Lung cancer - major changes in the American Joint Committee on Cancer eighth edition cancer staging manual.

Answer questions and earn CME/CNE The revision for the eighth edition of the tumor, node, and metastasis (TNM) classification of lung cancer was based on analyses of the International Association for the Study of Lung Cancer database, which included 77,156 evaluable patients diagnosed with lung cancer from 1999 to 2010. Among tumor (T) descriptors, the following new tumor-size groups were created: T1a, ≤1 cm; T1b, >1 to 2 cm; T1c, >2 to 3 cm; T2a, >3 to 4 cm; T2b, >4 to 5 cm; T3, >5 to 7 cm; and T4, >7 cm. Tis and T1mi were introduced for adenocarcinoma in situ and minimally invasive adenocarcinoma, respectively. Endobronchial tumors located <2 cm from the carina have better prognosis than those with any other T3 descriptor and were classified as T2. Total atelectasis/pneumonitis was classified as a T2 descriptor, because it has a T2 prognosis. Diaphragmatic invasion is now T4. Visceral pleural invasion remains unchanged, and mediastinal pleura invasion, which is seldom used, disappears as a T descriptor. The lymph node (N) component descriptors are unchanged, but the number of involved nodal stations has prognostic impact. For the metastasis (M) component, M1a (intrathoracic metastases) remains unchanged, but extrathoracic metastases are divided into a single extrathoracic metastasis (new M1b) and multiple extrathoracic metastases in a single organ or multiple organs (M1c). Stage IA is now divided into IA1, IA2, and IA3 to accommodate T1a, T1b, and T1cN0M0 tumors, respectively; all N1 disease is stage IIB except for T3-T4N1M0 tumors, which are stage IIIA; a new stage IIIC is created for T3-T4N3M0 tumors; and stage IV is divided into IVA (M1a and M1b) and IVB (M1c). This revision enhances our capacity for prognostication and will have an important impact in the management of patients with lung cancer and in future research. CA Cancer J Clin 2017;67:138-155. © 2017 American Cancer Society.

Clinicopathological predictors of postoperative long-term myasthenic status in resected thymoma with myasthenia gravis.

PURPOSE: Surgical patients with thymoma and myasthenia gravis (MG) must have their MG status and oncological outcomes critically monitored. We aimed to identify clinicopathological predictors of the postoperative MG status. METHODS: We conducted a retrospective review of 40 consecutive surgical patients with MG-related thymomas between 2002 and 2020. The quantitative myasthenia gravis score (QMGS) and Myasthenia Gravis Foundation of America post-intervention status (MGFA-PIS) were used to evaluate postoperative MG status. RESULTS: All patients underwent extended total thymectomy. The most common WHO type was type B2 (32%), while 65% of patients had type B1-B3 and 35% had type A-AB thymomas. Eleven patients (28%) achieved controlled MG status in MGFA-PIS 6 months after surgery. This controlled status was observed more frequently in type A-AB than in B1-B3 (57% vs. 12%, p = 0.007). In a multivariate analysis, WHO type (A-AB or B1-B3) was an independent predictor of worsening episodes of MG based on the QMGS (Type B1-B3, hazard ratio: 3.23, 95% confidence interval: 1.12-9.25). At the last follow-up, 23 patients (58%) achieved controlled MG status. The 5-year overall survival rate of all patients was 93.7%. CONCLUSION: The WHO type of thymoma is an informative predictor of postoperative MG status in patients with MG-related thymoma.

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.

Prognostic factors affecting survival in patients with non-small cell lung cancer treated with salvage surgery after drug therapy: a multi-institutional retrospective study.

