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This study investigated the early progression patterns of lung squamous cell carcinoma (SqCC) on computed tomography (CT) images.In total, 65 patients with SqCC who underwent surgical resection and two CT scans separated by an interval of at least 6 months were enrolled. We categorized the findings of the initial and at-diagnosis CT images into five patterns as previously reported. The volume doubling time (VDT) was calculated for measurable lesions.A single nodule pattern on CT images at-diagnosis was most common in 56 (86.2 %) patients, in line with practical clinical findings. However, the patterns were diverse in the initial images, with 28 (43.1 %) patients displaying atypical findings, including multiple nodules (3.1 %), endobronchial lesions (20.0 %), subsolid nodules (10.8 %), and cyst wall thickening (9.2 %). All endobronchial lesions were located in the central/middle zone of the lung field, whereas lesions presented as multiple nodules, subsolid nodules, and cyst wall thickening were predominantly observed in the peripheral zone. The differences in the developed zones were reflected in the median VDT, and the tumors with an initial endobronchial pattern had a significantly shorter VDT than those with a subsolid nodule pattern (median: 140 days vs 276 days, p 0.001).Lung SqCC initiated with various CT image patterns, although most tumors ultimately developed a single nodule pattern by diagnosis. The initial CT image patterns differed between the hilar and peripheral zones, suggesting a difference in the progression scheme, which was also supported by differences in VDT.

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.

Background In recent years, PET/MRI has been used clinically as a method to diagnose non-small cell lung cancer (NSCLC). However, no study has shown the usefulness of PET/MRI for lung tumor staging or its consistency with pathological staging compared to CT. This study aimed to evaluate the concordance of staging and prognostic ability of NSCLC patients using thin-section CT and 18F-FDG PET/MRI. Methods This retrospective study was performed on consecutive NSCLC patients who underwent both diagnostic CT and 18F-FDG PET/MRI before surgery between November 2015 and May 2019. The cTNM staging yielded from PET/MRI was compared with CT and pathological staging, and concordance was investigated. To assess the prognostic value of disease-free survival (DFS) and overall survival (OS), we dichotomized the typical prognostic factors and TNM classification staging (Stage I vs. Stage II or higher). Kaplan-Meier curves derived by the log-rank test were generated, and univariate and multivariate analyses were performed to identify the factors associated with DFS and OS. Results A total of 82 subjects were included; PET/MRI staging was more consistent (59 of 82) with pathological staging than with CT staging. There were a total of 21 cases of CT and 11 cases of PET/MRI that were judged as cStage I but were actually pStage II or pStage III. CT tended to judge pN0 as cN1 or cN2 compared to PET/MRI. There was a significant difference between NSCLC patients with Stage I and Stage II or higher by PET/MRI staging as well as prognosis prediction of DFS by pathological staging (P P = 0.009), and preoperative PET/MRI staging was a predictor of patient survival (P = 0.013). Conclusions In NSCLC, pathologic staging was better at predicting recurrence, and preoperative PET/MRI staging was better at predicting the patients’ survival. Preoperative staging by PET/MRI was superior to CT in diagnosing hilar and mediastinal lymph node metastases, which contributed to the high concordance with pathologic staging.

A cardiac herniation is a rare but life-threatening complication after pneumonectomy. In most cases, it manifests suddenly as severe hypotension and cardiac arrest within 24 h of pneumonectomy. Here, we report a case of sudden-onset cardiac herniation after right pneumonectomy during which the pericardium was incised. The diagnosis was made immediately based on chest X-ray and electrocardiogram findings, and the heart was repositioned by repeat thoracotomy as an urgent life-saving measure. Surgeons should be aware of this potential surgical complication as well as its clinical manifestations, given that delayed diagnosis would directly lead to a fatal outcome.

Objective Delineation of the intersegmental plane during pulmonary segmentectomy by systemic injection of indocyanine green (ICG) has been rapidly emerging. We evaluated the feasibility of the use of ICG in a large-scale cohort according to the type of segmentectomy and the presence of obstructive lung disorder and compared the demarcation status with air injection. Methods We collected the data of 209 patients who underwent segmentectomy using ICG at National Cancer Center Hospital, Tokyo, Japan. Data of the operation including the demarcation status of the intersegmental plane were analyzed retrospectively. Results The median operation duration and blood loss were 105 minutes (interquartile range, 94-118 minutes) and 12 mL (interquartile range, 5-24 mL), respectively. Good demarcation of the intersegmental plane by ICG was observed in 184 (88.0%) cases, with no correlation to the type of resected segments or the presence of obstructive lung disorder. Postoperative complications of Clavien–Dindo classification grade 3 or more were observed in 5 cases (2.4%), and no ICG-related adverse event was noted. High-frequency jet ventilation was also used in 160 cases (76.6%) to delineate the intersegmental inflation–deflation plane. The air injected by high-frequency jet ventilation tended to spread further beyond the intersegmental plane that was depicted by ICG. Conclusions The use of ICG might demarcate the intersegmental plane more restricted to the target segment compared with air injection. Delineation of the intersegmental plane by ICG is feasible regardless of the type of segmentectomy or the presence of obstructive lung disorder, and it can be commonly applicable in pulmonary segmentectomy., Graphical abstract

The standard treatment for pathological N2 Stage III non-small cell lung cancer with negative surgical margins in Japan is cisplatin-based adjuvant chemotherapy. However, recent studies suggest that the addition of thoracic radiotherapy after adjuvant chemotherapy prolongs survival. While thoracic radiotherapy is considered to prolong survival by improving locoregional control, it is known to increase radiation-induced adverse events. We began a randomized controlled trial in January 2021 in Japan to confirm the superiority of radiotherapy over observation after adjuvant chemotherapy in pathological N2 Stage III non-small cell lung cancer patients with negative surgical margins. We aim to accrue 330 patients from 47 institutions over 5 years. The primary endpoint is relapse-free survival; the secondary endpoints are overall survival, proportion of patients completing radiotherapy in the radiotherapy arm, early adverse events, late adverse events in the radiotherapy arm, serious adverse events and local recurrence.

