The Role of Emphysema on Postoperative Prognosis in Early-Stage Nonsmall Cell Lung Cancer.

BACKGROUND: Emphysema is generally considered a poor prognostic factor for patients with nonsmall cell lung cancer; however, whether the poor prognosis is due to highly malignant tumors or emphysema itself remains unclear. This study was designed to determine the prognostic value of emphysema in patients with early-stage nonsmall cell lung cancer. METHODS: A total of 721 patients with clinical stage IA nonsmall cell lung cancer who underwent complete resection between April 2007 and December 2018 were retrospectively analyzed regarding clinicopathological findings and prognosis related to emphysema. RESULTS: The emphysematous and normal lung groups comprised 197 and 524 patients, respectively. Compared with the normal lung group, lymphatic invasion (23.9% vs. 14.1%, P = 0.003), vascular invasion (37.6% vs. 17.2%, P < 0.001), and pleural invasion (18.8% vs. 10.9%, P = 0.006) were observed more frequently in the emphysema group. Additionally, the 5-year overall survival rate was lower (77.1% vs. 91.4%, P < 0.001), and the cumulative incidence of other causes of death was higher in the emphysema group (14.0% vs. 3.50%, P < 0.001). Multivariable Cox regression analysis of overall survival revealed that emphysema (vs. normal lung, hazard ratio 2.02, P = 0.0052), age > 70 years (vs. < 70 years, hazard ratio 4.03, P < 0.001), and SUVmax > 1.8 (vs. ≤ 1.8, hazard ratio 2.20, P = 0.0043) were independent prognostic factors. CONCLUSIONS: Early-stage nonsmall cell lung cancer with emphysema has a tendency for the development of highly malignant tumors. Additionally, emphysema itself may have an impact on poor prognosis.

Differences in postoperative prognosis between early-stage lung adenocarcinoma and squamous cell carcinoma.

BACKGROUND: Although prognosis and treatments differ between small-cell- and nonsmall-cell carcinoma, comparisons of the histological types of NSCLC are uncommon. Thus, we investigated the oncological factors associated with the prognosis of early-stage adenocarcinoma and squamous cell carcinoma. METHODS: We retrospectively compared the clinicopathological backgrounds and postoperative outcomes of patients diagnosed with pathological stage I-IIA adenocarcinoma and squamous cell carcinoma primary lung cancer completely resected at our department from January 2007 to December 2017. Multivariable Cox regression analysis for overall survival and recurrence-free survival was performed. RESULTS: The median follow-up duration was 55.2 months. The cohort consisted of 532 adenocarcinoma and 96 squamous cell carcinoma patients. A significant difference in survival was observed between the two groups, with a 5-year overall survival rate of 90% (95% confidence interval 86-92%) for adenocarcinoma and 77% (95% CI 66-85%) for squamous cell carcinoma (P < 0.01) patients. Squamous cell carcinoma patients had worse outcomes compared to adenocarcinoma patients in stage IA disease, but there were no significant differences between the two groups in stage IB or IIA disease. In multivariate analysis, invasion diameter was associated with overall survival in adenocarcinoma (hazard ratio 1.76, 95% confidence interval 1.36-2.28), but there was no such association in squamous cell carcinoma (hazard ratio 0.73, 95% confidence interval 0.45-1.14). CONCLUSIONS: The importance of tumor invasion diameter in postoperative outcomes was different between adenocarcinoma and squamous cell carcinoma. Thus, it is important to consider that nonsmall-cell carcinoma may have different prognoses depending on the histological type, even for the same stage.

Distribution and prognostic impact of EGFR and KRAS mutations according to histological subtype and tumor invasion status in pTis-3N0M0 lung adenocarcinoma.