BACKGROUND: The prevalence of salvage surgeries after drug therapy for non-small cell lung cancer (NSCLC) has risen, mainly due to recent progress in molecular-targeted drugs and immune checkpoint inhibitors for NSCLC. While the safety and effectiveness of salvage surgery after drug therapy for NSCLC have been studied, its indications remain unclear. We aimed to identify the prognostic factors affecting survival in patients with advanced-stage (stages III-IV) NSCLC treated with salvage surgery after drug therapy. METHODS: A retrospective investigation was conducted on patients who received salvage surgery after drug therapy at four hospitals between 2007 and 2020. Salvage surgery was defined as surgery after drug therapy for local progression, tumor conversion to resectable status, and discontinuation of prior drug therapy owing to serious complications. RESULTS: Thirty-two patients received cytotoxic agents alone (n = 12 [38%]), tyrosine kinase inhibitors (TKIs; n = 16 [50%]), or immune checkpoint inhibitors (n = 4 [13%]) as prior drug therapy. In 11 (34%) and 21 (66%) patients, the clinical stage before treatment was III or IV, respectively. The median initial and preoperative serum carcinoembryonic antigen (CEA) levels were 10.2 (range, 0.5-1024) ng/mL and 4.2 (range, 0.6-92.5) ng/mL, respectively. Among the patients, 28 (88%) underwent lobectomy, 2 (6%) underwent segmentectomy, and 2 (6%) underwent wedge resection. Complete resection of the primary lesion was accomplished in 28 (88%) patients. Postoperative complications were documented in six (19%) patients. Mortality rates were 0% at 30 days and 3% at 90 days post-operation. The 5-year overall survival rate stood at 66%, while the 5-year progression-free survival rate was 21%. Multivariate analyses showed that prior TKI therapy and preoperative serum CEA level < 5 ng/mL were prognostic factors influencing overall survival (hazard ratio [95% confidence interval]: 0.06 [0.006-0.68] and 0.03 [0.002-0.41], respectively). The 5-year overall survival in the 11 patients with both favorable prognosticators was 100%. CONCLUSIONS: In this study, prior TKI therapy and preoperative serum CEA level < 5 ng/mL were favorable prognostic factors for overall survival in patients with NSCLC treated with salvage surgery. Patients with these prognostic factors are considered good candidates for salvage surgery after drug therapy.

Long-term outcomes following surgical treatment for thymic epithelial tumor in Japan and an analysis of prognostic factors based on the Japanese Association for Research on the Thymus nationwide database.

PURPOSE: Patients with a thymic epithelial tumor (TET), comprising thymoma, thymic carcinoma (TC), and thymic neuroendocrine neoplasm (TNEN), are rarely encountered. The present study was conducted to determine the recent outcomes of surgical treatment for TET in Japan and clarify the significance of prognostic factors by analyzing a nationwide database created by the Japanese Association for Research on the Thymus (JART). METHODS: The JART database includes records of 2471 thymoma, 285 TC, and 56 TNEN cases surgically treated between 1991 and 2010. At the time of the final follow-up examination, 439 patients had died, with tumor the cause of death in 188. The disease-specific survival was examined using the Kaplan-Meier method, with Cox's proportional hazards model utilized to determine independent prognostic factors. RESULTS: The 10-year survival rate according to TNM-based Stage I, II, IIIA, IIIB, IVA, and IVB classification was 98.7%, 76.8%, 85.0%, 68.9%, 66.2%, and 59.8%, respectively. The T factor, M factor, and tumor size were independent prognostic factors in both thymoma and thymic carcinoma cases, while the N factor had tendency to be a prognostic factor in thymoma but not in thymic carcinoma cases. The WHO histological type was an independent factor in thymoma cases. CONCLUSION: The significance of pathology and TNM classification as prognostic factors was confirmed.

MUC6 expression is a preferable prognostic marker for invasive mucinous adenocarcinoma of the lung.

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.

DNA hypermethylation of the ZNF132 gene participates in the clinicopathological aggressiveness of 'pan-negative'-type lung adenocarcinomas.

Although some previous studies have examined epigenomic alterations in lung adenocarcinomas, correlations between epigenomic events and genomic driver mutations have not been fully elucidated. Single-CpG resolution genome-wide DNA methylation analysis with the Infinium HumanMethylation27 BeadChip was performed using 162 paired samples of adjacent normal lung tissue (N) and the corresponding tumorous tissue (T) from patients with lung adenocarcinomas. Correlations between DNA methylation data on the one hand and clinicopathological parameters and genomic driver mutations, i.e. mutations of EGFR, KRAS, BRAF and HER2 and fusions involving ALK, RET and ROS1, were examined. DNA methylation levels in 12 629 probes from N samples were significantly correlated with recurrence-free survival. Principal component analysis revealed that distinct DNA methylation profiles at the precancerous N stage tended not to induce specific genomic driver aberrations. Most of the genes showing significant DNA methylation alterations during transition from N to T were shared by two or more driver aberration groups. After small interfering RNA knockdown of ZNF132, which showed DNA hypermethylation only in the pan-negative group and was correlated with vascular invasion, the proliferation, apoptosis and migration of cancer cell lines were examined. ZNF132 knockdown led to increased cell migration ability, rather than increased cell growth or reduced apoptosis. We concluded that DNA hypermethylation of the ZNF132 gene participates in the clinicopathological aggressiveness of 'pan-negative' lung adenocarcinomas. In addition, DNA methylation alterations at the precancerous stage may determine tumor aggressiveness, and such alterations that accumulate after driver mutation may additionally modify clinicopathological features through alterations of gene expression.

