Pathological Pleural Invasion is a Risk Factor for Late Recurrence in Long-Term Survivors of Non-small Cell Lung Cancer after Complete Resection.

BACKGROUND: Information regarding late recurrence after pulmonary resection for non-small cell lung cancer (NSCLC) is limited. This study aimed to analyze the risk factors for late recurrence after surgery for NSCLC in the current era. PATIENTS AND METHODS: We conducted a retrospective study of patients who underwent complete resection for pathological I-III NSCLC between 2006 and 2015. Late recurrence was defined as a recurrence that met the following conditions: (1) the patient underwent chest computed tomography (CT) at or after 54 months after surgery and recurrence was not detected at that time, and (2) recurrence that occurred more than 5 years after surgery. The factors influencing late recurrence, relapse-free survival (RFS), and overall survival (OS) after surgery were analyzed. RESULTS: A total of 1275 with 5-year relapse-free survival after surgery were enrolled in this study. The mean age of the patients was 66.4 years and 54% of the patients were men. The median interval between surgery and the latest follow-up examination was 98 months. In total, 35 patients (2.7%) experienced late recurrence and 138 patients have died thus far. The cumulative recurrence, RFS, and OS rates at 10 years were 3.9%, 84.9%, and 86.3%, respectively. A multivariate analysis revealed that pleural invasion was an independent risk factor for late recurrence. Pleural invasion was a poor prognostic factor for both RFS and OS. CONCLUSIONS: Pleural invasion was a predictor of late recurrence. Age > 67 years, preoperative serum carcinoembryonic antigen (CEA) > 5 ng/ml, non-adenocarcinoma, and pleural invasion were poor prognostic factors for RFS.

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.

Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma.

BACKGROUND: Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblast activation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs. METHODS: We investigated the changes in protein expression during adenocarcinoma progression in the pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normal lung, AAH, AIS, and IA. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in the pre-existing alveolar structures. RESULTS: Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues when compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in the pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS. CONCLUSIONS: FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.

Outcomes and prognostic factors of repeat pulmonary metastasectomy.

OBJECTIVES: Information on prognostic factors after repeat pulmonary metastasectomy (PM) is limited, and outcomes after a third PM are not well documented. METHODS: A single-institute retrospective study was conducted. Between 2000 and 2020, 68 patients underwent repeat PM for pulmonary metastases from various cancers. Outcomes and prognostic factors for the second PM and outcomes after the third PM were analysed. RESULTS: This study included 39 men and 29 women. The mean age at second PM was 53.2 years old. The primary tumours were soft tissue sarcoma in 24 patients, colorectal cancer in 19 and osteosarcoma in 10. The interval between the first PM procedure and detection of pulmonary metastasis after the first PM (months) was ≤12 in 37 patients and >12 in 31 patients. At the second PM, 20 patients underwent lobectomy or bilobectomy, and 48 underwent sublobar resection. Complete resection was achieved in 60 patients, and 52 patients experienced recurrence after the second PM. The 5-year relapse-free survival and overall survival rates after the second PM were 27% and 48%, respectively. Multivariable analysis revealed that the interval between the first PM and the subsequent detection of pulmonary metastasis (≤12 months) was a poor prognostic factor for both relapse-free survival and overall survival after the second PM. Seventeen patients underwent a third PM, 3 of whom achieved a 3-year disease-free survival. CONCLUSIONS: Patients with a period of >12 months between the first PM and the subsequent detection of pulmonary metastases showed favourable outcomes and are thus considered good candidates for second PM. A third PM may be beneficial for selected patients.

Metastatic pathways to the lower zone by segment in patients with clinical T1 lower lobe non-small cell lung cancer.

