Oncofetal IGF2BP3-mediated control of microRNA structural diversity in the malignancy of early-stage lung adenocarcinoma.

The nature of microRNA (miRNA) dysfunction in carcinogenesis remains controversial because of the complex connection between miRNA structural diversity and biological processes. Here, we found that oncofetal IGF2BP3 regulates the selective production of a subset of 3'-isoforms (3'-isomiRs), including miR-21-5p and Let-7 family, which induces significant changes in their cellular seed occupancy and structural components, establishing a cancer-specific gene expression profile. The D-score, reflecting dominant production of a representative miR-21-5p+C (a 3'-isomiR), discriminated between clinical early-stage lung adenocarcinoma (LUAD) cases with low and high recurrence risks, and was associated with molecular features of cell cycle progression, epithelial-mesenchymal transition pressure, and immune evasion. We found that IGF2BP3 controls the production of miR-21-5p+C by directing the nuclear Drosha complex to select the cleavage site. IGF2BP3 was also involved in the production of 3'-isomiRs of miR-425-5p and miR-454-3p. IGF2BP3-regulated these three miRNAs are suggested to be associated with the regulation of p53, TGF-ß, and TNF pathways in LUAD. Knockdown of IGF2BP3 also induced a selective upregulation of Let-7 3'-isomiRs, leading to increased cellular Let-7 seed occupancy and broad repression of its target genes encoding cell cycle regulators. The D-score is an index that reflects this cellular situation. Our results suggest that the aberrant regulation of miRNA structural diversity is a critical component for controlling cellular networks, thus supporting the establishment of a malignant gene expression profile in early stage LUAD.

Multi-omics and clustering analyses reveal the mechanisms underlying unmet needs for patients with lung adenocarcinoma and identify potential therapeutic targets.

BACKGROUND: The cancer genome contains several driver mutations. However, in some cases, no known drivers have been identified; these remaining areas of unmet needs, leading to limited progress in cancer therapy. Whole-genome sequencing (WGS) can identify non-coding alterations associated with the disease. Consequently, exploration of non-coding regions using WGS and other omics data such as ChIP-sequencing (ChIP-seq) to discern novel alterations and mechanisms related to tumorigenesis have been attractive these days. METHODS: Integrated multi-omics analyses, including WGS, ChIP-seq, DNA methylation, and RNA-sequencing (RNA-seq), were conducted on samples from patients with non-clinically actionable genetic alterations (non-CAGAs) in lung adenocarcinoma (LUAD). Second-level cluster analysis was performed to reinforce the correlations associated with patient survival, as identified by RNA-seq. Subsequent differential gene expression analysis was performed to identify potential druggable targets. RESULTS: Differences in H3K27ac marks in non-CAGAs LUAD were found and confirmed by analyzing RNA-seq data, in which mastermind-like transcriptional coactivator 2 (MAML2) was suppressed. The down-regulated genes whose expression was correlated to MAML2 expression were associated with patient prognosis. WGS analysis revealed somatic mutations associated with the H3K27ac marks in the MAML2 region and high levels of DNA methylation in MAML2 were observed in tumor samples. The second-level cluster analysis enabled patient stratification and subsequent analyses identified potential therapeutic target genes and treatment options. CONCLUSIONS: We overcome the persistent challenges of identifying alterations or driver mutations in coding regions related to tumorigenesis through a novel approach combining multi-omics data with clinical information to reveal the molecular mechanisms underlying non-CAGAs LUAD, stratify patients to improve patient prognosis, and identify potential therapeutic targets. This approach may be applicable to studies of other cancers with unmet needs.

Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations.