Background: Capicua-double homeobox 4 (CIC-DUX4)-rearranged sarcomas (CDS) are extremely rare and highly aggressive sarcomas. There is no standard therapy for the patients with advanced CDS, and therapeutic development is needed. We evaluated preclinical efficacy of trastuzumab deruxtecan (T-DXd), a humanized monoclonal HER2-targeting antibody conjugated to a topoisomerase 1 inhibitor, DXd, in patient-derived xenograft (PDX) models with CDS. Methods: Patient-derived tumor tissue was transplanted into subcutaneous around the flank of female NOG mice, which were treated with vehicle or T-DXd (3 mg/kg, intravenous, Day0) when the mean tumor volume reached 200 mm3. Tumor volume was assessed twice weekly for 3 weeks to assess the efficacy of T-DXd. Results: This study included 3 CDS-derived PDXs. HER2 expression was low in one PDX and not expressed in two PDXs. One PDX was established from a specimen at initial diagnosis, two were established from specimens after prior-chemotherapy. T-DXd demonstrated significant tumor growth delay compared to vehicle in all PDX models investigated. One PDX with no efficacy was HER2-negative and had a treatment history of topoisomerase I inhibitor. In contrast, PDX of HER2-negative topoisomerase I inhibitor-resistant Ewing sarcoma was also administered T-DXd under the same conditions and was found to be refractory. Conclusion: The present study showed that a therapeutic potential of T-DXd in CDS patients, including HER2-negative. Citation Format: Yuki Kojima, Shigehiro Yagishita, Kazuki Sudo, Tatsunori Shimoi, Shintaro Iwata, Shun-ichi Watanabe, Chitose Ogawa, Akihiko Yoshida, Yasushi Yatabe, Kan Yonemori, Akinobu Hamada. Trastuzumab deruxtecan, antibody-drug conjugate targeting HER2, effectively inhibits growth of patient-derived xenograft model with CIC-rearranged sarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3995.

OBJECTIVES Even with current diagnostic technology, it is difficult to accurately predict pathological lymph node status (PLNS). This study aimed to develop a prediction model of PLNS in peripheral adenocarcinoma with a dominant solid component, based on clinical and radiological factors on thin-section computed tomography, to identify patients to whom wedge resection or other local therapies could be applied. METHODS Of 811 patients enrolled in a prospective multi-institutional study (JCOG0201), 420 patients with clinical stage IA peripheral lung adenocarcinoma having a dominant solid component were included. Multivariable logistic regression was performed to develop a model based on clinical and centrally reviewed radiological factors. Leave-one-out cross-validation and external validation analyses were performed, using independent data from 221 patients. Sensitivity, specificity and concordance statistics were calculated to evaluate diagnostic performance. RESULTS The formula for calculating the probability of pathological lymph node metastasis included the following variables: tumour diameter (including ground-glass opacity), consolidation-to-tumour ratio and density of solid component. The concordance statistic was 0.8041. When the cut-off value associated with the risk of incorrectly predicting negative pathological lymph node metastasis (pN−) was 4.9%, diagnostic sensitivity and specificity in predicting PLNS were 95.7% and 46.0%, respectively. The concordance statistic for the external validation set was 0.7972, and diagnostic sensitivity and specificity in predicting PLNS were 95.4% and 40.5%, respectively. CONCLUSIONS The proposed model is clinically useful and successfully predicts pN− in patients with clinical stage IA peripheral lung adenocarcinoma with a dominant solid component.

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.

Objective The aim of this study was to assess long-term outcomes after lobectomy in patients with clinical T1 N0 lung cancer based on thin-section computed tomography. Methods We collected the data of patients with pathological adenocarcinoma who had undergone lobectomy. The patients were categorized into 4 groups according to a consolidation tumor ratio and tumor size. Groups A and B included tumors with consolidation tumor ratio ≤0.5 and size ≤3 cm. Group A consisted of tumors ≤2 cm. Group B consisted of the remaining tumors. Groups C and D consisted of tumors with consolidation tumor ratio >0.5. Group C consisted of those with tumors ≤2 cm and Group D consisted of tumors of size 2 to 3 cm. The 10-year overall survival and recurrence-free survival rates were examined. Results Among the 543 patients, the 10-year overall survival was 80.4% and the 10-year recurrence-free survival rate was 77.1%. The 10-year overall survival for group A was 94.0%, 92.7% for group B, 84.1% for group C, and 68.8% for group D, and the 10-year recurrence-free survival rate for each group was 94.0%, 89.0%, 79.7%, and 66.1%, respectively. Group A + B showed better overall survival than group C + D (hazard ratio, 2.78; 95% confidence interval, 1.45-5.06) and better 10-year recurrence-free survival (hazard ratio, 2.74; 95% confidence interval, 1.55-4.88). No patient in group A had recurrence. Conclusions Those patients with total tumor size ≤3 cm and consolidation tumor ratio ≤0.5 showed excellent prognosis and might be suitable candidates for sublobar resection. If noninferior survival of segmentectomy compared with lobectomy is confirmed in an ongoing Japan Clinical Oncology Group trial, segmentectomy will be included in the standard of care.

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.

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 A history of radiotherapy and chemoradiotherapy (CRT) reportedly increases the efficacy of the PD-1 blockade in patients with advanced non-small cell lung cancer (NSCLC). We investigated the efficacy of anti-PD-(L)1 therapy after CRT failure and how CRT changes the status of PD-L1 expression on tumours and on tumour-infiltrated lymphocytes (TILs). Methods We retrospectively reviewed patients with unresectable locally advanced NSCLC (LA-NSCLC) who were treated with CRT between 2007 and 2018 and evaluated the efficacy of the PD-(L)1 blockade after CRT failure. We also compared the PD-L1 (clone: 22C3) expression levels and the tumoral and stromal distributions of CD8-positive TILs using paired formalin-fixed, paraffin-embedded specimens obtained before and after CRT. Results We identified 422 patients and 65 patients who had relapsed after CRT received anti-PD-(L)1 therapy. The objective response rate (ORR) and the progression-free survival (PFS) after anti-PD-(L)1 therapy were 48% and 8.7 months (95% CI, 4.5–13), respectively. The RR and PFS did not differ according to the pre-CRT PD-L1 expression levels. PD-L1 expression changed in 16 of the 18 patients between before and after CRT, but a specific trend was not seen (increased, 9 patients; decreased, 7 patients; no change, 2 patients). In contrast, the density of tumoral CD8-positive TILs increased after CRT treatment (pre-CRT median, 110/mm2 versus post-CRT median, 470/mm2; p = 0.025). Conclusions Anti-PD-(L)1 therapy was effective in patients with LA-NSCLC who had progressed after CRT regardless of their pre-CRT PD-L1 expression. The efficacy of anti-PD-(L)1 therapy for patients with NSCLC with CRT failure was superior to that of standard second-line treatment for patients with advanced NSCLC.

