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In our institution, computed tomography (CT)-guided percutaneous cryoablation has been performed in patients with malignant lung tumors under local anesthesia. This study aimed to examine the feasibility and safety of percutaneous cryoablation for the treatment of malignant lung tumors.From July 2002 to December 2016, 227 patients (56 with primary lung cancer and 171 with metastatic lung tumor) underwent percutaneous cryoablation for the treatment of malignant lung tumors using a cryosurgical unit at our institution. Demographic factors, duration of post-treatment hospitalization, and adverse event and mortality rates were retrospectively investigated in 366 treatment sessions targeting 609 lesions.The median diameter of the targeted tumor was 1.3 cm. All the cryoablation procedures were completed under local anesthesia, and the median duration of post-treatment hospitalization was two days. Adverse events (grade 2 or higher) were observed in 79 sessions (21.6%), with pneumothorax being the most common. In five sessions (1.4%), patients had grade 3 adverse events. There was no 30-day mortality; however, there were two 60-day mortality (0.5%) due to acute exacerbation of interstitial pneumonia. In multivariate analysis, independent predictors of adverse events were comorbid interstitial pneumonia [odds ratio (OR) =2.20; 95% confidence interval (CI): 1.04-4.64] and no history of pulmonary resection on the treated side (OR =3.04; 95% CI: 1.65-5.62).Cryoablation is a feasible and safe treatment for malignant lung tumors with acceptable adverse event rates. However, the mortality risk in patients with comorbid interstitial pneumonia should be fully recognized.

Stage classification provides a consistent and concise nomenclature about the anatomic extent of the cancer. This is a fundamental cornerstone in the management of patients; it enables reporting results and facilitates comparing one treatment to another and judging how closely clinical trial results apply to an individual patient. A nomenclature must be relatively static; however, periodical refinement is needed to adjust to a changing landscape of clinical relevance. Changes must be well justified and thoughtfully developed to maintain the ability to communicate clearly and facilitate comparisons across time.For thoracic malignancies (lung, pleura, thymus, and esophagus), the International Association for the Study of Lung Cancer (IASLC) has leveraged its worldwide multidisciplinary reach, permitting a sophisticated approach to this process. Refinement of stage classification for the ninth edition of TNM is underway; this article describes the approach adopted by the IASLC Staging and Prognostic Factors Committee.Key guiding principles include the ability to maintain communication over time, a classification that discriminates homogeneous cohorts of tumors consistently across the world in multiple settings, treatment approaches, and patient characteristics, including clinical relevance and practical applicability. The IASLC has again assembled a large international database to permit multifaceted analysis. Providing confidence that the classification performs consistently in multiple settings, treatments, and patients requires consistent discrimination in multiple subset analyses. Although observed outcomes of patients in the 2011 to 2019 database are essential, considerations about how the classification will be used are also important to ensure clinical relevance and applicability.The strategy developed by the Staging and Prognostic Factors Committee is carefully designed to provide useful refinements to the stage classification of thoracic malignancies for the ninth edition of TNM classification of cancers.

Thymic epithelial tumors are presently staged using a consistent TNM classification developed by the International Association for the Study of Lung Cancer (IASLC) and approved by the Union for International Cancer Control and the American Joint Committee on Cancer. The stage classification is incorporated in the eight edition of the TNM classification of thoracic malignancies. The IASLC Staging and Prognostic Factors Committee (SPFC)-Thymic Domain (TD) is in charge for the next (ninth) edition expected in 2024. The present article represents the midterm report of the SPFC-TD: in particular, it describes the unresolved issues identified by the group in the current stage classification which are worth being addressed and discussed for the ninth edition of the TNM classification on the basis of the available data collected in the central thymic database which will be managed and analyzed by Cancer Research And Biostatistics. These issues are grouped into issues of general importance and those specifically related to T, N, and M categories. Each issue is described in reference to the most recent reports on the subject, and the priority assigned by the IASLC SPFC-TD for the discussion of the ninth edition is provided.