BACKGROUND: In an extensive genomic analysis of lung adenocarcinomas (LUADs), driver mutations have been recognized as potential targets for molecular therapy. However, there remain cases where target genes are not identified. Super-enhancers and structural variants are frequently identified in several hundred loci per case. Despite this, most cancer research has approached the analysis of these data sets separately, without merging and comparing the data, and there are no examples of integrated analysis in LUAD. METHODS: We performed an integrated analysis of super-enhancers and structural variants in a cohort of 174 LUAD cases that lacked clinically actionable genetic alterations. To achieve this, we conducted both WGS and H3K27Ac ChIP-seq analyses using samples with driver gene mutations and those without, allowing for a comprehensive investigation of the potential roles of super-enhancer in LUAD cases. RESULTS: We demonstrate that most genes situated in these overlapped regions were associated with known and previously unknown driver genes and aberrant expression resulting from the formation of super-enhancers accompanied by genomic structural abnormalities. Hi-C and long-read sequencing data further corroborated this insight. When we employed CRISPR-Cas9 to induce structural abnormalities that mimicked cases with outlier ERBB2 gene expression, we observed an elevation in ERBB2 expression. These abnormalities are associated with a higher risk of recurrence after surgery, irrespective of the presence or absence of driver mutations. CONCLUSIONS: Our findings suggest that aberrant gene expression linked to structural polymorphisms can significantly impact personalized cancer treatment by facilitating the identification of driver mutations and prognostic factors, contributing to a more comprehensive understanding of LUAD pathogenesis.

Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments.

Overcoming resistance to immune checkpoint inhibitors is an important issue in patients with non-small-cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and "cold" tumor-immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype.

Clinical and Pathologic Differences between Small-Cell Carcinoma and Large-Cell Neuroendocrine Carcinoma of the Lung.

BACKGROUND: Both small-cell carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) of the lung are often clinically dealt with as being in the same category as neuroendocrine carcinoma, and their clinical differences have not been adequately assessed. METHODS: The postoperative prognosis was retrospectively analyzed using the data of 196 patients who underwent resection for SCLC or LCNEC. RESULTS: Of the patients included, 99 (50.5%) had SCLC and 97 (49.5%) had LCNEC. The median duration of follow-up was 39 months (interquartile range [IQR] 21-76) and 56 months (IQR 21-87) for SCLC and LCNEC, respectively. The estimated 5-year overall survival (OS) probabilities were 53.7% and 62.7% (p = 0.133) for patients with SCLC and LCNEC, respectively. In the SCLC group, a multivariate analysis showed that adjuvant chemotherapy (hazard ratio 0.54, 95% confidence interval 0.30-0.99, p = 0.04) was the only factor that was significantly associated with OS. In the LCNEC group, univariate analyses demonstrated that pathologic stage I (p = 0.01) was the only factor that was associated with better OS after surgery. CONCLUSIONS: We found different clinical features in SCLC and LCNEC; in patients with SCLC, because OS could be expected to significantly improve with postoperative adjuvant chemotherapy, patients with resected SCLC of any pathologic stage should receive adjuvant chemotherapy. For patients with LCNEC, because pathologic stage I LCNEC is related to better prognosis than any other stages, a thorough clinical staging, including invasive staging, according to present guidelines should be performed to identify clinical stage I LCNEC with the highest certainty.

Impact of 18F-FDG PET on TNM Staging and Prognosis in Thymic Epithelial Tumors.

BACKGROUND: Preoperative fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) of thymic epithelial tumors (TETs) is well known for identifying malignant-grade TETs; however, its predictive power for determining locally advanced tumors, lymph node (LN) metastasis, and prognosis remains unknown. PATIENTS AND METHODS: We retrospectively evaluated patients with resectable TETs who were preoperatively assessed using 18F-FDG PET from January 2012 to January 2023. The receiver operating characteristic curve was used to evaluate the cutoff value of the maximum standardized uptake value (SUVmax) to predict advanced-stage disease. Recurrence/progression-free survival (RFS/PFS) was analyzed using the Kaplan-Meier method. The staging was classified according to the tumor-node-metastasis system. RESULTS: Our study included 177 patients; 145 (81.9%) had pathological early-stage TET (stage I or II), and 32 (19.1%) had advanced stage (stage III or IV). The area under the curve value for predicting the advanced stage was 0.903, and the cutoff value was 5.6 (sensitivity 81.3%, specificity 84.8%). SUVmax > 5.6 was associated with worse prognosis for RFS/PFS. LN metastasis was preoperatively detected by FDG uptake in 30.8% of patients with pathological LN positivity, whereas LN metastasis was not pathologically detected in patients with SUVmax < 5.9. In patients with advanced-stage TETs, LN recurrence was more frequent in patients who were preoperatively detected by 18F-FDG PET than those who were not (75.0% versus 7.1%). CONCLUSIONS: 18F-FDG PET is a potentially valuable tool for predicting advanced stage and poor prognosis of recurrence in patients with TETs. SUVmax can help thoracic surgeons to guide them in selecting appropriate therapeutic strategies for TETs.

