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Objectives: Limited treatment options are available for non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD). The rationale for immunotherapy and its adverse events for NSCLC with ILD remains unclear. In this study, we examined T cell profiles and functions in the lung tissues of NSCLC patients with or without ILD to provide evidence for the potential mechanism of immune checkpoint inhibitor (ICI)-related pneumonitis in NSCLC patients with ILD., Material and Methods: We investigated T cell immunity in the lung tissues of NSCLC patients with ILD to support the application of immunotherapy for these patients. We analyzed T cell profiles and functions in surgically resected lung tissues from NSCLC patients with and without ILD. The T cell profiles of infiltrating cells in lung tissues were analyzed by flow cytometry. T cell functions were measured based on cytokine production by T cells stimulated with phorbol 12-myristate 13-acetate and ionomycin., Results: The percentages of CD4 +  T cells expressing immune checkpoint molecules (Tim-3, ICOS, and 4-1BB), CD103 + CD8 +  T cells, and regulatory T (Treg) cells were higher in NSCLC patients with than in those without ILD. A functional analysis of T cells in lung tissues indicated that CD103 + CD8 +  T cells positively correlated with IFNγ production, whereas Treg cells negatively correlated with IFNγ and TNFα production. Cytokine production by CD4 +  and CD8 +  T cells did not significantly differ between NSCLC patients with and without ILD, except for TNFα production by CD4 +  T cells being lower in the former than in the latter., Conclusion: In NSCLC patients with ILD stable for surgery, T cells were active participants and balanced in part by Treg cells in lung tissues, suggesting the potential development of ICI-related pneumonitis in NSCLC patients with ILD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Surgical treatment of superior sulcus tumors (SSTs) is clinically challenging. Definitive chemoradiotherapy (CRT) is a standard treatment for SST. In operable cases, multimodal therapy (CRT followed by surgery) is another option, at least for experienced institutions. Immune checkpoint inhibitors (ICIs) have recently been developed, and several clinical trials have investigated definitive CRT followed by ICIs for consolidation or maintenance therapy of unresectable local advanced non-small cell lung cancer (NSCLC), including SSTs. Clinical studies of salvage surgery after CRT followed by ICIs are also ongoing. However, the clinical outcomes of salvage surgery after multimodal therapies and histopathological analyses of surgical specimens after such treatments remain unclear. Here, we report the case of a patient with SST comprising squamous cell carcinoma with invasion of the second to third rib and vertebrae who underwent salvage surgery after concurrent definitive CRT followed by the ICI durvalumab, and show the results of clinicopathological analyses of the resected specimen., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: The surgical Apgar score (SAS) is a simple score that predicts postoperative complications based on 3 intraoperative valuables. The present study evaluated the association between the SAS and postoperative outcomes in non-small-cell lung cancer patients who underwent surgery., Methods: A total of 585 patients who underwent lung resection were enrolled in the present study. We calculated the SAS of each patient and investigated its influence on the short- and long-term outcomes., Results: Postoperative complications of any grade were detected in 164 cases (28%). The morbidity rate increased with decreasing SAS. When all the patients were divided into 2 groups (SAS <7 vs ≥7), postoperative complications were observed more frequently in the SAS <7 group than in the SAS ≥7 group (41% vs 25%, P < 0.001). In the multivariate analysis, the SAS was an independent risk factor for postoperative complications (odds ratio: 1.64 [1.03-2.61], P = 0.036). In terms of long-term outcomes, the 5-year disease-free survival (54.1% vs 73.2%, P < 0.001) and overall survival (73.8% vs 83.0%, P = 0.031) were significantly worse in the SAS <7 group than in the SAS ≥7 group. In a multivariate analysis, however, the SAS was not found to be an independent prognostic factor for either disease-free survival (hazard ratio: 1.39 [0.97-2.00], P = 0.075) or overall survival (hazard ratio: 0.90 [0.57-1.42], P = 0.642)., Conclusions: The SAS reflected preoperative and intraoperative characteristics and was able to stratify the morbidity rate, suggesting it to be a useful predictor of short-term outcomes in non-small-cell lung cancer patients who undergo surgery., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Introduction: The prognosis of non-small cell lung cancer greatly depends on the presence of lymph node metastasis, which limits the need for surgery and adjuvant therapy for advanced cancer. One-step nucleic acid amplification of cytokeratin19 (CK19) mRNA was used to detect lymph node metastasis. Automated Gene Amplification Detector RD-200 and the LYNOAMP CK19 gene amplification reagent as components of the new one-step nucleic acid amplification system, which has increased gene amplification efficiency by improving the reagent composition, have shorter preprocessing and measurement times than conventional systems. We aimed to compare the clinical performance of the new system with that of histopathology and the conventional system., Materials and Methods: 199 lymph nodes from 58 non-small cell lung cancer patients who underwent lymph node dissection were examined intraoperatively using the new system, conventional system, and histopathology., Results: Lymph node metastasis was diagnosed in 32, 42, and 44 patients using histopathological analysis, the new system, and the conventional system, respectively. Compared with histopathological analysis, the concordance rate, sensitivity, specificity, positive predictive value, and negative predictive value of the new system were 92.0%, 90.6%, 92.2%, 69.0%, and 98.1%, respectively, and compared with the conventional system, the values were 95.0%, 86.4%, 97.4%, 90.5%, and 96.2%, respectively., Conclusion: The clinical performance of the new one-step nucleic acid amplification system in detecting lymph node metastasis of lung cancer is comparable to that of histopathology and the conventional system; its performance was sufficient for determining the appropriate clinical treatment. The new rapid system can be effectively utilized during lung cancer treatment intraoperatively and postoperatively., Competing Interests: Naoko Ose, Yasushi Shintani, Yukiyasu Takeuchi, Yasushi Sakamaki and Yoshihisa Kadota had grant support from Sysmex Corp. and Mayuko Noguchi is an employee of Sysmex Corp. Hiromi Tsuji, Kunimitsu Kawahara and Kenji Urasaki declare no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Non-small cell lung cancer (NSCLC) patients with idiopathic pulmonary fibrosis (IPF) show poor prognosis. Periostin is an extracellular matrix protein highly expressed in the lung tissues of IPF. This study aimed to investigate the possibility that periostin secreted by fibroblasts derived from IPF lung might affect proliferation of NSCLC cells. Periostin was more highly expressed and secreted by fibroblasts from diseased human lung with IPF (DIPF) than by normal human lung fibroblasts (NHLF). Cocultivation of NSCLC cells with conditioned media (CM) from DIPF increased proliferation of NSCLC cells through pErk signaling, with this proliferation attenuated by periostin-neutralizing antibodies. Knockdown of integrin β3, a subunit of the periostin receptor, in NSCLC cells suppressed proliferation of NSCLC cells promoted by recombinant human periostin and CM of DIPF. On in vivo examination, DIPF promoted tumor progression more than NHLF, and knockdown of integrin β3 in NSCLC cells suppressed tumor progression promoted by DIPF. Fibroblasts derived from surgical specimens from IPF patients also increased secretion of periostin compared to those from non-IPF patients. Periostin secreted from IPF-activated fibroblasts plays critical roles in the proliferation of NSCLC cells. The present study provides a solid basis for considering periostin-targeted therapy for NSCLC patients with IPF., (© 2021. The Author(s).)