Advances in drug therapy and radiotherapy for non-small cell lung cancer resulted in an increased number of salvage surgeries for initially unresectable tumors. This study aimed to evaluate the safety and efficacy of salvage surgery for non-small cell lung cancer.We defined salvage surgery as (1) surgery for local recurrence/residual tumor after definitive chemoradiotherapy/radiotherapy (salvage surgery in a narrow sense) or (2) conversion surgery after non-surgical treatment. We retrospectively analyzed patients who underwent salvage surgery at four Keio University-affiliated hospitals.Forty-six patients were included. The initial clinical stage was I in 4 patients (9%), III in 19 (41%), and IV in 23 (48%). Initial treatment before salvage surgery was chemoradiotherapy in 10 patients (24%), radiotherapy in 4 (9%), and drug therapy in 32 (67%). Pneumonectomy, lobectomy, segmentectomy, and wedge resection were performed in 2 (4%), 37 (80%), 3 (7%), and 4 (9%) patients, respectively. Complete resection was achieved in 41 patients (89%). Postoperative complications occurred in 11 patients (24%). Initial chemoradiotherapy/radiotherapy was an independent predictor of postoperative complications (odds ratio 10, p = 0.03). The 30- and 90-day mortality rates were 0 and 2%, respectively. The 5-year overall and progression-free survival rates were 66 and 30%, respectively.The safety and efficacy of salvage surgery for non-small cell lung cancer were acceptable. Salvage surgery was a viable treatment option for selected patients with recurrent/residual tumors after non-surgical treatments.

Figure legends for suppremental Figure 1 to 5.

Multivariate analysis of clinicopathological factors and infiltrating immune cells

Neoplastic cancer cells and cancer stroma (including infiltrating immune cells) determine the biology and prognosis of cancer. Various types of adaptive and innate immune cells are known to infiltrate the cancer stroma. However, the patterns and spatial distribution of immune cell infiltration as well as its association with tumor histology remain poorly understood. To address these issues, we comprehensively analyzed the infiltrating immune cells present in lung adenocarcinoma. The principal types of both adaptive and innate infiltrating immune cells were immunohistochemically evaluated in the predominant histologic components of 111 lung adenocarcinomas. The same analysis was also carried out on 143 samples of histologic subtypes making up more than 20% of tumors. As a result, plasma cells and B cells with interfollicular distribution were almost exclusively observed in invasive histologic subtypes, while an increased number of mast cells were observed in noninvasive histologic subtypes. Cluster analysis revealed four distinct immunosubtypes (CD8, mast cell, macrophage/dendritic cell, and plasma cell subtypes) based on the infiltrating immune cell profiles. These immunosubtypes correlated with histologic subtypes, and univariate and multivariate analyses identified the plasma cell subtype as an independent negative prognostic factor. These plasma cells may be one of the major producers of the immunosuppressive cytokine IL35 in cancer stroma. Cancer Immunol Res; 4(3); 234–47. ©2016 AACR.

Figure S1. Infiltration of immune cells and grades of histological subtypes. Figure S2. Infiltration of interfollicular plasma cells and Kaplan-Meier curves for DFS. Figure S3. Infiltration of interfollicular mast cells and Kaplan-Meier curves for DFS. Figure S4. Plasma cell/CD8 ratio and Kaplan-Meier curves for DFS. Figure S5. Immunohistochemical staining for immunoglobulins and PD-L1.

Supplementary Table S1. Mutation signature analysis. Supplementary Table S2. Baseline characteristics of the transdifferentiated SCLC patients included in this study. Supplementary Table S3. Intensity of EGFR and Ki67 staining in lung cancer tissues obtained from the indicated patients. Supplementary Table S4. Baseline characteristics of the primary SCLC patients included in this study. Supplementary Table S5. Genetic alterations of the indicated lung cancer cell lines. Supplementary Figure S1. FGF9 immunohistochemistry staining in lung cancer cell lines. Supplementary Figure S2. List of the mutated genes before and after transdifferentiation. Supplementary Figure S3. Gene ontology term analysis in the context of upregulated (A) and downregulated (B) genes. Supplementary Figure S4. Computed tomography images of the patients (Case2-4) during the course of gefitinib therapy. Supplementary Figure S5. EGFR, Ki67 and FGFR1 immunohistochemistry staining of tissues from Cases #5 and #6. Supplementary Figure S6. mRNA expression levels of FGF family genes in lung cancer cell lines. Supplementary Figure S7. Expression of FGF9 and FGF2 in human NSCLC and SCLC cells. Supplementary Figure S8. Functional evaluations of FGF9 in human SCLC cell lines. Supplementary Figure S9. Tumor volumes after MLE12-EGFR transplantation. Supplementary Figure S10. Expression levels of Fgfr family genes in MLE12-FGF9 cells in vitro and in vivo. Supplementary Figure S11. Characteristics of lung adenocarcinoma cell lines. Supplementary Figure S12. In vivo evaluations of FGF9 in H2087 and H2110 cells.