Inflammatory spindle cell PEComa of the lung with YAP1::TFE3 fusion: a report of two cases and a potential relationship with clear cell stromal tumour.

AIMS: The PEComa family of tumours is defined by spindle/epithelioid cells with myomelanocytic differentiation. A small subset harbours TFE3 fusion; however, YAP1::TEE3 has not been reported. Clear cell stromal tumour of the lung (CCST-L) is an emerging entity characterized by spindle to epithelioid cells with focal cytoplasmic clearing, inflammatory infiltrates, no myomelanocytic differentiation, and YAP1::TFE3 fusion. Herein, we report two cases of lung tumours with myomelanocytic differentiation that showed inflammatory spindle cell histology, focal epithelioid clear cells, as well as YAP1::TFE3 fusion. METHODS AND RESULTS: The patients were both men, aged 61 and 68 years. The tumours in both cases presented as well-circumscribed solid masses involving the lung hilum. After lobectomy, no recurrence was observed at 7 and 32 months. Both tumours shared storiform to short fascicular growth of long spindle cells, with a minor component of epithelioid cells showing clear cytoplasm in the background of substantial intratumoral chronic inflammation and dilated blood vessels. One tumour showed focal melanin deposition. Both tumours were immunohistochemically positive for HMB45, Melan A, and h-caldesmon. Fluorescence in situ hybridization assays indicated the presence of YAP1::TFE3 fusions, which was confirmed by RNA sequencing in one case tested, and by immunohistochemical TFE3 expression and loss of YAP1 C-terminus staining. CONCLUSION: We present two cases of inflammatory spindle to epithelioid cell tumours of the lungs with myomelanocytic differentiation and YAP1::TFE3 fusion. This unique morphology and gene fusion suggest that these tumours may constitute a distinct subset of lung PEComa. Furthermore, morphological and molecular overlap with CCST-L gives rise to a hypothesis of a potential inherent relationship between PEComa and CCST-L.

Surgically resected sarcomatoid carcinoma of the lung: a nationwide retrospective study in 2010.

BACKGROUND: Sarcomatoid carcinoma of the lung is a rare histological type of non-small cell lung cancer with a poor prognosis. We aimed to investigate the clinicopathological characteristics and prognostic factors of surgically resected sarcomatoid carcinoma of the lung. METHODS: We retrospectively reviewed 14999 patients who underwent surgical resection for non-small cell lung cancer accumulated by the Japanese Joint Committee of Lung Cancer Registry in 2010. Clinicopathological characteristics and survival were compared between the sarcomatoid carcinoma and other non-small cell cancer groups. The prognostic factors in the sarcomatoid carcinoma group were identified using a multivariate Cox proportional hazard model. RESULTS: Patients with sarcomatoid carcinoma comprised 1.4% of all patients. The sarcomatoid carcinoma group demonstrated a more aggressive pathology with presentation at more advanced stages, requiring more frequent extensive surgical resections. The sarcomatoid carcinoma group had remarkably poorer overall and recurrence-free survival than the other non-small cell lung cancer group. Adjuvant chemotherapy was associated with improved survival for pathological stage II-III sarcomatoid carcinoma cases rather than for pathological stage I disease. In the multivariate analysis, larger tumor size, lymphatic permeation, and no adjuvant chemotherapy were associated with the sarcomatoid carcinoma group's overall and recurrence-free survival. CONCLUSIONS: Surgically resected sarcomatoid carcinoma of the lung has a higher aggressive and metastatic potential and a worse prognosis than other non-small cell lung cancers. Adjuvant chemotherapy, which was associated with enhanced survival in patients with pathological stage II-III of the disease, could be considered for treating patients with pathological stage II-III sarcomatoid carcinoma of the lung.

In vivo transfection of cytokine genes into tumor cells using a synthetic vehicle promotes antitumor immune responses in a visceral tumor model.