Inhibition of vascular adhesion protein-1 enhances the anti-tumor effects of immune checkpoint inhibitors.

Modulation of the immunosuppressive tumor microenvironment (TME) is essential for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs). Adhesion molecules and enzymes such as vascular adhesion protein-1 (VAP-1), which are expressed in some cancers and tumor vascular endothelial cells, may be involved in the generation of an immunosuppressive TME. In this study, the role of VAP-1 in TME was investigated in 2 murine colon cancer models and human cancer cells. Intraperitoneal administration of the VAP-1-specific inhibitor U-V296 inhibited murine tumor growth by enhancing IFN-γ-producing tumor antigen-specific CD8+ T cells. U-V296 exhibited significant synergistic anti-tumor effects with ICIs. In the TME of mice treated with U-V296, the expression of genes associated with M2-like macrophages, Th2 cells (Il4, Retnla, and Irf4), angiogenesis (Pecam1), and fibrosis (Acta2, Loxl2) were significantly decreased, and the Th1/Th2 balance was increased. H2 O2 , an enzymatic product of VAP-1, which promoted the production of IL-4 by mouse Th2 and inhibited IFN-γ by mouse Th1 and human tumor-infiltrating lymphocytes, was decreased in tumors and CD31+ tumor vascular endothelial cells in the TMEs of mice treated with VAP-1 inhibitor. TCGA database analysis showed that VAP-1 expression was a negative prognostic factor in human cancers, exhibiting a significant positive correlation with IL-4, IL4R, and IL-13 expression and a negative correlation with IFN-γ expression. These results indicated that VAP-1 is involved in the immunosuppressive TMEs through H2 O2 -associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs.

Clinical features and outcomes of patients with stage I multiple primary lung cancers.

The number of patients with multiple primary lung cancers (MPLC) is rising. We studied the clinical features and factors related to outcomes of MPLC patients using the database of surgically resected lung cancer (LC) cases compiled by the Japanese Joint Committee of Lung Cancer Registry. From the 18 978 registered cases, 9689 patients with clinical stage I non-small-cell lung cancer who achieved complete resection were extracted. Tumors were defined as synchronous MPLC when multiple LC was simultaneously resected or treatment was carried out within 2 years after the initial surgery; metachronous MPLC was defined as second LC treated more than 2 years after the initial surgery. Of these cases, 579 (6.0%) were synchronous MPLC and 477 (5.0%) metachronous MPLC, with 51 overlapping cases. Female sex, nonsmoker, low consolidation-tumor ratio (CTR), and adenocarcinoma were significantly more frequent in the synchronous MPLC group, whereas patients with metachronous MPLC had higher frequencies of male sex, smoker, chronic obstructive pulmonary disease (COPD), and nonadenocarcinoma. There was no significant difference in survival rate between patients with and without synchronous or metachronous MPLC. Age, gender, CTR for second LC, and histological combination of primary and second LC were prognostic indicators for both types of MPLC. Logistic regression analysis showed that female sex, history of malignant disease other than LC, and COPD were risk factors for MPLC incidence. The present findings could have major implications regarding MPLC diagnosis and identification of independent prognostic factors, and provide valuable information for postoperative management of patients with MPLC.

Pleural recurrence after transthoracic needle lung biopsy in stage I lung cancer: a systematic review and individual patient-level meta-analysis.