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9–FGFR axis as a therapeutic target for transdifferentiated SCLC.Significance:This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.

The status of lymph node involvement is a major compo-nent of the TNM staging system. The N categories for lung cancer have remained unchanged since the fourth edition of the TNM staging system, partly because of differences in nodal mapping nomenclature, partly because of insufficient details to verify possible alternative approaches for staging. In preparation for the rigorous analysis of the International Association for the Study of Lung Cancer database neces-sary for the ninth edition TNM staging system, members of the N-Descriptors Subcommittee of the International Asso-ciation for the Study of Lung Cancer Staging and Prognostic Factors Committee reviewed the evidence for alternative approaches to categorizing the extent of lymph node involvement with lung cancer, which is currently based solely on the anatomical location of lymph node metastasis. We reviewed the literature focusing on NSCLC to stimulate dialogue and mutual understanding among subcommittee members engaged in developing the ninth edition TNM staging system for lung cancer, which has been proposed for adoption by the American Joint Committee on Cancer and Union for International Cancer Control in 2024. The discussion of the range of possible revision options for the N categories, including the pros and cons of counting lymph nodes, lymph node stations, or lymph node zones, also provides transparency to the process, explaining why certain options may be discarded, others deferred for future consideration. Finally, we provide a preliminary discussion of the future directions that the N-Descriptors Subcommit-tee might consider for the 10th edition and beyond.(c) 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. 2024, the overview for of sixth ferred struction Society The spectively Study data gested deferred allow gory. adopted solution staging and database.4,10

The status of lymph node involvement is a major component of the tumor, node, metastasis (TNM) staging system. The N categories for lung cancer have remained unchanged since the 4

Objective: Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un). Methods: A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations were explored, lobe-specific nodal dissection, extracapsular extension, highest lymph node station status, carcinoma in situ at the bronchial resection margin, and pleural lavage cytologic examination result. Revised categories of R0, R(un), R1, and R2 were tested for survival impact. Results: In all, 14,293 cases were R0, 263 were R1, and 156 were R2 (median survivals not reached, 33 months, and 29 months, respectively). R status correlated with T and N categories. A total of 9290 cases (63%) had three or more N2 stations explored and 6641 cases (45%) had lobespecific nodal dissection, correlated with increasing pN2. Extracapsular extension was present in 62 of 364 cases with available data (17%). The highest station was positive in 942 cases (6.4%). The pleural lavage cytologic examination result was positive in 59 of 1705 cases (3.5%): 13 had carcinoma in situ at the bronchial resection margin. After reassignment because of inadequate nodal staging in 56% of cases, 6070 cases were R0, 8185 were R(un), 301 were R1, and 156 were R2. In node-positive cases, the median survival times were 70, 50, and 30 months for RO, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between RO and R(un) in pN0 cases. Conclusions: R descriptors have prognostic relevance, with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Primary malignant pericardial mesothelioma is an extremely rare disease. Malignant disease of the pericardium is an infrequent cause of cardiac tamponade. Hence, cardiac tamponade in the context of primary malignant mesothelioma of the pericardium is an uncommon clinical scenario. A 67-year-old male patient, an ex-smoker, complaining of progressive lethargy was referred to a hospital for investigation of persistent pericardial effusion. The pericardial fluid cytology was categorized as class Ⅲ. Thereafter, he was referred to our hospital for further evaluation. Fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed FDG accumulation in the pericardium and mediastinal lymph node. Surgical biopsy of the pericardium was performed through a subxiphoid approach for a definitive diagnosis. Histopathological examination revealed diffuse infiltration of the pericardium by a malignant tumor consisting of epithelioid cells with large round nuclei and prominent nucleoli, arranged in a tubular papillary pattern. Finally, the patient was diagnosed with primary malignant pericardial mesothelioma of epithelioid type. The patient died 6 weeks after admission. This diagnosis must be considered in patients having unexplained massive pericardial effusion. Furthermore, we should consider prompt cytological analysis and FDG PET to arrive rapidly at a definitive diagnosis to administer combination chemotherapy that may provide clinical benefit.