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

For the seafloor geodesy, the GNSS-A is an only tool to directly solve the global positions with the precision of centimeters. Different from the terrestrial GNSS observations, the GNSS-A has a lot of difficulties both in the observation operation and the error corrections. For the latter issue, the researchers should take care that the GNSS-A solutions strongly affected by the underwater sound speed perturbation because it uses acoustic waves for ranging between the sea-surface and seafloor instruments. To solve this issue, the authors had developed the GNSS-A analysis software named “GARPOS” (Watanabe et al., 2020, Front. Earth Sci.), which simultaneously solves the seafloor positions and the perturbation effects based on the empirical Bayes (EB) approach. It can search the appropriate strength of smoothness constraint to the temporal change of perturbation field using the statistical criterion, to avoid the overfitting of the travel-time residuals. This software provided the sufficiently stable solutions to discuss the time-dependent crustal deformation (e.g., Watanabe et al., 2021, Earth Planets Space). Meanwhile, to provide the information on the variance of estimated positions as the joint posterior probability, the probability distributions of hyperparameters should be accounted. Therefore, we developed the program for sampling from the full-Bayesian (FB) posterior probability, based on the Markov-Chain Monte Carlo (MCMC). In this presentation, we introduce the methodology of GARPOS and its expansion to the MCMC mode. We will also show the MCMC results for the GNSS-A data obtained at sites of the Seafloor Geodetic Observation Array (SGO-A) operated by the Japan Coast Guard, to discuss the difference between the EB-based and FB-based solutions.

The GNSS-A seafloor geodetic observation array (SGO-A) has been operated in about 20 years by the Japan Coast Guard [Ishikawa et al., 2020]. It has become possible to measure interplate coupling condition and shallow slow slip events along the Nankai Trough in recent years [Yokota et al., 2016; Yokota and Ishikawa, 2020], and it has become possible to interpret the time change of postseismic deformation following the 2011 Tohoku-oki earthquake [Watanabe et al., 2021]. For understanding the detail physical process of the plate boundary (e.g., SSE), it is necessary to understand the accuracy of the GNSS-A system and study the quantification and attenuation of the error source.SGO-A data is very useful for this purpose. This dataset is located in the SGO-A site, and basic analysis software GARPOS is also open to the public [Watanabe et al., 2020]. The format is also defined, and a lot of information necessary for error analysis is published.For example, using the estimation result of SGO-A data by GARPOS, the relationship between the vertical movement and the sound speed structure’s disturbance can be investigated from the residual of the vertical movement and the estimated sound speed structure. In addition, the existence of unexpected errors and their effects can be considered by examining the correlation with the position of the seafloor station.It is also possible to understand the disturbance in the ocean from the estimated disturbance of the sound speed structure. Recently, the theoretical background for this estimation has been organized and made easier to handle. Considering this result and the comparison of the ocean fields that are likely to occur in reality, it was also found that the observation accuracy is expected to be improved depending on the observation points. In this presentation, we introduce the interpretation method of GNSS-A data that is being developed in recent years. SGO-A data: https://www1.kaiho.mlit.go.jp/KOHO/chikaku/kaitei/sgs/datalist_e.htmlGARPOS: https://doi.org/10.5281/zenodo.4522027

The Japanese Islands lie along subduction zones where the Pacific Plate and the Philippine Sea Plate subduct, making the islands one of the most seismically active zones in the world. Japan, prone to earthquake disasters throughout its history, has constructed numerous seismic and geodetic observation networks to elucidate the mechanism of catastrophic megathrust earthquakes that occur along the plate boundary near the subduction zones.The Hydrographic and Oceanographic Department of the Japan Coast Guard (JCG) is one of the government branches that conduct geodetic observations to advance megathrust earthquake research. JCG conducts seafloor geodetic observation using the GNSS-Acoustic ranging combination technique (GNSS-A). GNSS-A enables us to measure the global coordinates of a seafloor reference point in precision of centimeters by simultaneously conducting GNSS observation of a sea surface platform (i.e., survey vessel, buoy, autonomous vehicle…) and trilateration of seafloor benchmarks using acoustic ranging. As of now, JCG regularly conducts GNSS-A observations at 27 seafloor sites along the Japan Trench and the Nankai Trough, named the Seafloor Geodetic Observation Array (SGO-A).JCG has been conducting GNSS-A seafloor geodetic observation since 2000, and numerous technological advancements have been made in the past 20 years, significantly improving the observation frequency and positioning precision. The observation system currently operated by the JCG using survey vessels enables us to measure 3-4 times per year per seafloor site (Ishikawa et al. 2020, Front. Earth Sci.). Recently, we have developed an open-source GNSS-A analysis software named “GARPOS”, which simultaneously estimates sound speed perturbation and seafloor benchmark positions using empirical Bayesian inversion (Watanabe et al. 2020, Front. Earth Sci.).Our regular observation at the SGO-A sites along the Japan Trench has revealed co- and postseismic processes of the 2011 Tohoku-oki Earthquake (Watanabe et al. 2021, EPS). Along the Nankai Trough, we have elucidated heterogeneous interplate coupling (Yokota et al. 2016, Nature) and shallow slow slip events (Yokota and Ishikawa 2020, Sci. Adv.). In this presentation, we review our observation and analysis methods, tectonic phenomena revealed from our observation, and the latest observation results at our SGO-A sites.