BACKGROUND: The prognostic impact of EGFR mutation as major targetable somatic gene variant on lung adenocarcinoma is controversial. KRAS is another major somatic variant in lung adenocarcinoma, and a therapeutic agent for KRAS G12C became available in clinical settings. These mutations represent clinicopathological features of lung adenocarcinoma and can guide the treatment choice after recurrence. We evaluated the prognostic impact of EGFR and KRAS mutations by considering other clinicopathological recurrence risks in resected pTis-3N0M0 lung adenocarcinoma. METHODS: Clinicopathological features related to recurrence and genetic status were estimated in consecutive 877 resected cases. Recurrence-free survival (RFS), cumulative recurrence rate (CRR), and overall survival (OS) were compared. Uni- and multivariate analyses for RFS were performed after excluding cases with little or no recurrence risks. RESULTS: EGFR mutation was more likely to be harbored in female, never-smoker, or patients accompanied by > 5% lepidic component. KRAS mutation was more likely to be harbored in patients with current/ex-smoking history, International Association for the Study of Lung Cancer (IASLC) grade 3, or accompanied lymphatic or vascular invasion. In IASLC grade 2 and 3 patients, EGFR or KRAS mutation cases had significantly worse 5-year RFS than wild type patients (76.9% vs. 85.0%, hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.62-6.41, P < 0.001). EGFR or KRAS mutation cases had significantly higher 5-year CRR than wild type patients (17.7% vs. 9.8%, HR = 1.69, 95% CI = 1.44-6.59, P = 0.0038). KRAS mutation cases had higher 5-year CRR than EGFR mutation cases (16.7% vs. 21.4%, HR = 1.62, 95% CI = 0.96-7.19, P = 0.061). There was no significant difference in OS between cohorts. Multivariate analysis revealed that a positive EGFR/KRAS mutation status was risk factor for worse RFS (HR = 2.007, 95% CI = 1.265-3.183, P = 0.003). CONCLUSION: Positive EGFR and KRAS mutation statuses were risk factors for recurrence in resected IASLC grade 2 and 3 patients. KRAS mutations were more likely to be confirmed in cases with an increased risk of recurrence. EGFR and KRAS mutation statuses should be evaluated simultaneously when assessing the risk of recurrence.

Preoperative predictors for recurrence sites associated with poor post-recurrence survival after surgery of non-small cell lung cancer: a multicenter study.

BACKGROUND: The recurrence site that influences post-recurrence survival (PRS) in patients with non-small cell lung cancer (NSCLC) undergoing surgery and the preoperative predictors of recurrence remain unclear. METHODS: Cohorts 1 and 2 had 4520 (who underwent complete resection for p-stage 0-IIIA NSCLC) and 727 (who experienced recurrence after surgery) patients, respectively. The initial sites of recurrence were the lungs (309 cases), thoracic lymph nodes (225 cases), pleura (112 cases), bone (110 cases), central nervous system (86 cases), adrenal gland (25 cases), abdomen (60 cases), cervical and axillary lymph nodes (38 cases), chest wall (13 cases), skin (5 cases), and eye and tongue (3 cases). For cohort 2 analysis, the initial recurrence site that resulted in poor PRS was analyzed by multivariable analysis using a Cox proportional hazard model. For cohort 1 analysis, the preoperative predictors of recurrence patterns with poor PRS were analyzed by multivariable analysis using a logistic regression model. RESULTS: In cohort 2 analysis, recurrence in the central nervous system (hazard ratio [HR], 1.70; p < 0.001), bone (HR, 1.75; p < 0.001), abdomen (HR, 2.39; p < 0.001), and pleura (HR, 1.69; p < 0.001) were independent poor prognostic recurrent sites for PRS and they were high-risk sites (HRS). Intrathoracic lymph nodes, cervical and axillary lymph nodes, lungs, chest wall, adrenal gland, eye and tongue, and skin were low-risk sites (LRS) that did not affect PRS. Patients with multiple LRS without HRS recurrence had a worse prognosis than those with a single LRS without HRS recurrence (5-year PRS 20.2% vs. 37.7%, p < 0.001) and were comparable to those with HRS recurrence (p = 1.000). In cohort 1 analysis, preoperative predictors for HRS and multiple LRS recurrences were positron emission tomography (PET) maximum standardized uptake value (maxSUV) ≥ 3.2 (HR, 5.09; p < 0.001), clinical nodal metastasis (HR, 2.00; p < 0.001), tumor size ≥ 2.4 cm (HR, 1.96; p < 0.001) and carcinoembryonic antigen (CEA) ≥ 5 ng/ml (HR, 1.41; p = 0.004). The cumulative incidence rates of HRS and multiple LRS recurrences within 5 years were 55.9%, 40.9%, 26.3%, 11.1%, and 3.5% (p < 0.001) in patients with 4, 3, 2, 1 and 0 of the above risks, respectively. CONCLUSIONS: HRS and multiple LRS were vital recurrences associated with poor PRS. Preoperative PET maxSUV, clinical nodal metastasis, tumor size, and CEA level predicted the incidence of vital recurrence.

Clinicopathologic study of stage I adenosquamous carcinoma of the lung.