OBJECTIVE: Segmentectomy and mediastinal lymph node dissection (LND) may increasingly be used for non-small cell lung cancer (NSCLC). Lymph node metastasis (LNM) distribution varies by lower lobe segments; however, its segment-specific spread to the lower zone (#8, 9) (LZ) in lower lobe NSCLC is seldom reported. METHODS: In total, 352 patients with clinical T1 lower lobe NSCLC who underwent lobectomy with systematic or lobe-specific LND were included for analysis between January 2006 and December 2018. RESULTS: Fifty-eight (16.2%) patients had LNM (pN1: 24, pN2: 34), and nine (2.6%) had LZ metastasis. LZ metastasis was significantly more frequent in tumors with diameter > 2 cm, tumors without ground-glass opacity on radiological findings, left lung cancer, and basal segment lung cancer (respectively, p = 0.039, 0.006, 0.0177, 0.0024). None of the S6 NSCLC patients had LZ metastasis. Two patients with right basal segment NSCLC had LZ metastases (tumor on S10) as well as N1 lymph node and subcarinal zone metastasis. Seven (8.4%) patients with left basal segment NSCLC had LZ metastasis (tumor on S8: 3, tumor on S10: 4). Of them, three patients with left basal NSCLC had isolated LZ metastasis. CONCLUSIONS: The LND of the LZ can be omitted for clinical T1 patients with S6 NSCLC. In addition, the LND of the LZ may be omitted in right basal NSCLC if intraoperative confirmation of negative N1 and subcarinal zone lymph nodes is obtained; however, it is necessary for left basal segment NSCLC.

Development of a multivariable prediction model for prolonged air leak after lung resection.

OBJECTIVES: Prolonged air leak (PAL) is a common complication of lung resection. Research on predictors of PAL using a digital drainage system (DDS) remains insufficient. In this study, we investigated the predictive factors of PAL to establish a novel early postoperative prediction model for PAL. METHODS: A retrospective cohort study and validation study were conducted. We examined patients who underwent lung resection with DDS at our institute. The relationship between the clinical factors and measurements of the DDS, including the difference between the set and measured intrapleural pressure (named: additional negative pressure [ANP]) at postoperative hour (POH) 3, with PAL was analyzed. RESULTS: A total of 494 patients were enrolled, 29 of whom had PAL. Percent forced expiratory volume in 1 s <60%, ANP <1 cmH2O, air leak flow >20 mL/min and pleural adhesion findings at surgery were independent predictors of PAL according to a multivariable analysis. The PAL rate was clearly stratified according to our novel risk scoring system, which simply notes the presence of the above four factors, that is, the rate increases when the score increases. The area under the curve (AUC) of the receiver operating characteristic (ROC) analysis for this scoring system was 0.818. Analysis of the validation cohort (n = 133) revealed that this scoring system showed a sufficient ability to predict PAL. CONCLUSIONS: ANP at POH 3 is an independent predictor of PAL. Thus, the risk-scoring system proposed in this study is useful for predicting PAL in the early postoperative period.

Benefit of Adjuvant Chemotherapy for Patients Older Than 75 Years With Completely Resected p-Stage II-IIIA Non-Small-Cell Lung Cancer: A Retrospective Cohort Study Using Japanese Nationwide Real-World Data.

BACKGROUND: The efficacy of adjuvant chemotherapy (ACT) in elderly patients with completely resected p-stage II-IIIA non-small-cell lung cancer (NSCLC) remains unclear because all previous randomized controlled trials on ACT have been conducted among patients aged <75 years. Thus, this study aimed to evaluate the effectiveness of ACT in elderly patients with completely resected NSCLC. PATIENTS: We extracted the nationwide data of 812 patients aged ≥75 years who underwent lobectomy with mediastinal nodal dissection in 2010 and were diagnosed with p-stage II-IIIA NSCLC, from nationwide registry data accumulated in 2016. METHODS: We classified the 812 patients into 2 groups based on the ACT administration status and analyzed the differences in their postoperative overall survival (OS). RESULTS: Overall, 295 patients received ACT (36.3%; group A), whereas 517 patients did not (63.70%; group N). Group A showed significantly better OS as a whole (hazard ratio [HR]: 0.650 [95% confidence interval {CI}: 0.526-0.804]), in the p-stage II subset (HR: 0.688 [95% CI: 0.513-0.925]), and p-stage IIIA subset (HR: 0.547 [95% CI: 0.402-0.743]) than group N. Even after propensity score matching, group A showed significantly better OS as a whole (HR: 0.626 [95% CI: 0.495-0.792]), in the p-stage II subset (HR: 0.690 [95% CI: 0.493-0.964]), and p-stage IIIA subset (HR: 0.554 [95% CI: 0.398-0.772]) than group N. CONCLUSION: ACT is recommended even in elderly patients with completely resected p-stage II-IIIA NSCLC. Hence, physicians should not avoid ACT in patients with completely resected NSCLC based solely on age.