The tumor microenvironment (TME) strongly affects the clinical outcomes of immunotherapy. This study aimed to activate the antitumor immune response by manipulating the TME by transfecting genes encoding relevant cytokines into tumor cells using a synthetic vehicle, which is designed to target tumor cells and promote the expression of transfected genes. Lung tumors were formed by injecting CT26.WT intravenously into BALB/c mice. Upon intravenous injection of the green fluorescent protein-coding plasmid encapsulated in the vehicle, 14.2% tumor-specific expression was observed. Transfection of the granulocyte-macrophage colony-stimulating factor (GM-CSF) and CD40 ligand (L)-plasmid combination and interferon gamma (IFNγ) and CD40L-plasmid combination showed 45.5% and 54.5% complete remission (CR), respectively, on day 60; alternate treatments with both the plasmid combinations elicited 66.7% CR, while the control animals died within 48 days. Immune status analysis revealed that the density of dendritic cells significantly increased in tumors, particularly after GM-CSF- and CD40L-gene transfection, while that of regulatory T cells significantly decreased. The proportion of activated killer cells and antitumoral macrophages significantly increased, specifically after IFNγ and CD40L transfection. Furthermore, the level of the immune escape molecule programmed death ligand-1 decreased in tumors after transfecting these cytokine genes. As a result, tumor cell-specific transfection of these cytokine genes by the synthetic vehicle significantly promotes antitumor immune responses in the TME, a key aim for visceral tumor therapy.

A randomized phase III trial of postoperative surveillance for pathological stage II and IIIA non-small cell lung cancer (JCOG2012, PHOENIX).

The goal of postoperative surveillance following non-small cell lung cancer surgery is to detect recurrence and second primary malignancies while curative treatment is still possible. Although several guidelines recommend that patients have computed tomography (CT) scans every 6 months for the first 2 years after resection, then once a year, there is no evidence that it is effective for survival, especially in locally advanced non-small cell lung cancer. In October 2022, we launched a multi-institutional, randomized controlled phase III trial for pathological stage II and IIIA non-small cell lung cancer patients to confirm the non-inferiority of less intensive surveillance with less frequent CT scans versus standard surveillance in terms of overall survival. The primary endpoint is overall survival. We intend to enroll 1100 patients from 45 institutions over 4 years. The trial has been registered in the Japan Registry of Clinical Trials under the code jRCT1030220361 (https://jrct.niph.go.jp/latest-detail/jRCT1030220361).

The effect of epidermal growth factor receptor mutation on adjuvant chemotherapy with tegafur/uracil for patients with completely resected, non-lymph node metastatic non-small cell lung cancer (> 2 cm): a multicenter, retrospective, observational study as exploratory analysis of the CSPOR-LC03 study.

BACKGROUND: The use of adjuvant osimertinib for epidermal growth factor receptor (EGFR) mutants is expected to expand to earlier stage I in the future, potentially competing with the current standard of care, oral tegafur/uracil (UFT), in Japan. However, the effect of EGFR mutation status on the therapeutic effect of UFT remains unclear. This study was conducted as an exploratory analysis of a retrospective observational study that investigated the real-world data of postoperative adjuvant chemotherapy in Japan (CSPOR-LC03). METHODS: Between 2008 and 2013, 1812 patients with completely resected adenocarcinoma diagnosed as pathologic stage I (T1 > 2 cm, TNM classification, sixth edition) who have maintained organ function, and no history of other cancers were included. The primary endpoint was the 5-year disease-free survival (DFS) rate, and we compared this rate between four groups classified based on the administration of adjuvant UFT and EGFR mutation status. RESULTS: Of the 933 (51%) patients with EGFR mutations, 394 underwent adjuvant UFT therapy. Of the 879 (49%) patients without EGFR mutations, 393 underwent adjuvant UFT therapy. The 5-year DFS of UFT+/EGFR+ and UFT-/EGFR+ patients were 82.0 and 87.1%, respectively, and those of UFT+/EGFR- and UFT-/EGFR- patients were 80.0 and 86.9%, respectively. DFS was significantly worse in the UFT+ group than in the UFT- group (P = 0.015). Adjuvant UFT therapy was not an independent prognostic factor for DFS, regardless of the EGFR mutation status. CONCLUSION: In pathologic stage I (>2 cm) lung adenocarcinomas with EGFR mutation, the survival benefit of adjuvant UFT was not observed.

Rare but clinically important salivary gland-type tumor of the lung: A review.