Objectives: With improvements in the outcome of treatment for non-small-cell lung cancer (NSCLC), other diseases may account for a high death rate after surgery in patients with stage I NSCLC. In the present study, we analysed the associations between the clinical factors and non-cancer death after surgery in these patients., Methods: The records of 514 patients with stage I NSCLC who underwent surgery were retrospectively reviewed; a proportional hazards model for the subdistribution of a competing risk was conducted to define the risk factors for non-cancer death., Results: The mean patient age was 67 years. A total of 367 patients (71%) underwent bilobectomy or lobectomy while 147 (29%) underwent sublobar resection. The pathological stage was IA in 386 (75%) and IB in 128 (25%) patients. Three patients (0.6%) died within 90 days after surgery, and 108 (21%) experienced postoperative complications. Until the time of writing this report, 83 patients had died during the follow-up. The cause of death was primary lung cancer in 38 (46%) patients and other diseases in 45 (54%) patients, including non-cancer causes in 29 patients, such as pneumonia, cardiac death and cerebral stroke. According to a multivariable competing risk analysis for non-cancer death age (≥70 years), sex (male), body mass index (BMI <18.5), postoperative complications and % forced expiratory volume in 1 s (<80) were identified as risk factors for postoperative non-cancer death., Conclusions: Advanced age (≥70 years), male sex, low BMI (<18.5), postoperative complications and low preoperative % forced expiratory volume in 1 s (<80) were found to be the risk factors for postoperative non-cancer death after surgery in patients with stage I NSCLC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Targeting cancer-associated fibroblasts (CAFs), as well as the crosstalk between stroma and cancer cells, could be of value in managing cancers. Pirfenidone (PFD) is an anti-fibrotic agent for idiopathic pulmonary fibrosis. This study aimed to investigate the possibility that PFD might exert an anti-tumor effect through inhibition of fibroblast activation and the tumor-stroma interaction in non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo. PFD significantly inhibited myofibroblast differentiation and activation of both primary cultured normal human lung fibroblasts and CAFs. Cocultivation of NSCLC cells with conditioned media (CM) of fibroblasts changed the morphology or epithelial to mesenchymal transition (EMT) status, and PFD suppressed these changes. Cocultivation of CAFs with CM of NSCLC cells also induced activation of CAFs, and these changes were suppressed by PFD. On in vivo examination, CAFs promoted tumor progression, and PFD suppressed tumor progression with an inhibitory effect on tumor-stroma crosstalk. PFD might inhibit not only fibroblast activity, but also the crosstalk between cancer cells and fibroblasts. PFD may have great potential as a novel treatment for NSCLC from multiple perspectives.