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

Neoadjuvant nivolumab plus chemotherapy in resectable non-small-cell lung cancer in Japanese patients from CheckMate 816.

In the open-label, phase III CheckMate 816 study (NCT02998528), neoadjuvant nivolumab plus chemotherapy demonstrated statistically significant improvements in event-free survival (EFS) and pathological complete response (pCR) versus chemotherapy alone in patients with resectable non-small-cell lung cancer (NSCLC). Here we report efficacy and safety outcomes in the Japanese subpopulation. Patients with stage IB-IIIA, resectable NSCLC were randomized 1:1 to nivolumab plus chemotherapy or chemotherapy alone for three cycles before undergoing definitive surgery within 6 weeks of completing neoadjuvant treatment. The primary end-points (EFS and pCR) and safety were assessed in patients enrolled at 16 centers in Japan. Of the Japanese patients randomized, 93.9% (31/33) in the nivolumab plus chemotherapy arm and 82.9% (29/35) in the chemotherapy arm underwent surgery. At 21.5 months' minimum follow-up, median EFS was 30.6 months (95% confidence interval [CI], 16.8-not reached [NR]) with nivolumab plus chemotherapy versus 19.6 months (95% CI, 8.5-NR) with chemotherapy; hazard ratio, 0.60 (95% CI, 0.30-1.24). The pCR rate was 30.3% (95% CI, 15.6-48.7) versus 5.7% (95% CI, 0.7-19.2), respectively; odds ratio, 7.17 (95% CI, 1.44-35.85). Grade 3/4 treatment-related adverse events were reported in 59.4% versus 42.9% of patients, respectively, with no new safety signals identified. Neoadjuvant nivolumab plus chemotherapy resulted in longer EFS and a higher pCR rate versus chemotherapy alone in Japanese patients, consistent with findings in the global population. These data support nivolumab plus chemotherapy as a neoadjuvant treatment option in Japanese patients with resectable NSCLC.

Utility of needle biopsy in centrally located lung cancer for genome analysis: a retrospective cohort study.

BACKGROUND: It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy. METHODS: We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period. RESULTS: Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected. CONCLUSIONS: For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS.

Lymph node dissection in small peripheral lung cancer: Supplemental analysis of JCOG0802/WJOG4607L.

OBJECTIVE: The optimal region of lymph node dissection (LND) during segmentectomy in patients with small peripheral non-small cell lung cancer requires clarification. Through a supplemental analysis of the Japan Clinical Oncology Group (JCOG) 0802/West Japan Oncology Group (WJOG) 4607L, we investigated the associated factors, distribution, and recurrence pattern of lymph node metastases (LNMs) and proposed the optimal LND region. METHODS: Of the 1106 patients included in the JCOG0802/WJOG4607L, 1056 patients with LNDs were included in this supplemental analysis. We investigated the distribution and recurrence pattern of LNMs along with the radiologic findings (with ground-glass opacity, part-solid tumor; without ground-grass opacity component, pure-solid tumor). RESULTS: The radiologic findings were the only significant factor for LNMs. Of 533 patients with part-solid tumors, 8 (1.5%) had LNMs. Further, only 3 (0.5%) patients had pN2 disease, and no patients had interlobar LNMs from nonadjacent segments. Of the 523 patients with pure-solid tumors, 55 (10.5%) had LNMs, and 28 (5.4%) had pN2 disease. Five patients had metastases to nonadjacent interlobar lymph nodes (LNs). Two (2.0%) patients with S6 tumors had upper mediastinal LNMs. In addition, the incidence of mediastinal LN recurrence in patients with S6 lung cancer was greater in those who underwent selective LND than those who underwent systematic LND (P = .0455). CONCLUSIONS: Nonadjacent interlobar and mediastinal LND have little impact on pathologic nodal staging in patients with part-solid tumors. In contrast, selective LND is recommended at least for patients with pure-solid tumors.

Is adjuvant chemotherapy for completely resected p-stage IA (>2 cm) and stage IB non-small-cell lung cancer beneficial for elderly patients? A large, retrospective cohort study based on real-world data from Japan.