OBJECTIVE: Adenosquamous carcinoma of the lung is a characteristic tumor that has both adenocarcinoma and squamous cell carcinoma components. Adenosquamous carcinoma is reported to have an aggressive clinical course, but its clinicopathological features and prognosis are unclear in the early stage. METHODS: Patients who underwent surgical resection for pathological stage I non-small cell lung cancer between April 2009 and December 2014 were retrospectively reviewed. Preoperative and postoperative data, histologic characteristics and outcomes of patients with adenosquamous carcinoma (n = 40) were compared to adenocarcinoma (n = 598) and squamous cell carcinoma (n = 131) patients. Factors affecting prognosis, particularly on recurrence, were assessed via Cox regression analyses. RESULTS: Patients with adenosquamous carcinoma had a worse prognosis than did patients with adenocarcinoma and squamous cell carcinoma in terms of 5 year overall (66.7%) and recurrence-free survival rates (44.9%), as well as a significantly higher recurrence rate (13/40 patients, 32.5%). Multivariable Cox regression analysis for recurrence-free survival rates revealed that the histology of adenosquamous carcinoma was an independent factor for recurrence (hazard ratio: 2.473, 95% confidence interval: 1.328-3.367; P = 0.0004). High serum carcinoembryonic antigen levels (hazard ratio: 5.962) and vascular invasion (hazard ratio: 4.899) were identified as risk factors for recurrence, and patients with adenosquamous carcinoma tended to have distant relapses, such as in the brain. CONCLUSIONS: Early-stage adenosquamous carcinoma of the lung is a histological type associated with severe prognosis and postoperative recurrence, often in distant sites, in approximately one-third of cases. High serum carcinoembryonic antigen levels and vascular invasion might be risk factors of recurrence.

A multicenter propensity score-matched analysis of lymphadenectomy in N1-positve lung cancer.

OBJECTIVES: Selective mediastinal lymph node dissection based on lobe-specific metastases is widely recognized in daily practice. However, the significance of mediastinal lymph node dissection for N1-positive tumors has not been elucidated. METHODS: We retrospectively reviewed 359 patients with N1-positive lung cancer who underwent lobectomy with systematic mediastinal lymph node dissection (systematic lymph node dissection) (n = 150) and lobe-specific mediastinal lymph node dissection (lobe-specific lymph node dissection) (n = 209). The operative and postoperative results and their propensity score-matched pairs were compared. The factors affecting survival were assessed using competing risk and multivariable analyses. RESULTS: The cumulative incidence of recurrence and the cumulative incidence of cancer-specific death were not significantly different between systematic and lobe-specific lymph node dissection in entire cohort. In the propensity score-matched cohort (83 pairs), systematic lymph node dissection tended to detect N2 lymph node metastasis more frequently (55.4 vs. 41%, P = 0.087). Eleven patients (13.2%) in the systematic lymph node dissection group had a metastatic N2 lymph node 'in the systematic lymph node dissection field' that lobe-specific lymph node dissection did not dissect. The oncological outcomes between patients undergoing systematic lymph node dissection (5-year cumulative incidence of recurrence, 62.1%; 5-year cumulative incidence of cancer-specific death, 27.9%) and lobe-specific lymph node dissection (5-year cumulative incidence of recurrence, 60.1%; 5-year cumulative incidence of cancer-specific death, 23.3%) were similar. The propensity score-adjusted multivariable analysis for cumulative incidence of recurrence revealed that the prognosis associated with systematic lymph node dissection was comparable with the prognosis with lobe-specific lymph node dissection (hazard ratio, 1.17; 95% confidence interval, 0.82-1.67; P = 0.37). CONCLUSIONS: The extent of lymph node dissection can affect accurate pathological staging; however, it was not associated with survival outcome in the treatment of N1-positive lung cancer.

Feasibility of repeated ipsilateral anatomical pulmonary resection.

PURPOSE: This study aimed to elucidate the feasibility of repeated ipsilateral anatomical pulmonary resection. METHODS: The subjects of this retrospective analysis were 50 patients who underwent ipsilateral anatomical pulmonary resection after major lung surgery. The patients were divided into two groups according to the type of primary operation performed: a repeated anatomical pulmonary resection group (RA group; n = 24) and an anatomical pulmonary resection after wedge resection group (AW group; n = 26). We compared the perioperative outcomes of the two groups. RESULTS: Completion lobectomy was performed in 9 of the 24 patients (38%) from the RA group and adhesion of the pulmonary hilum was more severe in this group (P = 0.004). Although the operative time was significantly longer in the RA group (P = 0.030), there was no significant difference in the amount of blood loss (P = 0.217) between the groups. A significantly higher rate of severe postoperative complications was observed in the RA group (42%) than in the AW group (12%) (P = 0.024). None of the patients who underwent repeated surgery died within 90 days postoperatively. CONCLUSION: Although repeated anatomical pulmonary resection is a more challenging procedure than anatomical resection after wedge resection, it does not increase short-term mortality; therefore, it is a feasible treatment option.

Prevalence of immune-related adverse events and anti-tumor efficacy following immune checkpoint inhibitor therapy in Japanese patients with various solid tumors.

