas (P <.01-0.001), no significant differences in apparent diffusion coefficient values in were observed., Conclusion: Diffusion-weighted magnetic resonance imaging is equivalent to positron emission tomography in distinguishing non-small cell lung cancer from benign pulmonary nodules but is not as useful for predicting aggressiveness of non-small cell lung cancer.

Objective: One of the deficiencies of positron emission tomography for N staging in lung cancer is a false-positive result caused by concurrent lymphadenitis. Recently, diffusion-weighted magnetic resonance imaging has been reported to be able to image tumors of body organs. The aim of this study is to examine the usefulness of diffusion-weighted magnetic resonance imaging for N staging of non-small cell lung cancer compared with positron emission tomography-computed tomography., Methods: Both positron emission tomography-computed tomography and diffusion-weighted magnetic resonance imaging were prospectively used in 88 patients before surgical intervention for non-small cell lung cancer to examine 734 lymph node stations. The diagnostic results of positron emission tomography-computed tomography and diffusion-weighted magnetic resonance imaging were compared. The diameters of the metastatic foci within lymph nodes were measured on hematoxylin and eosin-stained sections to compare the detectable size of metastatic foci between positron emission tomography-computed tomography and diffusion-weighted magnetic resonance imaging., Results: The accuracy of N staging in the 88 patients was 0.89 with diffusion-weighted magnetic resonance imaging, which was significantly higher than the value of 0.78 obtained with positron emission tomography-computed tomography (P = .012), because of less overstaging in the former. Among the 734 lymph node stations examined pathologically, 36 had metastases, and the other 698 did not. Although there was no significant difference in the diagnosis of the 36 metastatic lymph node stations between the 2 methods, diffusion-weighted magnetic resonance imaging was more accurate for diagnosing the 698 nonmetastatic stations than positron emission tomography-computed tomography because of fewer false-positive results (P = .002). The detectable size of metastatic foci within lymph nodes was 4 mm in both positron emission tomography-computed tomography and diffusion-weighted magnetic resonance imaging., Conclusions: Diffusion-weighted magnetic resonance imaging can be used in place of positron emission tomography-computed tomography for N staging of non-small cell lung cancer with fewer false-positive results compared with positron emission tomography-computed tomography.

Objective: A gamma probe can identify sentinel nodes before nodal dissection in the mediastinum but not in the hilum, owing to high radioactivity from primary tumors. We evaluated the utility of fused single photon emission computed tomography/computed tomography (SPECT/CT) images for the identification of sentinel nodes in the hilum for patients with clinical stage Ia non-small cell lung cancer., Methods: Technetium-99m tin colloid was injected into the peritumoral region approximately 18 hours before surgery in 63 patients with clinical stage Ia non-small cell lung cancer. On the morning of the operation, approximately 16 hours after administration of tin colloid, sentinel nodes were identified by fused SPECT/CT; this was followed by intraoperative sentinel node identification in the dissected lymph nodes by gamma probe. Because the gamma probe is a standard method for sentinel node identification, the sensitivity of fused SPECT/CT images was examined on the basis of the data of the gamma probe., Results: Fused SPECT/CT images could identify sentinel nodes at segmental and lobar lymph nodes with a sensitivity of 0.87 and 0.74, both of which were significantly higher than 0.40 in the mediastinum (P < .001 and P = .012, respectively). In 5 patients with pathologic N1 or N2 disease, both SPECT/CT and the gamma probe could identify sentinel nodes with metastases., Conclusions: SPECT/CT could identify sentinel nodes of the hilum especially in segmental and lobar lymph nodes but not in the mediastinum. Because the gamma probe can identify sentinel nodes before nodal dissection in the mediastinum but not in the hilum, a combination of SPECT/CT and the gamma probe can be used to identify sentinel nodes before nodal dissection in both the hilum and the mediastinum, which will enable sentinel node navigation surgery in non-small cell lung cancer.

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.

Objective: To determine the optimum selection of mediastinal lymph nodes for biopsy in non-small cell lung cancer (NSCLC), lymph nodes with or without metastasis at each mediastinal station were ranked in size in patients with pathological N2 disease., Methods: Twenty-five NSCLC patients with pathological N2 disease who underwent pulmonary resection with complete mediastinal lymph node clearance were examined. Of 114 mediastinal lymph node stations dissected, 47 had metastases and 67 did not. The sizes of 259 nodes in the 47 positive lymph node stations were measured. Of these 259 nodes, 137 had metastases and 122 did not. The short- and long-axis diameters of the 259 lymph nodes were ranked in each lymph node station., Results: Mean short- and long-axis diameters of lymph nodes with metastases were significantly greater than those without (p < 0.001). In 47 metastatic lymph node stations, the short- and long-axis diameters were greatest in a metastatic node in 44 (94%) and 42 (89%) respectively, whereas in the remaining 3 (6%) and 5 (11%), the second largest but not the largest node was positive. None of the largest lymph nodes with metastasis were smaller than the second largest lymph node at each station. Four of the 10 patients with adenocarcinoma (40%) had metastasis in the second largest but not in the largest node measured by long-axis diameter, a significant difference from one in eight (12.5%) among the squamous cell carcinoma cases (p = 0.04)., Conclusion: For mediastinal lymph node biopsy, both the largest and the second largest node at each station should be sampled, especially in adenocarcinoma. If only the largest lymph node is selected, false-negative results will occur at a rate of about 10%.