Introduction This study explored the predictors of a histological aggressive component in ground glass opacity-containing lung adenocarcinoma. Methods Of the 2388 patients who underwent resection for lung cancer at our institute between 2017 and 2020, we collected data on the 501 patients with ground glass opacity-containing adenocarcinoma with a total diameter of ≤2 cm. Using a historical cohort, we identified histological aggressive components that were related to a poor prognosis in early-stage adenocarcinoma. A multivariable analysis was conducted to identify predictors for the presence of a histological aggressive component. Results Lymphovascular invasion and predominant micropapillary or solid patterns were identified as histological aggressive components by a prognostic analysis using a historical cohort. Of the 501 patients included, 36 (7.2%) had at least one histological aggressive component. A multivariate analysis showed that a consolidation/tumour ratio > 0.5 (P 20 pack-years (P = 0.01) were predictors of the presence of a histological aggressive component. A total of 98% of cases without any of the above factors did not have a histological aggressive component. Conclusions Approximately 7% of ground glass opacity-containing small adenocarcinomas contained histological aggressive component. A consolidation/tumour ratio > 0.5, maximum standardized uptake value ≥ 1.5 and smoking index >20 pack-years were predictors for such cases. These predictors may be useful for screening patients with a potentially high risk of a poor prognosis and for prioritizing resection without delay.

Background Precision medicine in non-small cell lung cancer requires attainment of a sufficient amount of high-quality tumor tissue. Transbronchial cryobiopsy has emerged as a new diagnostic method for non-neoplastic lung disease with a better potential to assess morphology compared with conventional methods. However, the influence of cryobiopsy on specimen quality, particularly detection of protein expression, is unknown. We performed a comparative immunohistochemical study in specimens obtained by cryobiopsy versus conventional sampling to evaluate the feasibility of cryobiopsy for lung cancer diagnosis. Methods Pairs of artificial biopsy specimens, collected using a cryoprobe or conventional scalpel, were obtained from 43 surgically resected primary lung tumors. Formalin-fixed, paraffin-embedded blocks were prepared in an ISO15189-certified laboratory. Immunohistochemical staining of thyroid transcription factor-1, p40, Ki67 and programmed death-ligand 1 (22C3) was performed. The H-scores for thyroid transcription factor-1 and p40, labeling index for Ki67 and tumor proportion score for programmed death-ligand 1 were assessed. Pearson’s correlation coefficients between two sampling types were calculated. Results The thyroid transcription factor-1 and p40 H-scores showed perfect correlations between the cryobiopsy and conventional scalpel-obtained specimens (R2 = 0.977 and 0.996, respectively). Ki67 labeling index and PD-L1 tumor proportion score also showed strong correlations between the two sample types (R2 = 0.896 and 0.851, respectively). Five cases (11.6%) exhibited differences in tumor proportion score category between sample types, potentially because of intratumoral heterogeneity. Conclusions Immunohistochemical expression of certain tumor markers showed a high concordance between cryobiopsy and conventional scalpel sampling. Cryobiopsy is feasible for pathological diagnostics including PD-L1 evaluation.

Synovial sarcoma (SS) is an aggressive tumor that most often affects the deep soft tissues in young adults. Intrathoracic SS is rare and is associated with poor outcome, highlighting the urgent need for a novel therapeutic strategy. In the process of clinical sequencing, we identified two patients with intrathoracic SS harboring the BRAF V600E mutation. The patients were women aged 32 and 23 years, and both presented with SS18-SSX2-positive monophasic SS in the thoracic cavity. BRAF V600E mutations were detected by next generation sequencing, and validated immunohistochemically by diffuse intense positivity to BRAF V600E mutation-specific antibodies. The phosphorylated ERK (pERK) immunohistochemistry result was also positive. One patient received a combination therapy of dabrafenib and trametinib, which led to tumor shrinkage. However, the tumor growth progressed 7.5 months later with an additional NRAS Q61K mutation. Immunohistochemical screening of 67 archival SS tumor samples failed to identify additional samples with BRAF V600E mutation. However, 32% of BRAF V600E-negative cases was positive for pERK, and one of the six tumors showing the highest pERK expression harbored an FGFR2-activating mutation. This is the first report of targetable BRAF mutation in a small subset of SS. Our study suggests involvement of the mitogen-activated protein kinase pathway and the potential clinical implication of BRAF mutation screening in SS.

OBJECTIVES The prognosis of patients with mediastinal lymph node (LN) metastasis (pN2 stage III disease) is still unsatisfactory. Both systemic and local recurrence should be prevented after curative surgery. The aim of this study was to explore the pattern of recurrence in patients with completely resected pN2 non-small-cell lung cancer (NSCLC) in the era of adjuvant chemotherapy. METHODS We investigated 337 patients with completely resected cN0-1 and pN2 NSCLC from 2005 to 2016 at National Cancer Center Hospital, Japan. The patterns of recurrence were compared between patients who were managed by observation alone and those with adjuvant chemotherapy. In patients with regional LN recurrence, the pattern and site of recurrence were also explored. RESULTS There were 195 (58.5%) men and 142 (41.5%) women with a mean age of 63.2 years. Fifty-five (16.3%) patients developed only regional LN recurrence, 116 (32.6%) patients developed only distant recurrence and 65 (19.3%) patients developed both regional LN recurrence and distant recurrence. The difference in the pattern of recurrence between patients with observation alone and those with adjuvant chemotherapy was not statistically significant (P = 0.145). As for the pattern of regional LN recurrence, 68 (20.2%) patients had LN recurrence inside the systematic nodal dissection area. CONCLUSIONS Regional LN recurrence was observed in >30% of patients with completely resected pN2 NSCLC. About 20% of patients had recurrence inside the systematic nodal dissection area. Postoperative radiotherapy might be considered as an additional treatment strategy for these patients.

Anatomical segmentectomy or wedge resection is recommended for high-risk operable patients with clinical stage IA non-small cell lung cancer in guidelines of the National Comprehensive Cancer Network and the Japanese Lung Cancer Society. However, there is no clear evidence comparing the sublobar resections. The less invasive and more generally performed is wedge resection but anatomical segmentectomy may have better survival benefits than wedge resection owing to its superiority in locoregional control. In April 2020, we have initiated a randomized phase III trial in Japan to confirm the superiority of anatomical segmentectomy over wedge resection in high-risk operable patients with clinical stage IA non-small cell lung cancer. We plan to enroll a total of 370 patients from 47 institutions over a period of 5 years. The primary endpoint is overall survival; the secondary endpoints are adverse events, postoperative respiratory function, relapse-free survival, proportion of local recurrence, operative time and blood loss.

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.