BACKGROUND: While immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs, the prevalence of irAEs and potential risk factors have not been clarified. We identified irAE predictive factors and examined the relationship between the effect of ICIs and irAEs for patients with malignancies. METHODS: A total of 533 cases treated with ICIs, including programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), for various malignancies were included retrospectively. We recorded irAEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 5. Prevalence and predictive factors associated with immune-related liver injury and the relationship between irAE and treatment response were analyzed. RESULTS: During a median of 10 (1-103) cycles with a median follow-up after several ICI initiations of 384 (21-1715) days, irAEs with all grades and with grade ≥ 3 developed in 144 (27.0%) and 57 (10.7%) cases. Cumulative irAE development rates were 21.9, 33.5, and 43.0% in all grades and 8.8, 14.9, and 20.7% in grade ≥ 3 at 5, 10, and 20 cycles, respectively. Patients who received anti-CTLA4 therapy were more likely to develop irAEs compared to those who received anti-PD-1 or anti-PD-L1 monotherapy. Liver injury was the most common irAE. Multivariate analysis identified the combination of PD-1 and anti-CTL-4 antibodies (hazard ratio [HR], 17.04; P < 0.0001) and baseline eosinophil count ≥130/µL (HR, 3.01 for < 130; P = 0.012) as independent risk factors for the incidence of immune-related liver injury with grade ≥ 2. Patients who developed irAEs had a higher disease control rate (P < 0.0001) and an increased overall survival rate compared to those without irAEs (P < 0.0001). CONCLUSION: Combination therapy with anti-PD-1 and anti-CTL-4 antibodies resulted in higher a frequency of irAEs. Baseline absolute eosinophil count was found to be a predictive factor for immune-related liver injury. Occurrence of irAEs may be associated with higher efficacy of ICI treatment and longer survival among patients who receive ICI therapy.

Characteristic computed tomography features in mesenchymal-epithelial transition exon14 skipping-positive non-small cell lung cancer.

BACKGROUND: Mesenchymal-epithelial transition exon14 (METex14) skipping is one of the therapeutic driver oncogene mutations in non-small cell lung cancer (NSCLC), and can be treated with tepotinib and capmatinib. There is only one report on computed tomography (CT) findings of METex14 skipping-positive NSCLC, which shows that the primary tumor tends to have a large mass in the upper lobe, and extrathoracic metastases are common. This study examined the CT findings of METex14 skipping-positive NSCLC, focusing on the features of the margins and internal structures. METHODS: We consecutively included patients with METex14 skipping-positive NSCLC who were diagnosed between January 2018 and December 2020 at four independent institutions. We retrospectively reviewed the patient demographics and CT findings for tumor margins (invasion into surrounding tissue, lobulation, pleural indentation, spicula, and ground-glass opacity) and internal structures (air bronchograms, cavitation and internal low-density area). RESULTS: Fifteen patients with METex14 skipping-positive NSCLC were identified. Almost half of the patients were men (7/15; 46.7%), and their median age was 75.0 years. More than half were either current or former smokers (9/15; 60.0%). A vast majority of histological subtypes were adenocarcinoma (10/15; 66.7%), followed by pleomorphic carcinoma (3/15; 20.0%) and squamous cell carcinoma (2/15; 13.3%). With regard to CT findings, most primary tumors presented as masses larger than 30 mm (12/15; 80.0%) and were located in the upper lobes (12/15; 80.0%). Invasion into surrounding tissue and presence of internal low-density areas were observed in 60.0% (9/15) and 66.7% (10/15) of the primary tumors, respectively. Additionally, their frequencies increased to 72.7% (8/11) and 90.9% (10/11) in stage III/IV cases, respectively. In lymph node metastasis, internal low-density areas were observed in 8/10 cases (80.0%). Although these two CT features were rarely observed in distant metastases at diagnosis, they became apparent with progression of the metastatic tumor size. CONCLUSIONS: METex14 skipping-positive NSCLC tumors tend to invade surrounding tissue and possess internal low-density areas. These CT findings might be characteristic of METex14 skipping-positive NSCLC.

Patient Selection of Sublobar Resection Using Visual Evaluation of Positron-Emission Tomography (PET) for Early-Stage Lung Adenocarcinoma.