OBJECTIVE: The efficacy of tegafur-uracil as adjuvant chemotherapy for patients with completely resected stage I non-small-cell lung cancer is proven; however, its efficacy for elderly patients remains unclear. Herein, we evaluated the effectiveness of adjuvant chemotherapy for elderly patients with completely resected stage I non-small-cell lung cancer based on real-world Japanese data using propensity score matching. METHODS: This retrospective study extracted data from a nationwide registry study, performed in 2016, on patients ≥75 years who underwent lobectomy with mediastinal nodal dissection for non-small-cell lung cancer in 2010 and were diagnosed with p-stage IA (>2 cm) or stage IB non-small-cell lung cancer. We classified the 1294 patients into two groups-Group A, postoperative adjuvant chemotherapy (n = 295, 22.8%) and Group N, no adjuvant chemotherapy (n = 999, 77.2%)-and analyzed differences in postoperative overall survival between groups. RESULTS: Group A showed no advantage in overall survival over Group N as a whole (hazard ratio: 0.824 [95% confidence interval: 0.631-1.076]), in p-stage IA (hazard ratio: 0.617 [95% confidence interval: 0.330-1.156]) and in p-stage IB (hazard ratio: 0.806 [95% confidence interval: 0.597-1.088]) subsets. Even after propensity score matching, Group A showed no significant advantage in overall survival over Group N as a whole (hazard ratio: 0.975 [95% confidence interval: 0.688-1.381]), in p-stage IA (hazard ratio: 1.390 [95% confidence interval: 0.539-3.586]) and in p-stage IB (hazard ratio: 0.922 [95% confidence interval: 0.633-1.343]). CONCLUSIONS: adjuvant chemotherapy for completely resected p-stage IA (>2 cm) and stage IB non-small-cell lung cancer showed no benefit for recommendation for elderly patients; considering the risk of adverse events, we do not recommend adjuvant chemotherapy for elderly patients.

Prospective, Multi-Institutional Observational Study of Deterioration in Activities of Daily Living in Elderly Patients After Lung Cancer Surgery.

Introduction: To determine the rate of deteriorating activities of daily living (ADL) and to investigate predictive factors in elderly patients undergoing surgery for NSCLC. Methods: Patients with NSCLC aged 75 years or older who underwent curative surgical resection were evaluated using the Tokyo Metropolitan Institute of Gerontology Index of Competence Instrumental ADL (TMIG-IADL) and the Japanese version of EuroQol 5-dimensions 5-level (EQ-5D-5L) quality-of-life scale administered at baseline and at 6 months postoperative. The primary end point was the rate of living patients without substantial deterioration of TMIG-IADL, defined as a decline greater than or equal to three points. Multivariable logistic regression was performed to determine risk factors for deteriorating ADL. Results: Between May 2019 and May 2020, 876 of the 986 screened patients enrolled from 47 institutions were eligible and included in the analysis. TMIG-IADL and EQ-5D-5L scores were obtained from 96.0% and 92.6% of the patients, respectively. At 6 months postoperative, 745 patients (85.1%, 95% confidence interval: 82.5%-87.3%) reported no significant ADL deterioration, and 96 of 841 patients (11.4%) with postoperative score data reported significant deterioration. The social domain was the most frequently affected activity. In multivariable analysis, poor performance status, low G8 geriatric screening score, segmentectomy (versus wedge resection), and surgery lasting less than 3 hours were associated with deteriorating ADL. Worsening EQ-5D-5L scores by minimally important difference or more were observed in 22.1% of the patients. Changes in TMIG-IADL and EQ-5D-5L scores were poorly correlated. Conclusions: Approximately 15% of elderly patients with NSCLC experienced significant ADL deterioration at 6 months postoperative.

Features of anaplastic lymphoma kinase rearrangement in early-stage lung cancer: Analysis of a nationwide Japanese database.

BACKGROUND AND OBJECTIVES: Anaplastic lymphoma kinase (ALK) rearrangement is a representative driver mutation in lung cancer. However, the biology of early-stage ALK-rearranged lung cancer remains unclear. We aimed to assess the clinicopathological features, prognostic implications, and influence of ALK rearrangement on the postoperative course in surgically resected lung cancer. METHODS: We retrospectively analyzed data from the Japanese Joint Committee of Lung Cancer Registry database. Of the 12 730 patients with lung adenocarcinoma, 794 (6.2%) were tested for ALK rearrangement and were included. RESULTS: ALK rearrangements were detected in 76 patients (10%). The 5-year overall survival (OS) rate was significantly higher in the ALK rearrangement-positive group than in the ALK rearrangement-negative group (p = 0.030). Multivariable analysis revealed that ALK rearrangement was an independent prognostic factor for improved OS (hazard ratio, 0.521; 95% confidence interval, 0.298-0.911; p = 0.022). Regarding the postrecurrence state, there was no difference in the initial recurrence sites between both groups. Administration of ALK-tyrosine kinase inhibitors (TKIs) improved postrecurrence survival in any treatment lines. CONCLUSION: In one of the largest national surveys, ALK rearrangement was associated with improved long-term outcomes in surgically resected patients. ALK-TKIs may be an important treatment strategy for ALK rearrangement-positive lung adenocarcinoma in the postrecurrence state.