Background: The survival outcome in lung cancer patients with chronic kidney disease (CKD) has not been well evaluated. The aim of this study was to evaluate the survival outcomes following non-small cell lung cancer (NSCLC) surgery in patients with CKD as a preoperative comorbidity., Methods: Among 671 patients who underwent surgery for NSCLC between 2007 and 2014 at our hospital, 55 (8%) had CKD and we retrospectively analyzed the survival outcomes of these patients., Results: Most patients with CKD were elderly and male. Patients with CKD had a higher frequency of smoking habit, cardiovascular disease, and pulmonary diseases, and a notably lower pulmonary function, resulting in receiving limited pulmonary resection. There were no marked differences in the frequency of surgical complications between patients with and without CKD (p = 0.16). Squamous cell carcinoma was more frequently diagnosed in patients with CKD than in those without it. The 5-year disease-free survival rates in patients with and without CKD were 60.0% and 69.7% (p = 0.06), respectively, and the 5-year overall survival rates were 68.9% and 80.0%, respectively, showing significant differences (p = 0.01). The rate of receiving supportive care was higher in patients with CKD when recurrence observed., Conclusion: CKD is associated with a poorer overall survival in patients who undergo lung cancer resection for recurrent disease. As patients with CKD tend to have a poor respiratory function, thoracic surgeons should carefully select the resection type to balance the therapeutic benefit and invasiveness.

Feasibility is one of the major concerns during adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. A phase II clinical trial of adjuvant chemotherapy with four courses of carboplatin (AUC 5 at day 1) and S-1 (80 mg/m 2 /day for 2 weeks followed by a 2-week rest) was performed to evaluate the feasibility (UMIN 9101). The primary endpoint was the completion rate and the secondary endpoints were adverse events, 2-year overall survival and disease-free rates. Thirty-five non-small cell lung cancer patients were enrolled. The adjuvant chemotherapy completion rate was 85.3% (29/34); 17/34 (50%) patients completed 4 courses without dose reduction. There were no treatment-related deaths, and Grade 3/4 adverse events included neutropenia (38.2%), leukocytopenia (14.7%), anemia (20.6%), thrombocytopenia (20.6%), anorexia (5.9%), fatigue (5.9%), and oral mucositis (2.9%). Two-year overall and disease-free survival rates were 96.3% and 53.3%, respectively. Adjuvant chemotherapy with carboplatin plus S-1 is safe and feasible.

Purpose: Information on the short- and long-term outcomes of induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer is limited. We analyzed the short- and long-term outcomes of induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer., Methods: Patients with non-small cell lung cancer who underwent induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer were retrospectively reviewed (initial treatment group, n = 31). Their results were compared to those patients who underwent surgery as an initial treatment during the same period (initial surgery group, n = 35)., Results: Downstaging was achieved in 14 (45%) patients in the initial treatment group. R0 resection was achieved in 28 (90%) patients in the initial treatment group and 31 (88%) patients in the initial surgery group. The 90-day mortality rate was 3% in each group. Postoperative complications occurred in 16 (52%) patients in the initial treatment group and 13 (37%) patients in the initial surgery group. The 5-year overall survival rate of the initial treatment group was significantly higher than that of the initial surgery group (62.6% vs 43.5%, P = .04). The 5-year overall survival rates of the initial treatment N0-1 group and the initial surgery N0-1 group were 88.9% and 49.3%, respectively; the difference was statistically significant ( P = .02). Multivariate analysis using 4 factors (age [≤65 vs >65], cN [cN0-1 vs cN2], general condition [chemoradiotherapy fit vs chemoradiotherapy unfit], and treatment mode [induction chemoradiotherapy followed by surgery vs surgery as an initial treatment]) revealed that treatment mode (induction chemoradiotherapy followed by surgery) and cN status (cN0-1) were significantly associated with good overall survival and disease-free survival., Conclusions: Induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer could be performed with an acceptable degree of surgical risk. At present, it is thought to be one of the reasonable treatment approaches for selected patients with cT3-4 disease, even those with a cN0-1 status.