BACKGROUND: This study aimed to investigate the efficacy of the Deauville criteria (a 5-point visual scale criteria) in assessing the accumulation of [18F]-fluoro-2-deoxy-D-glucose (FDG) on positron-emission tomography (PET)/computed tomography (CT) for predicting prognosis of early-stage lung adenocarcinoma and selecting candidates for sublobar resection. METHODS: This retrospective study included 648 patients undergoing curative resection for clinical N0 lung adenocarcinoma with a whole tumor size of 3 cm or smaller between April 2007 and March 2019. Accumulations of the FDG on PET/CT scans were scored using the Deauville criteria (Deauville score), and correlations between the Deauville score and prognosis were analyzed. RESULTS: The recurrence-free survival (RFS) was significantly better for the patients with a Deauville score of 1 or 2 (n = 415, 5-year RFS, 92.6%) than for those with a score of 3 (n = 82, 5-year RFS, 72.7%; P < 0.001) or a score of 4 or 5 (n = 151, RFS, 70.8%; P < 0.001). The RFS did not differ significantly among the patients with Deauville scores of 1 and 2 who underwent wedge resection (n = 102, 5-year RFS, 90.5%), segmentectomy (n = 188, RFS, 95.1%; P = 0.355), and lobectomy (n = 125, RFS, 91.1%; P = 0.462). CONCLUSION: The 5-point-scale evaluation of FDG accumulation on PET/CT was useful in predicting the prognosis for patients with early-stage lung adenocarcinoma. Lung adenocarcinoma patients with a whole tumor size of 3 cm or smaller and a Deauville score of 1 or 2 can be candidates for sublobar resection.

Postoperative Pulmonary Function After Complex Segmentectomy.

BACKGROUND: Segmentectomy has been increasingly used for lung cancer treatment, however there are very limited data evaluating the postoperative pulmonary function of patients treated with complex segmentectomy. We evaluated the postoperative pulmonary function of patients who underwent complex segmentectomy compared with simple segmentectomy, wedge resection, and lobectomy. METHODS: We retrospectively analyzed data from 580 patients who underwent surgical resection. The patients were divided into four groups: complex segmentectomy (n = 135), simple segmentectomy (n = 83), wedge resection (n = 89), and lobectomy (n = 273). Functional testing included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and predicted diffusing capacity of the lung for carbon monoxide (%DLCO) measured preoperatively and at 12 months after surgery. RESULTS: During the postoperative course, the complex segmentectomy and simple segmentectomy groups showed a comparable course of pulmonary function. The complex segmentectomy group significantly preserved pulmonary function compared with the lobectomy group (FVC, p = 0.017; FEV1, p = 0.010; %DLCO, p = 0.0043). A similar trend was observed even when restricted to lung diseases in the right upper lobe. On the other hand, when comparing complex segmentectomy with wedge resection, complex segmentectomy showed a trend that was more disadvantageous than wedge resection, but this difference was not significant (FVC, p = 0.19; FEV1, p = 0.40; %DLCO, p = 0.96). CONCLUSIONS: Complex segmentectomy showed comparable postoperative pulmonary functions as simple segmentectomy. Complex segmentectomy could preserve pulmonary function significantly compared with lobectomy and did not result in significant loss compared with wedge resection.

Systematic Versus Lobe-Specific Mediastinal Lymphadenectomy for Hypermetabolic Lung Cancer.

BACKGROUND: The optimal extent of lymph node dissection (LND) for hypermetabolic tumors that are associated with high rates of nodal disease, recurrence, or mortality has not been elucidated. METHODS: We reviewed 375 patients who underwent lobectomy with lymphadenectomy for clinical T2-3 N0-1 M0 hypermetabolic non-small cell lung cancer (NSCLC) [maximum standard uptake value (SUVmax) ≥ 6.60] via a multicenter database. Extent of LND was classified into systematic mediastinal LND (systematic LND) and lobe-specific mediastinal LND (lobe-specific LND). Postoperative outcomes after lobectomy with systematic LND (n = 128) and lobe-specific LND (n = 247) were analyzed for all patients and their propensity-score-matched pairs. RESULTS: Cancer-specific survival (CSS) and recurrence-free interval (RFI) of the systematic LND group were not significantly different from those of the lobe-specific LND group in the nonadjusted whole cohort. In the propensity-score-matched cohort (101 pairs), systematic LND dissected significantly more lymph nodes (20.0 versus 16.0 nodes, P = 0.0057) and detected lymph node metastasis more frequently (53.5% vs. 33.7%, P = 0.0069). Six (5.9%) patients in the systematic LND group had a metastatic N2 lymph node "in the systematic LND field" that lobe-specific LND could not dissect. The systematic LND group tended to have better prognosis than the lobe-specific LND group (5-year CSS rates, 82.6% versus 69.6%; 5-year RFI rates, 56.6% vs. 47.3%). CONCLUSIONS: Systematic LND was found to harvest more metastatic lymph nodes and provide better oncological outcome than lobe-specific LND in a cohort of hypermetabolic NSCLC patients.

Prognostic role of interstitial pneumonia with or without emphysema in patients with clinical stage I lung cancer.