Background Although completion lobectomy is the treatment of choice for local recurrence of non-small cell lung cancer after segmentectomy, few cases have been reported. We report four patients who underwent completion lobectomies for staple line recurrence after segmentectomy for stage I non-small cell lung cancer. Case presentation Three women aged 65, 82, and 81 years underwent completion lower lobectomy after superior segmentectomy of the same lobe for local recurrence of stage I non-small cell lung cancer. A 67-year-old man, who had a tumor recurrence on the staple line after apical segmentectomy with superior mediastinal nodal dissection for stage I non-small cell lung cancer, underwent completion right upper lobectomy. These four patients underwent segmentectomy because of comorbidities or advanced age. Local recurrence was confirmed by computed tomography-guided needle biopsy. The interval between the two operations was 37, 39, 41, and 16 months, respectively. Although minimal hilar adhesion was seen for the three completion lower lobectomies, tight adhesions after apical segmentectomy made completion right upper lobectomy quite difficult to dissect, which led to injury of the superior pulmonary vein. No recurrence was recorded after completion lobectomies for 62, 70, 67, and 72 months, respectively. Conclusions Although completion lobectomy is one of the most difficult modes of resection, among several completion lobectomies, completion lower lobectomy after superior segmentectomy without superior mediastinal nodal dissection was relatively easy to perform because of fewer hilar adhesions.

OBJECTIVES Radiologically invasive non-small-cell lung cancer, defined as consolidation size to maximum tumour diameter ratio of over 0.5, is associated with pathological invasiveness and worse prognosis. However, there are no real-world, nationwide database studies on limited resections that consider radiological invasiveness. This study aimed to investigate the prognostic validity of limited resection, such as segmentectomy and wedge resection, in cStage IA (TNM 8th edition) radiologically invasive lung cancer. METHODS We conducted a retrospective analysis of patients who underwent complete resection according to the Japanese Joint Committee of Lung Cancer Registry Database. The relationship between surgical procedures and prognosis was examined using stratification by cT factor and radiological invasiveness. RESULTS Among the 5,692 patients enrolled, lobectomy, segmentectomy and wedge resection were performed in 4,323 (80.0%), 657 (11.5%) and 712 (12.5%) patients, respectively. Multivariable analysis with or without propensity score matching indicated that older age, poor performance status and wedge resection were significantly associated with worse prognosis and that patients who underwent segmentectomy showed an equivalent prognosis to those who underwent lobectomy. Subset analyses revealed that segmentectomy showed an equivalent prognosis to lobectomy in patients with cT1b or less, but not in those with cT1c, especially for non-pure radiological invasive cT1c; 5-year overall survival rates were 91.4% vs 90.4% in cT1b with non-pure radiological invasiveness and 80.0% vs 83.8% in cT1b with pure radiological invasiveness, respectively. CONCLUSIONS Segmentectomy can be an alternative to lobectomy in patients with radiologically invasive lung cancer with cT1b or less but not in those with cT1c.