The standard treatment for the patients with surgically resectable early non-small cell lung cancer (NSCLC) is lung lobectomy. However, if patients have idiopathic pulmonary fibrosis combined with early stage lung cancer, there is no standard treatment for this population. Patients with idiopathic pulmonary fibrosis have chronic progressive decline in respiratory function; thus, the preservation of respiratory function is essential. The aim of this trial is to confirm the clinical effectiveness of sublobar resection such as wedge resection or segmentectomy for early NSCLC with idiopathic pulmonary fibrosis compared with lobectomy in a randomized phase III trial. The primary endpoint is overall survival. If the non-inferiority of overall survival and minimal invasiveness are proven, it can be a new standard treatment for early NSCLC with idiopathic pulmonary fibrosis. A planned total 430 patients will be enrolled from 50 institutions over 5 years. This trial has been registered in the UMIN Clinical Trials Registry with code UMIN000032696 [http://www.umin.ac.jp/ctr/index.htm].

Thymic carcinoma is a rare malignant disease with no standard systemic chemotherapy. The purpose of the present study was to investigate tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME), focusing on the impact of TIIC and program death-ligand 1 (PD-L1) expression on clinical outcomes in thymic cancer. Patients with thymic carcinoma resected between 1973 and 2017 were investigated. The tissue specimens were analyzed through immunohistochemical staining to elucidate the prognostic effects of TIIC, their ratios and PD-L1 in a preliminary cohort (n = 10). The density of TIIC as well as PD-L1 expression was evaluated in intraepithelial and tumor-stromal areas on the representative whole section of tumors. The immune factors showing significant association with disease-free survival (DFS) were evaluated in the total cohort (n = 42). TIIC in the preliminary population showed no significant difference between the two groups. However, CD8, CD20, CD204, FOXP3 and CD20/CD204 ratio demonstrated a tendency to act as predictive markers for recurrence. In the total cohort, significant differences were observed for CD8+ , CD20+ and CD204+ cells in tumor islets, and for CD8+ , CD20+ and FOXP3+ cells as well as the CD8/CD204 and CD20/CD204 ratios in the stroma, indicating their prognostic effect. The prognostic effect of the PD-L1 expression in tumor cells could not be established, possibly because of intratumoral heterogeneity. CD8, CD20 and CD204 positive TIIC in stroma were identified as possible better prognostic biomarkers, considering the heterogeneity of other biomarkers. The present study paves the way for exploring strategies of combination immunotherapy targeting B cell immunity in thymic carcinoma.

OBJECTIVE. The purpose of this article was to assess thin-section CT features of ciliated muconodular papillary tumors (CMPTs) of the lung and correlations between radiologic and pathologic findings. MATERIALS AND METHODS. Thin-section CT findings of 16 patients (10 men and six women; mean age, 70.7 years) with surgically resected CMPTs were retrospectively analyzed. Size, location, and internal characteristics of the tumors were evaluated. The amount of mucin in the tumors was assessed histopathologically and compared with CT findings. Tumor growth speed was calculated on the basis of size changes on thin-section CT. RESULTS. In all 16 patients, tumors were detected as a solitary pulmonary nodule. Thirteen tumors (81.3%) were located in the lower lobes, and 10 (62.5%) were adjacent to the pleura. Mean maximal diameter of the tumors was 9.1 mm (range, 6-14 mm). One tumor (6.3%) presented as a pure ground-glass nodule (GGN), seven (43.8%) as dense GGNs, and eight (50.0%) as solid nodules. Pathologically, the pure GGN and five of seven dense GGNs had a large amount of mucin, whereas seven of eight solid nodules had an intermediate or small amount of mucin. The mean annual tumor growth rate (in diameter) was 0.49 mm/y. CONCLUSION. CMPTs appear as solitary, small, and peripheral pulmonary nodules with very slow growth rates. CMPTs appearing as pure GGNs and dense GGNs tend to contain more mucin than CMPTs appearing as solid nodules.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

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

The Japan Coast Guard (JCG) operates Satellite Laser Ranging (SLR) and Global Navigation Satellite System (GNSS) instruments at the Shimosato Hydrographic Observatory (SHO) in Wakayama Prefecture located at the southernmost area of the main island of Japan. SHO is a co-location site where SLR and GNSS can be linked by precisely measuring the local tie vector (relative position) between these two space geodetic techniques. In November 2020, JCG collaborated with the Geospatial Information Authority of Japan (GSI) and performed a local tie survey to precisely determine the local tie vector between the stone marker of the GNSS station and the invariant point (IVP) of the SLR telescope. The IVP of the SLR telescope was determined by an indirect method, in which the reflector targets mounted on the SLR telescope were precisely observed from the surrounding temporary marks. The SLR telescope was rotated at a constant interval during the survey so that the observed target positions form arcs, from which we determined the azimuth and elevation axes; the orthogonal projection of the elevation axis onto the azimuth axis was determined as the IVP. The resulting local tie vector and its variance-covariance information were submitted for the development of the upcoming International Terrestrial Reference Frame 2020 (ITRF2020).

ATF1, CREB1, and CREM constitute the CREB family of transcription factors. The genes encoding these factors are involved in gene fusion events in human tumors. EWSR1-ATF1 and EWSR1-CREB1 are the 2 most characterized fusions, whereas EWSR1-CREM has been less studied. To better understand the phenotypic spectrum of mesenchymal tumors associated with the EWSR1-CREM fusion, we investigated archival cases using fluorescence in situ hybridization and/or RNA sequencing. Among 33 clear cell sarcomas of soft tissue tested, we found 1 specimen, a hand tumor bearing the rearrangements of EWSR1 and CREM, with classic histology and immunophenotype. None of 6 clear cell sarcoma-like tumors of the gastrointestinal tract tested harbored the EWSR1-CREM fusion. Among 11 angiomatoid fibrous histiocytomas, we found that 3 tumors of myxoid variant harbored the rearrangements of EWSR1 and CREM. All 3 tumors occurred in middle-aged men and involved the distal extremities (N=2) and the lung (N=1). Prominent lymphoid cuff, fibrous pseudocapsule, and amianthoid fiber were present in 3, 2, and 2 tumors, respectively, whereas none showed pseudoangiomatoid spaces. All 3 tumors were immunohistochemically positive for epithelial membrane antigen and desmin. These cases suggested a closer relationship between angiomatoid fibrous histiocytoma and a recently proposed novel group of myxoid tumors with CREB family fusions. Our cohort also included 2 unclassifiable sarcomas positive for EWSR1-CREM. One of these was an aggressive pediatric tumor of the abdominal cavity characterized by proliferation of swirling spindle cells immunopositive for cytokeratin and CD34. The other tumor derived from the chest wall of an adult and exhibited a MUC4-positive sclerosing epithelioid fibrosarcoma-like histology. Our study demonstrates that a wider phenotypic spectrum is associated with the EWSR1-CREM fusion than previously reported.