Salivary gland-type tumor (SGT) of the lung, which arises from the bronchial glands of the tracheobronchial tree, was first recognized in the 1950s. SGT represents less than 1% of all lung tumors and is generally reported to have a good prognosis. Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC) are the two most common subtypes, comprising more than 90% of all SGTs. The reported 5-year survival rate of patients with SGT is 63.4%. Because this type of tumor develops in major bronchi, patients with SGT commonly present with symptoms of bronchial obstruction, including dyspnea, shortness of breath, wheezing, and coughing; thus, the tumor is usually identified at an early stage. Most patients are treated by lobectomy and pneumonectomy, but bronchoplasty or tracheoplasty is often needed to preserve respiratory function. Lymphadenectomy in the surgical resection of SGT is recommended, given that clinical benefit from lymphadenectomy has been reported in patients with MEC. For advanced tumors, appropriate therapy should be considered according to the subtype because of the varying clinicopathologic features. MEC, but not ACC, is less likely to be treated with radiation therapy because of its low response rate. Although previous researchers have learned much from studying SGT over the years, the diagnosis and treatment of SGT remains a complex and challenging problem for thoracic surgeons. In this article, we review the diagnosis, prognosis, and treatment (surgery, chemotherapy, and radiotherapy) of SGT, mainly focusing on MEC and ACC. We also summarize reports of adjuvant and definitive radiation therapy for ACC in the literature.

Updated review of perioperative treatment for non-small-cell lung cancer in the new era of immune checkpoint inhibitors: past, present, and future.

The perioperative treatments for non-small cell lung cancer (NSCLC) should control both local and microscopic systemic disease, because the survival of patients with NSCLC who underwent surgical resection alone has been dismal except in stage IA patients. One way to improve surgical outcome is the administration of chemotherapy before or after the surgical procedure. During the last two decades, many clinical studies have focused on developing optimal adjuvant or neoadjuvant cisplatin-based chemotherapy regimens that can be combined with surgical treatment and/or radiotherapy. Based on the results of those clinical studies, multimodality therapy has been considered to be an appropriate treatment approach for locally advanced NSCLC patients. When nodal involvement is discovered postoperatively, adjuvant cisplatin-based chemotherapy has conferred an overall survival benefit. More recently, neoadjuvant and/or adjuvant use of immunotherapy adding to the cisplatin-based chemotherapy has been revealed to improve survival of the patients with locally advanced NSCLC in many large-scale clinical trials; although, optimal treatment strategies are still evolving.

The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group: outstanding contribution and entering a new phase.

The Lung Cancer Surgical Study Group (LCSSG) of the Japan Clinical Oncology Group (JCOG) was organized in 1986 and initially included 26 collaborative institutions, which has increased to 52 institutions currently. JCOG-LCSSG includes thoracic surgeons, medical oncologists, pathologists, and radiotherapists. In the early period, the JCOG-LCSSG mainly focused on combined modality therapies for lung cancer. Since the 2000s, the JCOG-LCSSG has investigated adequate modes of surgical resection for small-sized and peripheral non-small cell lung cancer and based on the radiological findings of whole tumor size and ground-glass opacity. Trials, such as JCOG0802, JCOG0804, and JCOG1211, have shown the appropriateness of sublobar resection, which has significantly influenced routine clinical practice. With the introduction of targeted therapy and immunotherapy, treatment strategies for lung cancer have changed significantly. Additionally, with the increasing aging population and medical costs, tailored medicine is strongly recommended to address medical issues. To ensure comprehensive treatment, strategies, including surgical and nonsurgical approaches, should be developed. Currently, the JCOG-LCSSG has conducted numerous clinical trials to adjust the diversity of lung cancer treatment strategies. This review highlights recent advancements in the surgical field, current status, and future direction of the JCOG-LCSSG.

Clinical outcomes of left upper segmentectomy vs. lobectomy for early non-small-cell lung cancer: a nationwide database study in Japan.