Background: PDGFR-β is used as a stromal biomarker and is functional in mesenchymal cells of the tumor microenvironment. The significance of stromal PDGFR-β expression in non-small cell lung cancer (NSCLC) in patients undergoing preoperative chemo- or chemoradiotherapy had not been determined., Methods: Patients with NSCLC undergoing preoperative chemo- or chemoradiotherapy between 1996 and 2014 were assessed for expression of stromal PDGFR-β by immunohistochemistry using resected specimens. Relationships between stromal PDGFR-β expression and survival after operation were analyzed. Forty-three patients who underwent surgery without preoperative treatment in 2005 were also analyzed as a chemo-naïve control group., Results: The mean age of the 92 patients was 60.2 years. Seventy-eight (85%) were male, and 14 (15%) were female. Fifty-four patients (59%) underwent preoperative chemoradiotherapy, and 38 patients (41%) underwent preoperative chemotherapy. Regimens for preoperative chemotherapy were cisplatin (CDDP) based in 48 patients (52%) and carboplatin (CBDCA) based in 43 (42%). While stromal cells expressed PDGFR-β in 21 chemo-naïve patients (49%), stromal cells expressed PDGFR-β in 65 patients who underwent preoperative therapy (p = 0.02). The 5-year disease-free survival rate (DFS) of the PDGFR-β-positive group was significantly worse than that of the negative group (27 vs. 48%, p = 0.04). The 5-year disease-specific survival rate (DSS) in the stromal PDGFR-β-positive group was also significantly worse than in the negative group (43 vs. 70%, p = 0.01). On the other hand, stromal PDGFR-β expression did not influence survival in chemo-naïve patients., Conclusions: Stromal PDGFR-β expression is negatively associated with DFS and DSS in patients with NSCLC undergoing preoperative chemo- or chemoradiotherapy.

Objectives: Positron emission tomography with 2-[18F] fluoro-2-deoxy-D-glucose as a tracer and computed tomography (FDG-PET/CT) are utilized for the diagnosis of lymph node (LN) metastasis from lung cancer. In this study, we analyzed the diagnostic ability of FDG-PET for N staging by focusing on the clinical features of false-positive (FP) and false-negative (FN) cases., Methods: From March 2006 to February 2010, 112 patients underwent preoperative examinations using FDG-PET/CT followed by radical resection with hilar and mediastinal dissection. We analyzed their clinicopathological characteristics based on preoperative FDG-PET/CT findings and post-operative histopathological diagnosis of resected LNs., Results: Based on the PET/CT results, 17 patients were misdiagnosed (9 FN and 8 FP). The sensitivity, specificity, accuracy and negative and positive predictive values for N1/N2 were 50.0, 94.5, 84.0, 93.0 and 58.3%, respectively, whereas those for N2 were 57.8, 90.3, 84.8, 90.3 and 61.1%, respectively. FP findings more frequently occurred in cases with elevated white blood cell (WBC) count (P=0.015) and smokers (P=0.04). In the FN group, the maximum standardized uptake value for the primary tumour was lower than that in the true-positive (TP) group (P=0.01). The short-axis sizes of 71 LNs differently diagnosed by PET/CT and histopathology findings were significantly smaller in the FN group than the TP group (P<0.001), whereas there was no difference between TP and FP. As for FN LNs in the TP group, there was no significant difference., Conclusions: PET/CT showed a good ability to detect metastatic LNs, especially for N2 diagnosis. However, there were some limitations, especially in cases with elevated peripheral WBC count and/or smoking history.

A 64-year-old man, who had received chemoradiation therapy for stage IIIB non-small-cell lung cancer, underwent stent insertion with a covered expandable metallic stent for post-radiation bronchial stenosis. Stenosis due to formation of granulation tissue at the distal stent site resulted in critical respiratory failure. The stent was removed after 43 months, using rigid bronchoscopy.