Outcomes of surgical resection for pulmonary metastasis from pancreatic cancer.

PURPOSE: As the number of long-term survivors of pancreatic cancer is expected to increase thanks to recent advances in multidisciplinary treatment and earlier diagnoses of pancreatic cancer, we are likely to encounter more cases of postoperative pulmonary nodules. We analyzed the clinical course and prognosis of resection of pulmonary metastases from pancreatic cancer to clarify the prognostic implication of pulmonary metastasectomy for pancreatic cancer. METHOD: We retrospectively analyzed 35 patients who underwent resection of lung metastases after pancreatic cancer surgery. Short- and long-term outcomes and factors associated with the prognosis were analyzed. RESULTS: The observation period was 20 (range, 1-101) months, with 3- and 5-year survival rates of 88.3% and 64.5% from pancreatectomy and 44.1% and 28.3% from lung resection, respectively. A univariate analysis revealed that a period from pancreatic cancer resection to pulmonary nodule shadow detection of < 15 months was associated with a significantly lower overall survival from pancreatic resection than a longer period. Conversely, histological type, stage, size of lung metastases, and resection technique were not associated with the overall survival. CONCLUSION: A long-term prognosis may be expected in some cases with a disease-free interval of ≥ 15 months. Our findings suggest that the disease-free interval may influence the prognosis.

Analytical Performance of a Highly Sensitive System to Detect Gene Variants Using Next-Generation Sequencing for Lung Cancer Companion Diagnostics.

The recent increase in the number of molecular targeted agents for lung cancer has led to the demand for the simultaneous testing of multiple genes. Although gene panels using next-generation sequencing (NGS) are ideal, conventional panels require a high tumor content, and biopsy samples often do not meet this requirement. We developed a new NGS panel, called compact panel, characterized by high sensitivity, with detection limits for mutations of 0.14%, 0.20%, 0.48%, 0.24%, and 0.20% for EGFR exon 19 deletion, L858R, T790M, BRAF V600E, and KRAS G12C, respectively. Mutation detection also had a high quantitative ability, with correlation coefficients ranging from 0.966 to 0.992. The threshold for fusion detection was 1%. The panel exhibited good concordance with the approved tests. The identity rates were as follows: EGFR positive, 100% (95% confidence interval, 95.5-100); EGFR negative, 90.9 (82.2-96.3); BRAF positive, 100 (59.0-100); BRAF negative, 100 (94.9-100); KRAS G12C positive, 100 (92.7-100); KRAS G12C negative, 100 (93.0-100); ALK positive, 96.7 (83.8-99.9); ALK negative, 98.4 (97.2-99.2); ROS1 positive, 100 (66.4-100); ROS1 negative, 99.0 (94.6-100); MET positive, 98.0 (89.0-99.9); MET negative 100 (92.8-100); RET positive, 93.8 (69.8-100); RET negative, 100 (94.9-100). The analytical performance showed that the panel could handle various types of biopsy samples obtained by routine clinical practice without requiring strict pathological monitoring, as in the case of conventional NGS panels.

Extent of Lymph Node Dissection in Patients with Small-Sized Peripheral Non-Small Cell Lung Cancer during Intentional Segmentectomy.