Background The aim of this study was to identify patients with pathological stage I lung adenocarcinoma at high risk of recurrence. Methods We retrieved data from 536 patients with pathological stage I lung adenocarcinoma who underwent lobectomy and were enrolled in a prospective multiinstitutional study (the JCOG0201 study). Invasive component size, excluding lepidic component, was used as the tumor size. Recurrence-free survival (RFS) was estimated by the Kaplan-Meier method, and a multivariable Cox proportional hazards model identified independent prognostic factors associated with worse RFS. Results The all-patient 10-year RFS was 83.9% (median follow-up 10.2 years). Multivariable Cox analysis revealed that age greater than 65 years (hazard ratio [HR], 2.60; 95% confidence interval (CI), 1.66-4.07), invasive component size greater than 2 cm (HR, 2.70; 95% CI, 1.40-5.23), visceral pleural invasion (HR, 2.17; 95% CI, 1.23-3.81), and vascular invasion (HR, 2.59; 95% CI, 1.47-4.55) were potential independent prognostic factors for RFS. When patients were divided into a high-risk group for recurrence (invasive component size >2 cm or positive for visceral pleural invasion or for vascular invasion; n = 124) and a low-risk group (invasive component size ≤2 cm and negative for visceral pleural invasion and vascular invasion; n = 408), there was a significant difference in RFS between the high-risk and low-risk groups (high-risk group: HR, 3.61; 95% CI, 2.35-5.55). Conclusions Pathological stage I lung adenocarcinoma patients with an invasive component size greater than 2 cm, visceral pleural invasion, or vascular invasion were at high risk for recurrence.

To investigate the clinical usefulness of 18F-fluorodeoxyglucose (FDG) PET/MRI in differentiating anterior mediastinal lesions, including small ones.Among 96 patients who underwent 18F-FDG PET/MRI screening for anterior mediastinal lesions, we retrospectively reviewed images of 42 patients with histologically or clinically diagnosed thymic carcinomas, thymomas or anterior mediastinal cysts. MRI findings and maximum standardized uptake value (SUVmax) were compared among the three categories. In addition, small lesions measuring3.0 cm which did not show very high signal intensity (isointense to water) on T2 weighted images (T2WI) were sub-analyzed.Significant differences in SUVmax were observed among anterior mediastinal cysts (P 0.001, vs. thymomas and thymic carcinomas), thymomas (P = 0.032, vs. thymic carcinomas) and thymic carcinomas. Regarding the MRI findings, anterior mediastinal cysts showed higher T2WI signal intensity (P = 0.004 vs. thymomas and P = 0.042 vs. thymic carcinomas) and thymic carcinomas tended to show ill-defined contours (P = 0.024 vs. anterior mediastinal cysts and P = 0.036 vs. thymomas). SUVmax was also significantly higher in small thymic tumors than small anterior mediastinal cysts without very high T2WI signal intensity (P = 0.003).18F-FDG PET/MRI is clinically useful in differentiating anterior mediastinal lesions, including those smaller than 3 cm.

Purpose We aimed to examine the characteristics of imaging findings of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) in the lungs of smokers compared with those of non-smokers. Materials and methods We included seven cases of AIS and 20 cases of MIA in lungs of smokers (pack-years ≥ 20) and the same number of cases of AIS and MIA in lungs of non-smokers (pack-years = 0). We compared the diameter of the entire lesion and solid component measured on computed tomography (CT) images, pathological size and invasive component diameter measured from pathological specimens, and CT values of the entire lesion and ground-glass opacity (GGO) portions between the smoker and non-smoker groups. Results The diameters of AIS and MIA on CT images and pathological specimens of the smoker group were significantly larger than those of the non-smoker group (p = 0.036 and 0.008, respectively), whereas there was no significant difference in the diameter of the solid component on CT images or invasive component of pathological specimens between the two groups. Additionally, mean CT values of the entire lesion and GGO component of the lesions in the smoker group were significantly lower than those in the non-smoker group (p = 0.036 and 0.040, respectively). Conclusion AIS and MIA in smoker’s lung tended to have larger lesion diameter and lower internal CT values compared with lesions in non-smoker’s lung. This study calls an attention on smoking status in CT-based diagnosis for early stage adenocarcinoma.

The new grading system proposed by the Pathology Committee of the International Association for the Study of Lung Cancer in 2020 was based on the combination of the histologically predominant subtype and high-grade component. Because the predominant subtypes are associated with characteristic subsets, unique subsets can be identified by this grading system.We analyzed the clinicopathologic, genotypic, and prognostic features of a cohort of 781 consecutive patients with invasive nonmucinous adenocarcinoma of the lung.Grade 3 tumors were associated with younger age, male sex, a higher smoking dose, and aggressive features (tumor size, lymph node metastasis, stage, lymphovascular invasion, and pleural invasion). Recurrence-free survival and 3-year overall survival were well-stratified according to tumor grade, and the differences were confirmed with multivariate analysis using the Cox proportional hazard model. Radiologically, most grade 3 tumors exhibit a solid nodular pattern on computed tomography images and a high maximum standardized uptake value with positron emission tomography. Genotypically, 43% of the grade 3 adenocarcinomas lacked any driver mutations, although one of the driver mutations was detected in 79% of grade 1 or 2 tumors. Patient age, positive smoking history, solid nodule on computed tomography image, and higher maximum standardized uptake value were identified as significant preoperative predictive factors of grade 3 tumors, with a prediction rate greater than 90%.Besides stratifying the patient outcomes, the new grading system characterized unique clinicopathologic subsets and this study suggested that grade 3 tumors could be predicted using the preoperative variables.