OBJECTIVES: The prognostic role of interstitial pneumonia with emphysema in lung cancer is not fully understood. This study aimed to examine the prognostic role of the presence of emphysema in patients with clinical stage I lung cancer and interstitial pneumonia. METHODS: The presence of interstitial pneumonia and emphysema was evaluated on preoperative high-resolution computed tomography. In total, 836 consecutive patients with clinical stage I lung cancer who underwent complete resection between April 2007 and March 2016 were retrospectively analyzed using the log-rank test and Cox proportional hazard model to examine survival differences. RESULTS: There was a significant difference in 5-year overall survival between patients with interstitial pneumonia and emphysema (n = 65) and those without (n = 771) (62.6% vs. 86.5%; P < 0.001). However, in patients with interstitial pneumonia on high-resolution computed tomography, there was no significant difference in 5-year overall survival between patients with emphysema (n = 65) and those without emphysema (n = 50) (62.6% vs. 59.4%, P = 0.84). Multivariable backward stepwise Cox proportional hazard analysis in patients with interstitial pneumonia showed that histology, %diffusing capacity of the lungs for carbon monoxide, radiologic interstitial pneumonia pattern and surgical procedure were independent prognostic factors for overall survival, but the presence of emphysema was not. CONCLUSIONS: The presence of emphysema was not an independent prognostic factor for overall survival in patients with clinical stage I lung cancer with interstitial pneumonia. Poor survival of patients with IP and emphysema may be due to the presence of interstitial pneumonia.

Appropriate Extent of Lymphadenectomy in Segmentectomy: A Multicenter Study.

BACKGROUND: The significance of lymphadenectomy is yet to be fully examined in segmentectomy. We compared the oncological outcomes of mediastinal lymph node dissection (LND) and hilar LND for lung cancer treated with segmentectomy via a multicenter database using propensity score-matched analysis. METHODS: We reviewed 357 clinical stage IA radiologically solid-dominant lung cancer patients who underwent segmentectomy with lymphadenectomy. The extent of LND was classified into systematic/lobe-specific mediastinal LND and hilar LND only groups. Postoperative results after segmentectomy with mediastinal LND (n = 179) and hilar LND (n = 178) were analyzed for all patients and their propensity score-matched pairs. RESULTS: Cancer-specific survival (CSS) and recurrence-free interval (RFI) rates for the mediastinal LND group were determined to be not significantly different compared with the hilar LND group in all non-adjusted cohorts. In the propensity score-matched cohort (129 pairs), mediastinal LND harvested more lymph nodes compared with hilar LND, and both groups had significantly different pathological stages (P = 0.015). Adjuvant chemotherapy was performed in 10 (7.8%) patients in the mediastinal LND group and 4 (3.1%) in the hilar LND group. The mediastinal LND group tended to have better prognosis than the hilar LND group (5-year CSS rates, 97.4% vs 93.2%; 5-year RFI rates, 93.5% vs 88.5%). CONCLUSIONS: Mediastinal LND was found to provide more appropriate pathological staging compared with hilar LND in patients with segmentectomy by harvesting more lymph nodes. In addition, mediastinal LND might lead to better oncological outcome than hilar LND in segmentectomy.

Risk of death due to other causes is lower among octogenarians with non-small cell lung cancer after wedge resection than lobectomy/segmentectomy.

OBJECTIVE: We aimed to determine the influences of surgical procedures on the postoperative death of octogenarians with clinical Stage IA non-small cell lung cancer excluding cT1mi. METHODS: We compared overall survival and the cumulative incidence of death due to all and other causes among 1 130 279, and 191 consecutive patients aged ≤79 and ≥80 years after lobectomy, segmentectomy and wedge resection at three institutions. Death due to other causes was defined as death due to any cause except non-small cell lung cancer. RESULTS: The median followup was 53 months. The 5-year overall survival rates for patients aged ≥ 80 and ≤ 79 years after lobectomy, segmentectomy and wedge resection were respectively, 78.0% (95% confidence interval, 63.8%-87.2%) versus 91.2% (95% confidence interval, 89.0%-92.9%), 68.1% (95% confidence interval, 45.2%-83.1%) versus 90.0% (95% confidence interval, 84.6%-93.5%), and 62.7% (95% confidence interval, 44.0-76.7%) versus 84.4% (95% confidence interval, 76.3%-89.9%) (P < 0.01 for all). The cumulative incidence of death due to other causes after wedge resection was similar between patients aged ≥ 80 and ≤ 79 years (P = 0.45), but significantly higher in those aged ≥ 80, than ≤ 79 years after lobectomy or segmentectomy (P = 0.00015 and 0.00091, respectively). CONCLUSIONS: The influence of wedge resection on death due to other causes was lower than that of lobectomy or segmentectomy in patients with non-small cell lung cancer aged ≥ 80 years. Wedge resection might be a useful option for octogenarians even if they can tolerate lobectomy/segmentectomy to avoid postoperative death due to causes other than non-small cell lung cancer.