To elucidate the clinical, pathologic, and prognostic impacts of epidermal growth factor receptor (EGFR) mutation and mutation subtypes in early-stage lung cancer, the study investigators conducted a retrospective analysis of the Japanese Joint Committee of Lung Cancer Registry database (a nationwide database for patients with surgically resected lung cancer; n = 18,973).Of 13,951 patients classified as having nonsquamous non-small cell lung cancer in the database, 5780 patients (41.0%) had been tested for an EGFR mutation and were included in this study.An EGFR mutation was detected in 2410 patients (41.7%), and the presence of an EGFR mutation was significantly correlated with clinicopathologic factors such as the presence of ground-glass opacity (P.001) and better prognosis. Analysis of initial recurrence sites identified significantly higher frequencies of brain and adrenal gland metastases in patients with and without an EGFR mutation, respectively. Of 2410 patients with EGFR mutations, 983 (40.8%) had an exon 19 deletion (Exon 19 Del), 1170 (48.5%) had an L858R mutation, and 257 (10.7%) had other EGFR mutations. A higher smoking rate was found in patients with other EGFR mutations (P = .02). In the comparison of Exon 19 Del and L858R, we found that Exon 19 Del correlated with younger age (P.001), a higher rate of pure solid tumors (P.001), advanced pathologic stage (trend P.001), and poorer recurrence-free survival (P = .001).In addition to the clinicopathologic and prognostic impacts of EGFR mutation status, tumors with Exon 19 Del have a more aggressive phenotype and patients have a poorer prognosis than with L858R in early-stage lung cancers.

PURPOSE To verify the superiority of irinotecan plus cisplatin over etoposide plus cisplatin as postoperative adjuvant chemotherapy for patients with pathologic stage I-IIIA, completely resected, high-grade neuroendocrine carcinoma (HGNEC) of the lung. METHODS This was a randomized, open-label, phase III study on patients with completely resected stage I-IIIA HGNEC of the lung. They were randomly assigned to receive either etoposide (100 mg/m2, days 1-3) plus cisplatin (80 mg/m2, day 1) or irinotecan (60 mg/m2, days 1, 8, 15) plus cisplatin (60 mg/m2, day 1) up to four cycles. The primary end point was relapse-free survival (RFS) in the intention-to-treat population. This trial was registered with the Japan Registry of Clinical Trials (jRCTs031180216). RESULTS Between April 2013 and October 2018, 221 patients were enrolled (etoposide plus cisplatin arm, 111 patients; irinotecan plus cisplatin arm, 110 patients). In the second interim analysis, early termination of the trial was recommended because of futility. At a median follow-up of 24.1 months, the 3-year RFS was 65.4% for etoposide plus cisplatin and 69.0% for irinotecan plus cisplatin, with a hazard ratio of 1.076 (95% CI, 0.666 to 1.738; one-sided log-rank P = .619). Grade 3-4 adverse events were more frequent in the etoposide plus cisplatin arm, with febrile neutropenia (20% of 109 patients v 4% of 107 patients) and neutropenia (97% v 36%) being the most common. Meanwhile, grade 3-4 anorexia (6% v 11%) and diarrhea (1% v 8%) were more frequently observed in the irinotecan plus cisplatin arm. CONCLUSION Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving RFS in patients with completely resected HGNEC; thus, etoposide plus cisplatin remains the standard treatment.

OBJECTIVES The purpose of this study was to clarify the prevalence, clinical features and survival of patients with thymoma and non-myasthenia gravis autoimmune disease (NMAD) using a nationwide cohort. METHODS The Japanese Association for Research on the Thymus nationwide database, which includes data from 32 institutions, was examined to clarify the prevalence and characteristics of NMAD associated with thymomas and elucidate the prognostic impact of NMAD for thymoma patients. RESULTS Among the 2423 patients with thymomas who were surgically treated between 1991 and 2010, 114 (4.7%) were identified with NMAD. The most frequently observed NMAD was pure red cell aplasia (PRCA) in 44 (1.8%), followed by hypogammaglobulinaemia (0.5%) and rheumatic arthritis (0.5%). Twenty-eight percent of patients with NMAD had concomitant myasthenia gravis. The presence of NMAD was not an independent prognostic factor for overall survival (OS) irrespective of the type of NMAD [PRCA+: hazard ratio (HR) 1.99, 95% confidence interval 0.74–4.47; PRCA− NMAD: HR 1.28, 0.30–3.56]; however, there were more cases with advanced age and disease of the thymoma amongst PRCA+ patients and these showed a worse OS than patients with PRCA− NMAD (P CONCLUSIONS Although the presence of NMAD itself did not significantly affect survival after surgery for thymoma, the type of NMAD was associated with different clinical features and prognosis. The NMAD+ thymomas should be separately categorized according to the presence or absence of PRCA.