Chemoradiotherapy (CRT) followed by durvalumab treatment improved prognosis in unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). This study aimed to evaluate whether the status of the immune-related tumour microenvironment (TME) at baseline associates with the efficacy.This retrospective study evaluated immune-related TME factors, including programmed cell death ligand 1 (PD-L1) (clone: 22C3) expression on tumour cells and the density of CD8-positive tumour-infiltrating lymphocytes (TILs) at pre-CRT in patients with unresectable LA-NSCLC treated with CRT only (CRT alone group) and those treated with CRT followed by durvalumab (Durva group).A total of 551 patients were included (N = 113 in the Durva group). Progression-free survival (PFS) in the Durva group was significantly greater than that in the CRT alone group (not reached [NR] vs 12.9 months; p = 0.002). In the CRT alone group, neither PD-L1 expression nor TIL status affected PFS; in contrast, in the Durva group, high density of CD8-positive TILs (TILPD-L1+ and TIL

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.

Investigations of the co- and postseismic processes of the 2011 Tohoku-oki earthquake provide essential information on the seismic cycle in the Japan Trench. Although almost all of the source region lies beneath the seafloor, recent seafloor geophysical instruments have enabled to detect the near-field signals of both the coseismic rupture and the postseismic stress relaxation phenomena. Annual-scale seafloor geodesy contributed to refining the postseismic deformation models, specifically to the incorporation of viscoelastic effects. However, because of the insufficiency in the spatial coverage and observation period of seafloor geodetic observations, no consensus on crustal deformation models has been reached, especially on the along-strike extent of the main rupture, even for the coseismic process. To decompose the postseismic transient processes in and around the source region, i.e., viscoelastic relaxation and afterslip, long-term postseismic geodetic observations on the seafloor play an essential role. Here, from decadal seafloor geodetic data, we provide empirical evidence for offshore aseismic afterslip on the rupture edges that had almost decayed within 2–3 year. The afterslip regions are considered to have stopped the north–south rupture propagation due to their velocity strengthening frictional properties. In the southern source region (~ 37° N), despite not being resolved by coseismic geodetic data, shallow tsunamigenic slip near the trench is inferred from postseismic seafloor geodesy as a subsequent viscoelastic deformation causing persistent seafloor subsidence at a geodetic site off-Fukushima. After a decade from the earthquake, the long-term viscoelastic relaxation process in the oceanic asthenosphere is currently in progress and is still dominant not only in the rupture area, but also in the off-Fukushima region.

Background Endobronchial ultrasound-guided transbronchial needle aspiration is recommended for lymph node (LN) staging in lung cancer. Although 22-gauge needles are widely used, they may make some stations difficult to puncture owing to an acute angle. A thinner 25-gauge needle was introduced in Japan at the end of 2016 and offered structural advantages such as improved flexibility and penetrability. We aimed to validate the clinical utility of the 25-gauge needle in LN staging. Methods Patients who underwent endobronchial ultrasound-guided transbronchial needle aspiration for LN staging of lung cancer using the 25-gauge needle at our institution between November 2016 and March 2019 were included. Patient characteristics, staging procedures, pathology findings, and genetic testing success rates were assessed. Results Data of 130 patients were included in the analysis. The sampling rate was 87.6% (589/672 lesions). In addition to stations #4R, #7, and #11, which are generally easy to puncture, multiple stations (40.1%) were sampled. The diagnostic accuracy of combined computed tomography and fluorodeoxyglucose positron emission tomography was 82.3% and that of additional endobronchial ultrasound-guided transbronchial needle aspiration was 96.9%. The overall sensitivity, specificity, and positive and negative predictive values validated using resected specimens were 97.1% (34/35), 100% (41/41), 100% (34/34), and 97.6% (41/42), respectively. The success rate of genetic testing was 100% (34/34). Conclusions The new 25-gauge needle enabled us to approach a wide range of LNs with a desirable sampling rate and diagnostic accuracy in LN staging using endobronchial ultrasound-guided transbronchial needle aspiration, while providing enough tissue for genetic testing.

Estimation of lymph node status is essential in order to determine precise therapy for patients with non-small cell lung cancer (NSCLC). Furthermore, lymph node involvement is a very powerful prognostic factor in these patients. In this analysis, we aim to evaluate the predictive factors for lymph node metastasis in NSCLC-patients.In a prospectively-established database, we analyzed all data of patients with NSCLC, who underwent oncological surgical resections from 01/2007 to 12/2016, retrospectively. The correlation between clinicopathological parameters and lymph node metastasis was investigated by using univariate and binary logistic regression analysis.In this study, we operated on 204 consecutive patients, 142 men (71.7%) and 56 women (28.3%). Lymph node metastases were detected in 38.2% (78/204). Preoperatively, central tumor localization (OR = 2.6, 95% CI = 1.3-5.1, P = 0.005) and tumor size 3 cm (OR = 2.5, 95% CI = 1.3-4.4, P = 0.005) were found to be significant predictive factors for lymph node metastasis. Postoperatively, multivariate analysis showed that intratumoral lymph vessel invasion (L1-status) (OR = 17.3, 95% CI = 5.1-58.4, P 0.001) along with the central tumor localization (OR = 2.8, 95% CI = 1.4-5.8, P = 0.004) were significantly associated with lymph node metastasis. In small size tumors (≤3 cm), two predictive factors for lymph node metastasis were found: central tumor localization (OR = 19.4, 95% = 2.1-186.4, P = 0.01) and L1-status (OR = 43.9, 95% CI = 3.6-529.4, P = 0.003).A precise pre- and intraoperative assessment of the lymph node status is essential in patients with larger sized tumors and central localization. Furthermore, L1-status is a highly significant risk factor for lymph node metastasis in NSCLC-Patients. Therefore, an adjuvant therapy in patients with L1-status and pNX category should be considered.

Good prognosis following surgery for metachronous lung cancer has been reported. However, prognostic factors have not been fully investigated. The purpose of this study was to identify the preoperative predictor of survival in metachronous lung cancer.Patients who underwent a second pulmonary resection for metachronous lung cancer at our institution between 2000 and 2014 were analyzed.A retrospective chart review identified 86 eligible patients (of 6213; 1.4%). The 5-year overall survival was 77%. All 86 cancers met Martini and Melamed's criteria for second primary cancer. However, on pathological examination based on morphological concordance between the initial and metachronous cancer, 73 (85%) cases were diagnosed as second primary cancer and 13 (15%) as a possible recurrent tumor. The 5-year overall survivals were 82% for second primary cancers and 52% for possible recurrent tumors. Tumor doubling time 180 days (p 0.001), pathological diagnosis of second primary cancer (p = 0.013), pathological stage IA (p = 0.016), interval between resections 2 years (p = 0.040), and consolidation/tumor diameter ratio ≤ 0.5 (p = 0.045) were associated with superior overall survival. Multivariate Cox regression analysis identified tumor doubling time 180 days as the only independent predictor of overall survival (hazard ratio 3.600, 95% confidence interval 1.226-10.338; p = 0.0196).Surgical resection for metachronous lung cancer is effective and feasible. Particularly, a tumor doubling time 180 days is associated with superior survival in patients with metachronous lung cancer.