Serum S100 calcium-binding protein A4 as a novel predictive marker of acute exacerbation of interstitial pneumonia after surgery for lung cancer.

BACKGROUND: Acute exacerbation (AE) of interstitial pneumonia (IP) is the most fatal complication after lung resection for lung cancer. To improve the prognosis of lung cancer with IP, the risk factors of AE of IP after lung resection should be assessed. S100 calcium-binding protein A4 (S100A4) is a member of the S100 family of proteins and is a known marker of tissue fibrosis. We examined the usefulness of S100A4 in predicting AE of IP after lung resection for lung cancer. METHODS: This study included 162 patients with IP findings on preoperative high-resolution computed tomography scan who underwent curative-intent lung resection for primary lung cancer between April 2007 and March 2019. Serum samples were collected preoperatively. Resected lung tissue from 76 patients exhibited usual IP (UIP) pattern in resected lung were performed immunohistochemistry (IHC). Relationship between S100A4 and the incidence of AE of IP and short-term mortality was analyzed. RESULTS: The receiver operating characteristic area under the curve for serum S100A4 to predict postoperative AE of IP was 0.871 (95% confidence interval [CI], 0.799-0.943; P < 0.001), with a sensitivity of 93.8% and a specificity of 75.3% at the cutoff value of 17.13 ng/mL. Multivariable analysis revealed that a high serum S100A4 level (> 17.13 ng/mL) was a significant risk factor for AE of IP (odds ratio, 42.28; 95% CI, 3.98-449.29; P = 0.002). A 1-year overall survival (OS) was significantly shorter in patients with high serum levels of S100A4 (75.3%) than in those with low serum levels (92.3%; P = 0.003). IHC staining revealed that fibroblasts, lymphocytes, and macrophages expressed S100A4 in the UIP area, and the stroma and fibrosis in the primary tumor expressed S100A4, whereas tumor cells did not. CONCLUSIONS: Serum S100A4 had a high predictive value for postoperative AE of IP and short-term mortality after lung resection.

Biological Effects of Low-Dose Chest CT on Chromosomal DNA.

Background Although the National Lung Screening Trial reported a significant reduction in lung cancer mortality when low-dose (LD) CT chest examinations are used for a diagnosis, their biologic effects from radiation exposure remain unclear. Purpose To compare LD CT and standard-dose (SD) CT for DNA double-strand breaks and chromosome aberrations (CAs) in peripheral blood lymphocytes. Materials and Methods Between March 2016 and June 2018, 209 participants who were referred to a respiratory surgery department for chest CT studies were prospectively enrolled in this study. Individuals were excluded if they had undergone radiography examinations within the last 3 days or had undergone chemotherapy or radiation therapy. Peripheral blood samples were obtained before and 15 minutes after CT. The number of γ-H2AX foci and unstable CAs in lymphocytes was quantified by immunofluorescent staining of γ-H2AX and by fluorescence in situ hybridization by using peptide nucleic acid probes for centromeres and telomeres, respectively. The Wilcoxon signed rank test was used for statistical analysis. Bonferroni correction was applied for multiple comparisons. Results Of the 209 participants (105 women, 104 men; mean age, 67.0 years ± 11.3 [standard deviation]), 107 underwent chest LD CT and 102 underwent chest SD CT. Sex distribution, age, and body size metrics were similar between the two groups. The median effective dose of LD CT and SD CT was 1.5 and 5.0 mSv, respectively. The number of double-strand breaks and CAs increased after a SD CT examination (γ-H2AX, P < .001; CAs, P = .003); the number of double-strand breaks and CAs before and after LD CT was not different (γ-H2AX, P = .45; CAs, P = .69). Conclusion No effect of low-dose CT on human DNA was detected. In the same setting, DNA double-strand breaks and chromosome aberrations increased after standard-dose CT. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Brenner in this issue.

Intense Expression of EGFR L858R Characterizes the Micropapillary Component and L858R Is Associated with the Risk of Recurrence in pN0M0 Lung Adenocarcinoma with the Micropapillary Component.