The aim of this study was to evaluate the impact of the preoperative body mass index (BMI) on the postoperative outcomes in patients with completely resected non-small cell lung cancer (NSCLC).The data of patients with NSCLC in whom R0 resection was achieved were extracted from the database of NSCLC samples accumulated by the Japanese Joint Committee of Lung Cancer Registry in the year 2010, and the surgical outcomes including postoperative morbidity, mortality and the prognosis, were evaluated.Among 18,978 registered lung cancer cases, 16,509 patients (9996 men and 6513 women) were extracted. The median of age was 69 years old, and the histologic types included adenocarcinoma (n = 12,029), squamous cell carcinoma (n = 3286), large-cell carcinoma (n = 488) and others. The patients were divided into three groups according to their BMI: normal (BMI 18.5 to25), underweight (BMI 18.5) and overweight (BMI ≥ 25). Multivariate logistic regression analyses of factors associated with postoperative morbidity and mortality showed no significant differences among the three groups. In comparison to the normal group, the overall survival (OS) of the underweight group was significantly worse (p 0.001) while that of the overweight group was marginally better (p = 0.075). A multivariate analysis of factors associated with OS showed that in addition to the age, sex and clinical stage, the preoperative BMI (underweight group vs. normal group: hazard ratio [HR] 1.417 [95% confidence interval {CI}: 1.278-1.572, p 0.001], overweight group vs. normal group: HR 0.883 [95% CI: 0.806-0.967, p = 0.007]) was an independent prognostic factor. A multivariate analysis for the disease-free survival (DFS) also showed the preoperative BMI to be an independent significant prognostic factor.The preoperative BMI is an independent prognostic factor in patients with completely resected NSCLC. A low preoperative BMI was associated with significantly poor survival in Japan.

BACKGROUND: Pulmonary metastasectomy (PM) for breast cancer-derived pulmonary metastasis is controversial. This study aimed to assess the prognostic factors and implication of PM for metastatic breast cancer using a multi-institutional database. METHODS: Clinical data of 253 females with pulmonary metastasis of breast cancer who underwent PM between 1982 and 2017 were analyzed retrospectively. RESULTS: The median patient age was 56 years. The median follow-up period was 5.4 years, and the median disease-free interval (DFI) was 4.8 years. The 5- and 10-year survival rates after PM were 64.9% and 50.4%, respectively, and the median overall survival was 10.1 years. Univariate analysis revealed that the period of PM before 2000, a DFI

Introduction The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrence. As PC is insensitive to conventional chemotherapy, further clarification of the molecular mechanisms of metastasis is needed in order to develop targeted therapeutics. Methods We performed comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 cases of PC. Results We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively. Mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in a mutually exclusive manner in 36% (5/14). Pathway analysis of the mutated genes revealed enrichment of genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling. RNA sequencing revealed a total of 8 novel fusion transcripts including one derived from a chromosomal translocation between the TRIB2 and PRKCE genes. All of the 8 fusion genes were detected in primary PCs that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PCs that had relapsed after surgical resection. Conclusions In this study we identified novel somatic mutations and chromosomal rearrangements in PC by examining clinically aggressive cases that had developed postsurgical metastasis. It will be essential to validate the clinical significance of these genetic changes in a larger independent patient cohort.

BACKGROUND: This was an observational study of Japanese participants who underwent low-dose computed tomographic (LDCT) lung cancer screening between February 2004 and March 2012, to evaluate the lung cancers in never-smokers and smokers. METHODS: The study population consisted of a total of 12,114 subjects [never-smokers, 6,021 (49.70%); smokers with