PURPOSE: Segmentectomy and mediastinal lymph node dissection (MLND) are becoming standard procedures for small-sized (<2 cm) peripheral non-small cell lung cancer (NSCLC). Although the benefits of the less resected lung are proven, the extent of lymph node dissection remains unchanged. METHODS: We studied 422 patients who underwent lobectomy with MLND (lobe specific or systemic) for small peripheral NSCLC with clinical N0 disease. Patients with middle lobectomy (n = 39) and a consolidation-to-tumor (C/T) ratio ≤0.50 (n = 33) were excluded. We investigated the clinical factors, lymph node metastasis distributions, and lymph node recurrence patterns of 350 patients. RESULTS: Thirty-five (10.0%) patients had lymph node metastasis; none with C/T ratio <0.75 had lymph node metastasis and lymph node recurrence. None had solitary lymph node metastasis in the outside lobe-specific MLND. Six patients had mediastinal lymph node metastasis at the initial site of recurrence; none had mediastinal lymph node recurrence outside the lobe-specific MLND, except for two patients with S6 primary disease. CONCLUSION: NSCLC patients with small peripheral tumors and a C/T ratio <0.75 during segmentectomy may not require MLND. The optimal MLND for patients with a C/T ratio ≥0.75, except for those with S6 primary, may be lobe-specific MLND.

Clinical application of the AMOY 9-in-1 panel to lung cancer patients.

INTRODUCTION: To investigate the clinical performance of the AMOY 9-in-1 kit (AMOY) in comparison with a next-generation sequencing (NGS) panel in lung cancer patients. METHODS: Lung cancer patients enrolled in the LC-SCRUM-Asia program at a single institution were analyzed for the success rate of AMOY analysis, the detection rate of targetable driver mutations, the turn around time (TAT) from specimen submission to the result reporting, and the concordance rate of results with the NGS panel. RESULTS: Of the 406 patients included in the analysis, 81.3% had lung adenocarcinoma. The success rates of AMOY and NGS were 98.5% and 87.8%, respectively. With AMOY, genetic alterations were detected in 54.9% of cases. Of the 42 cases in which NGS analysis failed, targetable driver mutations were detected by AMOY in ten cases through analysis of the same sample. Of the 347 patients for whom the AMOY and NGS panels were successful, 22 showed inconsistent results. In four of the 22 cases, the mutation was detected only in the NGS panel because AMOY did not cover the EGFR mutant variant. Mutations were detected only by AMOY in five of the six discordant pleural fluid samples, with AMOY having a higher detection rate than NGS. The TAT was significantly shorter five days after AMOY. CONCLUSION: AMOY had a higher success rate, shorter turnaround time, and higher detection rate than NGS panels. Only a limited number of mutant variants were included; thus be careful not to miss promising targetable driver mutations.

Segmentectomy for ground-glass-dominant lung cancer with a tumour diameter of 3 cm or less including ground-glass opacity (JCOG1211): a multicentre, single-arm, confirmatory, phase 3 trial.

BACKGROUND: Although segmentectomy is a widely used surgical procedure, lobectomy is the standard procedure for resectable non-small-cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and safety of segmentectomy for NSCLC up to 3 cm in size, including ground-glass opacity (GGO) and predominant GGO. METHODS: A multicentre, single-arm, confirmatory phase 3 trial was conducted across 42 institutions (hospitals, university hospitals, and cancer centres) in Japan. Segmentectomy with hilar, interlobar, and intrapulmonary lymph node dissection was performed as protocol surgery for patients with a tumour diameter of up to 3 cm, including GGO and dominant GGO. Eligible patients were those aged 20-79 years with an Eastern Cooperative Oncology Group performance score of 0 or 1 and clinical stage IA tumour confirmed by thin-sliced CT. The primary endpoint was 5-year relapse-free survival (RFS). This study is registered with the University Hospital Medical Information Network Clinical Trials (UMIN000011819), and is ongoing. FINDINGS: A total of 396 patients were registered from Sept 20, 2013, to Nov 13, 2015, of whom 357 underwent segmentectomy. At a median follow-up of 5·4 years (IQR 5·0-6·0), the 5-year RFS was 98·0% (95% CI 95·9-99·1). This finding exceeded the 87% of the pre-set threshold 5-year RFS and the primary endpoint was met. Grade 3 or 4 early postoperative complications occurred in seven patients (2%), but no grade 5 treatment-related deaths occurred. INTERPRETATION: Segmentectomy should be considered as part of standard treatment for patients with predominantly GGO NSCLC with a tumour size of 3 cm or less in diameter, including GGO even if it exceeds 2 cm. FUNDING: National Cancer Centre Research and Development Fund and Japan Agency for Medical Research and Development.

Hazard Function Analysis of Recurrence in Patients with Curatively Resected Lung Cancer: Results from the Japanese Lung Cancer Registry in 2010.

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.