BACKGROUND: Lung adenocarcinoma with the micropapillary (MP) component poses a higher risk of recurrence even when the MP component is not predominant. This study explored genetic features associated with highly malignant behavior of lung adenocarcinoma with the MP component. METHODS: The MP and papillary (PaP) components were captured separately in three patients. Comprehensive mRNA expressions of somatic variants were compared between the MP and PaP components of each patient using next-generation sequencing (NGS). The protein expression of the NGS-detected variant was validated by immunohistochemistry. The prognostic impact of the detected variant was evaluated in 288 adenocarcinoma patients with resection of pN0M0. RESULTS: In two cases, NGS suggested higher RNA expression of EGFR L858R in the MP component than in the PaP component (allele frequency, 0.485 vs. 0.155 and 1.000 vs. 0.526, respectively; P < 0.001 for both). Immunohistochemistry validated intense expression of L858R in the MP component of 27 MP-positive (MP+) patients. Among 288 pN0M0 patients, L858R was more frequently harbored in the MP+ patients than in the MP-negative (MP-) patients. The MP+ patients harboring L858R showed significantly worse recurrence-free survival (RFS) than the MP+ patients without L858R (median RFS 38.7 and 55.0 months, respectively; hazard ratio [HR] 3.004; 95% confidence interval [CI] 1.306-9.132; P = 0.012). Multivariate analysis of the MP+ patients showed that positive L858R status was associated with poorer RFS (HR 2.976; 95% CI 1.190-7.442; P = 0.020). CONCLUSIONS: EGFR L858R was more frequently harbored in the MP+ adenocarcinoma patients than in the MP- adenocarcinoma patients. Intense expression of L858R in the MP component was suggested, and the MP+ patients harboring L858R were at comparatively higher risk of recurrence in the group with pN0M0 lung adenocarcinoma.

Prospective, randomized, cross-over pilot study of the effects of Rikkunshito, a Japanese traditional herbal medicine, on anorexia and plasma-acylated ghrelin levels in lung cancer patients undergoing cisplatin-based chemotherapy.

Purpose Anorexia induced by cytotoxic chemotherapy on delayed phase is a highly frequent adverse event. We aimed to determine the effects of rikkunshito (RKT) on chemotherapy-induced anorexia (CIA) in patients with lung cancer. Methods This prospective, randomized, cross-over pilot trial included 40 lung cancer patients scheduled to undergo cisplatin-based chemotherapy and randomized to either a group given RKT 7.5 g/day for 14 days (Group A, N = 20) or not (Group B, N = 20), then the treatments were switched. All patients received dexamethasone, palonosetron hydrochloride and aprepitant regardless of group assignment. Rescue drugs were allowed as required. The primary and key secondary endpoints were changes in caloric intake and in plasma acylated ghrelin (AG) levels, respectively. Average daily caloric intake during days 3 to 5 was compared with that on day 1 of each course. Results The primary and key secondary endpoints were analyzed in 31 patients (per protocol population) completing the study. Reduction rate of caloric intake was lower in RKT, than in control courses (18% vs. 25%, P = 0.025). Plasma AG levels significantly declined between days 1 and 3 in RKT (12.3 vs. 7.5 fmol/mL, P < 0.001) and control (10.8 vs. 8.6 fmol/mL, P < 0.001) courses. However, those obviously increased to 8.5 fmol/mL (P = 0.025) by day 5 in RKT course but not in control course (7.7 fmol/mL, P = 0.28). Conclusions Rikkunshito could mitigate CIA and ameliorate plasma AG levels during the delayed phase of CDDP-based chemotherapy in lung cancer patients. Clinical trial registration numbers: UMIN000010748.

Clinical features and prognosis of clinical N0 non-small cell lung cancer exceeding 30 mm.

OBJECTIVES: This study aimed to determine the characteristics, ground glass opacity ratio and prognosis of patients with clinical N0 non-small cell lung cancer tumours exceeding 30 mm in size. METHODS: Patients with clinical N0 non-small cell lung cancer and total tumour size >30 mm on preoperative computed tomography who underwent complete resection with lobectomy between January 2007 and December 2017 were included. The patients were divided into three groups: pure solid tumour, low ground glass opacity ratio (1-39%) tumour and high ground glass opacity ratio (≥40%) tumour. The cut-off line was determined based on the recurrence rate for every 10% ground glass opacity ratio. RESULTS: Among the 227 study patients, 129 (56.8%) had a pure solid tumour, 54 (23.8%) had a low ground glass opacity ratio tumour and 44 (19.4%) had a high ground glass opacity ratio tumour. Three-year recurrence-free survival was significantly shorter in patients with a pure solid tumour (57.4%) than in patients with a low ground glass opacity ratio (74.5%; P = 0.009) or a high ground glass opacity ratio tumour (92.1%; P < 0.001). Multivariable analysis showed that ground glass opacity ratio was a significant independent prognostic factor for recurrence-free survival (hazard ratio, 0.175; P = 0.037). CONCLUSION: Pure solid tumours comprised a large proportion of non-small cell lung cancer tumours >30 mm in size and their prognosis was poor. The presence of ground glass opacity and their relative proportion affect prognosis in patients with clinical N0 non-small cell lung cancer tumours >30 mm in size, similar to those with small-sized tumours.