INTRODUCTION: Conflicting results exist regarding whether preoperative transthoracic biopsy increases the risk of pleural recurrence in early lung cancer. We conducted a systematic, patient-level meta-analysis to evaluate the risk of pleural recurrence in stage I lung cancer after percutaneous transthoracic lung biopsy. METHODS: A systematic search of OVID-MEDLINE, Embase and the Cochrane Database of Systematic Reviews was performed through October 2018. Eligible studies were original articles on the risk of pleural recurrence in stage I lung cancer after transthoracic biopsy. We contacted the corresponding authors of eligible studies to obtain individual patient-level data. We used the Fine-Gray model for time to recurrence and lung cancer-specific survival and a Cox proportional hazards model for overall survival. RESULTS: We analysed 2394 individual patient data from 6 out of 10 eligible studies. Compared with other diagnostic procedures, transthoracic biopsy was associated with a higher risk for ipsilateral pleural recurrence, which manifested solely (subdistribution HR (sHR), 2.58; 95% CI 1.15 to 5.78) and concomitantly with other metastases (sHR 1.99; 95% CI 1.14 to 3.48). In the analysis of secondary outcomes considering a significant interaction between diagnostic procedures and age groups, reductions of time to recurrence (sHR, 2.01; 95% CI 1.11 to 3.64), lung cancer-specific survival (sHR 2.53; 95% CI 1.06 to 6.05) and overall survival (HR 2.08; 95% CI 1.12 to 3.87) were observed in patients younger than 55 years, whereas such associations were not observed in other age groups. DISCUSSION: Preoperative transthoracic lung biopsy was associated with increased pleural recurrence in stage I lung cancer and reduced survival in patients younger than 55 years.

Clinicopathological and prognostic features of operable non-small cell lung cancer patients with diabetes mellitus.

BACKGROUND: The aim of this study was to investigate the clinicopathological and prognostic features of operable non-small cell lung cancer (NSCLC) patients with diabetes mellitus (DM). METHODS: A total of 1231 surgically resected NSCLC patients were retrospectively reviewed. Clinicopathological characteristics were compared between patients with DM (DM group, n = 139) and those without DM (non-DM group, n = 1092). The clinical factors associated with postoperative complications and prognostic factors were identified. RESULTS: The DM group had distinct clinicopathological features. No significant differences in histological invasiveness or stage were found. The presence and control status of DM were independent predictors of postoperative complications. No significant differences in recurrence-free survival or cancer-specific survival were observed; however, the DM group had worse overall survival (OS). The DM group had a higher number of deaths from other diseases than the non-DM group, and these patients had significantly higher postoperative hemoglobin A1c levels than patients with cancer-related death. CONCLUSION: The presence and control status of preoperative DM are useful predictors of both postoperative complications and OS in operable NSCLC patients. Concomitant diabetes-related complications have a negative effect on long-term survival in diabetic NSCLC patients, and long-term glycemic control is important to prolong OS.

Limited resection for early-stage thymoma: minimally invasive resection does not mean limited resection.

Standard resection for patients with thymoma is resection of thymoma with total thymectomy (TTx) via median sternotomy. Hence, limited resection for thymoma means a lesser extent of resection of normal thymus compared with a standard procedure, i.e. resection of thymoma with partial thymectomy (PTx). In contrast, minimally invasive resection has been defined as resection of thymoma with TTx via a less-invasive approach. However, to date, few studies have precisely evaluated the differences in surgical and oncological outcomes among these three procedures. This report summarizes the differences among these three procedures with a review of studies (January 2000 to December 2020) focusing on the difference in surgical and oncological outcomes and presents current issues in the surgical management of thymoma. In this report, 16 studies were identified; 5 compared standard resection to limited resection, 9 compared standard resection to minimally invasive resection and 2 compared limited resection to minimally invasive resection. Most studies reported that the surgical and oncological outcomes of limited resection or minimally invasive resection were similar to those of standard resection in patients with early-stage thymoma. However, they did not include a sufficient follow-up period. Both limited resection and minimally invasive resection for early-stage thymoma might be reasonable treatment options. However, they are still promising modes of resection. Further studies with a long follow-up period are needed.

Debulking surgery for malignant tumors: the current status, evidence and future perspectives.

Debulking surgery, also called cytoreductive surgery, is a resection of the tumor as much as possible and an intended incomplete resection for unresectable malignant tumors. Since the most important principle in surgical oncology is complete R0 resection, debulking surgery goes against the basic principle and obscures the concept of operability. However, debulking surgery has been advocated for various types of advanced malignant tumors, including gynecological cancers, urological cancers, gastrointestinal cancers, breast cancers and other malignancies, with or without adjuvant therapy. Positive data from randomized trials have been shown in subsets of ovarian cancer, renal cell carcinoma, colorectal cancer and breast cancer. However, recent trials for renal cell carcinoma, colorectal cancer and breast cancer have tended to show controversial results, mainly according to the survival improvement of nonsurgical systemic therapy alone. On the other hand, debulking surgery still has a therapeutic role for slow-growing and borderline malignant tumors, such as pseudomyxoma peritonei and thymomas. The recent understanding of tumor heterogeneity and clonal evolution responsible for malignancy and drug resistance indicates that select patients may obtain prolonged survival by the synergistic effect of debulking surgery and novel systemic therapy. This review aimed to describe the current status and evidence of debulking surgery in a cross-organ manner and to discuss future perspectives in the current era with advances in systemic therapy.