PURPOSE: Given that left upper lobe and right upper and middle lobes share a similar anatomy, segmentectomy, such as upper division and lingulectomy, should yield identical oncological clearance to left upper lobectomy. We compared the prognosis of segmentectomy with that of lobectomy for early stage non-small-cell lung cancer (NSCLC) in the left upper lobe. METHODS: We retrospectively examined 2115 patients who underwent segmentectomy or lobectomy for c-stage I (TNM 8th edition) NSCLC in the left upper lobe in 2010. We compared the oncological outcomes of segmentectomy (n = 483) and lobectomy (n = 483) using a propensity score matching analysis. RESULTS: The 5-year recurrence-free and overall survival rates in the segmentectomy and lobectomy groups were comparable, irrespective of c-stage IA or IB. Subset analyses according to radiological tumor findings showed that segmentectomy yielded oncological outcomes comparable to those of lobectomy for non-pure solid tumors. In cases where the solid tumor exceeded 20 mm, segmentectomy showed a recurrence-free survival inferior to that of lobectomy (p = 0.028), despite an equivalent overall survival (p = 0.38). CONCLUSION: Segmentectomy may be an acceptable alternative to lobectomy with regard to the overall survival of patients with c-stage I NSCLC in the left upper lobe.

Quantitative identification of causes of instrumental acoustic signal distortion in Global Navigation Satellite System-Acoustics Combination observations.

The Seafloor Geodetic Observation-Array (SGO-A), operated by the Japan Coast Guard, relies on the Global Navigation Satellite System-Acoustics combination (GNSS-A) technique, which integrates satellite positioning systems and undersea acoustic ranging to determine seafloor crustal deformation at the centimeter level for earthquake disaster prevention. Recently, we found distortion in the SGO-A 10-kHz carrier wave that degraded the accuracy. Carrier wave distortion can cause errors on the scale of several centimeters to twenty centimeters, which greatly impedes centimeter-level observations. This study investigated this carrier wave degradation by an underwater acoustic communication experiment conducted in 2022, using a transducer similar to that used by SGO-A. Also, we reproduced degraded waveforms through a grid search-like method for quantitatively evaluating the extent to which the interior of the equipment contributed to deterioration. Our results underscore the importance of careful consideration in signal processing, as the observed waveform degradation is not solely attributed to hardware structures but also to internal electrical circuits. The findings suggest that conventional signal identification methods may lead to errors, providing motivation for a shift towards experimental and experiential timing-based waveform identification approaches to enhance accuracy in GNSS-A systems.

Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer.

BACKGROUND: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear. METHODS: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy. RESULTS: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3Low. In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3High cases than in DLL3Low cases (4.7 vs. 7.4 months, P = 0.01). CONCLUSIONS: Although SCLC with DLL3High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.

Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.

BACKGROUND: Lobectomy is the standard of care for early-stage non-small-cell lung cancer (NSCLC). The survival and clinical benefits of segmentectomy have not been investigated in a randomised trial setting. We aimed to investigate if segmentectomy was non-inferior to lobectomy in patients with small-sized peripheral NSCLC. METHODS: We conducted this randomised, controlled, non-inferiority trial at 70 institutions in Japan. Patients with clinical stage IA NSCLC (tumour diameter ≤2 cm; consolidation-to-tumour ratio >0·5) were randomly assigned 1:1 to receive either lobectomy or segmentectomy. Randomisation was done via the minimisation method, with balancing for the institution, histological type, sex, age, and thin-section CT findings. Treatment allocation was not concealed from investigators and patients. The primary endpoint was overall survival for all randomly assigned patients. The secondary endpoints were postoperative respiratory function (6 months and 12 months), relapse-free survival, proportion of local relapse, adverse events, proportion of segmentectomy completion, duration of hospital stay, duration of chest tube placement, duration of surgery, amount of blood loss, and the number of automatic surgical staples used. Overall survival was analysed on an intention-to-treat basis with a non-inferiority margin of 1·54 for the upper limit of the 95% CI of the hazard ratio (HR) and estimated using a stratified Cox regression model. This study is registered with UMIN Clinical Trials Registry, UMIN000002317. FINDINGS: Between Aug, 10, 2009, and Oct 21, 2014, 1106 patients (intention-to-treat population) were enrolled to receive lobectomy (n=554) or segmentectomy (n=552). Patient baseline clinicopathological factors were well balanced between the groups. In the segmentectomy group, 22 patients were switched to lobectomies and one patient received wide wedge resection. At a median follow-up of 7·3 years (range 0·0-10·9), the 5-year overall survival was 94·3% (92·1-96·0) for segmentectomy and 91·1% for lobectomy (95% CI 88·4-93·2); superiority and non-inferiority in overall survival were confirmed using a stratified Cox regression model (HR 0·663; 95% CI 0·474-0·927; one-sided p<0·0001 for non-inferiority; p=0·0082 for superiority). Improved overall survival was observed consistently across all predefined subgroups in the segmentectomy group. At 1 year follow-up, the significant difference in the reduction of median forced expiratory volume in 1 sec between the two groups was 3·5% (p<0·0001), which did not reach the predefined threshold for clinical significance of 10%. The 5-year relapse-free survival was 88·0% (95% CI 85·0-90·4) for segmentectomy and 87·9% (84·8-90·3) for lobectomy (HR 0·998; 95% CI 0·753-1·323; p=0·9889). The proportions of patients with local relapse were 10·5% for segmentectomy and 5·4% for lobectomy (p=0·0018). 52 (63%) of 83 patients and 27 (47%) of 58 patients died of other diseases after lobectomy and segmentectomy, respectively. No 30-day or 90-day mortality was observed. One or more postoperative complications of grade 2 or worse occurred at similar frequencies in both groups (142 [26%] patients who received lobectomy, 148 [27%] who received segmentectomy). INTERPRETATION: To our knowledge, this study was the first phase 3 trial to show the benefits of segmentectomy versus lobectomy in overall survival of patients with small-peripheral NSCLC. The findings suggest that segmentectomy should be the standard surgical procedure for this population of patients. FUNDING: National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Long-Term Prognosis and Prognostic Indicators of Stage IA Lung Adenocarcinoma.