OBJECTIVES To identify risk factors associated with extrathymic malignancy-related mortality after thymic epithelial tumour resection. METHODS The Japanese Association for Research on the Thymus database registered the records of 2835 patients collected from 32 Japanese institutions from 1991 to 2010. The cumulative incidence function of death due to extrathymic malignancies or recurrence was calculated, with other causes of death as competing risks. Relevant risk factors associated with extrathymic malignancy-related deaths in patients with thymoma were evaluated using the Fine and Gray model. RESULTS In total, 2701 patients were eligible for the analysis (thymoma, 2374; thymic carcinoma, 273; thymic neuroendocrine tumour, 54). The median follow-up period was 4.6 years. The cumulative incidence function of death due to extrathymic malignancies at 10 years was 2.2% (3.2% due to recurrence) in patients with thymoma, 1.6% (38.6% due to recurrence) in patients with thymic carcinoma and 0% (36.6% due to recurrence) in patients with thymic neuroendocrine tumour. In the multivariable analysis, age (every 10 years) at thymectomy [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.53–3.14; P CONCLUSIONS Continued management and early detection of extrathymic malignancies may improve survival of patients with thymoma who are male, of advanced age, or have previous malignancies. Prospective studies are required to further investigate the management of extrathymic malignancies.

The outcomes of surgically treating pulmonary metastases from hepatocellular carcinoma remain unclear. Therefore, we aimed to evaluate patients with hepatocellular carcinoma who underwent pulmonary metastasectomy to assess their survival outcome and prognostic factors. This retrospective single-center study included 30 patients who underwent pulmonary metastasectomy for hepatocellular carcinoma between January 1980 and December 2016 at the National Cancer Center Hospital. The 1-, 3-, and 5-year overall survival rates after pulmonary metastasectomy were 86.7%, 46.2%, and 33.6%, respectively (median survival time: 25.0 months). The univariate prognostic factors were viral hepatitis (P = 0.019), number of pulmonary metastases (P = 0.002), and other site recurrence before metastasectomy (P = 0.048). Multivariate analysis using a Cox proportional hazards model revealed viral hepatitis (hazard ratio: 3.611, 95% confidence interval: 1.226–10.64; P = 0.02) and ≥ 2 pulmonary metastases (hazard ratio: 4.031, 95% confidence interval: 1.594–10.19; P = 0.003) to be independent prognostic factors. Subgroup analyses of the three risk factors (viral hepatitis, number of pulmonary metastases, and other site recurrence before metastasectomy) revealed that the median survival times after pulmonary metastasectomy were 66.0 and 15.5 months for patients with 0–1 risk factors and those with 2–3 risk factors, respectively (P

OBJECTIVES The tumour, node and the metastasis (TNM) staging system for thymic epithelial tumours was adopted by the Union for International Cancer Control (UICC) in 2016. Although the T factor is defined by the invasive nature of a thymoma, tumour size is not considered. The aim of this study was to examine the clinical importance of tumour size using a nationwide retrospective database of cases treated from 1991 to 2010 compiled by the Japanese Association for Research of the Thymus. METHODS Tumour size was evaluated by the maximum diameter shown by computed tomography imaging prior to resection. Tumour size was available for 2083 thymoma patients undergoing upfront surgical treatment. The tumour size ranged from 0.6 to 19.4 cm (mean 5.1 cm, median 4.9 cm). Harrell’s C-index was adopted to determine the cut-off value of the tumour size in 0.5-cm increments. RESULTS The highest C-index value (0.7760) was obtained in terms of recurrence-free survival after the complete resection when the cut-off value was set at 5.0 cm. The 10-year recurrence-free survival rate was 93.8% in patients with a tumour ≤5.0 cm and 84.3% in patients with a tumour >5.0 cm (P CONCLUSIONS Tumour size is an important prognostic factor and should be considered when determining the treatment strategy for thymoma patients.

Introduction The Japanese Joint Committee of Lung Cancer Registry performed the fourth nationwide registry study of surgical cases. Demographics, safety and quality, prognostic information, and correlations between the seventh and the eighth editions of the TNM classification were investigated. The principal results were compared with those of previous Japanese Joint Committee of Lung Cancer Registry studies. Methods The clinicopathologic profiles, staging, and prognosis of patients who had an operation for primary lung cancer in 2010 were retrospectively collected in 2016 and analyzed. Results The cohort consisted of 18,973 patients from 297 hospitals (11,771 males, mean age 68.3 years). Tumor smaller than 2.0 cm was seen in 39.0% of patients, and limited resection was performed in 22.7%. The 30- and 90-day mortality rates were 0.43 and 1.26%, respectively. The overall and disease-free survival rates at 5 years were 74.7 and 67.8%, respectively. The respective 5-year survival rates by pathological stage in the seventh edition in the present study (2010) and in the previous study (2004) were 88.9% and 86.8% for stage IA, 76.7% and 73.9% for stage IB, 64.1% and 61.6% for stage IIA, 56.1% and 49.8% for stage IIB, 47.9% and 40.9% for stage IIIA, 30.2% and 27.8% for stage IIIB, and 36.1% and 27.9% for stage IV. The 5-year survival rates by clinical stage in the eighth edition in the present study were 97.0% for stage 0, 91.6% for stage IA1, 81.4% for stage IA2, 74.8% for stage IA3, 71.5% for stage IB, 60.2% for stage IIA, 58.1% for stage IIB, 50.6% for stage IIIA, 40.5% for stage IIIB, 37.5% for stage IIIC, and 36.0% for IVA/B. With restaging, the overall survival rates of clinical stage IA and IB in the seventh edition were stratified into stages 0 to IA3 and stages IA1 to IIA in the eighth edition, respectively. Conclusions This study demonstrates improved surgical results for lung cancer in Japan. The TNM revision for the eighth edition was supported by the assessment of stage migration from the previous edition and the prognostic stratification.