Four cases of completion lobectomy for locally relapsed lung cancer after segmentectomy.

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.

Infiltration of tumor-associated macrophages is involved in tumor programmed death-ligand 1 expression in early lung adenocarcinoma.

Programmed death-ligand 1 (PD-L1) is an immune modulator that promotes immunosuppression by binding to programmed death-1 of T-lymphocytes. Although tumor cell PD-L1 expression has been shown to be associated with the clinical response to anti-PD-L1 antibodies, its concise regulatory mechanisms remain elusive. In this study, we evaluated the associations of tumor PD-L1 expression and immune cell infiltrating patterns in 146 cases of early lung adenocarcinoma (AC) to investigate the possible extrinsic regulation of tumor PD-L1 by immune cells. Using immunohistochemistry, cell surface PD-L1 expression in tumor cells was observed in 18.5% of stage 0-IA lung AC patients. Tumor PD-L1 positivity was significantly associated with stromal invasion, which was accompanied by increased tumor-associated macrophages (TAM), CD8+ cytotoxic T cells and FoxP3+ regulatory T cells. Among these immune cells, TAM and CD8+ T cells significantly accumulated in PD-L1-positive carcinoma cell areas, which showed a tumor cell nest-infiltrating pattern. Although CD8+ T cells are known to induce tumor PD-L1 expression via interferon-É£ production, the increased TAM within tumors were also associated with tumor cell PD-L1 positivity, independently of CD8+ T cell infiltration. Our in vitro experiments revealed that PD-L1 expression in lung cancer cell lines was significantly upregulated by co-culture with M2-differentiated macrophages; expression of PD-L1 was reduced to baseline levels following treatment with a transforming growth factor-ß inhibitor. These results demonstrated that tumor-infiltrating TAM are extrinsic regulators of tumor PD-L1 expression, indicating that combination therapy targeting both tumor PD-L1 and stromal TAM might be a possible strategy for effective treatment of lung cancer.

A randomized Phase III trial of lobe-specific vs. systematic nodal dissection for clinical Stage I-II non-small cell lung cancer (JCOG1413).

In January 2017, the Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group commenced a randomized Phase III trial to confirm the clinical benefit of lobe-specific nodal dissection for clinical Stage I-II non-small cell lung cancer. The primary endpoint is overall survival, and the main objective is to confirm the non-inferiority of lobe-specific in comparison to systematic nodal dissection with regard to lobectomy. The secondary endpoints are relapse-free survival, %local recurrence, %regional lymph node recurrence, operation time, blood loss, length of hospitalization, duration of chest tube placement and adverse events. A total of 1700 patients will be accrued from 44 Japanese institutions within 5 years. This study is the first and large prospective trial to evaluate whether the difference in the area of nodal dissection affects the overall survival of patients with relatively early-stage non-small cell lung cancer. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000025530.

[Role of Surgery in Multimodality Treatment for Non-small Cell Lung Cancer;Current Status and Future Perspectives].

Recent improvement of outcomes for resected non-small cell lung cancer (NSCLC) has been contributed not only by increased detection of early-stage disease and improvement of preoperative diagnosis/perioperative management but also by improvement of multimodality treatment. The introduction of newly developed systemic therapies including molecular targeted agents and immune checkpoint inhibitors dramatically changed clinical outcomes of advanced NSCLC. Accordingly, the role of surgery during the multimodality treatment will be changed more than ever. In this article, we overviewed the current status of the multimodality treatment for clinical stageⅢ (N2)disease and postoperative adjuvant therapy and discussed the role of surgery during these situations. We also discussed the future perspectives of the role of surgery during the multimodality treatment for advanced NSCLC.

The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group: past activities, current status and future direction.