BACKGROUND: The 8th edition of the TNM stage classification of lung cancer was developed based on an evaluation of the 5-year prognosis using an international database. Since recurrence after 5 years postoperatively is known to develop, the applicability of the stage classification beyond 5 years after treatment needs to be evaluated. PATIENTS AND METHODS: Postoperative prognosis and prognostic indicators were analyzed using data for 648 patients of pathological stage IA adenocarcinoma, who underwent complete resection between 2007 and 2012. RESULTS: The median age was 66 years (interquartile range 60-73 years), and the median follow-up duration was 100 months (interquartile range 70-116 months). Overall survival probabilities for pathological stage IA1, IA2, and IA3 patients were 100%, 96.3%, and 91.5% at 5 postoperative years, and 94.2%, 89.8%, and 83.5% at 10 postoperative years, respectively (IA1 vs IA2: p = 0.05; IA2 vs IA3: p = 0.05). Multivariate analysis for overall survival of patients who survived without recurrence for 5 postoperative years revealed that age (hazard ratio 3.21, p = 0.02) was the only factor that was significantly associated with long-term survival. Stage classification (IA1, IA2, or IA3) was not an associated factor. The incidence of secondary primary lung cancer continued to increase, resulting in an estimated probability of 8.6% at 10 postoperative years. CONCLUSIONS: For patients who survived without recurrence for 5 postoperative years, age, not stage classification, was associated with survival thereafter. The long-term follow-up strategy does not need to be modified according to the stage classification, and screening for secondary primary lung cancer should be considered.

Dynamics of recurrence after curative resection of nonsmall cell lung cancer.

BACKGROUND AND OBJECTIVES: This study examined the trend of hazards for postoperative recurrence of lung cancer according to pathologic stages. METHODS: We reviewed the records of 1987 patients who underwent resection for lung cancer between 2007 and 2012. Postoperative recurrence and development of second primary lung cancer were analyzed to evaluate the trend of hazard rate. RESULTS: Recurrence-free survival (RFS) probabilities at 5 postoperative years in patients with stage I/II/III disease were 87.8%/54.7%,/33.4%, respectively. The hazard rate of RFS was consistently low (<0.005) for stage I patients for 5 years after surgery. The hazard rate of RFS for stage II patients showed a peak of 0.016 at 12.4 months after surgery, and that for stage III patients had a higher peak of 0.029 at 13.7 months after surgery, after which they showed a gradual decrease. The hazard rate for the development of second primary lung cancer exceeded that of recurrence of first primary lung cancer after 72 months postoperatively. CONCLUSIONS: Short-interval postoperative surveillance might be unnecessary for stage I patients but should be considered in stage II/III patients. Screening of second primary lung cancer rather than surveillance of recurrence might be beneficial after more than 6 years postoperatively.