Gastric gland mucin consists of core protein MUC6 with residues heavily glycosylated by unique O-glycans carrying α1,4-linked N-acetylglucosamine (αGlcNAc). αGlcNAc-glycosylated MUC6 protein is seen in normal gastric and duodenal glands. Decreased αGlcNAc glycosylation on MUC6-positive tumor cells is often observed in premalignant lesions of the stomach, pancreas, and bile duct, and decreased MUC6 expression is seen in invasive cancer of these organs. Lung cancer (LC) is the most common cause of cancer death worldwide. Recently, the adenocarcinoma subtype has become the most common histological subtype of LC, and one of its invasive forms is invasive mucinous adenocarcinoma (IMA). Currently, prognostic markers of LC IMA are unknown. Here, we analyzed MUC5AC, MUC6, and αGlcNAc expression in 54 IMA LC cases. MUC5AC was positively expressed in 50 (93%), MUC6 in 38 (70%), and αGlcNAc in 19 (35%). Each expression level was scored from 0 to 3. The αGlcNAc expression score was significantly decreased relative to MUC6 (P 0.001). Interestingly, disease-free survival was significantly higher in MUC6-positive than MUC6-negative cases based on the log-rank test (P = 0.021). For in vitro analysis, we ectopically expressed MUC6 in A549 cells, derived from LC and harboring a KRAS mutation. MUC6-expressing A549 cells showed significantly lower proliferation, motility, and invasiveness than control cells. Finally, F-actin staining in MUC6-expressing cells revealed a decrease or loss of filopodia associated with decreased levels of FSCN transcripts, which encodes an actin-bundling protein fascin1 necessary for cell migration. We conclude that MUC6 expression is a preferable prognostic biomarker in IMA LC.

To optimize postoperative surveillance of lung cancer patients, we investigated the hazard function of tumor recurrence in patients with completely resected lung cancer. We analyzed the records of 12,897 patients in the 2010 Japanese Joint Committee of Lung Cancer Registry who underwent lobectomy to completely resect pathological stage I–III lung cancer. The risk of postoperative recurrence was determined using a cause-specific hazard function. The hazard function for recurrence exhibited a peak at approximately 9 months after surgery, followed by a tapered plateau-like tail extending to 60 months. The peak risk for intrathoracic recurrence was approximately two-fold higher compared with that of extrathoracic recurrence. Subgroup analysis showed that patients with stage IIIA adenocarcinoma had a continuously higher risk of recurrence compared with patients with earlier-stage disease. However, the risk of recurrence in patients with squamous cell carcinoma was not significantly different compared with that more than 24 months after surgery, regardless of pathological stage. In conclusion, the characteristics of postoperative tumor recurrence hazard in a large cohort of lung cancer patients may be useful for determining the time after surgery at which patients are at the highest risk of tumor recurrence. This information may improve stage-related management of postoperative surveillance.

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.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 ratio0·5) 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.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 p0·0001 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% (p0·0001), 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).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.National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Objectives Micropapillary (MIP) and solid (SOL) subtypes of early-stage lung adenocarcinomas are associated with lymph node metastasis and local recurrence after limited resection. Preoperative identification of these components may influence the decisions of treatment strategy, additional lymph node evaluation, indication for limited resection, and extent of lymph node dissection. However, conventional biopsy specimens are insufficient for identifying these subtypes, especially MIP components. Cryobiopsy can collect larger tissue samples with fewer crush artifacts than conventional forceps biopsy, which would be helpful for detecting MIP/SOL components. Thus, this study aimed to analyze the feasibility of using cryobiopsy for MIP/SOL subtype detection. Material and methods Consecutive patients who underwent surgery for clinical IA lung cancer following a preoperative diagnosis of adenocarcinoma by cryobiopsy at our institution between October 2017 and July 2019 were retrospectively examined. The concordance rate of MIP/SOL subtypes between the specimens obtained by cryobiopsy and surgery was investigated. Results In total, 115 patients were evaluated. There were 26 (22.6%) and 14 (12.2%) patients with MIP and SOL subtypes, respectively. For concordance of MIP/SOL subtypes, the sensitivity was 65.7% (95% confidence interval [CI]: 57.7–65.7%). For the primary or secondary predominant patterns, a more satisfactory concordance rate of 72.2% (95% CI: 52.6–86.2%) was obtained. On assessing each subtype, high sensitivity was noted in SOL-predominant patterns (85.7%, 95% CI: 56.5%–96.0%) and MIP-secondary predominant patterns (83.3%, 95% CI: 45.8–97.0%). However, SOL-secondary predominant patterns revealed low sensitivity (0%, 95% CI, 0–38.2%). Overall, the MIP subtypes had higher sensitivity than the SOL subtypes (65.4% vs. 50.0%). Conclusion Cryobiopsy could be reliable for identifying MIP/SOL components, especially the MIP component, in clinical stage IA adenocarcinomas.