The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group was organized in 1986. Initially, 26 collaborative institutions participated. In the early period, the Lung Cancer Surgical Study Group focused on combined modality therapies and conducted nine trials, including JCOG9101: adjuvant chemotherapy for resected small-cell lung cancer, and JCOG9806: induction chemoradiotherapy followed by surgery for superior sulcus tumor, which greatly impacted the treatment strategies for some special kinds of lung cancer. Since the 2000s, the Lung Cancer Surgical Study Group has defined radiologically noninvasive adenocarcinoma: JCOG0201 and investigated adequate modes of surgical resection for small-sized non-small cell lung cancer: JCOG0802, JCOG0804 and JCOG1211. The accrual of these trials is now complete and we are waiting for the maturation of follow-up data. In addition, two adjuvant trials have been conducted: JCOG0707; a Phase III study of adjuvant chemotherapy for resected pathological stage I (T1 > 2 cm) non-small cell lung cancer, and JCOG1205; a Phase III study of adjuvant chemotherapy for completely resected pulmonary high-grade neuroendocrine tumor. The accrual of JCOG0707 is complete and we are waiting for the maturation of follow-up data. At present, 44 institutions are active members of the Lung Cancer Surgical Study Group. In addition to thoracic surgeons, medical oncologists, pathologists and radiotherapists are participating in the Lung Cancer Surgical Study Group. The Lung Cancer Surgical Study Group continues to conduct various clinical trials in an effort to improve survival in patients with lung cancer. In this review, we provide an overview of the past 30 years, as well as the present status and future direction of the Lung Cancer Surgical Study Group.

Limited resection for early-stage non-small cell lung cancer as function-preserving radical surgery: a review.

Since 'radical lobectomy' was reported by Cahan in 1960, the standard surgical care for lung cancer has been lobectomy, in which units of the lobe are excised with their specific regional hilar and mediastinal lymphatics. However, pulmonary function-preserving limited resection for lung cancer has gradually become more prevalent in the late 20th century. In 1995, Ginsberg et al. conducted a randomized controlled trial in which limited resection (segmentectomy and wide-wedge resection) and lobectomy for stage I lung cancer were compared and reported that limited resection should not be applied to healthy patients with clinical stage IA lung cancer. The detection of small-sized and early-stage lung cancers has improved with advancement in diagnostic technology. Ground-glass opacity of lung nodules, as recognized on thin-slice computed tomography, has also been widely recognized as being correlated with less-invasive pathological findings of alveolar epithelial cell replacement of cancer cells. The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group conducted a cohort study of early peripheral lung cancer and investigated the validity thin-slice computed tomography criteria to diagnose non-invasive lung adenocarcinoma for the preoperative prediction of pathological non-invasive cancer. Following this observational study, the on-going JCOG0802/WJOG4607L, JCOG0804/WJOG4507L and JCOG1211 trials were initiated to confirm the validity of limited resection for stage I lung cancer patients stratified according to preoperative thin-slice computed tomography findings; these trials will clarify whether limited resection for lung cancer is not function-preserving but also only curative surgery.

Mucinous micropapillary pattern in lung adenocarcinomas: a unique histology with genetic correlates.

AIMS: In lung adenocarcinoma (ADC), micropapillary carcinomas (MPCs) are associated with poor prognosis because these tumours exhibit higher metastatic potential. Despite this, there are no studies investigating the differences between mucinous and non-mucinous MPC. METHODS AND RESULTS: We evaluated the proportion of micropapillary components in lung ADCs, and compared the differences with respect to the presence or absence of associated mucin. Tumour specimens from 694 patients with consecutively resected primary lung ADC were reviewed, and 37 cases of invasive mucinous ADCs were excluded. A significant (≥5%) micropapillary component was noted in 320 (48.7%) of 657 evaluable cases. When the cases with micropapillary component were divided into 67 (20.9%) mucinous and 253 (79.1%) non-mucinous subtypes, tumours with mucinous micropapillary component exhibited significantly more aggressive pathological features, a higher proportion of HER2 mutations (P = 0.002) and ALK rearrangements (P < 0.001), and a lower proportion of EGFR mutations (P = 0.038) compared to those with a non-mucinous micropapillary component. In survival analyses, mucinous MPC tended to be more aggressive compared with non-mucinous MPC, but its prognostic value was not statistically significant (P = 0.076). CONCLUSIONS: Mucinous micropapillary pattern is an under-recognized unique growth associated significantly with HER2 mutation and ALK rearrangement.